CN1628109A - Novel aryl- and heteroarylpiperazines - Google Patents

Novel aryl- and heteroarylpiperazines Download PDF

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CN1628109A
CN1628109A CNA038033607A CN03803360A CN1628109A CN 1628109 A CN1628109 A CN 1628109A CN A038033607 A CNA038033607 A CN A038033607A CN 03803360 A CN03803360 A CN 03803360A CN 1628109 A CN1628109 A CN 1628109A
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R·霍尔威格
F·Z·多沃德
H·斯蒂芬森
I·彼得森
B·佩施克
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诺沃挪第克公司
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Abstract

新颖的芳基-与杂芳基-哌嗪、这些化合物作为药物组合物的用途、包含这些化合物的药物组合物和采用这些化合物与组合物的治疗方法。 Novel aryl - aryl and heteroaryl groups - piperazine, the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising these compounds, and methods of treating using such compounds and compositions. 这些化合物对组胺H3受体显示高的选择性结合亲和性,表明具有组胺H3受体拮抗、反激动或激动活性。 These compounds are highly selective histamine H3 receptor binding affinity, indicating histamine H3 receptor antagonistic having, agonistic or inverse agonistic activity displayed. 其结果是,这些化合物可用于治疗涉及组胺H3受体的疾病和障碍。 As a result, these compounds are useful for treating diseases and disorders involving histamine H3 receptor.

Description

新颖的芳基-与杂芳基-哌嗪 Novel aryl - aryl and heteroaryl groups - piperazine

发明领域本发明涉及新颖的芳基-与杂芳基哌嗪、涉及这些化合物作为药物组合物的用途,涉及包含这些化合物的药物组合物,还涉及采用这些化合物和组合物的治疗方法。 Field of the Invention The present invention relates to novel aryl - aryl and heteroaryl piperazine, relates to pharmaceutical compositions containing these compounds as pharmaceutical compositions comprising these compounds, and methods of treatment employing these compounds and compositions. 本发明化合物对组胺H3受体显示高的选择性结合亲和性,表明具有组胺H3受体拮抗、反激动或激动活性。 Compounds of the invention high selectivities histamine H3 receptor binding affinity, indicating histamine H3 receptor antagonistic having, agonistic or inverse agonistic activity displayed. 其结果是,这些化合物可用于治疗涉及组胺H3受体的疾病和障碍。 As a result, these compounds are useful for treating diseases and disorders involving histamine H3 receptor.

发明背景若干年前早已知道组胺H3受体的存在,该受体是目前新药物开发的兴趣所在。 Background of the Invention Several years ago, has long been aware of the existence of the histamine H3 receptor, the receptor is interested in the development of new drugs currently resides. 最近,人类组胺H3受体已被克隆。 Recently, the human histamine H3 receptor has been cloned. 组胺H3受体是一种突触前自身受体,位于中枢与外周神经系统、皮肤和器官中,例如肺、肠,主要是脾和胃肠道。 Histamine H3 receptor is a former synaptic autoreceptors, located in the central and peripheral nervous system, the skin and organs such as the lung, intestine, spleen, and the gastrointestinal tract mainly. 最近有证据提示,H3受体显示内在的组成型活性,体外以及体内均是如此(也就是说,在没有激动剂的存在下也是有活性的)。 Recent evidence suggests, H3 receptor show intrinsic constitutive activity, in vitro and in vivo is true (that is, in the absence of agonist is active). 充当反激动剂的化合物能够抑制这种活性。 A compound capable of acting as inverse agonists inhibit this activity. 组胺H3受体已被证明调节组胺以及其他神经递质的释放,例如血清素和乙酰胆碱。 Histamine H3 receptor has been shown to regulate the release of histamine and other neurotransmitters, such as serotonin and acetylcholine. 组胺H3受体拮抗剂或反激动剂因此将被预期增加这些神经递质在脑中的释放。 Histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of neurotransmitters in the brain. 相反,组胺H3受体激动剂引起组胺生物合成的抑制和组胺以及其他神经递质释放的抑制,例如血清素和乙酰胆碱。 In contrast, the histamine H3 receptor agonists cause inhibition of histamine and histamine biosynthesis and inhibition of release of other neurotransmitters, such as serotonin and acetylcholine. 这些发现提示了组胺H3受体激动剂、反激动剂和拮抗剂可能是神经元活动的重要介质。 These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists could be important mediators of neuronal activity. 因此,组胺H3受体是新治疗剂的重要目标。 Accordingly, the histamine H3 receptor is an important target for new therapeutic agents.

以前已经公开过与本发明化合物相似的化合物,参见J.Med.Chem.1999,42,336,J.Med.Chem.1992,35,2369,DE 2804096,J.Org.Chem.1996,61,3849,Bull.Soc.Chim.Fr.1969,319,WO 00/66578,WO 99/21845和J.Med.Chem.1968,11(6),1144-1150。 Have been disclosed previously a compound of the present invention with similar compounds, see J.Med.Chem.1999,42,336, J.Med.Chem.1992,35,2369, DE 2804096, J.Org.Chem.1996,61, 3849, Bull.Soc.Chim.Fr.1969,319, WO 00/66578, WO 99/21845 and J.Med.Chem.1968,11 (6), 1144-1150. 不过,这些参考文献既没有公开、也没有提示这些化合物可能具有组胺H3受体拮抗或激动活性。 However, these references neither disclose nor suggest that these compounds may have a histamine H3 receptor antagonistic or agonistic activity.

若干出版物公开了组胺H3激动剂和拮抗剂的制备和用途。 Several publications disclose the preparation and use of histamine H3 agonists and antagonists. 它们大多数是咪唑衍生物。 Most of these are imidazole derivatives. 不过,最近已经描述过一些组胺H3受体的无咪唑配体(例如参见Linney et al.,J.Med.Chem.2000,43,2362-2370;US 6,316,475,WO 01/66534和WO 01/74810)。 However, some of the non-imidazole histamine H3 receptor ligands (see e.g. Linney et al, J.Med.Chem.2000,43,2362-2370 recently been described; US 6,316,475, WO 01/66534 and WO 01 / 74810). 不过,这些化合物在结构上不同于本发明化合物。 However, these compounds differ from the compounds of the present invention in structure.

