CN105473574A - 新的生长抑制素受体亚型4(sstr4)激动剂 - Google Patents
新的生长抑制素受体亚型4(sstr4)激动剂 Download PDFInfo
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- CN105473574A CN105473574A CN201480040447.XA CN201480040447A CN105473574A CN 105473574 A CN105473574 A CN 105473574A CN 201480040447 A CN201480040447 A CN 201480040447A CN 105473574 A CN105473574 A CN 105473574A
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- alkyl
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- 125000000623 heterocyclic group Chemical class 0.000 claims description 5
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
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- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 19
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 18
- 238000001914 filtration Methods 0.000 description 17
- 150000002500 ions Chemical class 0.000 description 17
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- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 16
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Abstract
本发明涉及通式(I)的3-氮杂-双环[3.1.0]己烷-6-甲酸酰胺衍生物,其为生长抑制素受体亚型4(SSTR4)的激动剂,其适用于预防或治疗与SSTR4相关的医学病症。另外,本发明涉及制备药物组合物的方法以及制造本发明化合物的方法。
Description
发明领域
本发明涉及通式(I)的3-氮杂-双环[3.1.0]己烷-6-甲酸酰胺衍生物,其为生长抑制素受体亚型4(SSTR4)的激动剂,其适用于预防或治疗与SSTR4相关的医学病症。另外,本发明涉及制备药物组合物的方法以及制造本发明化合物的方法。
发明背景
生长抑制素或生长激素释放抑制因子(SRIF)为可见于人类中的环状肽。其广泛产生于人体中且全身与局部地用以抑制各种激素、生长因子及神经传递质分泌。生长抑制素的作用通过G蛋白质偶合受体家族介导,已知其中五个亚型。所述亚型分成两个子族,第一子族包含SSTR2、SSTR3及SSTR5且第二子族包含SSTR1及SSTR4。
生长抑制素与例如细胞增殖、葡萄糖内稳态、炎症及疼痛的过程的调节有关。
在此方面中,据信生长抑制素或其他生长抑制素肽家族的其他成员会经由SSTR4路径抑制疼痛及炎症过程。
已论述SSTR4激动剂的许多其他治疗领域,参见例如Crider,A;MiniRev.Med.Chem.2002,7,213(及其中的参考文献);WO2010/059922(及其中的参考文献)。
选择性SSTR4激动剂已例如公开于J.Am.Chem.Soc.1998,120,1368-1373中。
WO2010/059922提供SSTR4的吡咯烷甲酰胺激动剂。
然而,进一步需要选择性SSTR4激动剂,尤其是非肽激动剂,其展示高稳定性及其他有利特性,例如口服功效及代谢稳定性。
已论述经取代的3-氮杂双环[3.1.0]己烷衍生物用作甘氨酸1型转运体(WO2005/037216)的抑制剂,用作CCR2(趋化因子受体2)拮抗剂(WO2012/125661)或用于治疗肾脏损伤及高血压(CN102675290)。
发明目的
目前已发现本发明的通式(I)化合物为生长抑制素受体4(SSTR4)的有效激动剂。
除对生长抑制素受体4的激动特性之外,本发明化合物提供有利药物动力学特性。举例而言,本发明化合物展示高代谢稳定性。
此外,本发明化合物展示对SSTR4受体的选择性高于同一子族的其他亚型(包括SSTR1受体)。因此,产生副作用的概率降低。
因此,本发明的一个方面是指式(I)化合物及其盐、水合物或溶剂合物,其为生长抑制素受体4的激动剂。
本发明的另一个方面是指式(I)化合物及其盐、水合物或溶剂合物,其作为SSTR4的选择性激动剂,其选择性优于同一家族的其他亚型,包括选择性优于同一子族的另一亚型(SSTR1)。
本发明的另一个方面涉及本发明的通式(I)化合物与无机酸或有机酸的生理学上可接受的盐。
在另一个方面中,本发明涉及药物组合物,其含有至少一种式(I)化合物或其生理学上可接受的盐、水合物或溶剂合物,任选连同一或多种惰性载剂和/或稀释剂。
本发明的另一个方面涉及式(I)化合物或其生理学上可接受的盐或包含式(I)化合物或其生理学上可接受的盐的药物组合物,其用于预防和/或治疗与SSTR4相关的病症。
本发明的另一个方面涉及制造本发明化合物的方法。
本发明的另一个方面涉及式(I)化合物或其生理学上可接受的盐或包含式(I)化合物或其生理学上可接受的盐的药物组合物,其用于预防和/或治疗可受SSTR4活化影响的疾病或症状。在此方面中,本发明涉及式(I)化合物或其生理学上可接受的盐,其用于治疗各种来源的疼痛和/或炎症。
对于熟练技术人员而言,本发明的其他目标将自上述及以下说明中变得清楚。
发明详述
在第一方面中,本发明涉及通式(I)的化合物
其中
A选自由H及C1-6烷基组成的组A1;
R1及R2独立地选自由H、C1-6烷基及C3-6环烷基组成的组R1.1a、R2.1a,其中R1或R2中的至少一项为C1-6烷基或C3-6环烷基,
其中该C1-6烷基或该C3-6环烷基任选经卤素或甲氧基取代,或
其中R1及R2一起形成任选经卤素取代的2至5元亚烷基桥,其并入有0至2个独立地选自由N、O或S组成的组的杂原子;
W选自由以下组成的组W1:单或双环芳基、单或双环杂芳基、单或双环杂环基及单或双环环烷基。
其中所述各环系统任选经一或多个R3取代,且其中该杂芳基包含至多4个杂原子及一或两个5或6元环;
R3独立地选自由以下组成的组R3.1:C1-6烷基、C3-8环烷基、C1-6烷基-O-、苄基、卤素、HO-、NC-、单或双环杂芳基及含有一个选自由N、O或S(O)r组成的组的杂原子的5或6元单环杂环基,其中该杂芳基含有至多4个杂原子及一或两个5或6元环,且r为0、1或2,
其中该C1-6烷基、C3-8环烷基、C1-6烷基-O-、苄基、杂芳基及该杂环基任选经卤素、HO-、乙酰基、C1-6烷基-O-、氧代基(oxo)、R4-S(O)2-取代,其中R4为芳基、C3-6环烷基和/或C1-6烷基;
Y选自由以下组成的组Y1:键、-CH2-、-CH2CH2-及-CH2O-;
或任一以上化合物的盐。
除非另外说明,否则基团、残基及取代基,尤其是R1、R2、R3、R4、A、W及Y如上文及下文中所定义。若残基、取代基或基团在化合物中出现若干次,则其可具有相同或不同含义。下文将给出本发明化合物的基团及取代基之一些优选含义。
在本发明的另一个实施方式中
A选自由H或C1-3烷基组成的组A2。
在本发明的另一个实施方式中
A选自由H或H3C-组成的组A3。
在本发明的另一个实施方式中
A选自由H组成的组A4。
R1及R2独立地选自由H及C1-6烷基组成的组R1.1、R2.1,其中R1或R2中的至少一项为C1-6烷基,或
其中R1及R2一起形成2至5元亚烷基桥,其并入有0至2个独立地选自由N、O或S组成的组的杂原子;
在本发明的另一个实施方式中
R1及R2独立地选自由H及任选经卤素取代的C1-3烷基组成的组R1.2、R2.2,其中R1或R2中的至少一项独立地为任选经卤素取代的C1-3烷基,或
其中R1及R2一起形成任选经卤素取代的2至5元亚烷基桥,其并入有0至2个独立地选自由N、O或S组成的组的杂原子。
在本发明的另一个实施方式中
R1及R2选自由C1-3烷基组成的组R1.3及R2.3,或
其中R1及R2连同其所连接的C原子一起形成并入有0至2个选自由N、O及S组成的组的杂原子的3、4、5或6元环。
在本发明的另一个实施方式中
R1及R2选自由H3C-组成的组R1.4及R2.4,或其中R1及R2一起形成2或3元亚烷基桥。
在本发明的另一个实施方式中
R1及R2选自由H3C-组成的组R1.5及R2.5。
在本发明的另一个实施方式中
W选自由单或双环芳基、单或双环杂芳基及单或双环杂环基组成的组W2,其中所述各环系统任选经一或多个R3取代,且其中该杂芳基包含至多4个杂原子及一或两个5或6元环。
在本发明的另一个实施方式中
W选自由单环芳基、单环杂芳基及单环杂环基组成的组W3,
其中所述各环系统任选经一或多个R3取代,且其中该杂芳基包含至多4个杂原子及一个5或6元环。
在本发明的另一个实施方式中
W选自由双环芳基、双环杂芳基及双环杂环基组成的组W4,
其中所述各环系统任选经一或多个R3取代,且其中该杂芳基包含至多4个杂原子及两个5或6元环。
在本发明的另一个实施方式中
W选自由以下组成的组W5:
其中所述各环系统任选经一或多个R3取代。
在本发明的另一个实施方式中
W选自由以下组成的组W6:
其中所述各环系统任选经一或多个R3取代。
在本发明的另一个实施方式中
W选自由以下组成的组W7:
其中所述各环系统任选经一或多个R3取代。
在本发明的另一个实施方式中
W选自由以下组成的组W8:
其中所述各环系统任选经一或多个R3取代。
在本发明的另一个实施方式中
W选自由以下组成的组W9:
其中所述各环系统任选经一或多个R3取代。
在本发明的另一个实施方式中
W选自由以下组成的组W9a:
其中所述各环系统任选经一或多个R3取代。
在本发明的另一个实施方式中
W选自由以下组成的组W10:
其中所述各环系统任选经一或多个R3取代。
在本发明的另一个实施方式中
W选自由以下组成的组W11:
其中所述各环系统任选经一或多个R3取代。
在本发明的另一个实施方式中
W选自由以下组成的组W11a:
其中所述各环系统任选经一或多个R3取代。
在本发明的另一个实施方式中
W选自由以下组成的组W12:
其中所述各环系统优选如点线所示连接且任选经一或多个R3取代。
在本发明的另一个实施方式中
R3独立地选自由以下组成的组R3.2:C1-6烷基、C3-8环烷基、C1-6烷基-O-、苄基、卤素、HO-及NC-,其中该C1-6烷基、C3-8环烷基、C1-6烷基-O-及该苄基取代基任选经卤素和/或HO-取代;
在本发明的另一个实施方式中
R3独立地选自由以下组成的组R3.3:C1-3烷基、C3-6环烷基、C1-3烷基-O-、卤素、NC-,其中若R3连接至W的N原子,则R3选自由C1-3烷基及C3-6环烷基组成的组,其中该C1-3烷基、C3-6环烷基及C1-3烷基-O-取代基任选经卤素取代。
在本发明的另一个实施方式中
R3独立地选自由以下组成的组R3.4:H3C-、环丙基、H3CO-、F-、Cl-、NC-及F3C-,其中W的N原子任选经选自H3C-及环丙基的基团取代。
R3独立地选自由以下组成的组R3.4:H3C-、环丙基、H3CO-、F-、Cl-、NC-及F3C-,其中若R3连接至W的N原子,则R3为H3C-。
在本发明的另一个实施方式中
R3独立地选自由H3C-、F3C-及F-组成的组R3.4b,其中若R3连接至W的N原子,则R3为H3C-。
在本发明的另一个实施方式中
R3选自由H3C-及F3C-组成的组R3.5。
在本发明的另一个实施方式中
Y选自由键、-CH2CH2-及-CH2O-组成的组Y2。
在本发明的另一个实施方式中
Y选自由键、-CH2CH2-及-CH2O-组成的组Y3。
在本发明的另一个实施方式中
Y选自由键及-CH2O-组成的组Y3a。
在本发明的另一个实施方式中
Y选自由键组成的组Y4。
在本发明的另一个实施方式中
Y选自由-CH2O-组成的组Y5。
在另一个实施方式中,若W为单环,则至少一个R3优选连接于相对于W至Y的连接点的邻位或相邻位置。
在另一个实施方式中,若W为双环,则Y优选选自Y4。
在另一个实施方式中,若W为单环,则Y优选选自Y3,更优选为选自Y5。
在另一个方面中,本发明涉及药学上可接受的盐、水合物或溶剂合物,更特别是涉及用作药物的药学上可接受的盐、水合物或溶剂合物。
在另一个方面中,本发明涉及含有至少一种以上说明书的化合物或其药学上可接受的盐、水合物或溶剂合物连同一或多种药学上可接受的载剂的药物组合物。
在另一个方面中,本发明涉及以上说明书的化合物,其用于治疗或预防受SSTR4的调节影响的疾病或症状,例如用于治疗疼痛,例如急性疼痛、周边神经痛、慢性疼痛或骨关节炎。
在另一个方面中,本发明涉及以上说明书的化合物的药学上可接受的盐、水合物或溶剂合物,其用于治疗或预防可受SSTR4的调节影响的疾病或症状,例如用于治疗疼痛,例如急性疼痛、周边神经痛、慢性疼痛或骨关节炎。
在另一个方面中,本发明涉及含有至少一种以上说明书的化合物或其药学上可接受的盐、水合物或溶剂合物连同一或多种药学上可接受的载剂的药物组合物,其用于治疗或预防可受SSTR4的调节影响的疾病或症状,例如用于治疗疼痛,例如急性疼痛、周边神经痛、慢性疼痛或骨关节炎。
在另一个方面中,本发明涉及通式(II)的化合物
其为制造通式(I)化合物的中间物,其中R1、R2、Y、W及R3具有如通式(I)所述的含义,PG为氨基官能基的保护基,例如以下所概述:PeterG.M.Wuts,TheodoraW.Greene,Greene′sProtectiveGroupsinOrganicSynthesis,Wiley-Intercience;第4版(2006年10月30日),第7章。
优选保护基为叔丁氧羰基-、苄氧羰基-、9-芴基甲氧羰基-、苄基-及2,4-二甲氧基苄基-,最优选为叔丁氧羰基。
在另一个方面中,本发明涉及通式(III)的化合物
其为制造通式(I)化合物的中间物,其中R1、R2、Y、W及R3具有如通式(I)所述的含义,
各R1.x、R2.x、R3.x、Ax、Wx及Yx表示如上所述对应取代基的典型个别实施方式。因此,倘若有以上定义,则取代基R1、R2、R3、A、W及Y通过项目(R1.x、R2.x、R3.x、Ax、Wx及Yx)充分表征,其中对于各指数x,给出在“1”至上文给定的最大数目范围内的个别数字。本发明应包含参考以上定义完全置换指数x的括号中项目所述的所有个别实施方式。
以下表1以例示方式且大体上按由第一列至最后一列优先程度递增的次序展示视为优选的本发明的此类实施方式E-1至E-53。这意味着例如实施方式E-19至E-28优于较早的条目,例如E-1至E-7。
表1:本发明的优选实施方式E-1至E-53
其互变异构体、其立体异构体、其混合物、其盐、其水合物及其溶剂合物。
因此,举例而言,E-28涵盖式(I)化合物,其中
A为H,
R1及R2选自由H3C-组成的组,或其中R1及R2一起形成2或3元亚烷基桥,
W选自由以下组成的组:
其中所述各环系统任选经一或多个R3取代,
R3独立地选自由以下组成的组:H3C-、环丙基、H3CO-、F-、Cl-、NC-及F3C-,其中若R3连接至W的N原子,则R3为H3C-,
Y为键。
因此,举例而言,E-29涵盖式(I)化合物,其中
A为H,
R1及R2选自由H3C-组成的组,或其中R1及R2一起形成2或3元亚烷基桥,
W选自由以下组成的组:
其中所述各环系统任选经一或多个R3取代,
R3独立地选自由以下组成的组:
H3C-、环丙基、H3CO-、F-、Cl-、NC-及F3C-,其中,若R3连接至W的N原子,则R3为H3C-,
Y为-CH2O-。
本发明优选涉及以下化合物:
所用的术语及定义
一般定义:
在本文中未特定定义的术语应由本领域技术人员根据本公开内容及上下文来赋予其应具有的含义。然而,如本说明书中所使用,除非相反规定,否则以下术语具有指定的含义且将遵守以下约定。
在下文定义的基团、基或部分中,通常在基团之前指出碳原子数目,例如C1-6烷基是指具有1至6个碳原子的烷基。一般而言,对于包含两个或两个以上子基团的基团而言,最后提到的子基团为基团连接点,例如,取代基“芳基-C1-3烷基-”是指芳基结合于C1-3烷基,其中后者结合于连接取代基的核芯或基团。
W的取代基R3的数目优选为0至3,更优选为0至2,最优选为1或2。
对于Y为-CH2O-的情况,由此解释为-CH2O-的氧原子连接至W。
立体化学/溶剂合物/水合物:
除非特定说明,否则在整篇本说明书及随附申请专利范围中,指定化学式或名称将涵盖互变异构体及所有立体、光学及几何异构体(例如对映异构体、非对映异构体、E/Z异构体等)及其外消旋体,以及不同比例的各别对映异构体的混合物、非对映异构体的混合物、或此类异构体及对映异构体存在的任何上述形式的混合物、以及其盐(包括其药学上可接受的盐)及其溶剂合物(例如水合物),包括游离化合物的溶剂合物或化合物的盐的溶剂合物。
前缀“内消旋”指示在化学物质中存在第二类对称要素(镜面、反转中心、旋转反映轴)。
盐:
词组“药学上可接受”在本文中用以指在合理医学判断范畴内,适用于与人类及动物的组织接触而无过度毒性、刺激、过敏反应或其他问题或并发症、且与合理益处/风险比相匹配的那些化合物、物质、组合物和/或剂型。
如本文所使用,“药学上可接受的盐”是指所公开化合物的衍生物,其中母体化合物通过制成其酸性盐或碱性盐而改质。药学上可接受的盐的实施例包括(但不限于)碱性残基(例如胺)的无机酸盐或有机酸盐;酸性残基(例如羧酸)的碱金属盐或有机盐;及其类似物。举例而言,此类盐包括由以下形成的盐:氨、L-精氨酸、甜菜碱(betaine)、苄苯乙胺(benethamine)、苄星青霉素(benzathine)、氢氧化钙、胆碱、丹醇(deanol)、二乙醇胺(2,2′-亚氨基双(乙醇))、二乙胺、2-(二乙氨基)-乙醇、2-氨基乙醇、乙二胺、N-乙基-葡糖胺、海卓胺(hydrabamine)、1H-咪唑、离氨酸、氢氧化镁、4-(2-羟基乙基)-吗啉、哌嗪、氢氧化钾、1-(2-羟基乙基)-吡咯烷、氢氧化钠、三乙醇胺(2,2′,2"-氮基叁(乙醇))、氨丁三醇、氢氧化锌、乙酸、2,2-二氯-乙酸、己二酸、海藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、2,5-二羟基苯甲酸、4-乙酰胺基-苯甲酸、(+)-樟脑酸、(+)-樟脑-10-磺酸、碳酸、桂皮酸、柠檬酸、环己胺磺酸、癸酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基-乙磺酸、乙二胺四乙酸、甲酸、富马酸、半乳糖二酸、龙胆酸、D-葡糖庚酸、D-葡萄糖酸、D-葡糖醛酸、谷氨酸、戊二酸、2-氧代基-戊二酸、甘油磷酸、甘氨酸、乙醇酸、己酸、马尿酸、氢溴酸、盐酸、异丁酸、DL-乳酸、乳糖酸、月桂酸、离氨酸、顺丁烯二酸、(-)-L-苹果酸、丙二酸、DL-杏仁酸、甲磺酸、半乳糖二酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟碱酸、硝酸、辛酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸(恩波酸(embonicacid))、磷酸、丙酸、(-)-L-焦谷氨酸、柳酸、4-氨基-柳酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸及十一碳烯酸。其他药学上可接受的盐可由如铝、钙、锂、镁、钾、钠、锌等的金属阳离子形成(亦参见Pharmaceuticalsalts,Berge,S.M.等人,J.Pharm.Sci.,(1977),66,1-19)。
本发明的药学上可接受的盐可通过常规化学方法由含有碱性或酸性部分的母体化合物合成。一般而言,所述盐可通过使所述化合物的游离酸或游离碱形式与足量适当碱或酸在水或有机稀释剂(如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈)或其混合物中反应来制备。
除上文所述外的其他酸的盐,例如适用于纯化或分离本发明化合物的盐(例如三氟乙酸盐)亦构成本发明的一部分。
卤素:
术语“卤素”一般表示氟、氯、溴及碘。
烷基:
单独或与另一基团组合的术语“C1-n烷基”(其中n为2至n的整数)表示具有1至n个C原子的非环状、饱和、支链或直链烃基。举例而言,术语C1-5烷基涵盖基团H3C-、H3C-CH2-、H3C-CH2-CH2-、H3C-CH(CH3)-、H3C-CH2-CH2-CH2-、H3C-CH2-CH(CH3)-、H3C-CH(CH3)-CH2-、H3C-C(CH3)2-、H3C-CH2-CH2-CH2-CH2-、H3C-CH2-CH2-CH(CH3)-、H3C-CH2-CH(CH3)-CH2-、H3C-CH(CH3)-CH2-CH2-、H3C-CH2-C(CH3)2-、H3C-C(CH3)2-CH2-、H3C-CH(CH3)-CH(CH3)-及H3C-CH2-CH(CH2CH3)-。
亚烷基:
单独或与另一基团组合的术语“C1-n亚烷基”(其中n为2至n的整数)表示含有1至n个碳原子的非环状直链或支链二价烷基。举例而言,术语C1-4亚烷基包括-CH2-、-CH2-CH2-、-CH(CH3)-、-CH2-CH2-CH2-、-C(CH3)2-、-CH(CH2CH3)-、-CH(CH3)-CH2-、-CH2-CH(CH3)-、-CH2-CH2-CH2-CH2-、-CH2-CH2-CH(CH3)-、-CH(CH3)-CH2-CH2-、-CH2-CH(CH3)-CH2-、-CH2-C(CH3)2-、-C(CH3)2-CH2-、-CH(CH3)-CH(CH3)-、-CH2-CH(CH2CH3)-、-CH(CH2CH3)-CH2-、-CH(CH2CH2CH3)-、-CH(CH(CH3))2-及-C(CH3)(CH2CH3)-。
烯基:
术语“C2-n烯基”用于如在具有至少两个碳原子的“C1-n烷基”的定义中所定义的基团,其中该基团的那些碳原子中的至少两者经由双键彼此键结。
炔基:
术语“C2-n炔基”用于如在具有至少两个碳原子的“C1-n烷基”的定义中所定义的基团,其中该基团的那些碳原子中的至少两者经由叁键彼此键结。
环烷基:
单独或与另一基团组合的术语“C3-n环烷基”(其中n为4至n的整数)表示具有3至n个C原子的环状、饱和、非支链烃基。举例而言,术语C3-7环烷基包括环丙基、环丁基、环戊基、环己基及环庚基。
杂环基:
术语“杂环基”是指饱和或不饱和单或多环环系统,其包括含有选自N、O或S(O)r(其中r=0、1或2)的一或多个杂原子且由5至11个环原子组成的芳环系统,其中并无杂原子作为芳环的一部分。术语“杂环”意欲包括所有可能的异构形式。
因此,术语“杂环基”包括以下例示性结构,其未描绘成基团,因为各形式可经由共价键连接至任何原子,只要维持适当原子价即可:
芳基:
如本文所用,单独或与另一基团组合的术语“芳基”表示含有6个碳原子的碳环芳族基团,其可进一步稠合至第二个5元或6元碳环基团,该第二个5元或6元碳环基团可为芳族、饱和或不饱和碳环基团。芳基包括(但不限于)苯基、茚满基、茚基、萘基、蒽基、菲基、四氢萘基及二氢萘基。
杂芳基:
术语“杂芳基”是指单或双环环系统,其含有选自N、O或S(O)r(其中r=0、1或2)的一或多个杂原子且由5至10个环原子组成,其中至少一个杂原子作为芳环的一部分。术语“杂芳基”意欲包括所有可能的异构形式。本发明的优选杂芳基包含至多4个杂原子及至少一个5或6元环,更优选至少一个6元环。
因此,术语“杂芳基”包括以下例示性结构,其未描绘成基团,因为各形式可经由共价键连接于任何原子,只要维持适当原子价即可:
上文所提供的许多术语可重复用于化学式或基团的定义中且在各情况下彼此独立地具有上文所提供的含义之一。
制备方法
本发明化合物可使用大体上已知的合成方法获得。化合物优选通过下文更详细描述的本发明的以下方法获得。
以下流程应通过举例的方式说明一般如何制造通式(I)化合物及对应中间化合物。若在流程的上下文内未另外定义,则缩写取代基可如上文所定义。对于缩写清单,参见下文。
流程1
在流程1中,Hal=卤素。
流程1:在第一步骤中,在高温下,在例如N,N-二甲基乙酰胺的适当溶剂中在例如碳酸铯的适当碱存在下使甲苯-4-磺酸2-硝基乙酯的衍生物与醇反应。在例如甲醇的适当溶剂中在例如阮尼镍的适当催化剂存在下通过氢化作用、或在例如甲醇的适当溶剂中在HCl存在下通过用锌处理、或在高温下在例如乙醇的适当溶剂中通过用氯化锡(II)处理所得产物的硝基转化成相应伯胺。或者,在例如二烷的适当溶剂中在例如氢化钠的适当碱存在下使氨基醇与卤化物反应来制备氨基醚。在例如DMF的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使氨基醚与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(可购自ABCR或WuXiAppTec,1HNMR(500MHz,DMSO-d6):δ1.24(t,J=3.2,1H),1.38(s,9H),1.97(t,J=2.5Hz,2H),3.34(d,2H),3.48(d,J=11.0Hz,2H),12.21(br,1H))偶合。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程2
在流程2中,Hal=卤素。
流程2:在第一步骤中,在例如DMF的适当溶剂中及在偶合剂(例如HATU)及碱(例如DIPEA)存在下使氨基醇与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。在例如二烷的适当溶剂中在例如氢化钠的适当碱存在下使所得醇与卤化物反应。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程3
在流程3中,Hal=卤素,PG=针对氨基官能基的保护基,例如以下所概述:PeterG.M.Wuts,TheodoraW.Greene,Greene′sProtectiveGroupsinOrganicSynthesis,Wiley-Interscience;第4版(2006年10月30日)。
优选保护基为叔丁氧羰基-及苄氧羰基-。
流程3:在第一步骤中,在例如THF的适当溶剂中在1,1′-羰基二咪唑存在下使甲酸与氢氧化铵偶合。在例如DCM的适当溶剂中使用伯吉斯试剂(Burgessreagent)或在例如DCM的适当溶剂中使用三氟乙酸酐及吡啶使一级酰胺官能基转化成腈官能基。或者,当在高温下,在例如DMF或N,N-二甲基-乙酰胺的适当溶剂中,在钯来源(例如叁(二亚苄基丙酮)二钯(0)或1,1-双(二苯膦基)二茂铁二氯钯(II))、膦(例如1,1′-双(二苯膦基)二茂铁)、任选存在的锌存在下用氰化锌处理时,使经卤素取代的衍生物转化成腈。在高温下,在例如THF的适当溶剂中或者在例如甲苯的适当溶剂中在有格林纳试剂(Grignardreagent)的情况下使腈与氯化铈(III)及烷基锂反应(参见J.Org.Chem.1992,57,4521-452)。在例如DCM或DMF的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使所得胺与经保护的内消旋-(1R,5S,6r)-3-氮杂双环[3.1.0]己烷-6-甲酸(内消旋-(1R,5S,6r)-3-(苄氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸可购自MatrixScientific)偶合。若W经R3=卤素取代,则当在高温下,在例如DMF的适当溶剂中,在钯来源(例如1,1′-双(二苯膦基)二茂铁-二氯化钯(II)二氯甲烷络合物)存在下用锡烷或硼酸或三氟硼酸盐或环硼氧烷处理时此类基团可经取代。
在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。或者,在例如DCM的适当溶剂中在碱(例如2,6-二甲基吡啶)存在下通过用硅烷化剂(例如三氟甲磺酸叔丁基二甲基硅烷酯)处理,继之以在例如THF的适当溶剂中与氟化物来源(例如氟化四丁基铵)反应来实现Boc移除。在例如MeOH及水的适当溶剂中在催化剂(例如钯/碳)存在下通过氢化作用移除苄氧羰基保护基。
在例如乙酸的适当溶剂中在金属催化剂(例如水合氧化铂(IV))存在下通过氢化作用实现W的部分饱和。
流程4
流程4:在第一步骤中,在例如DCM及MeOH的适当溶剂中用三甲基硅烷基重氮甲烷将甲酸酯化。在例如THF的适当溶剂中使酯与例如格林纳试剂的适当有机金属试剂反应得到醇,其又在例如硫酸、乙酸或三氟乙酸的适当酸中用乙腈或氯乙腈处理。在例如1,2甲氧基乙醇及乙二醇的适当溶剂中或在浓酸水溶液(例如6MHCl)中在碱(例如氢氧化钾)存在下进行乙酰胺裂解。在例如DCM或DMF的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使所得胺与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程5
