CN110869017A - 细胞凋亡信号调节激酶1抑制剂及其使用方法 - Google Patents
细胞凋亡信号调节激酶1抑制剂及其使用方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
本发明公开一种式(I)的化合物或其药学上可接受的盐类、酯类、立体异构体、互变异构体、溶剂化物、水合物或它们的组合:
Description
相关申请
本申请主张于2017年5月12日提交的美国专利临时申请案申请号为62/505,202的优先权以及于2017年6月22日提交的美国专利临时申请案申请号为62/523,472的优先权以及于2017年8月28日提交的美国专利临时申请案申请号为62/550,960的优先权,上述申请的全部内容均通过引用并入本文作为参考。
技术领域
本发明是有关于一种作为ASK-1抑制剂的化合物和药物组合物。具体地,本发明特别是有关于一种作为ASK-1抑制剂的化合物及其制备和使用方法。
背景技术
细胞凋亡信号调节激酶1(ASK-1)是促***原活化蛋白激酶激酶(MAPKKK,MAP3K)家族的成员,活化后会磷酸化下游MAP激酶激酶(MAPKK,MAP2K),进而活化MAP激酶(MAPK)。MAPKs通过磷酸化细胞底物引发反应,从而调节最终控制基因表达的转录因子的活性。具体而言,ASK-1也被称为MAPKKK5,磷酸化MAPKK4/MAPKK7或MAPKK3/MAPKK6,随后分别磷酸化并活化c-Jun N末端蛋白激酶(JNK)和p38 MAPKs(H.Ichijo等人,细胞通讯信号,2009年,7,1-10;K.Takeda等人,毒物药理学修订版期刊,2008年,48,199-225;H.Nagai等人,生化分子生物学期刊,2007年,第40页,1-6)。JNK和p38的活化途径触发下游应激反应,例如细胞凋亡、炎症或分化(H.Ichijo等,Science 1997,275,90-94;K.Takeda等,J.Biol)。化学。2000、275、9805-9813;K.Tobiume等人,欧洲分子生物学会报告,2001年,222-228;K.Sayama等人,生化学期刊,2001年,276,999-1004)。
ASK-1的活性受硫氧还原蛋白(Trx)的调控,硫氧还原蛋白与ASK-1的N末端结合(M.Saitoh等人,欧洲分子生物学会报告,1998年,17,2596-2606)。对应于氧化刺激、脂多醣(LPS)、活性氧(ROS)、内质网(ER)刺激、细胞钙离子浓度增加、Fas配体和各种环境刺激、以及各种细胞因子,如肿瘤坏死因子(TNF),ASK-1在Thr838处在自动磷酸化作用之后被激活(H.Nishitoh等人,基因发展期刊,2002年,16,1345-1355;K.Takeda等人,欧洲分子生物学会报告,2004年5,161-166;A.Matsuzawa等人,国家免疫学期刊,2005年,6,587-592)。
ASK-1与自身免疫性疾病、神经退化性疾病、炎性疾病、慢性肾脏疾病、心血管疾病、新陈代谢疾病以及急性和慢性肝病相关(R.Hayakawa等人,日本制药期刊,B,2012年,88,434-453)。
更具体地说,ASK-1与肝脂肪变性相关,包括非酒精性脂肪肝疾病(NAFLD)和非酒精性脂肪性肝炎(NASH)。在小鼠模型中,高脂肪饮食引起肝脂肪变性,最终导致脂肪堆积和脂肪酸氧化。这导致ROS的产生,其引起肝细胞功能障碍和死亡(S.K.Mantena等人,自由基生物学与医学期刊,2008,44,1259-1272,S.K.Mantena等人,生物化学期刊,2009,417,183-193)。此外,肿瘤坏死因子对于通过ASK-1-JNK途径对肝细胞凋亡至关重要,肿瘤坏死因子缺乏小鼠表现出的肝脂肪变性和肝纤维化程度降低(W.Zhang等人,生物化学生理学研究社群,2010年,391,1731-1736)。
在以下出版物中公开了作为ASK-1抑制剂的小分子化合物:WO2008/016131、WO2009/027283、WO 2009/0318425、WO 2009/123986、US2009/0318425、WO 2011/041293、WO2011/097079、US 2011/0009410、GP Volynets等人,化学医学杂志,2011年,54,2680-2686、WO 2012/003387、WO 2012/011548、WO 2012/080735、Y.Terao等人,生物有机化学与医药化学通讯,2012年,22,7326-7329、WO 2013/112741、G.P.Volynets等人,欧洲医药化学杂志,2013年,16,104-115、US 2014/0018370、WO 2014/100541、WO 2015/095059、WO 2016/049069、WO 2016/049070。
故,有必要提供一种用于治疗和预防疾病的ASK-1抑制剂。本发明已经鉴定出抑制ASK-1的化合物以及使用这些化合物治疗疾病的方法。
发明内容
本发明是有关于一种作为ASK-1抑制剂的化合物和药物组合物。具体地,本发明特别是有关于一种作为ASK-1抑制剂的化合物及其制备和使用方法。另外,本发明包括制备所述化合物的方法。
在本发明的主要方面,本发明提供一种具有式(I)的化合物或其药学上可接受的盐类或酯类:
X1、X2和X3各自独立地选自N或C(R5);
R3、R4和R5各自独立地选自:
1)氢;
2)卤素;
3)-NO2;
4)氰基;
5)任选取代的C1-C8烷基;
6)任选取代的C3-C8环烷基;
7)任选取代的3至8元杂环烷基;以及
8)任选取代的C1-C8烷氧基;
R选自:
每个***或咪唑环任选被进一步取代;
R1选自由以下所组成的群组:
1)氢;
2)任选取代的C1-C8烷基;
3)任选取代的C2-C8烯基;
4)任选取代的C2-C8炔基;
5)任选取代的C3-C8环烷基;
6)任选取代的芳基;
7)任选取代的芳烷基;
8)任选取代的3至8元杂环烷基;
9)任选取代的杂芳基;
10)任选取代的杂芳基烷基;以及
11)-N(R6)(R7);
其中R6和R7独立地选自氢、优选为C1-C8烷基的C1-C15烷基、环烷基、杂环烷基、芳基和杂芳基所组成的群组,其中每个烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1至3个独立选自卤素、烷基、烷基氨基、二烷基氨基、烷基C(O)NH-、芳基C(O)NH-、杂芳基C(O)-NH、-CN、烷氧基、-CF3、芳基以及杂芳基的取代基所取代,或者,R7和R8与它们所连接的氮一起被形成杂环;
R2选自由以下所组成的群组:
1)氢;
2)卤素;
3)-NO2;
4)氰基;
5)任选取代的C1-C8烷基;
6)任选取代的C2-C8烯基;
7)任选取代的C2-C8炔基;
8)任选取代的C3-C8环烷基;
9)任选取代的芳基;
10)任选取代的芳烷基;
11)任选取代的3至8元杂环烷基;
12)任选取代的杂芳基;
13)任选取代的杂芳基烷基;
14)-N(R6)(R7);
15)-S(O)2N(R6)(R7);
16)-N(R6)C(O)(R7);以及
17)-N(R6)S(O)2(R7);
其中R6和R7如先前所定义。
在另一个实施例中,本发明提供了药物组合物,其包含治疗有效剂量的本发明的化合物或化合物的组合,或药学上可接受的盐类形式、立体异构体、溶剂化物、水合物或其组合,以及药学上可接受的载体或赋形剂。
在另一个实施例中,本发明提供了用于预防或治疗ASK-1调节的疾病或病症的方法。所述方法包括给予治疗有效剂量的式(I)化合物。本发明还提供了式(I)的化合物在制备用于预防或治疗ASK-1调节的疾病或病症的药物中的用途。这样的疾病包括自身免疫性疾病、神经退化性疾病、炎性疾病、慢性肾脏疾病、心血管疾病、代谢异常以及急性和慢性肝病。
具体实施方式
本发明的第一实施例是如上所述的由式(I)表示的化合物或其药学上可接受的盐类或酯类。
其中这些基团中的每一个在可能的情况下任选地被取代,并且R5和R4中的每一个如先前所定义。
在某些实施例中,本发明涉及式(I)的化合物及其药学上可接受的盐类和酯类,其中X1为-N-、-C(F)或-C(OMe)-。
在某些实施例中,本发明涉及式(I)的化合物及其药学上可接受的盐类和酯类,其中R1选自由以下所组成的群组:
其中这些基团中的每一个任选地被取代。
在某些实施例中,本发明涉及式(I)的化合物及其药学上可接受的盐类和酯类,其中R2选自由以下所组成的群组:
其中这些基团中的每一个任选地被取代。
在某些实施例中,本发明涉及式(I)的化合物及其药学上可接受的盐类和酯类,其中R3选自由以下所组成的群组:
其中上述多个基团中的每一个任选地被取代。
在一实施例中,本发明涉及式(Ia)、(Ib)、(Ic)或(Id)的化合物或一其药学上可接受的盐类或酯类:
在一实施例中,本发明提供式(IIa)或(IIb)的化合物或一其药学上可接受的盐类或酯类:
在一个实施例中,本发明提供由式(IIa-1)至式(IIa-4)和式(IIb-1)至式(IIb-4)之一表示的化合物,或其药学上可接受的盐类或酯类:
其中,R1、R2、R3以及X1如前所定义。
在一个实施例中,本发明提供由式(IIIa)或式(IIIb)表示的化合物,或其药学上可接受的盐类或酯类:
在一个实施例中,本发明提供由式(IIIa-1)至式(IIIa-4)和式(IIIb-1)至式(IIIb-4)之一表示的化合物,或其药学上可接受的盐类或酯类:
其中,R1、R2以及X1如前所定义。
在一个实施例中,本发明提供由式(IVa)或式(IVb)表示的化合物,或其药学上可接受的盐类或酯类:
在一个实施例中,本发明提供由式(IVa-1)至式(IVa-4)和式(IVb-1)至式(IVb-4)之一表示的化合物,或其药学上可接受的盐类或酯类:
其中,R1及R2如前所定义。
在一个实施例中,本发明提供由式(Va)或式(Vb)表示的化合物,或其药学上可接受的盐类或酯类:
在一个实施例中,本发明提供由式(Va-1)至式(Va-4)和式(Vb-1)至式(Vb-4)之一表示的化合物,或其药学上可接受的盐类或酯类:
其中,R1及R2如前所定义。
在一个实施例中,本发明提供由式(VIa)或式(VIb)表示的化合物,或其药学上可接受的盐类或酯类:
在一个实施例中,本发明提供由式(VIa-1)至式(VIa-4)和式(VIb-1)至式(VIb-4)之一表示的化合物,或其药学上可接受的盐类或酯类:
其中,R1及R2如前所定义。
表1
表2
表3
表4
表5
表6
在某些实施例中,本发明提供了用于预防或治疗ASK-1调节的疾病或病症的方法。所述方法包括给予治疗有效剂量的式(I)化合物。本发明还提供了式(I)的化合物在制备用于治疗ASK-1调节的疾病或病症的药物中的用途。
在某些实施例中,ASK-1调节的疾病或病症是自身免疫性疾病、神经退化性疾病、炎性疾病、慢性肾脏疾病、肾脏疾病、心血管疾病、代谢异常以及急性或慢性肝病。
在某些实施例中,慢性肝病是原发性胆汁性肝硬化(PBC)、脑黄瘤病(CTX)、原发性硬化性胆管炎(PSC)、药物诱发的胆汁淤积症、妊娠期肝内胆汁淤积症、肠外营养相关的胆汁淤积症(PNAC)、细菌过度生长或败血症相关的胆汁淤积症、自身免疫性肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、与移植物抗宿主病相关的肝移植、活体供体移植肝再生、先天性肝纤维化、胆总管结石症、肉芽肿性肝病、肝内或肝外恶性肿瘤、干燥综合症、结节病、威尔逊病、高雪氏病、血色病或α1-抗胰蛋白酶缺乏症。在某些实施例中,肠胃道疾病是炎性肠病(IBD)(包括克罗恩氏病和溃疡性结肠炎)、肠易激综合症(IBS)、细菌过度生长、吸收不良、放射后结肠炎或显微镜下结肠炎。
在某些实施例中,肾脏疾病是糖尿病性肾病、局灶性节段性肾小球硬化症(FSGS)、高血压性肾硬化、慢性肾小球肾炎、慢性移植性肾小球病、慢性间质性肾炎或多囊性肾病。
在某些实施例中,心血管疾病是动脉粥样硬化、动脉硬化、中风再灌注/缺血、心肌肥厚、呼吸***疾病、心脏病发作及心肌缺血。
在某些实施例中,代谢疾病是胰岛素抵抗、I型和II型糖尿病以及肥胖症。
在某些实施例中,慢性肾脏疾病是多囊肾病、肾盂肾炎、肾纤维化和肾小球肾炎。
本发明的另一目的是使用本文所述的任何合成方法来制备本文所述的任何化合物的方法。
定义:
下面列出了用于描述本发明的各种术语的定义。这些定义适用于在本文和权利要求书中所使用的术语,除非在特定情况下另有限制,无论是单独还是作为较广义的一部分。
如本文所用的术语“烷基”描述饱和的、直链或支链的烃基自由基。“C1-C3烷基”、“C1-C6烷基”、“C1-C10烷基”、“C2-C4烷基”或“C3-C6烷基”是指分别含有1个到3个、1个到6个、1个到10个碳原子、2个到4个和3个到6个碳原子的烷基。C1-C8烷基自由基的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、叔丁基、新戊基、正己基、庚基和辛基自由基。
本文所使用的术语“烯基”是指通过去除单个氢原子而具有至少一个碳碳双键的直链或支链烃自由基。“C2-C10烯基”、“C2-C8烯基”、“C2-C4烯基”或“C3-C6烯基”是指分别含有2个到10个、2个到8个、2个到4个或3个到6个碳原子的烯基。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基、辛基等。
本文所使用的术语“炔基”是指通过去除单个氢原子而具有至少一个碳碳三键的直链或支链烃自由基。“C2-C10炔基”、“C2-C8炔基”、“C2-C4炔基”或“C3-C6炔基”是指分别含有2个到10个、2个到8个、2个到4个或3个到6个碳原子的炔基。代表性炔基包括但不限于例如乙炔基、1-丙基、1-丁基、庚基、辛基等。
本文所用的术语“环烷基”指的是单环或多环饱和碳环或双环或三环基团稠合的、桥连的或螺环体系,并且碳原子可以任选地被氧取代或任选地被外环烯烃、亚胺基或肟双键取代。优选的环烷基包括C3-C12环烷基、C3-C6环烷基、C3-C8环烷基和C4-C7环烷基。C3-C12环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环戊基、环辛基、4-亚甲基环己基、双环[2.2.1]庚基、双环[3.1.0]己基、螺环[2.5]辛基、3-亚甲基双环[3.2.1]辛基、螺环[4.4]壬基等。
本文所用的术语“环烯基”是指具有至少一个碳-碳双键的单环或多环碳环或双或三环基团稠合、桥连或螺环体系,并且碳原子可以任选地被氧取代或任选地被外环烯烃、亚胺基或肟双键取代。优选的环烯基包括C3-C12环烯基、C3-C8环烯基或C5-C7环烯基。C3-C12环烯基的实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、双环[2.2.1]庚-2-烯基、双环[3.1.0]六角-2-烯基、螺环[2.5]辛-4-烯基、螺环[4.4]非-1-烯基、双环[4.2.1]非-3-烯-9-基等。
如本文所用术语“芳基”是指包含至少一个芳香族环的单环或多环碳环体系,所述芳香族环包括但不限于苯基、萘基、四氢萘基、茚满基和茚基。多环芳基是包含至少一个芳香环的多环***。多环芳基可包含稠环、共价连接的环或其组合。
本文所用的术语“杂芳基”是指具有一个或多个选自S、O和N的环原子的单环或多环芳香族基团。剩余的环原子是碳,其中环中包含的任何N或S都可以被任选地氧化。杂芳基包括但不限于吡啶基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、恶唑基、异恶唑基、噻二唑基、恶二唑基、噻吩基、呋喃基、喹啉基、异喹唑基、苯并咪唑基、苯并咪唑基。多环杂芳基可包含稠环、共价连接的环或其组合。
根据本发明,芳香族基团可以为被取代或未被取代。本文所用的术语“双环芳基”或“双环杂芳基”是指由两个环组成的环***,其中至少一个环为芳香族;两个环可以稠合或共价连接。
如本文所使用的术语“芳烷基”是指其中一个亚烷基链连接到一个芳基上的官能团,例如-CH2CH2苯基。本文所使用的术语“取代的芳基烷基”是指其中芳基被取代的芳基烷基官能团。类似地,本文所使用的术语术语“杂芳基烷基”是指其中亚烷基链连接至杂芳基的官能团。本文所使用的术语术语“取代的杂芳基烷基”是指杂芳基被取代的杂芳基烷基官能团。
如本文所用术语“亚烷基”是指支链或直链饱和烃链的双自由基,其通常具有1至20个碳原子(例如1至10个碳原子,或1、2、3、4、5或6个碳原子)。所述术语以诸如亚甲基(-CH2-)、乙烯(-CH2CH2-)、丙烯异构体(例如-CH2 CH2 CH2-和-CH(CH3)CH2-)等基团为例。