鉴于本领域对组胺H3受体激动剂、反激动剂和拮抗剂的兴趣,与组胺H3受体相互作用的新颖化合物将对本领域作出非常可取的贡献。 In view of the art of the histamine H3 receptor agonists, inverse agonists and antagonists of interest, with the histamine H3 receptor interaction will make the novel compounds of this highly desirable contribution to the art. 本发明基于下列发现而为本领域提供这样一种贡献,即一类新颖的芳基-与杂芳基-哌嗪对组胺H3受体具有高的特异性亲和性。 And the present invention provides such a contribution to the art based on the finding that a novel class of aryl - aryl and heteroaryl groups - piperazine having high specific affinity to the histamine H3 receptor.

由于它们与组胺H3受体的相互作用,本发明化合物可用于治疗广泛的病症和障碍,其中与组胺H3受体的相互作用是有益的。 Due to their interaction with the histamine H3 receptor, the compounds of the present invention may be used to treat a wide range of conditions and disorders, which interact with the histamine H3 receptor is beneficial. 因而,这些化合物例如可以用于治疗中枢神经系统、外周神经系统、心血管系统、肺系统、胃肠系统和内分泌系统的疾病。 Thus, these compounds may be used, for example, treating central nervous system, peripheral nervous system disorders, cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrine system.

定义在这里和本说明书全文所给出的结构式中,下列术语具有所示含义。 In the structural formulas defined herein and throughout this specification are given, the following terms have the meanings indicated.

术语“卤素”表示F、Cl、Br或I。 The term "halogen" means F, Cl, Br or I.

本文所用的术语“烷基”代表饱和的直链或支链烃基,具有所示数量的碳原子。 As used herein, the term "alkyl" represents a saturated straight or branched chain hydrocarbon radical, having the number of carbon atoms. 因而,本文所用的术语“C1-3-烷基”、“C1-8-烷基”和“C1-10-烷基”代表饱和直链或支链烃基,分别具有1至3个碳原子、1至8个碳原子和1至10个碳原子。 Thus, as used herein, the term "C 1-3 alkyl", "C1-8- alkyl" and "C1-10- alkyl" represents a straight-chain or branched-chain saturated hydrocarbon group, each having 1 to 3 carbon atoms, from 1 to 8 carbon atoms and 1 to 10 carbon atoms. 典型的烷基包括但不限于甲基、乙基、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基等。 Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

本文所用的术语“烯基”代表直链或支链烃基,具有所示数量的碳原子和至少一条双键。 As used herein, the term "alkenyl" represents a straight-chain or branched hydrocarbon group having the number of carbon atoms and at least one double bond. 因而,本文所用的术语“C2-8-烯基”和“C2-10-烯基”代表直链或支链烃基,分别具有2至8个碳原子和2至10个碳原子以及至少一条双键。 Thus, as used herein, the term "C2-8- alkenyl" and "C2-10- alkenyl" represents a straight-chain or branched hydrocarbon group, each having 2 to 8 carbon atoms and from 2 to 10 carbon atoms and at least one pair of key. 这类基团的实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、烯丙基、异丙烯基、1,3-丁二烯基、1-丁烯基、2-丁烯基、1-戊烯基、2-戊烯基、1-己烯基、2-己烯基、1-庚烯基、2-庚烯基、1-辛烯基、2-辛烯基、2-壬烯基、2-癸烯基等。 Examples of such groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, allyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl group, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 2- nonenyl, 2-decenyl and the like.

本文所用的术语“炔基”代表直链或支链烃基,具有所示数量的碳原子和至少一条叁键。 As used herein, the term "alkynyl" represents a straight-chain or branched hydrocarbon group having the number of carbon atoms and at least one triple bond. 因而,本文所用的术语“C2-8-烷基”代表直链或支链烃基,具有2至8个碳原子和至少一条叁键。 Thus, as used herein, the term "C2-8- alkyl" represents a straight-chain or branched hydrocarbon group having from 2 to 8 carbon atoms and at least one triple bond. 这类基团的实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基、2-庚炔基、1-辛炔基、2-辛炔基等。 Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1 - hexynyl, 2-hexynyl, 2-heptynyl, 1-octynyl, 2-octynyl and the like.

本文所用的术语“支链C4-6-烷基”代表饱和的支链烃基,具有4至6个碳原子。 As used herein, the term "branched C4-6- alkyl" represents a saturated branched hydrocarbon group having 4-6 carbon atoms. 典型的支链C4-8-烷基包括但不限于1-甲基丙基、叔丁基、1-乙基丙基、1,1-(二甲基)丙基、异戊基、1-乙基丁基、1,1-(二甲基)丁基、1,1-(二甲基)戊基、1-乙基戊基、1,1-(二甲基)己基、1-乙基己基等。 Typical branched alkyl groups include, but are not limited to, C4-8- 1-methylpropyl, tert-butyl, 1-ethylpropyl, 1,1- (dimethyl) propyl, isopentyl, 1- ethylbutyl, 1,1- (dimethyl) butyl, 1,1- (dimethyl) pentyl, 1-ethyl-pentyl, 1,1- (dimethyl) hexyl, 1-ethyl hexyl and the like.

本文所用的术语“支链C4-6-烯基”代表支链烃基,具有4至6个碳原子和至少一条双键。 As used herein, the term "branched C4-6- alkenyl" represents a branched hydrocarbon group having 4-6 carbon atoms and at least one double bond. 典型的支链C4-6-烯基包括但不限于1-乙基丙-2-烯基、1,1-(二甲基)丙-2-烯基、1-乙基丁-3-烯基、1,1-(二甲基)丁-2-烯基、1,1-(二甲基)戊-3-烯基、1-乙基戊-2-烯基、1,1-(二甲基)戊-3-烯基、1,1-(二甲基)己-3-烯基、1-乙基己-4-烯基等。 Typical branched C4-6- alkenyl groups include, but are not limited to 1-ethyl-2-enyl, 1,1- (dimethyl) prop-2-enyl, 1-ethyl-3-ene group, 1,1- (dimethyl) but-2-enyl, 1,1- (dimethyl) pent-3-enyl, pent-1-ethyl-2-enyl, 1,1- ( dimethyl) pent-3-enyl, 1,1- (dimethyl) hexyl-3-enyl, 1-ethyl-4-ene-yl and the like.

