CN113573713A - 离子通道调节剂 - Google Patents
离子通道调节剂 Download PDFInfo
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- CN113573713A CN113573713A CN201980078653.2A CN201980078653A CN113573713A CN 113573713 A CN113573713 A CN 113573713A CN 201980078653 A CN201980078653 A CN 201980078653A CN 113573713 A CN113573713 A CN 113573713A
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- compound
- methyl
- alkyl
- mixture
- phenyl
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- KTAVBOYXMBQFGR-MAODNAKNSA-J tetrasodium;(6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino-1-oxidoethylidene]amino]-3-[(2-methyl-5,6-dioxo-1h-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C KTAVBOYXMBQFGR-MAODNAKNSA-J 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
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- 229940078806 teveten Drugs 0.000 description 1
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- 229960000278 theophylline Drugs 0.000 description 1
- 125000005305 thiadiazolinyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/50—Pyridazines; Hydrogenated pyridazines
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Abstract
本发明部分地涉及可用于预防和/或治疗与电压门控钠离子通道功能异常例如异常的晚期/持续性钠电流有关的疾病或病症的稠合杂芳基化合物和组合物。本文还提供了治疗与钠离子通道功能异常有关的疾病或病症的方法,所述疾病或病症包括神经系统疾患(例如,Dravet综合征、癫痫)、疼痛和神经肌肉障碍。
Description
相关申请的交叉引用
本申请要求2018年9月28日提交的美国临时专利申请第62/738,508号的优先权和权益,将其通过引用以其整体并入本文。
背景技术
钠离子(Na+)通道主要以瞬时方式打开并迅速失活,从而产生快速Na+电流以启动动作电位。晚期或持续性钠电流(INaL)是心肌细胞和神经元快速Na+电流的持续组分。许多常见的神经系统病症和心脏病症与异常的INaL增强有关,其为哺乳动物中电和收缩功能障碍的发病的重要成因(参见,例如,Pharmacol Ther(2008)119:326-339)。因此,选择性调节钠通道活性(例如异常INaL)的药物化合物可用于治疗这样的疾病状态。
发明内容
本文描述了可用于预防和/或治疗疾病、疾患或病症,例如与钠离子通道功能异常,例如异常的晚期钠电流(INaL)有关的疾病、疾患或病症的稠合杂芳基化合物和组合物。
一方面,本发明提供了具有式I的化合物:
或其药学上可接受的盐;其中
X和Y各自独立地是CRd或N;
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R5是卤基、任选地被O-C1-4烷基或O-C3-6环烷基取代的C3-6环烷基或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
t是1或2;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基;并且
Rd是氢或C1-4烷基。
另一方面,本公开提供了具有式II的化合物:
或其药学上可接受的盐;其中
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R5是卤基、任选地被O-C1-4烷基或O-C3-6环烷基取代的C3-6环烷基或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
t是1或2;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;并且
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基。
另一方面,本公开提供了具有式III的化合物:
或其药学上可接受的盐;其中
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R5是卤基、任选地被O-C1-4烷基或O-C3-6环烷基取代的C3-6环烷基或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
t是1或2;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;并且
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基。
另一方面,本公开提供了具有式IV的化合物:
或其药学上可接受的盐;其中
X和Y各自独立地是CRd或N;
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基;并且
Rd是氢或C1-4烷基;
本文还提供了一种药物组合物,其包含本文公开的化合物(例如,式I、II、III或IV的化合物)或其药学上可接受的盐;和药学上可接受的载体。
另一方面,本文提供了一种治疗在有需要的受试者中的与钠离子通道功能异常有关的病症的方法,所述方法包括向受试者施用治疗有效量的本文公开的化合物(例如,式I、II、III或IV的化合物)或其药学上可接受的盐或本文公开的药物组合物。
在一些实施方案中,所述病症是神经系统或精神疾患。在一些实施方案中,所述病症是癫痫或癫痫综合征。在一些实施方案中,所述病症是遗传性癫痫或遗传性癫痫综合征。在一些实施方案中,所述病症是小儿癫痫或小儿癫痫综合征。在一些实施方案中,所述病症是癫痫性脑病。在一些实施方案中,癫痫性脑病选自由以下组成的组:Dravet综合征、婴儿痉挛或Lennox-Gastaut综合征。
在一些实施方案中,所述病症选自由以下组成的组:癫痫性脑病,伴SCN1A、SCN2A、SCN8A突变的癫痫性脑病,早期婴儿型癫痫性脑病,Dravet综合征,伴SCN1A突变的Dravet综合征,全身性癫痫伴热性惊厥,顽固性儿童癫痫伴全身性强直阵挛发作,婴儿痉挛,良性家族性新生儿-婴儿惊厥,SCN2A癫痫性脑病,伴SCN3A突变的局灶性癫痫,伴SCN3A突变的隐源性小儿部分性癫痫,SCN8A癫痫性脑病,癫痫猝死,Rasmussen脑炎,婴儿恶性游走性部分性癫痫发作,常染色体显性夜发性额叶癫痫,癫痫猝死(SUDEP),KCNQ2癫痫性脑病和KCNT1癫痫性脑病。
另一方面,本文提供了一种治疗神经系统疾患或精神疾患的方法,其中所述方法包括向有需要的受试者施用本文公开的化合物(例如,式I、II、III或IV的化合物)或其药学上可接受的盐或本文公开的药物组合物。
另一方面,本文提供了一种治疗疼痛的方法,其中所述方法包括向有需要的受试者施用本文公开的化合物(例如,式I、II、III或IV的化合物)或其药学上可接受的盐或本文公开的药物组合物。
通过考虑随后的具体实施方式、实施例和权利要求书,其他目的和优点对于本领域技术人员将变得显而易见。
具体实施方式
如本文总体描述,本发明提供了可用于预防和/或治疗疾病、疾患或病症,例如与钠离子通道功能异常,比如异常的晚期钠电流(INaL)有关的疾病、疾患或病症的化合物和组合物。示例性疾病、疾患或病症包括神经系统疾患(例如,癫痫或癫痫综合征、神经发育障碍或神经肌肉障碍)、精神疾患、疼痛或胃肠道疾患。
定义
化学定义
下文更详细地描述了特定官能团和化学术语的定义。根据CAS版本,Handbook ofChemistry and Physics,第75版,内封面的元素周期表来鉴定化学元素,并且特定官能团通常如其中所述进行定义。另外,有机化学的一般原理以及特定官能部分和反应性描述于Thomas Sorrell,Organic Chemistry,University Science Books,Sausalito,1999;Smith和March,March’s Advanced Organic Chemistry,第5版,John Wiley&Sons,Inc.,New York,2001;Larock,Comprehensive Organic Transformations,VCH Publishers,Inc.,New York,1989;和Carruthers,Some Modern Methods of Organic Synthesis,第3版,Cambridge University Press,Cambridge,1987中。
本文所述的化合物可以包含一个或多个不对称中心,并因此可以各种异构形式(例如,对映异构体和/或非对映异构体)存在。例如,本文所述的化合物可以是单独的对映异构体、非对映异构体或几何异构体的形式,或者可以是立体异构体混合物的形式,包括外消旋混合物和富含一种或多种立体异构体的混合物。可以通过本领域技术人员已知的任何方法(包括手性高压液相色谱(HPLC)和手性盐的形成和结晶)从混合物中分离异构体;或通过不对称合成来制备优选的异构体。参见,例如,Jacques等人,Enantiomers,Racematesand Resolutions(Wiley Interscience,New York,1981);Wilen等人,Tetrahedron 33:2725(1977);Eliel,Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);以及Wilen,Tables of Resolving Agents and Optical Resolutions第268页(E.L.Eliel编辑,Univ.of Notre Dame Press,Notre Dame,IN 1972)。本发明另外涵盖这样的化合物,其为基本上不含其他异构体的单独异构体以及可替代地为各种异构体的混合物。
如本文所用,纯对映异构体化合物基本上不含该化合物的其他对映异构体或立体异构体(即,对映异构体过量)。换言之,化合物的“S”形式基本上不含化合物的“R”形式,因此是“R”形式的对映异构体过量。术语“对映异构体纯的”或“纯对映异构体”表示该化合物包含大于75重量%、大于80重量%、大于85重量%、大于90重量%、大于91重量%、大于92重量%、大于93重量%、大于94重量%、大于95重量%、大于96重量%、大于97重量%、大于98重量%、大于98.5重量%、大于99重量%、大于99.2重量%、大于99.5重量%、大于99.6重量%、大于99.7重量%、大于99.8重量%或大于99.9重量%的对映异构体。在某些实施方案中,重量基于化合物的所有对映异构体或立体异构体的总重量。
在本文提供的组合物中,对映异构体纯的化合物可以与其他活性或非活性成分一起存在。例如,包含对映异构体纯的R-化合物的药物组合物可以包含例如约90%的赋形剂和约10%的对映异构体纯的R-化合物。在某些实施方案中,以化合物的总重量计,这样的组合物中的对映异构体纯的R-化合物可以例如包含至少约95重量%的R-化合物和至多约5重量%的S-化合物。例如,包含对映异构体纯的S-化合物的药物组合物可以包含例如约90%的赋形剂和约10%的对映异构体纯的S-化合物。在某些实施方案中,以化合物的总重量计,这样的组合物中的对映异构体纯的S-化合物可以例如包含至少约95重量%的S-化合物和至多约5重量%的R-化合物。在某些实施方案中,可以将活性成分与很少的(或没有)赋形剂或载体一起配制。
本文所述的化合物还可包含一个或多个同位素取代。例如,H可以呈任何同位素形式,包括1H、2H(D或氘)和3H(T或氚);C可以呈任何同位素形式,包括12C、13C和14C;O可以呈任何同位素形式,包括16O和18O;F可以呈任何同位素形式,包括18F和19F;等等。
下列术语预期具有下面与其一起呈现的含义,并且可用于理解本发明的描述和预期范围。除非另有说明,否则当描述本发明时,可包括化合物及其药学上可接受的盐、含有这样的化合物的药物组合物以及使用这样的化合物和组合物的方法,以下术语如果存在,则具有以下含义。还应当理解,当在本文中描述时,下面定义的任何部分都可以被多个取代基取代,并且各个定义预期将这样的取代部分包括在如下所述的范围内。除非另有说明,否则如下所述定义术语“取代的”。应当进一步理解的是,术语“基团”和“基”在本文中使用时可被认为是可互换的。可以在本文使用的冠词“一个”和“一种”(“a”和“an”)是指一个或多于一个(即,至少一个)该冠词的语法对象。举例来说,“类似物”意指一种类似物或多于一种类似物。
当列出值的范围时,预期将每个值和子范围涵盖在该范围内。例如,“C1-6烷基”旨在涵盖C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5和C5-6烷基。
如本文所用,“烷基”是指例如具有1至20个碳原子的直链或支链饱和烃基的基团(“C1-20烷基”)。在一些实施方案中,烷基具有1至10个碳原子(“C1-10烷基”)。在一些实施方案中,烷基具有1至9个碳原子(“C1-9烷基”)。在一些实施方案中,烷基具有1至8个碳原子(“C1-8烷基”)。在一些实施方案中,烷基具有1至7个碳原子(“C1-7烷基”)。在一些实施方案中,烷基具有1至6个碳原子(“C1-6烷基”)。在一些实施方案中,烷基具有1至5个碳原子(“C1-5烷基”)。在一些实施方案中,烷基具有1至4个碳原子(“C1-4烷基”)。在一些实施方案中,烷基具有1至3个碳原子(“C1-3烷基”)。在一些实施方案中,烷基具有1至2个碳原子(“C1-2烷基”)。在一些实施方案中,烷基具有1个碳原子(“C1烷基”)。C1-6烷基的实例包括甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、己基等。
如本文所用,“烯基”是指具有2至20个碳原子、一个或多个碳-碳双键(例如1、2、3或4个碳-碳双键)以及任选地一个或多个碳-碳三键(例如1、2、3或4个碳-碳三键)的直链或支链烃基的基团(“C2-20烯基”)。在某些实施方案中,烯基不含任何三键。在一些实施方案中,烯基具有2至10个碳原子(“C2-10烯基”)。在一些实施方案中,烯基具有2至9个碳原子(“C2-9烯基”)。在一些实施方案中,烯基具有2至8个碳原子(“C2-8烯基”)。在一些实施方案中,烯基具有2至7个碳原子(“C2-7烯基”)。在一些实施方案中,烯基具有2至6个碳原子(“C2-6烯基”)。在一些实施方案中,烯基具有2至5个碳原子(“C2-5烯基”)。在一些实施方案中,烯基具有2至4个碳原子(“C2-4烯基”)。在一些实施方案中,烯基具有2至3个碳原子(“C2-3烯基”)。在一些实施方案中,烯基具有2个碳原子(“C2烯基”)。所述一个或多个碳-碳双键可以在内部(比如在2-丁烯基中)或末端(比如在1-丁烯基中)。C2-4烯基的实例包括乙烯基(C2)、1-丙烯基(C3)、2-丙烯基(C3)、1-丁烯基(C4)、2-丁烯基(C4)、丁二烯基(C4)等。C2-6烯基的实例包括前述的C2-4烯基以及戊烯基(C5)、戊二烯基(C5)、己烯基(C6)等。烯基的其他实例包括庚烯基(C7)、辛烯基(C8)、辛三烯基(C8)等。
如本文所用,“炔基”是指具有2至20个碳原子、一个或多个碳-碳三键(例如1、2、3或4个碳-碳三键)以及任选地一个或多个碳-碳双键(例如1、2、3或4个碳-碳双键)的直链或支链烃基的基团(“C2-20炔基”)。在某些实施方案中,炔基不含任何双键。在一些实施方案中,炔基具有2至10个碳原子(“C2-10炔基”)。在一些实施方案中,炔基具有2至9个碳原子(“C2-9炔基”)。在一些实施方案中,炔基具有2至8个碳原子(“C2-8炔基”)。在一些实施方案中,炔基具有2至7个碳原子(“C2-7炔基”)。在一些实施方案中,炔基具有2至6个碳原子(“C2-6炔基”)。在一些实施方案中,炔基具有2至5个碳原子(“C2-5炔基”)。在一些实施方案中,炔基具有2至4个碳原子(“C2-4炔基”)。在一些实施方案中,炔基具有2至3个碳原子(“C2-3炔基”)。在一些实施方案中,炔基具有2个碳原子(“C2炔基”)。所述一个或多个碳-碳三键可以在内部(比如在2-丁炔基中)或末端(比如在1-丁炔基中)。C2-4炔基的实例包括但不限于乙炔基(C2)、1-丙炔基(C3)、2-丙炔基(C3)、1-丁炔基(C4)、2-丁炔基(C4)等。C2-6烯基的实例包括前述的C2-4炔基以及戊炔基(C5)、己炔基(C6)等。另外的炔基实例包括庚炔基(C7)、辛炔基(C8)等。
如本文所用,“亚烷基”、“亚烯基”和“亚炔基”分别是指烷基、烯基和炔基的二价基。当针对具体的“亚烷基”、“亚烯基”或“亚炔基”基团提供碳的范围或数量时,应当理解的是,范围或数量是指在直链碳二价链中的碳的范围或数量。“亚烷基”、亚烯基”和“亚炔基”可被如本文所述的一个或多个取代基取代或未被取代。
如本文所用,“芳基”是指单环或多环(例如,双环或三环)的4n+2芳香环系统(例如,具有在环状阵列中共享的6个、10个或14个电子)的基团,其具有提供在芳香环系统中的6-14个环碳原子和零个杂原子(“C6-14芳基”)。在一些实施方案中,芳基具有六个环碳原子(“C6芳基”;例如苯基)。在一些实施方案中,芳基具有十个环碳原子(“C10芳基”;例如萘基,比如1-萘基和2-萘基)。在一些实施方案中,芳基具有十四个环碳原子(“C14芳基”;比如,蒽基)。“芳基”还包括环系统,其中如上定义的芳基环与一个或多个碳环基或杂环基稠合,其中连接基或点在芳基环上,并且在这样的情况下,碳原子数继续指定芳基环系统中的碳原子数。典型的芳基包括但不限于衍生自醋蒽烯、苊烯、醋菲烯、蒽、薁、苯、蒄、荧蒽、芴、并六苯、己芬、并环己二烯(hexalene)、不对称-二环戊二烯并苯(as-indacene)、对称-二环戊二烯并苯(s-indacene)、茚满、茚、萘、并八苯、辛芬、辛搭烯(octalene)、卵苯(ovalene)、戊-2,4-二烯、并五苯(pentacene)、并环戊二烯(pentalene)、戊芬(pentaphene)、苝(perylene)、非那烯(phenalene)、菲(phenanthrene)、苉(picene)、七曜烯(pleiadene)、芘(pyrene)、皮蒽(pyranthrene)、玉红省(rubicene)、三亚苯(triphenylene)和联三萘(trinaphthalene)的基团。具体而言,芳基包括苯基、萘基、茚基和四氢萘基。
如本文所用,“杂芳基”是指5-10元单环或双环4n+2芳香环系统(例如,具有在环状阵列中共享的6个或10个电子)的基团,其具有提供在芳香环系统中的环碳原子和1-4个环杂原子,其中每个杂原子独立地选自氮、氧和硫(“5-10元杂芳基”)。在化合价允许的情况下,在含有一个或多个氮原子的杂芳基中,连接点可以是碳或氮原子。杂芳基双环系统可包括在一个或两个环中的一个或多个杂原子。“杂芳基”包括这样的环系统,其中如上定义的杂芳基环与一个或多个碳环基或杂环基稠合,其中连接点在杂芳基环上,并且在这样的情况下,环元数继续指定杂芳基环系统中的环元数。“杂芳基”还包括这样的环系统,其中如上定义的杂芳基环与一个或多个芳基稠合,其中连接点在芳基环或杂芳基环上,并且在这样的情况下,环元数指定稠合的(芳基/杂芳基)环系统中的环元数。对于其中一个环不含杂原子的双环杂芳基团(例如,吲哚基、喹啉基、咔唑基等),连接点可以位于任一环上,即,带有杂原子的环(例如2-吲哚基)或不含杂原子的环(例如5-吲哚基)。
在一些实施方案中,杂芳基是5-10元芳香环系统,其具有提供在芳香环系统中的环碳原子和1-4个环杂原子,其中每个杂原子独立地选自氮、氧和硫(“5-10元杂芳基”)。在一些实施方案中,“杂芳基”是5-8元芳香环系统,其具有提供在芳香环系统中的环碳原子和1-4个环杂原子,其中每个杂原子独立地选自氮、氧和硫(“5-8元杂芳基”)。在一些实施方案中,“杂芳基”是5-6元芳香环系统,其具有提供在芳香环系统中的环碳原子和1-4个环杂原子,其中每个杂原子独立地选自氮、氧和硫(“5-6元杂芳基”)。在一些实施方案中,5-6元杂芳基具有1-3个选自氮、氧和硫的环杂原子。在一些实施方案中,5-6元杂芳基具有1-2个选自氮、氧和硫的环杂原子。在一些实施方案中,5-6元杂芳基具有1个选自氮、氧和硫的环杂原子。
含有一个杂原子的示例性5元杂芳基包括但不限于吡咯基、呋喃基和噻吩基。含有两个杂原子的示例性5元杂芳基包括但不限于咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。含有三个杂原子的示例性5元杂芳基包括但不限于三唑基、噁二唑基和噻二唑基。含有四个杂原子的示例性5元杂芳基包括但不限于四唑基。含有一个杂原子的示例性6元杂芳基包括但不限于吡啶基。含有两个杂原子的示例性6元杂芳基包括但不限于哒嗪基、嘧啶基和吡嗪基。含有三个或四个杂原子的示例性6元杂芳基分别包括但不限于三嗪基和四嗪基。含有一个杂原子的示例性7元杂芳基包括但不限于氮杂环庚三烯基(azepinyl)、氧杂环庚三稀基(oxepinyl)和硫杂环庚三烯基(thiepinyl)。示例性5,6-双环杂芳基团包括但不限于吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基(benzothiophenyl)、异苯并噻吩基(isobenzothiophenyl)、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基(benzisoxazolyl)、苯并噁二唑基(benzoxadiazolyl)、苯并噻唑基(benzthiazolyl)、苯并异噻唑基(benzisothiazolyl)、苯并噻二唑基(benzthiadiazolyl)、吲哚嗪基(indolizinyl)和嘌呤基(purinyl)。示例性6,6-双环杂芳基团包括但不限于萘啶基、蝶啶基、喹啉基、异喹啉基、噌啉基(cinnolinyl)、喹喔啉基(quinoxalinyl)、酞嗪基(phthalazinyl)和喹唑啉基(quinazolinyl)。
代表性杂芳基的实例包括下列基团:
其中每个Z选自羰基、N、NR65、O和S;并且R65独立地是氢、C1-8烷基、C3-10碳环基、4-10元杂环基、C6-C10芳基和5-10元杂芳基。
如本文所用,“碳环基”或“碳环”是指非芳香环状烃基的基团,其具有在非芳香环系统中的3至10个环碳原子(“C3-10碳环基”)和零个杂原子。在一些实施方案中,碳环基具有3至8个环碳原子(“C3-8碳环基”)。在一些实施方案中,碳环基具有3至7个环碳原子(“C3-7碳环基”)。在一些实施方案中,碳环基具有3至6个环碳原子(“C3-6碳环基”)。在一些实施方案中,碳环基具有5至10个环碳原子(“C5-10碳环基”)。示例性C3-6碳环基包括但不限于环丙基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环己二烯基(C6)等。示例性C3-8碳环基包括但不限于前述的C3-6碳环基以及环庚烷基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)、环辛基(C8)、环辛烯基(C8)、二环[2.2.1]庚基(C7)、二环[2.2.2]辛基(C8)等。示例性C3-10碳环基包括但不限于前述的C3-8碳环基以及环壬基(C9)、环壬烯基(C9)、环癸基(C10)、环癸烯基(C10)、八氢-1H-茚基(C9)、十氢萘基(C10)、螺[4.5]癸基(C10)等。如前述实例所示,在某些实施方案中,碳环基是单环的(“单环碳环基”)或含有稠合、桥接或螺环系统,比如双环系统(“双环碳环基”),并且可以是饱和的或可以是部分不饱和的。“碳环基”还包括环系统,其中如上定义的碳环基环与一个或多个芳基或杂芳基稠合,其中连接点在碳环基环上,并且在这样的情况下,碳数继续指定基碳环环系统中的碳数。
术语“环烷基”是指本文所指的具有3-12、3-8、4-8或4-6个碳的单价饱和环状、双环或桥接环状(例如,金刚烷基)烃基,例如,衍生自环烷烃的“C4-8环烷基”。示例性环烷基包括但不限于环己烷、环戊烷、环丁烷和环丙烷。
如本文所用,“C3-6单环环烷基”或“单环C3-6环烷基”是指饱和的3至7元单环烃环系统。3至7元单环环烷基包括但不限于环丙基、环丁基、环戊基和环己基。在被指定为任选地经取代或经取代的情况下,环烷基上的取代基(例如,在任选地经取代的环烷基的情况下)可以存在于任何可取代的位置上,并且包括例如,在连接环烷基的位置。
如本文所用,“杂环基”或“杂环的”是指具有环碳原子和1至4个环杂原子的3至10元非芳香环系统的基团,其中每个杂原子独立地选自氮、氧、硫、硼、磷和硅(“3-10元杂环基”)。在化合价允许的情况下,在含有一个或多个氮原子的杂环基中,连接点可以是碳或氮原子。杂环基可以是单环的(“单环杂环基”)或稠合、桥接或螺环系统,比如双环系统(“双环杂环基”),并且可以是饱和的或可以是部分不饱和的。杂环基双环系统可包括在一个或两个环中的一个或多个杂原子。“杂环基”还包括这样的环系统,其中如上定义的杂环基环与一个或多个碳环基稠合,其中连接点在碳环基环或杂环基环上;或这样的环系统,其中如上定义的杂环基环与一个或多个芳基或杂芳基稠合,其中连接点在杂环基环上,并且在这样的情况下,环元数继续指定杂环基环系统中的环元数。术语“杂环”、“杂环基”、“杂环基环”、“杂环的基团”、“杂环部分”和“杂环基团”可以互换使用。
在一些实施方案中,杂环基是具有环碳原子和1-4个环杂原子的4-7元非芳香环系统,其中每个杂原子独立地选自氮、氧和硫(“4-7元杂环基”)。在一些实施方案中,“杂环基”是具有环碳原子和1-4个环杂原子的5至10元非芳香环系统,其中每个杂原子独立地选自氮、氧、硫、硼、磷和硅(“5-10元杂环基”)。在一些实施方案中,“杂环基”是具有环碳原子和1-4个环杂原子的5-8元非芳香环系统,其中每个杂原子独立地选自氮、氧和硫(“5-8元杂环基”)。在一些实施方案中,“杂环基”是具有环碳原子和1-4个环杂原子的5-6元非芳香环系统,其中每个杂原子独立地选自氮、氧和硫(“5-6元杂环基”)。在一些实施方案中,5-6元杂环基具有1-3个选自氮、氧和硫的环杂原子。在一些实施方案中,5-6元杂环基具有1-2个选自氮、氧和硫的环杂原子。在一些实施方案中,5-6元杂环基具有一个选自氮、氧和硫的环杂原子。
含有一个杂原子的示例性3元杂环基包括但不限于氮丙啶基(azirdinyl)、环氧乙烷基(oxiranyl)、硫杂环丙烷基(thiorenyl)。含有一个杂原子的示例性4元杂环基包括但不限于氮杂环丁基(azetidinyl)、氧杂环丁基(oxetanyl)和硫杂环丁基(thietanyl)。含有一个杂原子的示例性5元杂环基包括但不限于四氢呋喃基、二氢呋喃基、四氢噻吩基(tetrahydrothiophenyl)、二氢噻吩基(dihydrothiophenyl)、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。含有两个杂原子的示例性5元杂环基包括但不限于二氧戊环基(dioxolanyl)、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。含有三个杂原子的示例性5元杂环基包括但不限于三唑啉基(triazolinyl)、噁二唑啉基(oxadiazolinyl)和噻二唑啉基(thiadiazolinyl)。含有一个杂原子的示例性6元杂环基包括但不限于哌啶基(piperidinyl)、四氢吡喃基(tetrahydropyranyl)、二氢吡啶基(dihydropyridinyl)和硫杂环己基(thianyl)。含有两个杂原子的示例性6元杂环基包括但不限于哌嗪基(piperazinyl)、吗啉基(morpholinyl)、二硫杂环己基(dithianyl)和二氧杂环己基(dioxanyl)。含有两个杂原子的示例性6元杂环基包括但不限于三嗪烷基(triazinanyl)。含有一个杂原子的示例性7元杂环基包括但不限于氮杂环庚烷基(azepanyl)、氧杂环庚烷基(oxepanyl)和硫杂环庚烷基(thiepanyl)。含有一个杂原子的示例性8元杂环基包括但不限于氮杂环辛基(azocanyl)、氧杂环辛基(oxecanyl)和硫杂环辛基(thiocanyl)。与C6芳基环(本文中也称为5,6-双环杂环)稠合的示例性5元杂环基包括但不限于二氢吲哚基(indolinyl)、异二氢吲哚基(isoindolinyl)、二氢苯并呋喃基(dihydrobenzofuranyl)、二氢苯并噻吩基(dihydrobenzothienyl)、苯并噁唑啉酮基(benzoxazolinonyl)等。与芳基环(本文中也称为6,6-双环杂环)稠合的示例性6元杂环基包括但不限于四氢喹啉基(tetrahydroquinolinyl)、四氢异喹啉基(tetrahydroisoquinolinyl)等。
饱和或部分不饱和的杂环基的实例包括但不限于四氢呋喃基、四氢噻吩基、四氢吡喃基(terahydropyranyl)、吡咯烷基(pyrrolidinyl)、吡啶酮基(pyridinonyl),吡咯烷酮基(pyrrolidonyl)、哌啶基(piperidinyl)、噁唑烷基(oxazolidinyl)、哌嗪基(piperazinyl)、二噁烷基(dioxanyl)、二氧戊环基(dioxolanyl)、吗啉基(morpholinyl)、二氢呋喃基、二氢吡喃基(dihydropyranyl)、二氢吡啶基、四氢吡啶基(tetrahydropyridinyl)、二氢嘧啶基(dihydropyrimidinyl)、氧杂环丁基(oxetanyl)、氮杂环丁基(azetidinyl)和四氢嘧啶基(tetrahydropyrimidinyl)。在被指定为任选地经取代或经取代的情况下,在杂环基(例如,在任选地经取代的杂环的情况下)上的取代基可以存在于任何可取代的位置上,并且包括例如,在连接杂环基的位置。
当用于描述化合物或在化合物上存在的基团时,“杂”表示在化合物或基团中的一个或多个碳原子已被氮、氧或硫杂原子取代。杂可以应用于具有1至5个特别是1至3个杂原子的上述任何烃基,比如烷基,例如杂烷基;碳环基,例如杂环基;芳基,例如杂芳基;等等。
如本文所用,“氰基”是指-CN。
如本文所用的术语“卤代”和“卤素”是指选自氟(氟代,-F)、氯(氯代,-Cl)、溴(溴代,-Br)和碘(碘代,-I)的原子。在某些实施方案中,卤代基为氟代或氯代。
如本文所用,术语“烷氧基”是指经由氧原子与另一部分连接的烷基(-O-(烷基))。非限制性实例包括例如甲氧基、乙氧基、丙氧基和丁氧基。
“卤代烷氧基”是经由氧原子与另一部分连接的卤代烷基,例如但不限于–OCHCF2或–OCF3。
术语“卤代烷基”包括被一个或多个卤素原子取代的单、多和全卤代烷基,其中卤素独立地选自氟、氯、溴和碘。对于C1-4卤代烷基-O-C1-4烷基的组,连接点发生在被卤化的烷基部分上。
如本文所用,“硝基”是指-NO2。
如本文所用,“氧基”是指-C=O。
一般而言,术语“取代的”,无论之前是否为术语“任选地”,表示基团(例如碳或氮原子)上存在的至少一个氢被允许的取代基取代,所述取代基例如在取代后产生稳定化合物的取代基,所述稳定化合物例如不会自发地比如通过重排、环化、消除或其他反应而经历转化的化合物。除非另有说明,否则“取代的”基团可以具有在所述基团的一个或多个可取代位置的取代基,并且当在任何给定结构中的多于一个位置被取代时,所述取代基在每个位置上是相同或不同的。
在化合价允许的情况下,氮原子可以被取代或未被取代,并且包括伯、仲、叔和季氮原子。示例性氮原子取代基包括但不限于氢、-OH、–ORaa、–N(Rcc)2、–CN、–C(=O)Raa、–C(=O)N(Rcc)2、–CO2Raa、–SO2Raa、–C(=NRbb)Raa、–C(=NRcc)ORaa、–C(=NRcc)N(Rcc)2、–SO2N(Rcc)2、–SO2Rcc、–SO2ORcc、–SORaa、–C(=S)N(Rcc)2、–C(=O)SRcc、–C(=S)SRcc、–P(=O)2Raa、–P(=O)(Raa)2、–P(=O)2N(Rcc)2、–P(=O)(NRcc)2、C1-10烷基、C1-10全卤代烷基、C2-10烯基、C2-10炔基、C3-10碳环基、3-14元杂环基、C6-14芳基和5-14元杂芳基,或者,附接至氮原子的两个Rcc基团接合形成3-14元杂环基或5-14元杂芳基环,其中每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代,并且其中Raa、Rbb、Rcc和Rdd如上定义。
这些和其他示例性取代基更详细地描述于具体实施方式、实施例和权利要求书中。本发明无意以任何方式受到上述示例性取代基列表的限制。
其他定义
如本文所用,“药学上可接受的载体”是指不破坏与其一起配制的化合物的药理活性的无毒载体、佐剂或媒介物。可以在本文所述的组合物中使用的药学上可接受的载体、佐剂和媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(比如人血清白蛋白)、缓冲物质(比如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(比如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁)、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
如本文所用,术语“药学上可接受的盐”是指这样的盐类,所述盐类在合理医学判断范围内适用于与人类和低等动物的组织接触而没有异常毒性、刺激、过敏反应等,并且与合理的利益/风险比相称。药学上可接受的盐是本领域熟知的。例如,Berge等人,在J.Pharmaceutical Sciences(1977)66:1-19中详细描述了药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自适合的无机和有机的酸和碱的那些。药学上可接受的无毒的酸加成盐的实例是与无机酸(比如盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(比如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)或通过使用本领域中使用的诸如离子交换之类的其他方法形成的氨基盐。其他的药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐,苯磺酸酯、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐(glucoheptonate)、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、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、双羟萘酸盐、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,等等。衍生自适当碱的药学上可接受的盐包括碱金属、碱土金属、铵和N+(C1–4烷基)4的盐类。代表性碱金属或碱土金属盐类包括钠、锂、钾、钙、镁等。另外的药学上可接受的盐在适当时包括无毒的铵、季铵和使用抗衡离子比如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根形成的胺阳离子。