如本文所用术语“取代的”是指其上的一个、两个或三个或更多个氢原子被取代基独立取代,所述取代基包括但不限于氘、-F、-Cl、-Br、-I、-OH、被保护的羟基、-NO2、-CN、-NH2、N3、被保护的氨基、烷氧基、硫代烷氧基、氧取代基、C1-C6-烷基、C2-C12-烯基、C2-C12-炔基、-卤代-C1-C12-烷基、-卤代-C2-C12-烯基、-卤代-C2-C12-炔基、-卤代-C3-C12-环烷基、-NH-C1-C12-烷基、-NH-C2-C12-烯基、-NH-C2-C12-炔基、-NH–C3-C12-环烷基、-NH-芳基、-NH-杂芳基、-NH-杂环烷基、-二烷基氨基、-二芳基氨基、-二杂芳基氨基、-O-C1-C12-烷基、-O-C2-C12-烯基、-O-C2-C12-炔基、-O-C3-C12-环烷基、-O-芳基、-O-杂芳基、-O-杂环烷基、-C(O)-C1-C12-烷基、-C(O)-C2-C12-烯基、-C(O)-C2-C12-炔基、-C(O)-C3-C12-环烷基、-C(O)-芳基、-C(O)-杂芳基、-C(O)-杂环烷基、-CONH2、-CONH-C1-C12-烷基、-CONH-C2-C12-烯基、-CONH-C2-C12-炔基、-CONH-C3-C12-环烷基、-CONH-芳基、-CONH-杂芳基、-CONH-杂环烷基、-OCO2-C1-C12-烷基、-OCO2-C2-C12-烯基、-OCO2-C2-C12-炔基、-OCO2-C3-C12-环烷基、-OCO2-芳基、-OCO2-杂芳基、-OCO2-杂环烷基、-OCONH2、-OCONH-C1-C12-烷基、-OCONH-C2-C12-烯基、-OCONH-C2-C12-炔基、-OCONH-C3-C12-环烷基、-OCONH-芳基、-OCONH-杂芳基、-OCONH-杂环烷基、-NHC(O)-C1-C12-烷基、-NHC(O)-C2-C12-烯基、-NHC(O)-C2-C12-炔基、-NHC(O)-C3-C12-环烷基、-NHC(O)-芳基、-NHC(O)-杂芳基、-NHC(O)-杂环烷基、-NHCO2-C1-C12-烷基、-NHCO2-C2-C12-烯基、-NHCO2-C2-C12-炔基、-NH CO2-C3-C12-环烷基、-NHCO2-芳基、-NHCO2-杂芳基、-NHCO2-杂环烷基、-NHC(O)NH2、-NHC(O)NH-C1-C12-烷基、-NHC(O)NH-C2-C12-烯基、-NHC(O)NH-C2-C12-炔基、-NHC(O)NH-C3-C12-环烷基、-NHC(O)NH-芳基、-NHC(O)NH-杂芳基、-NHC(O)NH-杂环烷基、NHC(S)NH2、-NHC(S)NH-C1-C12-烷基、-NHC(S)NH-C2-C12-烯基,-NHC(S)NH-C2-C12-炔基、-NHC(S)NH-C3-C12-环烷基、-NHC(S)NH-芳基、-NHC(S)NH-异芳基、-NHC(S)NH-杂环烷基、-NHC(NH)NH2、-NHC(NH)NH-C1-C12-烷基、-NHC(NH)NH-C2-C12-烯基、-NHC(NH)NH-C2-C12-炔基、-NHC(NH)NH-C3-C12-环烷基、-NHC(NH)NH-芳基、-NHC(NH)NH-杂芳基、-NHC(NH)NH-杂环烷基、-NHC(NH)-C1-C12-烷基、-NHC(NH)-C2-C12-烯基、-NHC(NH)-C2-C12-炔基、-NHC(NH)-C3-C12-环烷基、-NHC(NH)-芳基、-NHC(NH)-杂芳基、-NHC(NH)-杂环烷基、-C(NH)NH-C1-C12-烷基、-C(NH)NH-C2-C12-烯基、-C(NH)NH-C2-C12-炔基、-C(NH)NH-C3-C12-环烷基、-C(NH)NH-芳基、-C(NH)NH-杂芳基、-C(NH)NH-杂环烷基、-S(O)-C1-C12-烷基、-S(O)-C2-C12-烯基、-S(O)-C2-C12-炔基、-S(O)-C3-C12-环烷基、-S(O)-芳基、-S(O)-杂芳基、-S(O)-杂环烷基-SO2NH2、-SO2NH-C1-C12-烷基、-SO2NH-C2-C12-烯基、-SO2NH-C2-C12-炔基、-SO2NH-C3-C12-环烷基、-SO2NH-芳基,-SO2NH-杂芳基、-SO2NH-杂环烷基、-NHSO2-C1-C12烷基、-NHSO2-C2-C12烯基、-NHSO2-C2-C12炔基、-NHSO2-C3-C12-环烷基、-NHSO2-芳基、-NHSO2-杂芳基、-NHSO2-杂环烷基、-CH2NH2,-CH2SO2CH3、-芳基、-芳烷基、-杂芳基、-杂芳基烷基、-杂环烷基、-C3-C12-环烷基,聚烷氧基烷基,聚烷氧基,-甲氧基甲氧基、-甲氧基乙氧基、-SH,-S-C1-C12-烷基、-S-C2-C12-烯基、-S-C2-C12-炔基、-S-C3-C12-环烷基、-S-芳基、-S-杂芳基、-S-杂环烷基、甲硫基甲基或–L'-R',其中L'为C1-C6亚烷基、C2-C6亚烯基或C2-C6亚炔基,R'为芳基、杂芳基、杂环、C3-C12环烷基或C3-C12环烯基。可以理解的是,芳基、杂芳基、烷基等可以被进一步取代。在一些情况下,取代基团中的每个取代基还任选被一个或多个基团取代,每个基团独立地选自C1-C6烷基、-F、-Cl、-Br、-I、-OH、-NO2、-CN或-NH2。
根据本发明,本文所述的任何芳香基、取代芳基、杂芳基和取代杂芳基可以是任何芳香基团。芳香族基团可以是取代的或未被取代的。
应理解的是,本文所描述的任何烷基、烯基、炔基、环烷基和环烯基部分也可以是脂肪族、脂环族或杂环族基团。“脂肪族基团”是非芳香族部分,其可包含碳原子、氢原子、卤素原子、氧、氮或其他原子的任何组合,并且任选地包含一个或多个不饱和单元,例如双键及/或三键。脂肪族可为直链、支链或环状,且优选包含约1个至约24个碳原子,更典型地包含约1个至约12个碳原子。除了脂肪族烃基之外,脂肪族还包括例如聚烷氧烷基,例如聚烷二醇、多胺和聚亚胺。这类脂肪族基团可进一步被取代。应理解,可使用脂肪族个取代本文所述的烷基、烯基、炔基、亚烷基、亚烯基和亚炔基。
如本文所用术语“脂环族”是指通过去除单个氢原子衍生自单环或多环饱和碳环化合物的单价基团。实施例包括但不限于环丙基、环丁基、环戊基、环己基、双环[2.2.1]庚基和双环[2.2.2]辛基。这样的脂环族基团可以被进一步取代。
如本文单独或与其他术语组合使用的所用术语“烷氧基”是指,除非另有说明,否则是指具有指定碳原子数的烷基通过氧原子与分子的其余部分连接的烷基,例如甲氧基、乙氧基、1-丙氧基、2-丙氧基(异丙氧基)以及更高的同系物和异构体。优选的烷氧基是(C1-C3)烷氧基。
如本文所用术语“芳氧基”是指芳基基团-O-,其中芳基如上所定义并且包括任选被取代的芳基也如上所定义。文所用术语术语“芳硫基”是指基团R-S-,其中R如对于芳基所定义。
如本文所用术语“杂环”或“杂环烷基”可以互换使用,并且是指非芳族环或稠合、桥连或螺环的双或三环基团,其中(i)每个环***独立地包含至少一个杂原子,(ii)每个环***可以是饱和的或不饱和的,(iii)氮和硫杂原子可以可选地被氧化,(iv)氮杂原子可以可选地被季铵化,(v)以上任何一个环可以稠合到芳环上,并且(vi)剩余的环原子是碳原子,其可以被氧代取代或被环外的烯烃、亚氨基或肟基双键取代。代表性的杂环烷基包括但不限于1,3-二氧戊环、吡咯烷基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、哌啶基、哌嗪基、恶唑烷基、异恶唑烷基、吗啉基、噻唑烷基、2-异噻唑烷基[2.2.1]-庚基,8-氮杂双环[3.2.1]辛基,5-氮杂螺[2.5]辛基,1-氧杂-7-氮杂螺[4.4]壬基,7-氧代氧杂-4-基和四氢呋喃基。这样的杂环基可以被进一步取代。杂芳基或杂环基团可以是C-连接或N-连接的(如果可能的话)。
应当理解的是,本文所述的任何烷基、烯基、炔基、环烷基、杂环和环烯基部分也可以是脂肪族基团或脂环族基团。
显而易见的是,在本发明的各种实施方案中,取代或未取代的烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基烷基、杂芳基烷基和杂环烷基旨在为单价或二价的。因此,亚烷基、亚烯基、亚炔基、亚环烷基,亚环烯基、亚环炔基、芳基亚烷基、杂芳基亚烷基和亚杂环基基团将包括在以上定义中,并且可用于为本文的式提供适当的化合价。
本文所用术语“卤代”和“卤素”是指选自氟、氯、溴和碘的原子。
如本文所用术语“任选地被取代”是指所提及的基团可以被取代或未被取代。在一个实施例中,参考基团任选被零个取代基取代,即参考基团是未被取代的。在另一个实施例中,所提及的基团任选地被一个或多个另外的基团单独和独立地选自本文所述的基团取代。
如本文所用术语术语“氢”包括氢和氘。另外,原子的列举包括所述原子的其他同位素,只要所得化合物是药学上可接受的。
在某些实施例中,本文每个式的化合物定义为包括同位素标记的化合物。“同位素标记的化合物”是这样的化合物,其中至少一个原子位置富含指定元素的特定同位素,其水平显着大于所述同位素的自然丰度。例如,化合物中的一个或多个氢原子位置可以增多到氘的水平显着大于氘的自然丰度,例如,增多到至少1%,优选至少20%或至少50%。这样的氘代化合物例如可以比其非氘代类似物更慢地代谢,因此当施用于受试者时表现出更长的半衰期。这样的化合物可以使用本领域已知的方法合成,例如通过使用氘化的起始原料。除非有相反的说明,同位素标记的化合物是药学上可接受的。
本文所述的化合物包含一个或多个不对称中心,因此产生对映异构体、非对映异构体和其他立体异构形式,这些形式可以按照绝对立体化学的方式定义为(R)-或(S)-或(D)-或(L)-表示氨基酸。本发明旨在包括所有这些可能的异构体,以及它们的外消旋和光学纯形式。旋光异构体可以通过上述步骤,或通过拆分外消旋混合物,由它们各自的旋光前体制备。拆分可在拆分剂存在下,通过色谱法或通过重复结晶或通过本领域技术人员已知的这些技术的某种组合来进行。有关拆分的更多详细信息,请参见Jacques等人的《对映异构体,外消旋体和拆分》(John Wiley&Sons,1981年)。当本文所述的化合物包含烯属双键,其他不饱和键或其他几何不对称中心时,除非另有说明,否则该化合物意图包括E式和Z式几何异构体或顺式和反式异构体。同样,也打算包括所有互变异构形式。互变异构体可以是环状或非环状的。选择本文中出现的任何碳-碳双键的构型仅是为了方便起见,并不旨在指定特定的构型,除非文中另有说明;因此,在本文中任意描述为反式的碳-碳双键或碳-杂原子双键可以是顺式、反式或两者的任何比例的混合物。
如本文所用术语“受试者”是指哺乳动物。因此,受试者是指例如狗、猫、马、牛、猪、豚鼠等。优选地,受试者是人类。当受试者是人类时,所述受试者在本文中可以称为患者。
如本文所用术语“药学上可接受的盐类”是指通过本发明的方法形成的化合物的那些盐,它们在合理的医学判断范围内适用于与人和低等动物的组织接触,没有过度的毒性,刺激性,过敏反应等,并且具有合理的收益/风险比。药学上可接受的盐是本领域众所周知的。
贝尔格等人,在药物科学期刊,66:1-19(1977)中详细描述了药物上可接受的盐类。这些盐类可以在本发明化合物的最终分离和纯化过程中原位制备,或通过使游离碱官能团与合适的有机酸反应而分开制备。药学上可接受的盐的实施例包括但不限于无毒的酸加成盐,例如,由无机酸形成的氨基的盐,如盐酸、氢溴酸、磷酸、硫酸和高氯酸或与乙酸、马来酸、酒石酸、柠檬酸等有机酸,琥珀酸或丙二酸或使用本领域中使用的其他方法,例如离子交换。其他医药上可接受的盐包括但不限于己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢钠、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸酯、葡萄糖酸盐,半硫酸盐、庚酸盐、己酸盐、碘化氢、2-羟基-乙磺酸盐、乳酸盐、月桂酸盐、月桂酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、尼龙酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐,琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。进一步的药学上可接受的盐类包括在适当的时候,使用例如卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、具有1至6个碳原子的烷基、磺酸盐和芳基磺酸盐等抗衡离子形成的无毒铵、季铵和胺阳离子。
如本文所用术语“药学上可接受的酯类”是指在体内水解并且包括在人体内容易分解而留下母体化合物或其盐的那些酯类。合适的酯类包括例如衍生自药学上可接受的脂族羧酸的那些,特别是烷酸、烷烯酸、环烷酸和烷二酸,其中每个烷基或烯基部分有利地具有不超过6个碳原子。特定酯的实例包括但不限于C1-C6链烷酸的酯,例如乙酸酯、丙酸酯、丁酸酯和新戊酸酯。
如本文所用术语“羟基活化基团”是指本领域已知的活化羟基的不稳定化学部分,从而其将在合成程序例如取代或消除反应中脱离。羟基活化基团的实施例包括但不限于甲磺酸酯、甲苯磺酸酯、三氟甲磺酸酯、对硝基苯甲酸酯、膦酸酯等。
如本文所用术语“活化的羟基”是指被如上定义的羟基活化基团活化的羟基,包括例如甲磺酸根、甲苯磺酸根、三氟甲磺酸根、对硝基苯甲酸酯基、膦酸酯基。
如本文所用术语“羟基保护基团”是指不稳定的化学部分,其在本领域中已知用于保护羟基免于在合成过程中发生不希望的反应。在所述合成步骤之后,可以选择性地除去本文所述的羟基保护基团。本领域已知的羟基保护基团一般在T.H.Greene和P.G.M.Wuts,《有机合成中的保护基》,第3版,John Wiley&Sons,纽约(1999年)中描述。羟基保护基团的实例包括苄氧基羰基、4-甲氧基苄氧基羰基、叔丁氧基羰基、异丙氧基羰基、二苯基甲氧基羰基、2,2,2-三氯乙氧基羰基、烯丙氧基羰基、乙酰基、甲酰基、氯乙酰基、三氟乙酰基、甲氧基乙酰基、苯氧基乙酰基、苯甲酰基、甲基、t-丁基、2,2,2-三氯乙基、2-三甲基甲硅烷基乙基、烯丙基、苄基、三苯基-甲基(三苯甲基)、甲氧基甲基、甲硫基甲基、苄氧基甲基、2-(三甲基甲硅烷基)-乙氧基甲基、甲磺酰基、三甲基甲硅烷基、三异丙基甲硅烷基等。
如本文所用术语“被保护的羟基”是指被如上所定义的羟基保护基团保护的羟基,包括例如苯甲酰基、乙酰基、三甲基甲硅烷基、三乙基甲硅烷基、甲氧基甲基。
如本文所用术语“羟基前药基团”是指本领域已知的通过覆盖或掩蔽羟基以瞬时方式改变母体药物的物理化学性质并因此改变其母体生物学特性的基团。在所述一种或多种合成方法之后,本文所述的羟基前药基团必须能够在体内还原成羟基。本领域已知的羟基前药基团在Kenneth B.Sloan的《前药,局部和眼部药物递送》(《药物与药学》;第53卷),Marcel Dekker,Inc.,纽约(1992年);和由S.S.Dhareshwar和V.J.Stella撰写的《酒精和苯酚的前药》,在《前药挑战和奖励》第2部分,(生物技术:制药方面),并由VJ Stella等人编辑,Springer和AAPSPress,2007年,第31-99页中描述。
如本文所用术语“氨基”是指基团-NH2。
如本文所用术语“取代的氨基”是指基团-NRR,其中每个R独立地选自氢、烷基、环烷基、芳基、杂芳基和杂环烷基,只要两个R基团都不为氢,或-Y-Z基团,其中Y是任选取代的亚烷基,Z是烯基、环烯基或炔基。
如本文所用术语“氨基保护基”是指不稳定的化学部分,其在本领域中已知在合成过程中保护氨基免于不期望的反应。在所述合成步骤之后,可以选择性地除去本文所述的氨基保护基。已知的氨基保护基一般在T.H.格林和PG M.Wuts,有机合成中的保护基,第三版,约翰·威利父子出版社,纽约(1999年)中描述。氨基保护基的实例包括但不限于叔丁氧羰基、9-芴基甲氧羰基、苄氧羰基等。
如本文所用术语“离去基团”是指可以在取代反应如亲核取代反应中被另一个官能团或原子取代的官能团或原子。举例来说,代表性的离去基团包括氯、溴和碘基;磺酸酯基,例如甲磺酸根、甲苯磺酸根、溴磺酸根、甲磺酸等;酰氧基,例如乙酰氧基、三氟乙酰氧基等。
如本文所用术语“药学上可接受的酯类”是指通过本发明的方法形成的化合物的酯类,其在体内水解并包括在人体内容易分解而留下母体化合物或其盐的那些。合适的酯基包括例如衍生自药学上可接受的脂族羧酸的那些,特别是烷酸、烯酸、链烷酸和烷二酸,其中每个烷基或烯基部分有利地具有不超过6个碳原子。特定酯的实例包括但不限于甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯和琥珀酸乙酯。
如本文所用术语“药学上可接受的前药”是指通过本发明的方法形成的化合物的那些前药,其在合理的医学判断范围内,适用于与人类和低等动物的组织接触,不具有不当的毒性,刺激性,过敏性反应等,对等具有合理的受益/风险比,且对其预期用途有效,以及在可能的情况下,本发明化合物的两性离子形式。如本文所用术语“前药”是指通过代谢手段(例如通过水解)在体内可转换以提供由本发明的配方所描述的任何化合物的化合物。本领域已知各种形式的前药,例如,如Bundgaard(编辑)的《前药设计》,Elsevier(1985);Widder等人(编辑)的《酶学方法》,第4卷,学术出版社(1985);Krogsgaard-Larsen等人(编辑)的”前药设计与应用,药物设计与开发教科书,第5章,113-191(1991);Bundgaard等人,《药物递送评论杂志》,8:1-38(1992);Bundgaard,药物科学期刊,77:285等。(1988);Higuchi和Stella(编辑),《前药作为新型药物传递***》,美国化学学会(1975);BernardTesta和Joachim Mayer,《药物和前药代谢中的水解:化学、生物化学和酶学》,约翰·威利父子出版社(2002)。
本文所用的术语“治疗”是指减轻、减缓、减少、消除、调节或改善,即引起疾病状态或病症的消退。治疗还可以包括抑制(即,阻止现有疾病状态或病症的发展)和缓解或改善(即导致现有疾病状态或病症的消退),例如当疾病状态或病症可能已经存在时。
如本文所用术语“预防”是指完全或几乎完全阻止疾病状态或病症在患者或受试者中发生,尤其是当患者或受试者易患这种疾病或处于患疾病状态的危险条件时。
另外,本发明的化合物,例如化合物的盐,可以以水合或非水合(无水)形式存在,或与其他溶剂分子以溶剂化物形式存在。水合物的非限制性实例包括单水合物、双水合物等。溶剂合物的非限制性实例包括乙醇溶剂合物、丙酮溶剂合物等。
如本文所用术语“溶剂化物”是指包含化学计量或非化学计量的溶剂添加形式。一些化合物倾向于以结晶固态捕获固定摩尔比的溶剂分子,从而形成溶剂化物。如果溶剂是水,则形成的溶剂化物是水合物,当溶剂是醇时,形成的溶剂化物是醇化物。水合物是由一种或多种水分子与一种物质结合而成的,其中一种物质能保持水的分子态为H2O,这种结合能够形成一种或多种水合物。
如本文所用术语“类似物”是指在结构上与另一种相似但组成略有不同的化合物(例如,一个原子被不同元素的原子取代或存在特定官能团时,或一个功能组被另一功能组取代)。因此,类似物是在功能和外观上与参考化合物相似或相当的化合物。
如本文所用术语“非质子溶剂”是指对质子活性相对惰性的溶剂,即不充当质子给体。实例包括但不限于烃,例如己烷和甲苯,例如卤代烃,例如二氯甲烷、氯乙烷、氯仿等、杂环化合物,例如四氢呋喃和N-甲基吡咯烷酮,以及醚,如***、双甲氧基甲基醚。这样的溶剂是本领域技术人员众所周知的,并且对于特定的化合物和反应条件,单独的溶剂或其混合物可能是优选的,这取决于例如试剂的溶解度、试剂的反应性和优选的温度范围等因素。非质子溶剂的进一步讨论可以在有机化学教科书或专门的专着中找到。例如:有机溶剂的物理性质和纯化方法,第4版,由John A.Riddick等人编辑,《化学技术丛书》系列第二集,约翰·威利父子出版社,纽约,1986年。
本文所用的术语“质子有机溶剂”或“质子溶剂”是指倾向于提供质子的溶剂,例如醇,例如甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇等。这样的溶剂是本领域技术人员众所周知的,并且对于特定的化合物和反应条件,单独的溶剂或其混合物可能是优选的,这取决于诸如试剂的溶解度、试剂的反应性和优选的温度范围等因素。关于质生溶剂的进一步讨论可以在有机化学教科书或专业专书中找到。例如:有机溶剂的物理性质和纯化方法,第4版,由John A.Riddick等人编辑,《化学技术丛书》系列第二集,约翰·威利父子出版社,纽约,1986年。