本文所用的术语“支链C4-6-炔基”代表支链烃基,具有4至6个碳原子和至少一条叁键。 As used herein, the term "branched C4-6- alkynyl" represents a branched hydrocarbon group having 4-6 carbon atoms and at least one triple bond. 典型的支链C4-6-炔基包括但不限于1-乙基丙-2-炔基、1,1-(二甲基)丙-2-炔基、1-乙基丁-3-炔基、1,1-(二甲基)丁-2-炔基、1,1-(二甲基)戊-3-炔基、1-乙基戊-2-炔基、1,1-(二甲基)戊-3-炔基、1,1-(二甲基)己-3-炔基、1-乙基己-4-炔基等。 Typical branched C4-6- alkynyl groups include, but are not limited to 1-ethyl-prop-2-ynyl, 1,1- (dimethyl) prop-2-ynyl, 1-ethyl-3-yn group, 1,1- (dimethyl) but-2-ynyl, 1,1- (dimethyl) pent-3-ynyl, pent-1-ethyl-2-ynyl, 1,1- ( dimethyl) pent-3-ynyl, 1,1- (dimethyl) hex-3-butynyl, 1-ethyl-hexyl-4-ynyl and the like.

本文所用的术语“C1-6-烷氧基”表示原子团-O-C1-6-烷基,其中C1-6-烷基是如上所定义的。 As used herein, the term "C1-6-alkoxy" represents a radical -O-C1-6- alkyl, wherein C1-6-alkyl is as defined above. 代表性实例有甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、仲丁氧基、叔丁氧基、戊氧基、异戊氧基、己氧基、异己氧基等。 Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, iso-pentyloxy, hexyloxy, isohexyloxy group.

本文所用的术语“C2-10-烷酰基”表示原子团-C(=O)C1-9-烷基,其中C1-9-烷基代表饱和的直链或支链烃基,具有1至9个碳原子。 As used herein, the term "C2-10- alkyl group" means the radical -C (= O) C1-9- alkyl, C1-9- alkyl group wherein Representative saturated straight or branched hydrocarbon group having 1 to 9 carbon atom. 代表性实例有乙酰基、丙酰基、丁酰基、戊酰基、己酰基、庚酰基、辛酰基、壬酰基、癸酰基等。 Representative examples are acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl and the like.

本文所用的术语“C1-6-烷基氨基”表示原子团-NH-C1-6-烷基,其中C1-6-烷基是如上所定义的。 As used herein, the term "C1-6-alkylamino" represents a radical -NH-C1-6- alkyl, wherein C1-6-alkyl is as defined above. 代表性实例有甲氨基、乙氨基、异丙氨基、正丙氨基、丁氨基、戊氨基、己氨基等。 Representative examples are methylamino, ethylamino, isopropylamino, n-propylamino, butylamino, pentylamino, hexylamino and the like.

本文所用的术语“二-C1-6-烷基氨基”表示原子团-N(C1-6-烷基)2,其中C1-6-烷基是如上所定义的。 As used herein, the term "di -C1-6- alkylamino" represents a radical -N (C1-6- alkyl) 2, wherein C1-6-alkyl is as defined above. 应当被理解的是,C1-6-烷基可以是相同或不同的。 It should be understood, C1-6- alkyl group may be the same or different. 代表性实例有二甲氨基、甲乙氨基、二乙氨基、二异丙氨基、二正丙氨基、二丁氨基、二戊氨基、二己氨基等。 Representative examples are dimethylamino, methylethylamino, diethylamino, diisopropylamino, di-n-propylamino, dibutylamino, dipentyl-amino, dihexylamino and the like.

本文所用的术语“C3-5-环烷基”代表单环碳环基团,具有3至8个碳原子。 As used herein, the term "C3-5- cycloalkyl" represents a monocyclic carbocyclic group having 3 to 8 carbon atoms. 代表性实例有环丙基、环丁基、环戊基等。 Representative examples are cyclopropyl, cyclobutyl, cyclopentyl and the like.

按照相同的方式,本文所用的术语“C3-6-环烷基”和“C3-8-环烷基”代表单环碳环基团,分别具有3至6个碳原子和3至8个碳原子。 In the same manner, as used herein, the term "C3-6-cycloalkyl" and "C3-8-cycloalkyl" represents a monocyclic carbocyclic group, each having from 3 to 6 carbon atoms and from 3 to 8 carbon atom.

本文所用的术语“C3-7-环烯基”代表单环碳环的非芳族基团,具有3至7个碳原子和至少一条双键。 As used herein, the term "C3_7-cycloalkenyl" represents a monocyclic non-aromatic carbocyclic group, having from 3 to 7 carbon atoms and at least one double bond. 代表性实例有环丙烯基、环丁烯基、环戊烯基等。 Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.

按照相同的方式,本文所用的术语“C3-6-环烯基”代表单环碳环的非芳族基团,具有3至6个碳原子和至少一条双键。 In the same manner, as used herein, the term "C3-6-cycloalkenyl" represents a non-aromatic monocyclic carbocyclic group having 3 to 6 carbon atoms and at least one double bond.

本文所用的术语“C3-6-环烷基-C1-3-烷基”表示原子团-C1-3-烷基-C3-6-环烷基,其中C3-6-环烷基和C1-3-烷基是如上所定义的。 As used herein, the term "C3-6-cycloalkyl -C1-3- alkyl" denotes an alkyl radical -C1-3- -C3-6- cycloalkyl, wherein C1-3 cycloalkyl and C3-6- - alkyl is as defined above.

本文所用的术语“C3-6-环烯基-C1-3-烷基”表示原子团-C1-3-烷基-C3-6-环烯基,其中C3-6-环烯基和C1-3-烷基是如上所定义的。 As used herein, the term "C3-6-cycloalkenyl -C1-3- alkyl" denotes an alkyl radical -C1-3- -C3-6- cycloalkenyl, wherein C3-6-cycloalkenyl and C1-3 - alkyl is as defined above.

本文所用的术语“C3-8-环烷氧基”表示原子团-O-C3-8-环烷基,其中C3-8-环烷基是如上所定义的。 As used herein, the term "C3-8-cycloalkoxy" represents a radical -O-C3-8- cycloalkyl, wherein C3-8-cycloalkyl is as defined above. 代表性实例有环丙氧基、环丁氧基、环戊氧基、环己氧基、环庚氧基、环辛氧基等。 Representative examples are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.