在流程5中,Hal=卤素,R3=对于W所定义的取代基。
流程5:当在高温下在例如1,2-二甲氧基乙烷、甲苯及水的适当溶剂中在钯来源(例如四(三苯基膦)钯(0)或乙酸钯(II)及三环己基膦)、碱(例如碳酸钾或磷酸三钾)存在下用硼酸或三氟硼酸盐处理时用R3使经卤素取代的衍生物官能基化。或者,在例如EtOH的适当溶剂中在钯存在下将经卤素取代的衍生物氢化。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程6
在流程6中,Hal=卤素
流程6:在第一步骤中,当在例如乙腈的适当溶剂中铜来源(例如碘化铜(I))、钯来源(例如二氯双(三苯基膦)钯(II))及碱(例如三乙胺)存在下用卤化物处理时,丙-2-炔基-氨基甲酸苯甲酯的衍生物经取代。在例如MeOH的适当溶剂中在钯存在下将所得产物氢化。在例如DMF的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使所得胺与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程7
在流程7中,R3=对于W所定义的取代基;独立地,E=C或N;PG=氨基官能基的保护基,例如以下所述:PeterG.M.Wuts,TheodoraW.Greene,Greene′sProtectiveGroupsinOrganicSynthesis,Wiley-Interscience;第4版(2006年10月30日)。
优选保护基为叔丁氧羰基-、苄氧羰基-及9-芴基甲氧羰基-。
流程7:在第一步骤中,在例如THF或DCM的适当溶剂中及在偶合剂(例如TBTU或HATU)及碱(例如TEA)存在下使甲酸与经2-(氨基甲基)取代的杂环偶合。在例如DCM的适当溶剂中使用伯吉斯试剂或在高温下使用氧氯化磷及DMF实现缩合。在例如乙醚的适当溶剂中用盐酸移除叔丁氧羰基保护基,而在例如MeOH及水的适当溶剂中在催化剂(例如钯/碳)存在下通过氢化作用来移除苄氧羰基-。在例如THF或DCM的适当溶剂中及在偶合剂(例如HATU)及碱(例如TEA)存在下使所得胺与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程8
在流程8中,Hal=卤素;LG=磺酸酯或卤素
流程8:在第一步骤中,通过在高温下在例如甲苯的适当溶剂中在钯来源(例如四(三苯基膦)钯(0))存在下使卤化物与适当锡试剂(例如三丁基(1-乙氧基乙烯基)锡)偶合,继之以酸性处理(例如于THF中的HCl水溶液)获得酮。或者,通过在高温下在例如甲苯的适当溶剂中用N,N-二甲基甲酰胺二甲基缩醛处理,继之以在高温下在例如DMF的适当溶剂中与氯丙酮及碘化钠反应由胺合成酮。在例如THF的适当溶剂中使所得酮与例如格林纳试剂的适当有机金属试剂反应得到醇,其又在例如TFA的适当酸中用叠氮化钠处理。或者,通过在例如THF的适当溶剂中用磺酰氯(例如甲磺酰氯)、碱(例如三乙胺)处理使醇转化成离去基,例如磺酸酯。在DMF中用叠氮化钠置换离去基得到叠氮化物。在例如EtOAc的适当溶剂中在钯存下通过氢化作用进行叠氮化物还原。在例如THF或DMF或DCM的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使所得胺与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程9
在流程9中,PG=氨基官能基的保护基,例如以下所概述:PeterG.M.Wuts,TheodoraW.Greene,Greene′sProtectiveGroupsinOrganicSynthesis,Wiley-Interscience;第4版(2006年10月30日)。
优选保护基为4-甲氧基-苄氧羰基-。
流程9:在第一步骤中,使羧基转化成对应酯(例如在DCM/MeOH中用三甲基硅烷基重氮甲烷)。通过在例如THF的适当溶剂中用碱(例如双(三甲基硅烷基)氨基锂)处理,继之以用烷基化剂(例如碘甲烷)处理使酯双烷基化。在例如THF及水的适当溶剂中用碱(例如氢氧化锂)使双烷基化酯水解成羧酸。在高温下在例如甲苯的适当溶剂中用二苯基磷酰基叠氮化物及碱(例如TEA)处理该羧酸,继之以酸性处理(例如4MHCl水溶液)。或者,在高温下在例如甲苯的适当溶剂中用二苯基磷酰基叠氮化物、碱(例如TEA)及醇(例如4-甲氧基苯甲醇)处理该羧酸。在例如DCM的适当溶剂中用TFA使4-甲氧基-苄氧羰基保护基脱除保护。在例如DCM或DMF的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使胺与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程10
在流程10中,Hal=卤素。
流程10:在例如DMF的适当溶剂中在例如三乙胺的适当碱存在下使仲胺与卤化物偶合。或者,通过在例如DMF的适当溶剂中与适当醛或酮、例如三乙酰氧基硼氢化钠的还原剂及乙酸反应进行还原胺化。
流程11
在流程11中,PG=杂芳基或杂环基氮的保护基,例如以下所概述:PeterG.M.Wuts,TheodoraW.Greene,Greene′sProtectiveGroupsinOrganicSynthesis,Wiley-Interscience;第4版(2006年10月30日)。
优选保护基为三甲基硅烷基乙氧基甲基-,R3=对于W所定义的取代基。
流程11:在第一步骤中,在例如THF的适当溶剂中在1,1′-羰基二咪唑存在下使甲酸与氢氧化铵偶合。在例如DCM的适当溶剂中使用伯吉斯试剂使一级酰胺官能基转化成腈官能基。通过在例如DMF的适当溶剂中与2-(三甲基硅烷基)乙氧基甲基氯化物、碱(例如氢化钠)反应安置三甲基硅烷基乙氧基甲基保护基。在高温下,在例如THF的适当溶剂中或者在例如甲苯的适当溶剂中在有格林纳试剂的情况下使经保护的腈化合物与氯化铈(III)及烷基锂反应(参见J.Org.Chem.1992,57,4521-452)。在例如DCM或DMF的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使所得胺与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。用氟化四丁基铵及乙二胺移除三甲基硅烷基乙氧基甲基保护基。通过在例如DMF或N,N-二甲基-乙酰胺的适当溶剂中在碱(例如碳酸铯)存在下用卤化物处理来引入非H的R3。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程12
在流程12中;Hal=卤素;R3=对于W所定义的取代基。
流程12:在第一步骤中,在DCM中用戴斯-马丁高碘烷(Dess-Martinperiodinane)使醇氧化成醛。在低温下在例如THF的适当溶剂中使醛与邻金属化卤化物反应得到醇,其又在DCM中用戴斯-马丁高碘烷氧化成酮。当在例如吡啶的适当溶剂中用羟胺盐酸盐处理时使酮转化成肟。在例如THF的适当溶剂中与碱(例如叔丁醇钾)反应产生任选经一或多个R3取代的苯并异唑。若R3=卤素,则当在高温下在例如DCM或DMF的适当溶剂中在钯来源(例如四(三苯基膦)钯(0))存在下用锡烷或硼酸或三氟硼酸盐处理时此类基团可经取代。
在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
或者,当在高温下在例如乙醇的适当溶剂中用任选经取代的肼处理时使酮转化成任选经一或多个R3取代的1H-吲唑。当用任选经取代的肼、碱(例如碳酸钾)及催化量的氧化铜(II)处理时获得任选一或多个R3取代的2H-吲唑。若R3=卤素,则当在高温下在例如环戊基甲醚及水的适当溶剂中在钯来源(例如乙酸钯(II))、膦(例如X-Phos)、碱(例如碳酸钾)存在下用锡烷或硼酸或三氟硼酸盐处理时此类基团可经取代。
在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程13
在流程13中,Hal=卤素。
流程13:在第一步骤中,通过在高温下在例如甲苯的适当溶剂中在钯来源(例例如甲苯四(三苯基膦)钯(0))存在下使卤化物与适当锡试剂(例如三丁基(1-乙氧基乙烯基)锡))偶合,任选继之以酸性处理(例如于THF中的HCl水溶液)获得酮。当在高温下在例如EtOH的适当溶剂中用羟胺盐酸盐及碱(例如TEA)处理时使酮转化成肟。在例如EtOH的适当溶剂中在例如阮尼镍(RaneyNickel)的适当催化剂及氢氧化铵存在下使肟转化成对应伯胺。在例如DCM或DMF的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使所得胺与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程14
在流程14中,PG=氨基官能基的保护基,例如以下所概述:PeterG.M.Wuts,TheodoraW.Greene,Greene′sProtectiveGroupsinOrganicSynthesis,Wiley-Interscience;第4版(2006年10月30日)。优选保护基为叔丁氧羰基-。
Hal=卤素;R3=对于W所定义的取代基。
流程14:在第一步骤中,在DCM中用戴斯-马丁高碘烷(Dess-Martinperiodinane)使醇氧化成醛。在低温下在例如THF的适当溶剂中使醛与邻金属化卤化物反应得到醇,其又在DCM中用戴斯-马丁高碘烷氧化成酮。当在高温下在例如乙醇的适当溶剂中用任选经取代的肼处理时使酮转化成任选经一或多个R3取代的1H-吲唑。若R3=卤素,则当在高温下,在例如DMF的适当溶剂中,在钯来源(例如1,1′-双(二苯膦基)二茂铁-二氯化钯(II)二氯甲烷络合物)、碱(例如碳酸钾)存在下用锡烷或硼酸或三氟硼酸盐处理时此类基团可经取代。当所得产物经Boc保护时,在例如二烷、甲醇或乙醚的适当溶剂中用盐酸实现脱除保护基。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。在例如DCM或DMF的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使所得胺与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
流程15
在流程15中,PG=氨基官能基的保护基,例如以下所概述:PeterG.M.Wuts,TheodoraW.Greene,Greene′sProtectiveGroupsinOrganicSynthesis,Wiley-Interscience;第4版(2006年10月30日)。
优选保护基为叔丁氧羰基-。
R3=对于W所定义的取代基。
流程15:在第一步骤中,在DCM中用戴斯-马丁高碘烷(Dess-Martinperiodinane)使醇氧化成醛。在低温下在例如THF的适当溶剂中使醛与通过卤素-金属交换由对应2-卤基乙酰苯胺制备的邻金属化乙酰苯胺反应得到醇,其又在DCM中用戴斯-马丁高碘烷氧化成酮。当在高温下在例如甲醇的适当溶剂中用氨及氯化铵处理时使酮转化成任选经一或多个R3取代的喹唑啉。当所得产物经Boc保护时,在例如二烷、甲醇或乙醚的适当溶剂中用盐酸实现脱除保护基。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。在例如DCM或DMF的适当溶剂中及在偶合剂(例如HATU或TBTU)及碱(例如TEA或DIPEA)存在下使所得胺与内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸偶合。在例如二烷、甲醇或乙醚的适当溶剂中用盐酸或在例如二氯甲烷的适当溶剂中用三氟乙酸使Boc保护基脱除保护。或者,当在高温下在例如水及甲醇的适当溶剂中加热时进行Boc裂解。
治疗方法
适应症
本发明涉及式(I)化合物的用途,其用于治疗和/或预防疾病或医学症状。
本发明涉及式(I)化合物或其药学上可接受的盐,其适用于预防和/或治疗SSTR4受体的活化具有治疗效益的疾病和/或症状,包括改良症状,包括(但不限于)治疗和/或预防任何种类的疼痛和/或炎症疾病和/或相关症状。
在另一个方面中,本发明涵盖以上所提及的通式(I)的化合物或其药学上可接受的盐,根据本发明其用作药物。
鉴于其药理学效应,所述物质适用于治疗:
(1)急性疼痛,例如牙痛、围手术期及手术后疼痛、创伤性疼痛、肌肉疼痛、由灼伤、晒伤所引起的疼痛、三叉神经痛、由胃肠道或子宫的绞痛以及痉挛所引起的疼痛;扭伤
(2)内脏疼痛,例如慢性骨盆疼痛、妇科疼痛、月经之前及月经期间的疼痛、由胰脏炎所引起的疼痛、消化性溃疡、间质性膀胱炎、肾绞痛、胆囊炎、前列腺炎、心绞痛、由肠激惹所引起的疼痛、非溃疡性消化不良及胃炎、前列腺炎、非心脏性胸部疼痛及由心肌局部缺血及心脏梗塞所引起的疼痛;
(3)神经痛,例如腰骶神经根病、下背痛、髋部疼痛、腿疼痛、非疱疹性神经痛、疱疹后神经痛、糖尿病性神经病变、神经损伤诱发性疼痛、获得性免疫缺陷综合征(AIDS)相关神经痛、头部创伤、毒素及化学疗法引起的神经损伤、幻肢痛、多发性硬化症、根部撕脱、疼痛性创伤性单神经病变、疼痛性多发性神经病变、丘脑性疼痛综合征、中风后疼痛、中枢神经系统损伤、手术后疼痛、腕管综合征、三叉神经痛、乳房切除术后综合征、胸廓切开术后综合征、残端痛、反复性运动痛、神经痛相关的痛觉过敏及异常疼痛、酒精中毒及其他药物诱发性疼痛;
(4)与疾病有关的炎性疼痛/受体介导的疼痛,所述疾病为例如骨关节炎、类风湿性关节炎、炎性关节病、风湿热、腱鞘炎、滑囊炎、肌腱炎、痛风及痛风性关节炎、创伤性关节炎、外阴疼痛、肌肉及筋膜的损坏及疾病、幼年型关节炎、脊椎炎、牛皮癣性关节炎、肌炎、牙齿疾病、流行性感冒及其他病毒感染(例如伤风)、全身性红斑狼疮或由灼伤所引起的疼痛;
(5)与癌症有关的肿瘤疼痛,所述癌症为例如淋巴或骨髓性白血病、霍奇金氏病(Hodgkin′sdisease)、非霍奇金氏淋巴瘤、颗粒性淋巴瘤病、淋巴肉瘤、实体恶性肿瘤及广泛转移灶;
(6)各种起因的头痛病,例如丛集性头痛、偏头痛(有或无先兆)及紧张性头痛;
(7)交感神经维持性疼痛,如I及II型复杂区域疼痛综合征;
(8)混合起因的疼痛症状,例如慢性背痛(包括腰痛或肌肉纤维疼痛)、坐骨神经痛、子宫内膜异位症、肾结石。
所述化合物亦适于治疗:
(9)皮肤及黏膜的炎症和/或水肿疾病,例如过敏性及非过敏性皮炎、异位性皮炎、牛皮癣、灼伤、晒伤、细菌性炎症、通过化学或天然物质(植物、昆虫、昆虫咬伤)触发的刺激及炎症、瘙痒;齿龈炎症、由灼伤所引起的创伤后的水肿、血管水肿或葡萄膜炎;
(10)炎症相关的血管及心脏疾病,如动脉粥样硬化(包括心脏移植物动脉粥样硬化)、结节性全动脉炎、结节性动脉周炎、颞肌动脉炎、韦格纳氏肉芽肿(Wegnergranulomatosis)、巨细胞关节炎、再灌注损伤及结节性红斑、血栓形成(例如深静脉血栓形成、肾、肝脏、门静脉血栓形成);冠状动脉病、动脉瘤、血管排斥反应、心肌梗塞、栓塞、中风、血栓形成(包括静脉血栓形成)、绞痛(包括不稳定型绞痛)、冠状动脉斑块炎症、细菌诱发性炎症(包括披衣菌诱发性炎症)、病毒诱发性炎症、及与手术操作相关的炎症,所述手术操作为例如血管移植术(包括冠状动脉旁路术)、血管再形成操作(包括血管成形术、血管支架放置、动脉内膜切除术)或涉及动脉、静脉及毛细血管的其他侵入操作、动脉再狭窄;
(11)与气管及肺的疾病有关的炎性变化,例如支气管哮喘,包括过敏性哮喘(异位性或非异位性)以及劳力性支气管痉挛、职业诱发性哮喘、现有哮喘的病毒性或细菌性恶化及其他非过敏诱发性哮喘疾病;慢性支气管炎及慢性阻塞性肺病(COPD)(包括肺气肿)、慢性支气管炎或慢性阻塞性支气管炎的病毒性或细菌性恶化、急性成人呼吸窘迫综合征(ARDS)、支气管炎、肺炎、过敏性鼻炎(季节性及全年性)、血管舒缩性鼻炎及肺中由粉尘所引起的疾病(例如矾土沉着病、炭末沉着病、石棉沉着病、石硝沉着病、铁质沉着病、硅肺病、烟末沉着病及棉屑沉着病)、外源性过敏性肺泡炎、肺纤维化、支气管扩张症、缺乏α1-抗胰蛋白酶的肺部疾病及咳嗽;
(12)胃肠道的炎症疾病,包括克罗恩氏病(Crohn′sdisease)及溃疡性结肠炎、肠激惹综合征、胰脏炎;
(13)耳、鼻、口及咽喉的炎症相关疾病,如流行性感冒及病毒/细菌感染,例如普通感冒、过敏性鼻炎(季节性及常年性)、咽炎、扁桃腺炎、齿龈炎、喉炎、窦炎及血管舒缩性鼻炎、发热、枯草热、甲状腺炎、耳炎、牙科症状(如牙痛)、围手术期及手术后症状、三叉神经痛、葡萄膜炎;虹膜炎、过敏性角膜炎、结膜炎、睑炎、视神经炎(neuritisnervioptici)、脉络膜炎、青光眼及交感神经眼炎以及其疼痛;
(14)糖尿病及其效应(例如糖尿病性异种移植血管病、糖尿病性神经病变、糖尿病性视网膜病、糖尿病性肾病)及胰岛炎中的糖尿病性症状(例如高血糖症、多尿症、蛋白尿及亚硝酸盐及激肽释放酶的肾脏排泄增加);豆安综合征(Doansyndrome)及起立性低血压;
(15)细菌感染后或创伤后的败血症及败血性休克;
(16)关节及结缔组织的炎性疾病,例如结缔组织的血管病、扭伤及骨折、及具有炎症症状的肌肉骨胳病(例如急性风湿热、风湿性多肌痛、反应性关节炎、类风湿性关节炎、椎关节炎以及骨关节炎)、及其他起因的结缔组织炎症、及所有起因的胶原性疾病(例如全身性红斑狼疮、硬皮病、多发性肌炎、皮肤肌炎、休格连氏综合征(syndrome)、史帝尔氏病(Still′sdisease)或费尔蒂综合征(Feltysyndrome));以及血管疾病,例如结节性全动脉炎、结节性多发性关节炎、结节性动脉周炎、颞肌动脉炎、韦格纳氏肉芽肿、巨细胞关节炎、动脉硬化症及结节性红斑;
(17)中枢神经系统的疾病及损坏,例如脑水肿及例如抑郁症的精神病的治疗及预防,及癫痫症的治疗及预防;
(18)呼吸道、生殖泌尿道、胃肠道(包括胆道或血管)结构及器官的运动或痉挛的病症;
(19)手术后发热;
(20)动脉硬化症及相关不适的治疗及预防;
(21)生殖尿道疾病的治疗及预防,例如尿失禁及相关不适、良性前列腺肥大及尿频、肾炎、膀胱炎(间质性膀胱炎);
(22)病态肥胖症及相关不适的治疗及预防;
(23)神经系统疾病,例如脑水肿及血管性水肿、大脑痴呆症(例如帕金森氏及阿尔茨海默氏病(Parkinson′sandAlzheimersdisease))、老年性痴呆;多发性硬化症、癫痫症、颞叶癫痫、耐药性癫痫、中风、重症肌无力、脑及脑膜感染(如脑脊髓炎、脑膜炎、HIV以及精神分裂症)、妄想症、自闭症、情感障碍及抽动障碍;
(24)与精神分裂症、阿兹海默氏病及其他神经系统病症及精神病症有关的认知能力障碍。相对于阿兹海默氏病,通式(I)的化合物亦可适用作疾病调节剂;
(25)工作有关疾病,如肺尘埃沉着病,包括矾土沉着病、炭末沉着病、石棉沉着病、石硝沉着病、驼鸟毛尘肺、铁质沉着病、硅肺病、烟末沉着病及棉屑沉着病;
(26)良性及恶性肿瘤及肿瘤形成,包括癌症,例如结肠直肠癌、脑癌、骨癌、上皮细胞源性肿瘤形成(上皮癌)(例如基底细胞癌)、腺癌、胃肠癌(例如唇癌、口癌、食道癌、大肠癌、小肠癌、胃癌、结肠癌、胃肠胰肿瘤、胃癌)、肝癌、膀胱癌、胰腺癌、卵巢癌、子宫颈癌、肺癌、乳癌、皮肤癌(例如鳞状细胞及基底细胞癌)、前列腺癌、肾细胞癌及对整个身体中上皮细胞起作用的其他已知癌症;肿瘤形成,如胃肠癌、巴雷特食道癌(Barrett′sesophagus)、肝癌、膀胱癌、胰脏癌、卵巢癌、前列腺癌、子宫颈癌、肺癌、乳癌及皮肤癌;腺瘤细胞增殖、甲状腺癌、Gl肿瘤、胆管癌、肝脏癌、膀胱癌、软骨肉瘤、恶性嗜铬细胞瘤、神经母细胞瘤、胸腺瘤、副神经节瘤、嗜铬细胞瘤、室管膜瘤、白血病(例如嗜碱性白血病、慢性淋巴细胞白血病、慢性骨髓白血病)、霍奇金病及非霍奇金淋巴瘤;腺瘤性息肉,包括家族性腺瘤息肉病(FAP)以及预防有发生FAP风险的患者中息肉形成。适合用途可包括用于治疗肢端肥大症、癌症、关节炎、类癌瘤及血管活性肠肽肿瘤;
(27)各种其他疾病病况及症状,如癫痫症、败血性休克(例如抗低血容量剂和/或抗低血压剂)、败血症、骨质疏松症、良性前列腺肥大及尿频、肾炎、瘙痒症、白斑症、呼吸、生殖泌尿、胃肠或血管区域的内脏运动紊乱、创伤、过敏性皮肤反应、混合型血管与非血管综合征、与细菌感染或创伤相关的败血性休克、中枢神经系统损伤、组织损伤及术后发烧、与瘙痒相关的综合征;
(28)焦虑症、抑郁症、精神分裂症、癫痫症、注意力缺乏及活性过高症及神经退化性疾病,例如痴呆症、阿兹海默氏病及帕金森氏病。情感障碍的治疗包括躁郁症(例如躁狂抑郁性精神病)、极端精神症状态(例如躁症及追求行为稳定的过度情绪波动)。焦虑状态的治疗包括广泛性焦虑症以及社会性焦虑症、畏旷症及特征为社会退缩的那些行为状态(例如阴性症状);
(29)涉及病理性血管增殖的疾病,例如血管生成、再狭窄、平滑肌增殖、内皮细胞增殖及需要激活新血管生成的新血管萌芽或症状。血管生成疾病可为例如年龄相关的黄斑部变性或与手术操作(例如血管成形术及AV分流)有关的血管增殖。其他可能存在的用途为治疗动脉硬化症、斑块新血管生成、肥厚性心肌病、心肌血管生成、瓣膜疾病、心肌梗塞、冠状动脉脉络病、脑脉络病及缺血性四肢血管生成;
(30)哺乳动物的视网膜和/或虹膜睫状体的病理性症状。此类症状可为高眼内压(lOP)和/或深眼部感染。可治疗的疾病可为例如青光眼、基质性角膜炎、虹膜炎、视网膜炎、白内障及结膜炎。与眼睛有关的其他疾病可为眼部及角膜血管生成症状,例如角膜移植物排斥反应、晶状体后纤维组织增生、欧西-韦伯综合征(Osier-WebberSyndrome)或潮红。
(31)本发明的化合物在标记(例如35-S、123-I、125-I、111-In、11-C等)直接并入化合物中或经由适合间隔基并入之后亦可用于健康或病组织和/或器官的成像,所述组织和/或器官为例如具有ssti和/或SSTR4受体的前列腺、肺、脑、血管或肿瘤。
根据本发明,优选使用式(I)化合物来治疗和/或预防疼痛;尤其是与任一种上文所列疾病或症状相关的疼痛。
本发明的另一方面为一种治疗和/或预防上述疾病及症状的方法,该方法包含向人类给予有效量的式(I)化合物。
剂量:
对于治疗上述疾病及症状而言,本发明化合物的治疗有效剂量一般在每公斤体重每剂量约0.01mg至约100mg的范围内,优选在每公斤体重每剂量约0.1mg至约20mg的范围内。举例而言,对于投药至70公斤者而言,本发明化合物的剂量范围为每剂量约0.7mg至约7000mg,优选每剂量约7.0mg至约1400mg。需要对日常剂量进行某种程度的优化以确定最优选给药量及模式。活性成分可一天给予1至6次。
实际医药有效量或治疗剂量当然将视本领域技术人员已知的因素而定,例如患者的年龄及体重、投药途径及疾病严重程度。在任何情况下,将以允许基于患者的独特情况传递医药有效量的剂量及方式给予组合。
药物组合物:
适用于给予式(I)化合物的制剂将为一般技术人员显而易知,且包括例如片剂、丸剂、胶囊、栓剂、口含锭、糖衣锭、溶液、糖浆、酏剂、药囊、可注射剂、吸入剂及散剂等。医药活性化合物的含量应在组合物整体的1至99重量%、优选10至90重量%、更优选20至70重量%的范围内。
适合片剂可通过例如混合一或多种式(I)化合物与已知赋形剂(例如惰性稀释剂、载剂、崩解剂、佐剂、表面活性剂、黏合剂和/或润滑剂)而获得。片剂亦可由若干层组成。
本发明的另一方面为一种医药制剂,其包括式(I)化合物以及药学上可接受的佐剂、稀释剂或载剂混合。
组合疗法
本发明化合物可与在此项技术中已知与治疗为本发明所关注的任何适应症的治疗相结合使用的其他治疗选项组合。
视为适于与本发明的治疗组合的此类治疗选项中有:
-非甾体抗炎药(NSAID),包括COX-2抑制剂;
-阿片受体激动剂;
-类大麻酚(cannabionoid)激动剂或内源性类大麻酚(endocannabinoid)路径抑制剂;
-钠离子通道阻断剂;
-N型钙离子通道阻断剂;
-血清素激导性及去甲肾上腺素激导性调节剂;
-皮质类固醇;
-组织胺H1、H2、H3及H4受体拮抗剂;
-质子泵抑制剂;
-白三烯拮抗剂及5-脂肪加氧酶抑制剂;
-局部麻醉剂;
-VR1激动剂及拮抗剂;
-烟碱型乙酰胆碱受体激动剂;
-P2X3受体拮抗剂;
-NGF激动剂及拮抗剂或抗NGF抗体;
-NK1及NK2拮抗剂;
-缓激肽B1拮抗剂;
-CCR2拮抗剂;
-iNOS或nNOS或eNOS抑制剂;
-NMDA拮抗剂;
-钾离子通道调节剂;
-GABA调节剂;
-血清素激导性及去甲肾上腺素激导性调节剂;
-抗偏头痛药;
-神经痛药,例如普瑞巴林(pregabaline)或度洛西汀(duloxetine)。
该清单不被视为具有限制性。
在下文中,将给出此类治疗选项的代表性实施例:
·非甾体抗炎药(NSAID),包括COX-2抑制剂:丙酸衍生物(阿明洛芬(alminoprofen)、苯洛芬(benoxaprofen)、布氯酸(bucloxicacid)、卡洛芬(carprofen)、芬护芬(fenhufen)、非诺洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚洛芬(indoprofen)、酮洛芬(ketoprofen)、咪洛芬(miroprofen)、萘普生(naproxen)、奥沙普秦(oxaprozin)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、舒洛芬(suprofen)、噻洛芬酸(tiaprofenicacid)及硫洛芬(tioxaprofen))、乙酸衍生物(吲哚美辛(indomethacin)、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、环氯茚酸(clidanac)、双氯芬酸(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozicacid)、芬替酸(fentiazac)、呋罗芬酸(furofenac)、异丁芬酸(ibufenac)、伊索克酸(isoxepac)、奥昔平酸(oxpinac)、舒林酸(sulindac)、硫平酸(tiopinac)、托美汀(tolmetin)、齐多美辛(zidometacin)及佐美酸(zomepirac))、芬那酸(fenamicacid)衍生物(甲氯芬那酸(meclofenamicacid)、甲芬那酸(mefenamicacid)及托芬那酸(tolfenamicacid))、联二苯-羧酸衍生物、昔康类(oxicams)(伊索昔康(isoxicam)、美洛昔康(meloxicam)、吡罗昔康(piroxicam)、舒多昔康(sudoxicam)及替诺昔康(tenoxican))、水杨酸盐类(乙酰水杨酸、柳氮磺吡啶(sulfasalazine))及吡唑酮类(pyrazolones)(阿扎丙宗(apazone)、苯哌隆(bezpiperylon)、非普拉宗(feprazone)、莫非布宗(mofebutazone)、羟布宗(oxyphenbutazone)、苯基丁氮酮(phenylbutazone))以及昔布类(塞莱昔布(celecoxib)、伐力昔布(valecoxib)、罗非昔布(rofecoxib)及依托昔布(etoricoxib))及其类似物;
·抗病毒药,如阿昔洛韦(acyclovir)、替诺福韦(tenovir)、普可那利(pleconaril)、帕拉米韦(peramivir)、普利醇(pocosanol)及其类似物;
·抗生素药,如庆大霉素(gentamicin)、链霉素(streptomycin)、格尔德霉素(geldanamycin)、多利培南(doripenem)、头孢力新(cephalexin)、头孢克洛(cefaclor)、塞夫他嗪(ceftazichine)、头孢吡肟(cefepime)、红霉素(erythromycin)、万古霉素(vancomycin)、胺曲南(aztreonam)、阿莫西林(amoxicillin)、杆菌肽(bacitracin)、依诺沙星(enoxacin)、磺胺米隆(mafenide)、多西环素(doxycycline)、氯霉素及其类似物;
·阿片受体激动剂:吗啡碱(morphine)、丙氧吩(propoxyphene)(达而丰(Darvon))、曲马多(tramadol)、丁丙诺啡(buprenorphin)及其类似物;
·糖皮类固醇,例如倍他米松(bethamethasone)、布地奈德(budesonide)、地塞米松(dexamethasone)、氢化可的松(hydrocortisone)、甲泼尼龙(methylprednisolone)、泼尼龙(prednisolone)、泼尼松(prednisone)、曲安西龙(triamcinolone)及地夫可特(deflazacort);免疫抑制药、免疫调节药或细胞抑制药,包括(但不限于)羟氯喹(hydroxychlorquine)、D-青霉胺(D-penicillamine)、柳氮磺吡啶(sulfasalizine)、金诺芬(auranofin)、金巯嘌呤(mercaptopurine)、他克莫司(tacrolimus)、西罗莫司(sirolimus)、霉酚酸吗啉乙酯(mycophenolatemofetil)、环孢灵(cyclosporine)、来氟米特(leflunomide)、甲胺喋呤(methotrexate)、硫唑嘌呤(azathioprine)、环磷酰胺(cyclophosphamide)及乙酸格拉默(glatirameracetate)及诺凡特龙(novantrone)、芬戈莫德(fingolimod)(FTY720)、二甲胺四环素(minocycline)及沙力度胺(thalidomide)及其类似物;