本发明所设想的取代基和变量的组合仅是导致形成稳定化合物的那些。如本文所用术语“稳定的”是指具有足以允许制造的稳定性并且将所述化合物的完整性维持足够长的时间以用于本文详述的目的(例如对于受试者具有治疗性或预防性的化合物)。
可以从反应混合物中分离合成的化合物,并通过诸如柱色谱法、高压液相色谱法或重结晶的方法进一步纯化。另外,各种合成步骤可以以交替的顺序或顺序进行以得到所需的化合物。另外,本文描述的溶剂、温度、反应持续时间等仅出于说明的目的,并且反应条件的变化可以产生所需的本发明的异恶唑产物。可用于合成本文所述化合物的合成化学转化和保护基方法(保护和脱保护)包括:例如,在R.Larock,综合有机转换,VCH出版社(1989);T.W.格林和P.G.M.伍兹,有机合成中的保护基,第二版,约翰·威利父子出版社(1991);L.Fieser和M.Fieser,《Fieser和Fieser的有机合成试剂》,约翰·威利父子出版社(1994);以及L.Paquette编辑的《有机合成试剂百科全书》,约翰·威利父子出版社(1995)中描述的那些。
本发明的化合物可以通过在本文中描述的合成方法附加各种功能性来进行修饰,以增强选择性生物特性。这些修饰包括增加对特定生物***(如血液、淋巴***、中枢神经***)的生物渗透,增加口服量,增加溶解度以允许通过注射给药,改变代谢和改变排出率。
药物组合物:
本发明的药物组合物包含治疗有效剂量的与一种或多种药学上可接受的载体一起配制的本发明的化合物。如本文所用术语“药学上可接受的载体”是指任何类型的无毒、惰性固体、半固体或液体填充剂、稀释剂、包囊材料或配制助剂。可以用作药学上可接受的载体的材料的一些实例是糖,例如乳糖、葡萄糖和蔗糖等等;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;黄芪粉麦芽;明胶;滑石;赋形剂,例如可可脂和栓剂蜡;花生油,棉籽油等油;红花油;芝麻油;橄榄油;玉米油和大豆油;乙二醇;或是丙二醇;酯,例如油酸乙酯和月桂酸乙酯;琼脂缓冲剂,例如氢氧化镁和氢氧化铝;海藻酸无热原水;等渗透压盐水;林格溶液;乙醇和磷酸盐缓冲溶液;以及其他无毒的兼容性润滑剂,如十二烷基硫酸钠和硬脂酸镁;以及着色剂,脱模剂、包覆剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂根据配方设计师的判断。本发明的药物组合物可以口服、经直肠、肠胃外、经脑、经***内、腹膜内、局部(如通过散剂、软膏剂或滴剂)、经口腔、或经口或经鼻喷雾剂施用于人和其他动物。
本发明的药物组合物可以口服、肠胃外、通过吸入喷雾、局部,经直肠、鼻、颊、***或经植入的储库给药,优选通过口服给药或通过注射给药。本发明的药物组合物可以包含任何常规的无毒的药学上可接受的载体、佐剂或媒介物。在某些情况下,可以用药学上可接受的酸、碱或缓冲剂调节制剂的pH值,以增强制剂化合物或其递送形式的稳定性。如本文所用术语肠胃外包括皮下、皮内、静脉内、肌肉、关节内、动脉内、滑膜内、胸骨内、鞘内、病变部位内和颅内注射或输注技术。
口服给药的液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和药丹粉剂。除活性化合物外,液体剂型还可包含本领域常用的惰性稀释剂,例如水或其他溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、芐基醇、苯甲酸芐酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脂肪酸酯脱水山梨醇及其混合物。除惰性稀释剂外,口服组合物还可包含佐剂,例如润湿剂、乳化剂和助悬剂,甜味剂、调味剂和加香剂。
可以根据现有技术使用合适的分散剂或湿润剂和助悬剂来配制可注射制剂,例如无菌的可注射水性悬浮液或油质悬浮液。无菌注射制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液、悬浮液或乳剂,例如在1,3-丁二醇中的溶液。可以使用的可接受的媒介物和溶剂是水,美国药典的林格氏溶液和等渗氯化钠溶液。另外,无菌的不挥发油通常用作溶剂或悬浮介质。为此,可以使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。另外,脂肪酸如油酸也用于制备注射制剂。
可注射制剂可以被灭菌,例如,通过细菌保留过滤器过滤,或通过掺入无菌固体组合物形式的灭菌剂,其可以在使用前溶解或分散在无菌水或其他无菌可注射介质中。
为了延长药物的作用,通常需要减慢皮下或肌内注射药物的吸收。这可以通过使用水溶性差的晶体或非晶材料的液体悬浮液来实现。然后,药物的吸收速率取决于其溶解速率,而溶解速率又取决于晶体尺寸和晶体形式。或者,通过将药物溶解或悬浮在油性载体中来实现肠胃外施用的药物形式的延迟吸收。通过在可生物降解的聚合物(例如聚丙交酯-聚乙交酯)中形成药物的微胶囊基质来制备可注射的储库形式。根据药物与聚合物的比例和所用特定聚合物的性质,可以控制药物的释放速率。其他可生物降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。还可以通过将药物包埋在与身体组织兼容的脂质体或微乳剂中来制备可注射的储库的制剂。
用于直肠或***给药的组合物优选是栓剂,其可以通过将本发明的化合物与合适的无刺激性的赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合而制备,其在环境温度下为固体但在体温下为液体因此在直肠或***腔中融化并释放出活性化合物。
口服的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中,将活性化合物与至少一种惰性的、药学上可接受的赋形剂或载体(例如柠檬酸钠或磷酸二钙)及/或:a)填充剂或增量剂(例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇);b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和***胶;c)湿润剂,例如甘油;d)崩解剂,例如琼脂、洋菜胶、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)阻滞剂(如石蜡);f)吸收促进剂,如季铵化合物;g)润湿剂,例如十六醇和单硬脂酸甘油酯;h)吸收剂,例如高岭土和膨润土粘土;以及i)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠及其混合物混合。在胶囊、片剂和丸的情况下,所述剂型还可包含缓冲剂。
相似类型的固体组合物也可以用作软和硬填充明胶胶囊中的填充剂,其使用诸如乳糖或乳糖以及高分子量聚乙二醇等赋形剂。
如上文所述,活性化合物也可与一种或多种赋形剂以微胶囊形式存在。片剂、糖衣丸、胶囊剂、丸剂和颗粒剂的固体剂型可以用包覆和衣壳例如肠溶衣、控释包覆材等包覆材和和药物配制领域众所周知的其他包覆材制备。在这种固体剂型中,活性化合物可与至少一种惰性稀释剂(例如蔗糖、乳糖或淀粉)混合。这种剂型还可以如通常做法那样,包括除惰性稀释剂以外的其他物质,例如压片润滑剂和其他压片助剂,例如硬脂酸镁和微晶纤维素。在胶囊、片剂和丸剂的情况下,所述剂型还可包括缓冲剂。它们可以任选地包含遮光剂,并且还可以是其仅释放活性成分的成分,或者优选地,任选地以延迟的方式在肠道的特定部分释放活性成分的成分。可使用的包埋成分的实例包括聚合物质和蜡。
用于本发明化合物的局部或透皮给药的剂型包括软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、散剂、溶液剂、喷雾剂、吸入剂或贴剂。将活性成分在无菌条件下与药学上可接受的载体和可能需要的任何所需的防腐剂或缓冲剂混合。眼用制剂、滴耳剂、眼药膏、粉剂和溶液剂也考虑在本发明的范围内。
除本发明的活性化合物外,软膏、糊剂、乳膏和凝胶剂还可包含赋形剂,例如动植物脂肪、油、蜡、石蜡、淀粉,黄洋菜胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸酸、滑石粉和氧化锌或其混合物。
除本发明的化合物外,粉末和喷雾剂还可包含赋形剂,例如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。喷雾剂还可以包含常规推进剂,例如氯氟烃。
透皮贴剂还有一个额外的优点,即可以向人体提供化合物的可控释放。这样的剂型可以通过将化合物溶解或分配在适当的介质中来制备。吸收促进剂也可用于增加化合物穿过皮肤的流量。可以通过提供速率控制膜或通过将化合物分散在聚合物基质或凝胶中来控制速率。
除非另有定义,否则本文所用的所有技术和科学术语均与本领域普通技术人员通常已知的含义一致。本文提及的所有出版物、专利、公开的专利申请和其他参考文献均通过引用全文并入本文。
缩写词:
在实例说明和以下示例中使用的缩写为:
BOP-Cl为双(2-氧代-3-恶唑烷基)次膦酰氯;
CDI为羰基二咪唑;
DBU为1,8-二氮杂双环十一烷基-7-烯;
DC为N,N’-二环己基碳二亚胺;
DCM为二氯甲烷;
DIPEA为N,N-二异丙基乙胺;
DMAP为N,N-二甲基氨基吡啶的;
DME为1,2-二甲氧基乙烷;
DMF为N,N-二甲基甲酰胺的;
DMPU为1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮;
EDC为1-(3-二乙基氨基丙基)-3-乙基碳二亚胺盐酸盐;
Et3N为三乙胺;
EtOAc为乙酸乙酯;
HATU为1-[双(二甲基氨基)亚甲基]-1H-1,2,3-***并[4,5-b]吡啶鎓3-氧化六氟磷酸盐;
HCl为盐酸;
mCPBA为间氯过氧苯甲酸;
NMO为N-甲基吗啉-N-氧化物;
PhMe为甲苯;
PyAOP为7-氮杂苯并***-1-基氧基)三吡咯烷基六氟磷;
PyBOP为六氟磷酸苯并***-1-基-氧基三吡咯烷基磷;
THF为四氢呋喃。
合成方法:
结合以下说明本发明化合物的制备方法的合成方案,将更好地理解本发明的化合物和方法,这些合成方案仅用作说明而不限制本发明的范围。对于所公开的实施例的各种改变和修改对本领域技术人员将是显而易见的,这些改变和修改包括但不限于与化学结构、取代基、衍生物有关的改变和修改,可以在不脱离本发明的精神和所附权利要求的范围的情况下进行本发明及/或本发明的方法的改变和修改。
如方案1所示,式(I)的化合物可以通过在合适的酰胺偶合条件下将羧酸化合物(1)和胺化合物(2)偶合来制备,其中,R、R2、R3、X1和如先前定义。关于羧酸化合物(1)的制备,参见US2016/0244430。因此,在有机碱的存在下,用合适的偶联剂处理在质子惰性溶剂中的羧酸化合物(1)和胺化合物(2)的一混合物,以形成式(I)的酰胺化合物。合适的偶联剂可以是例如但不限于BOP-Cl、CDI、DCC、EDC、HATU、PyAOP或PyBOP,有机碱可以是例如但不限于Et3N、DIPEA、吡啶或N-甲基吗啉。非质子溶剂可以例如但不限于是THF、DCM和DMF。反应温度为-20℃至80℃。
方案1
可替代地,式(I)的化合物还可以通过以下方法制备:首先将羧酸化合物(1)转化为酰氯化合物(3),然后在有机碱存在下使酰氯化合物(3)与胺化合物(2)反应(如方案2所示)来制备式(I)化合物。
方案2
因此,将羧酸化合物(1)在非质子溶剂(例如但不限于DCM或DMF)中用亚硫酰氯或草酰氯或其他酰氯形成试剂处理,得到酰氯化合物(3)。然后,在有机碱例如但不限于TEA、DIPEA、DMAP或吡啶的存在下,使酰基氯化合物(3)在非质子溶剂例如但不限于DCM或DMF中与胺化合物(2)反应得到式(I)的化合物。
制备式(I)化合物的另一种替代方法是,首先将羧酸化合物(1)转化为混合酸酐化合物(4),然后在有机碱存在下使混合酸酐化合物(4)与胺化合物(2)反应(如方案3所示)。
方案3
因此,在非质子溶剂例如但不限于DCM中,在碱例如但不限于TEA或DIPEA的存在下,用氯甲酸酯试剂例如但不限于氯甲酸异丁酯处理羧酸化合物(1)制得混合酸酐化合物(4)。然后,在有机碱(例如但不限于TEA、DIPEA、DMAP)的存在下,在非质子溶剂(例如但不限于DCM或DMF)中,使混合的酸酐化合物(4)与胺化合物(2)反应得到式(I)的化合物。
方案4至方案6说明了四唑化合物(2a)的合成。方案7说明四唑化合物(2b)的合成。文献中对四唑的合成进行了更详细的讨论,例如魏成锡、明边和龚国华(分子),2015,20,5528-5553。
如方案4所示,四唑化合物(6a)是通过在肼酸和腈化合物(5a)之间进行[3+2]环加成而制备的。因此,将化合物(5a)在刘易斯酸存在下于高温下在溶剂(例如但不限于DMF)中用NaN3或TMSN3处理,得到化合物(6a)。所述刘易斯酸可以是但不限于氯化铵Bu3SnO。反应温度为50℃至150℃。化合物(6a)在碱的存在下进一步用R1X烷基化,其中R1如先前所定义,优选为任选取代的烷基,且X为卤素,优选为氯或溴或碘,从而得到化合物(2a)。
方案4
方案(5)中显示了制备化合物(2a)的替代方法。通过胺化合物(8a)与原甲酸三乙酯和迭氮化钠在乙酸中的反应合成四唑化合物(9a)。化合物(9a)进一步与化合物(10a)偶联,其中X是卤素,优选氯或溴或碘,得到化合物(2a)。所述偶联反应中的溶剂可以是但不限于1,4-二恶烷。用于所述反应的催化剂可以是但不限于氯化双(三苯基膦)钯(II)。所述反应中使用的碱可以是但不限于碳酸铯。反应温度为0℃至50℃。
方案5
方案(6)中显示了制备化合物(2a)的另一种替代方法。化合物(12a)可以通过使羧酸化合物(11a)与胺化合物(8a)偶联来制备。因此,在有机碱的存在下,用合适的偶联剂处理在质子惰性溶剂中的羧酸化合物(11a)和胺化合物(8a)的混合物,以形成酰胺化合物(12a)。合适的偶联剂可以是例如但不限于BOP-Cl、CDI、DCC、EDC、HATU、PyAOP或PyBOP,有机碱可以是例如但不限于Et3N、DIPEA,吡啶或N-甲基吗啉。非质子溶剂可以是例如但不限于THF、DCM和DMF。反应温度为-20℃至80℃。然后,通过在质子惰性溶剂中用迭氮化钠和三氟甲磺酸酐处理,将酰胺化合物(12a)进一步转化为四唑化合物(13a)。这种非质子溶剂可以是但不限于乙腈。反应温度为-20℃至50℃。
方案6
如方案7所示,将二胺化合物(5a)用P基团保护,得到化合物(6b)。P可以是任何胺保护基团,例如但不限于Cbz、Boc和PMB。关于保护胺基的方法、试剂和条件的更详细的讨论描述在文献中,例如由T.W.格林和P.G.M.伍兹在“有机合成中的保护基”,第三版,约翰·威利父子出版社,1999年。化合物(8b)可以通过将所得的胺化合物(6b)与羧酸化合物(7b)偶联来制备。因此,在有机碱的存在下,用合适的偶联剂处理在质子惰性溶剂中的羧酸化合物(7b)和胺化合物(6b)的混合物,以形成酰胺化合物(8b)。合适的偶联剂可以是例如但不限于BOP-Cl、CDI、DCC、EDC、HATU、PyAOP或PyBOP,有机碱可以是例如但不限于Et3N、DIPEA、吡啶或N-甲基吗啉。非质子溶剂可以是例如但不限于THF、DCM和DMF。反应温度为-20℃至80℃。然后,通过在质子惰性溶剂中用五氯化磷和三甲基甲硅烷基迭氮化物处理,将酰胺化合物(8b)进一步转化为四唑化合物(9b)。这种非质子溶剂可以是但不限于乙腈和二氯乙烷。反应温度为-20℃至60℃。然后P基团的脱保护得到四唑化合物(2b)。胺保护基团脱保护的方法,试剂和条件的更详细的讨论描述在文献中,例如由T.W.W.格林和P.G.M.伍兹在“有机合成中的保护基”第三版,约翰·威利父子出版社,1999年。
方案7
实验例:
结合以下实施例将更好地理解本发明的化合物和方法,这些实施例仅用于举例说明,并不限制本发明的范围。对于所公开的实施例的各种改变和修改对本领域技术人员将是显而易见的,这些改变和修改包括但不限于与化学结构、取代基、衍生物有关的改变和修改,可以在不脱离本发明的精神和所附权利要求的范围的情况下进行本发明及/或本发明的方法的改变和修改。
6-(1-异丙基-1H-四唑-5-基)吡啶-2-胺的合成(化合物3a):
路径1
步骤1.合成1-异丙基-1H-四唑(化合物1a)
将丙-2-胺(3.44毫升,40毫摩尔),迭氮化钠(3.64克,56毫摩尔)和原甲酸三乙酯(9.31毫升,56.0毫摩尔)在乙酸(20毫升)中的溶液加热至90℃并在防爆板后面搅拌持续1天。然后将反应混合物冷却至室温,用EtOAc稀释。将混合物用1N HCl,饱和NaHCO3(x3)和盐水洗涤。经Na2SO4干燥,过滤并真空浓缩,得到所需产物,为浅黄色油状物(1.52克,34%)。氢核磁共振光谱(400兆赫,氯仿-d)δ8.62(s,1H),4.90(p,J=6.7赫兹,1H),1.68(d,J=6.7赫兹,6H)。
步骤2.合成6-(1-异丙基-1H-四唑-5-基)吡啶-2-胺(化合物3a)。
1-异丙基-1H-四唑(560毫克,4.99毫摩尔),6-氯吡啶-2-胺(2a)(642毫克,4.99毫摩尔),碘化亚铜(I)(47.6毫克,0.250毫摩尔),双的混合物将(三苯膦)-氯化钯(II)(351毫克,0.499毫摩尔)和碳酸铯(3254毫克,9.99毫摩尔)在1,4-二恶烷(2毫升)中的溶液脱气并加热至100℃,并在防爆板后面搅拌24小时。将反应冷却至室温,然后用EtOAc和水稀释。用EtOAc萃取水层,并用盐水洗涤合并的有机层,经Na2SO4干燥,过滤并浓缩。将残余物通过二氧化硅色谱法纯化,使用己烷/丙酮(100/0至50/50,15分钟),得到化合物3a,为浅黄色固体(330毫克,32%)。MS(m/z):205.10[M+H]+,氢核磁共振光谱(400兆赫,氯仿-d)δ7.75–7.60(m,2H),6.66(dd,J=7.3,1.8赫兹,1H),5.87(dq,J=13.4,6.7赫兹,1H),4.62(s,2H),1.68(d,J=6.7赫兹,6H)。
路径2
步骤1:合成N-异丙基-6-亚硝基苯甲酰胺(化合物5a)