本文所用的术语“C4-9-环烷酰基”表示原子团-C(=O)-C3-8-环烷基,其中C3-8-环烷基是如上所定义的。 As used herein, the term "C4-9- cycloalkyl group" means the radical -C (= O) -C3-8- cycloalkyl, C3-8- cycloalkyl wherein alkyl is as defined above. 代表性实例有环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基、环庚基羰基、环辛基羰基等。 Representative examples are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl group, a carbonyl group cycloheptyl, cyclooctyl group and the like.

本文所用的术语“C1-6-烷基磺酰基”表示原子团-S(=O)2-C1-6-烷基,其中C1-6-烷基是如上所定义的。 As used herein, the term "C1-6-alkylsulfonyl" means the radical -S (= O) 2-C1-6- alkyl, wherein C1-6-alkyl is as defined above. 代表性实例有甲基磺酰基、乙基磺酰基、异丙基磺酰基、正丙基磺酰基、丁基磺酰基、戊基磺酰基等。 Representative examples are methylsulfonyl group, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, butylsulfonyl, pentylsulfonyl and the like.

本文所用的术语“C1-6-烷硫基”表示原子团-S-C1-6-烷基,其中C1-6-烷基是如上所定义的。 As used herein, the term "C1-6-alkylthio" means the radical -S-C1-6- alkyl, wherein C1-6-alkyl is as defined above. 代表性实例有甲硫基、乙硫基、异丙硫基、正丙硫基、丁硫基、戊硫基等。 Representative examples are methylthio, ethylthio, isopropylthio, n-propylthio, butylthio, pentylthio and the like.

本文所用的术语“C3-8-杂环基”表示饱和的3至8元单环,含有一个或多个选自氮、氧和硫的杂原子。 As used herein, the term "C3-8-heterocyclyl" represents a saturated 3 to 8-membered monocyclic ring containing one or more hetero atoms selected from nitrogen, oxygen and sulfur. 代表性实例有吖丙啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、四氢呋喃基等。 Representative examples are aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl and the like.

本文所用的术语“C4-9-杂环烷酰基”表示原子团-C(=O)-C3-8-杂环基,其中C3-8-杂环基是如上所定义的。 As used herein, the term "C4-9- heterocyclyl alkanoyl" means the radical -C (= O) -C3-8- heterocyclyl, wherein C3-8- heterocyclyl group is as defined above. 代表性实例有吖丙啶基羰基、吡咯烷基羰基、哌啶基羰基、吗啉基羰基、哌嗪基羰基、四氢呋喃基羰基等。 Representative examples are aziridinyl carbonyl group, pyrrolidinyl carbonyl, piperidinyl carbonyl, morpholinyl carbonyl group, a piperazinyl carbonyl group, tetrahydrofuranyl group and the like.

本文所用的术语“芳基”打算包括碳环芳族环系,例如苯基、联苯基、萘基、蒽基、菲基、芴基、茚基、并环戊二烯基、薁基等。 As used herein, the term "aryl" is intended to include carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthryl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl and the like . 芳基也打算包括上面列举的碳环系统的部分氢化衍生物。 Aryl groups are intended to include the partially hydrogenated derivatives of the above-enumerated carbon ring system. 这类部分氢化衍生物的非限制性实例有1,2,3,4-四氢萘基、1,4-二氢萘基等。 Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.

本文所用的术语“芳氧基”表示原子团-O-芳基,其中芳基是如上所定义的。 As used herein, the term "aryloxy" means a radical -O- aryl, wherein aryl is as defined above. 非限制性实例有苯氧基、萘氧基、蒽氧基、菲氧基、芴氧基、茚氧基等。 Non-limiting examples are phenoxy, naphthoxy, anthracenyl group, phenanthrene group, fluorenyl group, indenyl group and the like.

本文所用的术语“芳酰基”表示原子团-C(=O)-芳基,其中芳基是如上所定义的。 As used herein, the term "aroyl" means the radical -C (= O) - aryl, wherein aryl is as defined above. 非限制性实例有苯甲酰基、萘甲酰基、蒽基羰基、菲基羰基、芴基羰基、茚基羰基等。 Non-limiting examples are benzoyl, naphthoyl group, a carbonyl group anthryl, phenanthryl a carbonyl group, a carbonyl group a fluorenyl group, indenyl group and the like.

本文所用的术语“芳基氨基”表示原子团-NH-芳基,其中芳基是如上所定义的。 As used herein, the term "aryl group" means a radical -NH- aryl, wherein aryl is as defined above. 非限制性实例有苯基氨基、萘基氨基、蒽基氨基、菲基氨基、芴基氨基、茚基氨基等。 Nonlimiting examples are phenyl group, naphthyl group, anthryl group, phenanthryl group, fluorenyl group, indenyl group and the like.

本文所用的术语“杂芳基”打算包括杂环芳族环系,含有一个或多个选自氮、氧和硫的杂原子,例如呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、异噁唑基、异噻唑基、1,2,3-三唑基、1,2,4-三唑基、吡喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、1,2,3-三嗪基、1,2,4-三嗪基、1,3,5-三嗪基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、四唑基、噻二嗪基、吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噻唑基、苯并异噻唑基、苯并噁唑基、苯并异噁唑基、嘌呤基、喹唑啉基、喹嗪基、喹啉基、异喹啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、氮杂基、二氮杂基、吖啶基等。 As used herein, the term "heteroaryl" is intended to include heterocyclic aromatic ring systems containing one or more hetero atoms selected from nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl , imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl , 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl oxazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2 , 5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl , benzimidazolyl, benzothiazolyl, benzo isothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl , quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,  group aza, diaza  group, acridinyl and the like. 杂芳基也打算包括上面列举的杂环系统的部分氢化衍生物。 Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. 这类部分氢化衍生物的非限制性实例有2,3-二氢苯并呋喃基、吡咯啉基、吡唑啉基、二氢茚基、二氢吲哚基、噁唑烷基、噁唑啉基、氧氮杂基等。 Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indanyl, indolinyl, oxazolidinyl, oxazolyl quinolinyl, oxazepine  group.

本文所用的术语“杂芳氧基”表示原子团-O-杂芳基,其中杂芳基是如上所定义的。 As used herein, the term "heteroaryloxy" means the radical -O- heteroaryl, wherein heteroaryl is as defined above.

本文所用的术语“杂芳酰基”表示原子团-C(=O)-杂芳基,其中杂芳基是如上所定义的。 As used herein, the term "heteroaryl group" means the radical -C (= O) - heteroaryl, wherein heteroaryl is as defined above.