·抗TNF抗体或TNF受体拮抗剂,例如(但不限于)依那西普(Etanercept);英利昔单抗(Infliximab);阿达木单抗(Adalimumab)(D2E7);CDP571;及Ro45-2081(来那西普(Lenercept));或针对例如(但不限于)CD-4、CTLA-4、LFA-1、IL-6、ICAM-1、C5的标靶的生物药物;及那他珠单抗(Natalizumab);及其类似物;
·IL-1受体拮抗剂,例如(但不限于)阿那白滞素(Kineret);
·钠离子通道阻断剂:卡马西平(carbamazepine)、美西律(mexiletine)、拉莫三嗪(lamotrigine)、特丁质(tectin)、拉科酰胺(lacosamide)及其类似物。
·N型钙离子通道阻断剂:齐考诺肽(Ziconotide)及其类似物;
·血清素激导性及去甲肾上腺素激导性调节剂:帕罗西汀(paroxetine)、度洛西汀(duloxetine)、可乐定(clonidine)、阿米曲替林(amitriptyline)、西它普兰(citalopram);
·组织胺H1受体拮抗剂:溴非尼拉敏(bromophtniramint)、氯芬尼拉明(chlorpheniramine)、右氯芬尼拉明(dexchlorpheniramine)、曲普利啶(triprolidine)、氯马斯汀(clemastine)、苯海拉明(diphenhydramine)、二苯拉林(diphenylpyraline)、曲吡那明(tripelennamine)、羟嗪(hydroxyzine)、甲地拉嗪(methdiJazine)、普敏太定(promethazine)、阿利马嗪(trimeprazine)、阿扎他啶(azatadine)、赛庚啶(cyproheptadine)、安他唑啉(antazoline)、芬尼拉明(pheniramine)、吡拉明(pyrilamine)、阿司咪唑(astemizole)、特非那定(terfenadine)、洛拉他定(loratadine)、西替利嗪(cetirizine)、去氯雷他定(deslo-ratadine)、非索非那定(fexofenadine)及左西替利嗪(levocetirizine)及其类似物;
·组织胺H2受体拮抗剂:西咪替丁(cimetidine)、法莫替丁(famotidine)及雷尼替丁(ranitidine)及其类似物;
·组织胺H3受体拮抗剂:环丙沙芬(ciproxifan)及其类似物
·组织胺H4受体拮抗剂:硫丙咪胺(thioperamide)及其类似物
·质子泵抑制剂:奥美拉唑(omeprazole)、泮托拉唑(pantoprazole)及埃索美拉唑(esomeprazole)及其类似物;
·白三烯拮抗剂及5-脂肪加氧酶抑制剂:扎鲁司特(zafirlukast)、孟鲁司特(montelukast)、普鲁司特(pranlukast)及齐留通(zileuton)及其类似物;
·局部麻醉剂,例如胺溴素(ambroxol)、利多卡因(lidocaine)及其类似物;
·钾离子通道调节剂,如瑞替加滨(retigabine);
·GABA调节剂:拉库酰胺(lacosamide)、普瑞巴林(pregabalin)、加巴喷丁(gabapentin)及其类似物;
·抗偏头痛药:舒马普坦(sumatriptan)、佐米曲坦(zolmitriptan)、那拉曲坦(naratriptan)、依来曲普坦(eletriptan)、特塞潘特(telcegepant)及其类似物;
·NGF抗体,例如RI-724及其类似物。
组合疗法亦有可能与新成分一起用于治疗疼痛,所述新成分例如为P2X3拮抗剂、VR1拮抗剂、NK1及NK2拮抗剂、NMDA拮抗剂、mGluR拮抗剂及其类似物。
化合物的组合优选为协同组合。如例如Chou及Talalay,Adv.EnzymeRegul.22:27-55(1984)所述当化合物组合给予时的效应大于化合物以单一药物单独给予时的叠加效应时,发生协同作用。一般而言,在化合物的次最优选浓度下,协同作用最为明显。协同作用可体现在组合相较于个别组分的细胞毒性较低、药理学作用增强或一些其他有益作用方面。
化学制造
缩写:
Ac乙酰基
ACN乙腈
APCI大气压力化学电离
Boc叔丁氧羰基
伯吉斯试剂氢氧化甲氧羰基胺磺酰基-三乙基铵内盐
CDI1,1′-羰基二咪唑
d天
dba二亚苄基丙酮
DCM二氯甲烷
DIPEA二异丙基乙胺
DME1,2-二甲氧乙烷
DMF二甲基甲酰胺
DMSO二甲亚砜
ESI电喷雾电离(以MS计)
EtOAc乙酸乙酯
EtOH乙醇
Exp.实施例
h小时
HATU六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲
HPLC高效液相色谱法
HPLC-MS耦联高效液相色谱-质谱分析
LC液相色谱
LC-MS耦联液相色谱-质谱分析
M摩尔浓度(mol/L)
MeOH甲醇
min分钟
MS质谱分析
NMP1-甲基-2-吡咯烷酮
RP反相
rt室温
Rt滞留时间(以HPLC/LC计)
TBTU四氟硼酸O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲
TEA三乙胺
TFA三氟乙酸
THF四氢呋喃
TLC薄层色谱
UPLC-MS超高效液相色谱-质谱分析
方法:
UPLC-MS及HPLC-MS方法:
方法1
仪器:LC/MSWatersAcquityUPLC系统DAD,SQD单级四偶极;管柱:HSSC181.8μm2.1×50mm,温度35℃;流动相:A=H2O90%+10%CH3CN+CF3COOH0.1%,B=CH3CN90%+H2O10%;梯度:0.0min0%B→1.20min100%B→1.45min100%B→1.55min0%B→1.75min0%B;流速:0.70mL/min;检测:UV254nm;检测:SQD,单级四偶极;离子源:ES+/ES-;扫描范围:90-900amu
方法2
仪器:LC/MSWatersAcquityUPLCSystemDAD,SQD单级四偶极;管柱:BEHC181.7μm2.1×50mm,温度35℃;流动相:A=H2O90%+10%CH3CN+NH4COOH5mmol,B=CH3CN90%+H2O10%;梯度:0.0min0%B→1.20min100%B→1.45min100%B→1.55min0%B→1.75min0%B;流速:0.70mL/min;检测:UV254nm;检测:SQD,单级四偶极;离子源:ES+/ES-;扫描范围:90-900amu
方法3
仪器:LC/MSWatersAcquityUPLC系统DAD,ELSD检测器,SQD单级四偶极;管柱:HSSC181.8μm2.1×50mm,温度35℃;流动相:A=H2O90%+10%CH3CN+CF3COOH0.1%,B=CH3CN90%+H2O10%;梯度:0.0min0%B→2.40min100%B→2.70min100%B→2.80min0%B→3.00min0%B;流速:0.70mL/min;检测:UV254nm;检测:ELSD检测器;检测:SQD,单级四偶极;离子源:ES+/ES-;扫描范围:90-900amu
方法4
仪器:LC/MSWatersAcquityUPLCSystemDAD,ELSD检测器,SQD单级四偶极;管柱:BEHC181.7μm2.1×50mm;流动相:A=H2O90%+CH3CN10%+NH4COOH5mM,B=CH3CN90%+H2O10%;梯度:0.0min0%B→2.40min100%B→2.70min100%B→2.80min0%B→3.00min0%B;流速:0.70mL/min;检测:UV254nm;检测:ELSD检测器;检测:SQD,单级四偶极;离子源:ES+/ES-;扫描范围:90-900amu
方法5
仪器:LC/MSWatersAcquityUPLCSystemDAD,ELSD检测器,SQD单级四偶极;管柱:HSSC181.8μm2.1×50mm,温度35℃;流动相:A=H2O90%+CH3CN10%+CF3COOH0.1%,B=CH3CN90%+H2O10%;梯度:0.0min0%B→2.40min100%B→2.70min100%B→2.80min0%B→3.00min0%B;流速:0.70mL/min;检测:UV254nm;检测:ELSD检测器;检测:SQD,单级四偶极;离子源:ES+/ES-;扫描范围:90-900amu
方法6
仪器:LC/MSThermoFinniganHPLCSurveyorDAD,LCQFleet离子阱;管柱:SimmetryShieldRP8,5μm,4.6×150mm;洗脱剂A:90%水+10%ACN+HCOOH0.1%;洗脱剂B=ACN90%+10%H2O+HCOOH0.1%;梯度:0.0min5%B→1.5min5%B→11.5min95%B→13.0min95%B→13.3min5%B→15.0min5%B;流速:1.0mL/min;UV检测:254nm;检测:FinniganFleet离子阱;离子源:ES+;扫描范围:100-900amu
方法7
仪器:LC/MSThermoFinnigan.HplcSurveyorDAD,MSQ四偶极;管柱:SynergiHydroRP100A,2.5μm,3×50mm;洗脱剂A:90%水+10%ACN+甲酸胺10mM;洗脱剂B=ACN90%+10%H2O+NH4COOH10mM;梯度:0.0min0%B→1.50min0%B→8.00min100%B→10.00min100%B→11.00min0%B→12.00min0%B;流速:0.7mL/min;UV检测:254nm;离子源:APCI+/APCI-。
方法7a
仪器:LC/MSThermoFinnigan.HplcSurveyorDAD,MSQ四偶极;管柱:SynergiHydroRP100A,2.5μm,3×50mm;洗脱剂A:90%水+10%ACN+甲酸胺10mM;洗脱剂B=ACN90%+10%H2O+NH4COOH10mM;梯度:0.0min0%B→0.50min0%B→6.50min100%B→7.50min100%B→8.00min0%B→9.00min0%B;流速:1.2mL/min;UV检测:254nm;离子源:APCI+/APCI-。
方法7b
仪器:LC/MSThermoFinnigan.HplcSurveyorDAD,MSQ四偶极;管柱:SynergiHydroRP100A,2.5μm,3×50mm;洗脱剂A:90%水+10%ACN+甲酸胺5mM;洗脱剂B=ACN90%+10%H2O;梯度:0.0min0%B→4.00min100%B→5.30min100%B→5.50min0%B→6.00min0%B;流速:1.2mL/min;UV检测:254nm;离子源:APCI+/APCI-。
方法8
仪器:LC/MSThermoFinnigan.HplcSurveyorDAD,MSQ四偶极;管柱:SynergiHydroRP100A,2.5μm,3×50mm;洗脱剂A:90%水+10%ACN+甲酸胺10mM;洗脱剂B=ACN90%+10%H2O+NH4COOH10mM;梯度:0.0min0%B→4.00min100%B→5.30min100%B→5.50min0%B→6.00min0%B;流速:1.2mL/min;UV检测:254nm;离子源:APCI+/APCI-。
方法9
仪器:LC/MSWatersAlliance2695HPLCSystemDAD,Quattro微三级四偶极;管柱:SunFireC183.5μm4.6×50mm;洗脱剂A:H2O90%+10%CH3CN+CF3COOH0.05%;洗脱剂B=CH3CN90%+10%H2O;梯度:0.0min0%B→4.50min100%B→5.80min100%B→6.00min0%B;流速:1.3mL/min;UV检测:254nm;离子源:ES+。
方法10
仪器:LC/MSWatersAlliance2695HPLCSystemDAD,Quattro微三级四偶极;管柱:AtlantisdC185μm4.6×50mm;洗脱剂A:H2O90%+10%CH3CN+CF3COOH0.05%;洗脱剂B=CH3CN90%+10%H2O;梯度:0.0min0%B→0.70min0%B→4.50min100%B→5.80min100%B→6.00min0%B;流速:1.3mL/min;UV检测:254nm;离子源:ES+。
方法11
仪器:LC/MSWatersAlliance2695HPLCSystemDAD,Quattro微三级四偶极;管柱:XbridgePhenyl3.5μm3×30mm;洗脱剂A:H2O90%+10%CH3CN+NH4HCO35mM;洗脱剂B=CH3CN90%+10%H2O;梯度:0.0min0%B→4.50min100%B→5.80min100%B→6.00min0%B;流速:1.3mL/min;UV检测:254nm;离子源:ES+/-
方法12
仪器:LC/MSThermoFinniganHPLCSurveyorDAD,LCQFleet离子阱;管柱:XselectCSH,2.5μm,4.6×50mm;洗脱剂A:H2O90%+10%CH3CN+HCOOH0.1%;洗脱剂B=CH3CN90%+H2O10%+HCOOH0.1%;梯度:0.0min0%B→4.00min100%B→5.30min100%B→5.50min0%B→6.00min0%B;流速:1.4mL/min;UV检测:254nm;离子源:ES+/-
方法12a
仪器:LC/MSWatersAlliance2695HPLCSystemDAD,Quattro微三级四偶极;管柱:ZorbaxEclipseXDB-C183.5μm4.6×50mm,温度35℃;洗脱剂A:H2O90%+10%CH3CN+NH4COOH5mM;洗脱剂B=CH3CN90%+10%H2O;梯度:0.0min0%B→4.50min100%B→5.80min100%B→6.00min0%B;流速:1.3mL/min;UV检测:254nm;离子源:ES+/-
GC-MS方法:
方法13
仪器:GC/MSThermoScientificTRACEGCULTRA,DSQIIMS单级四偶极;管柱:AgilentDB-5MS,25m×0.25mmol×0.25μm;运载气体:氦,1mL/min恒定流速;烘箱操作:以10℃/min由50℃达到100℃,以20℃/min达到200℃,以30℃/min达到320℃(维持10min);检测:DSQIIMS单级四偶极;离子源:EI;扫描范围:50-450amu
手性HPLC方法:
方法14
HPLC装置类型:Agilent1100;管柱:DaicelchiralpackAD-H,5.0μm,250mm×4.6mm;方法:洗脱剂己烷/IPA70:30;流速:1mL/min,温度:25℃;UV检测:230nm
方法15
HPLC装置类型:Agilent1100;管柱:DaicelchiralpackAD-H,5.0μm,250mm×4.6mm;方法:洗脱剂己烷/IPA85:15;流速:1mL/min,温度:25℃;UV检测:230nm
方法16
HPLC装置类型:Agilent1100;管柱:DaicelchiralpackAD-H,5.0μm,250mm×4.6mm;方法:洗脱剂己烷/IPA75:25;流速:1mL/min,温度:25℃;UV检测:230nm
方法17
HPLC装置类型:Agilent1100;管柱:DaicelchiralpackOJ-H,5.0μm,250mm×4.6mm;方法:洗脱剂己烷/乙醇93:7;流速:1mL/min,温度:25℃;UV检测:230nm
方法18
HPLC装置类型:Agilent1100;管柱:DaicelchiralpackAS-H,5.0μm,250mm×4.6mm;方法:洗脱剂己烷/乙醇95:5;流速:1mL/min,温度:25℃;UV检测:230nm
微波加热:
装备有10及35mL容器的CEM仪器
NMR设备:
经BrukerAvanceIII(500MHz)或Varian400(400MHz)仪器记录1HNMR光谱,其中使用氘化二甲亚砜(DMSO-d6)作为溶剂,四甲基硅烷(TMS)作为内部标准。以δ值(ppm)报导相对于TMS的化学位移。
实验:
实施例1a
在80℃下在无水N,N-二甲基乙酰胺(5mL)中加热2-甲基-2-硝基丙基-对甲苯磺酸酯(250mg,0.915mmol)、4-氟-2-甲基苯酚(115mg,0.915mmol)及碳酸铯(358mg,1.098mmol)隔夜。添加碳酸铯(596mg,1.830mmol)且在150℃下加热反应混合物2h。用水(5mL)及4MHCl(5mL)处理反应混合物且用乙酸乙酯萃取。用盐水洗涤有机层,经Na2SO4干燥且减压蒸发,得到残余物,通过快速色谱(洗脱剂0-30%EtOAc/环己烷)纯化,得到标题化合物(155mg,75%)。
1HNMR(300MHz,DMSO-d6):δ1.66(s,6H),2.07(s,3H),4.31(s,2H),6.94-7.03(m,3H)
UPLC-MS(方法2):Rt=1.31min
MS(ESI正):m/z=228(M+H)+
以下实施例类似于实施例1a的制备来合成:
实施例1q
实施例1q如实施例1a所述使用2-氟苯酚(148mg,1.317mmol)作为起始物质来制备且在130℃下加热反应物90分钟。用水处理反应混合物且用乙醚萃取。用盐水及5%K2CO3洗涤有机层,干燥且减压蒸发,得到标题化合物(170mg,62%)。
UPLC-MS(方法2):Rt=1.24min
MS(ESI正):m/z=214(M+H)+
实施例1r
将2-氯-5-氟-3-甲基吡啶(1g,6.870mmol)溶解于盐酸(37%,20mL)中且在150℃下在微波辐射下加热反应物15h。用水稀释混合物且用DCM洗涤。用NaOH碱化水层且用DCM再萃取若干次。分离有机层,干燥且蒸发,得到5-氟-3-甲基-吡啶-2-醇(140mg,含量74%,12%)。
UPLC-MS(方法2):Rt=0.50min
MS(ESI正):m/z=128(M+H)+
在150℃下在无水N,N-二甲基乙酰胺(5mL)中加热5-氟-3-甲基-吡啶-2-醇(139mg,1.098mmol)、2-甲基-2-硝基丙基-对甲苯磺酸酯(300mg,1.098mmol)及碳酸铯(429mg,1.317mmol)7h。用水(10mL)处理反应混合物且用乙酸乙酯(20mL)萃取。使有机层干燥且减压蒸发,得到残余物,通过快速色谱(洗脱剂0-25%EtOAc/环己烷)纯化,得到标题化合物(70mg,25%)。
UPLC-MS(方法2):Rt=1.20min
MS(ESI正):m/z=229(M+H)+
实施例2a
将阮尼镍(28mg,0.330mmol)添加至溶解于MeOH(10mL)中的实施例1a(150mg,0.660mmol)中,且在3巴下氢化混合物隔夜。通过过滤移除催化剂且减压蒸发反应物,得到标题化合物(96mg,74%),其以原样使用。
HPLC-MS(方法7):Rt=4.82min
MS(APCI):m/z=198(M+H)+
以下实施例类似于实施例2a的制备来合成:
实施例2k
实施例2k类似于实施例2a由实施例1r(70mg,0.273mmol)来制备。处理的残余物经SCX筒纯化,用MeOH洗涤且用甲醇氨洗脱。减压移除挥发物,得到标题化合物(17mg,28%)。
UPLC-MS(方法2):Rt=0.66min
MS(ESI正):m/z=199(M+H)+
实施例2l及实施例2m
将阮尼镍(50mg,0.584mmol)添加至溶解于含实施例1g(200mg,0.712mmol)的MeOH(10mL)中,且在3巴下氢化混合物2h。通过过滤移除催化剂且蒸发反应物,得到残余物,通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份且蒸发,得到实施例2l(90mg,35%)及实施例2m(152mg,65%)。
实施例2l:HPLC-MS(方法10):Rt=3.22min
MS(ESI正):m/z=234(M+H)+
实施例2m:HPLC-MS(方法10):Rt=1.07min
MS(ESI正):m/z=200(M+H)+
实施例2n
将实施例1e(1.4g,4.86mmol)溶解于无水MeOH(30mL)中,接着添加4MHCl的二烷溶液(18mL,73mmol)且在0℃下冷却混合物。逐份添加锌(1.9g,29.15mmol)且使反应物达到室温且搅拌隔夜。
经硅藻土衬垫过滤混合物,接着用1NNaOH使溶液碱化且通过过滤移除固体。添加DCM且用水洗涤反应物。分离有机层,干燥且减压蒸发,得到标题化合物(380mg,30%)。
UPLC-MS(方法2):Rt=1.00min
MS(ESI正):m/z=259(M+H)+
以下实施例类似于实施例2n的制备来合成:
实施例2s
将实施例1o(110mg,0.466mmol)及二水合氯化锡(II)(420mg,1.86mmol)溶解于无水绝对乙醇(20mL)中且加热至回流持续8h。
使反应混合物冷却且添加饱和Na2CO3溶液。经由硅藻土衬垫过滤移除固体且将EtOAc添加至所得混合物中。
依序用水、盐水洗涤有机层,接着分离,干燥且减压蒸发,得到标题化合物(100mg,94%)。
UPLC-MS(方法1):Rt=0.68min
MS(ESI正):m/z=207(M+H)+
实施例2t
将2-氨基-2-甲基-丙-1-醇(11mL,118.8mmol)溶解于二烷(20mL)中且在0℃下逐份添加氢化钠(于矿物油中的60%悬浮液,5.0g,124.7mmol),且在15分钟之后添加2-氟-3-甲基-吡啶(3mL,29.7mmol)。在100℃下加热所得混合物1h。用DCM稀释反应物且用水洗涤。分离有机层,干燥且减压蒸发,得到标题化合物(5.1g,95%),其以原样使用。
HPLC-MS(方法8):Rt=1.78min
MS(APCI):m/z=181(M+H)+
实施例2u
实施例2u类似于实施例2t使用3-氟-4-(三氟甲基)吡啶(8g,48.46mmol)作为起始物质来制备,其中改将最终残余物溶解于MeOH中且用正庚烷洗涤。减压移除挥发物,得到标题化合物(9.5g,84%)
HPLC-MS(方法11):Rt=1.97min
MS(ESI正):m/z=235(M+H)+
实施例3a
将HATU(95mg,0.251mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(52mg,0.228mmol,可购自ABCR或WuXiAppTec,1HNMR(500MHz,DMSO-d6):δ1.24(t,J=3.2,1H),1.38(s,9H),1.97(t,J=2.5Hz,2H),3.34(d,2H),3.48(d,J=11.0Hz,2H),12.21(br,1H))、实施例2a(45mg,0.228mmol)及DIPEA(118μl,0.684mmol)的DMF(1mL)中,且持续搅拌隔夜。减压蒸发挥发物,得到残余物,其通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化,得到标题化合物(72mg,78%)。
HPLC-MS(方法7):Rt=7.37min
MS(APCI):m/z=407(M+H)+
以下实施例类似于实施例3a的制备来合成:
实施例3i
将TBTU(70mg,0.218mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(45mg,0.198mmol)、实施例2c(46mg,含量91%,0.218mmol)及TEA(80μl,0.594mmol)的无水DMF(1.5mL)中且持续搅拌3h。用水稀释反应物且用乙醚洗涤。用NaHCO3饱和溶液及水洗涤有机层,接着分离,干燥且减压蒸发,得到标题化合物(85mg,86%),其以原样使用。
UPLC-MS(方法1):Rt=1.46min
MS(ESI正):m/z=403(M+H)+
以下实施例类似于实施例3i的制备来合成:
实施例3s
实施例3s如实施例3i所述使用1-(2,6-二甲基苯氧基)-2-甲基-丙-2-胺(68mg,0.352mmol)作为起始物质来制备。搅拌反应物2天。在常见处理之后,残余物通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份,且蒸发,得到标题化合物(95mg,62%)。
UPLC-MS(方法1):Rt=1.45min
MS(ESI正):m/z=403(M+H)+
以下实施例类似于实施例3s的制备来合成:
实施例3v
将实施例2t(5.1g,28.29mmol)、HATU(10.8g,28.295mmol)及DIPEA(15.5g,56.589mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(6.4g,28.295mmol)的DMF(10mL)中且持续搅拌3h。减压蒸发挥发物。添加EtOAc且依序用NaHCO3饱和溶液、盐水洗涤反应混合物。通过相分离筒分离有机层且蒸发溶剂,得到残余物,其通过快速色谱(洗脱剂20-50%EtOAc/环己烷)纯化,得到标题化合物(8.4克,76%)。
HPLC-MS(方法8):Rt=3.30min
MS(APCI):m/z=390(M+H)+
实施例3w
将实施例2u(3g,12.80mmol)、HATU(4.87g,12.809mmol)及DIPEA(4.46mL,25.617mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(2.62g,11.528mmol)的DMF(15mL)中且持续搅拌2h。减压蒸发挥发物,用EtOAc溶解粗物质且用NaHCO3饱和溶液及盐水洗涤有机层。使有机层干燥且蒸发,得到残余物,其通过快速色谱(洗脱剂40-70%EtOAc/环己烷)纯化,得到标题化合物(4g,含量98%,69%)。
UPLC-MS(方法2):Rt=1.12min
MS(ESI正):m/z=444(M+H)+
实施例4a
将HATU(12g,31.682mmol)、DIPEA(6mL,34.322mmol)及2-氨基-2-甲基-1-丙醇(2.5g,27.722mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(6g,26.402mmol)的无水DMF(40mL)中且持续搅拌隔夜。减压蒸发挥发物,得到残余物,溶解于EtOAc中,用10%柠檬酸、饱和NaHCO3洗涤且使用相分离筒干燥。减压蒸发所得溶液,得到残余物,其通过快速色谱(洗脱剂50-90%EtOAc/环己烷)纯化,得到标题化合物(6.2克,79%)。
1HNMR(500MHz,DMSO-d6),:δ1.15(s,6H),1.38(s,9H),1.43(t,J=3.3Hz,1H),1.77(m,2H),3.27-3.31(m,2H),3.35(d,J=5.3Hz,2H),3.45-3.48(m,2H),4.82(t,J=5.8Hz,1H),7.54(s,1H)
实施例5a
在氮气氛围下,将氢化钠(于矿物油中60%悬浮液,32mg,0.804mmol)添加至冷却至0℃的含实施例4a(120mg,0.402mmol)及4-氟-3-甲基苯甲腈(109mg,0.804mmol)的无水1,4-二烷(2mL)中且在室温下持续搅拌3h。减压蒸发挥发物,得到残余物,其通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份,减压蒸发乙腈,用饱和NaHCO3碱化水层且用DCM萃取。使用相分离筒干燥有机层,且减压蒸发所得溶液,得到标题化合物(105mg,63%)。
UPLC-MS(方法2):Rt=1.28min
MS(ESI正):m/z=414(M+H)+
以下实施例类似于实施例5a的制备来合成:
实施例5f
实施例5f如实施例5a所述使用1-氯异喹啉(164mg,1mmol)作为起始物质来制备,其中改在室温下搅拌混合物2h且接着在60℃下加热3h。减压蒸发挥发物,得到残余物,其通过快速色谱(洗脱剂20-50%EtOAc/环己烷)纯化,得到标题化合物(159mg,74%)。
HPLC-MS(方法8):Rt=3.57
MS(APCI):m/z=426(M+H)+
以下实施例类似于实施例5f的制备来合成:
实施例5h
在氮气下,将氢化钠(于矿物油中的60%悬浮液,62mg,1.54mmol)添加至冷却至0℃的含实施例4a(200mg,0.670mmol)及2-氟-3-(三氟-甲基)吡啶(221mg,1.34mmol)的无水1,4-二烷(4mL)中。使反应混合物达到室温,且接着在110℃下在微波辐射下加热50分钟。用DCM稀释反应混合物且依序用水、饱和NH4Cl洗涤,干燥且减压浓缩,得到残余物,其通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化,得到标题化合物(200mg,64%)。