在0℃下向6-亚硝基甲酸(10克,59.5毫摩尔)和Hunig碱(31.1毫升,178毫摩尔,3eq。)在干燥DMF(200毫升)中的溶液中添加异丙胺(6.64毫升,77毫摩尔,1.3eq),然后添加HATU(29.4克,77毫摩尔,1.3eq。)。将所得混合物加热至室温,搅拌数小时,然后通过添加水(500毫升)淬灭。将混合物用EtOAc(3×200毫升)萃取,并将合并的有机层用水(2×200毫升),盐水(200毫升)洗涤,干燥(Na2SO4)并浓缩。将残余物通过二氧化硅色谱法纯化(80克柱,100%己烷至40%EtOAc/己烷),得到浅黄色固体状的化合物N-异丙基-6-亚硝基苯甲酰胺(10.81克,87%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ8.58(dd,J=7.7,1.0赫兹,1H),8.36(dd,J=8.0,1.0赫兹,1H),8.21(t,J=7.8赫兹,1H),7.70(s,1H),4.31(hept,J=6.6赫兹,1H),1.32(d,J=6.6赫兹,6H)。
步骤2:2-(1-异丙基-1H-四唑-5-基)-6-硝基吡啶的合成(化合物6a)。
在氮气保护下,于0℃于防爆罩后,向N-异丙基-6-亚硝基苯甲酰胺(350毫克,1.673毫摩尔)和迭氮化钠(120毫克,1.840毫摩尔)在无水乙腈(5.58毫升)中的混合物中滴加三氟甲烷磺酸酐(1M DCM溶液,1.84毫升,1.840毫摩尔)。将所得混合物在0℃下搅拌1小时,然后在室温下搅拌2小时。然后将反应冷却至0℃,并用饱和NaHCO3(50毫升)淬灭。将混合物用EtOAc萃取两次。合并的有机层用饱和NaHCO3和盐水洗涤并浓缩。残余物深红色固体通过二氧化硅色谱法纯化(12克柱,100%己烷至35%EtOAc/己烷),得到化合物6a(170毫克,43%产率),为无色固体。氢核磁共振光谱(400兆赫,氯仿-d)δ8.74(dd,J=7.7,0.9赫兹,1H),8.41(dd,J=8.1,0.9赫兹,1H),8.32(t,J=7.9赫兹,1H),5.95(hept,J=6.7赫兹,1H),1.72(d,J=6.7赫兹,6H)。
步骤3:合成6-(1-异丙基-1H-四唑-5-基)吡啶-2-胺(化合物3a):
2-(1-异丙基-1H-四唑-5-基)-6-硝基吡啶(100毫克,0.427毫摩尔)和Pd/C(基于干基底的10%Pd,含有50%的水,23毫克,0.025eq)在在甲醇(1毫升)/EtOAc(1毫升)中的混合物在室温下在H2气球中搅拌过夜。然后将催化剂过滤并将滤液浓缩以提供化合物3a(85毫克,97%产率),其无需进一步纯化即可直接用于下一步。MS(m/z):163.05[M+H]+。氢核磁共振光谱(400兆赫,氯仿-d)δ7.72–7.54(m,2H),6.63(dd,J=7.4,1.7赫兹,1H),5.85(hept,J=6.7赫兹,1H),4.57(s,2H),1.65(d,J=6.7赫兹,6H)。
路径3
将6-氨基吡啶甲酸腈(542毫克,4.55毫摩尔),二丁基氧化锡(566毫克,2.275毫摩尔),甲苯(10毫升)和迭氮基三甲基硅烷(1.812毫升,13.65毫摩尔)的反应混合物在微波辐射照射下于200℃搅拌5分钟。TLC显示完全反应。过滤黄色悬浮液,用甲苯洗涤,真空干燥,得到黄色粉末6-(1H-四唑-5-基)吡啶-2-胺(1.2克,定量产率)。氢和碳核磁共振光谱显示产物含有二丁基氧化锡,其不会影响下一步反应。MS(m/z):205.10[M+H]+。氢核磁共振光谱(400兆赫,DMSO-d6)δ7.67(t,J=7.9赫兹,1H),7.36(d,J=7.2赫兹,1H),6.71(d,J=8.4赫兹,1H),6.57(s,2H)。
向50毫升的二颈圆底烧瓶中加入6-(1H-四唑-5-基)吡啶-2-胺(300毫克,1.850毫摩尔),DMF(9.250毫升),并将溶液冷却至0℃然后加入氢化钠(133毫克,3.33毫摩尔)。观察到起泡。在0℃下搅拌20分钟后,加入2-碘丙烷(0.333毫升,3.33毫摩尔),并将反应液在0℃下搅拌9小时。将反应混合物冷却至0℃,用水(~30毫升)淬灭。用DCM(~70毫升)萃取,用盐水洗涤。干燥,过滤,浓缩,用CombiFlash(24克二氧化硅,MeOH/DCM=0~100%)纯化,得到6-(1-异丙基-1H-四唑-5-基)吡啶-2-胺为白色固体(24毫克,6.35%产率)。MS(m/z):205.10[M+H]+。
6-(1-环丙基-1H-四唑-5-基)吡啶-2-胺的合成(化合物7a):
按照路径2,使用与化合物3a类似的所述的方法制备化合物7a。氢核磁共振光谱(400兆赫,DMSO-d6)δ7.61(dd,J=8.4,7.3赫兹,1H),7.29(dd,J=7.3,0.8赫兹,1H),6.65(dd,J=8.4,0.9赫兹,1H),6.38(s,2H),4.79(m,1H),1.33–1.12(m,4H)。
6-(1-(1-(1-甲基环丙基)-1H-四唑-5-基)吡啶-2-胺的合成(化合物8a):
按照路径2,通过使用与化合物3a所述类似的方法制备化合物8a。氢核磁共振光谱(400兆赫,DMSO-d6)δ7.59(dd,J=8.4,7.3赫兹,1H),7.18(dd,J=7.3,0.8赫兹,1H),6.64(dd,J=8.4,0.9赫兹,1H),6.29(s,2H),1.72(s,3H),1.12(m,4H)。
实施例1a:5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-异丙基-1H-四唑-5-基)吡啶-2-基)-4-甲基苯甲酰胺
向5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸(382毫克,1.469毫摩尔)在DCM(20毫升)中的悬浮液中加入1-氯-N,N,2-三甲基丙-1-烯-1-胺(Ghosez试剂,0.324毫升,2.448毫摩尔)。将反应混合物在室温搅拌40分钟以形成澄清溶液,然后真空浓缩。将残余物(化合物8a)放入DCM(40.0毫升)中,冷却至0℃,然后加入6-(1-异丙基-1H-四唑-5-基)吡啶-2-胺溶液(3a)(加入250毫克,1.224毫摩尔)和吡啶(0.594毫升,7.34毫摩尔)的DCM(20毫升)溶液。使反应混合物升温至室温,并搅拌4小时。将混合物浓缩,然后用EtOAc和盐水稀释。用EtOAc萃取水层。合并的有机层经Na2SO4干燥并浓缩。将残余物通过硅胶色谱法纯化,使用己烷/丙酮/MeOH(100/0/0至50/40/10,15分钟),得到实施例1a的化合物,为白色泡沫(440毫克,81%)。LC-MS(m/z):M-1=445.18,计算值。445.20;计算为M+1=447.20。447.20。氢核磁共振光谱(400兆赫,DMSO-d6)δ11.08(s,1H),8.34–8.26(m,1H),8.14(t,J=8.0赫兹,1H),8.05–7.97(m,1H),7.73–7.63(m,2H),7.51(d,J=10.7赫兹,1H),7.19(d,J=1.5赫兹,1H),6.00(p,J=6.7赫兹,1H),2.26(s,3H),1.84(m,1H),1.56(d,J=6.6赫兹,6H),0.86-0.76(m,2H),0.70-0.68(m,2H)。
实施例2a:5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-环丙基-1H-四唑-5-基)吡啶-2-基)-4-甲基苯甲酰胺。
通过使用与实施例1a的化合物所述类似的方法,由化合物7a制备实施例2a。LC-MS(m/z):M-1=443.17,计算值。443.18。氢核磁共振光谱(400兆赫,DMSO-d6)δ11.09(s,1H),8.35(dd,J=8.4,0.9赫兹,1H),8.15(dd,J=8.4,7.6赫兹,1H),7.98(dd,J=7.6,0.9赫兹,1H),7.72–7.62(m,2H),7.50(d,J=10.8赫兹,1H),7.18(d,J=1.4赫兹,1H),4.86(m,1H),2.25(s,3H),1.85(m,1H),1.32–1.12(m,4H),0.85–0.74(m,2H),0.74–0.66(m,2H)。
实施例3a:5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-(1-甲基环丙基)-1H-四唑-5-基)吡啶-2-基)-4-甲基苯甲酰胺。
采用与实施例1a化合物相同的方法,由化合物8a制备实施例3a。LC-MS(m/z):M-1=457.19,计算值。457.20。氢核磁共振光谱(400兆赫,DMSO-d6)δ10.75(s,1H),8.36(dd,J=8.4,0.9赫兹,1H),8.14(dd,J=8.4,7.6赫兹,1H),7.86(dd,J=7.6,0.9赫兹,1H),7.73–7.65(m,2H),7.49(d,J=11.1赫兹,1H),7.19(d,J=1.3赫兹,1H),2.25(s,3H),1.85(m,1H),1.74(s,3H),1.15(q,J=2.6赫兹,4H),0.87–0.77(m,2H),0.73–0.67(m,2H)。
实施例4a:(S)-2-(5-(6-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-苯甲酰胺基)吡啶-2-基)-1H-四唑-1-基)乙酸丙酯。
步骤1:合成(S)-2-(叔丁氧羰基氨基)乙酸丙酯
在0℃下,向(S)-2-氨基丙-1-醇(2.1克,28.0毫摩尔)的DCM(60毫升)溶液中加入BOC2O(9.74毫升,41.9毫摩尔)。将混合物在0℃下搅拌30分钟,然后温热至室温并搅拌16小时。浓缩混合物,得到无色油状的(S)-(1-羟基丙烷-2-基)氨基甲酸叔丁酯。氢核磁共振光谱(400兆赫,氯仿-d)δ4.64(s,1H),3.77(s,1H),3.64(dd,J=11.0,3.8赫兹,1H),3.51(dd,J=11.0,6.2赫兹,1H),1.45(s,9H),1.27(s,1H),1.15(d,J=6.8赫兹,3H)。
向粗制的(S)-(1-羟基丙烷-2-基)氨基甲酸叔丁酯中加入DCM(60毫升),碳酸钠(5.93克,55.9毫摩尔),然后加入乙酰氯(3.18毫升,44.7毫摩尔),将混合物在室温搅拌4小时。将混合物通过硅藻土过滤,并将滤液浓缩。将残余物用乙酸乙酯稀释,用NaHCO3溶液、NaOH溶液、水和盐水洗涤。干燥有机层,过滤并浓缩,得到无色油状的(S)-2-((叔丁氧基羰基)氨基)丙基乙酸酯(5.61克,92%)。氢核磁共振光谱(400兆赫,氯仿-d)δ4.57(s,1H),4.06-3.86(m,3H),2.08(s,3H),1.45(s,9H),1.16(d,J=6.7赫兹,3H)。
步骤2:合成(S)-2-(6-硝基吡啶甲酰胺)乙酸丙酯
向6-硝基吡啶甲酸(200毫克,1.190毫摩尔)在DCM(3毫升)中的悬浮液和一滴DMF中滴加草酰氯(0.714毫升,1.428毫摩尔,2M在DCM中)。将所得混合物在室温搅拌2小时,得到澄清溶液。将所述溶液在真空下浓缩,并用DCM追踪,得到呈黄色固体的6-硝基吡啶甲酰氯。向装有(S)-2-((叔丁氧基羰基)氨基)乙酸丙酯(388毫克,1.785毫摩尔)的DCM(2毫升)溶液的另一个烧瓶中加入TFA(2毫升),并将混合物在室温下搅拌2小时。浓缩混合物,并用DCM追踪,得到(S)-2-氨基丙烷-1-醇的TFA盐。
在0℃下,向新鲜制备的6-硝基吡啶甲酰氯中加入DCM(0.5毫升),然后加入TFA盐(S)-2-氨基丙烷-1-醇的DCM溶液(2毫升)和三乙胺(0.497毫升,3.57毫摩尔)。将混合物温热至室温并保持16小时。将混合物浓缩并将残余物通过CombiFlash纯化,用己烷洗脱至己烷中的乙酸乙酯达70%,得到乙酸(S)-2-(6-亚硝基苯并氨基)丙酯(175毫克,55%)。氢核磁共振光谱(400兆赫,氯仿-d)δ8.58(dd,J=7.6,1.0赫兹,1H),8.39(dd,J=8.1,1.0赫兹,1H),8.23(dd,J=8.8,6.9赫兹,1H),7.93(d,J=8.8赫兹,1H),4.59–4.39(m,1H),4.21(qd,J=11.3,5.0赫兹,2H),2.11(d,J=3.4赫兹,3H),1.36(d,J=6.9赫兹,3H)。
步骤3:(S)-2-(5-(6-硝基吡啶-2-基)-1H-四唑-1-基)乙酸丙酯的合成
在0℃下,向(S)-2-(6-硝基吡啶甲酰胺)乙酸丙酯(175毫克,0.655毫摩尔)和迭氮化钠(68.1毫克,1.048毫摩尔)在乙腈(3毫升)中的溶液中加入三氟甲磺酸酐(0.982毫升,0.982毫摩尔,1M的DCM)。将所得混合物搅拌30分钟,然后温热至室温,并搅拌1小时。将混合物用乙酸乙酯稀释,用NaHCO3溶液淬灭。分离有机层,用盐水洗涤、干燥、过滤并浓缩。残余物通过CombiFlash纯化,用己烷洗脱至己烷中的60%乙酸乙酯,得到黄色油状的乙酸(S)-2-(5-(6-硝基吡啶-2-基)-1H-四唑-1-基)丙基(148毫克)。(0.506毫摩尔,77%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ8.79(dd,J=7.7,0.9赫兹,1H),8.43(dd,J=8.1,1.0赫兹,1H),8.33(t,J=7.9赫兹,1H),6.17(td,J=7.1,4.6赫兹,1H),4.62(qd,J=11.8,6.1赫兹,2H),1.89(s,3H),1.82(d,J=6.9赫兹,3H)。
步骤4:合成(S)-2-(5-(6-氨基吡啶-2-基)-1H-四唑-1-基)乙酸丙酯
溶于乙醇(0.8毫升)和乙酸(0.8毫升)中的(S)-2-(5-(6-硝基吡啶-2-基)-1H-四唑-1-基)乙酸丙酯(40毫克,0.137毫摩尔)向其中加入铁(76毫克,1.369毫摩尔),并将得到的混合物在90℃下搅拌2小时。将混合物通过硅藻土过滤,并将滤液浓缩,用DCM追踪。残余物通过CombiFlash纯化,用己烷洗脱至己烷中的乙酸乙酯为70%,得到乙酸(S)-2-(5-(6-氨基吡啶-2-基)-1H-四唑-1-基)丙基(28毫克),0.107毫摩尔,78%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ7.85–7.48(m,2H),6.62(dd,J=8.0,1.1赫兹,1H),6.30(m,1H),4.96–4.58(m,3H),4.32(dd,J=11.4,9.5赫兹,1H),1.85(s,3H),1.68(d,J=7.0赫兹,3H)。
步骤5:(S)-2-(5-(6-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-苯甲酰胺基)吡啶-2-基)-1H-四唑-1-基)乙酸丙酯的合成(实施例4a)。
向在DCM(1.5毫升)中的5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸(33.3毫克,0.128毫摩尔)中加入一滴DMF和草酰氯(0.080毫升,0.160毫摩尔,2M的DCM溶液)。将所述悬浮液在室温搅拌45分钟,并变成澄清溶液。将混合物浓缩并用DCM追踪。向所述残余物中加入在DCM(1.5毫升)中的(S)-2-(5-(6-氨基吡啶-2-基)-1H-四唑-1-基)丙基乙酸酯(28毫克,0.107毫摩尔)和吡啶(0.043毫升,0.534毫摩尔)。将混合物在室温搅拌16小时并浓缩。将残余物用乙酸乙酯稀释,用水、盐水洗涤,干燥,过滤并浓缩。残余物通过CombiFlash纯化,用己烷在乙酸乙酯中洗脱至10%的MeOH,得到(S)-2-(5-(6-(5-(4-(4-环丙基-1H-咪唑-1-基)-2-氟)-乙酸4-(4-甲基苯甲酰胺基)吡啶-2-基)-1H-四唑-1-基)丙酯(36毫克,0.071毫摩尔,66.8%产率)。LC/MS实测值[M+H]505.20;实测值505.20。氢核磁共振光谱(400兆赫,氯仿-d)δ9.18(d,J=9.9赫兹,1H),8.41(dd,J=8.4,0.9赫兹,1H),8.02(dd,J=7.6,0.9赫兹,1H),7.95–7.73(m,2H),7.36(d,J=1.4赫兹,1H),7.11(d,J=11.6赫兹,1H),6.69(d,J=1.4赫兹,1H),6.07(dqd,J=9.2,6.9,4.7赫兹,1H),4.55(dd,J=11.4,4.8赫兹,1H),4.29(dd,J=11.4,9.2赫兹,1H),2.18(s,3H),1.80(tt,J=8.3,5.1赫兹,1H),1.69(s,3H),1.61(d,J=6.9赫兹,3H),0.83–0.69(m,4H)。
实施例5a:(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-(1-羟基丙烷-2-基)-1H-四唑-5-基)吡啶-2-基)-4-甲基苯甲酰胺。
对在MeOH(1毫升)中的(S)-2-(5-(6-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰胺)吡啶-2-基)-1H-四唑-1-基)乙酸丙酯(26毫克,0.052毫摩尔)加入LiOH(0.077毫升,0.077毫摩尔,1N的水溶液),并将得到的混合物在室温搅拌30分钟。将混合物浓缩并将残余物通过CombiFlash纯化,用正己烷在乙酸乙酯中洗脱至10%甲醇,得到(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-(1-(1-羟基丙烷-2-基)-1H-四唑-5-基)吡啶-2-基)-4-甲基苯甲酰胺(19.5毫克,0.042毫摩尔,82%产率)。LC/MS实测值[M+H]463.19;实测值463.19。氢核磁共振光谱(400兆赫,氯仿-d)δ9.14(d,J=15.7赫兹,1H),8.45(dd,J=8.3,0.9赫兹,1H),8.18–7.91(m,3H),7.45(d,J=1.5赫兹,1H),7.25–7.16(m,1H),6.80(d,J=1.5赫兹,1H),5.71(dddd,J=11.0,7.8,6.9,4.1赫兹,1H),4.14–4.06(m,2H),2.30(s,3H),1.91(tt,J=8.3,5.1赫兹,1H),1.70(d,J=6.8赫兹,3H),1.00–0.73(m,4H)。
实施例6a:(R)-2-(5-(6-(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-苯甲酰胺基)吡啶-2-基)-1H-四唑-1-基)乙酸丙酯。
实施例6a通过使用与实施例4a化合物所述相似的方法制备。LC/MS实测值[M+H]505.20;实测值505.20。氢核磁共振光谱(500兆赫,氯仿-d)δ9.62–9.38(m,2H),8.38(d,J=8.3赫兹,1H),8.07(d,J=7.5赫兹,1H),8.02-7.98(m,1H),7.92(t,J=8.0赫兹,1H),7.21(d,J=10.0赫兹,1H),6.85(s,1H),6.21(d,J=10.3赫兹,1H),4.57(dd,J=11.6,4.2赫兹,1H),4.33(dd,J=11.4,8.8赫兹,1H),2.30(s,3H),1.97(s,1H),1.73(s,3H),1.65(d,J=6.7赫兹,3H),1.10–0.87(m,4H)。