如本文所用,考虑施用的“受试者”包括但不限于人类(即,任何年龄组的男性或女性,例如,儿科受试者(例如,婴儿、儿童、青少年)或成人受试者(例如,年轻成人、中老年成人或老年人))和/或非人类动物,例如哺乳动物,比如灵长类动物(例如食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或犬。在某些实施方案中,受试者是人。在某些实施方案中,受试者是非人类动物。术语“人”、“患者”和“受试者”在本文中可互换使用。
疾病、疾患和病症在本文中可互换使用。
如本文所用,除非另有说明,否则术语“治疗”(treat)、“治疗”(treating)和“治疗”(treatment)意指在受试者患有特定疾病、疾患或病症时发生的作用,其降低疾病、疾患或病症的严重性,或延缓或减慢疾病、疾患或病症的进展(“治疗性治疗”),并且还意指在受试者开始遭受特定疾病、疾患或病症之前发生的作用(“预防性治疗”)。
如本文所用,化合物的“有效量”是指足以引出期望的生物反应的量。如本领域普通技术人员所理解的,本发明化合物的有效量可根据诸如期望的生物学终点、化合物的药代动力学、被治疗的疾病、施用方式、以及受试者的年龄、健康和状况等因素而变化。有效量涵盖治疗性和预防性治疗。
如本文所用,并且,除非另有说明,否则化合物的“治疗有效量”是足以在疾病、疾患或病症的治疗中提供治疗益处或足以将与疾病、疾患或病症有关的一种或多种症状延迟或减轻至最低限度的量。化合物的治疗有效量意指单独或与其他疗法联合的治疗剂的量,其在疾病、疾患或病症的治疗中提供治疗益处。术语“治疗有效量”可以涵盖改善总体治疗、减少或避免疾病或病症的症状或原因、或增强另一种治疗剂的治疗效果的量。
化合物
一方面,本发明提供了具有式I的化合物:
或其药学上可接受的盐;其中
X和Y各自独立地是CRd或N;
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R5是卤基、任选地被O-C1-4烷基或O-C3-6环烷基取代的C3-6环烷基或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
t是1或2;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基;并且
Rd是氢或C1-4烷基。
另一方面,本公开提供了具有式II的化合物:
或其药学上可接受的盐;其中
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R5是卤基、任选地被O-C1-4烷基或O-C3-6环烷基取代的C3-6环烷基或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
t是1或2;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;并且
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基。
另一方面,本公开提供了具有式III的化合物:
或其药学上可接受的盐;其中
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R5是卤基、任选地被O-C1-4烷基或O-C3-6环烷基取代的C3-6环烷基或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
t是1或2;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;并且
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基。
另一方面,本公开提供了具有式IV的化合物:
或其药学上可接受的盐;其中
X和Y各自独立地是CRd或N;
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基;并且
Rd是氢或C1-4烷基;
在一些实施方案中,X是N,并且Y是CRd。在一些实施方案中,X是CRd,并且Y是N。
在一些实施方案中,R2是C1-4卤代烷基。在一些实施方案中,R2是CF3。在一些实施方案中,R2是氢。
在一些实施方案中,R3是C1-4烷基,并且R4是氢或C1-4烷基。在一些实施方案中,R3和R4各自是C1-4烷基。在一些实施方案中,R3和R4各自是甲基。在一些实施方案中,R3是甲基,并且R4是氢。在一些实施方案中,R3和R4各自是氢。
在一些实施方案中,R6是CF2-ORc。在一些实施方案中,Rc是任选地被环丙基取代的C1-4烷基。在一些实施方案中,Rc是环丙基。在一些实施方案中,R6是CF2OCH3、CF2OCH2CH3、CF2OCH(CH3)2或CF2OCH2C3H5。
在一些实施方案中,R6是CH2-ORc。在一些实施方案中,Rc是任选地被环丙基或苯基取代的C1-4烷基。在一些实施方案中,Rc是环丙基。在一些实施方案中,R6是CH2OCH3、CH2OCH2CH3、CH2OCH2C3H5、CH2OCH2CH(CH3)2或CH2OCH2C6H5。
在一些实施方案中,R6是C(CH3)2-ORc。在一些实施方案中,Rc是C1-4烷基。在一些实施方案中,R6是C(CH3)2-OCH2CH3。
在一些实施方案中,Ra是氟代。
在一些实施方案中,t是1。在一些实施方案中,t是2。
在一些实施方案中,R5是卤代或任选地被OCH3或OC3H5取代的C1-4烷基。在一些实施方案中,R5是氟代。在一些实施方案中,R5是甲基。在一些实施方案中,R5是氟代、CH3、CH2CH3、CH2OCH3、CH(CH3)OCH3或CH2OC3H5。
在一些实施方案中,Rd是氢。
在一些实施方案中,所述化合物是
在一些实施方案中,所述化合物是
药物组合物和施用途径
通常以药物组合物的形式施用根据本发明提供的化合物。因此,本发明提供了药物组合物,其含有作为活性成分的一种或多种所述化合物或其药学上可接受的盐或酯以及一种或多种药学上可接受的赋形剂、载体,包括惰性固体稀释剂和填充剂、稀释剂,包括无菌水溶液和各种有机溶剂、渗透促进剂、增溶剂和助剂。可以单独地或与其他治疗剂联合施用所述药物组合物。以药学领域熟知的方式(参见,例如,Remington's PharmaceuticalSciences,Mace Publishing Co.,Philadelphia,Pa.第17版(1985);和ModernPharmaceutics,Marcel Dekker公司,第3版(G.S.Banker&C.T.Rhodes,Eds.)制备这样的组合物。
可以通过具有相似效用的药剂的任何公认的施用方式以单剂量或多剂量给予所述药物组合物,例如,如通过引用并入本文的那些专利和专利申请中描述的方式,包括直肠、颊、鼻内和经皮途径,通过动脉内注射、静脉内、腹膜内、胃肠外,肌肉内、皮下、口服、局部,作为吸入剂,或经由诸如支架之类的浸渍或包被的装置,或插入动脉的圆柱形聚合物。
一种施用方式是胃肠外施用,具体地是通过注射施用。可以掺入以便通过注射施用的本发明的新型组合物的形式包括具有芝麻油、玉米油、棉籽油或花生油的水性或油悬浮液或乳剂,以及酏剂,其具有甘露醇、右旋糖,或无菌水溶液以及相似的药物媒介物。盐水中的水溶液也常规地用于注射,但是在本发明的上下文中是不太优选的。还可以采用乙醇、甘油、丙二醇、液态聚乙二醇等(及其适合的混合物)、环糊精衍生物和植物油。通过例如使用包衣(比如卵磷脂)借助于维持在分散体情况下所需的粒径和通过使用表面活性剂,可以维持适当的流动性。通过各种抗细菌剂和抗真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等,可以带来微生物作用的防止。
通过将根据本发明的化合物以需要的量在必要时与以上列举的各种其他成分一起掺入适当的溶剂中,随后进行过滤灭菌,从而制备无菌注射溶液。通常,通过将各种灭菌的活性成分掺入无菌媒介物中来制备分散体,所述无菌媒介物含有基础分散介质和来自以上列举那些的所需要的其他成分。在用于制备无菌注射液的无菌粉末的情况下,优选的制备方法为真空干燥和冷冻干燥技术,由此从预先无菌过滤的溶液产生活性成分加上任何其他期望的成分的粉末。
口服施用是根据本发明化合物的另一种施用途径。可以通过胶囊或肠溶包衣片等进行施用。在包含至少一种本文所述化合物的药物组合物的制造中,通常将活性成分用赋形剂稀释并且/或者封装在这样的载体内,所述载体可以呈胶囊、小袋、纸或其他容器的形式。当将赋形剂用作稀释剂时,它可以呈固体、半固体或液体材料(如上文)的形式,其作为活性成分的媒介物、载体或介质起作用。因此,组合物可以是片剂、丸剂、散剂、锭剂、小袋、扁囊剂、酏剂、混悬剂、乳剂、溶液、糖浆、气雾剂(作为固体或在液体介质中)、含有例如高达按重量计10%的活性化合物的软膏、软和硬明胶胶囊、无菌注射溶液和无菌包装粉末的形式。
一些适合的赋形剂的实例包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、无菌水、糖浆和甲基纤维素。这些制剂可以另外包括:润滑剂,比如滑石、硬脂酸镁和矿物油;润湿剂;乳化剂和助悬剂;防腐剂,比如羟基苯甲酸甲酯和羟基苯甲酸丙酯;甜味剂;以及芳香剂。
可以配制本发明的组合物,以便通过采用本领域中已知的程序给予至患者后,提供活性成分的快速、持续或延迟释放。用于口服施用的控释释放药物递送系统包括渗透泵系统和溶出系统,其含有聚合物包衣的储库或药物-聚合物基质制剂。控释系统的实例在美国专利第3,845,770;4,326,525;4,902,514;和5,616,345号中给出。用于本发明方法的另一种制剂采用透皮递送装置(“贴剂”)。这样的透皮贴剂可用于以受控的量提供本发明化合物的连续或不连续输注。用于递送药剂的透皮贴剂的构造和使用是本领域熟知的。参见,例如,美国专利第5,023,252,4,992,445和5,001,139号。这样的贴剂可以构造成用于连续、搏动或按需要递送药剂。
优选地将组合物配制成单位剂型。术语“单位剂型”是指适合作为用于人类受试者和其他哺乳动物的单一剂量的物理离散单位,每个单位含有预定量的经计算产生所期望疗效的与适合的药物赋形剂相结合的活性物质(例如片剂、胶囊、安瓿)。通常以药学有效量给予化合物。优选地,对于口服施用,每个剂量单位含有1mg至2g本文所述化合物,并且对于胃肠外施用,优选地含有0.1至700mg本文所述化合物。然而,应当理解的是,将根据有关情况(包括有待治疗的病症、所选择的施用途径、所施用的实际化合物及其相对活性、个体患者的年龄、体重和反应、患者症状的严重性,等等)由医师来确定通常实际施用的化合物的量。
为了制备固体组合物,比如片剂,将主要活性成分剂与药物赋形剂混合,以形成含有本发明化合物的均质混合物的固体预制剂组合物。当提及这些预制剂组合物为均质之时,意味着活性成分均匀地分散在整个组合物中,使得该组合物可以容易地再分为同样有效的单位剂型,比如片剂、丸剂和胶囊。
本发明的片剂或丸剂可以被包衣或以其他方式混合,以提供具有延长作用的优点的剂型,或保护胃不受酸性条件的影响。例如,片剂或丸剂可以包括内剂量组分和外剂量组分,后者处于在前者上的包膜的形式。这两种组分可以被肠溶层分开,所述肠溶层用来抵抗胃中的崩解作用并且允许内组分完整地传送到十二指肠中或延迟释放。多种材料可以用于这样的肠溶层或包衣,这样的材料包括多种聚合物酸和聚合物酸与诸如虫胶、鲸蜡醇和乙酸纤维素之类的材料的混合物。
用于吸入或吹入的组合物包括在药学上可接受的水性或有机溶剂或其混合物中的溶液和混悬剂,以及散剂。所述液体或固体组合物可含有如上文所述的适合的药学上可接受的赋形剂。优选地,针对局部或全身作用,通过口或鼻的呼吸途径施用所述组合物。可通过使用惰性气体将优选地在药学上可接受的溶剂中的组合物雾化。可从雾化装置直接吸入雾化溶液,或者可将雾化装置连接到面罩上,或者连接到间歇性正压呼吸机上。可以从以适当的方式递送制剂的装置,优选地经口或经鼻施用溶液、悬浮液或粉末组合物。
在一些实施方案中,一种药物组合物包含公开的化合物或其药学上可接受的盐以及药学上可接受的载体。
治疗方法
本文所述的化合物和组合物通常可用于调节钠通道的活性,并且可用于治疗与钠通道离子通道的功能异常,例如异常的晚期钠(INaL)电流有关的病症。在一些实施方案中,本发明所提供的化合物在癫痫或癫痫综合征、神经发育障碍、疼痛或神经肌肉障碍的治疗中有效。所提供的化合物、其药学上可接受的盐或组合物还可以调节所有钠离子通道,或者可以仅对一个或多个钠离子通道具有特异性,所述钠离子通道例如NaV1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8和/或1.9。
在典型的实施方案中,本发明旨在涵盖本文公开的化合物以及这样的化合物的药学上可接受的盐、药学上可接受的酯、互变异构形式、多晶型物和前药。在一些实施方案中,本发明包括本文所述的化合物(例如式I、II、III或IV的化合物)的药学上可接受的加成盐、药学上可接受的酯、加成盐的溶剂化物(例如水合物)、互变异构形式、多晶型物、对映异构体、对映异构体的混合物、立体异构体或立体异构体的混合物(纯的或为外消旋或非外消旋混合物)。
癫痫和癫痫综合征
本文所述的化合物可用于治疗癫痫和癫痫综合征。癫痫是一种CNS疾患,其中大脑中的神经细胞活动受到破坏,引起癫痫发作或一段时间的异常行为、感觉和有时的意识丧失。癫痫发作的症状变化很大,从简单的茫然凝视几秒钟到癫痫发作期间其臂或腿的反复颤搐。
癫痫可涉及全身性癫痫发作或部分或局灶性癫痫发作。大脑的所有区域都参与全身性癫痫发作。遭受全身性癫痫发作的人可能喊叫或发出声音,僵硬几秒钟到一分钟,然后发生臂和腿的节律性运动。眼睛通常是张开的,病人可能看起来没有呼吸,并且可能实际上肤色发绀。意识逐渐恢复,病人可有从几分钟到几个小时的意识错乱。全身性癫痫发作有六种主要类型:强直阵挛性发作、强直性发作、阵挛性发作、肌阵挛性发作、失神发作和失张力发作。在部分性或局灶性癫痫发作中,仅一部分大脑参与,因此仅身体的一部分受累。取决于大脑异常电活动的部位,症状可变化。
如本文所述,癫痫包括全身性、部分性、复杂部分性、强直阵挛性、阵挛性、强直性、难治性癫痫发作、癫痫持续状态、失神发作、热性癫痫发作或颞叶癫痫。
本文所述的化合物(例如式I、II、III或IV的化合物)也可用于治疗癫痫综合征。至少部分地由癫痫的一些方面引起的具有弥漫性脑功能障碍的严重综合征也被称为癫痫性脑病。这些与抵抗治疗的癫痫频繁发作和严重认知功能障碍(例如West综合征)相关。
在一些实施方案中,癫痫综合征包括癫痫性脑病,比如Dravet综合征、天使人(Angelman)综合征、CDKL5障碍、额叶癫痫、婴儿痉挛、West综合征、青少年肌阵挛性癫痫、兰道-克莱夫纳(Landau-Kleffner)综合征、Lennox-Gastaut综合征、大田原(Ohtahara)综合征、PCDH19癫痫或Glut1缺乏症。
在一些实施方案中,癫痫或癫痫综合征是遗传性癫痫或遗传性癫痫综合征。在一些实施方案中,癫痫或癫痫综合征包括癫痫性脑病,伴SCN1A、SCN2A、SCN8A突变的癫痫性脑病,早期婴儿型癫痫性脑病,Dravet综合征,伴SCN1A突变的Dravet综合征,全身性癫痫伴热性惊厥,顽固性儿童癫痫伴全身强直性阵挛发作,婴儿痉挛,良性家族性新生儿-婴儿惊厥,SCN2A癫痫性脑病,伴SCN3A突变的局灶性癫痫,伴SCN3A突变的隐源性小儿部分性癫痫,SCN8A癫痫性脑病,癫痫猝死,Rasmussen脑炎,婴儿恶性游走性部分性癫痫发作,常染色体显性夜发性额叶癫痫,癫痫猝死(SUDEP),KCNQ2癫痫性脑病或KCNT1癫痫性脑病。
在一些实施方案中,本文所述的方法进一步包括在施用本文所述的化合物(例如,式I、II、III或IV的化合物)之前鉴定患有癫痫或癫痫综合征(例如,癫痫性脑病,伴SCN1A、SCN2A、SCN8A突变的癫痫性脑病,早期婴儿型癫痫性脑病,Dravet综合征,伴SCN1A突变的Dravet综合征,全身性癫痫伴热性惊厥,顽固性儿童癫痫伴全身性强直阵挛发作,婴儿痉挛,良性家族性新生儿-婴儿惊厥,SCN2A癫痫性脑病,伴SCN3A突变的局灶性癫痫,伴SCN3A突变的隐源性小儿部分性癫痫,SCN8A癫痫性脑病,癫痫猝死,Rasmussen脑炎,婴儿恶性游走性部分性癫痫发作,常染色体显性夜发性额叶癫痫,癫痫猝死(SUDEP),KCNQ2癫痫性脑病或KCNT1癫痫性脑病)的受试者。
在一方面,本发明的特征在于一种治疗癫痫或癫痫综合征(例如,癫痫性脑病,伴SCN1A、SCN2A、SCN8A突变的癫痫性脑病,早期婴儿型癫痫性脑病,Dravet综合征,伴SCN1A突变的Dravet综合征,全身性癫痫伴热性惊厥,顽固性儿童癫痫伴全身性强直阵挛发作,婴儿痉挛,良性家族性新生儿-婴儿惊厥,SCN2A癫痫性脑病,伴SCN3A突变的局灶性癫痫,伴SCN3A突变的隐源性小儿部分性癫痫,SCN8A癫痫性脑病,癫痫猝死,Rasmussen脑炎,婴儿恶性游走性部分性癫痫发作,常染色体显性夜发性额叶癫痫,癫痫猝死(SUDEP),KCNQ2癫痫性脑病和KCNT1癫痫性脑病)的方法,所述方法包括向有需要的受试者施用式(I)的化合物:
或其药学上可接受的盐,其中所有变量如本文所定义。
本发明的化合物(例如式I、II、III或IV的化合物)也可以用于治疗癫痫性脑病,其中所述受试者具有以下一个或多个突变:ALDH7A1、ALG13、ARHGEF9、ARX、ASAH1、CDKL5、CHD2、CHRNA2、CHRNA4、CHRNB2、CLN8、CNTNAP2、CPA6、CSTB、DEPDC5、DNM1、EEF1A2、EPM2A、EPM2B、GABRA1、GABRB3、GABRG2、GNAO1、GOSR2、GRIN1、GRIN2A、GRIN2B、HCN1、IER3IP1、KCNA2、KCNB1、KCNC1、KCNMA1、KCNQ2、KCNQ3、KCNT1、KCTD7、LGI1、MEF2C、NHLRC1、PCDH19、PLCB1、PNKP、PNPO、PRICKLE1、PRICKLE2、PRRT2、RELN、SCARB2、SCN1A、SCN1B、SCN2A、SCN8A、SCN9A、SIAT9、SIK1、SLC13A5、SLC25A22、SLC2A1、SLC35A2、SLC6A1、SNIP1、SPTAN1、SRPX2、ST3GAL3、STRADA、STX1B、STXBP1、SYN1、SYNGAP1、SZT2、TBC1D24和WWOX。
在一些实施方案中,本文所述的方法进一步包括在施用本文所述的化合物(例如,式I、II、III或IV的化合物)之前鉴定具有以下一个或多个突变的受试者:ALDH7A1、ALG13、ARHGEF9、ARX、ASAH1、CDKL5、CHD2、CHRNA2、CHRNA4、CHRNB2、CLN8、CNTNAP2、CPA6、CSTB、DEPDC5、DNM1、EEF1A2、EPM2A、EPM2B、GABRA1、GABRB3、GABRG2、GNAO1、GOSR2、GRIN1、GRIN2A、GRIN2B、HCN1、IER3IP1、KCNA2、KCNB1、KCNC1、KCNMA1、KCNQ2、KCNQ3、KCNT1、KCTD7、LGI1、MEF2C、NHLRC1、PCDH19、PLCB1、PNKP、PNPO、PRICKLE1、PRICKLE2、PRRT2、RELN、SCARB2、SCN1A、SCN1B、SCN2A、SCN8A、SCN9A、SIAT9、SIK1、SLC13A5、SLC25A22、SLC2A1、SLC35A2、SLC6A1、SNIP1、SPTAN1、SRPX2、ST3GAL3、STRADA、STX1B、STXBP1、SYN1、SYNGAP1、SZT2、TBC1D24和WWOX。
神经发育障碍
本文所述的化合物可用于治疗神经发育障碍。在一些实施方案中,神经发育障碍包括孤独症、孤独症伴癫痫、结节性硬化、脆性X综合征、雷特(Rett)综合征、天使人(Angelman)综合征、Dup15q综合征、22q13.3缺失综合征、普拉德-威利(Prader-Willi)综合征、软腭-心-面(velocardiofacial)综合征、史—李—欧(Smith-Lemli-Opitz)综合征或神经发育障碍伴癫痫。在一些实施方案中,本文所述的方法进一步包括在施用本文所述的化合物(例如,式I、II、III或IV的化合物)之前鉴定患有神经发育障碍(例如,孤独症、孤独症伴癫痫、结节性硬化、脆性X综合征、雷特(Rett)综合征、天使人(Angelman)综合征、Dup15q综合征、22q13.3缺失综合征、普拉德-威利(Prader-Willi)综合征、软腭-心-面(velocardiofacial)综合征、史—李—欧(Smith-Lemli-Opitz)综合征或神经发育障碍伴癫痫)的受试者。
在一方面,本发明的特征在于一种治疗神经发育障碍(例如,孤独症、孤独症伴癫痫、结节性硬化、脆性X综合征、雷特(Rett)综合征、天使人(Angelman)综合征、Dup15q综合征、22q13.3缺失综合征、普拉德-威利(Prader-Willi)综合征、软腭-心-面(velocardiofacial)综合征、史—李—欧(Smith-Lemli-Opitz)综合征或神经发育障碍伴癫痫)的方法,所述方法包括向有需要的受试者施用式(I)的化合物:
或其药学上可接受的盐,其中所有变量如本文所定义。
疼痛
本文所述的化合物可用于治疗疼痛。在一些实施方案中,疼痛包括神经性疼痛、三叉神经痛、偏头痛、偏瘫性偏头痛、家族性偏瘫性偏头痛、家族性偏瘫性偏头痛3型、丛集性头痛、三叉神经痛、小脑共济失调或有关的头痛疾患。在一些实施方案中,本文所述的方法进一步包括在施用本文所述的化合物(例如,式I、II、III或IV的化合物)之前鉴定患有疼痛(例如,神经性疼痛、三叉神经痛、偏头痛、偏瘫性偏头痛、家族性偏瘫性偏头痛、家族性偏瘫性偏头痛3型、丛集性头痛、三叉神经痛、小脑共济失调或有关的头痛疾患)的受试者。
在一方面,本发明的特征在于一种治疗头痛(例如,神经性疼痛、三叉神经痛、偏头痛、偏瘫性偏头痛、家族性偏瘫性偏头痛、家族性偏瘫性偏头痛3型、丛集性头痛、三叉神经痛、小脑共济失调或有关的头痛疾患)的方法,所述方法包括向有需要的受试者施用式(I)的化合物:
或其药学上可接受的盐,其中所有变量如本文所定义。
神经肌肉障碍
本文所述的化合物可用于治疗神经肌肉障碍。在一些实施方案中,神经肌肉障碍包括肌萎缩性侧索硬化、多发性硬化、肌强直、先天性副肌强直、钾加重肌强直、周期性麻痹、高钾性周期性麻痹、低钾性周期性麻痹或伴SCN4A突变的喉痉挛。在一些实施方案中,本文所述的方法进一步包括在施用本文所述的化合物(例如,式I、II、III或IV的化合物)之前鉴定患有神经肌肉障碍(例如,肌萎缩性侧索硬化、多发性硬化、肌强直、先天性副肌强直、钾加重肌强直、周期性麻痹、高钾性周期性麻痹、低钾性周期性麻痹或伴SCN4A突变的喉痉挛)的受试者。
在一方面,本发明的特征在于一种治疗神经肌肉障碍(例如,肌萎缩性侧索硬化、多发性硬化、肌强直、先天性副肌强直、钾加重肌强直、周期性麻痹、高钾性周期性麻痹、低钾性周期性麻痹或伴SCN4A突变的喉痉挛)的方法,所述方法包括向有需要的受试者施用式(I)的化合物:
或其药学上可接受的盐,其中所有变量如本文所定义。
其他疾患
在一些实施方案中,本发明的化合物(例如,式I、II、III或IV的化合物)可具有适当的药代动力学特性,使得它们对于中枢和/或周围神经系统具有活性。在一些实施方案中,本文提供的化合物用于治疗心血管疾病,比如房性和室性心律失常,包括心房颤动,Prinzmetal的(变异型)心绞痛,稳定型心绞痛,不稳定型心绞痛,心脏、肾脏、肝脏和脑的缺血和再灌注损伤,运动诱发的心绞痛,肺动脉高压,充血性心脏病(包括舒张和收缩性心力衰竭),反复缺血,脑缺血,中风,肾缺血,与器官移植相关的缺血,急性冠脉综合征,外周动脉疾病,间歇性跛行,和心肌梗死。在一些实施方案中,本文提供的化合物可用于治疗导致瘙痒、癫痫发作或瘫痪的累及神经肌肉系统的疾病,或用于治疗糖尿病或胰岛素敏感性降低以及与糖尿病有关的疾病状态,比如糖尿病周围神经病变。在一些实施方案中,所公开的方法包括施用药物组合物。
在一些实施方案中,本文提供了一种治疗神经系统疾患或精神疾患的方法,其中所述方法包括向有需要的受试者施用本文公开的化合物或其药学上可接受的盐或本文公开的药物组合物。
联合治疗
本文所述的化合物或组合物(例如,用于调节钠离子通道,例如晚期钠(INaL)电流)可以与另一种药剂或疗法联合施用。有待施用本文公开的化合物的受试者可具有将受益于另一种药剂或疗法的治疗的疾病、疾患或病症或其症状。这些疾病或病症可涉及癫痫或癫痫综合征、神经发育障碍、疼痛或神经肌肉障碍。
抗癫痫药
抗癫痫药包括布瓦西坦、卡马西平、氯巴占、氯硝西泮、地西泮、双丙戊酸钠、艾司利卡西平、乙琥胺、依佐加滨、非尔氨酯、加巴喷丁、拉科酰胺、拉莫三嗪、左乙拉西坦、劳拉西泮、奥卡西平、吡仑帕奈、苯巴比妥、苯妥英、普瑞巴林、扑米酮、卢非酰胺、噻加宾、托吡酯、丙戊酸、氨己烯酸、唑尼沙胺和大麻二酚。
心血管药物联合治疗
可以受益于本发明的钠通道阻滞剂与其他治疗剂的联合治疗的心血管有相关疾病或病症包括但不限于心绞痛,包括稳定型心绞痛、不稳定型心绞痛(UA)、运动诱发的心绞痛、变异型心绞痛;心律失常;间歇性跛行;心肌梗死,包括非STE心肌梗死(NSTEMI);肺动脉高压,包括肺动脉高血压;心力衰竭,包括充血性(或慢性)心力衰竭和舒张性心力衰竭以及射血分数保留型心力衰竭(舒张功能障碍)、急性心力衰竭;或反复缺血。
适合于治疗心血管相关疾病或病症的治疗剂包括抗心绞痛药、抗心力衰竭药、抗血栓形成药、抗心律失常药、抗高血压药和降脂药。
本发明的钠通道阻滞剂与适合于治疗心血管相关病症的治疗剂的共同施用允许患者目前正在接受的护理治疗标准的提高。
抗心绞痛药
抗心绞痛药包括β受体阻滞剂、钙通道阻滞剂和硝酸盐。β受体阻滞剂通过降低心脏的工作负荷来减少心脏对氧气的需求,导致心率降低和不太剧烈的心脏收缩。β受体阻滞剂的实例包括醋丁洛尔(Sectral)、阿替洛尔(Tenormin)、倍他洛尔(Kerlone)、比索洛尔/氢氯噻嗪(Ziac)、比索洛尔(Zebeta)、卡替洛尔(Cartrol)、艾司洛尔(Brevibloc)、拉贝洛尔(Normodyne,Trandate)、美托洛尔(Lopressor,Toprol XL)、纳多洛尔(Corgard)、普萘洛尔(Inderal)、索他洛尔(Betapace)和噻吗洛尔(Blocadren)。
硝酸盐扩张动脉和静脉,从而增加冠状动脉血流量并降低血压。硝酸盐的实例包括硝酸甘油、硝酸盐贴剂、硝酸异山梨酯和5-单硝酸异山梨酯。
钙通道阻滞剂阻止钙正常流入心脏和血管的细胞中,引起血管松弛,从而增加心脏的血液和氧气供应。钙通道阻滞剂的实例包括氨氯地平(Norvasc,Lotrel)、苄普地尔(Vascor)、地尔硫卓(Cardizem,Tiazac)、非洛地平(Plendil)、硝苯地平(Adalat,Procardia)、尼莫地平(Nimotop)、尼索地平(Sular)、维拉帕米(Calan,Isoptin,Verelan)和尼卡地平。
抗心力衰竭药
用于治疗心力衰竭的药剂包括利尿剂、ACE抑制剂、血管扩张剂和强心苷类。利尿剂可消除组织和循环系统中的多余液体,从而缓解许多心力衰竭症状。利尿剂的实例包括氢氯噻嗪、美托拉宗(Zaroxolyn)、呋塞米(Lasix)、布美他尼(Bumex)、螺内酯(Aldactone)和依普利酮(Inspra)。
血管紧张素转换酶(ACE)抑制剂通过扩张血管和降低血流阻力来降低心脏的工作负荷。ACE抑制剂的实例包括贝那普利(Lotensin)、卡托普利(Capoten)、依那普利(Vasotec)、福辛普利(Monopril)、赖诺普利(Prinivil,Zestril)、莫昔普利(Univasc)、培哚普利(Aceon)、喹那普利(Accupril)、雷米普利(Altace)和群多普利(Mavik)。
血管舒张剂通过使血管松弛和扩张来降低血管压力。血管扩张剂的实例包括肼屈嗪、二氮嗪、哌唑嗪、可乐定和甲基多巴。ACE抑制剂、硝酸盐、钾通道激活剂和钙通道阻滞剂也可用作血管扩张剂。
强心苷类是增强心脏收缩力的化合物。这些化合物可增强心脏的泵血能力,并改善不规则的心跳活动。强心苷类的实例包括洋地黄、地高辛和洋地黄毒苷。
抗血栓药
抗血栓药抑制血液的凝固能力。抗血栓药分有三种主要类型:血小板抑制剂、抗凝血剂和血栓溶解剂。
血小板抑制剂抑制血小板的凝固活性,从而减少动脉中的凝血。血小板抑制剂的实例包括乙酰水杨酸(阿司匹林)、噻氯匹定、氯吡格雷(plavix)、双嘧达莫、西洛他唑、潘生丁、磺吡酮、双嘧达莫、吲哚美辛和糖蛋白IIb/IIIa抑制剂,比如阿昔单抗、替罗非班和依替巴肽(Integrelin)。β受体阻滞剂和钙通道阻滞剂也具有抑制血小板的作用。
抗凝血剂可防止血凝块变大,并防止新的血凝块形成。抗凝血剂的实例包括比伐卢定(Angiomax)、华法林(Coumadin)、普通肝素、低分子量肝素、达那肝素、来匹卢定和阿加曲班。
血栓溶解剂的作用是分解现有的血凝块。血栓溶解剂的实例包括链激酶、尿激酶和替奈普酶(TNK),以及组织型纤溶酶原激活剂(t-PA)。
抗心律失常药
抗心律失常药用于治疗心率和心律的紊乱。抗心律失常药的实例包括胺碘酮、决奈达隆、奎尼丁、普鲁卡因胺、利多卡因和普罗帕酮。强心苷类和β受体阻滞剂也被用作抗心律失常药。
考虑到最近发现的钠通道阻滞剂雷诺嗪和胺碘酮和决奈达隆的协同作用,胺碘酮和决奈达隆的联合特别受关注。
抗高血压药
抗高血压药用于治疗高血压,高血压是血压持续高于正常的一种病症。高血压与心血管疾病的许多方面相关,包括充血性心力衰竭、动脉粥样硬化和推定的血凝块(clotfor illation)。抗高血压药的实例包括α-1-肾上腺素能拮抗剂,比如哌唑嗪(Minipress)、甲磺酸多沙唑嗪(Cardura)、盐酸哌唑嗪(Minipress)、哌唑嗪、泊利噻嗪(Minizide)和盐酸特拉唑嗪(Hytrin);β-肾上腺素能拮抗剂,比如普萘洛尔(Inderal)、纳多洛尔(Corgard)、噻吗洛尔(Blocadren)、美托洛尔(Lopressor)和吲哚洛尔(Visken);中枢α-肾上腺素受体激动剂,比如盐酸可乐定(Catapres)、盐酸可乐定和氯噻酮(Clorpres,Combipres)、氯苄氨胍醋酸盐(Wytensin)、盐酸胍法辛(Tenex)、甲基多巴(Aldomet)、甲基多巴和氯噻唑(Aldoclor)、甲基多巴和氢氯噻嗪(Aldoril);联合的α/β-肾上腺素能拮抗剂,比如拉贝洛尔(Normodyne,Trandate)、卡维地洛(Coreg);肾上腺素能神经元阻滞剂,比如胍乙啶(ismelin)、利血平(Serpasil);具有中枢神经系统作用的抗高血压药,比如可乐定(Catapres)、甲基多巴(Aldomet)、氯苄氨胍(Wytensin);抗血管紧张素II剂;ACE抑制剂,比如培哚普利(Aceon)、卡托普利(Capoten)、依那普利(Vasotec)、赖诺普利(Prinivil、Zestril);血管紧张素II受体拮抗剂,比如坎地沙坦(Atacand)、依普罗沙坦(Teveten)、厄贝沙坦(Avapro)、氯沙坦(Cozaar)、替米沙坦(Micardis)、缬沙坦(Diovan);钙通道阻滞剂,比维拉帕米(Calan,Isoptin)、地尔硫卓(Cardizem)、硝苯地平(Adalat,Procardia);利尿剂;直接血管扩张剂,比如硝普钠(Nipride)、二氮嗪(Hyperstat IV)、肼屈嗪(Apresoline)、米诺地尔(Loniten)、维拉帕米;以及钾通道激活剂,比如阿普卡林、比卡林、克罗卡林、依马卡林、尼可地尔和吡那地尔。
降脂药
降脂药用于降低血液中存在的胆固醇或脂肪糖的量。降脂药的实例包括苯扎贝特(Bezalip)、环丙贝特(Modalim),和他汀类,比如阿托伐他汀(Lipitor)、氟伐他汀(Lescol)、洛伐他汀(Mevacor,Altocor)、美伐他汀、匹伐他汀(Livalo,Pitava)、普伐他汀、瑞舒伐他汀(Crestor)和辛伐他汀(Zocor)。
在本发明中,表现出急性冠状动脉疾病事件的患者通常患有继发性医学病症,比如代谢性疾病、肺部疾病、外周血管疾病或胃肠疾病中的一种或多种。这样的患者可以受益于用联合治疗进行治疗,所述联合治疗包括向患者联合施用雷诺嗪和至少一种治疗剂。
肺部疾病联合治疗
肺部疾病是指与肺有关的任何疾病或病症。肺部疾病的实例包括但不限于哮喘、慢性阻塞性肺疾病(COPD)、支气管炎和肺气肿。
用于治疗肺部疾病的治疗剂的实例包括支气管扩张药,包括β2激动剂和抗胆碱能药、皮质类固醇和电解质补充剂。用于治疗肺部疾病的治疗剂的具体实例包括肾上腺素、特布他林(Brethaire,Bricanyl)、沙丁胺醇(Proventil)、沙美特罗(Serevent,SereventDiskus)、茶碱、异丙托溴铵(Atrovent)、噻托溴铵(Spiriva)、甲泼尼龙(Solu-Medrol,Medrol)、镁和钾。
代谢性疾病联合治疗
代谢性疾病的实例包括但不限于糖尿病,包括I型和II型糖尿病、代谢综合征、血脂异常、肥胖症、葡萄糖耐受不良、高血压、血清胆固醇升高和甘油三酯升高。
用于治疗代谢性疾病的治疗剂的实例包括抗高血压药和降脂药,如上文在“心血管药物联合治疗”一节中所述。用于治疗代谢性疾病的另外的治疗剂包括胰岛素、磺酰脲类、双胍类、α-葡萄糖苷酶抑制剂和肠降血糖素模拟物。
外周血管疾病联合治疗
外周血管疾病是与位于心脏和脑之外的血管(动脉和静脉)相关的疾病,包括例如外周动脉疾病(PAD),其为在由于动脉粥样硬化而向内部器官、臂和腿的供血的动脉被完全或部分阻塞时产生的一种病症。
胃肠疾病联合治疗
胃肠疾病是指与胃肠道相关的疾病和病症。胃肠疾病的实例包括胃食管反流病(GERD)、炎性肠病(IBD)、胃肠炎、胃炎和消化性溃疡病以及胰腺炎。
用于治疗胃肠疾病的治疗剂的实例包括质子泵抑制剂,例如泮托拉唑(Protonix)、兰索拉唑(Prevacid)、埃索美拉唑(Nexium)、奥美拉唑(Prilosec)、雷贝拉唑;H2阻滞剂,比如西咪替丁(Tagamet)、雷尼替丁(Zantac)、法莫替丁(Pepcid)、尼扎替丁(Axid);前列腺素类,比如米索前列醇(Cytotec);硫糖铝;和抗酸剂。
抗生素、镇痛药、抗抑郁药和抗焦虑药联合治疗
出现急性冠状动脉疾病事件的患者可能会表现出这样的病症,所述病症受益于与雷诺嗪联合施用一种或多种治疗剂的治疗,所述治疗剂为抗生素、镇痛药、抗抑郁药和抗焦虑药。
抗生素类
抗生素是杀死微生物(包括细菌和真菌)或阻止其生长的治疗剂。抗生素剂的实例包括β-内酰胺抗生素类,包括青霉素(阿莫西林)、头孢菌素类,例如头孢唑林、头孢呋辛、头孢羟氨苄(Duricef)、头孢氨苄(Keflex)、头孢拉定(Velosef)、头孢克洛(Ceclor)、头孢呋辛酯(Ceftin)、头孢丙烯(Cefzil)、氯碳头孢(Lorabid)、头孢克肟(Suprax)、头孢泊肟酯(Vantin)、头孢布烯(Cedax)、头孢地尼(Omnicef)、头孢曲松(Rocephin)、碳青霉烯和单酰胺菌素;四环素类,比如四环素;大环内酯类抗生素,比如红霉素;氨基糖苷类,比如庆大霉素、妥布霉素、阿米卡星;喹诺酮类,比如环丙沙星;环肽,比如万古霉素、链阳霉素类、多粘菌素类;林可酰胺类,比如克林霉素;噁唑烷酮类(oxazolidinoes),比如利奈唑胺;以及磺胺类抗生素,比如磺胺异噁唑。
镇痛药