本文所用的术语“杂芳基氨基”表示原子团-NH-杂芳基,其中杂芳基是如上所定义的。 As used herein, the term "heteroaryl group" means the radical -NH- heteroaryl, wherein heteroaryl is as defined above.

某些上述所定义的术语可能在结构式中出现一次以上,在这种情况下每一术语应当彼此独立地被定义。 Certain terms are as defined above may occur more than once in the structural formulas, each term shall be defined independently of one another in this case.

“芳基-C1-6-烷基”、“芳基-C1-6-烷氧基”等表示如上所定义的C1-6-烷基或C1-6-烷氧基,被如上所定义的芳基取代,例如: "Aryl -C1-6- alkyl", "aryl -C1-6- alkoxy" etc. represents C1-6- alkyl or C1-6- alkoxy group, as defined above, are as defined above, a substituted aryl group, for example: 本文所用的术语“可选被取代的”意味着有关基团是未取代的或者被一个或多个所指定的取代基取代。 As used herein, the term "optionally substituted" mean that the group is unsubstituted or substituted with one or more of the substituents specified. 当有关基团被一个以上取代基取代时,取代基可以是相同的或不同的。 When the group is related to a more substituents, the substituents may be the same or different.

本文所用的术语“治疗”表示出于对抗疾病、障碍或病症的目的而对患者所作的管理和护理。 As used herein, the term "treatment" means the management and care for the purpose of combating a disease, disorder or condition made while the patient. 该术语打算包括疾病、障碍或病症进展的延缓、症状与并发症的减轻或缓解、和/或疾病、障碍或病症的治愈或消除。 The term is intended to include the progression of the disease, disorder or condition delay, to alleviate the symptoms and complications or remission, cure or eliminate and / or disease, disorder or condition. 所要治疗的患者优选地是哺乳动物,特别是人类。 Preferably the patient to be treated is a mammal, especially humans.

发明说明本发明涉及通式(I)化合物: The present invention relates to illustrate the invention compounds of general formula (I): 其中(i)R1代表·支链C4-8-烷基、支链C4-8-烯基或支链C4-8-炔基,它们可以可选地被一个或多个卤素取代基取代,·C3-5-环烷基、C3-7-环烯基、C3-6-环烷基-C1-3-烷基或C3-6-环烯基-C1-3-烷基,它们可以可选地在任意位置被一个或多个卤素取代基取代,A代表 Wherein (i) R1 · Representative branched C4-8- alkyl, C4-8- alkenyl group or a branched-chain C4-8- branched alkynyl group which may optionally be substituted with one or more halogen substituents, · C3-5- cycloalkyl, C3_7-cycloalkenyl, C3-6-cycloalkyl or C3-6-cycloalkenyl group -C1-3- -C1-3- alkyl group, which may be optionally in any position substituted with one or more halogen, a representatives or 或者(ii)R1代表乙基、正丙基或异丙基,和A代表 Or (ii) R1 represents an ethyl, n-propyl or isopropyl group, and A represents Z和X独立地代表-N=、-CH=、-CF=或-C(CF3)=,W代表-N=或-CR3=,Y代表-N=或-CR4=, X and Z independently represent -N =, - CH =, - CF = or -C (CF3) =, W representatives -N = or -CR3 =, Y representative of -N = or -CR4 =,

R2a、R2b、R3和R4独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、芳基-C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷氧基、氰基、硝基、C1-6-烷硫基、C1-6-烷基磺酰基或-C(=O)NR4aR4b,其中R4a和R4b独立地是氢、C1-6-烷基或芳基-C1-6-烷基,·C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基,它们可以可选地在任意位置被一个或多个取代基取代,取代基选自芳基、杂芳基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基和C1-6-烷氧基,芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个取代基取代,取代基选自卤素、羟基、三氟甲基、三氟甲氧基、C1-6-烷氧基、C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、氰基、芳基、杂芳基和C3-8-环烷基,·芳酰基、杂芳 R2a, R2b, R3 and R4 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-10- alkyl, C2-10- alkenyl, C3-8-cycloalkyl, C1-6-alkoxy, aryl -C1-6- alkyl, amino, C1-6-alkylamino, di-alkylamino -C1-6-, C3-8-cycloalkoxy group, a cyano group, nitro, C1-6- alkylthio, C1-6- alkylsulfonyl, or -C (= O) NR4aR4b, wherein R4a and R4b are independently hydrogen, C1-6- alkyl or aryl, -C1-6 - alkyl group, · C2-10- alkyl group, an alkoxy group C4-9- cycloalkyl, C3-8-heterocyclyl or heterocycloalkyl C4-9- alkanoyl which may optionally be substituted with one or more at an arbitrary position substituents, substituents selected from aryl, heteroaryl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C1-6- alkoxy, aryl, aryl - C1-6- alkyl, -C1-6- alkoxy, aryl or heteroaryl group, which may optionally be substituted with one or more substituents, substituents selected from halogen, hydroxy, trifluoromethyl, tri difluoromethoxy, C1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylamino, di-alkylamino -C1-6-, cyano, aryl, heteroaryl, and C3-8- cycloalkyl, - aroyl, heteroaryl 基、芳氧基、杂芳氧基、芳基氨基或杂芳基氨基,它们可以可选地被一个或多个取代基取代,取代基选自芳基、杂芳基、C1-10-烷基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基、C1-6-烷氧基、氰基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基和羟基,·或者R2a、R2b、R3和R4中相邻位置的两个一起构成C1-6-亚烷基桥,其条件是该化合物必须不是 Group, aryloxy group, heteroaryloxy group, an aryl group or heteroaryl group, which may optionally be substituted with one or more substituents, the substituents selected from aryl, heteroaryl, C1-10- alkoxy yl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, cyano, amino, C1-6-alkylamino, di -C1-6- alkylamino and hydroxy, - or R2a, R2b, R3 and R4 together form two adjacent positions C1-6- alkylene bridge, with the proviso that the compound must not be

or 及其任意非对映体或对映体或互变形式、包括它们的混合物,或其药学上可接受的盐。 And any diastereomer or enantiomer or tautomeric form thereof including mixtures thereof, or a pharmaceutically acceptable salt thereof.