实施例7a:(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-(1-羟基丙-2-基)-1H-四唑-5-基)吡啶-2-基)-4-甲基苯甲酰胺。
实施例7a通过使用与实施例5a化合物所述相似的程序制备。LC/MS实测值[M+H]463.19;实测值463.19。氢核磁共振光谱(400兆赫,氯仿-d)δ9.13(d,J=14.8赫兹,1H),8.34(dd,J=8.4,0.9赫兹,1H),8.08–7.95(m,2H),7.90(t,J=8.0赫兹,1H),7.46(d,J=1.4赫兹,1H),7.12(d,J=12.2赫兹,1H),6.71(d,J=1.4赫兹,1H),5.82–5.52(m,1H),4.15–3.88(m,2H),2.21(s,3H),1.82(tt,J=8.3、5.1赫兹,1H),1.59(d,J=6.8赫兹,3H),0.87–0.69(m,4H)。
实施例19a
在0℃下,在DCM(7.3毫升)中的(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-(1-羟基丙烷-2-基)-1H-四唑-5-基)吡啶-2-基)-4-甲基苯甲酰胺(681毫克,1.47毫摩尔)溶液加入Dess-Martin高碘烷(750毫克,1.77毫摩尔)。将反应在0℃下搅拌1小时,用饱和碳酸氢钠水溶液淬灭。Na2S2O3溶液,用DCM(X3)萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。所得白色固体无需任何纯化即可直接用于以下转化。
向先前的粗产物(36毫克,0.075毫摩尔)的悬浮液2-甲基丁-2-烯(2.0M在THF中,0.19毫升)和NaH2PO4(13.5毫克,0.113毫摩尔)在tBuOH/水(0.8毫升,4/1)中,向其中加入NaClO2(34毫克,0.3毫摩尔)。将反应在室温搅拌3小时,用20%柠檬酸水溶液淬灭。溶液,并用EtOAc(X3)萃取。合并的EtOAc层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。将残余物通过硅胶色谱法纯化(0至10%MeOH的DCM溶液),得到实施例19a,为白色固体(12.8毫克,36%产率)。LC/MS实测值[M+1]:477.17。氢核磁共振光谱(400兆赫,DMSO-d6)δ11.08(s,1H),8.26(d,J=8.3赫兹,1H),8.08(t,J=8.0赫兹,1H),7.92(d,J=7.6赫兹),1H),7.72(d,J=1.4赫兹,1H),7.67(d,J=6.4赫兹,1H),7.48(d,J=10.7赫兹,1H),7.21(s,1H),6.02(s,br,1H),2.26(s,3H),1.89–1.83(m,1H),1.78(d,J=7.2赫兹,3H),0.80(dt,J=8.4,3.1赫兹,2H),0.73–0.68(m,2H)。
实施例29a
将DMSO(10毫升)中的4-叔丁基-1H-咪唑(130毫克,1.05毫摩尔),5-溴-2-氟-4-甲基苯甲酸(200毫克,0.86毫摩尔),Cu2O(7毫克,0.04毫摩尔),8-羟基喹啉(25毫克,0.17毫摩尔)和K3PO4(912毫克,4.3毫摩尔)的混合物在100℃下搅拌16小时。将反应冷却至室温,用60毫升水淬灭,通过8M HCl调节至pH 5,并用EtOAc(50毫升×2)萃取。有机层经饱和Na2SO4干燥并蒸发。通过制备型HPLC用0至100%MeCN/H2O纯化残留物,得到100毫克(42.2%)5-(4-叔丁基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸为白色固体。
将5-(4-叔丁基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸(60毫克,0.22毫摩尔)和(1-氯-2-甲基丙-1-烯-1-基)二甲基胺(36毫克,0.27毫摩尔)在DCM(2毫升)中的混合物在室温搅拌1小时。向上述混合物中加入吡啶(52毫克,0.66毫摩尔)和6-(1-异丙基-1H-四唑-5-基)吡啶-2-胺(68毫克,0.3毫摩尔)。将所得混合物在室温下再搅拌1小时。真空除去溶剂,并将残余物通过反相色谱法纯化,使用0至60%的MeCN/H2O,得到实施例29a(8.4毫克),为白色固体。
实施例30a
将5-(4-叔丁基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸(60毫克,0.22毫摩尔)和(1-氯-2-甲基丙-1-烯-1-基)二甲基胺(36毫克,0.27毫摩尔)在DCM(2毫升)中的混合物在室温搅拌1小时。向上述混合物中加入吡啶(52毫克,0.66毫摩尔)和(R)-2-(5-(6-氨基吡啶-2-基)-1H-四唑-1-基)丙基乙酸酯(87毫克,0.33毫摩尔)。将所得混合物在室温下再搅拌1小时。真空除去溶剂,并将残余物通过反相色谱法纯化,用0至60%MeCN/H2O纯化,得到(R)-2-(5-(6-(5-(4-(4-叔丁基-1H)-咪唑-呈白色固体状的乙酸1-yl)-2-氟-4-甲基苯甲酰胺基吡啶-2-基)-1H-四唑-1-基)丙基乙酸酯(50毫克,44%)。
将K2CO3(73毫克,0.53毫摩尔)添加到(R)-2-(5-(6-(5-(4-叔丁基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰胺基)吡啶-2-基)-1H-四唑-1-基)丙基乙酸酯(50毫克,0.096毫摩尔)在MeOH(5毫升)中的溶液。将得到的混合物在室温搅拌2小时。浓缩反应物,并通过制备型HPLC用0-100%MeCN/H2O纯化粗产物,得到16.3毫克的实施例30的白色固体。
按照与实施例29a类似的流程制备实施例27a。
按照与实施例30a类似的流程制备实施例28a。
实施例31a
步骤1:合成5-溴-2-氟-4-甲基苯甲酸甲酯
向5-溴-2-氟-4-甲基苯甲酸(5克,21.46毫摩尔)在MeOH(7毫升)中的悬浮液中逐滴添加浓硫酸(0.114毫升,2.15毫摩尔)。将所得溶液在回流下搅拌直至完成。然后将反应冷却至室温并浓缩。将粗产物溶解在EtOAc中并被碳酸氢钠溶液碱化。用EtOAc(X3)萃取水层。合并的EtOAc层用盐水洗涤并通过Na2SO4干燥。过滤并浓缩,得到5-溴-2-氟-4-甲基苯甲酸甲酯,为白色固体(4.06克,77%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ8.09(d,J=6.9赫兹,1H),7.04(d,J=11.0赫兹,1H),3.92(s,3H),2.43(s,3H)。
步骤2:合成5-溴-4-(二溴甲基)-2-氟苯甲酸甲酯
向5-溴-2-氟-4-甲基苯甲酸甲酯(3.13克,12.67毫摩尔)在CCl4(40毫升)中的溶液中添加NBS(6.76克,38毫摩尔)和过氧化苯甲酰(0.307克,1.27毫摩尔)。将反应在90℃下搅拌过夜。将粗产物冷却至室温,并通过短的硅藻土塞过滤,并用TBME洗涤两次。然后将滤液浓缩并通过硅胶色谱法纯化(0至10%EtOAc的己烷溶液),得到5-溴-4-(二溴甲基)-2-氟苯甲酸甲酯,为无色油状物(4.86克,95%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ8.10(d,J=6.6赫兹,1H),7.82(d,J=10.9赫兹,1H),6.94(d,J=1.2赫兹,1H),3.95(s,3H)。
步骤3:合成5-溴-2-氟-4-甲酰基苯甲酸甲酯
向5-溴-4-(二溴甲基)-2-氟苯甲酸甲酯(4.86克,12.0毫摩尔)在THF/水(3/1,60毫升)中的悬浮液中添加AgNO3(6.12克,36毫摩尔)。将反应在80℃下搅拌2小时。将粗产物用水淬灭,并用EtOAc(X3)萃取。合并的EtOAc层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。将残余物通过硅胶色谱法纯化(0至20%EtOAc的己烷溶液),得到5-溴-2-氟-4-甲酰基苯甲酸甲酯,为白色固体(2.76克,88%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ10.32(d,J=2.7赫兹,1H),8.23(d,J=6.1赫兹,1H),7.68(d,J=10.0赫兹,1H),3.98(s,3H)。
步骤4:5-溴-4-(二氟甲基)-2-氟苯甲酸甲酯的合成
在0℃下向5-溴-2-氟-4-甲酰基苯甲酸甲酯(2.03克,7.79毫摩尔)在DCM(20毫升)中的溶液中加入脱氧氟(9.23毫升,24.9毫摩尔)。然后将反应在室温搅拌过夜。反应用NaHCO3水溶液在0℃淬灭,并用DCM(X3)萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。粗产物通过硅胶色谱法纯化(0至10%MTBE的己烷溶液),得到5-溴-4-(二氟甲基)-2-氟苯甲酸甲酯,为浅黄色油状物(1.55克,70%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ8.18(d,J=6.4赫兹,1H),7.46(d,J=10.3赫兹,1H),6.85(td,J=54.3,0.9赫兹,1H),3.96(s,3H)。
步骤5:(5-溴-4-(二氟甲基)-2-氟苯基)甲醇的合成
在0℃下向5-溴-4-(二氟甲基)-2-氟苯甲酸甲酯(310毫克,1.1毫摩尔)在THF(5.5毫升)中的溶液中加入DIBAL-H(1.0M甲苯溶液,3.3毫升,3.3毫摩尔)将反应在相同温度下搅拌3小时,然后小心地用10%罗谢尔盐水溶液淬灭。将粗产物在室温搅拌1小时,并用EtOAc(X3)萃取。合并的EtOAc层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。粗产物通过硅胶色谱法纯化(0至30%EtOAc的己烷溶液),得到(5-溴-4-(二氟甲基)-2-氟苯基)甲醇,为无色油状物(252.3毫克,90%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ7.75(d,J=6.5,1H),7.35(d,J=9.8赫兹,1H),6.85(td,J=54.7,1.2赫兹,1H),4.80(s,2H)。
步骤6:((5-溴-4-(二氟甲基)-2-氟芐基)氧基)(叔丁基)二甲基硅烷的合成
向(5-溴-4-(二氟甲基)-2-氟苯基)甲醇(252.3毫克,0.99毫摩尔)的THF(5毫升)溶液中加入TBSCl(164毫克,1.09毫摩尔)和咪唑(168毫克,2.47毫摩尔)。将悬浮液在室温搅拌3天。将反应物过滤并浓缩。粗产物通过硅胶色谱法纯化(0至20%MTBE的己烷溶液),得到((5-溴-4-(二氟甲基)-2-氟芐基)氧基)(叔丁基)二甲基硅烷,为无色油状物(327毫克,产率90%)。氢核磁共振光谱(400兆赫,氯仿-d)δ7.73(dt,J=6.5,1.2赫兹,1H),7.31(d,J=9.9赫兹,1H),6.85(td,J=54.8,1.2赫兹,1H),4.79(s,2H),0.96(s,9H),0.13(s,6H)。
步骤7:1-(5-(((叔丁基二甲基甲硅烷基)氧基)甲基)-2-(二氟甲基)-4-氟苯基)-4-环丙基-1H-咪唑的合成
向反应瓶中加入在甲苯/1,4-二恶烷(1.0毫升,4/1)中的三(二亚芐基丙酮)二钯(0)(32.4毫克,0.035毫摩尔)和甲基四丁基磷(42.6毫克,0.089毫摩尔),并加热至120℃持续3分钟以进行预络合。将得到的深色溶液冷却至室温,并转移至装有((5-溴-4-(二氟甲基)-2-氟芐基)氧基)(叔丁基)二甲基硅烷(327毫克,0.885毫摩尔)、4-环丙基-1H-咪唑(192毫克,1.771毫摩尔)和K3PO4(376毫克,1.771毫摩尔)的甲苯/1,4-二氧六环(3.4毫升,4/1)中。反应混合物在氮气下剧烈脱气,并在120℃下搅拌过夜。反应冷却至室温,过滤并浓缩。用硅胶柱层析(0至30%EtOAc的己烷溶液)纯化粗产物,得到1-(5-(((叔丁基二甲基甲硅烷基)氧基)甲基)-2-(二氟甲基)-4-氟苯基)-4-环丙基-1H-咪唑,为浅棕色油状物(130毫克,37%产率)。
步骤8:(5-(4-环丙基-1H-咪唑-1-基)-4-(二氟甲基)-2-氟苯基)甲醇的合成
向1-(5-(((叔丁基二甲基甲硅烷基)氧基)甲基-2-(二氟甲基)-4-氟苯基)-4-环丙基-1H-咪唑(130毫克,0.328毫摩尔)的THF(1.6)溶液中加入TBAF(1.0M的THF溶液,0.66毫升,0.66毫摩尔)。将反应在室温搅拌1小时,用水淬灭,并用EtOAc(X3)萃取。合并的EtOAc层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过硅胶色谱法(0至100%EtOAc的己烷溶液)纯化粗产物,得到(5-(4-环丙基-1H-咪唑-1-基)-4-(二氟甲基)-2-氟苯基)甲醇,白色固体(58毫克,63%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ7.60(s,1H),7.55(d,J=6.3赫兹,1H),7.45(d,J=9.5赫兹,1H),6.86(s,1H),6.39(t,=54.2赫兹,1H),4.87(s,2H),1.97–1.79(m,1H),0.98–0.90(m,2H),0.86–0.76(m,2H)。
步骤9:5-(4-环丙基-1H-咪唑-1-基)-4-(二氟甲基)-2-氟苯甲醛的合成
于0℃下在DCM(0.92毫升)中向(5-(4-环丙基-1H-咪唑-1-基)-4-(二氟甲基)-2-氟苯基)甲醇(52毫克,0.184毫摩尔)的溶液中添加dess-马丁高碘酸盐(156毫克,0.368毫摩尔)。反应在0℃下搅拌1小时,用硫酸钠饱和水溶液淬火并用DCM(X3)萃取。用盐水冲洗结合的DCM层,经Na2SO4干燥,过滤并浓缩。粗产物在硅胶(己烷中0->50%丙酮)上通过色谱纯化,得到5-(4-环丙基-1H-咪唑-1-基)-4-(二氟甲基)-2-氟苯甲醛,无色油状(50毫克,97%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ10.40(s,1小时),7.98(s,1小时),7.88(d,J=5.8赫兹,1小时),7.67(d,J=9.6赫兹,1小时),6.88(s,1小时),6.53(t,J=54.0赫兹,1小时),2.00–1.93(m,1小时),1.04–0.96(m,2小时),0.94–0.85(m,2小时)。
步骤10:5-(4-环丙基-1H-咪唑-1-基)-4-(二氟甲基)-2-氟苯甲酸的合成
向5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲醛(50毫克,0.178毫摩尔)、2-甲基丁烯-2-烯(于THF中2.0M,2.2毫升)和KH2PO4(170毫克,1.25毫摩尔)在tBuOH/H2O(0.9毫升,4/1)中的悬浮液中添加NaClO2(182毫克,1.61毫摩尔)。反应在室温下搅拌过夜,用饱和NH4Cl溶液淬火。用EtOAc(X3)溶解并萃取。将合并的EtOAc层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。粗产物经硅胶层析纯化(DCM中0->100%甲醇),得到为白色固体的5-(4-环丙基-1H-咪唑-1-基)-4-(二氟甲基)-2-氟苯甲酸(25毫克,收率47%)。氢核磁共振光谱(500m赫兹,DMSO-d6)δ7.65(s,1小时),7.58(s,br,2小时),7.16(s,1小时),6.84(t,J=54.0赫兹,1小时),1.89-1.82(m,1小时),0.85-0.74(m,2小时),0.74-0.58(m,2小时)。
第11步:5-(4-环丙基-1H-咪唑-1-基)-4-(二氟甲基)-2-氟-N-(6-(1-异丙基-1H-四唑-5-基)吡啶-2-基)苯甲酰胺的合成
5-(4-环丙基-1H-咪唑-1-基)-4-(二氟甲基)-2-氟-N-(6-(1-异丙基-1H-四唑-5-基)吡啶-2-基)苯甲酰胺的制备方法与实施例31a的化合物的制备方法类似。LC/MS观察到[M+1]:483.18。3,8.4,5.0赫兹,1小时),1.55(d,J=6.6赫兹,6小时),0.84–0.78(m,2小时),0.72(dt,J=5.1,2.9赫兹,2小时)。
实施例32a是按照与实施例31a类似的流程制备的。
实施例33a
步骤1:合成5-溴-2-氟-4-(羟甲基)苯甲酸甲酯
在室温下,向5-溴-2-氟-4-甲酰基苯甲酸甲酯(3.5克,13.4毫摩尔)在THF(27毫升)中的溶液中添加NaBH4(0.534克,14.1毫摩尔)。使所得悬浮液冷却至0℃,然后加入MeOH(0.57毫升,1.41毫摩尔)。将反应在室温搅拌过夜,然后在0℃用水小心淬灭。粗产物用EtOAc(X3)萃取。合并的EtOAc层用盐水洗涤,经Na2SO4干燥,过滤并浓缩,得到白色固体。所得粗物质无需任何纯化即可直接用于随后的转化中。
步骤2:合成5-溴-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯甲酸甲酯
向0℃下的5-溴-2-氟-4-(羟甲基)苯甲酸甲酯(0.891克,3.39毫摩尔)和DIPEA(1.18毫升,6.77毫摩尔)在DCM(11毫升)中的溶液中添加MEMCl(0.65毫升,5.42毫摩尔)。将所得溶液在0℃下搅拌1小时,然后加热至室温过夜。用饱和碳酸钠水溶液淬灭反应,并用DCM(X3)萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。将粗产物通过硅胶色谱法纯化(0至30%EtOAc的己烷溶液),得到5-溴-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯甲酸甲酯,为无色油状物(923.8毫克,产率为78%)。氢核磁共振光谱(400兆赫,氯仿-d)δ8.10(d,J=6.6赫兹,1H),7.35(d,J=11.4赫兹,1H),4.89(s,2H),4.66(s,2H),3.93(s,3H),3.79–3.74(m,2H),3.60–3.53(m,2H),3.40(s,3H)。