UPLC-MS(方法2):Rt=1.26min
MS(ESI正):m/z=444(M+H)+
以下实施例类似于实施例5h的制备来合成:
实施例5k
实施例5k如实施例5a所述使用2-氯-3-甲基吡嗪(86mg,0.67mmol)作为起始物质来制备,其中改在室温下搅拌混合物2h且接着在60℃下加热隔夜。在制备型HPLC纯化之后,通过快速色谱(洗脱剂20-50%EtOAc/环己烷)纯化所得物质,得到标题化合物(42mg,32%)。
HPLC-MS(方法8):Rt=2.90
MS(APCI):m/z=391(M+H)+
实施例5l
在氮气流下将2-氟-3-碘吡啶(300mg,1.34mmol)、环丙基三氟硼酸钾(498mg,3.36mmol)、乙酸钯(II)(30mg,0.135mmol)溶解于甲苯(4mL)中。添加三环己基膦(75mg,0.27mmol)、磷酸三钾(1.1g,5.38mmol)及水(0.4mL)且在微波辐射(130℃)下加热反应混合物2h。在室温下,添加水且用DCM萃取水层。接着用水及盐水洗涤有机层,分离且干燥,得到3-环丙基-2-氟-吡啶(200mg,97%)。
UPLC-MS(方法2):Rt=0.94min
MS(ESI正):m/z=138(M+H)+
实施例5l如实施例5h所述使用3-环丙基-2-氟-吡啶作为起始物质(184mg,1.34mmol)来制备。
UPLC-MS(方法2):Rt=1.28min
MS(ESI正):m/z=416(M+H)+
实施例6a
向1-甲基吲唑-3-甲酸(1g,5.67mmol)于无水THF(15mL)中的溶液中添加CDI(1g,6.24mmol)。在室温下搅拌混合物1.5h,接着添加氢氧化铵(13mL30%水溶液),且再搅拌混合物15min。蒸发溶剂,将粗物质溶解于EtOAc中,用0.1N盐酸、饱和NaHCO3及盐水洗涤。分离有机层,干燥且真空蒸发,获得标题化合物(840mg,83%),其未经任何进一步纯化即用于下一步骤。
1HNMR(300MHz,DMSO-d6):δ4.12(s,3H),7.26(ddd,J=1.0,6.7,7.6Hz,1H),7.33(br,s,1H),7.46(ddd,J=1.0,6.8,8.0Hz,1H),7.65(br,s,1H),7.71(dd,J=8.2Hz,1H),8.16(dd,J=8.2Hz,1H)
以下实施例类似于实施例6a的制备来合成:
实施例6i
将碳酸铯(1.37g,4.19mmol)添加至6h(800mg,3.49mmol)于DMF(10mL)中的溶液中。在15min之后,将碘甲烷(215μl,3.49mmol)逐滴添加至反应混合物中。在5min之后,用EtOAc稀释反应物,用饱和氯化铵及水洗涤。分离有机层且用相分离筒干燥且真空蒸发,获得标题化合物(800mg,含量85%,80%),其以原样使用。
UPLC-MS(方法2):Rt=0.93
MS(ESI正):m/z=244(M+H)+
以下实施例类似于实施例6a的制备来合成:
实施例7a
将伯吉斯试剂(1.7g,7.19mmol)添加至6a(840mg,4.79mmol)于DCM(15mL)中的溶液中,且在35℃下加热混合物3h。用DCM稀释反应物,用0.2N盐酸及盐水洗涤。分离有机层且用相分离筒干燥且真空蒸发,获得粗物质,其通过快速色谱(洗脱剂0-20%EtOAc/环己烷)纯化,得到标题化合物(680mg,90%)。
GC-MS(方法13):Rt=9.74min
MS(EI正):m/z=157[M]+
以下实施例类似于实施例7a的制备来合成:
实施例7e
将三氟乙酸酐(1.16mL,8.37mmol)添加至6e(600mg,3.35mmol)于吡啶(6mL)及DCM(15mL)中的溶液中。在30min之后,用EtOAc稀释反应物,用饱和NaHCO3、饱和NH4Cl、水及盐水洗涤。分离有机层且用相分离筒干燥且真空蒸发,得到标题化合物(500mg,93%),其以原样使用。
UPLC-MS(方法2):Rt=0.91
MS(ESI正):m/z=162(M+H)+
以下实施例类似于实施例7e的制备来合成:
实施例7i
将碳酸铯(1.31g,4.03mmol)添加至7e(500mg,3.10mmol)于DMF(10mL)中的溶液中。在15min之后,将碘甲烷(192μl,3.10mmol)逐滴添加至反应混合物中。在搅拌隔夜之后,用EtOAc稀释反应物,用饱和氯化铵及水洗涤。分离有机层且用相分离筒干燥且真空蒸发,获得粗物质,其通过快速色谱(洗脱剂0-20%EtOAc/环己烷)纯化,得到标题化合物(340mg,63%)。
UPLC-MS(方法2):Rt=0.99
MS(ESI正):m/z=176(M+H)+
以下实施例类似于实施例7i的制备来合成:
实施例7k
在100℃下加热含1-氯-4-甲基酞嗪(5.00g,28.00mmol)、氰化锌(3.62g,30.79mmol)、1,1′-双(二苯膦基)二茂铁(1.40g,2.52mmol)、叁(二亚苄基丙酮)二钯(0)(1.03g,1.12mmol)的DMF(50mL)3h。用EtOAc/水稀释反应物。分离有机层,用盐水洗涤,干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-60%EtOAc/环己烷)纯化,得到标题化合物(4.17g,88%)。
GC-MS(方法13):Rt=10.85min
MS(ESI正):m/z=169[M]+
以下实施例类似于实施例7k的制备来合成:
实施例7m
将氨的甲醇溶液(7M,3.5ml,24mmol)添加至含8-溴-5-甲基咪唑并[1,2-a]吡啶盐酸盐(3.00g,12.1mmol)的DCM(5mL)中。蒸发挥发物,添加DCM及水,分离有机层,用盐水洗涤,干燥且减压蒸发,得到残余物(2.55g)。在150℃下在微波辐射下加热含一部分此类物质(1.00g,4.74mmol)、氰化锌(601mg,5.12mmol)、锌(31mg,0.47mmol)、1,1′-双(二苯膦基)二茂铁]二氯钯(II)(347mg,0.47mmol)、1,1′-双(二苯膦基)二茂铁(263mg,0.47mmol)的N,N-二甲基乙酰胺(10mL)1h。用EtOAc/水稀释反应物。分离有机层,用盐水洗涤,干燥且减压蒸发,得到残余物,用DCM洗涤且通过过滤收集所得固体,得到(650mg,含量98%,86%)。
HPLC-MS(方法7a):Rt=2.43min
MS(APCI):m/z=158(M+H)+
实施例7n
在-78℃下将正丁基锂(2.5M己烷溶液,29mL,72mmol)逐滴添加至含N-叔丁基-4-氯吡啶-2-甲酰胺(7.00g,32.9mmol)的THF(70mL)中。在-78℃下1h之后,添加碘甲烷(6.8mL,109mmol)且持续搅拌1h。添加饱和NH4Cl(10mL)且分离有机层,干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-20%EtOAc/环己烷)纯化,得到N-叔丁基-4-氯-3-甲基-吡啶-2-甲酰胺(5.7g,76%)。
UPLC-MS(方法2):Rt=1.08
MS(ESI正):m/z=227(M+H)+
在-78℃下将正丁基锂(2.5M己烷溶液,28mL,70mmol)逐滴添加至含二异丙基胺(10mL,70mmol)的THF(100mL)中。在-78℃下1h及在0℃下15min之后,使反应混合物冷却至-50℃且逐滴添加含N-叔丁基-4-氯-3-甲基-吡啶-2-甲酰胺(5.7g,25mmol)的THF(50mL)中且在-40℃下持续搅拌30min。添加乙酸甲酯(2.2mL,28mmol)且在-40℃下持续搅拌30min。添加饱和NH4Cl(2mL)、水(6mL)及乙酸乙酯,且分离有机层,干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-10%EtOAc/环己烷)纯化得到4-氯-3-(2-氧代基-丙基)-吡啶-2-甲酸叔丁基酰胺(3.7g,55%)。
UPLC-MS(方法2):Rt=1.05
MS(ESI正):m/z=269(M+H)+
将三甲基环硼氧烷(5.7mL,41mmol)添加至含4-氯-3-(2-氧代基-丙基)-吡啶-2-甲酸叔丁基酰胺(3.63g,13.5mmol)、碳酸钾(9.33g,67.5mmol)及1,1′-双(二苯膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(1.10g,1.35mmol)的DMF(60mL)中且在100℃下加热反应混合物隔夜。减压蒸发挥发物且用EtOAc/水溶解残余物。分离有机层,干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-30%EtOAc/环己烷)纯化,得到4-甲基-3-(2-氧代基-丙基)-吡啶-2-甲酸叔丁基酰胺(2.61g,78%)。
UPLC-MS(方法2):Rt=0.96min
MS(ESI正):m/z=249(M+H)+
依序将乙酸铵(10.0g,130mmol)、4-甲基-3-(2-氧代基-丙基)-吡啶-2-甲酸叔丁基酰胺(1.61g,6.48mmol)添加至乙酸(20mL)中且在110℃下加热反应混合物3h。使反应混合物冷却至室温且添加20%NaOH直至pH值为6至7。用DCM萃取水层(3次)且用盐水洗涤合并的有机层,干燥且减压蒸发,得到4,6-二甲基-[1,7]萘啶-8-醇(1.12g,99%),其以原样使用。
UPLC-MS(方法2):Rt=0.62min
MS(ESI正):m/z=175(M+H)+
在100℃下加热含4,6-二甲基-[1,7]萘啶-8-醇(1.26g,7.23mmol)及氧氯化磷(6.7mL,72mmol)的甲苯(18mL)中隔夜。添加氧氯化磷(20mL,215mmol)且在104℃下加热反应混合物1d。使反应混合物冷却至室温且在搅拌下倾倒于冰与水的混合物中。在30min之后,添加20%NaOH直至pH值为6至7。用DCM萃取水层且用盐水洗涤合并的有机层,干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-50%EtOAc/环己烷)纯化,得到8-氯-4,6-二甲基-[1,7]萘啶(920mg,66%)。
UPLC-MS(方法2):Rt=0.96min
MS(ESI正):m/z=193(M+H)+
在100℃下加热含8-氯-4,6-二甲基-[1,7]萘啶(1.34g,6.96mmol)、氰化锌(898mg,7.65mmol)、1,1′-双(二苯膦基)二茂铁(347mg,0.63mmol)、叁(二亚苄基丙酮)二钯(0)(255mg,0.28mmol)的DMF(20mL)中隔夜。用EtOAc/水稀释反应物。分离有机层,用盐水洗涤,干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-50%EtOAc/环己烷)纯化,得到标题化合物(1.02g,80%)。
UPLC-MS(方法2):Rt=0.88min
MS(ESI正):m/z=184(M+H)+
以下实施例类似于实施例7a的制备来合成:
实施例8a
在氮气氛围下,在0℃下将无水THF(22mL)添加至无水氯化铈(III)(3.2g,13mmol)中。使反应物达到室温且搅拌2h。在-78℃下添加甲基锂与碘化锂的络合物(1.6M乙醚溶液,8.1mL,13.1mmol)且在-78℃下持续搅拌30分钟。将7a(680mg,4.32mmol)于无水THF(3mL)中的溶液添加至混合物中且在-78℃下持续搅拌30分钟,且接着在室温下隔夜。将饱和NH4Cl及NaOH(50%水溶液)添加至混合物中直至沉淀形成。经硅藻土衬垫滤出未溶解物质。用水洗涤滤出物,分离且用相分离筒干燥。减压蒸发溶剂,获得粗物质(350mg,30%),其未经任何进一步纯化即用于下一步骤。
GC-MS(方法13):Rt=9.85min
MS(ESI正):m/z=189[M]+
以下实施例类似于实施例8a的制备来合成:
实施例8f
实施例8f如实施例8a所述使用3-甲基异喹啉-1-甲腈(350mg,2.08mmol)作为起始物质来制备。在处理之后,所得残余物通过快速色谱(洗脱剂100%DCM至95:5:0.5DCM/MeOH/NH4OH)纯化,得到标题化合物(162mg,39%)。
GC-MS(方法13):Rt=10.28
MS(ESI正):m/z=200[M]+
以下实施例类似于实施例8f的制备来合成:
实施例8h
实施例8h如实施例8a所述使用1-氰基异喹啉(400mg,2.6mmol)作为起始物质来制备。在反应完成时,将3-丙醇(3mL)添加至混合物中。使反应混合物分配于DCM与水之间。分离有机相且用相分离筒干燥。减压蒸发溶剂,获得粗物质(350mg,30%),其通过快速色谱(洗脱剂100%DCM至95:5:0.5DCM/MeOH/NH4OH)纯化,得到标题化合物(37mg,6%)。
UPLC-MS(方法2):Rt=0.65
MS(ESI正):m/z=187(M+H)+
实施例8i
在0℃下将溴化甲基镁于2-甲基四氢呋喃中的溶液(3.2M,6.3mL,20.10mmol)逐滴添加至含2-氰基-3-甲基-吡啶(1g,8.04mmol)的无水甲苯(7mL)中。使反应物达到室温且在90℃下持续加热72h。添加2NHCl且分离水层且接着用4NNH4OH碱化。添加乙酸乙酯且分离有机层,使用相分离筒干燥且减压蒸发所得溶液,得到残余物,其以原样使用(840mg,30%)
UPLC-MS(方法2):Rt=0.55
MS(ESI正):m/z=151(M+H)+
以下实施例类似于实施例8i的制备来合成:
以下实施例类似于实施例8a的制备来合成:
实施例9a
将HATU(326mg,0.858mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(150mg,0.660mmol)、实施例8i(397mg,含量30%,0.92mmol)及DIPEA(345μl,1.98mmol)的无水DMF(2mL)中且持续搅拌2h。减压蒸发挥发物,得到残余物,用乙酸乙酯稀释且用饱和NaHCO3及盐水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到残余物,通过快速色谱(洗脱剂DCM100%至DCM\MeOH\NH4OH95\5\0.5)纯化,得到标题化合物(104mg,95%)。
1HNMR(300MHz,DMSO-d6):δ1.39(s,9H),1.49(t,J=3.5Hz,1H),1.54(s,6H),1.69(brt,2H),2.35(s,3H),3.26-3.30(brd,J=11.7,Hz2H),3.45-3.49(brd,J=11.7,Hz2H),7.08(dd,J=4.7,7.5Hz,1H),7.39(dd,J=1.5,7.6Hz,1H),8.25(dd,J=1.6,5Hz,1H),8.35(s,1H)
以下实施例类似于实施例9a的制备来合成:
实施例9g
实施例9g如实施例9a所述使用8d(130mg,含量60%,0.445mmol)作为起始物质来制备。在处理之后,残余物通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份,减压蒸发乙腈,用饱和NaHCO3碱化水层且用DCM萃取。分离有机层且使用相分离筒干燥,且减压蒸发所得溶液,得到标题化合物(142mg,83%)。
HPLC-MS(方法8):Rt=2.62min
MS(APCI):m/z=385(M+H)+
实施例9h
实施例9h如实施例9a所述使用8e(100mg,含量90%,0.483mmol)作为起始物质来制备。在处理之后,残余物通过快速色谱(洗脱剂60-100%EtOAc/环己烷)纯化。合并含有标题化合物的洗脱份,减压蒸发溶剂,得到标题化合物(144mg,76%)。
HPLC-MS(方法8):Rt=2.85
MS(APCI):m/z=396(M+H)+
以下实施例类似于实施例9h的制备来合成:
实施例9l
实施例9l如实施例9a所述使用8j(620mg,含量30%,0.964mmol)作为起始物质来制备。在处理之后,残余物通过快速色谱(洗脱剂30-100%EtOAc/环己烷)纯化。合并含有标题化合物的洗脱份,减压蒸发溶剂,得到残余物,其通过制备型HPLC(固定相XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)再纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。用DCM萃取水层,分离且蒸发DCM,得到标题化合物(62mg,16%)。
HPLC-MS(方法10):Rt=2.84
MS(ESI正):m/z=396(M+H)+
以下实施例类似于实施例9h的制备来合成:
实施例9q
实施例9q如实施例9a所述使用8p(1.70g,含量13%,1.10mmol)作为起始物质来制备。在处理之后,残余物通过快速色谱(洗脱剂EtOAc,接着含5%MeOH的DCM)纯化。合并含有标题化合物的洗脱份,减压蒸发溶剂,得到残余物,其通过制备型HPLC(固定相:XTerraC18OBD5μm30×100mm;流动相:ACN/H2O+NH4COOH5mM)进一步纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。用DCM萃取水层,分离且蒸发DCM,得到标题化合物(110mg,含量98%,24%)。
HPLC-MS(方法7a):Rt=4.05
MS(APCI):m/z=411(M+H)+
实施例9r
实施例9r如实施例9a所述使用8q(190mg,含量80%,0.76mmol)作为起始物质来制备。在处理之后,残余物通过制备型HPLC(固定相:XTerraC18OBD5μm30×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。用DCM萃取水层,分离且蒸发DCM,得到标题化合物(240mg,含量98%,76%)。
HPLC-MS(方法4):Rt=2.00
MS(ESI正):m/z=411(M+H)+
实施例9s
实施例9s如实施例9a所述使用8r(390mg,含量6%,0.12mmol)作为起始物质来制备。在处理之后,残余物通过制备型HPLC(固定相:XTerraC18OBD5μm30×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。用DCM萃取水层,分离且蒸发DCM,得到残余物,其通过快速色谱(洗脱剂0-10%MeOH/DCM)进一步纯化。合并含有标题化合物的洗脱份,减压蒸发挥发物,得到标题化合物(20mg,41%)。
1HNMR(500MHz,DMSO-d6):1.39(9H,s),1.48(1H,dd,J=3.2,3.2Hz),1.64(6H,s),1.67-1.70(2H,m),2.68(3H,s),3.25(2H,dd,J=9.5,9.5Hz),3.46(2H,dd,J=10.6,10.6Hz),7.32(1H,d,J=9.7Hz),7.40(1H,d,J=9.4Hz),7.59(1H,d,J=1.2Hz),7.79(1H,t,J=1.2Hz),8.52(1H,s)。
以下实施例类似于实施例9h的制备来合成:
以下实施例类似于实施例9q的制备来合成:
实施例9v
将HATU(223mg,0.587mmol)添加至含内消旋-(1R,5S,6r)-3-(苄氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(可购自MatrixScientific,118mg,0.451mmol)、实施例8u(100mg,含量85%,0.451mmol)及DIPEA(236μl,1.35mmol)的无水DMF(5mL)中且持续搅拌2h。减压蒸发挥发物,得到残余物,用乙酸乙酯稀释且用饱和NaHCO3及盐水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到残余物,通过快速色谱(洗脱剂0-25%EtOAc/环己烷)纯化,得到标题化合物(135mg,含量98%,68%)。
UPLC-MS(方法2):Rt=1.26min
MS(ESI正):m/z=432(M+H)+
以下实施例类似于实施例9h的制备来合成:
以下实施例类似于实施例9h的制备来合成:
通过HPLC使用手性固定相分离实施例9af的立体异构体。
分离方法:
HPLC装置类型:Waters600泵,2767自动取样器,UV检测器2489;管柱:DaicelchiralpackAD-H,5.0μm,250mm×20mm;方法:洗脱剂己烷/IPA80:20;流速:15mL/min,温度:25℃;UV检测:230nm。
以下实施例类似于实施例9h的制备来合成:
以下实施例类似于实施例9h的制备来合成:
通过HPLC使用手性固定相分离实施例9aj的立体异构体。
分离方法:
HPLC装置类型:Waters600泵,2767自动取样器,UV检测器2489;管柱:DaicelchiralpackAD-H,5.0μm,250mm×20mm;方法:洗脱剂己烷/IPA75:25;流速:15mL/min,温度:25℃;UV检测:230nm。
实施例10a
将三甲基硅烷基重氮甲烷(于乙醚中10%,10.5,6.17mmol)逐滴添加至冷却至0℃的含2-色满烷甲酸(1g,5.61mmol)的无水DCM(8mL)及MeOH(0.8mL)中。持续搅拌60min,接着减压蒸发溶剂,得到标题化合物(1g,95%)。
UPLC-MS(方法2):Rt=1.06min
MS(ESI正):m/z=193(M+H)+
实施例11a
在氮气流下,将溴化甲基镁于2-甲基四氢呋喃中的溶液(3.2M,3mL,9.74mmol)逐滴添加至冷却至0℃的溶解于无水THF(20mL)中的实施例10a(1g,4.82mmol)中。在0℃下持续搅拌5min,之后在室温下2h。使反应混合物冷却至0℃且逐滴添加NH4Cl的饱和溶液。添加EtOAc,分离有机层,用盐水洗涤,经Na2SO4干燥且减压浓缩,得到标题化合物(915mg,89%)。
HPLC-MS(方法8):Rt=2.72min
MS(APCI):m/z=193(M+H)+
实施例12a
将硫酸(0.27mL,4.71mmol)逐滴添加至冷却至0℃的溶解于无水ACN(0.900mL)及乙酸(0.51mL,8.56mmol)中的实施例11a(1g,4.82mmol)中。在0℃下持续搅拌5min,之后在室温下隔夜。依序将5MNH4OH、EtOAc添加至反应混合物中。用盐水洗涤有机层,经相分离筒干燥且减压浓缩,得到残余物,其通过快速色谱(洗脱剂30-60%EtOAc/环己烷)纯化,得到标题化合物(215mg,21%)。
HPLC-MS(方法8):Rt=2.82min
MS(APCI):m/z=234(M+H)+
实施例13a
将氢氧化钾(289mg,5.14mmol)添加至溶解于1,2甲氧基乙醇(1mL)及乙二醇(1mL)中的实施例12a(150mg,0.643mmol)中。在回流下加热反应混合物隔夜。将水及EtOAc添加至冷却至室温的反应混合物中,分离有机层且使用相分离筒干燥。减压移除溶剂,得到残余物,通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份,减压蒸发乙腈,用饱和NaHCO3碱化水层且用DCM萃取。分离有机层且使用相分离筒干燥,且减压蒸发所得溶液,得到标题化合物(40mg,32%)。
HPLC-MS(方法8):Rt=2.20min
MS(APCI):m/z=192(M+H)+
实施例14a
将HATU(103mg,0.272mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(48mg,0.21mmol)、实施例13a(40mg,0.21mmol)及DIPEA(109μl,0.627mmol)的无水DMF(1mL)中且在室温下持续搅拌2h。减压蒸发挥发物,得到残余物,用乙酸乙酯稀释且用饱和NaHCO3及盐水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到残余物,通过快速色谱(洗脱剂30-50%EtOAc/环己烷)纯化,得到标题化合物(48mg,56%)。
HPLC-MS(方法8):Rt=3.73min
MS(APCI):m/z=401(M+H)
实施例15a
将实施例3e(150mg,0.330mmol)、环丙基三氟硼酸钾(122mg,0.827mmol)、乙酸钯(II)(22mg,0.099mmol)、三环己基膦(56mg,0.199mmol)及磷酸三钾(246mg,1.16mmol)溶解于甲苯(2mL)及水(0.200mL)中且在120℃下在微波辐射下加热反应混合物2h。用DCM/水稀释反应物。分离有机层,干燥且减压蒸发,得到残余物,其通过制备型HPLC(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份,减压蒸发且冷冻干燥,得到标题化合物(105mg,77%)。
UPLC-MS(方法2):Rt=1.42min
MS(ESI正):m/z=415(M+H)+
以下实施例类似于实施例15a的制备来合成:
实施例15c
用氮气流将含实施例5i(85mg,0.17mmol)及环丙基硼酸(22mg,0.254mmol)的无水1,2-二甲氧基乙烷(1mL)脱气5分钟。添加碳酸钾(0.25mL,0.51mmol)及四(三苯基膦)钯(0)(20mg,0.017mmol)且在90℃下加热反应混合物隔夜。添加环丙基硼酸(43mg,0.50mmol)及四(三苯基膦)钯(0)(39mg,0.034mmol)且在120℃下在微波辐射下加热反应混合物40min。减压移除溶剂,得到残余物,其通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份且减压蒸发,得到标题化合物(48mg,含量83%,57%)。
UPLC-MS(方法2):Rt=1.12min
MS(ESI正):m/z=416(M+H)+
实施例15d
将实施例5g(140mg,0.283mmol)溶解于EtOH(15mL)中且添加钯(30mg,0.028mmol)。在2巴下氢化混合物3h。通过过滤移除催化剂且用MeOH洗涤。减压蒸发所得溶液,得到残余物,其通过快速色谱(洗脱剂60-90%EtOAc/环己烷)纯化,得到标题化合物(60mg,54%)。
HPLC-MS(方法8):Rt=2.83min
MS(APCI):m/z=391(M+H)+
实施例16a
在0℃下将N-(苄氧羰基氧基)琥珀酰亚胺(5.2g,20.90mmol)添加至1,1-二甲基炔丙胺(2mL,19mmol)及TEA(3mL,20.90mmol)于无水THF(60mL)中的溶液中。使混合物达到室温且持续搅拌隔夜。减压蒸发挥发物且用EtOAc溶解所得残余物且用水及盐水洗涤。使有机层干燥且减压蒸发,得到残余物,通过快速色谱(洗脱剂0-20%EtOAc/环己烷)纯化,得到标题化合物(2.7g,65%)。
HPLC-MS(方法8):Rt=2.87min
MS(APCI):m/z=218(M+H)+
实施例17a
在室温下将2-溴-3-(三氟甲基)吡啶(1.5g,6.63mmol)添加至实施例16a(500mg,2.21mmol)于TEA(3.5mL,25.25mmol)及无水ACN(14mL)中的溶液中。接着添加碘化铜(I)(84mg,0.442mmol)及二氯双(三苯基膦)钯(II)(155mg,0.221mmol)且持续搅拌隔夜。减压蒸发溶剂且通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化粗物质,得到标题化合物(800mg,99%)。
UPLC-MS(方法2):Rt=1.23min
MS(ESI正):m/z=363(M+H)+
以下实施例类似于实施例17a的制备来合成:
实施例18a
将实施例17a(800mg,2.075mmol)溶解于MeOH(30mL)中且添加钯(50mg,0.470mmol)。在1巴下氢化混合物隔夜,且接着在3巴下72h。通过过滤移除催化剂且用MeOH洗涤。减压蒸发所得溶液,得到标题化合物(432mg,90%)。
HPLC-MS(方法8):Rt=1.93min
MS(APCI):m/z=233(M+H)+
以下实施例类似于实施例18a的制备来合成:
实施例19a
将HATU(184mg,0.484mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(100mg,0.440mmol)、实施例18a(102mg,0.440mmol)及DIPEA(228μl,1.32mmol)的无水DMF(6mL)中且持续搅拌2h。减压蒸发挥发物且用乙酸乙酯溶解粗物质且用饱和NaHCO3及盐水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-70%EtOAc/环己烷)纯化,得到标题化合物(142mg,73%)。