在一种实施方式中,R1是支链C4-8-烷基、C3-5-环烷基或C3-6-环烷基-C1-3-烷基,它们可以可选地被一个或多个卤素取代基取代。 In one embodiment embodiment, R1 is a branched C4-8- alkyl, C3-5- alkyl or C3-6- cycloalkyl -C1-3- cycloalkyl group, which may optionally be substituted with one or more halogen substituents.

在另一种实施方式中,R1是支链C4-8-烷基、C3-5-环烷基或C3-6-环烷基-C1-3-烷基。 In another embodiment, R1 is a branched C4-8- alkyl, C3-5- alkyl or C3-6- cycloalkyl -C1-3- cycloalkyl group.

在另一种实施方式中,R1是1,1-(二甲基)丙基、1-乙基丙基、环丙基甲基、环丙基、环丁基、环戊基或1-环丙基-1-甲基乙基。 In another embodiment, R1 is 1,1- (dimethyl) propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1- propyl-1-methylethyl.

在另一种实施方式中,R1是1-乙基丙基、环丙基甲基、环丙基或环戊基。 In another embodiment, R1 is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

在另一种实施方式中,R1是支链C4-8-烷基或C3-5-环烷基,它们可以可选地被一个或多个卤素取代基取代。 In another embodiment, R1 is a branched alkyl or C3-5- C4-8- cycloalkyl, which may be optionally substituted with one or more halogen substituents.

在另一种实施方式中,R1是支链C4-8-烷基或C3-5-环烷基。 In another embodiment, R1 is a branched alkyl or C3-5- cycloalkyl, C4-8-.

在另一种实施方式中,R1是1-乙基丙基、环丙基或环戊基。 In another embodiment, R1 is 1-ethylpropyl, cyclopropyl or cyclopentyl.

在另一种实施方式中,R1是异丙基。 In another embodiment, R1 is an isopropyl group.

在另一种实施方式中,A是 In another embodiment, A is

or 其中R2a、R2b、R3和R4是如式(I)所定义的。 Wherein R2a, R2b, R3 and R4 are as defined in formula (I).

在另一种实施方式中,A是 In another embodiment, A is 其中R2a、R3和R4是如式(I)所定义的。 Wherein R2a, R3 and R4 are as defined in formula (I).

在另一种实施方式中,A是 In another embodiment, A is 其中R2a、R3和R4是如式(I)所定义的。 Wherein R2a, R3 and R4 are as defined in formula (I).

在另一种实施方式中,A是 In another embodiment, A is 其中R2a、R2b、R3和R4是如式(I)所定义的。 Wherein R2a, R2b, R3 and R4 are as defined in formula (I).

在另一种实施方式中,R2a、R2b、R3和R4独立地选自·氢、羟基、卤素、三氟甲基、三氟甲氧基、C2-10-烷酰基、C4-9-环烷酰基或C4-9-杂环烷酰基,或者·芳基-C1-6-烷基、芳基-C1-6-烷氧基或芳酰基,它们可以可选地如式(I)所定义被取代。 In another embodiment, R2a, R2b, R3 and R4 are independently selected from-hydrogen, hydroxy, halo, trifluoromethyl, trifluoromethoxy, C2-10- alkyl group, C4-9- cycloalkyl acyl or C4-9- heterocycloalkyl group, an aryl group or • -C1-6- alkyl, -C1-6- alkoxy, aryl or aralkyl group, which may optionally be as defined in formula (I) is replaced.

在另一种实施方式中,R2a、R2b、R3和R4独立地选自·氢、羟基、卤素、三氟甲基、三氟甲氧基、C2-10-烷酰基、C4-9-环烷酰基或C4-9-杂环烷酰基,·苯基-C1-6-烷基、苯基-C1-6-烷氧基或苯甲酰基,它们可以可选地被一个或两个取代基取代,取代基选自卤素和C1-6-烷氧基。 In another embodiment, R2a, R2b, R3 and R4 are independently selected from-hydrogen, hydroxy, halo, trifluoromethyl, trifluoromethoxy, C2-10- alkyl group, C4-9- cycloalkyl acyl or a heterocyclic C4-9- alkanoyl, phenyl--C1-6- alkyl, -C1-6- alkoxy, phenyl or benzoyl, which may be optionally substituted with one or two substituents substituents selected from halogen and C1-6- alkoxy.

在另一种实施方式中,R2a、R2b和R4是氢,R3不是氢。 In another embodiment, R2a, R2b and R4 are hydrogen, R3 is not hydrogen.

在另一种实施方式中,R3是卤素、三氟甲基或三氟甲氧基。 In another embodiment, R3 is halo, trifluoromethyl or trifluoromethoxy.

在另一种实施方式中,本发明涉及通式(I1)化合物: In another embodiment, the present invention relates to compounds of the formula (I1): 其中A是如式(I)或上述实施方式任意一种所定义的。 Wherein A is as defined in formula (I) or any of the above-described embodiments as defined herein.

在另一种实施方式中,本发明涉及通式(I2)化合物: In another embodiment, the present invention relates to compounds of the formula (I2): 其中A是如式(I)或上述实施方式任意一种所定义的。 Wherein A is as defined in formula (I) or any of the above-described embodiments as defined herein.

在另一种实施方式中,本发明涉及通式(I3)化合物: In another embodiment, the present invention relates to compounds of the formula (I3): 其中R1是·支链C4-8-烷基、支链C4-8-烯基或支链C4-8-炔基,它们可以可选地被一个或多个卤素取代基取代,·C3-5-环烷基、C3-7-环烯基、C3-6-环烷基-C1-3-烷基或C3-6-环烯基-C1-3-烷基,它们可以可选地在任意位置被一个或多个卤素取代基取代,·乙基、正丙基或异丙基,R2a、R2b、R3和R4是如式(I)所定义的。 Wherein R1 is a branched-chain C4-8- alkyl, C4-8- alkenyl group or a branched-chain C4-8- branched alkynyl group which may optionally be substituted with one or more halogen substituents, of C3-5- - cycloalkyl, C3_7-cycloalkenyl, C3-6-cycloalkyl or C3-6-cycloalkenyl group -C1-3- -C1-3- alkyl group, any of which may optionally be position with one or more halo substituents, ethyl, n-propyl or isopropyl group, R2a, R2b, R3 and R4 are as defined in formula (I) as defined above.