步骤3:(5-溴-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯基)甲醇的合成
在0℃下向5-溴-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯甲酸甲酯(3.03克,8.63毫摩尔)在THF(28.8毫升)中的溶液中添加DIBAL-H(1.0M的甲苯溶液,25.9毫升,25.9毫摩尔)。将反应在相同温度下搅拌3小时,然后小心地用10%罗谢尔盐水溶液淬灭。将粗产物在室温搅拌1小时,并用EtOAc(X3)萃取。合并的EtOAc层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过硅胶色谱法(0至70%EtOAc的己烷溶液)纯化粗产物,得到(5-溴-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯基)甲醇,为无色油状物(2.14克,77%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ7.62(d,J=6.8赫兹,1H),7.23(d,J=10.6赫兹,1H),4.87(s,2H),4.74(s,2H),4.64(s,2H),3.79–3.75(m,2H),3.62–3.55(m,2H),3.40(s,3H)。
步骤4:(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯基)甲醇的合成
向微波反应容器中加入(5-溴-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯基)甲醇(640毫克,1.98毫摩尔)、4-环丙基-1H-咪唑(428毫克,3.96毫摩尔)、Cu2O(28.3毫克,0.198毫摩尔)、8-羟基喹啉(57.5毫克,0.396毫摩尔)和K3PO4(841毫克,3.96毫摩尔)在DMSO(6.6毫升)中的溶液。用氮气(X 3)吹扫反应,并在160℃下照射1小时。用水淬灭反应,并用DCM(X3)萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。将粗产物通过硅胶色谱法纯化(0至10%MeOH的DCM溶液),得到(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-((((2-甲氧基乙氧基))(甲氧基)甲基)苯基)甲醇(534.3毫克,产率77%),为深色油状物。氢核磁共振光谱(400兆赫,DMSO-d6)δ7.61(d,J=1.4赫兹,1H),7.38(d,J=6.赫兹,1H),7.35(d,J=10.5赫兹,1H),7.11(d,J=1.4赫兹,1H),5.40(t,J=5.7赫兹,1H),4.66(s,2H),4.58(d,J=5.7赫兹,2H),4.37(s,2H),3.57–3.52(m,2H),3.44–3.39(m,2H),3.22(s,3H),1.89–1.77(m,1H),0.82–0.77(m,2H),0.71–0.66(m,2H)。
步骤5:5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯甲醛的合成
在0℃下向(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯基)甲醇(534毫克,1.52毫摩尔)的DCM溶液中加入(7.6毫升)dess-马丁高碘酸盐(776毫克,1.83毫摩尔)。将反应在0℃下搅拌1小时,用饱和碳酸氢钠水溶液淬灭,用DCM(X3)萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过硅胶色谱法(0至5%MeOH的DCM溶液)纯化粗产物,得到浅黄色固体形式的5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(((2-甲氧基乙氧基)甲氧基)甲基)苯甲醛(171毫克,32%产率)。氢核磁共振光谱(400兆赫,DMSO-d6)δ10.20(s,1H),7.77(d,J=6.3赫兹,1H),7.70(d,J=1.4赫兹,1H),7.61(d,J=11.1赫兹),1H),7.20(d,J=1.4赫兹,1H),4.71(s,2H),4.49(s,2H),3.61-3.55(m,2H),3.47-3.39(m,2H),3.21(s,3H),1.90–1.79(m,1H),0.86–0.80(m,2H),0.73–0.64(m,2H)。
步骤6:5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯甲酸的合成
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-((((2-甲氧基乙氧基)甲氧基)甲基)苯甲醛(170毫克,0.488毫摩尔),2-甲基丁2加入叔丁基苯(2.0M,在THF中,1.13毫升)和NaH2PO4(82毫克,0.683毫摩尔)在tBuOH/H2O(4.9毫升,4/1)中的悬浮液,加入NaClO2(123毫克,0.98毫摩尔)。将反应在室温搅拌过夜,用饱和Na2SO3水溶液淬灭,并用DCM(X3)萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥,过滤并浓缩,得到80毫克浅黄色固体粗物质,其无需任何纯化即可直接用于随后的转化中。
步骤7:合成(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(羟甲基)-N-(6-(1-(1-羟丙烷-2-yl)-1H-四唑-5-基)吡啶-2-基)苯甲酰胺
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(羟甲基)-N-(6-(1-(1-(1-羟丙-2-基)-1H-通过使用与实施例33a化合物所述相似的方法制备四唑-5-基)吡啶-2-基)苯甲酰胺。观察到的LC/MS[M+1]:479.20。氢核磁共振光谱(400兆赫,DMSO-d6)δ11.13(s,1H),8.31(d,J=8.3赫兹,1H),8.14(t,J=8.0赫兹,1H),7.97(d,J=7.7赫兹,1H),7.72(s,1H),7.70(d,J=6.3赫兹,1H),7.55(d,J=10.7赫兹,1H),7.22(s,1H),5.92–5.82(m,1H),5.62(t,J=5.4赫兹,1H),4.91(t,J=5.6赫兹,1H),4.42(d,J=5.5赫兹,2H),3.79–3.68(m,2H),1.85(td,J=8.4,4.2赫兹,1H),1.55(d,J=6.8赫兹,3H),0.81(dt,J=8.5,3.0赫兹,2H),0.73-0.67(m,2H)。
实施例37a
在0℃下,将硼烷二甲硫醚络合物(0.36毫升,3.8毫摩尔)逐滴添加至5-溴-2-氟-4-(三氟甲基)苯甲酸(344毫克,1.2毫摩尔)的THF(3.4毫升)溶液中。将反应搅拌过夜,逐渐升温至室温。将反应冷却至0℃,并用MeOH小心淬灭。将得到的混合物在减压下浓缩。所得无色油通过柱色谱法纯化,用己烷/EtOAc(0%EtOAc至20%EtOAc)洗脱,得到(5-溴-2-氟-4-氟-4-(三氟甲基)苯基)甲醇(295毫克,1.1毫摩尔,90产率%)为无色固体:氢核磁共振光谱(400兆赫,氯仿-d)δ7.86(dd,J=6.6,0.9赫兹,1H),7.39(d,J=9.9赫兹,1H),4.82(s,2H),1.87(br s,1H)。
将TBS-Cl(280毫克,1.86毫摩尔)添加到(5-溴-2-氟-4-(三氟甲基)苯基)甲醇(362毫克,1.33毫摩尔)和咪唑(253毫克,3.71毫摩尔)的DMF溶液中(2.7毫升),反应在环境温度下搅拌6小时。用水淬灭反应,并用MTBE稀释。分离各层,并将水层用MTBE(1×10毫升)萃取。合并的有机层用10%柠檬酸、水、饱和NaHCO3溶液和盐水洗涤。干燥(MgSO4)有机层,过滤,并在减压下浓缩。所得无色油通过柱色谱法纯化,用己烷/EtOAc(0%EtOAc至4%EtOAc)洗脱,得到((5-溴-2-氟-4-(三氟甲基)芐基)氧基)(叔丁基)二甲基硅烷(423毫克,1.09毫摩尔,82%产率),为无色油状:氢核磁共振光谱(500兆赫,氯仿-d)δ7.84(d,J=6.7赫兹,1H),7.34(d,J=9.9赫兹,1H),4.80(s,2H),0.96(s,9H),0.14(s,6H)。
将Pd2(dba)3(9.5毫克,10.3微摩尔)和甲基叔丁基磷(12.4毫克,0.03毫摩尔)在0.5毫升4:1PhMe:1,4-二恶烷中的混合物吹入氮气2分钟。将反应在120℃下加热5分钟以预形成活性Pd物质。将反应冷却至室温。在一个单独的小瓶中,将((5-溴-2-氟-4-氟-4-(三氟甲基)芐基)氧基)(叔丁基)二甲基硅烷(100毫克,0.26毫摩尔),4-环丙基-1H-咪唑(55.8,在0.7毫升4:1PhMe:1,4-二恶烷中的K3PO4(110毫克,0.52毫摩尔)和氮气鼓泡5分钟。将催化剂溶液加入到剩余的反应混合物中,并将反应在120℃加热过夜。通过硅藻土过滤反应,用DCM冲洗,并在减压下浓缩。所得棕色油状物通过柱色谱法纯化,用己烷/EtOAc(0%EtOAc→20%EtOAc)洗脱,得到浅黄色油状的1-(5-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-氟-2-(三氟甲基)苯基)-4-环丙基-1H-咪唑(23.3毫克,0.06毫摩尔,产率22%)。:LCMS(m/z)415.17[M+1];氢核磁共振光谱(400兆赫,氯仿-d)δ7.70(s,1H),7.55(d,J=6.2赫兹,1H),7.47(d,J=9.4赫兹,1H),6.84(s,1H),4.85(s,2H),1.98(ddd,J=13.3,8.4,5.1赫兹,1H),0.98(dt,J=8.0,2.7赫兹,2H),0.94-0.91(comp,11H),0.14(s,6H)。
将TBAF(0.11毫升的1.0M THF溶液,0.11毫摩尔)逐滴添加至在THF(0.79毫升)中的1-(5-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-氟-2-(三氟甲基)苯基)-4-环丙基-1H-咪唑的溶液中(23毫克,0.06毫摩尔),将反应搅拌1小时。通过柱色谱法纯化反应,用己烷/EtOAc(0%EtOAc至80%EtOAc)洗脱,得到黄色固体的(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(三氟甲基)苯基)甲醇(12.8毫克,0.04毫摩尔,77%产率):LCMS(m/z)301.07[M+1];氢核磁共振光谱(400兆赫,氯仿-d)δ8.02(s,1H),7.69(d,J=6.2赫兹,1H),7.40(d,J=9.3赫兹,1H),6.81(s,1H),4.82(s,2H),1.90(tt,J=8.3,5.1赫兹,1H),0.98–0.89(m,2H),0.89–0.79(m,2H)。
在0℃下将于DCM(0.37毫升)中dess-马丁高碘酸盐(62.7毫克,0.15毫摩尔)添加到(5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(三氟甲基)苯基)甲醇(22.2毫克,加入0.07毫摩尔),并将反应在0℃下搅拌1.5小时。用饱和Na2S2O3淬灭反应。并用DCM(3×2毫升)萃取。将合并的有机层干燥(MgSO4),过滤,并在减压下浓缩。所得浅黄色粗产物通过柱色谱法纯化,用己烷/EtOAc(0%EtOAc至55%EtOAc)洗脱,得到5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(三氟甲基)苯甲醛(21毫克,0.07毫摩尔,95%产率),为无色胶状物:LCMS(m/z)299.06[M+1];氢核磁共振光谱(400兆赫,氯仿-d)δ10.40(s,1H),7.87(d,J=6.0赫兹,1H),7.67(d,J=9.6赫兹,1H),7.49(s,1H),6.81(s,1H),1.89(tt,J=8.3,5.1赫兹,1H),0.93–0.85(m,2H),0.85–0.78(m,2H)。
将亚氯酸钠(71.6毫克,0.63毫摩尔)添加到5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(三氟甲基)苯甲醛(21毫克,0.07毫摩尔)、2-甲基丁-2-烯(0.88毫升的2.0M THF溶液,1.76毫摩尔)和磷酸二氢钾(67.1毫克,0.49毫摩尔)的THF(0.75毫升)/水(0.25毫升)溶液,搅拌反应1小时用饱和NH4Cl(5毫升)淬灭反应,并用EtOAc(5毫升)稀释。分离各层,水层用EtOAc(2×5毫升)萃取。将合并的有机层干燥(MgSO4),过滤,并在减压下浓缩。所得白色固体通过柱色谱法纯化,用CH2Cl2/MeOH(0%MeOH至25%MeOH)洗脱,得到5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(三氟甲基)苯甲酸(10.7毫克,0.03毫摩尔,产率48%),为白色固体:LCMS(m/z)315.05[M+1];氢核磁共振光谱(400兆赫,甲醇-d4)δ8.19(s,1H),7.97(d,J=6.1赫兹,1H),7.80(d,J=9.8赫兹,1H),7.23(s,1H),1.94(ddd,J=8.5,5.1,3.4赫兹,1H),1.01–0.93(m,2H),0.82–0.75(m,2H)。
将草酰氯(7微升,0.08毫摩尔)添加到5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(三氟甲基)苯甲酸(6毫克,0.02毫摩尔)和在DCM(55微升)中的DMF(1滴)中,将反应搅拌30分钟。将反应物减压浓缩并真空干燥。所得黄色粗产物无需纯化即可直接用于下一步。
将6-(1-异丙基-1H-四唑-5-基)吡啶-2-胺(5.9毫克,0.03毫摩尔)添加至5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-(三氟甲基)苯甲酰氯(6.4毫克,0.02毫摩尔)在DCM(27微升)/吡啶(27微升)的溶液中。将反应搅拌1小时。减压浓缩反应物。通过柱色谱法纯化得到橙色粗产物,用CH2Cl2/MeOH(0%MeOH至5%MeOH)洗脱,得到实施例37a(4.2毫克,8.4毫摩尔,44%收率),为透明胶状物。
实施例40a
步骤1:将4-环丙基-1H-咪唑(1.95克,18.1毫摩尔)、2-氯-5-氟-4-碘吡啶(3.1克,12.0毫摩尔)、Cu2O(105毫克,0.6毫摩尔)、8-羟基喹啉(353毫克,2.4毫摩尔)以及Cs2CO3(11.7g,36毫摩尔)的混合物在丁腈(100毫升)中在65℃下搅拌16小时。冷却至室温后,加入100毫升水,并将所得混合物用EtOAc(100毫升×2)萃取。有机层经Na2SO4干燥,过滤并蒸发。残余物通过硅胶柱色谱法用PE/EtOAc(3∶1)纯化,得到1.7克(57%)的为白色固体的2-氯-4-(4-环丙基-1H-咪唑-1-基)-5-氟吡啶。
步骤2:在50毫升高压釜中,将2-氯-4-(4-环丙基-1H-咪唑-1-基)-5-氟吡啶(1.7克,7.1毫摩尔),Pd(dppf)Cl2(539毫克、0.7毫摩尔)和Et3N(2.13克,21毫摩尔)在BuOH(30毫升)中的混合物在70℃下于10个大气压的一氧化碳中搅拌16小时。将得到的混合物在减压下浓缩。残余物通过硅胶柱色谱法用PE/EtOAc(3∶1)纯化,得到呈黄色油状的4-(4-环丙基-1H-咪唑-1-基)-5-氟吡啶甲酸丁酯(1.6克,73.7%)。
步骤3:向在乙腈(5毫升)中的4-(4-环丙基-1H-咪唑-1-基)-5-氟吡啶甲酸丁酯(800毫克,2.64毫摩尔)溶液中加入1M HCl(5毫升)。将所得混合物在氮气下在100℃下搅拌过夜。减压除去溶剂。将残余物通过反相色谱法纯化,用0%至30%MeCN/水纯化,得到4-(4-环丙基-1H-咪唑-1-基)-5-氟吡啶-2-羧酸(320毫克,49.0%),为白色固体。
步骤4:将4-(4-环丙基-1H-咪唑-1-基)-5-氟吡啶-2-羧酸(300毫克,1.21毫摩尔)、6-[1-(丙-2-基)-1H-1,2,3,4-四唑-5-基]吡啶-2-胺(371.7毫克,1.82毫摩尔)、HATU(922.8毫克,2.43毫摩尔)和NMM(368.2毫克,3.64毫摩尔)在DMF(5毫升)中的混合物在室温下搅拌过夜。溶剂在真空下被除去。用0-60%CH3CN/水通过反相色谱法纯化粗产物,为白色固体,得到实例39a(100毫克,19.01%)。
步骤5:将实施例39a(20毫克,50毫摩尔)溶解于哌啶(1毫升)中并在70℃下搅拌1小时。在真空下浓缩所得混合物。用0至75%CH3CN/水通过反相色谱法纯化粗产物,为浅棕色固体,得到实例40a(7毫克,30.4%)。
实施例41a
步骤1:将4-(4-环丙基-1H-咪唑-1-基)-5-氟吡啶-2-羧酸(200毫克,0.8毫摩尔)、2-(1-异丙基-1H-四唑-5-基)噻唑-4-胺(245.3毫克,1.2毫摩尔)、HATU(615.2毫克,1.6毫摩尔)和NMM(254.4毫克,2.4毫摩尔)在DMF(5毫升)中的混合物在室温下搅拌过夜。所得混合物在真空下浓缩。用0至60%的CH3CN/H2O通过反相色谱纯化粗产物,得到实例38a(160毫克,45.5%),为白色固体。
步骤2:将实施例38(30毫克,0.068毫摩尔)在哌啶(1毫升)中的溶液在70℃下搅拌1小时。在真空下浓缩反应混合物。用0至75%的CH3CN/H2O通过反相色谱法纯化粗产物,为浅棕色固体,得到实例41(12毫克,34.8%)。
实施例42a、44a和45a是按照与实施例41a类似的流程制备的。
实施例43a、46a和47a是按照与实施例40a类似的流程制备的。
实施例52a
实施例52a