UPLC-MS(方法2):Rt=1.24min
MS(ESI正):m/z=442(M+H)+
以下实施例类似于实施例19a的制备来合成:
实施例20a
依序将2-(氨基甲基)吡啶(532mg,4.920mmol)、TEA(2mL,14.760mmol)及TBTU(1.6g,4.920mmol)添加至溶解于无水THF(10mL)中的2-叔丁氧羰基氨基-2-甲基丙酸(1g,4.920mmol)中。在室温下持续搅拌隔夜。蒸发溶剂,用乙酸乙酯稀释残余物且用1NNaOH溶液及盐水洗涤。使有机层干燥,过滤且减压蒸发,得到残余物,其通过快速色谱(洗脱剂50-100%EtOAc/环己烷)纯化,得到标题化合物(835mg,58%)。
UPLC-MS(方法2):Rt=0.79min
MS(ESI正):m/z=294(M+H)+
以下实施例类似于实施例20a的制备来合成:
实施例20c
将4-氨基甲基嘧啶(1g,9.16mmol)溶解于无水DCM(20mL)中,添加TEA(3.8mL,27.849mmol)、HATU(3.5g,9.16mmol)、N-苄氧羰基-2-甲基丙氨酸(2.1g,9.16mmol)且在室温下搅拌混合物隔夜。用水稀释反应物,用1NNaOH及盐水洗涤有机层,干燥,过滤且蒸发,得到残余物,其通过快速色谱(洗脱剂EtOAc100%)纯化,得到标题化合物(1.6g)。
UPLC-MS(方法2):Rt=0.76min
MS(ESI正):m/z=329(M+H)+
实施例20d
将C-(4-三氟甲基-吡啶-2-基)-甲基胺二盐酸盐(0.5g,2.01mmol)、2-叔丁氧羰基氨基-2-甲基丙酸(0.45g,2.21mmol)、TBTU(0.71g,2.21mmol)及三乙胺(1.15mL,8.23mmol)组合于二氯甲烷(10mL)中且搅拌混合物1小时。用0.2MNaOH水溶液洗涤混合物,经硫酸钠干燥且真空移除溶剂。残余物通过快速色谱(洗脱剂0-100%乙酸乙酯/环己烷)纯化,得到标题化合物(703mg,97%)。
UPLC-MS(方法2):Rt=1.00min
MS(ESI正):m/z=362(M+H)+
以下实施例类似于实施例20d的制备(使用HATU作为特定偶合剂)来合成:
实施例21a
将实施例20a(685mg,2.335mmol)溶解于DCM(10mL)中且冷却至0℃,接着添加伯吉斯试剂(610mg,2.560mmol)。使混合物达到室温且持续搅拌隔夜。用水及盐水洗涤反应混合物。使有机层干燥,过滤且减压蒸发,得到残余物,其通过快速色谱(洗脱剂EtOAc/环己烷30:70)纯化,得到标题化合物(258mg,40%)。
UPLC-MS(方法2):Rt=0.91min
MS(ESI正):m/z=276(M+H)+
以下实施例类似于实施例21a的制备来合成:
实施例21c
将实施例21a(400mg,1.453mmol)、N-碘琥珀酰亚胺(654mg,2.905mmol)及对甲苯磺酸吡啶(36mg,0.15mmol)溶解于DCM(5mL)中且搅拌反应物1h。
使混合物与10%硫代硫酸钠溶液一起震荡,分离各相,干燥有机相且移除溶剂。残余物通过快速色谱(0-100%EtOAc/环己烷)纯化,得到标题化合物(260mg,含量90%,45%)。
UPLC-MS(方法2):Rt=1.17min
MS(ESI正):m/z=402(M+H)+
实施例21d
将实施例21c(260mg,含量90%,0.583mmol)、2,2-二氟-2-(氟磺酰基)乙酸酯(0.370mL,2.916mmol)及碘化铜(I)(133mg,0.700mmol)溶解于1-甲基-2-吡咯烷酮(4mL)中且在110℃下搅拌反应物90分钟。使混合物冷却,用水稀释且用乙酸乙酯萃取。使有机萃取物干燥且移除溶剂。残余物通过快速色谱(0-50%EtOAc/环己烷)纯化,得到标题化合物(51mg,含量90%,23%)。
UPLC-MS(方法2):Rt=1.21min
MS(ESI正):m/z=344(M+H)+
实施例21e
使实施例20c(841mg)悬浮于氧氯化磷(17mL,177.39mmol)中且添加8滴无水DMF。在100℃下加热混合物3h。使混合物冷却且蒸发溶剂。使残余物分配于1NNaOH与EtOAc的混合物中。用盐水洗涤有机层,干燥,过滤且蒸发,得到残余物,通过快速色谱(第一洗脱剂EtOAc100%,第二洗脱剂MeOH100%)纯化,得到标题化合物(70mg)。
UPLC-MS(方法2):Rt=0.73min
MS(ESI正):m/z=311(M+H)+
实施例21f
将实施例21a(998mg,3.62mmol)溶解于二氯甲烷(10mL)中且冷却至0℃。添加N-溴琥珀酰亚胺(677mg,3.81mmol)且搅拌混合物一小时。添加饱和硫代硫酸钠水溶液,震荡混合物,分离各相,使有机相干燥且真空移除溶剂。残余物通过快速色谱(0-50%乙酸乙酯/环己烷)纯化,得到标题化合物(785mg,61%)。
UPLC-MS(方法2):Rt=1.13min
MS(ESI正):m/z=354/356(M+H)+
实施例21g
使实施例21f(200mg,0.56mmol)、环丙基三氟硼酸钾(167mg,1.13mmol)、三磷酸钾(419mg,1.98mmol)、三环己基膦(32mg,0.11mmol)及乙酸钯(II)(13mg,0.06mmol)于微波小瓶中悬浮于甲苯(5mL)与水(0.2mL)的混合物中且用氮气流脱气5分钟。在120℃下在微波辐射下加热混合物5小时,接着冷却且用乙酸乙酯及水稀释。分离各相,经硫酸钠干燥有机相且真空移除溶剂。残余物通过快速色谱(0-2%甲醇/二氯甲烷)纯化,得到标题化合物(40mg,23%)。
UPLC-MS(方法2):Rt=1.16min
MS(ESI正):m/z=316(M+H)+
实施例21h
标题化合物作为制备实施例21d的不纯副产物得以分离出。
UPLC-MS(方法2):Rt=1.03min
MS(ESI正):m/z=322(M+H)+
实施例21i
使实施例21h(52mg,粗物质)悬浮于0.5M氨溶液的无水二烷溶液中且搅拌混合物隔夜。真空移除溶剂,得到呈粗物质的标题化合物,其未经进一步纯化即使用(52mg,含量50%)。
UPLC-MS(方法2):Rt=0.86min
MS(ESI正):m/z=319(M+H)+
实施例21j
使实施例21i(51mg,含量50%)及伯吉斯试剂(38mg,0.16mmol)悬浮于无水二氯甲烷(5mL)中且搅拌混合物隔夜。添加水,分离各相,使有机相经硫酸钠干燥且真空移除溶剂。残余物通过快速色谱(0-50%乙酸乙酯/环己烷)纯化,得到标题化合物(22mg,91%)。
UPLC-MS(方法2):Rt=1.00min
MS(ESI正):m/z=301(M+H)+
实施例21k
使实施例21f(229mg,0.65mmol)、3,6-二氢-2H-吡喃-4-基(三氟)硼钾(184mg,0.97mmol)、三磷酸钾(412mg,1.94mmol)及四(三苯基膦)钯(0)(75mg,0.06mmol)于螺旋盖管中悬浮于二烷(5mL)与水(0.5mL)的混合物中且用氩气流脱气5分钟。在100℃下加热混合物4小时,接着使其冷却且用乙酸乙酯及水稀释。分离各相,用盐水洗涤有机相且真空移除溶剂。残余物通过快速色谱(0-100%乙酸乙酯/环己烷)纯化,得到标题化合物(41mg)。
UPLC-MS(方法1):Rt=0.81min
MS(ESI正):m/z=358(M+H)+
实施例21l
使实施例20h(1.51g,4.67mmol)悬浮于DCM(40mL)中且添加伯吉斯试剂(1.22g,5.14mmol)。使混合物搅拌隔夜,接着用0.2MNaOH水溶液洗涤。使有机层干燥,过滤且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-100%乙酸乙酯/环己烷)纯化,得到标题化合物(751mg,53%)。
UPLC-MS(方法1):Rt=0.77min
MS(ESI正):m/z=306(M+H)+
以下实施例类似于实施例21l的制备来合成:
实施例21ad
使实施例21q(200mg,0.68mmol)悬浮于DCM(4mL)中且冷却至0℃。添加N-碘琥珀酰亚胺(153mg,0.68mmol)且在0℃下搅拌混合物30分钟。添加10%硫代硫酸钠水溶液,震荡混合物且分离各相。减压蒸发有机层,得到残余物,其通过快速色谱(洗脱剂0-50%乙酸乙酯/环己烷)纯化,得到标题化合物(200mg,70%)。
UPLC-MS(方法2):Rt=1.17min
MS(ESI正):m/z=420(M+H)+
实施例21ae
使实施例21ad(200mg,0.48mmol)、2,2-二氟-2-(氟磺酰基)乙酸甲酯(182μL,1.43mmol)及碘化铜(I)(136mg,0.72mmol)悬浮于N-甲基吡咯烷酮(4mL)中且在110℃下加热50分钟。用冰使混合物冷却,用水稀释且用乙酸乙酯萃取。减压蒸发有机层,得到残余物,其通过快速色谱(洗脱剂0-50%乙酸乙酯/环己烷)纯化,得到标题化合物(150mg,78%)。
UPLC-MS(方法12):Rt=3.68min
MS(ESI正):m/z=462(M+H)+
实施例21af
使实施例21q(1.3g,4.43mmol)悬浮于DCM(12mL)中且冷却至0℃。添加N-溴琥珀酰亚胺(0.83g,4.65mmol)且在0℃下搅拌混合物60分钟。添加饱和硫代硫酸钠水溶液,搅拌混合物30分钟且分离各相。减压蒸发有机层,得到残余物,其通过快速色谱(洗脱剂0-50%乙酸乙酯/环己烷)纯化,得到标题化合物(600mg,36%)。
UPLC-MS(方法2):Rt=1.22min
MS(ESI正):m/z=372/374(M+H)+
实施例21ag
使实施例21af(600mg,1.61mmol)、环丙基三氟硼酸钾(477mg,3.22mmol)、三磷酸钾(1.20g,5.64mmol)、三环己基膦(90mg,0.32mmol)及乙酸钯(II)(36mg,0.16mmol)于微波小瓶中悬浮于甲苯(17mL)与水(0.2mL)的混合物中且用氮气流脱气5分钟。在120℃下在微波辐射下加热混合物2×5小时,接着冷却且用乙酸乙酯及水稀释。分离各相,经由淡水硅藻土(decalite)过滤有机相且真空移除溶剂。残余物通过快速色谱(0-20%乙酸乙酯/环己烷)纯化,得到标题化合物(170mg,30%)。
UPLC-MS(方法2):Rt=1.34min
MS(ESI正):m/z=334(M+H)+
实施例21ah
使实施例21af(270mg,0.73mmol)、三甲基环硼氧烷(274mg,2.18mmol)、碳酸钾(1.20g,5.64mmol)及二氯化钯(II)(dppf)二氯甲烷络合物(59mg,0.07mmol)悬浮于DMF(3mL)中且用氮气流脱气5分钟。在100℃下于密封管中加热混合物2小时,接着冷却且用乙酸乙酯及水稀释。分离各相且在真空下移除溶剂。残余物通过快速色谱(0-20%乙酸乙酯/环己烷)纯化,得到标题化合物(110mg,42%)。
UPLC-MS(方法2):Rt=1.11min
MS(ESI正):m/z=308(M+H)+
实施例21ai
使实施例20u(220mg,0.67mmol)悬浮于氧氯化磷(3mL)中且在100℃下加热2h。使混合物冷却且蒸发溶剂。使残余物分配于1NNaOH与EtOAc的混合物中。用盐水洗涤有机层,干燥,过滤且蒸发,得到残余物,通过快速色谱(洗脱剂乙酸乙酯/环己烷8:3)纯化,得到标题化合物(38mg)。
HPLC-MS(方法9):Rt=2.12min
MS(ESI正):m/z=311(M+H)+
实施例21aj
标题化合物类似于实施例20a及实施例21a的合成所述的操作由Cbz-Aib-OH替代Boc-Aib-OH作为起始物来制备。
HPLC-MS(方法2):Rt=1.04min
MS(ESI正):m/z=310(M+H)+
以下实施例类似于实施例21l的制备来合成:
实施例22a
将2M氯化氢的乙醚溶液(3mL,6mmol)添加至溶解于无水乙醚(7mL)中的实施例21a(258mg,0.937mmol)中。在室温下持续搅拌5h。蒸发溶剂且以原样使用残余物(187mg,90%)。
UPLC-MS(方法2):Rt=0.57min
MS(ESI正):m/z=176(M+H)+
以下实施例类似于实施例22a的制备来合成:
实施例22d
将实施例21e(70mg)溶解于MeOH(30mL)及水(2mL)中且在钯(于碳上10%,46mg)存在下氢化(3巴)溶液1h。
经由淡水硅藻土(dicalite)过滤来移除固体且蒸发所得溶液,得到标题化合物(53mg),其以原样使用。
UPLC-MS(方法2):Rt=0.28min
MS(ESI正):m/z=177(M+H)+
实施例22da
将实施例21ai(34mg)溶解于乙酸乙酯(2mL)中且在钯(于碳上10%,24mg)存在下氢化(1.6巴)溶液2h。
经由淡水硅藻土过滤来移除固体且蒸发所得溶液,得到标题化合物(13mg),其以原样使用。
UPLC-MS(方法1):Rt=0.73min
MS(ESI正):m/z=159(M-NH2)+
实施例22e
将4M氯化氢的1,4-二烷溶液(1mL,4mmol)添加至实施例21g(40mg,0.12mmol)中且搅拌混合物1小时。蒸发溶剂且残余物未经纯化即使用(30mg,99%)。
UPLC-MS(方法1):Rt=0.571min
MS(ESI正):m/z=199(M-NH2)+
以下实施例类似于实施例22e的制备来合成:
实施例22ac
使实施例21aj(99mg,0.30mmol)悬浮于乙醇中,添加10%钯/活性碳(15mg),在3.5巴下氢化混合物隔夜。经由硅藻土过滤混合物且移除溶剂,得到粗标题化合物(59mg)。
HPLC-MS(方法2):Rt=0.72min
MS(ESI正):m/z=180(M+H)+
以下实施例类似于实施例22e的制备来合成:
实施例23a
依序将内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(215mg,0.946mmol)、TEA(600μL,4.300mmol)、HATU(360mg,0.946mmol)添加至溶解于THF(10mL)中的实施例22a(182mg,0.817mmol)中。
在室温下持续搅拌72h。依序用1NHCl溶液、1NNaOH溶液及盐水洗涤反应物。使有机层干燥,过滤且减压蒸发,得到残余物,其通过快速色谱(洗脱剂EtOAc/环己烷15:85)纯化,得到标题化合物(255mg,81%)。
UPLC-MS(方法2):Rt=0.94min
MS(ESI正):m/z=385(M+H)+
实施例23b
实施例23b类似于实施例23a由实施例22b(41mg,含量90%,0.132mmol)作为起始物质来制备。在搅拌反应物隔夜之后,移除挥发物且所得残余物通过快速色谱(洗脱剂0-60%EtOAc/环己烷)纯化,得到标题化合物(41mg,含量95%,69%)。
UPLC-MS(方法2):Rt=1.20min
MS(ESI正):m/z=453(M+H)+
以下实施例类似于实施例23b的制备来合成:
实施例23d
依序将内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(66mg,0.290mmol)、TEA(167μL,1.20mmol)、HATU(110mg,0.290mmol)添加至溶解于无水DCM(7mL)中的实施例22d(51mg)中。在室温下持续搅拌20h。依序用水、1NNaOH溶液及盐水洗涤反应物。再用盐水稀释水层且用EtOAc/MeOH9:1的混合物萃取。使有机层干燥,过滤且减压蒸发,得到残余物,其通过快速色谱(洗脱剂EtOAc/MeOH9:2)纯化,得到标题化合物(25mg)。
UPLC-MS(方法2):Rt=0.74min
MS(ESI正):m/z=386(M+H)+
实施例23e
使实施例22e(30mg,0.12mmol)、内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(33mg,0.140mmol)、Et3N(53μL,0.38mmol)及HATU(54mg,0.140mmol)悬浮于无水THF(5mL)中且搅拌混合物过周末。移除溶剂,将残余物再溶解于DCM中,用0.2MNaOH水溶液及盐水洗涤。使有机层干燥,过滤且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-100%EtOAc/环己烷)纯化,得到标题化合物(产量35mg)。
UPLC-MS(方法2):Rt=1.11min
MS(ESI正):m/z=425(M+H)+
以下实施例类似于实施例23e的制备来合成:
实施例23ad
在0℃下使实施例23l(420mg,1.05mmol)悬浮于二氯甲烷(8mL)中且添加N-碘琥珀酰亚胺(236mg,1.05mmol)。搅拌混合物10分钟,接着与5%硫代硫酸钠溶液一起震荡,分离各相,使有机相干燥且移除溶剂。残余物通过快速色谱(洗脱剂;50%EtOAc/环己烷)纯化,得到标题化合物(409mg,70%)。
LC-MS(方法2):Rt=1.22min
MS(ESI正):m/z=525(M+H)+
实施例23ae
使实施例23ad(100mg,0.18mmol)、环丙基三氟硼酸钾(266mg,1.80mmol)、三磷酸钾(670mg,3.15mmol)、三环己基膦(56mg,0.20mmol)及乙酸钯(II)(22mg,0.10mmol)中悬浮于甲苯(15mL)与水(0.6mL)的混合物中且用氮气流脱气5分钟。在90℃下加热混合物24小时,接着冷却且用二氯甲烷及水稀释。分离各相,使有机物干燥,过滤且真空移除溶剂。残余物通过快速色谱(洗脱剂:40%乙酸乙酯/环己烷)纯化,得到标题化合物(28mg)。
UPLC-MS(方法2):Rt=1.26min
MS(ESI正):m/z=439(M+H)+
实施例23af
将实施例23ad(200mg,0.36mmol)、2,2-二氟-2-(氟磺酰基)乙酸酯(219mg,3.13mmol)及碘化铜(I)(108mg,1.56mmol)溶解于无水1-甲基-2-吡咯烷酮(4mL)中及在110℃下搅拌反应物60分钟。使混合物冷却,用水稀释且用乙酸乙酯萃取。使有机萃取物干燥且移除溶剂。残余物通过快速色谱(洗脱剂:0-50%EtOAc/环己烷)之后通过反相制备型HPLC纯化,得到标题化合物(43mg,25%)。
UPLC-MS(方法2):Rt=1.24min
MS(ESI正):m/z=467(M+H)+
实施例23ag
使实施例23q(140mg,含量50%,0.17mmol)、环丙基三氟硼酸钾(50mg,0.33mmol)、三磷酸钾(124mg,0.58mmol)、三环己基膦(9mg,0.03mmol)及乙酸钯(II)(4mg,0.02mmol)悬浮于甲苯(0.7mL)与水(0.2mL)的混合物中且用氮气流脱气5分钟。在120℃下在微波辐射下加热混合物2小时。接着再添加一当量的环丙基三氟硼酸钾、三磷酸钾、三环己基膦及乙酸钯(II)且在140℃下在微波辐射下加热混合物5小时,接着冷却且用乙酸乙酯及水稀释。分离各相,使有机相干燥,过滤且真空移除溶剂。残余物通过快速色谱(洗脱剂:5%甲醇/二氯甲烷)纯化,得到标题化合物(20mg)。
UPLC-MS(方法1):Rt=0.91min
MS(ESI正):m/z=425(M+H)+
以下实施例类似于实施例23e的制备来合成:
实施例24a
将3-氨基哒嗪(1g,10.5mmol)溶解于甲苯(7mL)中且添加N,N-二甲基甲酰胺二甲基缩醛(1.8mL,13.67mmol)。在65℃下加热混合物且持续搅拌隔夜。再添加N,N-二甲基甲酰胺二甲基缩醛(1.8mL,13.67mmol)且在室温下持续搅拌3天。再添加N,N-二甲基甲酰胺二甲基缩醛(3.6mL,27.34mmol)且在85℃下加热反应物5h。减压移除挥发物且用正己烷湿磨所得残余物,得到标题化合物(1.4g,91%)。
UPLC-MS(方法2):Rt=0.40min
MS(ESI正):m/z=151(M+H)+
实施例25a
将3-溴-2-甲酰吡啶(5g,26.88mmol)及甲肼(1.70mL,32.25mmol)溶解于乙醇(10mL)中且在80℃下加热2h。减压移除挥发物,且再蒸发残余物若干次,得到N-[1-(3-溴-吡啶-2-基)-亚甲基]-N′-甲基-肼(5.70g,99%)。
UPLC-MS(方法2):Rt=0.77min
MS(ESI正):m/z=215(M+H)+
使N-[1-(3-溴-吡啶-2-基)-亚甲基]-N′-甲基-肼(5.7g,26.63mmol)、碘化铜(I)(507mg,2.66mmol)、反-N,N′-二甲基环己烷-1,2-二胺(76mg,0.533mmol)及碳酸钾(7.36g,53.25mmol)悬浮于1-甲基-2-吡咯烷酮(20mL)中且在120℃下加热3h。用饱和氯化铵溶液及乙酸乙酯稀释混合物。过滤所得乳液,分离各相且用盐水洗涤有机相,干燥且减压蒸发挥发物。使残余物再溶解于乙醚中,用盐水洗涤且移除溶剂。残余物通过快速色谱(0-60%EtOAc/环己烷)纯化、得到1-甲基-1H-吡唑并[4,3-b]吡啶(580mg,含量85%,14%)。
1HNMR(300MHz,DMSO-d6):δ4.08(s,3H),7.40(dd,J=4.60,8.60Hz,1H),8.14(dd,J=1.10,8.40Hz,1H),8.25(d,J=1.0Hz,1H),8.53(dd,J=1.40,4.40Hz,1H)
将含溴(2.37g,14.810mmol)的NaOH溶液(2M水溶液,10mL,20mmol)逐滴添加至冷却至0℃的含1-甲基-1H-吡唑并[4,3-b]吡啶(580mg,含量85%,3.70mmol)的二烷(20mL)中。使混合物达到室温且接着搅拌6小时。再逐滴添加溴(2.17g,13.570mmol)且搅拌混合物30分钟。用100mL10%硫代硫酸钠溶液稀释混合物且用EtOAc萃取。
使合并的有机萃取物经硫酸钠干燥且减压蒸发挥发物。使所得残余物悬浮于DCM中,通过过滤移除固体且蒸发残余物,得到标题化合物(630mg,80%)。
1HNMR(500MHz,DMSO-d6):δ4.09(s,3H),7.52(dd,J=4.3,8.6Hz,1H),8.23(dd,J=1.3,8.6Hz,1H),8.59(dd,J=1.3,4.3Hz,1H)
实施例26a
使实施例24a(1.4g,9.59mmol)溶解于无水DMF(80mL)中且添加碘化钠(1.4g,9.59mmol)及氯丙酮(1.6g,17.26mmol)。在80℃下加热混合物隔夜。使反应混合物分配于水与乙酸乙酯之间且经由淡水硅藻土衬垫过滤。用1NNaOH、水洗涤有机层,且接着经Na2SO4干燥。蒸发挥发物且所得残余物通过快速色谱(洗脱剂70-100%EtOAc/环己烷)纯化,得到标题化合物(132mg,9%)。
UPLC-MS(方法2):Rt=0.51min
MS(ESI正):m/z=162(M+H)+
实施例26b
使3-溴-1-甲基-吡唑并[3,4-b]吡啶(100mg,0.472mmol)溶解于甲苯(5mL)中且将三丁基(1-乙氧基乙烯基)锡(187mg,0.519mmol)及四(三苯基膦)钯(0)(54mg,0.047mmol)添加至溶液中且回流反应物2h。减压蒸发挥发物且使所得残余物悬浮于THF/2MHCl水溶液(1:1)中且持续搅拌1h。用Na2CO3饱和溶液碱化反应混合物,且用乙酸乙酯萃取。使有机层干燥,蒸发且所得残余物通过快速色谱(洗脱剂0-100%EtOAc/环己烷)纯化,得到标题化合物(70mg,85%)。
UPLC-MS(方法2):Rt=0.78min
MS(ESI正):m/z=176(M+H)+
以下实施例类似于实施例26b的制备来合成:
实施例26d
使4-氯-8-甲基喹唑啉(5.10g,25.13mmol)溶解于甲苯(50mL)中且将三丁基(1-乙氧基乙烯基)锡(9.98g,27.64mmol)及四(三苯基膦)钯(0)(1.45g,1.26mmol)添加至溶液且回流反应物3h。减压蒸发挥发物且用盐水及乙酸乙酯稀释所得混合物。分离各相且用盐水洗涤有机相,干燥且减压蒸发挥发物。残余物通过快速色谱(0-30%EtOAc/环己烷)纯化,得到4-(1-乙氧基-乙烯基)-8-甲基-喹唑啉(4.80g,89%)。
UPLC-MS(方法2):Rt=1.15min
MS(ESI正):m/z=215(M+H)+
使4-(1-乙氧基-乙烯基)-8-甲基-喹唑啉(4.80g,22.40mmol)悬浮于1MHCl水溶液(100mL)中且持续搅拌3h。用Na2CO3饱和溶液碱化反应混合物,且用乙酸乙酯萃取。使有机层干燥,蒸发,得到标题化合物(4.02g,96%),其以原样使用。
UPLC-MS(方法2):Rt=1.07min
MS(ESI正):m/z=187(M+H)+
实施例27a
在0℃下将溴化甲基镁(1.4MTHF溶液,1mL,1.4mmol)添加至含实施例26a(132mg,0.819mmol)的THF(10mL)中。在0℃下搅拌混合物30min,且在室温下60min。依序将饱和NH4Cl、EtOAc添加至冷却至0℃的反应混合物中。使有机层干燥,过滤且蒸发,得到残余物,其通过快速色谱(洗脱剂EtOAc100%)纯化,得到标题化合物(94mg,65%)。
UPLC-MS(方法2):Rt=0.60min
MS(ESI正):m/z=178(M+H)+
以下实施例类似于实施例27a的制备来合成:
实施例27c
实施例27c类似于实施例27a由实施例26b(70mg,0.400mmol)来制备,但不通过快速色谱纯化。标题化合物(68mg,89%)以原样使用。
UPLC-MS(方法2):Rt=0.64min
MS(ESI正):m/z=192(M+H)+
以下实施例类似于实施例27a的制备来合成:
实施例28a
在0℃下将叠氮化钠(172mg,2.65mmol)添加至含实施例27a(94mg,0.531mmol)的TFA(1.5mL,19.56mmol)中。使反应物达到室温且持续搅拌隔夜。用水稀释反应混合物,用饱和K2CO3碱化且用EtOAc溶解。使有机层干燥且过滤,得到3-(1-叠氮基-1-甲基-乙基)-咪唑并[1,2-b]哒嗪(呈于EtOAc中的溶液)。
UPLC-MS(方法2):Rt=0.88min
MS(ESI正):m/z=203(M+H)+
在钯(于碳上5%,15mg,0.007mmol)存在下氢化(1巴)3-(1-叠氮基-1-甲基-乙基)-咪唑并[1,2-b]哒嗪(于乙酸乙酯中的溶液)1h。
经由淡水硅藻土过滤来移除固体且蒸发所得溶液,得到标题化合物(100mg),其以原样使用。
UPLC-MS(方法2):Rt=0.34min
MS(ESI正):m/z=177(M+H)+
实施例28b
在0℃下将叠氮化钠(116mg,1.78mmol)逐份添加至含实施例27c(68mg,0.356mmol)的TFA(1mL,13.04mmol)中。使反应物达到室温且持续搅拌隔夜。使反应物冷却至0℃,用水稀释且用饱和Na2CO3碱化。添加EtOAc,使有机层干燥且过滤,得到3-(1-叠氮基-1-甲基-乙基)-1-甲基-1H-吡唑并[3,4-b]吡啶(呈于乙酸乙酯中的溶液)。
UPLC-MS(方法2):Rt=1.06min
MS(ESI正):m/z=217(M+H)+
在钯(于碳上5%,50mg,0.023mmol)存在下氢化(1巴)3-(1-叠氮基-1-甲基-乙基)-1-甲基-1H-吡唑并[3,4-b]吡啶(于乙酸乙酯中的溶液)45min。
经由淡水硅藻土过滤来移除固体且蒸发所得溶液,得到标题化合物(56mg),其以原样使用。
UPLC-MS(方法2):Rt=0.55min
MS(ESI正):m/z=191(M+H)+
实施例28c
在0℃下将叠氮化钠(175mg,2.69mmol)添加至含实施例27b(103mg,0.54mmol)的TFA(2mL)中。使反应物达到室温且持续搅拌2h。接着再添加TFA(2mL)且持续搅拌2h。在0℃下冷却反应混合物,用水稀释,用饱和Na2CO3碱化且用EtOAc溶解。使有机层干燥且过滤,得到3-(1-叠氮基-1-甲基-乙基)-1-甲基-1H-吡唑并[4,3-b]吡啶(呈于EtOAc中的溶液)。
UPLC-MS(方法2):Rt=0.97min
MS(ESI正):m/z=217(M+H)+
在钯(于碳上5%,15mg,0.007mmol)存在下氢化(1巴)3-(1-叠氮基-1-甲基-乙基)-1-甲基-1H-吡唑并[4,3-b]吡啶(于EtOAc中的溶液)45min。经由硅藻土过滤来移除固体且蒸发所得溶液,得到标题化合物(101mg,99%)。
UPLC-MS(方法2):Rt=0.55min
MS(ESI正):m/z=191(M+H)+
实施例28d
在-78℃下将甲磺酰氯(0.61mL,7.91mmol)逐滴添加至含27d(500mg,含量80%,1.98mmol)及三乙胺(1.4mL,7.9mmol)的THF(20mL)中。在室温下持续搅拌1.5h。用水及乙酸乙酯稀释反应混合物。分离各相且使有机相干燥且蒸发挥发物,得到甲磺酸1-甲基-1-(8-甲基-喹唑啉-4-基)-乙酯(680mg,含量78%,96%),其以原样使用。