镇痛药是用于减轻疼痛的治疗剂。镇痛药的实例包括阿片类和吗啡类似物,比如芬太尼和吗啡;扑热息痛;NSAID和COX-2抑制剂。鉴于本发明的钠通道阻滞剂具有通过抑制Nav 1.7和1.8钠通道来治疗神经性疼痛的能力,因此特别考虑了与镇痛药的联合。参见美国专利申请公开20090203707。
抗抑郁药和抗焦虑药
抗抑郁药和抗焦虑药包括那些用于治疗焦虑症、抑郁症的药物,以及用作镇静药和镇静剂的药物。抗抑郁药和抗焦虑药的实例包括苯二氮卓类,比如地西泮、劳拉西泮和咪达唑仑;苯二氮卓类;巴比妥类;格鲁米特;水合氯醛;甲丙氨酯;舍曲林(Zoloft,Lustral,Apo-Sertral,Asentra,Gladem,Serlift,Stimuloton);依他普仑(Lexapro,Cipralex);氟西汀(Prozac,Sarafem,Fluctin,Fontex,Prodep,Fludep,Lovan));文拉法辛(Effexor XR,Efexor);西酞普兰(Celexa,Cipramil,Talohexane);帕罗西汀(Paxil,Seroxat,Aropax);曲唑酮(Desyrel);阿米替林(Elavil);和安非他酮(Wellbutrin,Zyban)。抗抑郁药和抗焦虑药可包括神经活性类固醇和氯胺酮以及相关的NMDA受体拮抗剂。
因此,本发明的一个方面提供了一种包含本发明的钠通道阻滞剂和至少一种治疗剂的组合物。在一个替代实施方案中,所述组合物包含本发明的钠通道阻滞剂和至少两种治疗剂。在进一步的替代实施方案中,所述组合物包含本发明的钠通道阻滞剂和至少三种治疗剂、本发明的钠通道阻滞剂和至少四种治疗剂、或本发明的钠通道阻滞剂和至少五种治疗剂。
联合治疗方法包括含有本发明的钠通道阻滞剂和一种或多种治疗剂的单一制剂的共同施用,包含本发明的钠通道阻滞剂和一种或多种治疗剂的多于一种制剂的大致同时施用,和本发明的钠通道阻滞剂和一种或多种治疗剂以任何顺序的连续施用,其中优选地存在这样一段时间,其中本发明的钠通道阻滞剂和一种或多种治疗剂同时发挥其治疗作用。
实施例
以下代表性实施例旨在帮助说明本发明,而不旨在也不应被解释为限制本发明的范围。
使用以下通用方法和程序,可以从可易于获得的起始原料容制备本文提供的化合物。应当理解,在给定典型的或优选的工艺条件(即,反应温度、时间、反应物的摩尔比、溶剂、压力等)的情况下,除非另有说明,否则还可使用其他工艺条件。最佳反应条件可以随使用的特定反应物或溶剂而变化,但是这样的条件可以由本领域技术人员通过常规优化来确定。
另外,对于本领域技术人员显而易见的是,常规的保护基对于防止某些官能团经历不希望的反应可能是必需的。针对特定官能团选择适合的保护基以及用于保护和脱保护的适合条件是本领域熟知的。例如,在T.W.Greene和P.G.M.Wuts,Protecting Groups inOrganic Synthesis,第二版,Wiley,New York,1991以及其中引证的参考文献中描述了许多保护基以及它们的引入和去除。
可以通过已知的标准程序分离和纯化本文提供的化合物。这样的程序包括重结晶、过滤、快速色谱、研磨、高压液相色谱(HPLC)或超临界流体色谱(SFC)。注意的是,快速色谱既可以手动执行,也可以通过自动化系统执行。可以通过已知的标准程序比如核磁共振波谱法(NMR)或液相色谱质谱法(LCMS)来表征本文提供的化合物。NMR化学位移被报告为百万分之几(ppm),且使用本领域技术人员熟知的方法生成NMR化学位移。
用于分析LCMS的示例性通用方法包括方法A(Xtimate C18(2.1mm x 30mm,3μm);A=H2O(0.04%TFA)和B=CH3CN(0.02%TFA);50℃;1.2mL/min;经0.9分钟从10%到80%B,然后用80%
B持续0.6分钟)和方法B(Chromolith Flash RP-18封端的C18(2mm x25mm);A=H2O(0.04%TFA)和B=CH3CN(0.02%TFA);50℃;1.5mL/min;经0.7min从5%到95%B,然后用95%B持续0.4min)。
缩写列表:
Pd(dppf)Cl2 [1,1'-双(二苯基膦)二茂铁]二氯化钯(II)
PdCl2(PPh3)2 双(三苯基膦)二氯化钯(II)
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
Pd(t-Bu3P)2 双(三-叔-丁基膦)钯(0)
TEA 三乙胺
AgOTf 三氟甲磺酸银
DMF N,N-二甲基甲酰胺
MeOH 甲醇
EtOH 乙醇
i-Pr2O 二异丙醚
THF 四氢呋喃
DCM 二氯甲烷
AcN或MeCN 乙腈
EtOAc 乙酸乙酯
PE 石油醚
DMSO 二甲亚砜
AcOH 乙酸
NBS N-溴代琥珀酰亚胺
MeONa 甲醇钠
EtONa 乙醇钠
TsOH 对-甲苯磺酸
DEA N,N-二乙苯胺
TFA 三氟乙酸
KOAc 乙酸钾
TBAI 四丁基碘化铵
MsCl 甲磺酰氯
Tf2O 三氟甲磺酸酐
DIEA N,N-二异丙基乙胺
MeI 甲基碘
TBAB 四丁基溴化铵
MeMgBr 甲基溴化镁
PCy3 三环己基膦
Ph3P 三苯基膦
BnBr 苄基溴
XPhos 2-二环己膦基-2′,4′,6′-三异丙基联苯
PyBOP (苯并三唑-1-基氧基)三吡咯烷基磷鎓六氟磷酸盐
TMSCF3 三氟甲基三甲基硅烷
实施例1:合成化合物1-(3-[二氟(甲氧基)甲基]-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
A2:2-氯-5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪
将在1,4-二噁烷(10mL)和水(2mL)的混合溶剂中的2-溴-5-氯-吡嗪(250mg,1.29mmol)、2-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(429.25mg,1.29mmol)、碳酸铯(842.22mg,2.58mmol)和Pd(dppf)Cl2(141.85mg,0.19mmol)的混合物在50℃搅拌4小时。在冷却至RT之后,将反应混合物用水(20mL)稀释并且用EtOAc(20mL×2)萃取。将合并的有机相用盐水(15mL)洗涤,经Na2SO4干燥,并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%)纯化粗产物,得到产物(300mg,0.31mmol,24%产率),呈油状物。在1.5min的色谱中,LCMSRt=0.95min,5-95AB,MS ESI计算值C13H11ClF3N2O2[M+H]+319.0,实测值319.0。
A3:[5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]肼
将在MeCN(8mL)中的2-氯-5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪(300mg,0.94mmol)和肼(301.71mg,9.41mmol)的混合物加热至90℃,并且搅拌16小时。在冷却至RT之后,将反应混合物浓缩,得到残余物。然后,用H2O(15mL)稀释残余物并用EtOAc(15mL x 2)萃取。将合并的有机相用盐水(10mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到产物(300mg,0.25mmol,27%产率),呈油状物。在1.5min的色谱中,LCMS Rt=0.74min,5-95AB,MS ESI计算值C13H14F3N4O2[M+H]+315.1,实测值315.1。
A4:3-[氯(二氟)甲基]-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
向甲苯(10mL)中的[5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(300mg,0.95mmol)的混合物添加2-氯-2,2-二氟-乙酸(2-氯-2,2-二氟-乙酰基)酯(0.35g,1.43mmol)和4A分子筛(400mg,0.95mmol)。将反应混合物在110℃搅拌48小时。在冷却至RT之后,将反应混合物浓缩,得到残余物。用水(20mL)稀释残余物并用EtOAc(20mL x 2)萃取混合物。将合并的有机相用盐水(15mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到残余物。在硅胶上通过快速色谱(EtOAc在PE中=0%至20%)纯化残余物,得到产物(154mg,0.22mmol,23%产率),呈油状物。在1.5min的色谱中,LCMSRt=0.92min,5-95AB,MS ESI计算值C15H11ClF5N4O2[M+H]+409.0,实测值409.1。
化合物1:3-[二氟(甲氧基)甲基]-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲醇(1mL)和DMF(1mL)中的3-[氯(二氟)甲基]-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(154mg,0.38mmol)和AgOTf(0.97g,3.77mmol)的混合物在90℃下搅拌72小时。在冷却至RT之后,将反应混合物用盐水(15mL)处理,并将得到的沉淀物过滤。将滤液用EtOAc(15mL×2)萃取。将合并的有机相经Na2SO4干燥,浓缩,得到粗产物。通过制备型HPLC(Waters Xbridge150mm x 25mm 5μm)A=H2O(10mM NH4HCO3)并且B=CH3CN;经8分钟从48%到62%B)纯化粗产物,得到产物(5.58mg,0.01mmol,4%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.52(d,1H),8.63(s,1H),7.71(d,1H),7.46(s,1H),7.35(d,1H),4.48(s,2H),3.94(s,3H),3.45(s,3H)。在2min的色谱中,LCMSRt=1.21min,10-80AB,MS ESI计算值C16H14F5N4O3[M+H]+405.1,实测值404.9。
实施例2:合成化合物2-(3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
A6:2-氯-5-[2-甲基-4-(三氟甲氧基)苯基]吡嗪
将在1,4-二噁烷(50mL)和水(10mL)中的2-溴-5-氯-吡嗪(1000mg,5.17mmol)、4,4,5,5-四甲基-2-[2-甲基-4-(三氟甲氧基)苯基]-1,3,2-二氧杂环戊硼烷(1561.81mg,5.17mmol)、碳酸铯(3368.87mg,10.34mmol)、Pd(dppf)Cl2(567.41mg,0.78mmol)的混合物在50℃搅拌8小时。在冷却至RT之后,将反应混合物用水(30mL)稀释,并且用EtOAc(30mL×2)萃取。将合并的有机相用盐水(20mL)洗涤,经Na2SO4干燥,浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%)纯化粗产物,得到产物(1200mg,1.75mmol,34%产率),呈油状物。在1.5min的色谱中,LCMS Rt=0.96min,5-95AB,MS ESI计算值C12H9ClF3N2O[M+H]+289.0,实测值288.9。
A7:[5-[2-甲基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼
将在MeCN(20mL)中的2-氯-5-[2-甲基-4-(三氟甲氧基)苯基]吡嗪(1.2g,4.16mmol)和肼(1.33g,41.57mmol)的混合物加热至90℃,并且搅拌16小时。在冷却至RT之后,将反应混合物浓缩,得到残余物。然后,用H2O(30mL)稀释残余物,并且将混合物用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(20mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到粗产物(1200mg,2.08mmol,50%产率),呈油状物。在1.5min的色谱中,LCMS Rt=0.73min,5-95AB,MS ESI计算值C12H12F3N4O[M+H]+285.1,实测值285.1。
A8:3-[氯(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
向甲苯(20mL)中的[5-[2-甲基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(1g,3.52mmol)的混合物添加2-氯-2,2-二氟-乙酸(2-氯-2,2-二氟-乙酰基)酯(1.28g,5.28mmol)和4A分子筛(1000mg,3.52mmol)。将反应混合物在110℃搅拌48小时。在冷却至RT之后,将反应混合物浓缩,得到残余物。用饱和水性NaHCO3(30mL)稀释残余物,并且将混合物用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(20mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到残余物。在硅胶上通过快速色谱(EtOAc在PE中=0%至20%)纯化残余物,得到产物(900mg,1.53mmol,44%产率),呈固体。在1.5min的色谱中,LCMS Rt=0.93min,5-95AB,MSESI计算值C14H9ClF5N4O[M+H]+379.0,实测值379.0。
化合物2:3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲醇(7mL)和DMF(7mL)中的3-[氯(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(900mg,2.38mmol)和AgOTf(6.11g,23.77mmol)的混合物在90℃搅拌48小时。在冷却至RT之后,将反应混合物用盐水(20mL)处理,并将得到的沉淀物过滤。将滤液用EtOAc(20mL x 2)萃取。将合并的有机相经Na2SO4干燥,浓缩,得到粗产物。通过制备型HPLC(Waters Xbridge 150mm x 25mm 5μm)A=H2O(10mM NH4HCO3)并且B=CH3CN;经8分钟从52%到62%B)纯化粗产物,得到产物(39.44mg,0.10mmol,4%产率)。1HNMR(400MHz,CDCl3)δH 9.51(d,1H),8.22(d,1H),7.47(d,1H),7.25-7.17(m,2H),3.94(s,3H),2.43(s,3H)。在2min的色谱中,LCMS Rt=1.21min,10-80AB,MS ESI计算值C15H12F5N4O2[M+H]+375.1,实测值374.9。
实施例3:合成化合物3-(3-二氟(甲氧基)甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
将在甲苯(20mL)中的[5-[2-甲基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(1.19g,4.19mmol)和2-甲氧基乙酰氯(500mg,4.61mmol)的混合物搅拌1小时。然后添加TsOH(216.38mg,1.26mmol),将混合物加温至120℃,并且搅拌16小时。在冷却至RT之后,将混合物减压浓缩。加入水(30mL),并且用EtOAc(30mL x 2)萃取水层。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过硅胶快速色谱柱(EtOAc在PE中=0%至60%至80%)纯化粗产物,得到不纯的产物。通过制备型HPLC(PhenomenexGemini-NX(150mm x 30mm,5μm)A=H2O(0.05%NH4OH)并且B=CH3CN;经8min从40%到70%B)纯化不纯的产物,得到产物(190.54mg,563.3μmol,95%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.43(d,1H),8.21(d,1H),7.47(d,1H),7.21-7.19(m,2H),5.10(s,2H),3.45(s,3H),2.44(s,3H)。在2min的色谱中,LCMS Rt=1.19min,10-80AB,MS ESI计算值C15H14F3N4O2[M+H]+339.1,实测值338.9。
实施例4:合成化合物4-(3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
将在DCM(10mL)中的3-[氯(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(500mg,1.32mmol)、EtONa(179.7mg,2.64mmol)和TBAI(146.3mg,0.79mmol)的溶液在20℃搅拌3小时。将该溶液加入到饱和水性NH4Cl(20mL)中。在相分离之后,将有机相用盐水(10mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(Waters XBridge(150mm x 25mm,5μm)A=H2O(10mM NH4HCO3)并且B=CH3CN;经10分钟从45%到75%B)纯化粗产物,得到产物(96.32mg,0.25mmol,48%产率),呈固体。1H NMR(400M Hz,CDCl3)δH=9.51(d,1H),8.24(d,1H),7.49(d,1H),7.25-7.17(m,2H),4.34(q,2H),2.45(s,3H),1.47(t,3H)。在2.0min的色谱中,LCMS Rt=1.36min,10-80AB,MS ESI计算值C16H14F5N4O2[M+H]+389.1,实测值389.0。
实施例5:合成化合物5-(3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
将在甲苯(20mL)中的[5-[2-甲基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(500mg,1.76mmol)和2-乙氧基乙酰氯(237.13mg,1.93mmol)的溶液在20℃搅拌1小时。然后向混合物添加TsOH(90.87mg,0.53mmol),将混合物加温至120℃,并且搅拌16小时。在冷却至RT之后,将混合物浓缩,得到残余物。用H2O(20mL)稀释残渣并用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(20mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。通过硅胶快速色谱柱(EtOAc在PE中=0%至60%至80%)纯化粗产物,得到产物(150mg,0.38mmol,21%产率),呈固体。通过制备型HPLC(Phenomenex Gemini-NX(150mm x 30mm,5μm)A=H2O(0.05%NH4OH)并且B=CH3CN;经8min从46%到76%B)进一步纯化产物,得到产物(87.43mg,0.25mmol,58%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.42(d,1H),8.25(d,1H),7.48(d,1H),7.23-7.16(m,2H),5.14(s,2H),3.63(q,2H),2.44(s,3H),1.25(t,3H)。在2.0min的色谱中,LCMSRt=1.22min,10-80AB,MS ESI计算值C16H16F3N4O2[M+H]+353.1,实测值353.0。
实施例6和7:合成化合物6和7-(3-(苄氧基甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪和3-(异丁氧基甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
化合物6:3-((苄氧基)甲基)-6-(2-甲基-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
将在甲苯(100mL)中的[5-[2-甲基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(4g,14.07mmol)和2-苄氧基乙酰氯(2.86g,15.48mmol)的溶液搅拌1小时。然后,向混合物添加TsOH(726.99mg,4.22mmol),将混合物加温至120℃,并且搅拌16小时。在冷却至RT之后,将混合物浓缩,得到残余物。用H2O(100mL)稀释残余物并用EtOAc(100mL x 2)萃取。将合并的有机相用盐水(100mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。通过硅胶快速色谱柱(EtOAc在PE中=0%至60%至80%)纯化粗产物,得到产物。通过制备型HPLC(PhenomenexGemini-NX(150mm x 30mm,5μm)A=H2O(0.05%NH4OH)并且B=CH3CN;经8min从49%到79%B)纯化产物,得到产物(119.34mg,0.29mmol,75%产率),呈固体。1H NMR(400MHz,DMSO-d6)δH9.51(d,1H),8.64(d,1H),7.58(d,1H),7.41-7.34(m,2H),7.32-7.24(m,5H),5.16(s,2H),4.62(s,2H),2.38(s,3H)。在2min的色谱中,LCMS Rt=1.32min,10-80AB,MS ESI计算值C21H18F3N4O2[M+H]+415.13,实测值415.0。
A9:乙酸[6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪-3-基]甲酯
将3-(苄氧基甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(2.5g,6.03mmol)和HBr/AcOH(5mL,6.03mmol)的溶液在20℃搅拌12小时。用H2O(20mL)稀释混合物,用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(20mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到粗产物(2g,3mmol,49%产率),呈油状物。在1.5min的色谱中,LCMS Rt=0.84min,5-95AB,MS ESI计算值C16H14F3N4O3[M+H]+367.09,实测值367.1。
A10:[6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪-3-基]甲醇
将在THF(5mL)和水(5mL)中的乙酸[6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪-3-基]甲酯(2g,5.46mmol)和LiOH·H2O(0.92g,21.84mmol)的溶液在40℃搅拌2小时。在冷却至RT之后,将混合物浓缩,得到残余物。用H2O(30mL)稀释残余物并用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(30mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。通过硅胶快速色谱柱(EtOAc在PE中=0%至60%至100%)纯化粗产物,得到产物(450mg,1.35mmol,24%产率),呈固体物。在1.5min的色谱中,LCMSRt=0.79min,5-95AB,MSESI计算值C14H12F3N4O2[M+H]+325.08,实测值324.8。
A11:3-(氯甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将在DCM(10mL)中的[6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪-3-基]甲醇(600mg,1.85mmol)、MsCl(0.59mL,7.68mmol)和TEA(0.51mL,3.7mmol)混合物在20℃搅拌5小时。将混合物减压浓缩以除去DCM,加入H2O(20mL),然后将混合物用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(10mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到粗产物(550mg,1.6mmol,87%产率),呈固体。在1.5min的色谱中,LCMS Rt=0.87min,5-95AB,MSESI计算值C14H11ClF3N4O[M+H]+343.05,实测值342.8。
化合物7:3-(异丁氧基甲基)-6-(2-甲基-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
将在MeCN(5mL)中的3-(氯甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(50mg,0.15mmol)、异丁醇(5mL,16.86mmol)和AgOTf(374.88mg,1.46mmol)的混合物在80℃搅拌16小时。在冷却至RT之后,将混合物浓缩,得到残余物。用H2O(20mL)稀释残余物并用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(20mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。将粗产物在硅胶(EtOAc在PE中=0%至40%至60%)上通过快速色谱柱纯化,得到产物。通过制备型HPLC(Phenomenex Gemini-NX(150mm x 30mm,5μm)A=H2O(0.05%NH4OH)并且B=CH3CN;经8min从51%到81%B)纯化产物,得到产物(46.35mg,0.12mmol,46%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.43(d,1H),8.24(d,1H),7.45(d,1H),7.23-7.16(m,2H),5.14(s,2H),3.31(d,2H),2.43(s,3H),1.95-1.84(m,1H),0.90(d,6H)。在2.0min的色谱中,LCMS Rt=1.33min,10-80AB,MS ESI计算值C18H20F3N4O2[M+H]+381.15,实测值381.0。
实施例8:合成化合物8-(3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-b]哒嗪)
将在1,4-二噁烷(7.5mL)和水(1.5mL)中的4,4,5,5-四甲基-2-[2-甲基-4-(三氟甲氧基)苯基]-1,3,2-二氧杂环戊硼烷(296.61mg,0.98mmol)、6-氯-3-(甲氧基甲基)-[1,2,4]三唑并[4,3-b]哒嗪(150mg,0.76mmol)、Pd(t-Bu3P)2(57.90mg,0.11mmol)和K3PO4(320.68mg,1.51mmol)的混合物在75℃在N2下搅拌16小时。将反应混合物冷却至RT并通过硅藻土过滤。将滤液浓缩,得到残余物。将水(10mL)添加至残余物并用EtOAc(20mL x 2)萃取。将合并的有机相经无水Na2SO4干燥,过滤,浓缩,得到粗产物。通过制备型HPLC(WatersXBridge(150mm x 25mm,5μm)A=H2O(10mM NH4HCO3)并且B=CH3CN;经9min从35%到62%B)纯化粗产物,得到产物(76.62mg,0.23mmol,29%产率),呈固体。1H NMR(400MHz,DMSO-d6)δH8.48(d,1H),7.69(d,1H),7.64(d,1H),7.48-7.37(m,2H),4.93(s,2H),3.35(s,3H),2.44(s,3H)。在2min的色谱中,LCMSRt=1.20min,10-80AB,MS ESI计算值C15H14F3N4O2[M+H]+339.1,实测值338.9。
实施例9:合成化合物9-(3-[二氟(甲氧基)甲基]-6-[3-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
将在DCM(10mL)中的3-[氯(二氟)甲基]-6-[3-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(500mg,1.32mmol)、EtONa(179.7mg,2.64mmol)和TBAI(292.62mg,0.79mmol)的溶液在20℃搅拌3小时。向该溶液加入饱和水性NH4Cl(30mL)。在相分离之后,将有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%至20%至50%)纯化粗产物,得到产物(61.05mg,154.0μmol,11%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.52(d,1H),8.47(d,1H),7.88(d,1H),7.78(dd,1H),7.37(dd,1H),4.37(q,2H),2.44(s,3H),1.51(t,3H)。在2.0min的色谱中,LCMS Rt=1.40min,10-80AB,MS ESI计算值C16H14F5N4O2[M+H]+389.1,实测值389.0。
实施例10:合成化合物10-(3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
将在DCM(2mL)中的3-[氯(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(200mg,0.53mmol)、2-丙醇钠盐(86.7mg,1.06mmol)和TBAI(117.05mg,0.32mmol)的混合物在25℃搅拌2小时。用H2O(10mL)稀释混合物并用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(10mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(Kromasil Waters XBridge(150mm x25mm,5μm)A=H2O(10mM NH4HCO3)并且B=CH3CN;经10min从50%到80%B)纯化粗产物,得到产物(26.4mg,0.07mmol,52%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.51(d,1H),8.23(d,1H),7.50(d,1H),7.25-7.18(m,2H),5.02-4.95(m,1H),2.46(s,3H),1.48(d,6H)。在2.0min的色谱中,LCMS Rt=1.39min,10-80AB,MS ESI计算值C17H16F5N4O2[M+H]+403.1,实测值403.0。
实施例11:合成化合物11-(3-[二氟(甲氧基)甲基]-6-[3-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
A14:4,4,5,5-四甲基-2-[3-甲基-4-(三氟甲氧基)苯基]-1,3,2-二氧杂环戊硼烷
将在1,4-二噁烷(20mL)中的1-溴-2-甲基-4-(三氟甲氧基)苯(5g,19.61mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(14.94g,58.82mmol)、KOAc(3.85g,39.21mmol)和Pd(dppf)Cl2(1.43g,1.96mmol)的混合物在85℃在N2下搅拌16小时。在冷却至RT之后,将混合物浓缩,通过硅藻土过滤,并用EtOAc(100mL×2)洗脱,并将滤液浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至3%至5%至10%)纯化粗产物,得到产物(4.56g,14.36mmol,73%产率),呈油状物。1HNMR(400MHz,CDCl3)δH7.71(s,1H),7.66(d,1H),7.20(d,1H),2.32(s,3H),1.35(s,12H)。
A15:2-氯-5-[3-甲基-4-(三氟甲氧基)苯基]吡嗪
将在1,4-二噁烷(280mL)和水(28mL)中的Pd(dppf)Cl2(1g,1.37mmol)、Cs2CO3(8.93g,27.4mmol)、4,4,5,5-四甲基-2-[3-甲基-4-(三氟甲氧基)苯基]-1,3,2-二氧杂环戊硼烷(4.55g,15.05mmol)和2-溴-5-氯-吡嗪(2.65g,13.7mmol)的混合物在60℃在N2下搅拌5小时。将混合物冷却至RT,并用EtOAc(40mL)稀释,然后通过硅藻土垫过滤,用EtOAc(40mL)洗涤。将滤液浓缩,给出粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至3%至5%)纯化粗产物,得到产物(3.5g,12.12mmol,88%产率),呈固体。1H NMR(400MHz,CDCl3)δH8.77(d,1H),8.64(d,1H),7.91(d,1H),7.83(dd,1H),7.35(dd,1H),2.42(s,3H)。
A16:[5-[3-甲基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼
将在MeCN(50mL)中的2-氯-5-[3-甲基-4-(三氟甲氧基)苯基]吡嗪(3.5g,12.13mmol)和N2H4·H2O(7.13g,121.25mmol)的混合物在90℃在N2下搅拌16小时。将混合物冷却至RT,用饱和水性NH4Cl(40mL)淬灭,并且将混合物用EtOAc(40mL x 2)萃取。将合并的有机相用盐水(40mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱柱(EtOAc在PE中=0至5%至10%至30%)纯化粗产物,得到产物(2.5g,8.79mmol,72%产率),呈固体。1H NMR(400MHz,CDCl3)δH8.46(d,1H),8.28(d,1H),7.80(d,1H),7.71(dd,1H),7.29(d,1H),6.05(s,1H),3.92(s,2H),2.39(s,3H)。
A17:3-[氯(二氟)甲基]-6-[3-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲苯(30mL)中的(2-氯-2,2-二氟-乙酰基)2-氯-2,2-二氟-乙酸酯(1.96g,8.08mmol)和[5-(4-叔丁氧基-3-甲基-苯基)吡嗪-2-基]肼(2g,7.34mmol)的溶液在90℃搅拌2小时。然后向混合物添加TsOH(379.36mg,2.2mmol),将混合物加热至130℃,并且搅拌16小时。在冷却至RT之后,将混合物浓缩,得到残余物。用H2O(50mL)稀释残余物,用EtOAc(50mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。通过硅胶快速色谱柱(EtOAc在PE中=0%至10%至20%)纯化粗产物,得到产物(600mg,1.58mmol,21%产率),呈油状物。1H NMR(400MHz,CDCl3)δH9.58(s,1H),8.43(s,1H),7.89(s,1H),7.82(d,1H),7.38(d,1H),2.45(s,3H)。