在另一种实施方式中,本发明涉及选自如下的化合物:4-(4-环戊基哌嗪-1-基)苯酚,1-环戊基-4-[4-(4-氟苄氧基)苯基]哌嗪,1-(3-氯苯基)-4-环戊基哌嗪,1-[4-(4-环戊基哌嗪-1-基)苯基]乙酮,1-(3,4-二氯苯基)-4-(1-乙基丙基)哌嗪,{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}苯基甲酮,1-(4-苄基苯基)-4-(1-乙基丙基)哌嗪,环丙基-{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}甲酮,(2-氯苯基)-{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}甲酮,{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}-(4-氟苯基)甲酮,1-环戊基-4-(6-三氟甲基吡啶-2-基)哌嗪,1-环戊基-4-(5-三氟甲基吡啶-2-基)哌嗪,1-环戊基-4-(3-三氟甲基吡啶-2-基)哌嗪,2-[4-(1-乙基丙基)哌嗪-1-基]喹啉,7-氯-4-[4-(1-乙基丙基)哌嗪-1-基]喹啉,[4-(4-环戊基哌嗪-1-基)苯基]-(3,4-二甲氧基苯基)甲酮,[4-(4-环戊基哌嗪-1-基)-3,5-二氟苯基]苯基甲酮,2-(4-环戊基哌嗪-1-基)喹喔啉 In another embodiment, the present invention relates to compounds selected from: 4- (4-cyclopentyl-piperazin-1-yl) phenol, 1-cyclopentyl-4- [4- (4-fluorobenzyl oxy) phenyl] piperazine, 1- (3-chlorophenyl) -4-cyclopentyl-piperazine, 1- [4- (4-cyclopentyl-piperazin-1-yl) phenyl] ethanone 1- (3,4-dichlorophenyl) -4- (1-ethylpropyl) piperazine, {4- [4- (1-ethylpropyl) piperazin-1-yl] phenyl phenyl} methanone, 1- (4-benzyl-phenyl) -4- (1-ethylpropyl) piperazine, cyclopropyl - {4- [4- (1-ethylpropyl) piperazine 1-yl] phenyl} methanone, (2-chlorophenyl) - {4- [4- (1-ethylpropyl) piperazin-1-yl] phenyl} methanone, {4- [ 4- (1-ethylpropyl) piperazin-1-yl] phenyl} - (4-fluorophenyl) methanone, 1-cyclopentyl-4- (6-trifluoromethyl-2- yl) piperazine, 1-cyclopentyl-4- (5-trifluoromethyl-pyridin-2-yl) piperazine, 1-cyclopentyl-4- (3-trifluoromethyl-pyridin-2-yl) piperazine, 2- [4- (1-ethylpropyl) piperazin-1-yl] quinoline, 7-chloro-4- [4- (1-ethylpropyl) piperazin-1-yl] quinoline, [4- (4-cyclopentyl-piperazin-1-yl) phenyl] - (3,4-dimethoxyphenyl) methanone, [4- (4-cyclopentyl-piperazin - 3,5-difluorophenyl-1-yl)] phenyl methanone, 2- (4-cyclopentyl-piperazin-1-yl) quinoxaline 2-(4-环丙基甲基哌嗪-1-基)喹喔啉,[6-(4-环戊基哌嗪-1-基)吡啶-3-基]哌啶-1-基甲酮,2-(4-环戊基哌嗪-1-基)喹啉,2-(4-环戊基哌嗪-1-基)-7-甲氧基-3-(4-甲氧基苯基)喹啉,{6-[4-(1-环丙基-1-甲基乙基)哌嗪-1-基]吡啶-3-基}苯基甲酮, 2- (4-cyclopropylmethyl-piperazin-1-yl) quinoxaline, [6- (4-cyclopentyl-piperazin-1-yl) pyridin-3-yl] piperidin-1-A -one, 2- (4-cyclopentyl-piperazin-1-yl) quinoline, 2- (4-cyclopentyl-piperazin-1-yl) -7-methoxy-3- (4-methoxy phenyl) quinoline, {6- [4- (1-cyclopropyl-1-methylethyl) piperazin-1-yl] pyridin-3-yl} phenyl methanone,