UPLC-MS(方法2):Rt=1.08min
MS(ESI正):m/z=281(M+H)+
将叠氮化钠(492mg,7.57mmol)添加至含甲磺酸1-甲基-1-(8-甲基-喹唑啉-4-基)-乙酯(680mg,含量78%,1.89mmol)的DMF(1.5mL,19.56mmol)中且持续搅拌4天。用饱和Na2CO3及EtOAc稀释反应混合物。用盐水洗涤有机层,干燥且过滤,得到4-(1-叠氮基-1-甲基-乙基)-8-甲基-喹唑啉(呈于EtOAc中的溶液)。
UPLC-MS(方法2):Rt=1.39min
MS(ESI正):m/z=228(M+H)+
在钯(于碳上10%,14mg,0.013mmol)存在下氢化(1.5巴)4-(1-叠氮基-1-甲基-乙基)-8-甲基-喹唑啉(于乙酸乙酯中的溶液)2h。
经由硅藻土过滤来移除固体且蒸发所得溶液,得到标题化合物(250mg,含量80%),其以原样使用。
UPLC-MS(方法2):Rt=0.87min
MS(ESI正):m/z=202(M+H)+
实施例29a
将HATU(205mg,0.540mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(123mg,0.540mmol)、实施例28a(100mg)及TEA(301μl,2.160mmol)的无水DCM(1mL)中且持续搅拌1h。用1NNaOH及盐水洗涤混合物。分离有机相,干燥且减压蒸发。所得残余物通过快速色谱(洗脱剂0-5%MeOH/EtOAc)纯化,得到标题化合物(118mg)。
UPLC-MS(方法2):Rt=0.90min
MS(ESI正):m/z=386(M+H)+
实施例29b
将HATU(134mg,0.353mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(80mg,0.353mmol)、实施例28b(56mg,0.294mmol)及TEA(90μl,0.648mmol)的无水THF(5mL)中且持续搅拌2h。移除溶剂且所得残余物通过快速色谱(洗脱剂0-100%EtOAc/环己烷)纯化,得到标题化合物(107mg,91%)
UPLC-MS(方法2):Rt=0.96min
MS(ESI正):m/z=400(M+H)+
以下实施例类似于实施例29b的制备来合成:
实施例29d
将HATU(295mg,0.775mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(136mg,0.596mmol)、实施例28d(150mg,含量80%,0.596mmol)及DIPEA(312μl,1.79mmol)的DMF(2mL)中且持续搅拌隔夜。减压蒸发挥发物,得到残余物,用乙酸乙酯稀释且用饱和NaHCO3及盐水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到残余物,通过快速色谱(洗脱剂0-50%EtOAc/环己烷)纯化,得到标题化合物(150mg,61%)。
UPLC-MS(方法2):Rt=1.17min
MS(ESI正):m/z=411(M+H)+
以下实施例类似于实施例29d的制备来合成:
实施例30a
在室温下将羟胺盐酸盐(7.5g,107.93mmol)添加至羟基香豆素(5g,30.84mmol)于MeOH(50mL)中的溶液中。经1.5h逐份添加乙酸钠(8.8g,107.93mmol)。在室温下搅拌反应物1.5h,且接着在回流下加热隔夜。蒸发挥发物,添加水且用冰水浴冷却混合物。用4NHCl酸化水层至pH=3。滤出沉淀且用水洗涤若干次。在50℃下减压干燥沉淀,得到苯并[d]异唑-3-基-乙酸(4.3g,78%)
HPLC-MS(方法11):Rt=0.32min
MS(ESI正):m/z=178(M+H)+
在0℃下将三甲基硅烷基重氮甲烷(9.7mL,19.40mmol)逐滴添加至含苯并[d]异唑-3-基-乙酸(3.3g,17.64mmol)的DCM/MeOH11:1(22mL/2mL)中且在0℃下持续搅拌1h。蒸发挥发物得到标题化合物(3.3g,99%)
UPLC-MS(方法2):Rt=0.88min
MS(ESI正):m/z=192(M+H)+
以下实施例类似于实施例30a的制备来合成:
实施例31a
将实施例30a(1.5g,7.85mmol)溶解于无水THF(30mL)中且在0℃下冷却混合物。逐滴添加1M双(三甲基硅烷基)氨基锂的THF溶液(29mL,29mmol),使反应物达到室温且搅拌2h。逐滴添加碘甲烷(1.8mL,29mmol)且在室温下搅拌反应物隔夜。
添加NH4Cl饱和溶液且用EtOAc萃取反应物。用盐水洗涤有机相,干燥且蒸发,得到残余物,其通过快速色谱(洗脱剂0-10%EtOAc/环己烷)纯化,得到标题化合物(870mg,51%)。
UPLC-MS(方法2):Rt=1.09min
MS(ESI正):m/z=220(M+H)+
实施例31b
在0℃下将氢化钠(于矿物油中的60%悬浮液,973mg,24.32mmol)逐份添加至含实施例30b(1.42g,含量95%,6.57mmol)的DMF(12mL)中。使反应物达到室温且搅拌30min。逐滴添加碘甲烷(2.1mL,33.20mmol)至在0℃下冷却的反应混合物中且在室温下搅拌反应物隔夜。
添加水且用EtOAc萃取反应物。用盐水洗涤有机相,干燥且蒸发,得到残余物,其通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化,得到标题化合物(1.47g,96%)。
GC-MS(方法13):Rt=10.32min
MS(EIpos):m/z=233[M]+
实施例32a
将单水合氢氧化锂(500mg,11.90mmol)添加至含实施例31a(870mg,3.97mmol)的水/THF1:1(9mL)中且在室温下搅拌反应物2h。
蒸发THF,用冰水浴冷却混合物。用1NHCl将水层酸化至pH=4-5且用DCM萃取。经相分离筒干燥有机层且蒸发,得到标题化合物(810mg,含量98%,97%)
UPLC-MS(方法2):Rt=0.53min
MS(ESI正):m/z=206(M+H)+
以下实施例类似于实施例32a的制备来合成:
实施例33a
将二苯基磷酰基叠氮化物(0.450mL,2.112mmol)添加至含实施例32a(402mg,含量98%,1.92mmol)及TEA(0.320mL,2.304mmol)的甲苯(3mL)中且在室温下搅拌混合物1h。将混合物添加至在90℃下加热的甲苯(3mL)中且在此温度下持续加热2h。接着使反应物达到室温且搅拌隔夜。将混合物倾入4NHCl中,分离各相,用NaHCO3饱和溶液碱化水层至pH=10且用DCM萃取。用盐水洗涤有机层,干燥及蒸发,得到残余物,其通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并洗脱份,用NaHCO3饱和溶液碱化且蒸发ACN。用DCM萃取水层,干燥且蒸发,得到标题化合物(70mg,含量80%,18%)。
UPLC-MS(方法1):Rt=0.59min
MS(ESI正):m/z=177(M+H)+
实施例33b
将二苯基磷酰基叠氮化物(0.596mL,2.773mmol)添加至含实施例32b(640mg,2.919mmol)及TEA(0.386mL,2.773mmol)的甲苯(5.4mL)中且在室温下搅拌1h且在80℃下2h。添加4-甲氧基苯甲醇(0.364mL,2.919mmol)及TEA(0.386mL,2.773mmol)且在80℃下持续搅拌隔夜。用EtOAc稀释混合物,用10%柠檬酸洗涤,用盐水洗涤,干燥且蒸发,得到残余物,其通过快速色谱(洗脱剂0-20%EtOAc/环己烷)纯化,得到[1-甲基-1-(7-甲基-苯并[d]异唑-3-基)-乙基]-氨基甲酸4-甲氧基-苯甲酯(794mg,77%)。
UPLC-MS(方法12):Rt=3.73min
MS(ESI正):m/z=377(M+Na)+
在0℃下将TFA(4.3mL)添加至含[1-甲基-1-(7-甲基-苯并[d]异唑-3-基)-乙基]-氨基甲酸4-甲氧基-苯甲酯(350mg,0.988mmol)的DCM(4.4mL)。在室温下搅拌30min之后,减压蒸发挥发物得到标题化合物(300mg,含量98%,98%),其以原样使用。
HPLC-MS(方法2):Rt=0.66min
MS(ESI正):m/z=191(M+H)+
实施例34a
将HATU(184mg,0.484mmol)添加至于含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(84mg,0.371mmol)、实施例33a(77mg,含量85%,0.371mmol)及DIPEA(194μl,1.114mmol)的无水DMF(1mL)中且持续搅拌2h。减压蒸发挥发物且用乙酸乙酯溶解粗物质且用饱和NaHCO3及盐水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化,得到标题化合物(60mg,含量98%,41%)。
HPLC-MS(方法12):Rt=3.43min
MS(ESI正):m/z=408(M+Na)+
实施例34b
将HATU(378mg,1.26mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(220mg,0.966mmol)、实施例33b(300mg,含量98%,0.966mmol)及DIPEA(505μl,2.90mmol)的无水DMF(2mL)中且持续搅拌2h。减压蒸发挥发物且用乙酸乙酯溶解粗物质且用饱和NaHCO3及盐水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化,得到标题化合物(276mg,72%)。
HPLC-MS(方法11):Rt=2.97min
MS(ESI正):m/z=400(M+H)+
实施例35a
实施例35a类似于实施例6a由7-甲基-1H-吲唑-3-甲酸(13.1mmol)来制备,得到标题化合物(730mg,含量77%,25%)。
HPLC-MS(方法2):Rt=0.69min
MS(ESI正):m/z=176(M+H)+
实施例36a
实施例36a类似于实施例7e由实施例35a(650mg,含量77%,2.86mmol)来制备,得到标题化合物(109mg,含量91%,22%)。
HPLC-MS(方法2):Rt=0.96min
MS(ESI正):m/z=158(M+H)+
实施例37a
在0℃下将氢化钠(于矿物油中的60%悬浮液,31mg,0.76mmol)添加至36a(109mg,含量91%,0.63mmol)于DMF(1mL)中的溶液中。在20min之后,将2-(三甲基硅烷基)乙氧基甲基氯(157μl,0.88mmol)逐滴添加至反应混合物中。在室温下搅拌1h之后,用EtOAc稀释反应物,用NaHCO3饱和溶液及盐水洗涤。分离有机层且用相分离筒干燥且真空蒸发,得到残余物,其通过快速色谱(洗脱剂0-10%EtOAc/环己烷)纯化,得到标题化合物(182mg)。
UPLC-MS(方法2):Rt=1.61
MS(ESI正):m/z=288(M+H)+
以下实施例类似于实施例39c的制备来合成:
实施例38a
在氮气氛围下,在0℃下将无水THF(7.6mL)添加至无水氯化铈(III)(410mg,1.66mmol)中。使反应物达到室温且搅拌2h。在-78℃下添加甲基锂与碘化锂的络合物(1.6M乙醚溶液,1.1mL,1.7mmol)且在-78℃下持续搅拌30分钟。将37a(160mg,0.56mmol)于无水THF(3mL)中的溶液添加至混合物中且在-78℃下持续搅拌30分钟,且接着在室温下隔夜。在-30℃下将饱和NH4Cl及NaOH(32%水溶液)添加至混合物中直至沉淀形成。经硅藻土衬垫滤出未溶解物质。用DCM洗涤滤出物,分离且用相分离筒干燥。减压蒸发溶剂获得粗物质,其以原样使用。
将HATU(263mg,0.692mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(121mg,0.379mmol)、来自先前步骤的粗物质及DIPEA(278μl,1.60mmol)的无水DMF(1mL)中且持续搅拌隔夜。减压蒸发挥发物,得到残余物,用乙酸乙酯稀释且用饱和NaHCO3及盐水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂10-40%EtOAc/环己烷)纯化,得到标题化合物(160mg,经2个步骤为54%)。
UPLC-MS(方法7a):Rt=6.32-6.62min
MS(ESI正):m/z=529(M+H)+
以下实施例类似于实施例38a的制备来合成:
实施例39a
使实施例38a(160mg,0.303mmol)、氟化四丁基铵(1.0MTHF溶液,3.9mL,3.9mmol)及乙二胺(121μl,1.82mmol)回流隔夜。减压蒸发挥发物,得到残余物,用乙酸乙酯稀释且用水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到残余物,通过快速色谱(洗脱剂0-80%DCM:MeOH:NH395:5:0.5/DCM)纯化,得到标题化合物(62mg,51%)。
UPLC-MS(方法7a):Rt=4.39min
MS(APCI):m/z=399(M+H)+
以下实施例类似于实施例39a的制备来合成:
实施例39c
将碳酸铯(149mg,0.46mmol)添加至实施例39b(156mg,含量94%,0.38mmol)于DMF(5mL)中的溶液中。在15分钟之后,将碘乙烷(31μl,0.38mmol)逐滴添加至反应混合物中。在搅拌过周末之后,减压蒸发挥发物,用EtOAc稀释反应物,用NaHCO3饱和溶液及盐水洗涤。分离有机层且用相分离筒干燥且真空蒸发,得到残余物,其通过快速色谱(洗脱剂10-60%EtOAc/环己烷)纯化,得到标题化合物(147mg,93%)。
UPLC-MS(方法11):Rt=3.01
MS(ESI负):m/z=411(M-H)-
以下实施例类似于实施例37a的制备来合成:
实施例40a
将戴斯-马丁高碘烷(54.7g,129.0mmol)逐份添加至冷却至0℃的含实施例4a(35.0g,117.3mmol)的DCM(240mL)且在室温下持续搅拌隔夜。添加10%硫代硫酸钠溶液(200mL)且持续搅拌30min。分离有机层,用饱和NaHCO3溶液洗涤,经相分离筒干燥且减压蒸发,得到标题化合物(34.7g,100%),其以原样使用。
UPLC-MS(方法7a):Rt=3.63min
MS(APCI):m/z=297(M+H)+
实施例41a
在-78℃下将正丁基锂(2.0M环己烷溶液,67.5mL,135mmol)添加至含1,2-二氟苯(12.3g,108mmol)的THF(250mL)中。持续搅拌1小时。在-78℃下将含实施例40a(16.0g,54.0mmol)的THF(5mL)添加至反应混合物中且在该温度下持续搅拌3h。在-78℃下将饱和NH4Cl(15mL)添加至反应混合物中。使反应混合物升温至室温。分离有机层,用盐水洗涤,用相分离筒干燥且真空蒸发,得到残余物,其通过快速色谱(洗脱剂20-40%EtOAc/环己烷)纯化,得到标题化合物(11.2g,50%)。
1HNMR(300MHz,DMSO-d6):δ1.13(s,3H),1.24(brs,3H),1.33-1.42(m,10H),1.83(d,J=2.7Hz,2H),3.29(brs,2H),3.46(d,J=10.9Hz,2H),5.23(d,J=5.6Hz,1H),5.99(d,J=5.6Hz,1H),7.11-7.39(m,3H),7.62(brs,1H).
以下实施例类似于实施例41a的制备来合成:
实施例41d
在-78℃下将正丁基锂(2.0M环己烷溶液,19.4mL,38.9mmol)添加至含2-氟甲苯(3.4mL,31mmol)的THF(65mL)中。持续搅拌1小时。在-78℃下将含实施例40a(4.70g,含量98%,15.54mmol)的THF(5mL)添加至反应混合物中且在该温度下持续搅拌1h。在-78℃下将正丁基锂(2.0M环己烷溶液,15.5mL,31.1mmol)添加至含叔丁醇钾(3.49g,31.08mmol)的THF(15mL)中且在-78℃下将所得混合物添加至含实施例40的反应混合物中。在1h之后,在-78℃下将饱和NH4Cl(50mL)添加至反应混合物中。使反应混合物升温至室温。分离有机层,用盐水洗涤,用相分离筒干燥且真空蒸发,得到残余物,其通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化,得到标题化合物(1.70g,含量97%,26%)。
UPLC-MS(方法7a):Rt=4.95min
MS(APCI):m/z=407(M+H)+
实施例42a
将戴斯-马丁高碘烷(12.7g,29.9mmol)逐份添加至冷却至0℃的含实施例41a(11.2g,27.2mmol)的DCM(200mL)中且在室温下持续搅拌隔夜。添加10%硫代硫酸钠溶液且持续搅拌30min。分离有机层,用饱和NaHCO3溶液洗涤,经相分离筒干燥且减压蒸发,得到标题化合物(10.4g,94%),其以原样使用。
UPLC-MS(方法7a):Rt=4.72min
MS(APCI):m/z=409(M+H)+
以下实施例类似于实施例42a的制备来合成:
实施例43a
将羟胺盐酸盐(3.93g,56.62mmol)添加至含实施例42a(9.25g,22.65mmol)的吡啶(30mL)中且在50℃下持续搅拌过周末。减压蒸发挥发物,添加DCM及水。分离有机层,用盐水洗涤,经相分离筒干燥且减压蒸发,得到标题化合物(8.85g,92%),其以原样使用。
UPLC-MS(方法7a):Rt=4.52min
MS(APCI):m/z=424(M+H)+
以下实施例类似于实施例43a的制备来合成:
实施例43c
将羟胺盐酸盐(429mg,6.18mmol)添加至含实施例42c(1.05g,2.47mmol)的吡啶(20mL)中且在室温下持续搅拌2h且在50℃下过周末。减压蒸发挥发物且首先在室温下用DCM,且接着用沸腾AcOEt/丙酮湿磨残余物,得到标题化合物(550mg,51%)。
1HNMR(300MHz,DMSO-d6):δ1.13-1.43(m,13H),1.57(brs,3H),1.79(brs,2H),3.30(brs,4H),7.00(t,J=7.9Hz,1H),7.26(t,J=7.9Hz,1H),7.52-7.66(m,1H),7.97(s,1H),10.95(s,1H)。
实施例44a
将叔丁醇钾(175mg,1.56mmol)添加至含实施例43a(600mg,1.42mmol)的THF(30mL)中且回流反应混合物2h。用EtOAc稀释反应物,用水及盐水洗涤。分离有机层且用相分离筒干燥且真空蒸发,得到残余物,其通过快速色谱(洗脱剂0-30%EtOAc/环己烷)纯化,得到标题化合物(340mg,60%)。
UPLC-MS(方法1):Rt=1.22min
MS(ESI正):m/z=404(M+H)+
以下实施例类似于实施例44a的制备来合成:
实施例44d
将环戊基甲醚(2mL)及水(0.2mL)添加至实施例44c(140mg,0.32mmol)、环丙基三氟硼酸钾(47mg,0.32mmol)、乙酸钯(II)(2mg,0.01mmol)、X-Phos(9mg,0.02mmol)及碳酸钾(13mg,0.10mmol)且在100℃下加热反应混合物隔夜。用EtOAc/盐水稀释反应物。分离有机层,干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-30%EtOAc/环己烷)纯化,得到标题化合物(105mg,78%)。
UPLC-MS(方法7a):Rt=5.37min
MS(APCI):m/z=426(M+H)+
实施例45a
在微波辐射(160℃)下加热含实施例42a(1.00g,2.45mmol)及甲肼(645μl,12.2mmol)的EtOH(2mL)20min。减压蒸发挥发物,得到残余物,其通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化,得到标题化合物(630mg,62%)。
UPLC-MS(方法2):Rt=1.20min
MS(ESI正):m/z=417(M+H)+
实施例45b
在微波辐射(150℃)下加热含实施例42c(350mg,0.82mmol)及甲肼(217μl,4.12mmol)的EtOH(3mL)60min。减压蒸发挥发物,得到残余物,其通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化,得到标题化合物(220mg,62%)。
UPLC-MS(方法2):Rt=1.31min
MS(ESI正):m/z=433(M+H)+
实施例45c
将实施例45b(1.50g,含量98%,3.40mmol)、四(三苯基膦)钯(0)(157mg,0.136mmol)及四甲基锡(1.3mL,9.5mmol)溶解于DMF(12mL)中,分成相等的2批且在微波辐射(175℃)下加热35min。用EtOAc/盐水稀释反应物。分离有机层,干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-40%EtOAc/环己烷)纯化,得到残余物,其又通过C18色谱(洗脱剂25-90%ACN/H2O)纯化,得到标题化合物(1.16g,83%)。
UPLC-MS(方法2):Rt=1.22min
MS(ESI正):m/z=413(M+H)+
实施例45d
在110℃下加热实施例42d(1.10g,2.72mmol)、氧化铜(II)(11mg,0.14mmol)、碳酸钾(564mg,4.08mmol)及甲肼(917μl,17.41mmol)3d。经硅藻土衬垫过滤反应物,用EtOAc洗涤。用水洗涤滤出物且接着干燥。减压蒸发挥发物,得到残余物,其通过快速色谱(洗脱剂0-100%EtOAc/环己烷)纯化,得到标题化合物(95mg,9%)。亦获得实施例45c作为副产物。
UPLC-MS(方法2):Rt=1.11min
MS(ESI正):m/z=413(M+H)+
实施例45e
在微波辐射(120℃)下加热含实施例42a(1.50g,3.67mmol)及水合肼(3mL,60mmol)的EtOH(2mL)8h。减压蒸发挥发物得到残余物,其通过制备型HPLC(固定相:XBridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份,且冷冻干燥,得到标题化合物(40mg,3%)。
UPLC-MS(方法2):Rt=1.05min
MS(ESI正):m/z=403(M+H)+
实施例45f
在微波辐射(140℃)下加热含实施例42b(150mg,0.327mmol)及水合肼(56μl,1.15mmol)的EtOH(2mL)15min。减压蒸发挥发物,得到残余物,用EtOAc/水溶解。分离有机层,用盐水洗涤,干燥且减压蒸发,得到标题化合物(132mg,89%),其以原样使用。
UPLC-MS(方法7a):Rt=4.73min
MS(APCI):m/z=453(M+H)+
实施例46a
在微波辐射(120℃)下加热含1-(1-甲基-1H-吲唑-3-基)乙酮(800mg,4.59mmol)、羟胺盐酸盐(479mg,6.89mmol)及TEA(958μl,6.89mmol)的EtOH(4mL)20min。用EtOAc/水稀释反应混合物。分离有机层,用盐水洗涤,干燥且减压蒸发,得到标题化合物(800mg,92%),其以原样使用。
UPLC-MS(方法2):Rt=0.91min
MS(ESI正):m/z=190(M+H)+
实施例47a(外消旋混合物)
将阮尼镍(100mg,1.17mmol)添加至含实施例46a(200mg,1.06mmol)及氢氧化铵(300μl,2.31mmol)的EtOH(10mL)中,且在3.5巴下氢化混合物3h。通过经硅藻土过滤来移除催化剂,用EtOH及水洗涤。降低蒸发EtOH且添加DCM。分离有机层,干燥且减压蒸发,得到标题化合物(140mg,76%),其以原样使用。
UPLC-MS(方法2):Rt=0.62min
MS(ESI正):m/z=159(M-NH2)+
实施例48a(立体异构体的混合物)
将HATU(414mg,1.09mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(165mg,0.726mmol)、实施例47a(140mg,0.799mmol)及DIPEA(379μl,2.18mmol)的无水DMF(5mL)中且持续搅拌隔夜。用乙酸乙酯稀释反应混合物且用水及盐水洗涤。分离有机层,经相分离筒干燥且减压蒸发,得到标题化合物(250mg,90%),其以原样使用。
UPLC-MS(方法2):Rt=1.09min
MS(ESI正):m/z=385(M+H)+
通过HPLC使用手性固定相分离标题化合物的立体异构体。
分离方法:
HPLC装置类型:Waters600泵,2767自动取样器,UV检测器2489;管柱:DaicelchiralpackAD-H,5.0μm,250mm×20mm;方法:洗脱剂己烷/IPA90:10;流速:12mL/min,温度:21-22℃;UV检测:220nm
实施例49a(外消旋混合物)
将戴斯-马丁高碘烷(12.3g,29.1mmol)逐份添加至冷却至0℃的含N-BOC-2-氨基-1-丙醇(5.00g,28.5mmol)的DCM(75mL)中且在室温下持续搅拌隔夜。添加10%硫代硫酸钠溶液且持续搅拌30min。分离有机层,用饱和NaHCO3溶液洗涤,经相分离筒干燥且减压蒸发,得到标题化合物(4.68g,95%),其以原样使用。
1HNMR(300MHz,DMSO-d6):δ1.12(d,J=7.3Hz,3H),1.39(br,s,9H),3.86(m,1H),7.31(br,d,J=6.4Hz,1H),9.42(d,J=0.7,1H)
实施例50a(立体异构体的混合物)
在-78℃下将正丁基锂(2.5M己烷溶液,16.2mL,40.4mmol)添加至含1-氯-2-氟苯(3.6mL,34.6mmol)的THF(76mL)中。持续搅拌1小时。在-78℃下将含实施例49a(2.00g,11.6mmol)的THF(15mL)添加至反应混合物中且在该温度下持续搅拌1h。在-78℃下将饱和NH4Cl(100mL)添加至反应混合物中。使反应混合物升温至室温。分离有机层,用盐水洗涤,用相分离筒干燥且真空蒸发,得到残余物,其通过快速色谱(洗脱剂0-30%EtOAc/环己烷)纯化,得到标题化合物(1.65g,47%)。
UPLC-MS(方法2):Rt=1.15min
MS(ESI正):m/z=304(M+H)+
实施例51a(外消旋混合物)
将戴斯-马丁高碘烷(2.46g,5.79mmol)逐份添加至冷却至0℃的含实施例50a(1.60,5.27mmol)的DCM(10mL)中且在室温下持续搅拌2h。添加10%硫代硫酸钠溶液且持续搅拌30min。分离有机层,用饱和NaHCO3溶液洗涤,经相分离筒干燥且减压蒸发,得到标题化合物(1.50g,含量89%,84%),其以原样使用。
UPLC-MS(方法2):Rt=1.25min
MS(ESI正):m/z=302(M+H)+
实施例52a(外消旋混合物)
在75℃下加热含实施例51a(1.50g,含量89%,4.42mmol)及甲肼(2.8mL,53mmol)的EtOH(7mL)隔夜,之后在80℃下4h。减压蒸发挥发物,得到残余物,其通过快速色谱(洗脱剂0-30%EtOAc/环己烷)纯化,得到标题化合物(620mg,45%)。
1HNMR(300MHz,DMSO-d6):δ1.37(br,s,9H),1.48(d,J=7.0Hz,3H),4.26(s,3H),5.06(m,1H),7.08(dd,J=7.6,8.2Hz,1H),7.42(m,2H),7.83(dd,J=0.9,8.0Hz,1H)。
实施例52b(外消旋混合物)
将三甲基环硼氧烷(542μl,3.87mmol)添加至含实施例52a(400mg,1.291mmol)、碳酸钾(892mg,6.46mmol)及1,1′-双(二苯膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(105mg,0.129mmol)的DMF(6mL)中且在100℃下加热反应混合物隔夜。将三甲基环硼氧烷(542μl,3.87mmol)、碳酸钾(892mg,6.46mmol)及1,1′-双(二苯膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(105mg,0.129mmol)添加至冷却至室温的反应混合物中且在100℃下加热反应混合物1d。减压蒸发挥发物且用EtOAc/水溶解残余物。分离有机层,干燥且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-20%EtOAc/环己烷)纯化,得到标题化合物(175mg,含量95%,45%)。