化合物11:3-(二氟(甲氧基)甲基)-6-(3-甲基-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
将在DCM(10mL)中的3-[氯(二氟)甲基]-6-[3-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(500mg,1.32mmol)、MeONa(142.65mg,2.64mmol)和TBAI(292.62mg,0.79mmol)的溶液在20℃搅拌3小时。将该溶液加入到饱和水性NH4Cl(40mL)中。在相分离之后,将有机相用盐水(40mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%至20%)纯化粗产物,得到产物(71.66mg,191.5μmol,14%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.53(d,1H),8.45(d,1H),7.88(d,1H),7.79(dd,1H),7.40-7.34(m,1H),3.98(s,3H),2.45(s,3H)。在2.0min的色谱中,LCMS Rt=1.35min,10-80AB,MS ESI计算值C15H12F5N4O2[M+H]+375.1,实测值375.0。
实施例12:合成化合物12-(3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
向在DMF(3mL)中的环丙醇(70.54mg,1.21mmol)、3-[氯(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(250mg,0.61mmol)的混合物添加叔丁醇钾(272.56mg,2.43mmol)。将反应混合物在20℃搅拌10分钟。用H2O(10mL)稀释混合物并用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(10mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(Welch Xtimate C18(150mm x 25mm x 5μm)A=H2O(10mMNH4HCO3)并且B=CH3CN;经6.5min从60%到80%B)纯化粗产物,得到产物(18.81mg,0.05mmol,37%产率),呈油状物。1H NMR(400MHz,CDCl3)δH9.51(d,1H),8.20(s,1H),7.48(d,1H),7.24-7.19(m,2H),4.21-4.11(m,1H),2.44(s,3H),1.01-0.95(m,2H),0.84-0.78(m,2H)。在2.0min的色谱中,LCMS Rt=1.37min,10-80AB,MS ESI计算值C17H14F5N4O2[M+H]+401.1,实测值401.0。
实施例13:合成化合物13(3-(乙氧基甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-b]哒嗪)
A19:6-氯-3-(乙氧基甲基)-[1,2,4]三唑并[4,3-b]哒嗪
在25℃向在甲苯(40mL)中的2-甲氧基乙酰氯(1.24g,11.41mmol)滴加(6-氯哒嗪-3-基)肼(1.5g,10.38mmol)。将溶液在25℃搅拌30min,添加TsOH(0.54g,3.11mmol)。将混合物在120℃回流16小时。在冷却至RT之后,用H2O(40mL)稀释混合物并用EtOAc(40mL x 2)萃取。将合并的有机相用盐水(40mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至90%至100%)纯化粗产物,得到产物(1.2g,5.64mmol,54%产率),呈固体。1H NMR(400MHz,CDCl3)δH8.10(d,1H),7.16(d,1H),5.09-5.02(m,2H),3.71(q,2H),1.26(t,3H)。
化合物13:3-(乙氧基甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-b]哒嗪
将在1,4-二噁烷(7.5mL)和水(1.5mL)中的4,4,5,5-四甲基-2-[2-甲基-4-(三氟甲氧基)苯基]-1,3,2-二氧杂环戊硼烷(277.04mg,0.92mmol)、Pd(t-Bu3P)2(54.08mg,0.11mmol)、K3PO4(299.52mg,1.41mmol)和6-氯-3-(乙氧基甲基)-[1,2,4]三唑并[4,3-b]哒嗪(150mg,0.71mmol)的混合物在85℃在N2下搅拌16小时。将反应混合物冷却至RT并通过硅藻土过滤。将滤液浓缩,得到残余物。将水(10mL)添加至残余物并用EtOAc(20mL x 2)萃取。将合并的有机相经无水Na2SO4干燥,过滤,浓缩,得到粗产物。通过制备型HPLC(WatersXBridge(150mm x 25mm,5μm)A=H2O(10mM NH4HCO3)并且B=CH3CN;经10min 35-65%B)纯化粗产物,得到产物(172.63mg,488.6μmol,69%产率),呈固体。1H NMR(400MHz,DMSO-d6)δH=8.48(d,1H),7.69(d,1H),7.63(d,1H),7.45(s,1H),7.41(d,1H),4.97(s,2H),3.59(q,2H),2.45(s,3H),1.11(t,3H)。在2.0min的色谱中,LCMS Rt=1.24min,10-80AB,MS ESI计算值C16H16F3N4O2[M+H]+353.1,实测值353.0。
实施例14:合成化合物14-(3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-b]哒嗪)
A20:6-氯-3-[氯(二氟)甲基]-[1,2,4]三唑并[4,3-b]哒嗪
向在甲苯(120mL)中的(2-氯-2,2-二氟-乙酰基)2-氯-2,2-二氟-乙酸酯(20.17g,83.01mmol)的混合物添加(6-氯哒嗪-3-基)肼(10g,69.18mmol)。将反应混合物在110℃搅拌12小时。在冷却至RT之后,将反应混合物浓缩,得到残余物。用饱和水性NaHCO3(100mL)稀释残余物,并且将混合物用EtOAc(100mL x 2)萃取。将合并的有机相用盐水(100mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至50%)纯化粗产物,得到产物(14g,58.6mmol,85%产率),呈固体。1H NMR(400MHz,CDCl3)δH8.22(d,1H),7.34(d,1H)。
A21:3-[氯(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-b]哒嗪
将在水(25mL)和1,4-二噁烷(125mL)中的Pd(t-Bu3P)2(962.2mg,1.88mmol)、K3PO4(5.33g,25.1mmol)、4,4,5,5-四甲基-2-[2-甲基-4-(三氟甲氧基)苯基]-1,3,2-二氧杂环戊硼烷(4.93g,16.32mmol)和6-氯-3-[氯(二氟)甲基]-[1,2,4]三唑并[4,3-b]哒嗪(3.g,12.55mmol)的混合物在85℃在N2下搅拌16小时。将反应混合物冷却至RT并通过硅藻土过滤。将滤液浓缩,得到残余物。将水(40mL)添加至残余物,将混合物用EtOAc(30mL x 2)萃取。将合并的有机相经无水Na2SO4干燥,过滤,浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至30%至50%)纯化粗产物,得到产物(4g,7.43mmol,59%产率),呈固体。1H NMR(400MHz,CDCl3)δH 8.31(m,1H),7.54(dd,1H),7.48(d,1H),7.28-7.17(m,2H),2.53(s,3H)。
化合物24:3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-b]哒嗪
将在甲醇(5mL)中的3-[氯(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-b]哒嗪(500mg,1.32mmol)和AgBF4(2.57g,13.2mmol)的混合物在密封管中在90℃搅拌6小时。在冷却至RT之后,将混合物用盐水(20mL)淬灭,用EtOAc(20mL)稀释,并且通过硅藻土过滤。将滤液分离,并且将水相用EtOAc(20mL)萃取。将合并的有机相浓缩,得到粗产物。将粗产物在硅胶(EtOAc在PE中=0%至30%至50%)上通过快速色谱纯化,得到产物。将产物用i-Pr2O(2mL)研磨,得到产物(81.22mg,0.21mmol,16%产率),呈固体。1HNMR(400MHz,CDCl3)δH 8.26(d,1H),7.54(d,1H),7.40(d,1H),7.26-7.21(m,2H),3.89(s,3H),2.52(s,3H)。在2min的色谱中,LCMSRt=1.29min,10-80AB,MS ESI计算值C15H12F5N4O2[M+H]+375.1,实测值375.0。
实施例15:合成化合物15-(3-[乙氧基(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-b]哒嗪)
将在乙醇(5mL)中的AgBF4(2.57g,13.2mmol)和3-[氯(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-b]哒嗪(500mg,1.32mmol)的混合物在密封管中在90℃搅拌6小时。在冷却至RT之后,将混合物用盐水(20mL)淬灭,用EtOAc(20mL)稀释,并且通过硅藻土过滤。在分离滤液之后,将水相用EtOAc(20mL)萃取。将合并的有机相浓缩,得到粗产物。将粗产物在硅胶(EtOAc在PE中=0%至30%至50%)上通过快速色谱纯化,得到产物。将产物用i-Pr2O(2mL)研磨,得到产物(39.96mg,0.10mmol,7%产率),呈固体。1H NMR(400MHz,CDCl3)δH 8.26(d,1H),7.56-7.51(m,1H),7.39(d,1H),7.26-7.20(m,2H),4.29(q,2H),2.52(s,3H),1.43(t,3H)。在2min的色谱中,LCMS Rt=1.33min,10-80AB,MS ESI计算值C16H14F5N4O2[M+H]+389.1,实测值389.0。
实施例16:合成化合物16-(3-(环丙基甲氧基甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
将在MeCN(5mL)中的3-(氯甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(50mg,0.15mmol)、环丙烷甲醇(5mL,17.33mmol)和AgOTf(374.88mg,1.46mmol)的混合物在80℃搅拌16小时。在冷却至RT之后,将混合物浓缩,得到残余物。用H2O(10mL)稀释残余物并用EtOAc(10mL x 2)萃取混合物。将合并的有机相用盐水(10mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱柱(EtOAc在PE中=0%至40%至60%)纯化粗产物,给出粗产物。通过制备型HPLC(Phenomenex Gemini-NX(150mmx 30mm,5μm)A=H2O(0.05%NH4OH)并且B=CH3CN;经8min45-75%B)纯化粗产物,得到产物(32.55mg,0.09mmol,32%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.42(d,1H),8.29(d,1H),7.48(d,1H),7.23-7.16(m,2H),5.19(s,2H),3.41(d,2H),2.45(s,3H),1.11-1.00(m,1H),0.59-0.52(m,2H),0.23-0.17(m,2H)。在2min的色谱中,LCMSRt=1.27min,10-80AB,MSESI计算值C18H18F3N4O2[M+H]+379.13,实测值379.0。
实施例17:合成化合物17-(3-(甲氧基甲基)-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
A23:4,4,5,5-四甲基-2-[3-甲基-4-(三氟甲氧基)苯基]-1,3,2-二氧杂环戊硼烷
将在乙醇(50.00mL)中的2-溴-1-氯-4-(三氟甲氧基)苯(40.0g,145.22mmol)、Pd(dppf)Cl2(10.63g,14.52mmol)和TEA(40.37mL,290.43mmol)的混合物在CO(50psi)下在80℃搅拌32小时。将混合物冷却至25℃并浓缩,得到残余物。用饱和水性NaCl(50mL)稀释残余物,并将混合物用EtOAc(50mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0至3%至5%至10%)纯化粗产物,得到产物(13.00g,48.40mmol,33%产率),呈油状物。1H NMR(400MHz,CD3OD)δH7.69(d,1H),7.52-7.46(m,1H),7.32-7.27(m,1H),4.49-4.37(m,2H),1.42(t,3H)。
A24:[2-(氯甲基)-5-(三氟甲氧基)苯基]甲醇
在-40℃向在THF(30.00mL)中的2-(氯甲基)-5-(三氟甲氧基)苯甲酸乙酯(12.0g,42.46mmol)溶液缓慢加入LiAlH4(1.93g,50.95mmol)。将反应在-40℃搅拌1小时。将反应用饱和水性NH4Cl(0.4mL)淬灭,并用EtOAc(30mL)稀释。形成固体,将混合物通过硅藻土垫过滤,并用EtOAc(30mL)洗脱。将滤液浓缩,得到残余物。将残余物通过硅胶柱(EtOAc在PE中=0%至10%至20%)纯化,得到产物(10.00g,39.54mmol,93%产率),呈固体。1H NMR(400MHz,CD3OD)δH7.47-7.41(m,1H),7.40-7.35(m,1H),7.15-7.07(m 1H),4.80(d,2H)。
A25:1-氯-2-(甲氧基甲基)-4-(三氟甲氧基)苯
在0℃向在THF(30mL)中的[2-氯-5-(三氟甲氧基)苯基]甲醇(2.8g,12.36mmol)溶液缓慢加入NaH(355.9mg,14.83mmol)。将混合物在0℃搅拌30min,然后加入MeI(5.26mg,37.07mmol)。将反应混合物在20℃搅拌16小时。将混合物用饱和水性NH4Cl(40mL)淬灭,并且将混合物用EtOAc(40mL x 2)萃取。将合并的有机相用盐水(40mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0至3%至10%至20%至50%)纯化粗产物,得到产物(1.65g,6.86mmol,55%产率),呈油状物。1H NMR(400MHz,CD3OD)δH7.43-7.33(m,2H),7.15-7.05(m,1H),4.54(s,2H),3.50(s,3H)。
A1a:2-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
将在1,4-二噁烷(20.00mL)中的4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(3.58g,14.11mmol)、KOAc(2.31g,23.52mmol)、1-氯-2-(甲氧基甲基)-4-(三氟甲氧基)苯(2.83g,11.76mmol)和Pd2(dba)3(1.08g,1.18mmol)的混合物在80℃在N2下搅拌16小时。将混合物冷却至25℃并浓缩,得到残余物。将残余物用饱和水性NH4Cl(40mL)淬灭,并且将混合物用EtOAc(40mL x 2)萃取。将合并的有机相用盐水(40mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(DCM在PE中=0至10%至50%至80%)纯化粗产物,得到产物,呈油状物。1H NMR(400MHz,CD3Cl3)δH 7.82(d,1H),7.33(s,1H),7.11(d,1H),4.72(s,2H),3.44(s,3H),1.35(s,12H)。
A2a:2-氯-5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪
将在1,4-二噁烷(10mL)和水(2.5mL)中的Pd(dppf)Cl2(330.47mg,0.45mmol)、Cs2CO3(1.96g,6.02mmol)、2-溴-5-氯-吡嗪(640.65mg,3.31mmol)和2-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(1.00g,3.01mmol)的混合物在50℃在N2下搅拌5小时。在冷却至25℃之后,将反应混合物用EtOAc(100mL)稀释,通过硅藻土垫过滤,将其用EtOAc(100mL)洗脱。将滤液浓缩,得到残余物,通过快速色谱(EtOAc在PE中0%至10%)纯化残余物,得到产物(610.00mg,1.81mmol,60%产率),呈固体。1H NMR(400MHz,CD3Cl3)δH 8.66-8.70(m,1H),8.56-8.63(m,1H),7.53-7.56(m,1H),7.50-7.52(m,1H),7.28-7.33(m,1H),4.55(s,2H),3.38(s,3H)。
A3a:[5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]肼
将在MeCN(5mL)中的2-氯-5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪(1.10g,3.45mmol)和肼(860.00mg,17.26mmol)的混合物在90℃在N2下搅拌16小时。在冷却至25℃之后,将反应混合物用水稀释,并且用EtOAc(30mL x 3)萃取。将合并的有机相用盐水(20mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到粗产物(1.00g,3.18mmol,74%产率),呈液体。在1.5min的色谱中,LCMS Rt=0.71min,5-95AB,MS ESI计算值C13H14F3N4O2[M+H]+314.8,实测值314.8。
化合物17:3-(甲氧基甲基)-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲苯(5mL)中的[5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(200mg,0.64mmol)和2-甲氧基乙酰氯(82.88mg,0.76mmol)的溶液在25℃搅拌1小时。然后向混合物添加TsOH(219.18mg,1.27mmol),将混合物加热至120℃,并且搅拌16小时。在冷却至25℃之后,将反应混合物用水(30mL)稀释并且用EtOAc(30mL x 3)萃取。将合并的有机相用盐水(20mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到粗产物(150mg,0.40mmol,64%产率),呈液体。通过制备型HPLC(Boston Green ODS(150mm x 30mm,5μm)A=H2O(0.075%NH4OH)并且B=CH3CN;经7min从46%到76%B)纯化粗产物,得到产物(21.54mg,0.06mmol,43%产率),呈固体。1H NMR(400MHz,CD3Cl3)δH9.26-9.58(m,1H),8.37-8.62(m,1H),7.60-7.75(m,1H),7.38-7.54(m,1H),7.30-7.36(m,1H),4.98-5.18(m,2H),4.43-4.59(m,2H),3.34-3.54(m,6H)。在2min的色谱中,LCMS Rt=1.164min,10-80AB,MS ESI计算值C16H16F3N4O3[M+H]+369.0,实测值369.0。
实施例18:合成化合物18-(3-[环丙基甲氧基(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
A26:3-[溴(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
在25℃将[5-[2-甲基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(1g,3.52mmol)添加到在THF中的2-溴-2,2-二氟-乙酰氯(1.2g,6.21mmol)的溶液中。将混合物在25℃搅拌1小时。将混合物倾入水(30mL)中并用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(30mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到粗产物(1.5g,3.4mmol,97%产率),呈固体,其用于下一个步骤而不用纯化。
将在甲苯(20mL)中的2-溴-2,2-二氟-N'-[5-[2-甲基-4-(三氟甲氧基)苯基]吡嗪-2-基]乙酰肼(1.2g,2.72mmol)和TsOH(140.52mg,0.82mmol)的溶液在120℃搅拌16小时。在冷却至RT之后,将混合物浓缩,得到残余物。用H2O(30mL)稀释残余物并用EtOAc(30mLx 2)萃取。将合并的有机相用盐水(30mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至30%至50%)纯化粗产物,得到产物(600mg,1.3371mmol,57%产率),呈油状物。在4.0min的色谱中,LCMS Rt=2.86min,10-80AB,MSESI计算值C14H9BrF5N4O[M+H]+422.98,实测值424.7。
化合物18:3-[环丙基甲氧基(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
在25℃在N2下向避光的在环丙烷甲醇(127.81mg,1.77mmol)中的3-[溴(二氟)甲基]-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(150mg,0.35mmol)的悬浮液中添加AgBF4(138.02mg,0.71mmol)。将混合物在60℃搅拌2小时。将该溶液加入到饱和水性NaCl(20mL)中并过滤。将滤液用EtOAc(10mL x 2)萃取。将合并的有机相用盐水(10mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(PhenomenexGemini-NX(150mm x 30mm,5μm)A=H2O(0.05%NH4OH)并且B=CH3CN;经8min 51-81%B)纯化粗产物,得到产物(55.12mg,0.13mmol,38%产率),呈固体。1HNMR(400MHz,CDCl3)δH9.52(d,1H),8.30(s,1H),7.49(d,1H),7.25-7.17(m,2H),4.09(d,2H),2.46(s,3H),1.36-1.24(m,1H),0.74-0.64(m,2H),0.48-0.35(m,2H)。在2.0min的色谱中,LCMS Rt=1.37min,10-80AB,MS ESI计算值C18H16F5N4O2[M+H]+415.11,实测值415.0。
实施例19:合成化合物19-(3-[乙氧基(二氟)甲基]-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
A27:2-溴-2,2-二氟-N'-[5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]乙酰肼
将在THF(5mL)中的2-溴-2,2-二氟-乙酸(267.19mg,1.53mmol)、DMF(0.05mL)和草酰氯(323.12mg,2.55mmol)的混合物在25℃在N2下搅拌2小时。然后向混合物添加[5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(400mg,1.27mmol),将所得混合物在25℃在N2下搅拌2小时。将反应用饱和水性NaCl(10mL)淬灭,并用EtOAc(20mL)稀释。将混合物过滤,并将滤液用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(15mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到产物(500mg,1.06mmol),呈油状物。在1.5min的色谱中,LCMS Rt=0.96min,5-95AB,MS ESI计算值C15H13BrF5N4O3[M+H]+471.0,实测值470.8。
A28:3-[溴(二氟)甲基]-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
向在甲苯(5mL)中的2-溴-2,2-二氟-N'-[5-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]乙酰肼(500mg,1.06mmol)的混合物中添加TsOH(109.64mg,0.64mmol),将所得混合物在120℃在N2下搅拌16小时。在冷却至25℃之后,将混合物用饱和水性NaHCO3(20mL)淬灭,并且将混合物用EtOAc(20mL x 3)萃取。将合并的有机相用盐水(20mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%至30%)纯化粗产物,得到产物(400mg,0.88mmol),呈油状物。在4.0min的色谱中,LCMS Rt=2.80min,10-80AB,MS ESI计算值C15H11BrF5N4O2[M+H+2]+455.0,实测值454.7。
化合物19:3-[乙氧基(二氟)甲基]-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
向在乙醇(5mL)中的3-[溴(二氟)甲基]-6-[2-(甲氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(400mg,0.88mmol)的混合物添加AgBF4(343.67mg,1.77mmol),将所得混合物在避光的同时50℃在N2下在搅拌5小时。将反应用饱和水性NaCl(10mL)淬灭,并用EtOAc(20mL)稀释。将混合物过滤并用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(15mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(WelchXtimate C18(150mm x 25mm,5μm)A=H2O(0.075%NH4OH)并且B=CH3CN;经11min 53-83%B)纯化粗产物,得到产物(58.92mg,0.14mmol),呈油状物。1H NMR(400MHz,CDCl3)δH9.51(d,1H),8.62(s,1H),7.70(d,1H),7.47(s,1H),7.32-7.37(m,1H),4.50(s,2H),4.34(q,2H),3.44(s,3H),1.47(t,3H)。在2min的色谱中,LCMS Rt=1.35min,10-80AB,MS ESI计算值C17H16F5N4O3[M+H]+419.1,实测值418.9。
实施例20:合成化合物20-(3-(环丙氧基甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
A11a:3-(氯甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
在25℃向在DCM(5mL)中的[6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪-3-基]甲醇(200mg,0.62mmol)的溶液添加SOCl2(0.07mL,0.93mmol)。将混合物在25℃搅拌1小时。将混合物倾入水(30mL)中并用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经Na2SO4干燥,过滤,浓缩,得到粗产物(200mg,0.58mmol),呈固体。1H NMR(400MHz,CDCl3)δH=9.48(d,1H),8.16(d,1H),7.49(d,1H),7.23-7.19(m,2H),5.20(s,2H),2.45(s,3H)。
化合物20:3-(环丙氧基甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
在25℃向环丙醇(2mL,0.62mmol)中添加3-(氯甲基)-6-[2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(211mg,0.62mmol)和K2CO3(170.15mg,1.23mmol)。将混合物在40℃搅拌3小时。用H2O(20mL)稀释混合物并用EtOAc(10mL x 2)萃取。将合并的有机相用水(50mL)和盐水(50mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(Welch Xtimate C18(150mm x 25mm,5μm);A=H2O(10mM NH4HCO3)并且B=CH3CN;经7.5min50-80%B)纯化粗产物,得到产物(74.38mg,0.2mmol,33%产率),呈固体。1HNMR(400MHz,CDCl3)δH 9.42(d,1H),8.17(d,1H),7.48(d,1H),7.24-7.16(m,2H),5.18(s,2H),3.43-3.38(m,1H),2.44(s,3H),0.67-0.62(m,2H),0.60-0.55(m,2H)。在2.0min的色谱中,LCMS Rt=1.28min,10-80AB,MS ESI计算值C17H16F3N4O2[M+H]+365.11,实测值365.1。
实施例21:合成化合物21-(3-(二氟(甲氧基)甲基)-6-(2-甲基-4-(2,2,2-三氟乙氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪)
A30:1-溴-2-甲基-4-(2,2,2-三氟乙氧基)苯
在0℃向DMF(20.0mL)中的4-溴-3-甲基-苯酚(2.0g,10.69mmol)的搅拌溶液添加三氟甲磺酸2,2,2-三氟乙酯(2.48g,10.69mmol)和碳酸铯(4.53g,13.9mmol)。将该反应混合物缓慢加温至RT并搅拌12小时。将该反应混合物用水(40mL)处理,并且用EtOAc(2x30mL)萃取。将有机层用盐水(30mL)洗涤,经无水Na2SO4干燥并浓缩,得到粗产物。在硅胶上通过柱色谱用5%EtOAc/PE纯化粗产物,得到产物,呈液体(2.7g,9.97mmol,93%产率)。1H NMR(400MHz,CDCl3):δH 7.46(d,1H),6.87(d,1H),6.68(dd,1H),4.33(q,2H),2.40(s,3H)。
A31:4,4,5,5-四甲基-2-(2-甲基-4-(2,2,2-三氟乙氧基)苯基)-1,3,2-二氧杂环戊硼烷
向在1,4-二噁烷(30mL)中的1-溴-2-甲基-4-(2,2,2-三氟乙氧基)苯(2.7g,9.97mmol)和双(频哪醇合)二硼(3.04g,11.97mmol)的搅拌溶液添加乙酸钾(1.96g,19.95mmol)。在氮气气氛下,将Pd(dppf)Cl2·DCM(0.81g,1.0mmol)添加至反应混合物中,并在80℃加热12小时。将反应混合物冷却至RT,通过硅藻土过滤,减压浓缩,得到粗产物。在硅胶上通过柱色谱用5%EtOAc/PE纯化粗产物,得到产物,呈液体(2.93g,9.28mmol,93%产率)。LCMS:柱:ZORBAX XDB C-18(50x4.6mm),3.5μm;流动相:A:0.1%HCOOH,在水:ACN(95:5)中,B:ACN:流速:1.5mL/min;316.2(M+H),Rt 3.00min。
A33:3-(氯二氟甲基)-6-(2-甲基-4-(2,2,2-三氟乙氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
向在1,4-二噁烷(15mL)中的6-氯-3-[氯(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(1.1g,4.6mmol)和4,4,5,5-四甲基-2-(2-甲基-4-(2,2,2-三氟乙氧基)苯基)-1,3,2-二氧杂环戊硼烷(1.43g,4.6mmol)的搅拌溶液添加水(1.5mL)和Cs2CO3(3.02g,9.28mmol)。在氮气气氛下,将Pd(dppf)Cl2·DCM(0.38g,0.46mmol)添加至反应混合物中,并在80℃加热12小时。将反应混合物冷却至RT,通过硅藻土过滤,减压浓缩,得到粗产物。在硅胶上通过柱色谱用25%EtOAc/PE纯化粗产物,得到产物(205mg,0.52mmol,11%产率),呈固体。LCMS:柱:ZORBAX XDB C-18(50x4.6mm),3.5μm;流动相:A:0.1%HCOOH,在水:ACN(95:5)中,B:ACN:流速:1.5mL/min;393.1(M+H),Rt2.42min。
化合物21:3-(二氟(甲氧基)甲基)-6-(2-甲基-4-(2,2,2-三氟乙氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
向在MeCN(8.0mL)中的3-(氯二氟甲基)-6-(2-甲基-4-(2,2,2-三氟乙氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪(165mg,0.42mmol)的搅拌溶液添加Cs2CO3(810mg,2.5mmol)和甲醇(0.17mL,4.2mmol)。将反应在RT搅拌1小时。将该反应混合物用水(20mL)处理,并且用EtOAc(2x20mL)萃取。将有机层用盐水(15mL)洗涤,经无水Na2SO4干燥并浓缩,得到粗产物。通过制备型HPLC纯化粗产物,得到产物,呈固体(60mg,0.15mmol,36%产率)。制备型HPLC法:Rt 8.9;柱:XBridge C8(150X19mm),5.0μm;流动相:10%NH4OAc,在水/乙腈中;流速:15.0mL/min。HPLC:Rt 4.79min,柱:XBridge C8(50X4.6)mm,3.5μm;流动相:A:0.1%TFA,在水中,B:0.1%TFA,在ACN中;流速:2.0mL/min。LCMS:389.0(M+H),Rt 2.23min,柱子:XBridge C8(50X4.6mm),3.5μm;流动相:A:0.1%TFA,在水:ACN(95:5)中,B:0.1%TFA,在ACN中;流速:1.5mL/min。1H NMR(400MHz,CD3OD):δH 9.51(d,1H),8.45(s,1H),7.47(d,1H),7.04-6.98(m,2H),4.62(q,2H),3.95(s,3H),2.41(s,3H)。