步骤1:将4-溴-2-氯-5-甲基吡啶(600毫克,2.9毫摩尔)添加到4-(叔丁基)-1H-咪唑(431毫克,3.48毫摩尔)和Cs2CO3(2.83克,8.7毫摩尔)的DMF(2毫升)溶液的混合物中。将所得溶液在100℃下搅拌过夜。将混合物冷却至室温,用EtOAc(100毫升)稀释,并用水(30毫升×2)和盐水(30毫升)洗涤。有机层经Na2SO4干燥,过滤,并真空浓缩。用30%EtOAc/PE在硅胶柱上纯化残余物,得到400毫克(55%)4-(4-(叔丁基)-1H-咪唑-1-基)-2-氯-5-甲基吡啶,为浅黄色固体。
步骤2:在50毫升高压釜中,将2-氯-5-甲基-4-(4-(三氟甲基)-1H-咪唑-1-基)吡啶(400毫克,1.6毫摩尔)、Pd(dppf)Cl2(195毫升,0.24毫摩尔)和在BuOH(20毫升)溶液中的Et3N(485毫克,4.8毫摩尔)的混合物在10大气压的一氧化碳中于70℃中搅拌16小时。将反应混合物在减压下浓缩。将残余物通过硅胶柱色谱法用PE/EtOAc(3:1)纯化,得到4-(4-(叔丁基)-1H-咪唑-1-基)-5-甲基吡啶甲酸丁酯(380毫克,75%)为白色固体。
步骤3:将4-(4-(叔丁基)-1H-咪唑-1-基)-5-甲基吡啶甲酸丁酯(50毫克,0.15毫摩尔)添加到6-[1-(丙-2-基)-1H-1,2,3,4-四唑-5-基]吡啶-2-胺(43毫克,0.18毫摩尔)和Cs2CO3(146毫克,0.45毫摩尔)在DMF(2毫升)中的混合物中。将所得混合物在100℃下搅拌2小时,冷却至室温,并过滤。用0-100%的MeCN/H2O通过快速制备高效液相色谱纯化滤液,得到12.4毫克的实施例52,为白色固体。
实施例48a和实施例50a是按照与实施例52a类似的流程制备的。
实施例53a
于0℃下,将Me3Al(1毫升,在2M甲苯中)加入在DCM中的(R)-2-(5-(6-氨基吡啶-2-基)-1H-四唑-1-基)丙-1-醇(43毫克,0.18毫摩尔)的溶液中,且将所得混合物在此温度下搅拌1小时。加入4-(4-(叔丁基)-1H-咪唑-1-基)-5-甲基吡啶甲酸丁酯(50毫克,0.15毫摩尔)在DCM(2毫升)中的溶液。所得溶液在35℃下搅拌过夜。反应用罗谢尔盐猝灭,用乙酸乙酯萃取。有机层经无水Na2SO4干燥、过滤并在真空中浓缩。用0-100%的MeCN/H2O通过快速制备高效液相色谱法纯化粗产物,得到9.4毫克为白色固体的实施例53a。
实施例49a和实施例51a是按照与实施例53a类似的流程制备的
实施例55a
步骤1:向密封管中加入4-氯-5-甲基吡啶-2-羧酸甲酯(3克,16.16毫摩尔)、NBS(14.4克,80.81毫摩尔)、AIBN(1.3克,8.08毫摩尔)和CCl4(60毫升)。将所得混合物在90℃氮气环境下搅拌过夜。将反应混合物冷却至室温,用DCM稀释,用水和盐水洗涤。有机层经无水Na2SO4干燥,过滤,减压浓缩。用硅胶柱层析法,在PE(0~10%)中用EA纯化残渣,得到4-氯-5-(二溴甲基)吡啶-2-羧酸甲酯(4.4克,79.3%),灰色固体。
步骤2:将4-氯-5-(二溴甲基)吡啶-2-羧酸甲酯(4.4克,12.81毫摩尔)和AgNO3(6.5克,38.44毫摩尔)在EtOH(90毫升)和水(9毫升)中的混合物在50℃搅拌过夜。反应混合物经硅藻土过滤,滤液减压浓缩。用硅胶柱层析法纯化聚乙烯中残留的乙醇酸乙酯(0-50%),得到4-氯-5-甲酰吡啶-2-羧酸甲酯(1.4克,54.7%),为黄色固体。
步骤3:4-氯-5-甲酰吡啶-2-羧酸甲酯(1.4克,7.01毫摩尔)和DAST(2.8克,17.54毫摩尔)于DCM(15毫升)中于室温下搅拌2小时。所得混合物在真空下浓缩,残渣用硅胶柱层析法纯化,并在PE(0-10%)中加入乙酸乙酯,得到4-氯-5-(二氟甲基)吡啶-2-羧酸甲酯(0.9克,57.9%),为黄色固体。
步骤4:将4-氯-5-(二氟甲基)吡啶-2-羧酸甲酯(700毫克,3.16毫摩尔)、4-环丙基-1H-咪唑(409.9毫克,3.79毫摩尔)和Cs2CO3(2058.5毫克,6.32毫摩尔)在DMF(10毫升)中的混合物在100℃下搅拌2小时。将混合物冷却至室温并用HCl(溶液)酸化至pH 3~4。溶剂在真空下去除,粗产物用0-20%的MeCN/H2O反相色谱纯化,得到4-(4-环丙基-1H-咪唑-1-基)-5-(二氟甲基)吡啶-2-羧酸(550毫克,62.4%),为黄色固体。
步骤5:4-(4-环丙基-1H-咪唑-1-基)-5-(二氟甲基)吡啶-2-羧酸(100毫克,0.36毫摩尔)、甲醇(22.9毫克,0.72毫摩尔)、PPh3(187.8毫克,0.72毫摩尔)和DIAD(144.8毫克,将0.72毫摩尔)于THF(2毫升)中于室温氮气气氛下搅拌2小时。真空下除去溶剂,用20-30%的CH3CN/水反相色谱纯化残渣,得到4-(4-环丙基-1H-咪唑-1-基)-5-(二氟甲基)吡啶-2-羧酸甲酯(80毫克,76.2%),为无色油状。
步骤6:在0℃下,向DCM(10毫升)中的(2R)-2-[5-(6-氨基吡啶-2-基)-1H-1,2,3,4-四唑-1-基]丙-1-醇(180.2毫克,0.82毫摩尔)的搅拌溶液中滴入氮气中的2M的Me3Al溶液(2毫升,4.1毫摩尔)。将混合物在0℃搅拌1小时,并添加4-(4-环丙基-1H-咪唑-1-基)-5-(二氟甲基)吡啶-2-羧酸甲酯(240毫克,0.818毫摩尔)。将所得混合物在35℃下搅拌1小时。用罗谢尔盐将反应淬火并用DCM萃取。有机层在无水Na2SO4上干燥并在减压下浓缩。用0-35%的MeCN/H2O通过反相色谱法纯化残余物,得到实施例55a(115.1毫克,29.21%),为白色固体。
实施例54a和实施例56a是按照与实施例55a类似的流程制备的。
实施例57a
步骤1:将2,4-二氯-5-(三氟甲基)吡啶(800毫克,3.7毫摩尔)在DMF(2毫升)中的溶液、4-环丙基-1H-咪唑(482毫克,4.4毫摩尔)和K2CO3(1.53克,11.1毫摩尔)放入用氮气吹扫的50毫升圆底烧瓶中。将所得混合物在70℃下搅拌过夜。溶剂在真空中被除去。在硅胶柱上用30%的乙醇酸/聚乙烯纯化粗产物,得到360毫克(38%)2-氯-4-(4-环丙基-1H-咪唑-1-基)-5-(三氟甲基)吡啶,为黄色固体。
步骤2:在50毫升高压釜中,在70℃的10大气压的一氧化碳下将2-氯-4-(4-环丙基-1H-咪唑-1-基)-5-(三氟甲基)吡啶(360毫克,1.25毫摩尔)、Pd(dppf)Cl2(152毫克,0.187毫摩尔)和Et3N(387毫克,3.75毫摩尔)在BuOH(20毫升)中的混合物搅拌16小时。所得混合物在减压下浓缩。用硅胶柱层析和PE/EtOAc(3:1)纯化粗产物,得到4-(4-环丙基-1H-咪唑-1-基)-5-(三氟甲基)吡啶甲酸丁酯(270毫克,61%),为黄色油状。
步骤3:将4-(4-环丙基-1H-咪唑-1-基)-5-(三氟甲基)吡啶甲酸丁酯(60毫克,0.17毫摩尔)加入6-[1-(丙-2-基)-1H-1,2,3,4-四唑-5-基]吡啶-2-胺(49毫克,0.2毫摩尔)和二氯甲烷(2毫升)中的K2CO3(70毫克,0.5毫摩尔)的混合物中。将所得混合物在100℃下搅拌2小时。在真空中去除溶剂,并使用0-100%的MeCN/H2O通过快速制备高效液相色谱纯化粗产物,得到25.3毫克(31%)的实施例57a,为白色固体。
实施例58a
步骤1:4-(4-环丙基-1H-咪唑-1-基)-5-(三氟甲基)吡啶甲酸丁酯(50毫克,0.14毫摩尔)和在MeOH(6毫升)中的NaOH(56毫克,1.4毫摩尔)和水(2毫升)在室温下搅拌2小时。在真空中除去溶剂,并用0至100%的MeCN/H2O通过快速制备高效液相色谱纯化粗产物,以得到25毫克(59%)4-(4-环丙基-1H-咪唑-1-基)-5-(三氟甲基)吡啶酸,为白色固体。
步骤2:4-(4-环丙基-1H-咪唑-1-基)-5-(三氟甲基)吡啶酸(25毫克,0.08毫摩尔)、(R)-2-(5-(6-氨基吡啶-2-基)-1H-四唑-1-基)乙酸丙酯(27毫克,0.1毫摩尔)、HATU(61毫克,0.16毫摩尔)以及在二氯甲烷(2毫升)中的DIEA(31毫克,0.24毫摩尔)于室温下搅拌2小时。在真空中去除溶剂,并用0至100%的MeCN/H2O通过快速制备高效液相色谱法纯化粗品,以获得20毫克(44%)白色固体形式的(R)-2-(5-(6-(4-(4-环丙基-1H-咪唑-1-基)-5-(三氟甲基)吡啶酰胺基-2-基)-1H-四氮唑-1-基)乙酸丙酯。
步骤3:将K2CO3(15毫克,0.11毫摩尔)添加到甲醇(5毫升)中的(R)-2-(5-(6-(4-(4-环丙基-1H-咪唑-1-基)-5-(三氟甲基)吡啶酰胺基)吡啶-2-基)-1H-四唑-1-基)乙酸丙酯(20毫克,0.037毫摩尔)溶液中。将所得混合物在室温下搅拌2小时。在真空中去除溶剂,并使用0至100%的MeCN/H2O通过快速制备高效液相色谱法纯化粗产物,以得到9.7毫克(51%)
实施例58,为白色固体。
实施例59a是按照与实施例57a类似的流程制备的。
实施例8a-18a、实施例20a-26a、实施例34a-36a、实施例60a和实施例61a是按照与实施例1a类似的方法制备的。
实施例1b
步骤1:合成6-(5-异丙基-1H-四唑-1-基)吡啶-2-胺(化合物1b):
步骤1的路径1:
步骤1-1a:氨基甲酸芐基(6-氨基吡啶-2-基)(化合物3)的合成
在-78℃下,向在THF(23毫升)中的吡啶2,6-二胺(1.017克,9.32毫摩尔)溶液中缓慢加入在己烷(6.41毫升,10.25毫摩尔)中的1.0M nBuLi溶液。在添加CbzCl(1.38毫升,9.32毫摩尔)之前,使反应在相同温度下搅拌1小时。然后使反应缓慢升温至室温并再搅拌2小时。反应用NH4Cl溶液淬灭。用EtOAc萃取水层。合并的有机层经Na2SO4干燥并浓缩。残余物通过硅胶色谱法纯化,使用0至100%的EtOAc的己烷溶液洗脱,得到0.93克油,为化合物3(41%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ7.53–7.26(m,8H),6.19(d,J=8.0赫兹,1H),5.20(s,2H),4.38(br,3H)。
步骤1-2a:(6-异丁酰胺基吡啶并-2-基)氨基甲酸酯的合成(化合物4)
在室温下向在吡啶(13毫升)中的芐基(6-氨基吡啶-2-基)氨基甲酸酯(0.93克,3.82毫摩尔)溶液中滴加异丁酰氯(0.48毫升,4.59毫摩尔)。将反应搅拌2小时。浓缩并通过40克柱纯化,用0至100%的EtOAc的己烷溶液洗脱,得到0.984毫克白色固体,为化合物4(82%收率)。LC-MS(m/z):M+1=314.13,计算值为314.14。
步骤1-3a和1-4a:(6-(5-异丙基-1H-四唑-1-基)吡啶-2-基)氨基甲酸芐酯的合成(化合物6)
向在DCE(11毫升)中的芐基(6-异丁酰胺基吡啶并-2-基)氨基甲酸酯(666毫克,2.13毫摩尔)溶液中加入PCl5(531毫克,2.55毫摩尔)。将得到的透明溶液在60℃下搅拌过夜,得到浑浊的浅黄色溶液。浓缩得到浅黄色固体,为化合物5。粗产物不经任何纯化直接用于步骤4。
向所得化合物5(554毫克,1.67毫摩尔)的DCE(8毫升)溶液中加入TMSN3(0.43毫升,3.34毫摩尔)。将得到的浑浊溶液在60℃下搅拌过夜。用NaHCO3溶液淬灭粗产物。用EtOAc萃取水层。合并的有机层经Na2SO4干燥并浓缩。残余物通过硅胶色谱法纯化,使用0至30%的EtOAc的己烷溶液洗脱,得到369.3毫克白色固体,为化合物6(65%产率)。LC-MS(m/z):M+1=339.14,计算值为339.15。氢核磁共振光谱(400M赫兹,氯仿-d)δ8.14(d,J=8.3赫兹,1H),7.96(t,J=8.1赫兹,1H),7.60(dd,J=7.8,0.8赫兹,1H),7.46–7.35(m,5H),7.31(br,1H),5.26(s,2H),3.85(p,J=6.9赫兹,1H),1.43(d,J=6.9赫兹,6H)。
步骤1-5a:合成6-(5-异丙基-1H-四唑-1-基)吡啶-2-胺(化合物1b)。
向在EtOH(6.2毫升)中的氨基甲酸芐基(6-(5-异丙基-1H-四唑-1-基)吡啶-2-基)氨基甲酸酯(421毫克,1.24毫摩尔)溶液中添加Pd/C(21毫克)。将反应物用氢气吹扫3次,并在室温于1大气压氢气下搅拌过夜。通过硅藻土栓塞过滤并浓缩。然后将粗产物通过硅胶色谱法纯化,使用0至5%的MeOH的DCM溶液洗脱,得到218.6毫克白色固体,为化合物1b(86%产率)。LC-MS(m/z):M+1=205.10,计算值为205.11。氢核磁共振光谱(400M赫兹,氯仿-d)δ7.71–7.61(m,1H),7.18(dd,J=7.7,0.7赫兹,1H),6.59(dd,J=8.2,0.7赫兹,1H),4.62(s,2H),3.89(p,J=6.9赫兹,1H),1.44(d,J=7.0赫兹,6H)。
步骤2的路径2:
步骤1-1b:合成N-(6-氯吡啶-2-基)异丁酰胺
在0℃下,向6-氯吡啶-2-胺(1.04克,8.09毫摩尔)的吡啶/DCM(16.4毫升,1/4)溶液中滴加异丁酰氯(0.91毫升,8.49毫摩尔)。将反应在0℃下搅拌30分钟,然后在室温下搅拌1小时。粗反应物用DCM稀释,并用NH4Cl和盐水溶液洗涤。然后将有机层经Na2SO4干燥,过滤并浓缩。粗残余物通过硅胶色谱法纯化(0至20%的丙酮的己烷溶液),得到N-(6-氯吡啶-2--2-基)异丁酰胺,为白色固体(1.523g,95%)。氢核磁共振光谱(500兆赫,氯仿-d)δ8.19(d,J=8.2赫兹,1H),7.85(s,br,1H),7.68(t,J=8.0赫兹,1H),7.08(d,J=7.8赫兹,1H),2.62–2.48(m,1H),1.29(d,J=6.9赫兹,6H)。
步骤1-2b:(Z)-N-(6-氯吡啶-2-基)异丁酰亚胺基氯的合成
向N-(6-氯吡啶-2-基)异丁酰胺(1.523克,7.67毫摩尔)在DCM(38毫升)中的溶液中添加PCl5(1.764克,8.05毫摩尔)。将得到的澄清溶液在室温搅拌1小时。浓缩粗产物,无需纯化即可直接用于步骤3。
步骤1-3b:2-氯-6-(5-异丙基-1H-四唑-1-基)吡啶的合成
向(Z)-N-(6-氯吡啶-2-基)异丁酰亚胺基氯(0.887克,4.09毫摩尔)在MeCN(10.2毫升)中的溶液中加入TMSN3(1.09毫升,8.17毫摩尔)。将反应在60℃下搅拌2天。将该粗产物冷却至室温,用NaHCO3溶液淬灭。并用EtOAc(X3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过硅胶色谱法(0至30%的EtOAc的己烷溶液)纯化粗残余物,得到白色固体状的2-氯-6-(5-异丙基-1H-四唑-1-基)吡啶(396毫克,43%产率)。氢核磁共振光谱(400兆赫,氯仿-d)δ8.00–7.93(m,2H),7.56–7.43(m,1H),4.06–3.94(m,1H),1.51(d,J=6.9赫兹,6H)。
步骤1-4b:合成N-(6-(5-异丙基-1H-四唑-1-基)吡啶-2-基)-1,1-二苯基甲亚胺
向2-氯-6-(5-异丙基-1H-四唑-1-基)吡啶(102毫克,0.456毫摩尔)在甲苯(2.3毫升)中的溶液中加入二苯基甲亚胺(0.115毫升,0.685毫摩尔),三(二芐叉基丙酮)二钯(0)(20.9毫克,0.023毫摩尔),BINAP(28.4毫克,0.046毫摩尔)和叔丁醇钠(65.8毫克,0.685毫摩尔)。将反应在60℃下搅拌过夜。反应用NaHCO3溶液淬灭,并用EtOAc(X3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。将粗残余物通过硅胶色谱法纯化(0至20%的EtOAc的己烷溶液),得到N-(6-(5-异丙基-1H-四唑-1-基)吡啶-2-基)-1,1-二苯基甲亚胺,为灰白色固体(112.4毫克,67%产率)。LC-MS[M+H]=369.16。
步骤1-5b:合成6-(5-异丙基-1H-四唑-1-基)吡啶-2-胺
向N-(6-(5-异丙基-1H-四唑-1-基)吡啶-2-基)-1,1-二苯基甲亚胺(112.4毫克,0.305毫摩尔)在THF(1.5毫升)中的溶液中添加。HCl溶液(6N,0.763毫升)。然后将反应在室温搅拌1小时。反应用NaHCO3溶液淬灭,并用EtOAc(X3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过硅胶色谱法(0至60%的EtOAc的己烷溶液)纯化粗残余物,得到白色固体状的6-(5-异丙基-1H-四唑-1-基)吡啶-2-胺(47毫克,75%产率)。
步骤2:5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-异丙基-1H-四唑-1-基)吡啶-2-基)-4-甲基苯甲酰胺的合成(实施例1b)
向在DCM(0.6毫升)中的5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸(89毫克,0.343毫摩尔)悬浮液中加入1-氯-N,N,2-三甲基丙-1-烯-1-胺(Ghosez’s试剂,0.14毫升,1.02毫摩尔)。将反应混合物在室温搅拌1小时以形成澄清溶液,然后真空浓缩。将残余物(化合物8b)放入吡啶(0.6毫升)中,冷却至0℃,加入6-(5-异丙基-1H-四唑-1-基)吡啶-2-胺(1)(加入50毫克,0.245毫摩尔)的DCM(0.6毫升)溶液。使反应混合物升温至室温,并搅拌4小时。将混合物浓缩,然后用EtOAc和盐水稀释。用EtOAc萃取水层。合并的有机层经Na2SO4干燥并浓缩。将残余物通过硅胶色谱法纯化,使用0至5%的MeOH的DCM溶液洗脱,得到实施例1b的化合物,为白色固体(94毫克,86%产率)。LC-MS(m/zM+1=447.19,计算值447.20。氢核磁共振光谱(400兆赫,DMSO-d6)δ11.18(s,1H),8.34(d,J=7.7赫兹,1H),8.23(t,J=8.1赫兹,1H),7.72(d,J=7.8赫兹,1H),7.70(d,J=1.4赫兹,1H),7.65(d,J=6.6赫兹,1H),7.48(d,J=10.9赫兹,1H),7.18(d,J=1.4赫兹,1H),3.91(p,J=6.8赫兹,1H),2.25(s,3H),1.89–1.82(m,1H),1.31(s,3H),1.30(s,3H),0.83–0.77(m,2H),0.72–0.67(m,2H)。
按照与实施例1b类似的方法制备实施例2b至实施例6b。
实施例1c:
步骤1:合成6-(3-异丙基-4H-1,2,4-***-4-基)吡啶-2-胺(化合物4c)