UPLC-MS(方法2):Rt=1.21min
MS(ESI正):m/z=290(M+H)+
实施例53a(外消旋混合物)
使实施例52a(220mg,0.710mmol)悬浮于MeOH/水1:1(1mL/1mL)中微波辐射(140℃)下加热50min。反应混合物经SCX筒纯化,用MeOH及DCM洗涤,且接着用含NH3的MeOH洗脱,得到标题化合物(145mg,97%)
UPLC-MS(方法2):Rt=0.71min
MS(ESI正):m/z=193(M-NH2)+
以下实施例类似于实施例53a的制备来合成:
以下实施例类似于实施例34b的制备来合成:
通过HPLC使用手性固定相分离实施例54a的立体异构体。
分离方法:
HPLC装置类型:Waters600泵,2767自动取样器,UV检测器2489;管柱:DaicelchiralpackAD-H,5.0μm,250mm×20mm;方法:洗脱剂己烷/IPA85:15;流速:10mL/min,温度:25℃;UV检测:230nm
以下实施例类似于实施例34b的制备来合成:
通过HPLC使用手性固定相分离实施例54d的立体异构体。
分离方法:
HPLC装置类型:Waters600泵,2767自动取样器,UV检测器2489;管柱:DaicelchiralpackAD-H,5.0μm,250mm×20mm;方法:洗脱剂己烷/IPA85:15;流速:15mL/min,温度:25℃;UV检测:230nm
实施例55a
将2-溴乙酰苯胺(1.68g,含量90%,7.06mmol)溶解于无水THF(15mL)中且在氮气氛围下冷却至-78℃。逐滴添加正丁基锂(2.5M己烷溶液,5.93mL,14.8mmol)且在-78℃下搅拌混合物30分钟。逐滴添加含2-甲酰基丙-2-基氨基甲酸叔丁酯(1.39g,7.42mmol)的无水THF(10mL)且在-78℃下搅拌混合物30分钟,接着经1小时升温至-50℃。添加饱和氯化铵水溶液(20mL),使混合物升温至室温且分离各相。用盐水洗涤有机相,干燥且移除溶剂。残余物通过快速色谱(洗脱剂0-2%MeOH/DCM)纯化,得到标题产物(370mg,16%)。
LC-MS(方法1):Rt=1.02min
MS(ESI正):m/z=323(M+H)+
以下实施例类似于实施例55a的制备来合成:
实施例56a
使实施例55a(210mg,0.65mmol)悬浮于DCM中且添加戴斯马丁高碘烷(304mg,0.72mmol)。搅拌混合物10分钟且接着与10%硫代硫酸钠水溶液一起震荡且分离各相。用饱和碳酸氢钠水溶液洗涤有机相,干燥且移除溶剂,得到标题产物(208mg,100%)。
LC-MS(方法1):Rt=1.13min
MS(ESI正):m/z=321(M+H)+
以下实施例类似于实施例56a的制备来合成:
实施例56i
分离作为实施例57b的制备步骤1的副产物的标题化合物(参见下文)(157mg,含量85%)。
LC-MS(方法1):Rt=1.09min
MS(ESI正):m/z=279(M+H)+
实施例56j
使实施例56i(157mg,含量85%,0.48mmol)悬浮于DCM(5mL)中且添加环丙基甲酰氯(65μL,0.71mmol)及三乙胺(200μL,1.44mmol)。搅拌混合物隔夜,接着用DCM稀释,用0.2MHCl水溶液、0.2MNaOH及盐水洗涤,干燥且真空移除溶剂。残余物通过快速色谱(洗脱剂:10%EtOAc/环己烷)纯化,得到标题产物(166mg,92%)。
LC-MS(方法1):Rt=1.28min
MS(ESI正):m/z=347(M+H)+
实施例57a
使实施例56a(205mg,0.64mmol)及氯化铵(300mg,5.58mmol)悬浮于7M氨的甲醇溶液(4mL)中且在140℃下在微波辐射下加热16小时。移除溶剂,使残余物悬浮于甲醇中且过滤器,以移除过量氯化铵,接着加载于预洗SCX筒上,用水及甲醇洗涤且用7M氨的甲醇溶液洗脱。真空移除溶剂,得到粗标题产物(106mg)。
LC-MS(方法1):Rt=0.58min
MS(ESI正):m/z=202(M+H)+
实施例57b
步骤1:
使实施例56b(1.25mg,3.34mmol)及氯化铵(0.9g,16.5mmol)悬浮于7M氨的甲醇溶液(30mL)中且在120℃下在微波辐射下加热40分钟。用乙酸乙酯稀释混合物,用水洗涤,使有机相干燥且移除溶剂。残余物通过快速色谱(洗脱剂DCM)纯化,得到经Boc保护的产物(112mg)。
LC-MS(方法1):Rt=1.38min
MS(ESI正):m/z=356(M+H)+
步骤2:
使来自步骤1的中间物悬浮于4MHCl的二烷溶液中且搅拌30分钟。蒸发溶剂且真空干燥残余物,得到标题产物(90mg)。
LC-MS(方法1):Rt=0.69min
MS(ESI正):m/z=256(M+H)+
以下实施例类似于实施例57a的制备来合成:
以下实施例类似于实施例57b的制备来合成:
实施例58a
使实施例57a(80mg,0.40mmol)、内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(108mg,0.48mmol)、Et3N(138μL,0.99mmol)及HATU(181mg,0.48mmol)悬浮于DCM(5mL)中且搅拌混合物隔夜。用DCM稀释混合物且用水洗涤。使有机层干燥,过滤且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-3%MeOH/DCM)纯化,得到标题化合物(产量140mg,86%)。
UPLC-MS(方法1):Rt=0.92min
MS(ESI正):m/z=411(M+H)+
以下实施例类似于实施例58a的制备来合成:
通过HPLC使用手性固定相分离实施例58h的立体异构体。
分离方法:
HPLC装置类型:Waters600泵,2767自动取样器,UV检测器2489;管柱:DaicelchiralpackOJ-H,5.0μm,250mm×20mm;方法:洗脱剂己烷/乙醇93:7;流速:15mL/min,温度:25℃;UV检测:230nm
通过HPLC使用手性固定相分离实施例58i的立体异构体。
分离方法:
HPLC装置类型:Waters600泵,2767自动取样器,UV检测器2489;管柱:DaicelchiralpackAS-H,5.0μm,250mm×20mm;方法:洗脱剂己烷/乙醇95:5;流速:8mL/min,温度:25℃;UV检测:230nm
实施例59a
步骤1:
使Boc-AIB-OH(0.50g,2.44mmol)、2-肼基-3-甲基吡啶(1.0g,8.24mmol)、HATU(3.70g,9.73mmol)及三乙基胺(2.48mL,17.8mmol)悬浮于DCM中且搅拌混合物隔夜。过滤混合物,移除溶剂且残余物通过快速色谱(洗脱剂0-100%乙酸乙酯/环己烷)纯化,得到不纯的酰肼中间物(800mg),其直接用于下一步骤中。
步骤2:
使来自步骤1的物质悬浮于无水DCM(20ML)中且添加以聚合物为载体的三苯基膦(3mmol/g,1.3g,3.9mmol)、三甲基硅烷基叠氮(520μL,3.9mmol)及偶氮二甲酸二乙酯(2.03mL,4.7mmol)。搅拌混合物隔夜,过滤且移除溶剂。残余物通过快速色谱(洗脱剂0-100乙酸乙酯/环己烷)纯化,得到标题产物(产量180mg)。
UPLC-MS(方法2):Rt=0.76min
MS(ESI正):m/z=291(M+H)+
实施例60a
使实施例59a(180mg,0.62mmol)悬浮于4MHCl的二烷溶液(4ML)中且搅拌3小时。真空移除溶剂,得到标题产物(150mg,含量90%)。
UPLC-MS(方法2):Rt=0.49min
MS(ESI正):m/z=191(M+H)+
实施例61a
标题产物类似于实施例58a的合成所述的操作由实施例60a(100mg,0.44mmol)来合成(产量150mg,85%)。
UPLC-MS(方法2):Rt=0.84min
MS(ESI正):m/z=400(M+H)+
实施例62a
使5-氯-7-甲基-[1,6]萘啶(J.Chem.Soc.Perkin1,1972,705-709,340mg,1.9mmol)、氰化锌(246mg,2.09mmol)、1,1-双(二苯膦基)二茂铁(95mg,0.17mmol)及叁(二亚苄基丙酮)二钯(0)(70mg,0.08mmol)悬浮于无水DMF(5mL)中且在100℃下加热隔夜。使混合物冷却至室温,用水稀释且用乙酸乙酯萃取。用盐水洗涤有机萃取物,干燥且真空移除溶剂。残余物通过快速色谱(洗脱剂20%EtOAc/环己烷)纯化,得到标题化合物(产量240mg)。
UPLC-MS(方法2):Rt=0.78min
MS(ESI正):m/z=170(M+H)+
实施例62b
标题产物类似于实施例62a的合成所述的操作使用0-50%EtOAc/环己烷作为用于纯化的洗脱剂由1-氯-3-甲基-[2,6]萘啶(J.Chem.Soc.Perkin1,1972,705-709,726mg,4.06mmol)来合成(产量380mg)。
LC-MS(方法12):Rt=2.52min
MS(ESI正):m/z=170(M+H)+
实施例63a
在140℃下在真空下加热氯化铈(III)(1.05g,4.26mmol)10分钟,接着在氮气氛围下冷却至0℃且添加无水THF(12mL)。在室温下搅拌混合物2小时,接着冷却至-78℃。添加甲基锂LiCl络合物(1.6M乙醚溶液,2.66mL,4.26mmol)且在-78℃下搅拌混合物30分钟。逐滴添加溶解于无水THF(3mL)中的实施例62a(240mg,1.42mmol),在-78℃下搅拌混合物40分钟,接着缓慢升温至-20℃且逐滴添加饱和氯化铵溶液直至形成沉淀。经由硅藻土过滤混合物用大量DCM洗涤。用水洗涤有机相,干燥且移除溶剂,得到含有标题化合物的粗混合物(产量230mg)。
UPLC-MS(方法2):Rt=0.59min
MS(ESI正):m/z=216(M+H)+
实施例63b
标题产物类似于实施例63a的合成所述的操作由实施例62b(380mg,2.25mmol)来合成(粗产量560mg)。
LC-MS(方法2):Rt=0.56min
MS(ESI正):m/z=170(M+H)+
实施例64a
标题产物类似于实施例58a的合成所述的操作由实施例63a(230mg)来合成(产量21mg)。
LC-MS(方法2):Rt=1.15min
MS(ESI正):m/z=425(M+H)+
实施例64b
标题产物类似于实施例58a的合成所述的操作由实施例63b(200mg)来合成(产量51mg)。
LC-MS(方法1):Rt=0.91min
MS(ESI正):m/z=425(M+H)+
实施例65a
使2-甲基咪唑并[1,2-a]吡啶-3-甲酸乙酯(3.30g,16.1mmol)悬浮于无水THF中且在氮气氛围下冷却至-20℃。逐滴添加溴化甲基镁(1.4MTHF/甲苯,35mL,48.5mmol),使混合物升温至室温且搅拌隔夜。添加饱和氯化铵水溶液且用乙酸乙酯萃取混合物。使有机萃取物干燥且移除溶剂。残余物通过快速色谱(洗脱剂0-100%EtOAc/环己烷)纯化,得到标题产物(产量1.20g,39%)。
1HNMR(500MHz,DMSO-d6):δ1.64(s,6H),2.44(s,3H),5.40(s,1H),6.82(dd,1H),7.16(dd,1H),7.43(d,1H),8.84(dd,1H)。
实施例66a
使实施例65a(1.2g,6.31mmol)悬浮于氯乙腈(15mL)及TFA(15mL)中且搅拌混合物隔夜。蒸发溶剂且残余物通过快速色谱(洗脱剂0-10%MeOH/DCM)纯化,得到标题产物(产量0.5g,30%)。
LC-MS(方法1):Rt=0.60min
MS(ESI正):m/z=266/268(M+H)+
实施例67a
使实施例66a(100mg,0.38mmol)悬浮于6MHCl水溶液(2mL)中且在80℃下加热隔夜。将混合物加载于预洗SCX筒上,用水及甲醇洗涤且用7MNH3的甲醇溶液洗脱。移除溶剂得到标题产物(产量70g,98%)。
1HNMR(500MHz,DMSO-d6):δ1.57(s,6H),2.44(s,3H),6.74(dd,1H),7.08(dd,1H),7.34(d,1H),9.15(dd,1H)。NH2未观察到。
实施例68a
标题产物类似于实施例58a的合成所述的操作由实施例67a(70mg)来合成(产量40mg)。
LC-MS(方法1):Rt=0.80min
MS(ESI正):m/z=399(M+H)+
实施例69a
标题产物类似于实施例65a至实施例68a的合成所述的操作由8-甲基咪唑并[1,2-a]吡啶-3-甲酸乙酯(1.0g,类似于Bioorg.Med.Chem.Lett,2012,1870-1873中所述的操作制备)来合成(产量68mg)。
LC-MS(方法2):Rt=1.02min
MS(ESI正):m/z=399(M+H)+
实施例70a
标题产物类似于实施例55a至实施例56a的合成所述的操作由2-溴吡啶来合成(产量218mg)。
LC-MS(方法2):Rt=1.14min
MS(ESI正):m/z=265(M+H)+
实施例71a
使实施例70a(218mg,0.82mmol)、乙酸铵(326mg,8.25mmol)及氰基硼氢化钠(62mg,0.99mmol)组合于无水甲醇(5mL)中且搅拌混合物隔夜,接着在90℃下在密封管中加热6小时。移除溶剂,将残余物溶解于乙酸乙酯中,用水及盐水洗涤,干燥且移除溶剂,得到粗标题产物(产量220mg)。
LC-MS(方法2):Rt=0.97min
MS(ESI正):m/z=266(M+H)+
实施例72a
使实施例71a(220mg)、乙酰氯(89μL,1.24mmol)及三乙胺(345μL,2.49mmol)组合于无水DCM(5mL)中且搅拌混合物2小时。用DCM稀释混合物,用水洗涤,干燥且移除溶剂。残余物通过快速色谱(洗脱剂0-100%EtOAc/环己烷)纯化,得到标题产物(产量77mg)。
LC-MS(方法2):Rt=0.97min
MS(ESI正):m/z=308(M+H)+
实施例73a
使实施例72a(77mg,0.25mmol)及伯吉斯试剂(90mg,0.38mmol)组合于无水DCM(5mL)中且搅拌混合物隔夜。用DCM稀释混合物,用水洗涤,干燥且移除溶剂。残余物通过快速色谱(洗脱剂0-50%EtOAc/环己烷)纯化,得到标题产物(产量54mg)。
LC-MS(方法2):Rt=1.06min
MS(ESI正):m/z=290(M+H)+
实施例74a
使实施例73a(54mg)悬浮于2MHCl的乙醚溶液中且搅拌混合物隔夜。真空移除溶剂,得到粗标题产物(产量42mg)。
LC-MS(方法2):Rt=0.75min
MS(ESI正):m/z=173(M-NH2)+
实施例75a
标题产物类似于实施例58a的合成所述的操作使用0-5%MeOH/DCM作为用于纯化的洗脱剂由实施例74a(42mg)来合成(产量37mg)。
LC-MS(方法2):Rt=1.05min
MS(ESI正):m/z=399(M+H)+
实施例76a
在140℃下在真空下加热氯化铈(III)(18.12g,74mmol)3小时,接着在氮气氛围下冷却至室温且添加无水THF(200mL)。在室温下搅拌混合物隔夜,接着冷却至-78℃。添加甲基锂LiCl络合物(1.6M乙醚溶液,46mL,74mmol)且在-78℃下搅拌混合物2小时。逐滴添加含吡唑并[1,5-a]吡啶-3-甲腈(1.05g)的无水THF(25mL),在-78℃下搅拌混合物2小时,接着依序添加饱和氯化铵溶液、浓氨水。使混合物升温至室温,经由硅藻土过滤,用大量DCM洗涤。用水洗涤有机相,干燥且移除溶剂,得到含有标题化合物的粗混合物(产量1.27g)。
UPLC-MS(方法2):Rt=0.55min
MS(ESI正):m/z=159(M-NH2)+
实施例77a
标题产物类似于实施例58a的合成所述的操作使用50-70%EtOAc/环己烷作为用于纯化的洗脱剂由实施例76a(154mg)来合成(产量246mg)。
LC-MS(方法2):Rt=1.00min
MS(ESI正):m/z=385(M+H)+
实施例78a
使3-甲基吡啶(5.0g,53.7mmol)悬浮于乙腈中且添加氯乙腈(6.76mL,107.4mmol)。在室温下搅拌混合物4小时且通过过滤收集沉淀且在真空下干燥,得到标题化合物(7.0g)。
1HNMR(500MHz,DMSO-d6):δ2.53(s,3H),δ6.04(s,2H),8.16(dd,J=6.0,8.0Hz,1H),8.58(d,J=8.0,1H),9.09(d,J=6.0Hz,1H),9.17(s,1H)。
实施例79a
使实施例78a(2.0g,11.9mmol)、1-硝基-2,2-双-甲基-巯基-乙烯(1.96g,11.9mmol)及三乙胺(3.30mL,23.7)悬浮于乙醇(30mL)中且回流6小时。蒸发溶剂且残余物通过快速色谱(洗脱剂0-10%乙酸乙酯/环己烷)纯化,得到标题化合物(0.75g)。
1HNMR(500MHz,DMSO-d6):δ2.42(s,3H),2.62(s,3H),6.69(2,1H),6.90(dd,1H),7.00(d,1H),8.24(d,1H)。
实施例80a
使实施例79a(0.5g,2.47mmol)及过量阮尼镍(约2g)悬浮于乙醇中且搅拌6小时。蒸发溶剂且残余物通过快速色谱(洗脱剂0-10%乙酸乙酯/环己烷)纯化,得到标题化合物(88mg)。
LC-MS(方法2):Rt=1.15min
MS(ESI正):m/z=157(M+H)+
实施例81a
在140℃下在真空下加热氯化铈(III)(1.39g,5.63mmol)3小时,接着在氮气氛围下冷却至室温且添加无水THF(10mL)。在室温下搅拌混合物隔夜,接着冷却至-78℃。添加甲基锂LiCl络合物(1.6M乙醚溶液,3.52mL,5.63mmol)且在-78℃下搅拌混合物2小时。逐滴添加含实施例80a(88mg,0.56mmol)的无水THF(5mL),在-78℃下搅拌混合物2小时,接着依序添加饱和氯化铵溶液、32%氨水。使混合物升温至室温,经由硅藻土过滤,用大量DCM洗涤。用水洗涤有机相,干燥且移除溶剂,得到含有标题化合物的粗混合物(88mg)。
UPLC-MS(方法2):Rt=1.12min
MS(ESI正):m/z=172(M-NH2)+
实施例82a
标题产物类似于实施例58a的合成所述的操作使用0-50%EtOAc/环己烷作为用于纯化的洗脱剂由实施例81a(88mg)来合成(产量60mg)。
LC-MS(方法2):Rt=1.30min
MS(ESI正):m/z=398(M+H)+
例示性实施方式
实施例1
将HATU(8mg,0.022mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(4.5mg,0.020mmol)、1-(4-碘-2-甲基-苯氧基甲基)-环丙胺(3mg,0.010mmol;如WO2012/028676中所述制备)及DIPEA(6μl,0.035mmol)的DMF(0.200mL)中且在室温下持续搅拌18h。经碱性氧化铝衬垫过滤反应物,用DMF/MeOH9:1(600μl)洗涤且接着干燥。用0.500ml二烷及0.200mL4NHCl的二烷溶液稀释残余物且持续搅拌隔夜。蒸发溶剂得到标题化合物(4.8mg,100%)。
UPLC-MS(方法3):Rt=1.36
MS(ESI正):m/z=413(M+H)+
以下实施例类似于实施例1的制备来合成:
实施例5
将HATU(84mg,0.220mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(45mg,0.200mmol)、2-甲基-1-(萘-1-基)丙-2-胺(47mg,0.200mmol)及DIPEA(120μl,0.700mmol)的DMF(3mL)中且在室温下持续搅拌隔夜。反应物通过制备型HPLC(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份且冷冻干燥。用HCl的乙醚溶液(2M,1.2mL,25.610mmol)处理含残余物的MeOH(3mL)。在搅拌3h之后,减压蒸发挥发物且将所得残余物再溶解于ACN/H2O1:1中且冷冻干燥,得到标题化合物(44.7mg,65%)。
UPLC-MS(方法4):Rt=1.25
MS(ESI正):m/z=309(M+H)+
以下实施例类似于实施例5的制备来合成:
实施例9
实施例9由如实施例5所述的1-苯基环己-1-胺盐酸盐(42mg,0.200mmol)来制备,但在首次纯化之后,首先通过制备型HPLC(固定相:XbridgeC185μm19x100mm;流动相:ACN/H2O+NH4COOH5mM),且接着经WaterCX0.4g筒再纯化化合物,得到标题化合物(22.9mg,40%)。
UPLC-MS(方法4):Rt=1.23
MS(ESI正):m/z=285(M+H)+
实施例10
将HATU(125mg,0.330mmol)添加至含内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(68mg,0.300mmol)、(S)1-(1-萘基)乙胺(56mg,0.330mmol)及DIPEA(78μl,0.450mmol)的DMF(3mL)中且在室温下持续搅拌18h。经碱性氧化铝衬垫过滤反应物,用DMF/MeOH9:1(6ml)洗涤且接着干燥。用DMF(1mL)稀释残余物且加载于WatersRP2g筒上,用H2O/MeOH95:5(20mL)洗涤且用MeOH(10mL)洗脱。蒸发粗物质且溶解于DCM(2mL)中,接着添加TFA(100μL,13mmol)且在室温下持续搅拌4h。蒸发溶剂且用H2O/ACN1:1稀释残余物,接着经WatersCX2g筒纯化,用MeOH/H2O95:5(40mL)洗涤,用5%NH4OH的MeOH溶液(10mL)洗脱。蒸发溶剂且将粗物质再溶解于ACN/H2O1:1(4mL)中且冷冻干燥,得到标题化合物(84mg,100%)。
UPLC-MS(方法3):Rt=1.19
MS(ESI正):m/z=281(M+H)+
实施例11
依序将TEA(6mL,44.985mmol)、TBTU(5.3g,16.511mmol)添加至含4-氯-邻苯二胺(2.1g,15.001mmol)及α-(Boc-氨基)异丁酸(Boc-α-甲基丙氨酸)(3.3g,16.247mmol)的THF(50mL)中。在室温下搅拌3d之后,减压蒸发挥发物,将残余物溶解于EtOAc中,用5%柠檬酸、2MNaOH洗涤,经Na2SO4干燥,过滤且减压蒸发,得到残余物,其通过快速色谱(洗脱剂50%EtOAc/环己烷)纯化,得到加合物的混合物(4.2g,85%)。在60℃下于乙酸(35mL)中加热此类混合物隔夜。减压蒸发挥发物,得到残余物,溶解于EtOAc中,用2MNaOH洗涤,经MgSO4干燥,过滤且减压蒸发,得到残余物。使此类残余物悬浮于DCM(25mL)中且用TFA(10mL)处理。持续搅拌2h。减压蒸发挥发物且用甲基叔丁基醚溶解所得残余物,用0.5MHCl洗涤且减压蒸发。用EtOH溶解所得混合物并蒸发两次,得到残余物(3.4g)。将57mg含此类残余物(0.2mmol)及DIPEA(65μl,0.4mmol)的DMF(1mL)添加至含HATU(84mg,0.220mmol)、内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(45mg,0.200mmol)及DIPEA(113μl,0.700mmol)的DMF(2mL)中且在室温下持续搅拌隔夜且反应混合物通过制备型HPLC(固定相:XBridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份且冷冻干燥。用HCl的乙醚溶液(2M,1.2mL,25.610mmol)处理含残余物的MeOH(3mL)。在搅拌3h之后,减压蒸发挥发物且将所得残余物再溶解于ACN/H2O1:1中且冷冻干燥,得到标题化合物(86mg,100%)。
UPLC-MS(方法4):Rt=0.83min
MS(ESI正):m/z=319(M+H)+
实施例12
将实施例3b(84mg,0.19mmol)溶解于乙醚(1mL)中,冷却至0℃且接着逐滴添加2M氯化氢的乙醚溶液(1mL,2mmol)。在室温下持续搅拌隔夜。移除溶剂且用乙醚溶解粗产物并接着干燥且减压蒸发两次,得到标题化合物(60mg,84%)。
HPLC-MS(方法7):Rt=6.32min
MS(APCI):m/z=343(M+H)+
以下实施例类似于实施例12的制备来合成:
实施例32
实施例32类似于实施例12使用SCX筒纯化由残余物获得的残余物由实施例29b(107mg,0.268mmol)来制备。减压蒸发用甲醇氨溶液洗脱时获得的洗脱份,得到标题化合物(59mg,74%)。
HPLC-MS(方法10):Rt=2.40min
MS(ESI正):m/z=300(M+H)+
以下实施例类似于实施例32的制备来合成:
实施例36
实施例36类似于实施例12使用制备型HPLC纯化残余物(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)由实施例5c(75mg,0.169mmol)来制备。合并含有标题化合物的洗脱份且减压蒸发ACN。用DCM萃取水层,分离且蒸发DCM。将残余物溶解于MeOH中且加载于SCX筒上。蒸发用甲醇氨溶液洗脱时获得的洗脱份,得到标题化合物(15mg,26%)。
HPLC-MS(方法8):Rt=2.17min
MS(APCI):m/z=344(M+H)+
实施例37
实施例37类似于实施例12使用MeOH作为溶剂由实施例5k(42mg,0.108mmol)来制备。接着用NH3的MeOH溶液碱化反应混合物且用制备型HPLC(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。用DCM萃取水层,分离且蒸发DCM,得到标题化合物(5.5mg,18%)。
HPLC-MS(方法8):Rt=1.89min
MS(APCI):m/z=291(M+H)+
实施例38
实施例38类似于实施例12由实施例3d(109mg,含量98%,0.274mmol)来制备。将残余物溶解于HCl的MeOH溶液中且通过制备型HPLC(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份且蒸发,再溶解于MeOH中,经SCX筒纯化且用甲醇氨溶液洗脱,得到标题化合物(26mg,33%)。
HPLC-MS(方法7):Rt=5.45min
MS(APCI):m/z=290(M+H)+
实施例39
将实施例3i(85mg,含量81%,0.17mmol)溶解于甲醇(4mL)中且接着添加2M氯化氢的乙醚溶液(0.86mL,1.71mmol)。在室温下持续搅拌隔夜。减压移除溶剂,得到残余物,其通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份且减压蒸发。用HCl的乙醚溶液(1mL)溶解残余物,接着减压蒸发,得到标题化合物(28mg,48%)。
HPLC-MS(方法7):Rt=5.91min
MS(APCI):m/z=303(M+H)+
以下实施例类似于实施例39的制备来合成:
实施例42
实施例42类似于实施例39使用SCX纯化由制备型HPLC获得的残余物由实施例3t(65mg,0.159mmol)来制备。减压蒸发用甲醇氨溶液洗脱时获得的洗脱份,得到残余物。用MeOH溶解残余物且添加2M氯化氢的乙醚溶液。减压蒸发残余物,得到标题化合物(47mg,86%)。
HPLC-MS(方法7):Rt=5.47min
MS(APCI):m/z=309(M+H)+
实施例43
实施例43类似于实施例39经SCX筒纯化由制备型HPLC纯化获得的残余物由实施例3n(85mg,含量87%,0.190mmol)来制备。减压蒸发用甲醇氨溶液洗脱时获得的洗脱份,得到标题化合物(27mg,49%)。
HPLC-MS(方法6):Rt=6.55min
MS(ESI正):m/z=289(M+H)+
实施例44
实施例44类似于实施例12使用MeOH作为溶剂由实施例3p(92mg,0.210mmol)来制备。倾析溶液,将残留沉淀溶解于MeOH中且用乙醚再进行沉淀。过滤沉淀且干燥,得到标题化合物(61mg,89%)。
HPLC-MS(方法7):Rt=4.45min
MS(APCI):m/z=290(M+H)+
实施例45
实施例45类似于实施例39使用MeOH(1mL)及乙醚(8mL)作为溶剂由实施例23c(220mg,0.552mmol)来制备。蒸发混合物且使残余物分配于水与DCM之间。蒸发水层得到标题化合物(50mg,27%)。
HPLC-MS(方法11):Rt=1.48min
MS(ESI正):m/z=297(M+H)+
实施例46