实施例22:合成化合物22-(3-(二氟(甲氧基)甲基)-6-(4-异丙氧基-2-甲基苯基)-[1,2,4]三唑并[4,3-a]吡嗪)
A35:3-(氯二氟甲基)-6-(4-异丙氧基-2-甲基苯基)-[1,2,4]三唑并[4,3-a]吡嗪
向在1,4-二噁烷(18mL)中的6-氯-3-[氯(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(1.0g,4.18mmol)和(4-异丙氧基-2-甲基苯基)硼酸(0.97g,5.02mmol)的搅拌溶液添加水(2mL)和K2CO3(1.16g,8.37mmol)。在氮气气氛下,将PdCl2(PPh3)2(0.29g,0.42mmol)添加至反应混合物中,并在80℃加热16小时。将反应混合物冷却至RT,通过硅藻土过滤,减压浓缩,得到粗产物。在硅胶上通过柱色谱用18%EtOAc/PE纯化粗产物,得到产物(0.85g,2.41mmol,57%产率)。LCMS:353.2(M+H),Rt 2.54min;柱:ZORBAX XDB C-18(50X4.6mm),3.5μm;流动相:A:0.1%HCOOH,在水:ACN(95:5)中,B:ACN;流速:1.5mL/min。
化合物22:3-(二氟(甲氧基)甲基)-6-(4-异丙氧基-2-甲基苯基)-[1,2,4]三唑并[4,3-a]吡嗪
向在MeCN(9mL)中的3-(氯二氟甲基)-6-(4-异丙氧基-2-甲基苯基)-[1,2,4]三唑并[4,3-a]吡嗪(200mg,0.56mmol)的搅拌溶液添加Cs2CO3(1.1g,3.39mmol)和甲醇(0.46mL,11.29mmol)。将该反应物在室温下搅拌3小时。将该反应混合物用水(20.0mL)处理,并且用EtOAc(2x20mL)萃取。将有机层用盐水(15mL)洗涤,经无水Na2SO4干燥并浓缩,得到粗产物。在硅胶上通过柱色谱用18%EtOAc/PE纯化粗产物,得到产物(147mg,0.42mmol,74%产率),呈固体。HPLC:Rt 4.70min,柱:XBridge C8(50X4.6)mm,3.5μm;流动相:A:0.1%TFA,在水中,B:0.1%TFA,在ACN中;流速:2.0mL/min。LCMS:349.1(M+H),Rt 2.24min,柱:XBridge C8(50X4.6mm),3.5μm;流动相:A:0.1%TFA,在水:ACN(95:5)中,B:0.1%TFA,在ACN中;流速:1.5mL/min。1H NMR(400MHz,CD3OD):δH9.50(d,1H),8.41(d,1H),7.40(d,1H),6.91-6.87(m,2H),4.71-4.68(m,1H),3.95(s,3H),2.38(s,3H),1.36(d,6H)。
实施例23:合成化合物23-(3-(乙氧基二氟甲基)-6-(4-异丙氧基-2-甲基苯基)-[1,2,4]三唑并[4,3-a]吡嗪)
向在MeCN(9.0mL)中的3-(氯二氟甲基)-6-(4-异丙氧基-2-甲基苯基)-[1,2,4]三唑并[4,3-a]吡嗪(200mg,0.56mmol)的搅拌溶液添加Cs2CO3(1.1g,3.39mmol)和乙醇(0.66mL,11.29mmol)。将该反应混合物在室温下搅拌4小时。将该反应混合物用水(20.0mL)处理,并且用乙酸乙酯(2x20mL)萃取。将有机层用盐水(20mL)洗涤,经无水Na2SO4干燥并浓缩,得到粗产物。在硅胶上通过柱色谱用11%EtOAc/PE纯化粗产物,得到一种固体(103mg,0.28mmol,50%产率)。HPLC:Rt 5.02min,柱:XBridge C8(50X4.6)mm,3.5μm;流动相:A:0.1%TFA,在水中,B:0.1%TFA,在ACN中;流速:2.0mL/min。LCMS:363.2(M+H),Rt 2.50min,柱:ZORBAX XDB C-18(50X4.6mm),3.5μm;流动相:A:0.1%HCOOH,在水:ACN(95:5)中,B:ACN;流速:1.5mL/min。1H NMR(400MHz,CD3OD):δH 9.49(d,1H),8.40(d,1H),7.41(d,1H),6.90-6.86(m,2H),4.72-4.66(m,1H),4.34(q,2H),2.39(s,3H),1.44(t,3H),1.35(d,6H)。
实施例24:合成化合物24-(3-(二氟(甲氧基)甲基)-6-(4-异丙氧苯基)-[1,2,4]三唑并[4,3-a]吡嗪)
A37:2-(4-异丙氧苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
向在1,4-二噁烷(30mL)中的1-溴-4-异丙氧基苯(3.0g,13.95mmol)和双(频哪醇合)二硼(4.25g,16.74mmol)的搅拌溶液添加乙酸钾(2.74g,27.9mmol)。Pd(dppf)Cl2·在氮气气氛下,将DCM(1.14g,1.39mmol)添加至反应混合物中,并在80℃加热12小时。将反应混合物冷却至室温,通过硅藻土过滤,减压浓缩,得到粗产物。在硅胶上通过柱色谱用5%EtOAc/PE纯化粗产物,得到产物(3.2g,12.1mmol,87%产率)。1H NMR(400MHz,CDCl3):δH7.74(d,2H),6.88(d,2H),4.64-4.59(m,1H),1.36(s,12H),1.35(d,6H)。
A38:3-(氯二氟甲基)-6-(4-异丙氧苯基)-[1,2,4]三唑并[4,3-a]吡嗪
向在1,4-二噁烷(15mL)中的6-氯-3-[氯(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(1.5g,6.27mmol)和2-(4-异丙氧苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(1.5g,5.7mmol)的搅拌溶液添加水(1.5mL)和Cs2CO3(3.71g,11.4mmol)。在氮气气氛下,将Pd(dppf)Cl2·DCM(0.47g,0.57mmol)添加至反应混合物中,并在80℃加热12小时。将反应混合物冷却至室温,通过硅藻土过滤,减压浓缩,得到粗产物。在硅胶上通过柱色谱用8%EtOAc/PE纯化粗产物,得到产物,呈固体(340mg,1.0mmol,17%产率)。LCMS:339.0(M+H),Rt2.33min柱:XBridge C8(50X4.6mm),3.5μm;流动相:A:0.1%TFA,水:ACN(95:5)中,B:0.1%TFA,在ACN中;流速:1.5mL/min。
化合物24:3-(二氟(甲氧基)甲基)-6-(4-异丙氧苯基)-[1,2,4]三唑并[4,3-a]吡嗪)
向在MeCN(8mL)中的3-(氯二氟甲基)-6-(4-异丙氧苯基)-[1,2,4]三唑并[4,3-a]吡嗪(170mg,0.50mmol)的搅拌溶液添加Cs2CO3(0.98g,3.0mmol)和甲醇(0.2mL,5.0mmol)。将该反应物在室温下搅拌2小时。将该反应混合物用水(20mL)处理,并且用乙酸乙酯(2x20mL)萃取。将有机层用盐水(15mL)洗涤,经无水Na2SO4干燥并浓缩,得到粗产物。通过制备型HPLC纯化粗产物,得到产物,呈固体(45mg,0.13mmol,27%产率)。制备型HPLC法:Rt11.51;柱:XBridge C8(150X19mm),5.0μm;流动相:0.1%TFA,在水/乙腈中;流速:15.0mL/min。HPLC:Rt 4.90min,柱:XBridge C8(50X4.6)mm,3.5μm;流动相:A:0.1%TFA,在水中,B:0.1%TFA,在ACN中;流速:2.0mL/min。LCMS:335.1(M+H),Rt 2.53min,柱:Atlantis dC18(50X4.6mm),3.5μm;流动相:A:0.1%HCOOH,在水:ACN(95:5)中,B:ACN;流速:1.5mL/min.1HNMR(400MHz,CD3OD):δH9.50(d,1H),8.63(s,1H),8.02-7.98(m,2H),7.05(dd,2H),4.75-4.68(m,1H),3.99(s,3H),1.37(d,3H).1.36(d,3H)。
实施例25:合成化合物25-(3-(乙氧基二氟甲基)-6-(4-异丙氧苯基)-[1,2,4]三唑并[4,3-a]吡嗪)
向在MeCN(8.0mL)中的3-(氯二氟甲基)-6-(4-异丙氧苯基)-[1,2,4]三唑并[4,3-a]吡嗪(210mg,0.51mmol)的搅拌溶液添加Cs2CO3(1.0g,3.06mmol)和乙醇(0.3mL,5.1mmol)。将该反应混合物在室温下搅拌2小时。将该反应混合物用水(15.0mL)处理,并且用乙酸乙酯(2x25mL)萃取。将有机层用盐水(20mL)洗涤,经无水Na2SO4干燥并浓缩,得到粗产物。通过制备型HPLC纯化粗产物,得到产物,呈固体(18mg,0.05mmol,10%产率)。制备型HPLC法:Rt 16.21;柱:X-Select(150X19mm),5.0μm;流动相:0.1%TFA,在水/乙腈中;流速:15.0mL/min。HPLC:Rt 4.95min,98.9%柱:XBridge C8(50X4.6)mm,3.5μm;流动相:A:0.1%TFA,在水中,B:0.1%TFA,在ACN中;流速:2.0mL/min。LCMS:349.3(M+H),Rt 2.51min,99.6%柱:ZORBAX XDB C-18(50X4.6mm),3.5μm;流动相:A:0.1%HCOOH,在水:ACN(95:5)中,B:ACN;流速:1.5mL/min。1H NMR(400MHz,CD3OD):δ9.51(s,1H),8.64(s,1H),7.98(d,2H),7.06(d,2H),4.74-4.70(m,1H),4.38(q,2H),1.50(t,3H),1.37(d,6H)。
实施例26:合成化合物26-(3-[二氟(甲氧基)甲基]-6-[2-乙基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪)
A39:1-氯-2-乙基-4-(三氟甲氧基)苯
向在DMF(75mL)中的2-溴-1-氯-4-(三氟甲氧基)苯(4.2g,15.25mmol)、Pd(dppf)Cl2(2.23g,3.05mmol)和K2CO3(4.21g,30.5mmol)的混合物添加二乙基锌(60.99mL,60.99mmol,1M,在甲苯中)。将生成的混合物在80℃在N2下搅拌16小时。在冷却至室温之后,将反应混合物用水(100mL)稀释。将混合物通过硅藻土垫过滤,并用EtOAc(100mL)洗脱。将滤液用EtOAc(50mL x 2)萃取。将合并的有机相用盐水(300mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过快速色谱(PE)纯化粗产物,得到产物(2.3g,10.24mmol,67%产率),呈油状物。1H NMR(400MHz,CDCl3)δH=7.36(d,1H),7.11(d,1H),7.01(dd,1H),2.77(q,2H),1.26(t,3H)。
A40:2-[2-乙基-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
将在1,4-二噁烷(25mL)中的1-氯-2-乙基-4-(三氟甲氧基)苯(2.3g,10.24mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(3.12g,12.29mmol)、KOAc(2.01g,20.48mmol)、X-Phos(0.98g,2.05mmol)和Pd2(dba)3(0.94g,1.02mmol)的混合物在80℃在N2下搅拌16小时。在冷却至25℃之后,通过硅藻土垫过滤反应混合物。将滤液浓缩,给出粗产物。通过快速色谱(PE)纯化粗产物,得到产物(1.7g,5.15mmol,50%产率),呈油状物。1HNMR(400MHz,CDCl3)δH7.80(d,1H),7.05-6.99(m,2H),2.94(q,2H),1.35(s,12H),1.21(t,3H)。
A41:2-氯-5-[2-乙基-4-(三氟甲氧基)苯基]吡嗪
将在1,4-二噁烷(15mL)和水(1.5mL)中的2-溴-5-氯-吡嗪(600mg,3.1mmol)、2-[2-乙基-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(1.16g,3.67mmol)、Cs2CO3(2.02g,6.2mmol)和Pd(dppf)Cl2(340.45mg,0.47mmol)的混合物在55℃在N2下搅拌16小时。在冷却至室温之后,通过硅藻土过滤混合物,浓缩,得到残余物。将残余物再溶解在EtOAc(50mL)中,用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过快速色谱(EtOAc在PE中=0%至15%)纯化粗产物,得到产物(900mg,2.28mmol,73%产率),呈油状物。1H NMR(400MHz,CDCl3)δH8.68(d,1H),8.47(d,1H),7.40(d,1H),7.22(s,1H),7.18(d,1H),2.74(q,2H),1.17(t,3H)。在1.5min的色谱中,LCMSRt=0.99min,5-95AB,MS ESI计算值C13H11ClF3N2O[M+H]+303.0,实测值302.8。
A42:[5-[2-乙基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼
将在MeCN(20mL)中的2-氯-5-[2-乙基-4-(三氟甲氧基)苯基]吡嗪(900mg,2.29mmol)和水合肼(1.15g,22.87mmol)的混合物在100℃搅拌16小时。将混合物冷却至室温并浓缩,得到残余物。向残余物添加水(20mL),并将混合物用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过快速色谱(EtOAc在PE中=0%至50%至80%)纯化粗产物,得到产物(680mg,2.28mmol,99%产率),呈油状物。1H NMR(400MHz,DMSO-d6)δH8.21-8.17(m,1H),8.14-8.06(m,2H),7.43(d,1H),7.29(s,1H),7.24(d,1H),4.33(s,2H),2.71(q,2H),1.05(t,3H)。
A43:2-溴-N'-[5-[2-乙基-4-(三氟甲氧基)苯基]吡嗪-2-基]-2,2-二氟-乙酰肼
向在THF(10mL)中的2-溴-2,2-二氟-乙酸(600mg,3.43mmol)的溶液添加一滴DMF和(COCl)2(0.35mL,4.12mmol)。将生成的混合物在20℃搅拌1小时。向溶液中添加[5-[2-乙基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(680mg,2.28mmol)。将生成的混合物在20℃搅拌1小时。将混合物倾入水(30mL)中,将所得混合物用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物(1g,2.20mmol,96%产率),呈油状物。在1.5min的色谱中,LCMS Rt=0.92min,5-95AB,MS ESI计算值C15H13BrF5N4O2[M+H]+457.0,实测值456.7。
A44:3-[溴(二氟)甲基]-6-[2-乙基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲苯(10mL)中的2-溴-N'-[5-[2-乙基-4-(三氟甲氧基)苯基]吡嗪-2-基]-2,2-二氟-乙酰肼(1g,2.2mmol)和TsOH(113.49mg,0.66mmol)的混合物在130℃搅拌16小时。在冷却至室温之后,向溶液添加水(20mL),并将混合物用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过快速色谱(EtOAc在PE中=0%至15%至30%)纯化粗产物,得到产物(660mg,1.51mmol,68%产率),呈油状物。1H NMR(400MHz,CDCl3)δH9.60(d,1H),8.22(s,1H),7.45(d,1H),7.27(s,1H),7.22(d,1H),2.76(q,2H),1.23(t,3H)。
化合物26:3-[二氟(甲氧基)甲基]-6-[2-乙基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲醇(6mL)中的3-[溴(二氟)甲基]-6-[2-乙基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(660mg,1.51mmol)和AgBF4(585.78mg,3.02mmol)的混合物在暗处在60℃搅拌1小时。添加盐水(30mL)和EtOAc(30mL),并将混合物通过硅藻土过滤。将滤液分离并且将水层用EtOAc(20mL)萃取。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过快速色谱(EtOAc在PE中=0%至20%至40%)纯化粗产物,得到产物(434.49mg,1.10mmol,73%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.51(d,1H),8.22(d,1H),7.43(d,1H),7.25(s,1H),7.20(d,1H),3.94(s,3H),2.74(q,2H),1.22(t,3H)。在2.0min的色谱中,LCMSRt=1.36min,10-80AB,MS ESI计算值C16H14F5N4O2[M+H]+389.1,实测值389.2。
实施例27和28:合成化合物27和28-(R)-3-(二氟(甲氧基)甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪和(S)-3-(二氟(甲氧基)甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
A46:2-甲基-1-硝基-4-(2,2,2-三氟-1-甲基-乙氧基)苯
在25℃向在DMF(150mL)中的4-氟-2-甲基-1-硝基-苯(10g,64.46mmol)和1,1,1-三氟丙烷-2-醇(8.82g,77.35mmol)溶液添加Cs2CO3(42g,128.92mmol)。将混合物在80℃搅拌16小时。将混合物倾入水(500mL)中并过滤。将滤饼用水(100mL x 2)洗涤,浓缩,得到产物(15g,60.2mmol),呈固体。1H NMR(400MHz,CDCl3)δH8.10(d,1H),6.88-6.85(m,2H),4.80-4.74(m,1H),2.64(s,3H),1.56(d,3H)。
A47:2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯胺
将在乙醇(150mL)和水(50mL)中的2-甲基-1-硝基-4-(2,2,2-三氟-1-甲基-乙氧基)苯(15g,60.2mmol)、NH4Cl(6.44g,120.39mmol)和Fe(6.72g,120.39mmol)的混合物在80℃搅拌2小时。将混合物倾入水(500mL)中。将混合物用EtOAc(200mL x 2)萃取。将合并的有机相用盐水(200mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到产物(13g,59.31mmol),呈油状物。1H NMR(400MHz,DMSO-d6)δH 6.70(d,1H),6.66-6.63(m,1H),6.56-6.53(m,1H),4.85-4.76(m,1H),4.61(brs,2H),2.03(s,3H),1.34(d,3H)。
A48:1-溴-2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯
向在MeCN(40mL)中的TBAB(11.03g,34.22mmol)、CuBr2(305.68mg,1.37mmol)和亚硝酸异戊酯(1.92g,16.42mmol)的混合物添加2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯胺(3g,13.69mmol)和TsOH·H2O(3.38g,17.79mmol)。将混合物在20℃下搅拌12小时。用H2O(100mL)稀释混合物并用DCM(100mL x 2)萃取混合物。将合并的有机相用水(40mL x 2)和盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶(EtOAc在PE中=0%至2%)上通过快速色谱纯化粗产物,得到产物(3g,10.60mmol,77%产率),呈油状物。1HNMR(400MHz,CDCl3)δH 7.45(d,1H),6.87(d,1H),6.78(dd,8.8Hz,1H),4.62-4.56(m,1H),2.38(s,3H),1.50(d,3H)。
A49:4,4,5,5-四甲基-2-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]-1,3,2-二氧杂环戊硼烷
将1-溴-2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯(3g,10.6mmol)、KOAc(2080.05mg,21.19mmol)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(3229.31mg,12.72mmol)和在1,4-二噁烷(30mL)中的Pd(dppf)Cl2(775.41mg,1.06mmol)的混合物在80℃在N2下搅拌16小时。将混合物倾入水(100mL)中,将水层用EtOAc(50mL x 2)萃取。将合并的有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0%至5%至10%)纯化粗产物,得到产物(2.5g,7.57mmol,71%产率),呈油状物。1H NMR(400MHz,CDCl3)δH7.75(d,1H),6.77-6.74(m,2H),4.72-4.69(m,1H),2.53(s,3H),1.50(d,3H),1.34(s,12H)。
A50:2-氯-5-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]吡嗪
将在水(6mL)和1,4-二噁烷(24mL)中的Pd(dppf)Cl2(554.07mg,0.76mmol)、Cs2CO3(4.93g,15.14mmol)、2-溴-5-氯-吡嗪(1.76g,9.09mmol)和4,4,5,5-四甲基-2-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]-1,3,2-二氧杂环戊硼烷(2.5g,7.57mmol)的混合物在55℃在N2下搅拌16小时。将混合物倾入水(100mL)中,将水层用EtOAc(50mL x2)萃取。将合并的有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至5%至10%)纯化粗产物,得到产物(2g,6.31mmol,83%产率),呈固体。1H NMR(400MHz,CDCl3)δH 8.66(d,1H),8.47(d,1H),7.41(d,1H),6.93-6.90(m,2H),4.74-4.71(m,1H),2.41(s,3H),1.55(d,3H)。
A51:[5-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]吡嗪-2-基]肼
在25℃向在MeCN(30mL)中的2-氯-5-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]吡嗪(2g,6.31mmol)的溶液添加N2H4·H2O(3.16g,63.15mmol)。将混合物在100℃搅拌24小时。在冷却至25℃之后,将反应物倾入水(100mL)中。将混合物用EtOAc(30mL x 2)萃取,用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物(1.8g,5.8mmol),呈固体。在1.5min的色谱中,LCMS Rt=0.79min,5-95AB,MS ESI计算值C14H16F3N4O[M+H]+313.1,实测值313.0。
A52:2-溴-2,2-二氟-N'-[5-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]吡嗪-2-基]乙酰肼
在25℃向在THF(15mL)中的2-溴-2,2-二氟-乙酸(1.51g,8.65mmol)、DMF(6.32mg,0.09mmol)的溶液添加(COCl)2(1.32g,10.37mmol)。将混合物在25℃搅拌30min。在25℃将在THF(20mL)中的[5-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]吡嗪-2-基]肼(1.8g,5.76mmol)添加到以上混合物中。将生成的混合物在25℃搅拌1小时。将混合物倾入水(50mL)中,将水层用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到粗产物(2.7g,5.75mmol),呈固体。在1.5min的色谱中,LCMS Rt=0.89min,5-95AB,MS ESI计算值C16H15BrF5N4O2[M+H]+469.0,实测值468.9。
A53:3-[溴(二氟)甲基]-6-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲苯(30mL)中的2-溴-2,2-二氟-N'-[5-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]吡嗪-2-基]乙酰肼(2.7g,5.75mmol)和TsOH(297.28mg,1.73mmol)的溶液在130℃搅拌16小时。加入水(50ml),并且用EtOAc(30mL x 2)萃取水层。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=10%至20%)纯化粗产物,得到产物(800mg,1.77mmol,31%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.57(s,1H),8.18(s,1H),7.44(d,1H),6.98-6.92(m,2H),4.76-4.71(m,1H),2.43(s,3H),1.57(d,3H)。
A54:3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
在25℃在N2下向甲醇(3mL)中的3-[溴(二氟)甲基]-6-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(300mg,0.66mmol)的悬浮液中添加AgBF4(257.98mg,1.33mmol)。使混合物避光,在60℃搅拌2小时。将溶液加入到盐水(10mL)中并过滤。将滤液用EtOAC(20mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%至20%)纯化粗产物,得到产物(220mg,0.55mmol,82%产率),呈固体。在1.5min的色谱中,LCMS Rt=1.23min,5-95AB,MS ESI计算值C17H16F5N4O2[M+H]+403.1,实测值403.1。
化合物27和28:(R)-3-(二氟(甲氧基)甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪和(S)-3-(二氟(甲氧基)甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
纯化3-(二氟(甲氧基)甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪(220mg,0.55mmol),所述纯化借助于SFC(DAICELCHIRALCEL OJ-H(250mm x 30mm,5mm);A=CO2并且B=0.1%NH3·H2O-EtOH;60mL/min;15%B;80次进样,给出对映异构体1,将其随机指定为化合物27(66.33mg,0.16mmol,30%产率)(峰1,Rt=1.450min),呈固体;以及对映异构体2,将其随机指定为化合物28(70.41mg,0.17mmol,32%产率)(峰2:Rt=1.609min),呈固体。化合物的立体化学是随机指定的。
分析型SFC:(Chiralcel OJ-3 100A 4.6mm内径,3mm,流动相:A:CO2 B:乙醇(0.05%DEA),梯度:在4min内从5%到40%的B并且保持40%持续2.5min,然后为5%B持续1.5min,流速:2.8mL/min,柱温:35℃,ABPR:1500psi)显示两个峰(峰1:Rt=1.450min,峰2:Rt=1.609min)。
化合物27:1H NMR(400MHz,CD3CN)δH 9.40(d,1H),8.32(d,1H),7.43(d,1H),7.02(s,1H),6.97-6.95(m,1H),5.03-4.96(m,1H),3.88(s,3H),2.36(s,3H),1.51(d,3H)。在2min的色谱中,LCMS Rt=1.36min,10-80AB,MS ESI计算值C17H16F5N4O2[M+H]+403.1,实测值403.2。
化合物28:1H NMR(400MHz,CD3CN)δH 9.40(d,1H),8.32(d,1H),7.43(d,1H),7.02(s,1H),6.97-6.95(m,1H),5.03-4.96(m,1H),3.88(s,3H),2.36(s,3H),1.51(d,3H)。在2min的色谱中,LCMS Rt=1.36min,10-80AB,MS ESI计算值C17H16F5N4O2[M+H]+403.1,实测值403.2。
实施例29和30:合成化合物29和30-(R)-3-(乙氧基二氟甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪和(S)-3-(乙氧基二氟甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
A55:3-[二氟(甲氧基)甲基]-6-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
在25℃在N2下向乙醇(3mL)中的3-[溴(二氟)甲基]-6-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(300mg,0.66mmol)的悬浮液中添加AgBF4(257.98mg,1.33mmol)。使混合物避光,在60℃搅拌2小时。将溶液加入到盐水(50mL)中并过滤。将滤液用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%至20%)纯化粗产物,得到产物(222mg,0.53mmol,80%产率),呈固体。在1.5min的色谱中,LCMS Rt=1.27min,5-95AB,MS ESI计算值C18H18F5N4O2[M+H]+417.1,实测值417.1。
化合物29和30:(R)-3-(乙氧基二氟甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪和(S)-3-(乙氧基二氟甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
纯化3-(乙氧基二氟甲基)-6-(2-甲基-4-((1,1,1-三氟丙烷-2-基)氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪(222mg,0.53mmol),所述纯化借助于SFC(DAICEL CHIRALCELOJ-H(250mm x 30mm,5mm);A=CO2并且B=0.1%NH3·H2O-EtOH;60mL/min;15%B;80次进样,给出对映异构体1,将其随机指定为化合物29(峰1,Rt=1.325min),呈固体;以及对映异构体2,将其随机指定为化合物30(63.55mg,0.15mmol,28%产率)(峰2:Rt=1.486min),呈固体。化合物的立体化学是随机指定的。
分析型SFC:(Chiralcel OJ-3 100A4.6mm内径,3um,流动相:A:CO2,B:乙醇(0.05%DEA),梯度:在4min内从5%到40%的B并且保持40%持续2.5min,然后为5%B持续1.5min,流速:2.8mL/min,柱温:35℃,ABPR:1500psi)显示两个峰(峰1:Rt=1.325min,峰2:Rt=1.486min)。
化合物29:1H NMR(400MHz,CD3CN)δH 9.41(d,1H),8.32(s,1H),7.45(d,1H),7.01(s,1H),6.98-6.95(m,1H),5.03-4.96(m,1H),4.28(q,2H),2.37(s,3H),1.51(d,3H),1.39(t,3H)。在2min的色谱中,LCMS Rt=1.39min,10-80AB,MS ESI计算值C18H18F5N4O2[M+H]+417.2,实测值417.1。
化合物30:1H NMR(400MHz,CD3CN)δH 9.41(d,1H),8.32(s,1H),7.45(d,1H),7.02(s,1H),6.98-6.95(m,1H),5.03-4.96(m,1H),4.28(q,2H),2.37(s,3H),1.51(d,3H),1.39(t,3H)。在2min的色谱中,LCMS Rt=1.39min,10-80AB,MS ESI计算值C18H18F5N4O2[M+H]+417.3,实测值417.1。
实施例31和32:合成化合物31和32-(R)-3-(二氟(甲氧基)甲基)-6-(2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪和(S)-3-(二氟(甲氧基)甲基)-6-(2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
A56:2-氯-5-(三氟甲氧基)苯甲醛
向在氯仿(120mL)中的[2-氯-5-(三氟甲氧基)苯基]甲醇(3.7g,16.33mmol)溶液添加MnO2(7.1g,81.65mmol)。将混合物在70℃下搅拌12小时。在冷却至RT之后,通过硅藻土过滤混合物,并将滤饼用DCM(20x2mL)洗脱。将滤液减压浓缩,得到粗产物(2.6g,11.58mmol),呈油状物。1H NMR(400MHz,DMSO-d6)δH10.27(s,1H),7.84-7.66(m,3H)。
A57:1-[2-氯-5-(三氟甲氧基)苯基]乙醇