向1-肼基-3-甲基丁-2-酮(673毫克,5.5毫摩尔)在乙腈(4毫升)中的悬浮液中加入1,1-二甲氧基-N,N-二甲基甲胺(0.731毫升,5.50毫摩尔),并将所得混合物(澄清溶液)加热至50℃并搅拌30分钟。然后加入吡啶2,6-二胺(612毫克,5.5毫摩尔)的乙酸(5毫升/乙腈(1毫升)溶液,并将混合物加热至120℃保持23小时,冷却至室温,并浓缩。将残余物用EtOAc稀释,用饱和NaHCO3洗涤,并再次浓缩。粗产物通过硅胶色谱法纯化,使用DCM/MeOH(100/0至90/10,10分钟),得到所需产物4。LC-MS[M+H]=204.09,计算值204.12;氢核磁共振光谱(400兆赫,DMSO-d6)δ8.66(s,1H),7.59(t,J=7.5赫兹,1H),6.65(d,J=7.5赫兹,1H),6.53(d,J=8.3赫兹,1H),6.43(s,2H),3.49–3.41(m,1H),1.21(d,J=6.9赫兹,6H)。
步骤2:5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(3-异丙基-4H-1,2,4-***-4-基)吡啶-2-基)-4-甲基苯甲酰胺的合成。
向在DCM(1毫升)中的5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸(5)(30.5毫克,0.117毫摩尔)悬浮液中加入1-氯-N,N,2-三甲基丙-1-烯-1-胺(Ghosez’s试剂,0.033毫升,0.251毫摩尔)。将反应混合物在室温搅拌40分钟(澄清溶液),然后真空浓缩。将残余物(化合物6)放入DCM(1毫升)中,冷却至0℃,并加入6-(3-异丙基-4H-1,2,4-***-4-基)吡啶2-胺(4c)(17毫克,0.084毫摩尔)和吡啶(0.041毫升,0.502毫摩尔)的DCM(1毫升)溶液,使反应混合物升温至室温,搅拌过夜,然后浓缩。残余物通过硅胶色谱法纯化,使用DCM/MeOH(100/0至70/30,15分钟),得到所需产物(实施例1c),为白色固体,LC-MS[MH]=444.20,计算值444.20。氢核磁共振光谱(400兆赫,DMSO-d6)δ11.24(s,1H),9.33(d,J=1.7赫兹,1H),8.92(s,1H),8.27(d,J=8.2赫兹,1H),8.17(t,J=8.0赫兹,1H),7.94(d,J=8.0赫兹,1H),7.77(d,J=1.6赫兹,1H),7.59(d,J=10.赫兹,1H),7.52(d,J=7.7赫兹,1H),3.61-3.41(m,1H),2.29(s,3H),2.10-2.01(m,1H),1.21(d,J=6.9赫兹,6H),1.05(dt,J=8.6,3.3赫兹,2H),0.92–0.83(m,2H)。
实施例2c:N-(6-(4H-1,2,4-***-4-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰胺。
实施例2c通过使用与实施例1c的化合物所述类似的程序制备。LC-MS[MH]=444.20,计算值444.20。氢核磁共振光谱(400兆赫,DMSO-d6)δ11.22(s,1H),9.32(d,J=1.6赫兹,1H),9.23(s,2H),8.22–8.10(m,2H),7.93(d,J=6.4赫兹1H),7.79(d,J=1.6赫兹,1H),7.67(dd,J=7.2,1.3赫兹,1H),7.60(d,J=10.8赫兹,1H),2.30(s,3H),2.08-2.02(m,1H),1.11–0.99(m,2H),0.92–0.83(m,2H)。
实施例3c:
步骤1:合成6-(2-异丙基-1H-咪唑-1-基)吡啶-2-胺(化合物7c):
加热在DMA(4毫升)中的6-氟吡啶-2-胺(448毫克,4.00毫摩尔)、2-异丙基-1H-咪唑(880毫克,7.99毫摩尔)和碳酸铯(3906毫克,11.99毫摩尔)的混合物,在氮气下升至120℃并搅拌过夜,冷却至室温,用水稀释,并用EtOAc萃取。合并的有机层用盐水洗涤并浓缩。将残余物通过硅胶色谱法纯化,使用己烷/丙酮(100/0至50/50,10分钟),得到期望的产物(7c),为灰白色固体,将其用EtOAc洗涤以除去一些剩余的SM。氢核磁共振光谱(500兆赫,DMSO-d6)δ7.54(t,J=7.8赫兹,1H),7.25(d,J=1.3赫兹,1H),6.85(d,J=1.3赫兹,1H),6.53(d,J=7.4赫兹,1H),6.46(d,J=8.2赫兹,1H),6.28(s,2H),3.44(h,J=6.8赫兹,1H),1.16(d,J=6.8赫兹,6H)。
步骤2:5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(2-异丙基-1H-咪唑-1-基)吡啶-2-基)-4-甲基苯甲酰胺的合成(实施例3c)。
向在DCM(2毫升)中的5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸(5)(64.9毫克,0.249毫摩尔)悬浮液中加入1-氯-N,N,2-三甲基丙-1-烯-1-胺(0.071毫升,0.534毫摩尔)。将反应混合物在室温搅拌40分钟(澄清溶液),然后冷却至0℃,然后加入6-(2-异丙基-1H-咪唑-1-基)吡啶-2-胺溶液(36毫克,0.178毫摩尔)和吡啶(0.086毫升,1.068毫摩尔)的DCM(2毫升)溶液。使反应混合物升温至室温并搅拌过夜,然后用EtOAc稀释,用饱和NaHCO3洗涤,并浓缩。将残余物通过硅胶色谱法纯化,使用己烷/丙酮(100/0至20/80,15分钟),得到实施例3,为白色固体。LC-MS[M+H]=445.20,计算值445.21。氢核磁共振光谱(400兆赫,DMSO-d6)δ11.03(s,1H),8.21(d,J=8.1赫兹,1H),8.08(t,J=8.0赫兹,1H),7.72–7.60(m,2H),7.49–7.39(m,2H),7.37–7.30(m,2H),7.18(d,J=1.4赫兹,1H),6.92(d,J=1.5赫兹,1H),3.52(p,J=6.8赫兹,1H),2.24(s,3H),1.84(td,J=8.5,4.3赫兹,1H),1.15(d,J=6.8赫兹,6H),0.85–0.74(m,2H),0.74–0.65(m,2H)。
实施例4c:
步骤1:合成6-(1-异丙基-1H-1,2,3-***-5-基)吡啶-2-胺(化合物12c)
在0℃下,向含有1H-1,2,3-***(3.06克,44.3毫摩尔)和i-PrOH(3.7毫升,48.7毫摩尔)的烧瓶中,滴加96%H2SO4(16.11毫升),并在0℃下搅拌持续5小时,在室温持续43小时。将反应混合物倒在冰(100克)上。将混合物用DCM(3×50毫升)萃取。在搅拌下向水层中缓慢加入Na2CO3(32克)(放热,鼓泡)。将所得的乳状混合物用DCM(50毫升×3)萃取。将合并的DCM层用水(50毫升)洗涤,然后用盐水(50毫升)洗涤。干燥,过滤并浓缩,得到化合物9(2.8克),其为无色油状。氢核磁共振光谱(400兆赫,氯仿-d)δ7.67(d,J=0.8赫兹,1H),7.53(d,J=0.8赫兹,1H),4.85(m,J=6.8赫兹,1H),1.57(d,J=6.8赫兹,6H)。
在-78℃下,将在正己烷中的正丁基锂(1.6M)(315微升,0.504毫摩尔)添加到上述THF(0.97毫升)中的1-异丙基-1H-1,2,3-***(56毫克,0.504毫摩尔)溶液。在-78℃下搅拌30分钟后,逐滴加入2-溴-6-硝基吡啶(123毫克,0.605毫摩尔)的THF(0.97毫升)溶液。将混合物在-78℃下搅拌至室温过夜,然后用水稀释,然后用乙酸乙酯(20毫升×2)萃取。合并的有机层用盐水洗涤,并用Na2SO4干燥。蒸发并通过柱色谱法纯化,得到所需的化合物10的产物(13毫克)。LCMS:267.0(M+1);269.0(M+1);氢核磁共振光谱(400兆赫,氯仿-d)δ7.95(s,1H),7.64(t,J=8.0赫兹,1H),7.54(dd,J=8.0,0.8赫兹,1H),7.48(dd,J=8.0,0.8赫兹,1H),5.54(m,J=6.8赫兹,1H),1.65(d,J=6.8赫兹,6H)。
于室温下,向上述在甲苯(0.45毫升)中的2-溴-6-(1-异丙基-1H-1,2,3-***-5-基)吡啶(12毫克,0.045毫摩尔)、Pd2(dba)3(2.057毫克,2.246微摩尔)、BINAP(4.20毫克,6.74微摩尔)以及和叔丁醇钠(8.63毫克,0.090毫摩尔)的溶液中在氮气下加入二苯甲酮亚胺(9.8毫克,0.054毫摩尔)。将混合物在氮气下在100℃下搅拌15小时。用0.1N的NaOH溶液淬灭反应,用EtOAc萃取3次。合并的有机层用盐水洗涤,用硫酸钠干燥,过滤并浓缩,得到黄色残余物(27毫克)。将残余物溶于THF(2毫升)。加入6N的HCl溶液(0.25毫升)。将混合物在室温搅拌1小时。加入0.1N的HCl(1毫升)和水(2毫升)溶液。将混合物用EtOAc萃取两次。保持水层,用1N的NaOH溶液调节pH到大于9,用DCM萃取3次。合并有机层,用硫酸钠干燥、过滤并浓缩,得到粗残余物(11毫克)。粗残余物通过柱色谱纯化,得到化合物12c(6毫克),为白色固体。LCMS:204.09(M+1);氢核磁共振光谱(400兆赫,氯仿-d)δ7.87(s,1H),7.55(t,J=8.0赫兹,1H),6.88(d,J=8.0赫兹,1H),6.58(d,J=8.0赫兹,1H),5.49–5.39(m,1H),4.99(s,2H),1.62(d,J=6.8赫兹,6H)。
步骤2:5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(1-异丙基-1H-1,2,3-***-5-基)吡啶-2-基)-4-甲基苯甲酰胺的合成。(实施例4c)
实施例4c通过使用与实施例1c的化合物所述类似的程序制备。LCMS:446.20(M+1);氢核磁共振光谱(400兆赫,氯仿-d)δ9.09(d,J=15.2赫兹,1H),8.35(dd,J=8.0,0.8赫兹,1H),8.06(d,J=7.2赫兹,1H),7.92(s,1H),7.87(t,J=8.0赫兹,1H),7.54(s,1H),7.37(dd,J=8.0,0.8赫兹,1H),7.20(d,J=12.0赫兹,1H),6.78(d,J=1.2赫兹,1H),5.44(m,J=6.8赫兹,1H),2.28(s,3H),1.96–1.79(m,1H),1.67(d,J=6.8赫兹,6H),0.95-0.87(m,2H),0.87-0.79(m,2H)。
检验
ASK1购自Thermofisher(产品目录号PV4011),ATP购自Sigma(产品目录号A7699),KinEASETM分析***购自Cisbio(马萨诸塞州贝德福德)。1/2区板购自Perkin Elmer(产品目录号6005560)。KinEASETM-STK是使用时间分辨荧光共振能量转移(TR-FRET)免疫测定法测量丝氨酸/苏氨酸激酶活性的通用方法。在化合物以及固定量的ATP和肽底物存在下(浓度范围为0至10微摩尔每升)来确定每种化合物的IC50值。将测试化合物、1微摩尔的STK3肽底物和5纳摩尔的ASK1激酶与含有50毫摩尔HEPES且pH值为7.5、0.01%的BRIJ-35、10毫摩尔的MgCl2和1毫摩尔的EGTA的激酶反应缓冲液培养30分钟。加入100微摩尔的ATP以启动激酶反应,并培养3小时。用Eu3+穴状配体标记的STK3抗体和125纳摩尔的链霉亲和素XL665与Cisbio试剂盒提供的用于终止激酶反应的终止试剂一次性混合。使用PerkinElmer的Envision Multilabeled 2014阅读器检测荧光。在615nm(穴状配体)和665nm(XL665)处测量荧光,并为每个孔计算665nm/615nm之比。所得的TR-FRET与磷酸化水平成正比。星形孢菌素用作阳性对照。IC50由XLfit 5.3测定。
通过使用上述方法,测试了ASK1对式(I)化合物的抑制。IC50范围如下:A<1nM;1nM<B<10nM;10nM<C<100nM;100nM<D<1 M;E>1M。
表5
尽管已经参考本发明的优选实施例具体示出和描述了本发明,但是本领域技术人员将可以理解,在不脱离后附的权利要求书所涵盖的本发明范围的情况下,可以在形式和细节上进行各种改变。
Claims (26)
1.一种化合物,其特征在于:所述化合物是以式(I)表示的或其药学上可接受的盐类或其酯类:
X1、X2和X3各自独立地选自N或C(R5);
R3、R4和R5各自独立地选自:
1)氢;
2)卤素;
3)-NO2;
4)氰基;
5)任选取代的C1-C8烷基;
6)任选取代的C3-C8环烷基;
7)任选取代的3至8元杂环烷基;以及
8)任选取代的C1-C8烷氧基;
R选自:
在可能的情况下,每一个都可以选择性地被取代;
R1选自由以下所组成的群组:
1)氢;
2)任选取代的C1-C8烷基;
3)任选取代的C2-C8烯基;
4)任选取代的C2-C8炔基;
5)任选取代的C3-C8环烷基;
6)任选取代的芳基;
7)任选取代的芳烷基;
8)任选取代的3至8元杂环烷基;
9)任选取代的杂芳基;
10)任选取代的杂芳基烷基;以及
11)-N(R6)(R7);
1)氢;
2)卤素;
3)-NO2;
4)氰基;
5)任选取代的C1-C8烷基;
6)任选取代的C2-C8烯基;
7)任选取代的C2-C8炔基;
8)任选取代的C3-C8环烷基;
9)任选取代的芳基;
10)任选取代的芳烷基;
11)任选取代的3至8元杂环烷基;
12)任选取代的杂芳基;
13)任选取代的杂芳基烷基;
14)-N(R6)(R7);
15)-S(O)2N(R6)(R7);
16)-N(R6)C(O)(R7);以及
17)-N(R6)S(O)2(R7);
其中R6和R7独立地选自氢、优选为C1-C8烷基的C1-C15烷基、环烷基、杂环烷基、芳基和杂芳基所组成的群组,其中每个烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1至3个独立选自卤素、烷基、烷基氨基、二烷基氨基、烷基C(O)NH-、芳基C(O)NH-、杂芳基C(O)-NH、-CN、烷氧基、-CF3、芳基以及杂芳基的取代基所取代,或者,R7和R8与它们所连接的氮一起被形成杂环。
14.一种药物组合物,其特征在于:所述药物组合物包含:一有效剂量的一种或多种根据权利要求1至13中任一项的式(I)的化合物;以及一药学上可接受的载体或赋形剂。
15.一种用于对于有此需要的一受试者治疗ASK-1调节的疾病或症状的方法,其特征在于:所述方法包括:向所述受试者施用一治疗有效剂量的一种或多种根据权利要求1至13中任一项的式(I)的化合物。
16.如权利要求15所述的方法,其特征在于:所述ASK-1调节的疾病或症状选自由以下所组成的群组:自身免疫性疾病、神经退化性疾病、炎性疾病、慢性肾脏疾病、肾脏疾病、心血管疾病、代谢性疾病或急性或慢性肝病。
17.如权利要求16所述的方法,其特征在于:所述慢性肝病选自以下所组成的群组:原发性胆汁性肝硬化(PBC)、脑黄瘤病(CTX)、原发性硬化性胆管炎(PSC)、药物诱发的胆汁淤积症、妊娠期肝内胆汁淤积症、肠外营养相关的胆汁淤积症(PNAC)、细菌过度生长或败血症相关的胆汁淤积症、自身免疫性肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、与移植物抗宿主病相关的肝移植、活体供体移植肝再生、先天性肝纤维化、胆总管结石症、肉芽肿性肝病、肝内或肝外恶性肿瘤、干燥综合症、结节病、威尔逊病、高雪氏病、血色病或α1-抗胰蛋白酶缺乏症。
18.如权利要求16所述的方法,其特征在于:所述肾脏疾病选自以下所组成的群组:糖尿病性肾病、局灶性节段性肾小球硬化症(FSGS)、高血压性肾硬化、慢性肾小球肾炎、慢性移植性肾小球病、慢性间质性肾炎、肾纤维化和多囊性肾病。
19.如权利要求16所述的方法,其特征在于:所述心血管疾病选自以下所组成的群组:动脉粥样硬化、动脉硬化、中风再灌注/缺血、心肌肥厚、呼吸***疾病、心脏病发作及心肌缺血。
20.如权利要求16所述的方法,其特征在于:所述代谢性疾病选自以下所组成的群组:胰岛素抵抗、I型和II型糖尿病以及肥胖症。
21.如权利要求16所述的方法,其特征在于:所述慢性肾脏疾病选自以下所组成的群组:多囊肾病、肾盂肾炎、肾纤维化和肾小球肾炎。
22.一种用于对于有需要的一受试者治疗一疾病的方法,所述疾病选自以下所组成的群组:肾小球肾炎、类风湿性关节炎、***性红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性中性粒细胞减少症、慢性血小板减少症、特应性皮炎、活动性肝炎、重症肌无力、多发性硬化症、炎症性肠病、溃疡性结肠炎、克罗恩氏病、牛皮癣、移植物抗宿主病、多发性硬化症或舍格伦氏综合症,其特征在于:所述方法包括:向所述受试者施用一治疗有效剂量的根据权利要求1至13中任一项的式(I)的化合物。
23.一种用于对于有需要的一受试者治疗一疾病的方法,所述疾病选自以下所组成的群组:脑中风的缺血/再灌注、心脏病发作、心肌缺血、器官缺氧、血管增生、心脏肥大、肝缺血、充血性心脏衰竭、例如由T细胞活化引起的病理性免疫反应和凝血酶诱导的血小板聚集,其特征在于:所述方法包括:向所述受试者施用一治疗有效剂量的根据权利要求1至13中任一项的式(I)的化合物。
24.一种用于对于有需要的一受试者治疗一疾病的方法,所述疾病选自以下所组成的群组:骨质疏松、骨关节炎与多发性骨髓瘤相关的骨病变,其特征在于:所述方法包括向所述受试者施用一治疗有效剂量的根据权利要求1至13中任一项的式(I)的化合物。
25.一种用于对于有需要的一受试者治疗一疾病的方法,所述疾病选自以下所组成的群组:阿尔茨海默症、帕金森氏症、肌萎缩性侧索硬化症(ALS)、癫痫、癫痫发作、亨廷顿病、多聚谷氨酰胺病、创伤性脑损伤、缺血性和出血性脑中风、脑缺血或神经退化性疾病,包括由外伤、急性缺氧、局部缺血或谷氨酸神经毒性引起的细胞凋亡引起的神经退化性疾病,其特征在于:所述方法包括:向所述受试者施用一治疗有效剂量的根据权利要求1至13中任一项的式(I)的化合物。
26.一种化合物的用途,其特征在于:所述用途包括根据权利要求1至13中任一项的化合物用于制备用于治疗ASK-1调节的疾病或病症的多种药物组合物。
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