实施例46类似于实施例39使用MeOH(1mL)及乙醚(8mL)作为溶剂由实施例29a(115mg,0.298mmol)来制备。蒸发混合物且使残余物分配于水与DCM之间。蒸发水层,将所得残余物再溶解于MeOH中且经SCX筒纯化且用甲醇氨溶液洗脱,得到标题化合物(33mg,82%)。
HPLC-MS(方法8):Rt=1.82min
MS(APCI):m/z=286(M+H)+
实施例47
使实施例3v(13g,33.37mmol)悬浮于MeOH/水1:1(35mL/35mL)中,分成相等的7批且在微波辐射(150℃)下加热70min。减压移除溶剂,得到残余物,其通过快速色谱(洗脱剂100%DCM至93:7:0.7DCM/MeOH/NH3)纯化,得到标题化合物(7g,72%)。
UPLC-MS(方法2):Rt=0.68min
MS(ESI正):m/z=290(M+H)+
以下实施例类似于实施例47的制备来合成:
实施例50
实施例50如实施例47所述经SCX筒纯化反应残余物由实施例9c(30mg,0.062mmol)来制备,用MeOH及DCM洗涤,且接着用NH3的MeOH溶液洗脱,得到标题化合物(22mg,95%)。
HPLC-MS(方法10):Rt=3.63min
MS(ESI正):m/z=375(M+H)+
以下实施例类似于实施例50的制备来合成:
实施例52
使实施例5h(200mg,0.451mmol)悬浮于MeOH(1mL)中及水(1.5mL)且在微波辐射(150℃)下加热混合物50min,且接着再加热一小时。减压移除挥发物,得到残余物,其通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。碱化水层且用DCM萃取。蒸发分离的有机层,得到标题化合物(95mg,61%)。
HPLC-MS(方法11):Rt=2.33min
MS(ESI正):m/z=344(M+H)+
实施例53
将实施例3c(95mg,0.208mmol)溶解于无水DCM(1mL)中,冷却至0℃且接着添加2M氯化氢的乙醚溶液(1mL,2mmol)。在室温下持续搅拌5h,使得形成沉淀。倾析溶液且将残留沉淀溶解于MeOH中且加载于SCX筒上。减压蒸发用甲醇氨溶液洗脱时获得的洗脱份,得到标题化合物(64mg,86%)。
HPLC-MS(方法10):Rt=3.51min
MS(ESI正):m/z=360(M+H)+
以下实施例类似于实施例53的制备来合成:
实施例56
实施例56类似于实施例53由实施例5f(158mg,0.371mmol)来制备。用NH3的MeOH溶液碱化反应混合物且通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份且用NaHCO3饱和溶液碱化。移除溶剂且将残余物加载于SCX筒上。减压蒸发用甲醇氨溶液洗脱时获得的洗脱份,得到标题化合物(38mg,31%)。
HPLC-MS(方法8):Rt=2.80min
MS(APCI):m/z=326(M+H)+
实施例57
实施例57类似于实施例53由实施例15c(94mg,含量83%,0.197mmol)来制备。用NH3的MeOH溶液碱化反应混合物且通过制备型HPLC(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份且用NH3的MeOH溶液碱化,接着通过快速色谱(洗脱剂95:5:0.5DCM/MeOH/NH4OH)纯化,得到标题化合物(15mg,24%)。
HPLC-MS(方法8):Rt=2.19min
MS(APCI):m/z=316(M+H)+
以下实施例类似于实施例57的制备来合成:
实施例59
将4M氯化氢的二烷溶液(3mL,12mmol)添加至实施例3r(30mg,0.080mmol)中且持续搅拌3h。蒸发溶剂且减压干燥残余物,得到标题化合物(10mg,40%)。
HPLC-MS(方法8):Rt=2.50min
MS(APCI):m/z=275(M+H)+
以下实施例类似于实施例59的制备来合成:
实施例63
将实施例3w(25.9g,58.4mmol)分成相等的4份,且将每一份溶解于MeOH(6.5mL)中,冷却至0℃且用2M氯化氢的乙醚溶液(37mL,73mmol)处理。持续搅拌隔夜。减压移除挥发物且将残余物再溶解于MeOH中,经SCX筒纯化,用DCM/MeOH1:1洗涤且用2N甲醇氨溶液洗脱且合并,得到标题化合物(20.05g,100%)。
HPLC-MS(方法10):Rt=3.09min
MS(ESI正):m/z=344(M+H)+
实施例64
实施例64类似于实施例59由实施例5l(90mg,0.195mmol)来制备。在挥发物蒸发之后,残余物通过制备型HPLC(固定相:SunfireC18ODB5μm19x100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。碱化水层且用DCM萃取。蒸发分离的有机层,得到标题化合物(35mg,57%)。
HPLC-MS(方法10):Rt=3.28min
MS(ESI正):m/z=316(M+H)+
以下实施例类似于实施例64的制备来合成:
以下实施例类似于实施例47的制备来合成:
实施例67
将实施例5d(20mg,含量98%,0.05mmol)溶解于MeOH(0.5mL)中,冷却至0℃,且接着逐滴添加2M氯化氢的乙醚溶液(1mL,2mmol)。在室温下持续搅拌1h。逐滴添加2M氯化氢的乙醚溶液(1mL,2mmol)且在室温下进一步持续搅拌2h。减压蒸发挥发物,得到标题化合物(16mg,97%)。
HPLC-MS(方法8):Rt=1.78min
MS(APCI):m/z=291(M+H)+
实施例68
实施例68如实施例67所述使用乙醚作为溶剂由实施例23a(105mg,0.273mmol)来制备。过滤反应期间形成的沉淀且用乙醚洗涤且干燥。接着将残余物溶解于水中且用DCM洗涤。冻干水层得到标题化合物(55mg,63%)。
HPLC-MS(方法12):Rt=0.27min
MS(ESI正):m/z=285(M+H)+
实施例69
实施例69如实施例67所述使用MeOH作为溶剂(1mL)由实施例23d(25mg,0.065mmol)来制备。蒸发挥发物,接着将残余物溶解于水中且用DCM洗涤。冻干水层得到标题化合物(16mg,78%)。
HPLC-MS(方法12):Rt=0.25min
MS(ESI正):m/z=286(M+H)+
实施例70
将实施例15a(105mg,0.253mmol)溶解于DCM(2mL)中且添加4M氯化氢的二烷溶液(1.2mL,0.506mmol)且持续搅拌隔夜。减压移除挥发物,得到残余物,其通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%)纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。用10%NaOH碱化水层且用DCM萃取。减压蒸发分离的有机层。将所得残余物溶解于EtOH中且添加4M氯化氢的二烷溶液(0.200mL)。减压蒸发挥发物,得到标题化合物(53mg,59%)。
HPLC-MS(方法8):Rt=3.27min
MS(APCI):m/z=315(M+H)+
实施例71
将TEA(0.144mL,1.041mmol)及碘甲烷(0.032mL,0.521mmol)添加至溶解于DMF中的实施例40(110mg,0.347mmol)中且持续搅拌2天。
用水及乙醚稀释反应混合物。干燥分离的有机层且减压蒸发,得到残余物,其通过快速色谱(洗脱剂98:2:0.2至80:20:2DCM/MeOH/NH4OH)纯化。将所得残余物溶解于EtOH中且用4MHCl的二烷溶液处理。减压蒸发挥发物,得到标题化合物(23mg,22%)。
HPLC-MS(方法7):Rt=6.04min
MS(APCI):m/z=303(M+H)+
实施例72
将乙酸(104μL,1.734mmol)及丙酮(51μL,0.694mmol)添加至溶解于DMF(2mL)中的实施例40(100mg,0.347)中。在1h之后,将三乙酰氧基硼氢化钠(147mg,0.694mmol)添加至混合物中且搅拌隔夜。用水稀释反应混合物且用乙醚萃取。减压移除挥发物且通过制备型HPLC(固定相:SunfireC18ODB5μm19×100mm;流动相:ACN/H2O+CF3COOH0.05%),接着通过制备型HPLC(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化残余物。合并含有标题化合物的洗脱份且减压蒸发。将所得残余物溶解于DCM中且用水洗涤。减压移除挥发物且通过快速色谱(洗脱剂98:2:0.2至90:10:1DCM/MeOH/NH4OH)纯化残余物。将残余物溶解于MeOH中且用4MHCl的二烷溶液处理。减压蒸发挥发物,得到标题化合物(22mg,17%)。
HPLC-MS(方法7):Rt=5.97min
MS(APCI):m/z=331(M+H)+
以下实施例类似于实施例47的制备来合成:
实施例74
将4M氯化氢的二烷溶液(2mL,8.0mmol)添加至实施例9n(80mg,含量22%,0.042mmol)中且持续搅拌5h。反应混合物通过添加甲醇氨溶液碱化,添加水及DCM,分离有机层,通过相分离筒干燥且蒸发溶剂,得到残余物,其通过制备型HPLC(固定相:XTerraC18OBD5μm30×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。用DCM萃取水层,分离且蒸发DCM,得到标题化合物(12mg,90%)。
HPLC-MS(方法7a):Rt=2.75min
MS(APCI):m/z=317(M+H)+
以下实施例类似于实施例74的制备来合成:
以下实施例类似于实施例50的制备来合成:
实施例78
实施例78如实施例50所述通过快速色谱(洗脱剂95:5:0.5DCM/MeOH/NH4OH)纯化来自SCX筒的残余物由实施例9r(120mg,含量98%,0.29mmol)来制备,得到标题化合物(81mg,91%)。
HPLC-MS(方法11):Rt=2.19min
MS(ESI正):m/z=311(M+H)+
以下实施例类似于实施例50的制备来合成:
以下实施例类似于实施例32的制备来合成:
实施例82
将实施例9v(65mg,含量98%,0.148mmol)溶解于MeOH中且添加钯(16mg,0.015mmol)。在1巴下氢化混合物2h。通过过滤移除催化剂且用MeOH洗涤。减压蒸发所得溶液,得到残余物,其通过快速色谱(洗脱剂0-4%MeOH+1%NH4OH/DCM)纯化,得到标题化合物(28mg,64%)。
HPLC-MS(方法12):Rt=2.16min
MS(ESI正):m/z=298(M+H)+
以下实施例类似于实施例50的制备来合成:
以下实施例类似于实施例47的制备来合成:
以下实施例类似于实施例50的制备来合成:
以下实施例类似于实施例32的制备来合成:
以下实施例类似于实施例12的制备来合成:
以下实施例类似于实施例50的制备来合成:
以下实施例类似于实施例47的制备来合成:
以下实施例类似于实施例32的制备来合成:
以下实施例类似于实施例50的制备来合成:
实施例100
将三氟甲磺酸叔丁基二甲基硅烷酯(162μL,0.71mmol)添加至含实施例9ab(92mg,0.23mmol)及2,6-二甲基吡啶(108μL,0.92mmol)的DCM(2.8mL)。在2h之后,用饱和氯化铵及盐水洗涤反应混合物。分离有机层且用相分离筒干燥,且真空蒸发,获得残余物,在-30℃下溶解于THF(1mL)中且用氟化四丁基铵(1.0MTHF溶液,87μL,0.087mmol)处理。在-30℃下搅拌30min之后,减压蒸发挥发物且通过快速色谱(洗脱剂0-10%MeOH+1%NH4OH/DCM)纯化所得残余物。合并含有标题化合物的洗脱份且经SCX筒进一步纯化,用MeOH洗涤且用甲醇氨溶液洗脱。减压移除挥发物,得到标题化合物(21mg,30%)。
UPLC-MS(方法11):Rt=1.67
MS(ESI正):m/z=299(M+H)+
以下实施例类似于实施例47的制备来合成:
以下实施例类似于实施例50的制备来合成:
以下实施例类似于实施例78的制备来合成:
实施例105
将4M氯化氢的二烷溶液(15mL,60mmol)添加至含实施例45a(2.45g,5.88mmol)的MeOH(5mL)中且持续搅拌5h。反应混合物通过添加甲醇氨溶液(7N)碱化。通过过滤移除固体且用DCM洗涤。蒸发挥发物得到残余物,用乙醚湿磨,得到标题化合物(1.60g,86%)。
HPLC-MS(方法7a):Rt=3.06min
MS(APCI):m/z=317(M+H)+
实施例106
将4M氯化氢的二烷溶液(3mL,12mmol)添加至含实施例45b(220mg,0.51mmol)的MeOH(5mL)中且持续搅拌4h。反应混合物通过添加甲醇氨溶液(7N)碱化。通过过滤移除固体且用DCM洗涤。蒸发挥发物,得到残余物,其通过快速色谱(10/1/90MeOH/NH4OH/DCM)、之后通过制备型HPLC(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4HCO35mM)纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。用DCM萃取水层,分离且蒸发DCM,得到标题化合物(30mg,18%)。
HPLC-MS(方法11):Rt=2.38min
MS(ESI正):m/z=333(M+H)+
以下实施例类似于实施例50的制备来合成:
实施例109
将4M氯化氢的二烷溶液(2mL,8mmol)添加至实施例45e(40mg,0.10mmol)中且持续搅拌4h。反应混合物通过添加氢氧化铵碱化。用DCM稀释反应混合物。分离有机层,减压蒸发挥发物,得到残余物,其通过制备型HPLC(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4COOH5mM)纯化。合并含有标题化合物的洗脱份且减压蒸发ACN。用DCM萃取水层,分离且蒸发DCM,得到残余物,其通过快速色谱(10/1/90MeOH/NH4OH/DCM)纯化,得到标题化合物(10mg,33%)。
HPLC-MS(方法7a):Rt=2.41min
MS(APCI):m/z=303(M+H)+
以下实施例类似于实施例47的制备来合成:
实施例111(立体异构体的混合物)
将4M氯化氢的二烷溶液(3mL,12mmol)添加至含实施例48a(220mg,0.51mmol)的DCM(2mL)中且持续搅拌4h。反应混合物通过添加NH4OH(30%)碱化。用DCM稀释反应混合物。分离有机层,用盐水洗涤,减压蒸发挥发物,得到残余物,用乙醚湿磨,得到标题化合物(100mg,56%)。
HPLC-MS(方法10):Rt=2.88min
MS(ESI正):m/z=285(M+H)+
以下实施例类似于实施例111的制备来合成:
以下实施例类似于实施例50的制备来合成:
实施例120
使实施例23e(35mg,0.08mmol)悬浮于4MHCl的二烷溶液(2ML)中且搅拌1小时。移除溶剂,将残余物再溶解于水中,用DCM洗涤且蒸发水相,得到标题化合物(29mg,98%)。
HPLC-MS(方法11):Rt=2.04min
MS(ESI负):m/z=323[M-H]-
以下实施例类似于实施例120的制备来合成:
实施例132
使实施例23j(26mg,0.06mmol)悬浮于2MHCl的乙醚溶液(1mL)中且搅拌1小时。真空移除溶剂得到标题化合物(22mg,100%)。
HPLC-MS(方法10):Rt=2.63min
MS(ESI正):m/z=310[M+H]+
以下实施例类似于实施例132的制备来合成:
实施例138
使实施例58a(100mg,0.24mmol)悬浮于DCM(5mL)中且添加TFA(0.5mL)。搅拌混合物30分钟且真空移除溶剂。将残余物加载于SCX筒上,用甲醇洗涤且用7M氨的甲醇溶液洗脱。真空移除溶剂,得到标题化合物(72mg,95%)。
HPLC-MS(方法11):Rt=2.05min
MS(ESI正):m/z=311[M+H]+
以下实施例类似于实施例138的制备来合成:
实施例167
将2,6-二甲基吡啶(212mg,1.98mmol)及三氟甲磺酸叔丁基二甲基硅烷酯(290mg,1.1mmol)添加至悬浮于无水DCM(7mL)中的实施例77a(85mg)中且搅拌混合物15分钟。用水洗涤溶液,干燥且移除溶剂。使残余物悬浮于无水THF(5mL)中且添加氟化四丁基铵(1MTHF溶液,220μL,0.22mmol)且搅拌混合物15分钟。蒸发溶剂,使混合物分配于水与DCM之间,分离各相,使有机相干燥且移除溶剂。通过制备型HPLC纯化产物得到标题化合物(28mg)。
HPLC-MS(方法7a):Rt=2.70min
MS(ESI正):m/z=285[M+H]+
实施例168
使实施例167(148mg)悬浮于乙醇(25mL)中且在3.5巴下使用10%钯/活性碳作为催化剂氢化隔夜。混合物经由硅藻土过滤且移除溶剂。残余物通过快速色谱(洗脱剂DCM/MeOH/NH4OH90:10:1)纯化得到标题化合物(88mg)。
HPLC-MS(方法11):Rt=1.71min
MS(ESI正):m/z=289[M+H]+
实施例169
在0℃下逐份添加N,N′-二环己基碳二亚胺(1.75g,8.5mmol)至含4-氯-邻苯二胺(1.21g,8.5mmol)及3-叔丁氧羰基氨基-四氢-呋喃-3-甲酸(1.97g,8.5mmol)的THF(50mL)中。在室温下搅拌隔夜之后,过滤反应混合物且减压蒸发,得到残余物,其通过快速色谱(洗脱剂0-5%EtOH/DCM)纯化,得到[3-(5-氯-1H-苯并咪唑-2-基)-四氢-呋喃-3-基]-氨基甲酸叔丁酯(2.35g,78%)。
[将3-(5-氯-1H-苯并咪唑-2-基)-四氢-呋喃-3-基]-氨基甲酸叔丁酯(2.09g,6.19mmol)溶解于DCM(100mL)中且用TFA(10mL)处理。持续搅拌2h。减压蒸发挥发物且用乙醚溶解所得残余物并减压蒸发两次,得到呈三氟乙酸盐粗物质形式的3-(5-氯-1H-苯并咪唑-2-基)-四氢-呋喃-3-基胺(2.2g)。
将内消旋-(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(43mg,0.19mmol)溶解于DMF(1mL)中且添加HATU(143mg,0.38mmol)及DIPEA(146μl,0.85mmol)。在搅拌15分钟之后,添加呈三氟乙酸盐粗物质形式的3-(5-氯-1H-苯并咪唑-2-基)-四氢-呋喃-3-基胺(60mg,0.17mmol)且在室温下持续搅拌隔夜。反应混合物通过制备型HPLC(固定相:XbridgeC185μm19×100mm;流动相:ACN/H2O+NH4HCO35mM)纯化。合并含有内消旋-(1R,5S,6r)-6-[3-(6-氯-1H-苯并咪唑-2-基)-四氢-呋喃-3-基胺甲酰基]-3-氮杂-双环[3.1.0]己烷-3-甲酸叔丁酯的洗脱份且冻干。用HCl的二烷溶液(4M,0.43mL,1.71mmol)处理含残余物的二烷(1mL)。在室温下搅拌隔夜之后,减压蒸发挥发物且将所得残余物溶解于ACN/H2O1:1中且冻干,得到标题化合物(40mg,61%)。
UPLC-MS(方法3):Rt=0.77min
MS(ESI正):m/z=347(M+H)+
以下实施例类似于实施例50的制备来合成:
以下实施例类似于实施例100的制备来合成:
以下实施例类似于实施例50的制备来合成:
实施例176
将实施例49(61mg,含量93%,0.19mmol)溶解于乙酸(3mL)中且添加水合氧化铂(IV)(25mg,0.10mmol)。在3巴下氢化混合物3h。反应混合物经SCX筒纯化,用MeOH洗涤且用甲醇氨溶液洗脱。减压移除挥发物,得到残余物,其通过快速色谱(洗脱剂0-10%MeOH+1%NH4OH/DCM)纯化,得到标题化合物(44mg,77%)。
HPLC-MS(方法11):Rt=1.73min
MS(ESI正):m/z=303(M+H)+
以下实施例类似于实施例50的制备来合成:
以下实施例类似于实施例138的制备来合成:
cAMP分析
人类生长抑制素4受体的cAMP分析的方法描述
SSTR4受体(Gi偶合)的活化致使在用弗斯可林(Forskolin)刺激之后细胞内cAMP得以抑制,其可使用适合分析试剂盒及适当培养盘读取器来计量。此技术用以使用表达hSSTR4的H4细胞表征SSTR4受体激动剂的药理学效应。
描述:
将化合物溶解且稀释于DMSO中。最终测试溶液含有1%DMSO。用含有1%DMSO的分析缓冲液(具有0.1%BSA、5mMHEPES、0.5MIBMX的HBSS,pH7.4)制备cAMP标准物(LancecAMP384试剂盒;PerkinElmer,目录号AD0264),且cAMP标准曲线至少包括在一个培养盘上。
使细胞离心且悬浮于分析缓冲液(包括1:100稀释的Alexa抗体)中。
对于分析而言,将5μl细胞悬浮液(约5000个细胞/孔)(包括Alexa抗体(1:100稀释))添加至384孔MTP微量滴定盘中,其中一个列或行(视培养盘布局而定)除外,保留其供标准曲线用。接着添加2μl化合物样品作为浓度反应曲线(例如1e-5M至6e-10M),通常一式三份。各分析含有用媒剂对照替代化合物作为非抑制性cAMP产生的对照进行培育(100%CTL;‘高值’)及用1μM生长抑制素作为完全抑制及背景的对照进行培育(0%CTL;‘低值’)。在约10至15min培育时间之后,添加3μl弗斯可林(溶解于DMSO中,最终浓度15μM)。接着简短震荡培养盘且在室温下培育60min。在60min之后,将10μl检测混合物添加至所有孔中,之后再培育1h的时间。用适合培养盘读取器读取培养盘。
数据分析为基于供体及受体荧光团的时差式荧光测量的“比率”(激发波长:320nm;发射波长1:665nm;发射波长2:615nm;比率665/615)。由此比率,由标准曲线来计算cAMP浓度且通过最小平方曲线拟合程序估算EC50。
放射性配位体结合分析
使用表达重组体人类SSTR1或人类SSTR2或人类SSTR3或人类SSTR4或人类SSTR5的CHO细胞膜的人类生长抑制素受体的结合分析的方法描述。
受体结合分析是指经标记的受体配位体用以检测与受体的结合的技术。在竞争实验中,未经标记的测试化合物与经标记配位体的结合侧竞争。用测试化合物替换经标记配位体会产生减弱的信号。
操作:
对于结合实验而言,使用200μL来自以下量的一种蛋白质的膜匀浆:hSSTR1(40μg/孔);hSSTR2(25μg/孔);hSSTR3(1.5μg/孔);hSSTR4(0.5μg/孔);hSSTR5(25μg/孔)。在室温下除浓度递增的测试化合物或媒剂(100%结合)外用0.05nM放射性配位体([3-125I-Tyr]-生长抑制素-(1-14))培育该匀浆180min,其中使用Hepes缓冲液(10mM,EDTA1mM、MgCl25mM、pH7.6、BSA0.5%、杆菌肽0.003%、DMSO1%)使总体积达250μL。使用细胞收集器与冰冷NaCl0.9%一起经由经聚乙烯亚胺处理(0.3%)的GF/B玻璃纤维过滤器过滤使培育终止。用适合读取器测量蛋白质结合放射性。将非特异性结合定义为在培育期期间在1μM生长抑制素-14存在下结合的放射性。
通过计算机辅助的非线性最小平方曲线拟合法使用一个受体结合位点的模型进行浓度-结合曲线的分析。
代谢稳定性
本发明化合物的代谢稳定性可如下进行研究:
在37℃下用汇集的人类肝微粒体分析测试化合物的代谢降解。每时间点100μl的最终培育体积含有TRIS缓冲液(在室温下为pH7.6)(0.1M)、氯化镁(5mM)、微粒体蛋白质(1mg/mL)及最终浓度为1μM的测试化合物。在37℃下短预培育期之后,通过添加还原形式的β-烟酰胺腺嘌呤二核苷酸磷酸酯(NADPH,1mM)引发反应,且通过在不同时间点之后将等分试样转移至溶剂中而终止。在离心(10000g,5min)之后,通过LC-MS/MS分析上清液的等分试样中本发明化合物的量。通过浓度-时间分布概况的半对数图的斜率来确定半衰期。
生物活性
由表2中的数据表明上文所述实施例的激动活性。借助于上文所述cAMPASSAY获得EC50值。
表2:本发明化合物的激动活性
选择性
借助于上文所述的放射性配位体结合分析获得选择性数据。
表3:本发明化合物对SSTR4的选择性优于其他SSTR
稳定性
由上文所述的实验操作获得稳定性数据。
表4:人类肝微粒体中本发明化合物的稳定性
Claims (17)
1.一种式(I)化合物,
其中
A选自由以下组成的组:
H及C1-6烷基;
R1及R2独立地选自由H、C1-6烷基及C3-6环烷基组成的组,其中R1或R2中的至少一项为C1-6烷基或C3-6环烷基,
其中该C1-6烷基或该C3-6环烷基任选经卤素或甲氧基取代,或
其中R1及R2一起形成任选经卤素取代的2至5元亚烷基桥,其并入有0至2个独立地选自由N、O或S组成的组的杂原子;
W选自由以下组成的组:单或双环芳基、单或双环杂芳基、单或双环杂环基及单或双环环烷基,
其中所述各环系统任选经一或多个R3取代,且
其中该杂芳基包含至多4个杂原子及一或两个5或6元环;
R3独立地选自由以下组成的组:C1-6烷基、C3-8环烷基、C1-6烷基-O-、苄基、卤素、HO-、NC-、单或双环杂芳基及含有一个选自由N、O或S(O)r组成的组的杂原子的5或6元单环杂环基,其中该杂芳基含有至多4个杂原子及一或两个5或6元环,且r为0、1或2,
其中该C1-6烷基、C3-8环烷基、C1-6烷基-O-、苄基、杂芳基及该杂环基任选经卤素、HO-、乙酰基、C1-6烷基-O-、氧代基、R4-S(O)2-取代,其中R4为芳基、C3-6环烷基和/或C1-6烷基;
Y选自由以下组成的组:键、-CH2-、-CH2CH2-及-CH2O-;
或任一以上化合物的盐。
2.如权利要求1的化合物,其中
A为H。
3.如权利要求1或2的化合物,其中
W选自由以下组成的组:单或双环芳基、单或双环杂芳基及单或双环杂环基,
其中所述各环系统任选经一或多个R3取代,且其中该杂芳基包含至多4个杂原子及一或两个5或6元环。
4.如权利要求1或2的化合物,其中
W选自由以下组成的组:
其中所述各环系统任选经一或多个R3取代。
5.如权利要求1或2的化合物,其中
W选自由以下组成的组:
其中所述各环系统任选经一或多个R3取代。
6.如权利要求1或2的化合物,其中
W选自由以下组成的组:
其中所述各环系统任选经一或多个R3取代。
7.如权利要求1至6中任一项的化合物,其中
R3选自由以下组成的组:
C1-3烷基、C3-6环烷基、C1-3烷基-O-、卤素、NC-,
其中,若R3连接至W的N原子,则R3选自由C1-3烷基及C3-6环烷基组成的组,
其中该C1-3烷基、C3-6环烷基及该C1-3烷基-O-取代基任选经卤素取代。
8.如权利要求1至6中任一项的化合物,其中
R3选自由以下组成的组:
H3C-、F-及F3C-,
其中若R3连接至W的N原子,则R3为H3C-。
9.如权利要求1至8中任一项或多项的化合物,其中
R1及R2独立地选自由H及任选经卤素取代的C1-3烷基组成的组,其中R1或R2中的至少一项独立地为任选经卤素取代的C1-3烷基,或其中R1及R2一起形成任选经卤素取代的2至5元亚烷基桥,其并入有0至2个独立地选自由N、O或S组成的组的杂原子。
10.如权利要求1至8的化合物,其中
R1与R2皆为H3C-。
11.如权利要求1至10中任一项或多项的化合物,其中
Y选自由以下组成的组:
键、-CH2CH2-及-CH2O-。
12.如权利要求1至10中任一项或多项的化合物,其中
Y选自由以下组成的组:
键及-CH2O-。
13.如权利要求1的化合物,其中该化合物选自由以下组成的组:
或任一以上化合物的盐。
14.如权利要求1至13中任一项或多项的化合物或其药学上可接受的盐,其用作药物。
15.一种药物组合物,其含有至少一种如权利要求1至13中一项或多项的化合物或其药学上可接受的盐以及一或多种药学上可接受的载剂。
16.如权利要求1至13中一项或多项的化合物或其药学上可接受的盐或如权利要求15的药物组合物,其用于治疗或预防可受SSTR4活化影响的疾病或症状。
17.如权利要求1至13中一项或多项的化合物或其药学上可接受的盐或如权利要求15的药物组合物,其用于治疗和/或预防疼痛。
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WO2021233427A1 (zh) | 2020-05-21 | 2021-11-25 | 广州费米子科技有限责任公司 | 并环化合物及其制备方法、药物组合物和应用 |
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CN113717161B (zh) * | 2020-05-21 | 2023-06-09 | 广州费米子科技有限责任公司 | 含氮饱和杂环化合物及其制备方法、药物组合物和应用 |
CN113929693A (zh) * | 2020-07-13 | 2022-01-14 | 广州费米子科技有限责任公司 | 含氮杂环化合物、药物组合物和应用 |
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