在0℃向在THF(30mL)中的2-氯-5-(三氟甲氧基)苯甲醛(2.5g,11.13mmol)的溶液添加MeMgBr(5.57mL,16.7mmol)(3M,在乙醚中)。将混合物在0℃搅拌2小时。将混合物用饱和水性NH4Cl(20mL)淬灭。将水层用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%)纯化粗产物,得到产物(2.5g,10.39mmol,93%产率),呈油状物。1H NMR(400MHz,DMSO-d6)δH7.56-7.49(m,2H),7.31-7.25(m,1H),5.61(d,1H),5.03-4.93(m,1H),1.31(d,3H)。
A58:1-氯-2-(1-甲氧基乙基)-4-(三氟甲氧基)苯
在0℃以三个部分向在THF(20mL)中的1-[2-氯-5-(三氟甲氧基)苯基]乙醇(2.5g,10.39mmol)的溶液添加NaH(831.22mg,20.78mmol,60%,在油中)。将混合物在0℃搅拌30min。然后在0℃将CH3I(0.97mL,15.59mmol)添加到溶液中。将混合物在25℃搅拌16小时。将混合物用饱和水性NH4Cl(40mL)淬灭。将水层用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%)纯化粗产物,得到产物(2.2g,8.64mmol,83%产率),呈油状物。1HNMR(400MHz,CDCl3)δH7.41-7.33(m,2H),7.12-7.02(m,1H),4.71(q,1H),3.28(s,3H),1.41(d,3H)。
A59:2-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
将在1,4-二噁烷(20mL)中的1-氯-2-(1-甲氧基乙基)-4-(三氟甲氧基)苯(1.9g,7.46mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(2.27g,8.95mmol)、KOAc(1.46g,14.92mmol)、Pd2(dba)3(683.29mg,0.75mmol)、三环己基膦(523.13mg,1.87mmol)的混合物在120℃搅拌16小时。在冷却至25℃之后,通过硅藻土过滤反应混合物。将滤液减压浓缩,给出粗产物。在硅胶上通过快速色谱(PE 100%)纯化粗产物,得到产物(1g,2.89mmol,38%产率),呈油状物。1H NMR(400MHz,CDCl3)δH7.79(d,1H),7.37-7.34(m,1H),7.11-7.06(m,1H),5.01(q,1H),3.25(s,3H),1.40(d,3H),1.36(s,12H)。
A60:2-氯-5-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]吡嗪
将在1,4-二噁烷(10mL)和水(1mL)中的2-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(1g,2.89mmol)、2-溴-5-氯-吡嗪(670.56mg,3.47mmol)、Cs2CO3(1.88g,5.78mmol)、Pd(dppf)Cl2(211.38mg,0.29mmol)的混合物在55℃搅拌16小时。在冷却至RT之后,用H2O(20mL)稀释混合物。将水层用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至10%)纯化粗产物,得到产物(400mg,0.97mmol,34%产率),呈油状物。1H NMR(400MHz,CDCl3)δH8.69(d,1H),8.49(s,1H),7.54(s,1H),7.44-7.38(m,1H),7.26-7.23(m,1H),4.56(q,1H),3.15(s,3H),1.43(d,3H)。
A61:[5-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]吡嗪-2-基]肼
在25℃向在MeCN(8mL)中的2-氯-5-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]吡嗪(400mg,0.97mmol)的溶液添加N2H4·H2O(486.61mg,9.73mmol)。将混合物在100℃搅拌16小时。在冷却至20℃之后,将反应物倾入水(20mL)中。将水层用EtOAc(20mL x 2)萃取。将合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到产物(330mg,0.96mmol),呈油状物。1H NMR(400MHz,DMSO-d6)δH 8.20-8.15(m,2H),8.11(s,1H),7.49(d,1H),7.39(s,1H),7.36-7.30(m,1H),4.66-4.58(m,1H),4.34(brs,2H),3.03(s,3H),1.32(d,3H)。在1.5min的色谱中,LCMS Rt=0.76min,5-95AB,MS ESI计算值C14H16F3N4O2[M+H]+329.1,实测值328.9。
A62:2-溴-N-(2-溴-2,2-二氟-乙酰基)-2,2-二氟-N'-[5-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]吡嗪-2-基]乙酰肼
向在THF(3mL)中的2-溴-2,2-二氟-乙酸(300mg,1.71mmol)的溶液添加DMF(6.27mg,0.09mmol)和(COCl)2(0.17mL,2.06mmol)。将生成的混合物在20℃搅拌30min。生成的溶液直接用于下一步。将在THF(2mL)中的[5-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(330mg,0.96mmol)溶液添加到以上混合物中。将混合物在20℃搅拌1小时。加入水(20mL),并且用EtOAc(20mL x 2)萃取水层。将合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到产物(600mg,0.93mmol),呈油状物。在1.5min的色谱中,LCMS Rt=1.0min,5-95AB,MS ESI计算值C18H14BrF7N4O4[M+H]+642.9,实测值642.7。
A63:3-[溴(二氟)甲基]-6-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
向在甲苯(20mL)中的2-溴-N-(2-溴-2,2-二氟-乙酰基)-2,2-二氟-N'-[5-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]吡嗪-2-基]乙酰肼(600mg,0.93mmol)的溶液添加TsOH(48.27mg,0.28mmol)。将混合物在130℃搅拌16小时。加入水(30mL),并且用EtOAc(30mLx2)萃取水层。将合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~20%)纯化粗产物,得到产物(200mg,0.35mmol,37%产率),呈油状物。1H NMR(400MHz,CDCl3)δH9.57(s,1H),8.27(s,1H),7.56(s,1H),7.48-7.45(m,1H),7.32-7.27(m,1H),4.60-4.52(m,1H),3.21(s,3H),1.46(d,3H)。
A64:3-[二氟(甲氧基)甲基]-6-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
向在甲醇(2mL)中的3-[溴(二氟)甲基]-6-[2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(200mg,0.35mmol)的溶液添加AgBF4(135.12mg,0.70mmol)。将混合物在60℃搅拌4小时。添加盐水(10mL),通过硅藻土过滤混合物。将滤液分离并且将水相用EtOAc(10mL x 2)萃取。将合并的有机相用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0%~30%)纯化粗产物,得到产物(70mg,164.7mmol,47%产率),呈固体。在1.5min的色谱中,LCMS Rt=0.90min,5-95AB,MS ESI计算值C17H16F5N4O3[M+H]+419.1,实测值419.0。
化合物31和32:(R)-3-(二氟(甲氧基)甲基)-6-(2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪和(S)-3-(二氟(甲氧基)甲基)-6-(2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
分离3-(二氟(甲氧基)甲基)-6-(2-(1-甲氧基乙基)-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪(70mg,164.7mmol),所述分离借助于SFC(DAICEL CHIRALPAK AS(250mm x 30mm,10mm);A=己烷并且B=EtOH(0.5%氨水);38℃;30mL/min;10%B;11min运行;12次进样),得到对映异构体1,将其随机指定为化合物31(15.98mg,38.2mmol,23%产率)(峰1的Rt=6.14min),呈固体;以及对映异构体2,将其随机指定为化合物32(15.45mg,36.9mmol,22%产率)(峰2的Rt=8.0min),呈固体。化合物的立体化学是随机指定的。
分析型SFC:分析借助于SFC(Chiralpak AS-3 100x46mm I.D,3mm;流动相:A:己烷(0.1%DEA)B:IPA,等度:A:B=90:10,流速:1mL/min;柱温:25℃)显示在6.14min(50%)和8.00min(50%)的两个峰。
化合物31:1H NMR(400MHz,DMSO-d6)δH9.66(s,1H),8.65(s,1H),7.64-7.58(m,1H),7.49-7.42(m,2H),4.62-4.53(m,1H),3.87(s,3H),3.06(s,3H),1.36(d,3H)。在2.0min的色谱中,LCMSRt=1.22min,10-80AB,MS ESI计算值C17H16F5N4O3[M+H]+419.1,实测值419.1。
化合物32:1H NMR(400MHz DMSO-d6)δH9.65(s,1H),8.65(s,1H),7.65-7.55(m,1H),7.48-7.39(m,2H),4.62-4.51(m,1H),3.86(s,3H),3.05(s,3H),1.35(d,3H)。在2.0min的色谱中,LCMSRt=1.21min,10-80AB,MS ESI计算值C17H16F5N4O3[M+H]+419.1,实测值419.1。
实施例33:合成化合物33-6-[2-环丙基-4-(三氟甲氧基)苯基]-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
A65:1-氯-2-环丙基-4-(三氟甲氧基)苯
将在甲苯(50mL)和水(5mL)中的2-溴-1-氯-4-(三氟甲氧基)苯(3g,10.89mmol)、环丙基硼酸(982.34mg,11.44mmol)、K3PO4(8.09g,38.12mmol)、PCy3(610.85mg,2.18mmol)和Pd(OAc)2(244.52mg,1.09mmol)的混合物在80℃在N2下搅拌16小时。在冷却至RT之后,添加水(50mL),通过硅藻土过滤混合物。将滤液用EtOAc(50mL x2)萃取。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至2%)纯化粗产物,得到产物(2.57g,10.86mmol,99%产率),呈油状物。1HNMR(400MHz,CDCl3)δH7.36(d,1H),7.01-6.95(m,1H),6.78(d,1H),2.21(tt,1H),1.13-1.04(m,2H),0.73-0.67(m,2H)。
A66:2-[2-环丙基-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
将在1,4-二噁烷(50mL)中的1-氯-2-环丙基-4-(三氟甲氧基)苯(2.57g,10.86mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(3.31g,13.03mmol)、KOAc(2.13g,21.72mmol)、X-phos(1.04g,2.17mmol)和Pd2(dba)3(0.99g,1.09mmol)的混合物在80℃在N2下搅拌16小时。在冷却至室温之后,添加水(50mL),通过硅藻土过滤混合物。将滤液用EtOAc(80mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至2%)纯化粗产物,得到产物(2.5g,7.62mmol,70%产率),呈油状物。1H NMR(400MHz,CDCl3)δH7.77(d,1H),6.98-6.96(m,1H),6.64(s,1H),2.75-2.68(m,1H),1.36(s,12H),1.04-1.00(m,2H),0.70-0.66(m,2H)。
A67:2-氯-5-[2-环丙基-4-(三氟甲氧基)苯基]吡嗪
将在1,4-二噁烷(20mL)和水(1.5mL)中的2-溴-5-氯-吡嗪(1.35g,6.98mmol)、2-[2-环丙基-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(2.5g,7.62mmol)、Cs2CO3(4.55g,13.96mmol)和Pd(dppf)Cl2(766.01mg,1.05mmol)的混合物在55℃在N2下搅拌16小时。在冷却至室温之后,添加水(20mL),通过硅藻土过滤混合物。将滤液用EtOAc(50mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至2%至5%)纯化粗产物,得到产物(1.9g,4.64mmol,66%产率),呈油状物。1H NMR(400MHz,CDCl3)δH8.70(d,1H),8.65(d,1H),7.48(d,1H),7.17-7.14(m,1H),6.94-6.90(m,1H),2.05-2.00(m,1H),0.99-0.93(m,2H),0.72-0.67(m,2H)。
A68:[5-[2-环丙基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼
将在MeCN(20mL)中的2-氯-5-[2-环丙基-4-(三氟甲氧基)苯基]吡嗪(1.9g,4.64mmol)和水合肼(2.33g,46.45mmol)的溶液在100℃搅拌16小时。在冷却至室温之后,添加水(50mL),并将混合物用EtOAc(50mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=30%至50%至80%)纯化粗产物,得到产物(1.44g,4.64mmol,99%产率),呈油状物。1H NMR(400MHz,DMSO-d6)δH8.23-8.18(m,2H),8.11(s,1H),7.47(d,1H),7.25-7.19(m,1H),6.93(s,1H),4.33(brs,2H),2.17-2.06(m,1H),0.92-0.85(m,2H),0.70-0.63(m,2H)。
A69:2-溴-N'-[5-[2-环丙基-4-(三氟甲氧基)苯基]吡嗪-2-基]-2,2-二氟-乙酰肼
向在THF(10mL)中的2-溴-2,2-二氟-乙酸(680mg,3.89mmol)的溶液添加一滴DMF和(COCl)2(0.39mL,4.66mmol)。将生成的混合物在20℃搅拌1小时。然后将在THF(3mL)中的[5-[2-环丙基-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(0.8g,2.58mmol)的溶液添加到以上混合物中。将生成的混合物在20℃搅拌1小时。将混合物倾入水(30mL)中,将水层用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物(1.2g,2.57mmol,99%产率),呈油状物。在1.5min的色谱中,LCMSRt=0.90min,5-95AB,MS ESI计算值C16H13BrF5N4O2[M+H]+469.0,实测值468.7。
A70:3-[溴(二氟)甲基]-6-[2-环丙基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲苯(15mL)中的2-溴-N'-[5-[2-环丙基-4-(三氟甲氧基)苯基]吡嗪-2-基]-2,2-二氟-乙酰肼(1.2g,2.57mmol)和TsOH(132.69mg,0.77mmol)的混合物在130℃搅拌16小时。在冷却至室温之后,添加水(30mL),并将混合物用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至20%至40%)纯化粗产物,得到产物(630mg,1.40mmol,54%产率),呈油状物。1H NMR(400MHz,CDCl3)δH9.63(d,1H),8.47(s,1H),7.61(d,1H),7.25-7.18(m,1H),6.98(d,1H),2.10-2.02(m,1H),1.05-0.98(m,2H),0.82-0.75(m,2H)。
化合物33:6-[2-环丙基-4-(三氟甲氧基)苯基]-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲醇(10mL)中的3-[溴(二氟)甲基]-6-[2-环丙基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(630mg,1.4mmol)和AgBF4(544.2mg,2.81mmol)的混合物在暗处在60℃搅拌1小时。在冷却至室温之后,添加盐水(50mL)和EtOAc(50mL),通过硅藻土过滤混合物。将滤液分离并且将水层用EtOAc(30mL x 2)萃取。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(YMC Triart C18(150mmx 25mm,5mm)A=H2O(10mM NH4HCO3)并且B=CH3CN;经8分钟从53%到83%B)纯化粗产物,得到产物(327.19mg,817.4mmol,58%产率),呈油状物。1H NMR(400MHz,CDCl3)δH9.53(d,1H),8.45(s,1H),7.57(d,1H),7.19(dd,1H),6.95(s,1H),3.94(s,3H),2.09-2.02(m,1H),1.02-0.96(m,2H),0.80-0.75(m,2H)。在2.0min的色谱中,LCMS Rt=1.27min,10-80AB,MS ESI计算值C17H14F5N4O2[M+H]+401.1,实测值401.0。
实施例34:合成化合物34-6-[2-环丙基-4-(三氟甲氧基)苯基]-3-[乙氧基(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
向在乙醇(5mL)中的3-[溴(二氟)甲基]-6-[2-环丙基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(140mg,0.31mmol)的溶液添加AgBF4(120.93mg,0.62mmol)。将混合物在60℃搅拌6小时。添加盐水(20mL),通过硅藻土过滤混合物。将滤液分离并且将水相用EtOAc(20mL x 2)萃取。将合并的有机相用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC[Welch Xtimate C18(150mm x 25mm,5μm)A=H2O(10mMNH4HCO3)并且B=CH3CN;经8分钟60-80%B)纯化粗产物,得到产物(32.74mg,0.079mmol,25%产率),呈油状物。1H NMR(400MHz,CDCl3)δH9.52(d,1H),8.45(s,1H),7.57(d,1H),7.22-7.15(m,1H),6.95(s,1H),4.33(q,2H),2.12-1.98(m,1H),1.46(t,3H),1.05-0.95(m,2H),0.82-0.72(m,2H)。在2.0min的色谱中,LCMS Rt=1.46min,10-80AB,MS ESI计算值C18H16F5N4O2[M+H]+414.9,实测值415.2。
实施例35:合成化合物35-6-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
A125:1-溴-2-甲基-4-(三氟甲氧基)苯
向2-甲基-4-(三氟甲氧基)苯胺(5g,26.16mmol)、亚硝酸异戊酯(3.68g,31.39mmol)和CuBr2(584.23mg,2.62mmol)以及在MeCN(100mL)中的TBAB(18.55g,57.55mmol)的混合物缓慢添加TsOH.H2O(5.97g,31.39mmol)。将混合物在25℃搅拌12小时。用H2O(200mL)稀释混合物并用EtOAc(50mL x 2)萃取混合物。将合并的有机相用水(50mL)和盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至2%)纯化粗产物,得到产物(3.7g,14.51mmol,55%产率),呈油状物。1HNMR(400MHz,CDCl3)δH7.56(d,1H),7.11(s,1H),6.95(d,1H),2.42(s,3H)。
A72:1-溴-2-(溴甲基)-4-(三氟甲氧基)苯
向在CCl4(40mL)中的1-溴-2-甲基-4-(三氟甲氧基)苯(4.4g,17.25mmol)和NBS(3.68g,20.7mmol)的混合物添加BPO(417.92mg,1.73mmol)。将混合物在80℃搅拌16小时。加入水(50ml),并且用DCM(50mL x 3)萃取水层。将合并的有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤,减压浓缩,得到A71a和A71b的混合物(5.6g,16.77mmol),呈油状物。
向在MeCN(50mL)中的A71a和A71b(5.6g,16.77mmol)和亚磷酸二乙酯(3471.39mg,25.15mmol)的混合物添加DIEA(8.3mL,50.31mmol)。将混合物在20℃搅拌3小时。将混合物减压浓缩,去除MeCN。加入水(150mL),并且用EtOAc(50mLx2)萃取水层。将合并的有机层用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤,减压浓缩,得到粗产物。在硅胶上通过快速色谱(PE)纯化粗产物,得到产物(2.5g,7.49mmol,45%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 7.62(d,1H),7.34(d,1H),7.08(d,1H),4.57(s,2H)。
A73:1-溴-2-(环丙氧基甲基)-4-(三氟甲氧基)苯
向在DMF(25mL)中的1-溴-2-(溴甲基)-4-(三氟甲氧基)苯(2.5g,7.49mmol)的溶液添加环丙醇(1.42mL,22.46mmol)和K2CO3(3103.94mg,22.46mmol)。将混合物在40℃搅拌16小时。加入水(50ml),并且用EtOAc(20mL x 2)萃取水层。将合并的有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤,减压浓缩,得到粗产物。在硅胶上通过快速色谱(PE)纯化粗产物,得到产物(1.2g,3.86mmol,52%产率),呈油状物。1H NMR(400MHz,CDCl3)δH7.56(d,1H),7.35(s,1H),7.03(d,1H),4.60(s,2H),3.48-3.43(m,1H),0.72-0.69(m,2H),0.57-0.54(m,2H)。
A74:2-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
向1-溴-2-(环丙氧基甲基)-4-(三氟甲氧基)苯(1.2g,3.86mmol)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(1.18g,4.63mmol)以及在1,4-二噁烷(5mL)中的KOAc(757.11mg,7.71mmol)和PCy3(216.34mg,0.77mmol)的混合物添加Pd2dba3(353.33mg,0.39mmol)。将混合物在100℃搅拌10小时。将混合物过滤,将滤液减压浓缩,给出粗产物。在硅胶上通过快速色谱(PE)纯化粗产物,得到产物(900mg,2.51mmol,65%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 7.83(d,1H),7.31(s,1H),7.11(d,1H),4.81(s,2H),3.42-3.39(m,1H),1.36(s,12H),0.68-0.67(m,2H),0.52-0.49(m,2H)。
A75:2-氯-5-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]吡嗪
将在1,4-二噁烷(10mL)和水(2mL)中的2-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(900mg,2.51mmol)和2-溴-5-氯-吡嗪(583.27mg,3.02mmol)和Pd(dppf)Cl2(183.86mg,0.25mmol)和Cs2CO3(1.64g,5.03mmol)的混合物在50℃在N2下搅拌16小时。在冷却至25℃之后,将反应物倾入水(50mL)中。将混合物用EtOAc(20mL x 2)萃取。将合并的有机相用水(50mL)和盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至1%至3%至5%)纯化粗产物,得到产物(550mg,1.60mmol,63%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 8.68(s,1H),8.59(s,1H),7.54(d,1H),7.48(s,1H),7.22(d,1H),4.64(s,2H),3.34-3.31(m,1H),0.68-0.67(m,2H),0.52-0.49(m,2H)。
A76:[5-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]肼
在25℃向在MeCN(5mL)中的2-氯-5-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]吡嗪(550mg,1.6mmol)的溶液添加N2H4·H2O(797.75mg,15.95mmol)。将混合物在100℃搅拌16小时。在冷却至25℃之后,将反应物倾入水(20mL)中。将混合物用EtOAc(10mL x 2)萃取。将合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到粗产物(500mg,1.47mmol),呈固体。在1.5min的色谱中,LCMS Rt=0.77min,5-95AB,MS ESI计算值C15H16F3N4O2[M+H]+341.1,实测值340.9。
A77:2-溴-N'-[5-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]-2,2-二氟-乙酰肼
在25℃向2-溴-2,2-二氟-乙酸(51.25mg,0.29mmol)和在DCM(1mL)中的一滴DMF的溶液添加(COCl)2(44.63mg,0.35mmol)。将混合物在25℃搅拌15min。在25℃将在DCM(2mL)中的[5-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]肼(100mg,0.29mmol)添加到以上溶液中。将生成的混合物在25℃搅拌1小时。将混合物倾入水(10mL)中,将水层用EtOAc(10mL)萃取。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶柱上通过快速色谱(EtOAc在PE中=15%至30%)纯化粗产物,得到产物(80mg,0.16mmol,55%产率),呈油状物。1H NMR(400MHz,DMSO-d6)δH 11.41(brs,1H),9.53(s,1H),8.35(s,1H),8.16(s,1H),7.64(d,1H),7.46(s,1H),7.41(d,1H),4.64(s,2H),3.35-3.28(m,1H),0.48-0.45(m,2H),0.43-0.41(m,2H)。
A78:3-[溴(二氟)甲基]-6-[2-甲基-4-(2,2,2-三氟-1-甲基-乙氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
向在DCM(2mL)中的2-溴-N'-[5-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]吡嗪-2-基]-2,2-二氟-乙酰肼(80mg,0.16mmol)的混合物添加2-甲氧基吡啶(0.04mL,0.35mmol)和Tf2O(0.03mL,0.19mmol)。将混合物在25℃搅拌2小时。加入水(20mL),并且用EtOAc(10mLx2)萃取水层。将合并的有机相用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中=0%至15%)纯化粗产物,得到产物(30mg,0.06mmol,39%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 9.59(s,1H),8.69(s,1H),7.73(d,1H),7.45(s,1H),7.37(d,1H),4.62(s,2H),3.38-3.35(m,1H),0.63-0.62(m,2H),0.54-0.53(m,2H)。
化合物35:6-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
在25℃在N2下向甲醇(1mL)中的3-[溴(二氟)甲基]-6-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(30mg,0.06mmol)的悬浮液中添加AgBF4(24.29mg,0.13mmol)。使混合物避光,在60℃搅拌2小时。将混合物加入到盐水(10mL)中并过滤。将滤液用EtOAc(10mL)萃取。将合并的有机相用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(YMC Triart C18 150x25mm x 5μm,A=H2O(10mM NH4HCO3)并且B=CH3CN;经9.5分钟52-82%)纯化粗产物,得到产物(4.7mg,0.01mmol,17%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.52(s,1H),8.63(s,1H),7.69(d,1H),7.45(s,1H),7.35(d,1H),4.60(s,2H),3.95(s,3H),3.38-3.36(m,1H),0.63-0.60(m,2H),0.54-0.52(m,2H)。在2min的色谱中,LCMS Rt=1.43min,10-80AB,MS ESI计算值C18H16F5N4O3[M+H]+431.1,实测值431.2。
实施例36:合成化合物36-6-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]-3-[乙氧基(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
在25℃在N2下向乙醇(1mL)中的3-[溴(二氟)甲基]-6-[2-(环丙氧基甲基)-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(35mg,0.07mmol)的悬浮液中添加AgBF4(28.34mg,0.15mmol)。使混合物避光,在60℃搅拌2小时。将该溶液加入到饱和水性NaCl(10mL)中并过滤。将滤液用EtOAc(10mL)萃取。将有机相用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(YMC Triart C18 150x25mm x 5μm,A=H2O(10mM NH4HCO3)并且B=CH3CN经9.5分钟从60%到90%)纯化粗产物,得到产物(15.76mg,0.04mmol,48%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.52(s,1H),8.60(s,1H),7.68(d,1H),7.45(s,1H),7.35(d,1H),4.61(s,2H),4.34(q,2H),3.39-3.34(m,1H),1.46(t,3H),0.62-0.60(m,2H),0.54-0.52(m,2H)。在2min的色谱中,LCMS Rt=1.47min,10-80AB,MSESI计算值C19H18F5N4O3[M+H]+445.1,实测值445.3。
实施例37:化合物37-6-[4-(3,3-二氟环丁氧基)苯基]-3-[乙氧基(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪的合成
A79:溴-4-(2,2-二氟环丙基)苯
在N2下向在甲苯(15mL)中的Ph3P(2.67g,10.18mmol)的溶液添加DIAD(2.1g,10.18mmol)。然后将混合物在0℃搅拌10min。然后,将在甲苯(3mL)中的3,3-二氟环丁醇(1g,9.25mmol)溶液添加到混合物中。将混合物在25℃搅拌10min。然后,将4-溴苯酚(1.6g,9.25mmol)添加到混合物中,将生成的混合物在110℃搅拌16小时。将混合物用EtOAc(20mLx 3)萃取。将合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(PE)纯化粗产物,得到产物(380mg,1.44mmol,15%产率),呈油状物。1H NMR(400MHz,CDCl3)δH7.46-7.40(m,2H),6.76-6.68(m,2H),4.67-4.57(m,1H),3.15-3.03(m,2H),2.87-2.70(m,2H)。
A80:2-[4-(3,3-二氟环丁氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
向在1,4-二噁烷(5mL)中的1-溴-4-(3,3-二氟环丁氧基)苯(380mg,1.44mmol)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(440mg,1.73mmol)和KOAc(284mg,2.89mmol)的混合物添加Pd(dppf)Cl2(106mg,0.14mmol)。将混合物在100℃搅拌3小时。将混合物过滤,并将滤液减压浓缩。加入水(20mL),并且用EtOAc(20mL x 3)萃取水层。将合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到残余物。在硅胶上通过快速色谱(EtOAc在PE中0~10%)纯化残余物,得到产物(400mg,1.29mmol,89%产率),呈油状物。1H NMR(400MHz,CDCl3)δH7.80-7.75(m,2H),6.82-6.73(m,2H),4.75-4.62(m,1H),3.15-3.05(m,2H),2.83-2.70(m,2H),1.34(s,12H)。
A81:2-氯-5-[4-(3,3-二氟环丁氧基)苯基]吡嗪
向在1,4-二噁烷(5mL)和水(0.5mL)中的2-[4-(3,3-二氟环丁氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(400mg,1.29mmol)和2-溴-5-氯-吡嗪(299mg,1.55mmol)和Cs2CO3(840mg,2.58mmol)的混合物添加Pd(dppf)Cl2(94mg,0.13mmol)。将混合物在80℃搅拌4小时。将混合物过滤,并将混合物减压浓缩。加入水(10mL),并且用EtOAc(10mLx3)萃取水层。将合并的有机层用盐水(10mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~20%)纯化粗产物,得到产物(180mg,0.61mmol,47%产率),呈固体。1H NMR(400MHz,CDCl3)δH8.74(s,1H),8.60(s,1H),7.96(dd,2H),6.94(dd,2H),4.78-4.65(m,1H),3.20-3.08(m,2H),2.88-2.75(m,2H)。
A82:[5-[4-(2,2-二氟环丁氧基)苯基]吡嗪-2-基]肼
向在MeCN(3mL)中的2-氯-5-[4-(3,3-二氟环丁氧基)苯基]吡嗪(180mg,0.61mmol)的溶液添加N2H4·H2O(303mg,6.07mmol)。将混合物在80℃搅拌16小时。在冷却至RT之后,添加水(10mL),并将混合物用EtOAc(10mL x 3)萃取。将合并的有机层用盐水(10mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(MeOH在DCM中0~20%)纯化粗产物,得到产物(140mg,0.48mmol,79%产率),呈固体。在1.5min的色谱中,LCMSRt=0.78min,5-95AB,MS ESI计算值C14H15F2N4O[M+H]+293.0,实测值293.0。
A84:2-溴-N'-[5-[4-(3,3-二氟环丁氧基)苯基]吡嗪-2-基]-2,2-二氟-乙酰肼
向在甲苯(2mL)中的2-溴-2,2-二氟-乙酸(0.13g,0.72mmol)的溶液添加DMF(2.62mg,0.04mmol)和(COCl)2(0.07mL,0.86mmol)。将生成的混合物在28℃搅拌1小时。将在甲苯(3mL)中的[5-[4-(3,3-二氟环丁氧基)苯基]吡嗪-2-基]肼(140mg,0.48mmol)溶液添加到以上混合物中。将混合物在28℃搅拌2小时。
将TsOH(25mg,0.14mmol)添加到混合物中。将混合物在130℃搅拌16小时。在冷却至RT之后,添加水(20mL),并将水层用EtOAc(20mL x 3)萃取。将合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~20%)纯化粗产物,得到产物(30mg,0.07mmol,15%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.55(d,1H),8.37(s,1H),8.00-7.96(m,2H),7.02-6.95(m,2H),4.80-4.65(m,1H),3.23-3.05(m,2H),2.90-2.75(m,2H)。
化合物37:6-[4-(3,3-二氟环丁氧基)苯基]-3-[乙氧基(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
向在乙醇(3mL)中的3-[溴(二氟)甲基]-6-[4-(3,3-二氟环丁氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪(30mg,0.07mmol)的溶液添加AgBF4(27mg,0.14mmol)。将混合物在60℃搅拌3小时。在冷却至RT之后,添加盐水(10mL)和EtOAc(10mL)。将混合物过滤并将滤饼用EtOAc(10mL x 3)洗涤。分离滤液,将有机层用盐水(10mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC[YMC Triart C18 150*25mm*5μm.A=水(10mM NH4HCO3)并且B=CH3CN;经9.5分钟62%-92%B)]纯化粗产物,得到产物(5.04mg,0.013mmol,19%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.50(s,1H),8.42(s,1H),7.90(d,2H),6.96(d,2H),4.80-4.67(m,1H),3.36(q,2H),3.21-3.10(m,2H),2.90-2.72(m,2H),1.50(t,3H)。在2.0min的色谱中,LCMS Rt=1.39min,10-80AB,MS ESI计算值C18H17F4N4O2[M+H]+397.1,实测值397.2。
实施例38:合成化合物38-6-[4-(3,3-(二氟环丁氧基)-2-甲基-苯基]-3-[乙氧基(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
A85:1-溴-4-(3,3-二氟环丁氧基)-2-甲基-苯
在0℃向在甲苯(50mL)中的Ph3P(3.64g,13.88mmol)溶液滴加DIAD(2.81g,13.88mmol)。将混合物在0℃搅拌30min。然后将在甲苯(5mL)中的3,3-二氟环丁醇(1g,9.25mmol)添加到混合物中。将混合物在25℃搅拌30min。然后将4-溴-3-甲基-苯酚(2.07g,11.1mmol)添加到混合物中,并将生成的混合物在110℃搅拌16小时。将混合物减压浓缩,给出粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~30%)纯化粗产物,得到产物(770mg,2.78mmol,30%产率),呈油状物。1H NMR(400MHz,CDCl3)δH7.41(d,1H),6.71(d,1H),6.52(dd,1H),4.65-4.55(m,1H),3.16-3.00(m,2H),2.81-2.67(m,2H),2.37(s,3H)。
A86:2-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
向在1,4-二噁烷(10mL)中的1-溴-4-(3,3-二氟环丁氧基)-2-甲基-苯(770mg,2.78mmol)溶液添加4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(847mg,3.33mmol)和KOAc(545mg,5.56mmol)。然后在N2下将Pd(dppf)Cl2(203mg,0.28mmol)添加到上述混合物中。将混合物在100℃搅拌16小时。将混合物过滤,将滤液浓缩,给出粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~4%)纯化粗产物,得到产物(900mg,2.78mmol,100%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 7.72(d,1H),6.67-6.57(m,2H),4.72-4.62(m,1H),3.15-3.02(m,2H),2.82-2.68(m,2H),2.52(s,3H),1.34(s,12H)。
A87:2-氯-5-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]吡嗪
向在1,4-二噁烷(10mL)和水(1mL)中的2-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(900mg,2.78mmol)溶液添加2-溴-5-氯-吡嗪(591mg,3.05mmol)和Cs2CO3(1.8g,5.55mmol)。然后将Pd(dppf)Cl2(203mg,0.28mmol)添加到混合物中,将生成的混合物在90℃搅拌16小时。添加水(20mL),过滤混合物。将滤液减压浓缩并且将水层用EtOAc(20mL x 3)萃取。将合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤,减压浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~10%)纯化粗产物,得到产物(500mg,1.61mmol,58%产率),呈固体。1H NMR(400MHz,CDCl3)δH 8.65(s,1H),8.47(s,1H),7.38(d,1H),6.80-6.72(m,2H),4.76-4.65(m,1H),3.20-3.06(m,2H),2.87-2.75(m,2H),2.40(s,3H)。
A88:[5-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]吡嗪-2-基]肼
向在乙腈(5mL)中的2-氯-5-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]吡嗪(500mg,1.61mmol)溶液添加水合肼(806mg,16.09mmol)。将混合物在100℃搅拌16小时。在冷却至RT之后,添加水(20mL),并将水层用EtOAc(20mLx3)萃取。将合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~50%)纯化粗产物,得到产物(320mg,1.04mmol,65%产率),呈固体。1H NMR(400MHz,DMSO-d6)δH 8.16(d,1H),8.05(d,1H),7.97(s,1H),7.28(d,1H),6.83-6.73(m,2H),4.83-4.73(m,1H),4.30(brs,2H),3.27-3.15(m,2H),2.77-2.60(m,2H),2.30(s,3H)。
A89:2-溴-N'-[5-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]吡嗪-2-基]-2,2-二氟-乙酰肼
向在THF(2mL)中的2-溴-2,2-二氟-乙酸(219mg,1.25mmol)溶液添加(COCl)2(0.13mL,1.5mmol)和一滴DMF。将混合物在30℃搅拌0.5小时。然后将在THF(2mL)中的[5-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]吡嗪-2-基]肼(320mg,1.04mmol)溶液添加到混合物中。将混合物在30℃搅拌1小时。加入水(20mL),并且用EtOAc(20mL x3)萃取水层。将合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到产物(483mg,1.04mmol),呈油状物,用于下一个步骤中。
A90:3-[溴(二氟)甲基]-6-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]-[1,2,4]三唑并[4,3-a]吡嗪
向在甲苯(5mL)中的2-溴-N'-[5-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]吡嗪-2-基]-2,2-二氟-乙酰肼(483mg,1.04mmol)溶液添加TsOH(54mg,0.31mmol)。将混合物在145℃搅拌16小时。加入水(20mL),并且用EtOAc(20mL x 3)萃取水层。将合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~30%)纯化粗产物,得到产物(280mg,0.63mmol,60%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.56(s,1H),8.17(s,1H),7.50-7.37(m,1H),6.85-6.75(m,2H),4.80-4.68(m,1H),3.23-3.05(m,2H),2.90-2.72(m,2H),2.43(s,3H)。
化合物38:6-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]-3-[乙氧基(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
向在乙醇(2mL)中的3-[溴(二氟)甲基]-6-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]-[1,2,4]三唑并[4,3-a]吡嗪(140mg,0.31mmol)溶液添加AgBF4(122mg,0.63mmol)和Na2CO3(67mg,0.63mmol)。将混合物在70℃搅拌1小时。加入水(10mL),并且用EtOAc(10mL x3)萃取水层。将合并的有机层用盐水(10mL)洗涤,经无水Na2SO4干燥,过滤,减压浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~30%)纯化粗产物,得到产物(54.29mg,0.13mmol,42%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.49(s,1H),8.19(s,1H),7.40(d,1H),6.82-6.72(m,2H),4.78-4.67(m,1H),4.32(q,2H),3.22-3.07(m,2H),2.88-2.74(m,2H),2.41(s,3H),1.46(t,3H)。在2.0min的色谱中,LCMS Rt=1.20min,10-80AB,MS ESI计算值C19H19F4N4O2[M+H]+411.1,实测值411.1。
实施例39:合成化合物39-6-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
向在甲醇(2mL)中的3-[溴(二氟)甲基]-6-[4-(3,3-二氟环丁氧基)-2-甲基-苯基]-[1,2,4]三唑并[4,3-a]吡嗪(140mg,0.31mmol)溶液添加AgBF4(122mg,0.63mmol)和Na2CO3(67mg,0.63mmol)。将混合物在70℃搅拌1小时。加入水(10mL),并且用EtOAc(10mL x3)萃取水层。将合并的有机层用盐水(10mL)洗涤,经无水Na2SO4干燥,过滤,减压浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在PE中0~30%)纯化粗产物,得到产物(73.04mg,0.18mmol,57%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.50(s,1H),8.18(s,1H),7.38(d,1H),6.82-6.72(m,2H),4.78-4.67(m,1H),3.94(s,3H),3.22-3.07(m,2H),2.87-2.72(m,2H),2.40(s,3H)。在2.0min的色谱中,LCMS Rt=1.17min,10-80AB,MS ESI计算值C18H17F4N4O2[M+H]+397.1,实测值397.1。
实施例40:合成化合物40-3-[二氟(甲氧基)甲基]-6-[5-氟-2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
A91:4-溴-2-氟-5-甲基-苯酚
在搅拌的同时向DCM(1200mL)和甲醇(800mL)中的2-氟-5-甲基-苯酚(20.0g,158.57mmol)溶液滴加四丁基三溴化铵(76.46g,158.57mmol)。将混合物在25℃搅拌3小时。加入水(150mL),并将混合物减压浓缩。将水层用DCM(300mL x 3)萃取。将合并的有机层用盐水(600mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0~15%)纯化粗产物,得到产物(30.0g,146.33mmol,92%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 7.22(d,1H),6.96(d,1H),2.29(s,3H)。
A92:1-苄氧基-4-溴-2-氟-5-甲基-苯
向在MeCN(300mL)中的4-溴-2-氟-5-甲基-苯酚(29.0g,141.45mmol)溶液添加BnBr(24.19g,141.45mmol)和K2CO3(29.32g,212.17mmol)。将混合物在30℃搅拌1小时。将混合物过滤,浓缩滤液,从而得到产物(35.1g,118.92mmol),呈固体。1H NMR(400MHz,CDCl3)δH7.45-7.25(m,6H),6.87(d,1H),5.09(s,2H),2.30(s,3H)。
A93:2-(4-苄氧基-5-氟-2-甲基-苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
向在1,4-二噁烷(300mL)中的1-苄氧基-4-溴-2-氟-5-甲基-苯(35.0g,118.58mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(33.12g,130.44mmol)、KOAc(23.28g,237.17mmol)、XPhos(5.65g,11.86mmol)的混合物添加Pd2dba3(5.43g,5.93mmol)。将混合物在100℃在N2下搅拌12小时。在冷却至30℃之后,通过硅藻土过滤反应混合物。将滤液减压浓缩。加入水(300mL),并且用EtOAc(300mL x 3)萃取水层。将合并的有机层用盐水(300mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0~10%)纯化粗产物,得到产物(30.0g,61.37mmol,52%产率),呈固体。1H NMR(400MHz,CDCl3)δH 7.50-7.25(m,6H),6.83-6.78(m,1H),5.15(s,2H),2.47(s,3H),1.33(s,12H)。
A94:2-(4-苄氧基-5-氟-2-甲基-苯基)-5-氯-吡嗪
向在1,4-二噁烷(250mL)和水(50mL)中的2-(4-苄氧基-5-氟-2-甲基-苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(25.0g,51.14mmol,70%纯)和2-溴-5-氯-吡嗪(9.89g,51.14mmol)的混合物添加Cs2CO3(33.32g,102.28mmol)。然后将Pd(dppf)Cl2(3.74g,5.11mmol)添加到混合物中。将生成的混合物在50℃搅拌3小时。将混合物与另一批次(从5.0g化合物A93获得)混合。将混合物过滤,并将滤液浓缩。加入水(300mL),并且用EtOAc(300mL x 3)萃取水层。将合并的有机层用盐水(300mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中0~10%)纯化粗产物,得到产物(15.0g,45.62mmol,74%产率),呈固体。1H NMR(400MHz,CDCl3)δH8.66(s,1H),8.46(s,1H),7.52-7.30(m,5H),7.24(d,1H),6.95(d,1H),5.20(s,2H),2.36(s,3H)。
A95:[5-(4-苄氧基-5-氟-2-甲基-苯基)吡嗪-2-基]肼
向在MeCN(100mL)中的2-(4-苄氧基-5-氟-2-甲基-苯基)-5-氯-吡嗪(15.0g,45.62mmol)溶液添加水合肼(22.8g,456.25mmol)。将混合物在90℃搅拌24小时。加入水(500mL),并且用EtOAc(300mL x 3)萃取水层。将合并的有机层用盐水(300mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中0~60%)纯化粗产物,得到产物(9.8g,30.21mmol,66%产率)。1H NMR(400MHz,DMSO-d6)δH 8.17(s,1H),8.10(s,1H),8.05(s,1H),7.50-7.30(m,5H),7.24(d,1H),7.18(d,1H),5.21(s,2H),4.30(s,2H),1.99(s,3H)。在2.0min的色谱中,LCMS Rt=1.04min,10-80AB,MS ESI计算值C18H18FN4O[M+H]+325.1,实测值325.2。
A96:N'-[5-(4-苄氧基-5-氟-2-甲基-苯基)吡嗪-2-基]-2-溴-2,2-二氟-乙酰肼
向在THF(40mL)中的2-溴-2,2-二氟-乙酸(4.04g,23.12mmol)溶液添加(COCl)2(2.4mL,27.75mmol)和5滴DMF。将混合物在30℃搅拌1小时。将在THF(10mL)中的[5-(4-苄氧基-5-氟-2-甲基-苯基)吡嗪-2-基]肼(5.0g,15.42mmol)溶液滴加到混合物中。将混合物在30℃搅拌10小时。加入水(50mL),并且用EtOAc(50mL x 3)萃取水层。将合并的有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中0~20%)纯化粗产物,得到产物(2.9g,6.03mmol,39%产率),呈油状物。1HNMR(400MHz,CDCl3)δH 8.27(s,1H),8.22(s,1H),7.50-7.32(m,5H),7.24(d,1H),6.92(d,1H),5.18(s,2H),2.31(s,3H)。在1.5min的色谱中,LCMS Rt=1.00min,5-95AB,MS ESI计算值C20H17BrF3N4O2[M+H]+481.0,实测值480.8。
A97:6-(4-苄氧基-5-氟-2-甲基-苯基)-3-[溴(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
向在甲苯(50mL)中的N'-[5-(4-苄氧基-5-氟-2-甲基-苯基)吡嗪-2-基]-2-溴-2,2-二氟-乙酰肼(2.9g,6.03mmol)溶液添加TsOH(311mg,1.81mmol)。将混合物在130℃搅拌16小时。加入水(50mL),并且用EtOAc(50mL x 3)萃取水层。将合并的有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中0~15%)纯化粗产物,得到产物(2.2g,4.75mmol,79%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.56(d,1H),8.17(s,1H),7.50-7.25(m,6H),6.99(d,2H),5.23(s,2H),2.40(s,3H)。
A98:6-(4-苄氧基-5-氟-2-甲基-苯基)-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
向在甲醇(30mL)中的6-(4-苄氧基-5-氟-2-甲基-苯基)-3-[溴(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(2.2g,4.75mmol)溶液添加AgBF4(2.76g,14.25mmol)和Na2CO3(1.51g,14.25mmol)。将混合物在70℃搅拌5小时。添加盐水(100mL),过滤悬浮液。将滤液用EtOAc(50mL x 3)萃取。将合并的有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中0~30%)纯化粗产物,得到产物(1.3g,3.14mmol,66%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.49(s,1H),8.18(s,1H),7.50-7.35(m,5H),7.24(s,1H),6.98(d,1H),5.22(s,2H),3.94(s,3H),2.36(s,3H)。
A99:4-[3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪-6-基]-2-氟-5-甲基-苯酚
将在HBr/HOAc(15mL,33%)中的6-(4-苄氧基-5-氟-2-甲基-苯基)-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(1.3g,3.14mmol)溶液在30℃搅拌2小时。加入水(50mL),并且用EtOAc(50mL x 3)萃取水层。将合并的有机层用饱和NaHCO3溶液(30mL x 3)和盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中0~90%)纯化粗产物,得到产物(710mg,2.19mmol,70%产率),呈固体。1H NMR(400MHz,DMSO-d6)δH 10.11(s,1H),9.62(d,1H),8.49(s,1H),7.30(d,1H),6.91(d,1H),3.87(s,3H),2.26(s,3H)。
化合物40:3-[二氟(甲氧基)甲基]-6-[5-氟-2-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将AgOTf(2.38g,9.25mmol)在200℃(热风枪)真空干燥20min。然后在手套箱中添加4-[3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪-6-基]-2-氟-5-甲基-苯酚(600mg,1.85mmol)、select F(3.28g,9.25mmol)、CsF(1.69g,11.1mmol),随后添加甲苯(10mL)、2-氟吡啶(0.9g,9.25mmol)和TMSCF3(1.32g,9.25mmol)。将混合物在30℃搅拌16小时。通过硅藻土过滤混合物并将滤饼用DCM(20mL x 4)洗涤。浓缩滤液,并通过快速色谱(DCM在MeOH中0~5%)和制备型HPLC([Phenomenex Gemini-NX 80x30mm x 3mm,A=H2O(10mM NH4HCO3)并且B=CH3CN;经9.5分钟41%-71%]进行纯化,得到产物(7.27mg,0.0185mmol,10%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 9.52(s,1H),8.24(s,1H),7.35(d,1H),7.30(d,1H),3.95(s,3H),2.40(s,3H)。在3.0min的色谱中,LCMS Rt=1.95min,10-80CD,MS ESI计算值C15H11F6N4O2[M+H]+393.1,实测值393.1。
实施例41:合成化合物41–3-(1-乙氧基-1-甲基-乙基)-6-[2-甲基-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
A100:(5-氯吡嗪-2-基)肼
将在乙醇(150mL)中的N2H4·H2O(50.34g,1mol)和2,5-二氯吡嗪(30g,201.37mmol)的混合物在90℃搅拌12小时。在冷却至RT之后,添加水(500mL),并将水层搅拌1小时。过滤水层,将滤饼干燥,得到产物(22g,152.19mmol,75%产率),呈固体。1H NMR(400MHz,CDCl3)δH8.05-8.03(m,2H),6.00(brs,1H),3.84(brs,2H)。
A101:N'-(5-氯吡嗪-2-基)-2-乙氧基-2-甲基-丙酰肼
向在DCM(25mL)中的2-乙氧基-2-甲基-丙酸(2g,15.13mmol)、PyBOP(11.81g,22.7mmol)和DIPEA(5.27mL,30.27mmol)的混合物添加(5-氯吡嗪-2-基)肼(2.2g,15.22mmol)。将混合物在25℃搅拌2小时。加入水(100mL),并且用EtOAc(100mL x 2)萃取混合物。将合并的有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中0%至15%至30%)纯化粗产物,得到产物(3.9g,15.08mmol,99%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 8.70(d,1H),8.08(s,1H),7.86(s,1H),7.36(s,1H),3.55(q,2H),1.45(s,6H),1.25(t,3H)。
A102:6-氯-3-(1-乙氧基-1-甲基-乙基)-[1,2,4]三唑并[4,3-a]吡嗪
在0℃向在DCM(40mL)中的N'-(5-氯吡嗪-2-基)-2-乙氧基-2-甲基-丙酰肼(3.9g,15.08mmol)溶液添加2-甲氧基吡啶(3.17mL,30.15mmol)然后添加Tf2O(3.06mL,18.09mmol)。将混合物在25℃搅拌1小时。加入水(100mL),并且用EtOAc(100mL x 2)萃取混合物。将合并的有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至15%至30%)纯化粗产物,得到产物(1.1g)。通过制备型HPLC(Xtimate C18(150mm x 40mm,5mm)A=H2O(0.1%TFA)并且B=CH3CN;经8分钟26%B)进一步纯化产物(1.1g),得到产物(350mg,1.45mmol,9%产率),其一种为固体。在4.0min的色谱中,LCMSRt=2.17min,0-60AB,MS ESI计算值C10H14ClN4O[M+H]+241.1,实测值241.1。
化合物41:3-(1-乙氧基-1-甲基-乙基)-6-[2-甲基-4-(三氟甲氧基)苯基)-[1,2,4]三唑并[4,3-a]吡嗪
将在1,4-二噁烷(5mL)和水(0.5mL)中的6-氯-3-(1-乙氧基-1-甲基-乙基)-[1,2,4]三唑并[4,3-a]吡嗪(350mg,1.45mmol)、4,4,5,5-四甲基-2-[2-甲基-4-(三氟甲氧基)苯基]-1,3,2-二氧杂环戊硼烷(439.3mg,1.45mmol)、Cs2CO3(947.53mg,2.91mmol)以及还有Pd(dppf)Cl2(159.6mg,0.22mmol)的混合物在90℃在N2下搅拌3小时。在冷却至RT之后,添加水(50mL)和EtOAc(50mL),通过硅藻土过滤混合物。在层分离之后,将水相用EtOAc(50mL)萃取。将合并的有机相用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过制备型HPLC(Kromasil(150mm x 25mm,10mm)A=H2O(0.05%NH4OH)并且B=CH3CN;经8分钟从50%到80%B)纯化粗产物,得到产物(103.24mg,270.9mmol,18%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.42(d,1H),8.51(s,1H),7.45(d,1H),7.23-7.16(m,2H),3.28(q,2H),2.45(s,3H),1.84(s,6H),1.17(t,3H)。在2.0min的色谱中,LCMS Rt=1.22min,10-80AB,MSESI计算值C18H20F3N4O2[M+H]+381.1,实测值381.1。
实施例42:合成化合物42–3-[二氟(甲氧基)甲基]-6-[2-氟-5-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
A103:4-溴-5-氟-2-甲基-苯酚
向DCM(1.2L)和甲醇(800mL)中的5-氟-2-甲基-苯酚(20g,158.57mmol)溶液添加四丁基三溴化铵(76.46g,158.57mmol)。将混合物在25℃搅拌3小时。浓缩溶液,给出残余物,将残余物重新溶解于石油醚:EtOAc=5:1(2L)中,并通过300-400目硅胶过滤。将硅胶饼用石油醚:EtOAc=5:1(5L)洗涤,浓缩,得到产物(23g,112.18mmol,70%产率),呈油状物。1H NMR(400MHz,CDCl3)δH7.25(d,1H),6.63(d,1H),5.93(brs,1H),2.18(s,3H)。
A104:1-苄氧基-4-溴-5-氟-2-甲基-苯
向在MeCN(200mL)中的4-溴-5-氟-2-甲基-苯酚(23g,112.18mmol)和K2CO3(23.25g,168.28mmol)的混合物添加溴甲基苯(13.32mL,112.18mmol)。将混合物在25℃搅拌16小时。通过硅藻土过滤混合物。将滤饼用EtOAc(50mL x 2)洗涤。将合并的有机相浓缩,得到粗产物(32g,108.42mmol),呈油状物。1H NMR(400MHz,CDCl3)δH 7.27-7.11(m,6H),6.54(d,1H),4.89(s,2H),2.07(s,3H)。
A105:2-(4-苄氧基-2-氟-5-甲基-苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
向在1,4-二噁烷(200mL)中的1-苄氧基-4-溴-5-氟-2-甲基-苯(32g,108.42mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(30.29g,119.26mmol)、KOAc(21.28g,216.84mmol)、XPhos(5.17g,10.84mmol)的混合物添加Pd2dba3(4.96g,5.42mmol)。将混合物在95℃在N2下搅拌6小时。在冷却至RT之后,通过硅藻土过滤混合物。将滤饼用EtOAc(50mL x 2)洗涤。将合并的有机相浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0~2%)纯化粗产物,得到产物(33g,96.43mmol,88%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 7.51(d,1H),7.45-7.35(m,5H),6.60(d,1H),5.08(s,2H),2.23(s,3H),1.36(s,12H)。
A106:2-(4-苄氧基-2-氟-5-甲基-苯基)-5-氯-吡嗪
将在1,4-二噁烷(350mL)和水(35mL)中的2-(4-苄氧基-2-氟-5-甲基-苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(33g,96.43mmol)、2-溴-5-氯-吡嗪(15.5g,80.13mmol)、Cs2CO3(52.21g,160.26mmol)以及还有Pd(dppf)Cl2(2.93g,4.01mmol)的混合物在55℃在N2下搅拌3小时。在冷却至RT之后,将混合物减压浓缩。添加水(500mL)和EtOAc(500mL),并通过硅藻土过滤混合物。在相分离之后,将水相用EtOAc(250mLx2)萃取。将合并的有机相用盐水(500mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中0%至10%至20%)纯化粗产物,得到产物(24g,73mmol,91%产率),呈固体。在2.0min的色谱中,LCMSRt=1.44min,10-80AB,MS ESI计算值C18H15ClFN2O[M+H]+329.1,实测值329.1。
A107:[5-(4-苄氧基-2-氟-5-甲基-苯基)吡嗪-2-基]肼
将在MeCN(300mL)中的2-(4-苄氧基-2-氟-5-甲基-苯基)-5-氯-吡嗪(24g,73mmol)和水合肼(36.54g,730mmol)的混合物在100℃搅拌6小时。在冷却至RT之后,将混合物倾入水(500mL)中。将混合物用EtOAc(500mL x 2)萃取。将合并的有机相用盐水(500mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至30%至50%)纯化粗产物,得到产物(7.2g,22.20mmol,30%产率),呈固体。1HNMR(400MHz,DMSO-d6)δH 8.31(s,1H),8.22(s,1H),8.10(s,1H),7.67(d,1H),7.51-7.47(m,2H),7.42(t,2H),7.37-7.32(m,1H),7.01(d,1H),5.19(s,2H),4.33(brs,2H),2.21(s,3H)。
A108:N'-[5-(4-苄氧基-2-氟-5-甲基-苯基)吡嗪-2-基]-2-溴-2,2-二氟-乙酰肼
在0℃向在THF(100mL)中的2-溴-2,2-二氟-乙酸(6.5g,37.16mmol)溶液添加一滴DMF,然后添加草酰氯(3.77mL,44.59mmol)。将生成的混合物在25℃搅拌1小时。将5-(4-苄氧基-2-氟-5-甲基-苯基)吡嗪-2-基]肼(6g,18.5mmol添加到混合物中,并且将混合物在25℃搅拌2小时。浓缩混合物,得到粗产物(8.9g,18.49mmol),呈固体。在2.0min的色谱中,LCMS Rt=1.35min,10-80AB,MS ESI计算值C20H17BrF3N4O2[M+H]+481.0,实测值480.9。
A109:6-(4-苄氧基-2-氟-5-甲基-苯基)-3-[溴(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲苯(100mL)中的N'-[5-(4-苄氧基-2-氟-5-甲基-苯基)吡嗪-2-基]-2-溴-2,2-二氟-乙酰肼(9.9g,20.57mmol)和TsOH(1.06g,6.17mmol)的混合物在125℃搅拌16小时。在冷却至RT之后,将混合物减压浓缩。加入水(200mL),并且用EtOAc(200mL x 3)萃取水层。将合并的有机相用盐水(300mL x 2)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至40%至80%)纯化粗产物,然后从MeOH(30mL)中重结晶,得到产物(6.6g,14.25mmol,69%产率),呈固体。在7.0min的色谱中,LCMSRt=4.10min,10-80AB,MS ESI计算值C20H15BrF3N4O[M+H]+463.0,实测值463.2。
A110:6-(4-苄氧基-2-氟-5-甲基-苯基)-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
将在甲醇(25mL)中的6-(4-苄氧基-2-氟-5-甲基-苯基)-3-[溴(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(2.6g,5.61mmol)、Na2CO3(1.19g,11.23mmol)和AgBF4(2.18g,11.23mmol)的混合物在60℃在暗处搅拌8小时。在冷却至RT之后,添加盐水(100mL)和EtOAc(100mL),通过硅藻土过滤混合物。在相分离之后,将有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至50%至80%)纯化粗产物,然后通过制备型HPLC(Phenomenex luna C18(250mm x 50mm,10mm)A=H2O(0.1%TFA)并且B=CH3CN;经8分钟从50%到80%B),得到产物(310mg,748.1mmol,13%产率),呈固体。在7.0min的色谱中,LCMSRt=3.85min,10-80AB,MS ESI计算值C21H18F3N4O2[M+H]+415.1,实测值415.3。
A111:4-[3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪-6-基]-5-氟-2-甲基-苯酚
将在HBr/AcOH(5mL,33%,在HOAc中)中的6-(4-苄氧基-2-氟-5-甲基-苯基)-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(310mg,0.75mmol)溶液在25℃搅拌2小时。加入水(20mL),并且用EtOAc(30mL x 2)萃取混合物。将合并的有机层用饱和水性NaHCO3溶液(30mL x 2)和盐水(50mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至50%至100%)纯化粗产物,得到产物(130mg,0.4mmol,53%产率),呈固体。1H NMR(400MHz,DMSO-d6)δH 10.33(s,1H),9.66(s,1H),8.58(s,1H),7.84(d,1H),6.74(d,1H),3.88(s,3H),2.17(s,3H)。在7.0min的色谱中,LCMS Rt=2.35min,10-80AB,MS ESI计算值C14H12F3N4O2[M+H]+325.1,实测值325.1。
化合物42:3-[二氟(甲氧基)甲基]-6-[2-氟-5-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将AgOTf(400mg,1.54mmol)放入三颈瓶中,在200℃真空干燥20min。在手套箱中添加4-[3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪-6-基]-5-氟-2-甲基-苯酚(100mg,0.31mmol)、select F(546.26mg,1.54mmol)、CsF(281.07mg,1.85mmol)、甲苯(10mL)、2-氟吡啶(149.73mg,1.54mmol)和TMSCF3(219.25mg,1.54mmol)。将混合物在25℃搅拌16小时。通过硅藻土过滤混合物并将滤饼用DCM(20mL x 2)洗脱。将滤液减压浓缩,给出粗产物。通过硅胶快速色谱(MeOH,在=0%至4%至8%DCM中)然后通过制备型HPLC[Phenomenex Gemini-NX 80x30mm x 3mm,A=H2O(10mM NH4HCO3)并且B=CH3CN;经8分钟47%-77%]纯化粗产物,得到产物(12.11mg,30.3mmol,9%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.53(s,1H),8.75(s,1H),8.16(d,1H),7.15(d,1H),3.97(s,3H),2.39(s,3H)。在2.0min的色谱中,LCMSRt=1.35min,10-80AB,MS ESI计算值C15H11F6N4O2[M+H]+393.1,实测值393.0。
实施例43:合成化合物43–3-[二氟(甲氧基)甲基]-6-[2-氟-6-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
A112:4-溴-3-氟-5-甲基-苯酚
在25℃在搅拌下向在DCM(1.8L)和甲醇(1.2L)中的3-氟-5-甲基-苯酚(30.0g,237.85mmol)溶液滴加四丁基三溴化铵(114.69g,237.85mmol)。将混合物在25℃搅拌2小时。将混合物浓缩。加入水(500ml),并且用DCM(500mL x 3)萃取水层。将合并的有机层用盐水(1L)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至15%)纯化粗产物,得到产物(25.0g,121.94mmol),呈油状物。1H NMR(400MHz,CDCl3)δH 6.56-6.49(m,2H),2.37(s,1H)
A113:(4-溴-3-氟-5-甲基-苯氧基)-叔丁基-二甲基-硅烷
向在DCM(100mL)中的4-溴-3-氟-5-甲基-苯酚(8.0g,39.02mmol)溶液添加叔丁基-氯-二甲基-硅烷(8.82g,58.53mmol)和咪唑(5.3g,78.04mmol)。将混合物在25℃搅拌3小时。在冷却至25℃之后,将水(200mL)加入到混合物中,并将水层用EtOAc(100mL x 3)萃取。将合并的有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(石油醚)纯化粗产物,得到产物(10.0g,31.32mmol,80%产率),呈油状物。1H NMR(400MHz,CDCl3)δH 6.55(s,1H),6.48(dd,1H),2.37(s,3H),0.98(s,9H),0.22(s,6H)。
A114:叔丁基-[3-氟-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯氧基]-二甲基-硅烷
向在1,4-二噁烷(50mL)中的(4-溴-3-氟-5-甲基-苯氧基)-叔丁基-二甲基-硅烷(5.0g,15.66mmol)的混合物添加4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(4.8g,18.79mmol)和KOAc(3.07g,31.32mmol)。然后将Pd2(dba)3(1.43g,1.57mmol)和XPhos(1.49g,3.13mmol)添加到混合物中。将混合物在100℃在N2下搅拌12小时。在冷却至室温之后,通过硅藻土过滤混合物。将滤液减压浓缩,去除1,4-二噁烷。加入水(50mL),并且用EtOAc(100mL x 3)萃取水层。将合并的有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至20%)纯化粗产物,得到产物(4.0g,8.73mmol),呈油状物。1H NMR(400MHz,CDCl3)δH6.45(s,1H),6.33(dd,1H),2.41(s,3H),1.37(s,12H),0.97(s,9H),0.19(s,6H)。
A115:叔丁基-[4-(5-氯吡嗪-2-基)-3-氟-5-甲基-苯氧基]-二甲基-硅烷
将在1,4-二噁烷(40mL)和水(4mL)中的2-溴-5-氯-吡嗪(1.86g,9.61mmol)、叔丁基-[3-氟-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯氧基]-二甲基-硅烷(4g,8.73mmol)、Cs2CO3(5.69g,17.47mmol)和Pd(dppf)Cl2(639mg,0.87mmol)的混合物在55℃在N2下搅拌4小时。在冷却至25℃之后,添加水(50mL)。将水层用EtOAc(30mL x 2)萃取。将合并的有机层用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到残余物。在硅胶上通过快速色谱(EtOAc在石油醚中=0~5%)纯化残余物,得到产物(2g,5.67mmol,65%产率),呈油状物。1H NMR(400MHz,CDCl3)δH8.70(s 1H),8.44(s,1H),6.61(s,1H),6.52(d,1H),2.22(s,3H),1.00(s,9H),0.25(s,6H)。在1.5min的色谱中,LCMS Rt=1.13min,5-95AB,MS ESI计算值C17H23ClFN2OSi[M+H]+353.1,实测值353.3。
A116:4-(5-氯吡嗪-2-基)-3-氟-5-甲基-苯酚
在25℃向在甲醇(30mL)中的叔丁基-[4-(5-氯吡嗪-2-基)-3-氟-5-甲基-苯氧基]-二甲基-硅烷(2g,5.67mmol)溶液添加NH4HF2(1.62g,28.34mmol)。将混合物在60℃搅拌12小时。在冷却至RT之后,将混合物浓缩,并在硅胶上通过快速色谱(EtOAc在石油醚中=0%至30%)纯化,得到产物(900mg,3.77mmol,66%产率),呈固体。1H NMR(400MHz,CDCl3)δH8.70(s,1H),8.44(s,1H),6.59(s,1H),6.53(d,1H),5.62(brs,1H),2.22(s,3H)。在1.5min的色谱中,LCMS Rt=0.80min,5-95AB,MS ESI计算值C11H9ClFN2O[M+H]+239.0,实测值238.9。
A117:2-(4-苄氧基-2-氟-6-甲基-苯基)-5-氯-吡嗪
向在MeCN(10mL)中的4-(5-氯吡嗪-2-基)-3-氟-5-甲基-苯酚(900mg,3.77mmol)溶液添加K2CO3(729.55mg,5.28mmol)。然后将溴甲基苯(644.99mg,3.77mmol)滴加到混合物中。将混合物在25℃在N2下搅拌16小时。将混合物过滤,将滤液减压浓缩,给出粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至15%)纯化粗产物,得到产物(1g,3.04mmol,80%产率),呈固体。1H NMR(400MHz,CDCl3)δH 8.70(s,1H),8.44(s,1H),7.47-7.32(m,5H),6.76(s,1H),6.66(d,1H),5.10(s,2H),2.25(s,3H)。在1.5min的色谱中,LCMS Rt=1.01min,5-95AB,MS ESI计算值C18H15ClFN2O[M+H]+329.1,实测值328.9。
A118:[5-(4-苄氧基-2-氟-6-甲基-苯基)吡嗪-2-基]肼
在25℃向在MeCN(10mL)中的2-(4-苄氧基-2-氟-6-甲基-苯基)-5-氯-吡嗪(1g,3.04mmol)溶液添加N2H4·H2O(1.52g,30.42mmol)。将混合物在100℃搅拌16小时。在冷却至25℃之后,向混合物中添加水(20mL)。在层分离之后,将水层用EtOAc(20mL x 2)萃取。将合并的有机层用盐水(40mL)洗涤,经无水Na2SO4干燥,过滤,浓缩,得到产物(980mg,3.02mmol),呈固体。1H NMR(400MHz,DMSO-d6)δH8.19(s,1H),8.06(s,1H),7.95(s,1H),7.49-7.30(m,5H),6.87-6.77(m,2H),5.14(s,2H),4.31(brs,2H),2.14(s,3H)。在1.5min的色谱中,LCMS Rt=0.77min,5-95AB,MS ESI计算值C18H18FN4O[M+H]+325.1,实测值325.3。
A119:N'-[5-(4-苄氧基-2-氟-6-甲基-苯基)吡嗪-2-基]-2-溴-2,2-二氟-乙酰肼
向在THF(2mL)中的2-溴-2,2-二氟-乙酸(205mg,1.17mmol)溶液添加一滴DMF和(COCl)2(0.12mL,1.41mmol)。将生成的混合物在25℃搅拌30分钟。将[5-(4-苄氧基-2-氟-6-甲基-苯基)吡嗪-2-基]肼(250mg,0.77mmol)添加到混合物中。将混合物在25℃搅拌18小时。加入水(20mL),并且用EtOAc(20mL x 2)萃取水层。将合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至40%至100%)纯化粗产物,得到产物(270mg,0.56mmol,72%产率),呈固体。1HNMR(400MHz,DMSO-d6)δH 11.35(br s,1H),9.46(s,1H),8.15(s,2H),7.49-7.31(m,5H),6.89-6.81(m,2H),5.16(s,2H),2.15(s,3H)。在1.5min的色谱中,LCMSRt=1.01min,5-95AB,MSESI计算值C20H17BrF3N4O2[M+H]+481.0,实测值482.8。
A120:6-(4-苄氧基-2-氟-6-甲基-苯基)-3-[溴(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
向在甲苯(5mL)中的N'-[5-(4-苄氧基-2-氟-6-甲基-苯基)吡嗪-2-基]-2-溴-2,2-二氟-乙酰肼(390mg,0.81mmol)溶液添加TsOH(41.86mg,0.24mmol)。将混合物在130℃搅拌12小时。加入水(30ml),并且用EtOAc(30mL x 2)萃取水层。将合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至30%至40%)纯化粗产物,得到产物(210mg,0.45mmol,55%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.58(s,1H),8.21(s,1H),7.51-7.30(m,5H),6.80(s,1H),6.69(dd,1H),5.12(s,2H),2.31(s,3H)。在1.5min的色谱中,LCMS Rt=1.05min,5-95AB,MSESI计算值C20H15BrF3N4O[M+H]+463.0,实测值464.8。
A121:6-(4-苄氧基-2-氟-6-甲基-苯基)-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
在28℃向在甲醇(2mL)中的6-(4-苄氧基-2-氟-6-甲基-苯基)-3-[溴(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(210mg,0.45mmol)溶液添加AgBF4(175.89mg,0.91mmol)和Na2CO3(96.09mg,0.91mmol)。将混合物在70℃搅拌3小时。添加盐水(20mL),通过硅藻土过滤混合物。将滤饼用EtOAc(10mL x 2)洗涤。将滤液分离并且将水层用EtOAc(30mL x 2)萃取。将合并的有机层用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。在硅胶上通过快速色谱(EtOAc在石油醚中=0%至15%%至30%)纯化粗产物,得到产物(130mg,0.31mmol,69%产率),呈固体。将产物(50mg,0.12mmol)真空干燥,得到产物(43.8mg,105.7μmol,87%产率),呈固体。1H NMR(400MHz,CDCl3)δH 9.52(s,1H),8.21(s,1H),7.50-7.34(m,5H),6.79(s,1H),6.68(dd,1H),5.12(s,2H),3.93(s,3H),2.28(s,3H)。在2.0min的色谱中,LCMS Rt=1.21min,10-80AB,MS ESI计算值C21H18F3N4O2[M+H]+415.1,实测值415.2。
A122:4-[3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪-6-基]-3-氟-5-甲基-苯酚
将在HBr/HOAc(1mL,33%,在HOAc中)中的6-(4-苄氧基-2-氟-6-甲基-苯基)-3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(80mg,0.19mmol)的混合物在25℃搅拌2小时。加入水(10mL),并且用EtOAc(15mL x 3)萃取混合物。将合并的有机相用饱和水性NaHCO3(20mL x 1)和盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。通过硅胶快速色谱(EtOAc在石油醚中=0%至20%至50%)和制备型HPLC[YMC Triart C18(150x25mm x 5μm)A=H2O(10mM NH4HCO3)并且B=CH3CN;经9.5分钟36%到66%B]纯化粗产物,得到产物(6.71mg,20.7μmol,10%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.52(d,1H),8.21(s,1H),6.65(s,1H),6.58-6.57(m,1H),5.80(s,1H),3.93(s,3H),2.26(s,3H)。在2.0min的色谱中,LCMSRt=1.20min,10-80AB,MS ESI计算值C14H11F3N4O2[M+H]+325.1,实测值325.1。
化合物43:3-[二氟(甲氧基)甲基]-6-[2-氟-6-甲基-4-(三氟甲氧基)苯基]-[1,2,4]三唑并[4,3-a]吡嗪
将AgOTf(435.81mg,1.7mmol)放入三颈瓶中,在200℃(热风枪)真空干燥20分钟。然后在手套箱中添加4-[3-[二氟(甲氧基)甲基]-[1,2,4]三唑并[4,3-a]吡嗪-6-基]-3-氟-5-甲基-苯酚(110mg,0.34mmol)、select F(600.89mg,1.7mmol)、CsF(309.18mg,2.04mmol)随后添加甲苯(3mL)、2-氟吡啶(164.7mg,1.7mmol)和TMSCF3(241.18mg,1.7mmol),得到混合物。将混合物在28℃搅拌16小时。通过硅藻土过滤混合物并将滤饼用DCM(20mL x 2)洗脱。将滤液减压浓缩,给出粗产物。通过硅胶快速色谱(MeOH,在=0%至10%DCM中)和制备型HPLC[Phenomenex Gemini-NX8 80x30mm x 3μm,A=H2O(10mMNH4HCO3)并且B=CH3CN;经9.5分钟40%-70%]纯化粗产物,得到产物(8.85mg,22.4μmol,6%产率),呈固体。1H NMR(400MHz,CDCl3)δH9.54(s,1H),8.26(s,1H),7.05(s,1H),6.98(d,1H),3.94(s,3H),2.34(s,3H)。在2.0min的色谱中,LCMSRt=1.17min,10-80AB,MS ESI计算值C15H11F6N4O2[M+H]+393.1,实测值393.0。
实施例44:合成A12-6-氯-3-(甲氧基甲基)-[1,2,4]三唑并[4,3-b]哒嗪
在25℃向在甲苯(80mL)中的(6-氯吡嗪-3-基)肼(3g,20.75mmol)溶液滴加2-甲氧基乙酰氯(2.48g,22.83mmol)。将溶液在25℃搅拌30min,并且在120℃回流24小时。在冷却至室温之后,用H2O(40mL)稀释混合物并用EtOAc(40mL x 2)萃取。将合并的有机相用盐水(40mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物。将粗产物用i-Pr2O(10mL)研磨,得到产物(1500mg,7.31mmol,35%产率),呈固体。在1.5min的色谱中,LCMSRt=0.43min,5-95AB,MS ESI计算值C7H8ClN4O[M+H]+198.0,实测值199.0。
实施例45:合成A32-6-氯-3-(氯二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪
A123:2-氯-N'-(5-氯吡嗪-2-基)-2,2-二氟乙酰肼
在0℃向在甲苯(50mL)中的2-氯-5-肼基吡嗪(5.0g,33.99mmol)的搅拌溶液添加氯二氟乙酸酐(6.54mL,37.39mmol)。将反应混合物在110℃加热1小时。将反应混合物冷却至室温并浓缩,得到残余物。将残余物用水(50mL)处理,并且用乙酸乙酯(2x50mL)萃取。将有机层用盐水(30mL)洗涤,经Na2SO4干燥,并浓缩成固体(6g)。将其直接用于下一个步骤而无需进一步纯化。
A32:6-氯-3-(氯二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪
在0℃向在DCM(120mL)中的2-氯-N'-(5-氯吡嗪-2-基)-2,2-二氟乙酰肼(6.0mg,23.34mmol)的搅拌溶液添加三氟甲磺酸酐(4.73mL,28.01mmol)和2-甲氧基吡啶(4.91mL,46.69mmol)。将反应混合物缓慢加温至室温并搅拌2小时。将反应混合物用10%碳酸氢钠溶液(50mL)处理,并用乙酸乙酯(2x50mL)萃取。将有机层用盐水(50mL)洗涤,经Na2SO4干燥并浓缩,得到粗产物。在硅胶上通过柱色谱用15%EtOAc/PE纯化粗产物,得到产物(4.0g,16.5mmol,71%产率),呈固体。LCMS:239.0(M+H),Rt 1.66min柱:ZORBAX XDB C-18(50X4.6mm),3.5μm流动相:A:0.1%HCOOH,在水:ACN(95:5)中,B:ACN;流速:1.5mL/min。
实施例46:示例性化合物在调节晚期钠电流(INaL)中的效果
使用PatchXpressTM高通量电生理平台(Molecular Devices,Sunnyvale,CA)完成了示例性化合物调节由NaV1.6电压门控钠通道表现的INaL的功能表征。使表达重组人NaV1.6(hNaV1.6)的HEK-293细胞在DMEM/高葡萄糖Dulbecco改良的含有10%FBS、2mM丙酮酸钠、10mM HEPES和400μg/mL G418的培养基中生长。使细胞生长至50%-80%汇合,然后收获细胞。将胰蛋白酶消化的细胞洗涤,使其恢复1小时,然后以1x106/个细胞/ml的浓度重悬于细胞外记录溶液中。使用PatchXpress的机载液体处理设施(onboard liquid handlingfacility)来分配细胞和施加测试化合物。通过应用300nM ATX-II诱发NaV晚期电流。通过以0.1Hz的频率使脉冲从非失活保持电位(例如-120mV)去极化到0mV持续200ms来诱发INaL。通过分析测试脉冲的最后20ms的平均电流幅值来确定INaL幅值和稳定性。在用示例性化合物(例如,如本文所述)进行稳态阻滞之后,添加含有不渗透阳离子(例如,胆碱或NDMG)的无Na+溶液,以证实钠电流的标识。INaL的稳态抑制百分比计算如下:[(INaL_化合物)/(INaL_对照)]*100,其中INaL_化合物和INaL_对照分别代表在化合物存在或不存在时记录的INaL。
下表1总结了与hNaV1.6对INaL的抑制百分比有关的测定结果(使用与上述相似的方法测量,但使用表达1μM的重组人NaV 1.6(hNaV 1.6)的HEK-293细胞)。在这个表中,“A”指示小于30%的抑制;“B”指示在约30%至约70%之间的抑制;并且“C”指示大于70%的抑制。
表1
虽然我们已经描述了许多实施方案,但是显然可以改变我们的基本实施例,以提供利用本发明的化合物和方法的其他实施方案。因此,将理解的是,将由所附权利要求书而不是由示例性表示的特定实施方案来限定本发明的范围。
特此明确地将贯穿本申请的引用的所有参考文献(包括文献参考、发布的专利、公布的专利申请以及共同未决的专利申请)的内容通过引用以其整体并入本文。除非另有定义,否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解一致的含义。
Claims (49)
1.一种具有式I的化合物:
或其药学上可接受的盐;其中
X和Y各自独立地是CRd或N;
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R5是卤基、任选地被O-C1-4烷基或O-C3-6环烷基取代的C3-6环烷基或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
t是1或2;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基;并且
Rd是氢或C1-4烷基。
2.一种具有式II的化合物:
或其药学上可接受的盐;其中
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R5是卤基、任选地被O-C1-4烷基或O-C3-6环烷基取代的C3-6环烷基或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
t是1或2;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;并且
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基。
3.一种具有式III的化合物:
或其药学上可接受的盐;其中
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R5是卤基、任选地被O-C1-4烷基或O-C3-6环烷基取代的C3-6环烷基或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
t是1或2;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;并且
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基。
4.一种具有式IV的化合物:
或其药学上可接受的盐;其中
X和Y各自独立地是CRd或N;
R2是氢、任选地被一个或多个Rb取代的C1-4卤代烷基或单环C3-6环烷基;
R3是氢、C1-4烷基或C1-4卤代烷基;
R4是氢或C1-4烷基;
R6是C1-4烷基或C1-4卤代烷基,其中所述C1-4烷基或C1-4卤代烷基各自被ORc取代;
Ra和Rb各自独立地选自卤基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;
Rc是任选地被C3-6环烷基或苯基取代的C1-4烷基,或C3-6环烷基;并且
Rd是氢或C1-4烷基;
5.如权利要求1或4所述的化合物,其中X是N并且Y是CRd。
6.如权利要求1或4所述的化合物,其中X是CRd并且Y是N。
8.如权利要求1-6中任一项所述的化合物,其中R1是任选地被一个或多个Ra取代的环丁基。
9.如权利要求1-6中任一项所述的化合物,其中R1是CF3。
10.如权利要求1-7中任一项所述的化合物,其中R2是C1-4卤代烷基。
11.如权利要求1-7和10中任一项所述的化合物,其中R2是CF3。
12.如权利要求1-7和10中任一项所述的化合物,其中R2是氢。
13.如权利要求1-7和10-12中任一项所述的化合物,其中R3是C1-4烷基并且R4是氢或C1-4烷基。
14.如权利要求1-7和10-12中任一项所述的化合物,其中R3和R4各自是C1-4烷基。
15.如权利要求1-7和10-14中任一项所述的化合物,其中R3和R4各自是甲基。
16.如权利要求1-7和10-13中任一项所述的化合物,其中R3是甲基并且R4是氢。
17.如权利要求1-7、10和11中任一项所述的化合物,其中R3和R4各自是氢。
18.如权利要求1-17中任一项所述的化合物,其中R6是CF2-ORc。
19.如权利要求1-18中任一项所述的化合物,其中Rc是任选地被环丙基取代的C1-4烷基。
20.如权利要求1-18中任一项所述的化合物,其中Rc是环丙基。
21.如权利要求1-19中任一项所述的化合物,其中R6是CF2OCH3、CF2OCH2CH3、CF2OCH(CH3)2或CF2OCH2C3H5。
22.如权利要求1-17中任一项所述的化合物,其中R6是CH2-ORc。
23.如权利要求1-17和22中任一项所述的化合物,其中Rc是任选地被环丙基或苯基取代的C1-4烷基。
24.如权利要求1-17和22中任一项所述的化合物,其中Rc是环丙基。
25.如权利要求1-17和22-23中任一项所述的化合物,其中R6是CH2OCH3、CH2OCH2CH3、CH2OCH2C3H5、CH2OCH2CH(CH3)2或CH2OCH2C6H5。
26.如权利要求1-17中任一项所述的化合物,其中R6是C(CH3)2-ORc。
27.如权利要求1-17和26中任一项所述的化合物,其中Rc是C1-4烷基。
28.如权利要求1-17和26-27中任一项所述的化合物,其中R6是C(CH3)2-OCH2CH3。
29.如权利要求1-6、8和18-28中任一项所述的化合物,其中Ra是氟。
30.如权利要求1-3和5-29中任一项所述的化合物,其中t是1。
31.如权利要求1-3和5-29中任一项所述的化合物,其中t是2。
32.如权利要求1-3和5-31中任一项所述的化合物,其中R5是卤代或任选地被OCH3或OC3H5取代的C1-4烷基。
33.如权利要求1-3和5-32中任一项所述的化合物,其中R5是氟。
34.如权利要求1-3和5-32中任一项所述的化合物,其中R5是甲基。
35.如权利要求1-3和5-31中任一项所述的化合物,其中R5是氟、CH3、CH2CH3、CH2OCH3、CH(CH3)OCH3或CH2OC3H5。
36.如权利要求1和4-35中任一项所述的化合物,其中Rd是氢。
39.一种药物组合物,其包含如权利要求1-38中任一项所述的化合物或其药学上可接受的盐;和药学上可接受的载体。
40.一种治疗在有需要的受试者中的与钠离子通道功能异常有关的病症的方法,所述方法包括向受试者施用治疗有效量的如权利要求1-38中任一项所述的化合物或其药学上可接受的盐或如权利要求39所述的药物组合物。
41.如权利要求40所述的方法,其中所述病症是神经系统或精神疾患。
42.如权利要求40或要41所述的方法,其中所述病症是癫痫或癫痫综合征。
43.如权利要求40-42中任一项所述的方法,其中所述病症是遗传性癫痫或遗传性癫痫综合征。
44.如权利要求40-42中任一项所述的方法,其中所述病症是小儿癫痫或小儿癫痫综合征。
45.如权利要求40-42中任一项所述的方法,其中所述病症是癫痫性脑病。
46.如权利要求45所述的方法,其中所述癫痫性脑病选自由以下组成的组:Dravet综合征、婴儿痉挛或Lennox-Gastaut综合征。
47.如权利要求40或41所述的方法,其中所述病症选自由以下组成的组:癫痫性脑病,伴SCN1A、SCN2A、SCN8A突变的癫痫性脑病,早期婴儿型癫痫性脑病,Dravet综合征,伴SCN1A突变的Dravet综合征,全身性癫痫伴热性惊厥,顽固性儿童癫痫伴全身性强直阵挛发作,婴儿痉挛,良性家族性新生儿-婴儿惊厥,SCN2A癫痫性脑病,伴SCN3A突变的局灶性癫痫,伴SCN3A突变的隐源性小儿部分性癫痫,SCN8A癫痫性脑病,癫痫猝死,Rasmussen脑炎,婴儿恶性游走性部分性癫痫发作,常染色体显性夜发性额叶癫痫,癫痫猝死(SUDEP),KCNQ2癫痫性脑病和KCNT1癫痫性脑病。
48.一种治疗神经系统疾患或精神疾患的方法,其中所述方法包括向有需要的受试者施用如权利要求1-38中任一项所述的化合物或其药学上可接受的盐或如权利要求39所述的药物组合物。
49.一种治疗疼痛的方法,其中所述方法包括向有需要的受试者施用如权利要求1-38中任一项所述的化合物或其药学上可接受的盐或如权利要求39所述的药物组合物。
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---|---|---|---|---|
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