{4-[4-(1-环丙基-1-甲基乙基)哌嗪-1-基]-3,5-二氟苯基}苯基甲酮,{4-[4-(1-环丙基-1-甲基乙基)哌嗪-1-基]-3,5-二氟苯基}苯基甲醇,[4-(4-环丙基甲基哌嗪-1-基)-3,5-二氟苯基]-(4-氟苯基)甲酮,{4-[4-(1-乙基丙基)哌嗪-1-基]-3,5-二氟苯基}-(4-氟苯基)甲酮,2-[4-(1-乙基丙基)哌嗪-1-基]-6,7-二甲氧基喹啉,2-[4-(1-乙基丙基)哌嗪-1-基]-4-三氟甲基喹啉,2-(4-环丙基甲基哌嗪-1-基)-6-甲氧基-4-三氟甲基喹啉,[4-(4-环丙基甲基哌嗪-1-基)-3,5-二氟苯基]苯基甲酮,[4-(4-环丙基甲基哌嗪-1-基)-3,5-二氟苯基]-(3-氟-4-甲氧基苯基)-甲酮,{6-[4-(1-乙基丙基)哌嗪-1-基]吡啶-3-基}苯基甲酮,{2-[4-(1-乙基丙基)哌嗪-1-基]吡啶-4-基}苯基甲酮,{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}-(4-羟基苯基)甲酮,{6-[4-(1-乙基丙基)哌嗪-1-基]吡啶-3-基}哌啶-1-基-甲酮,N-苄基-6-[4-(1-乙基丙基)哌嗪-1-基]-N-甲基烟酰胺,2-[4- {4- [4- (1-cyclopropyl-1-methylethyl) piperazin-1-yl] -3,5-difluorophenyl} phenyl methanone, {4- [4- (1 - cyclopropyl-1-methylethyl) piperazin-1-yl] -3,5-difluorophenyl} phenyl methanol, [4- (4-cyclopropylmethyl-piperazin-1-yl ) -3,5-difluorophenyl] - (4-fluorophenyl) methanone, {4- [4- (1-ethylpropyl) piperazin-1-yl] -3,5-difluoro- phenyl} - (4-fluorophenyl) methanone, 2- [4- (1-ethylpropyl) piperazin-1-yl] -6,7-dimethoxy-quinoline, 2- [4 - (1-ethylpropyl) piperazin-1-yl] -4-trifluoromethyl-quinoline, 2- (4-cyclopropylmethyl-piperazin-1-yl) -6-methoxy - 4-trifluoromethyl-quinoline, [3,5-difluorophenyl 4- (4-cyclopropylmethyl-piperazin-1-yl)] phenyl methanone, [4- (4-cyclopropyl -3,5-difluorophenyl methyl piperazin-1-yl)] - (3-fluoro-4-methoxyphenyl) - methanone, {6- [4- (1-ethyl-propyl yl) piperazin-1-yl] pyridin-3-yl} phenyl methanone, {2- [4- (1-ethylpropyl) piperazin-1-yl] pyridin-4-yl} phenyl methyl ketone, {4- [4- (1-ethylpropyl) piperazin-1-yl] phenyl} - (4-hydroxyphenyl) methanone, {6- [4- (1-ethylpropyl ) piperazin-1-yl] pyridin-3-yl piperidin-1-yl} - methanone, N- benzyl-6- [4- (1-ethylpropyl) piperazin-1-yl] - N- methyl-nicotinamide, 2- [4- (1-乙基丙基)哌嗪-1-基]-6-甲氧基喹啉,6-[4-(1-乙基丙基)哌嗪-1-基]-N-甲基-N-苯基烟酰胺,{6-[4-(1-乙基丙基)哌嗪-1-基]吡啶-3-基}-(4-氟苯基)甲酮,2-[4-(1-乙基丙基)哌嗪-1-基]-4-甲基喹啉,2-[4-(1-乙基丙基)哌嗪-1-基]-5,6,7,8-四氢喹啉,2-(4-环丙基甲基哌嗪-1-基)-6-甲氧基喹啉,2-(4-异丙基哌嗪-1-基)-6-甲氧基喹啉,2-[4-(1-乙基丙基)哌嗪-1-基]-6-氟-4-甲基喹啉,2-(4-环丙基哌嗪-1-基)-6-三氟甲基喹啉,2-(4-环丙基哌嗪-1-基)-6-丙基喹啉,2-(4-乙基哌嗪-1-基)喹啉,及其任意非对映体或对映体或互变形式、包括它们的混合物,或其药学上可接受的盐。 (1-ethylpropyl) piperazin-1-yl] -6-methoxy-quinoline, 6- [4- (1-ethylpropyl) piperazin-1-yl] -N- methyl - N- phenyl-nicotinamide, {6- [4- (1-ethylpropyl) piperazin-1-yl] pyridin-3-yl} - (4-fluorophenyl) methanone, 2- [4- (1-ethylpropyl) piperazin-1-yl] -4-methyl-quinoline, 2- [4- (1-ethylpropyl) piperazin-1-yl] -5,6,7,8 8- tetrahydroquinoline, 2- (4-cyclopropylmethyl-piperazin-1-yl) -6-methoxy-quinoline, 2- (4-isopropyl-piperazin-1-yl) -6 - methoxy quinoline, 2- [4- (1-ethylpropyl) piperazin-1-yl] -6-fluoro-4-methyl quinoline, 2- (4-cyclopropyl-piperazin - 1- yl) -6-trifluoromethyl-quinoline, 2- (4-cyclopropyl-piperazin-1-yl) -6-propyl-quinoline, 2- (4-ethyl-piperazin-1-yl ) quinoline, and any diastereomer or enantiomer or tautomeric form thereof including mixtures thereof, or a pharmaceutically acceptable salt thereof.

在另一方面,本发明涉及通式(I”)化合物: In another aspect, the present invention relates to compounds of general formula (I "): 其中R1代表·支链C4-8-烷基、支链C4-8-烯基或支链C4-8-炔基,它们可以可选地被一个或多个卤素取代基取代,·C3-5-环烷基、C3-7-环烯基、C3-6-环烷基-C1-3-烷基或C3-6-环烯基-C1-3-烷基,它们可以可选地被一个或多个卤素取代基取代,A代表 Wherein R1 represents a branched-chain C4-8- alkyl, C4-8- alkenyl group or a branched-chain C4-8- branched alkynyl group which may optionally be substituted with one or more halogen substituents, of C3-5- - cycloalkyl, C3_7-cycloalkenyl, C3-6-cycloalkyl or C3-6-cycloalkenyl group -C1-3- -C1-3- alkyl group, which may optionally be substituted with one or more halo substituents, A representatives or Z和X独立地代表-N=、-CH=、-CF=或-C(CF3)=,W代表-N=或-CR3=,Y代表-N=或-CR4=,R2、R3和R4独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、芳基-C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷氧基或氰基,或·C2-10-烷酰基或C4-9-环烷酰基,它们可以可选地被一个或多个取代基取代,取代基选自芳基、杂芳基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基和C1-6-烷氧基,芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个取代基取代,取代基选自卤素、羟基、三氟甲基、三氟甲氧基、C1-6-烷氧基、C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、氰基、芳基、杂芳基和C3-8-环烷基,或·芳酰基、杂芳酰基、芳氧基、杂芳氧基、芳基氨基或杂芳基氨基,它们可以 X and Z independently represent -N =, - CH =, - CF = or -C (CF3) =, W representatives -N = or -CR3 =, Y representative of -N = or -CR4 =, R2, R3 and R4 · independently represent hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-10- alkyl, C2-10- alkenyl, C3-8-cycloalkyl, C1-6-alkoxy, , aryl -C1-6- alkyl, amino, C1-6-alkylamino, di-alkylamino -C1-6-, C3-8-cycloalkoxy group or a cyano group, or an alkoxy · C2-10- acyl or C4-9- cycloalkyl group, which may optionally be substituted with one or more substituents, the substituents selected from aryl, heteroaryl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C1-6- alkoxy, aryl, aryl -C1-6- alkyl, -C1-6- alkoxy, aryl or heteroaryl group, which may optionally be substituted with one or more substituents, substituents selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylamino, two -C1-6- alkylamino, cyano, aryl, heteroaryl and C3-8- cycloalkyl, or - aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or a heteroaryl group, which may be 选地被一个或多个取代基取代,取代基选自芳基、杂芳基、C1-10-烷基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基、C1-6-烷氧基、氰基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基和羟基,其条件是该化合物必须不是 Optionally substituted with one or more substituents, the substituents selected from aryl, heteroaryl, C1-10- alkyl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, cyano, amino, C1-6-alkylamino, di-alkylamino, and hydroxy -C1-6-, with the proviso that the compound must not be

or 及其任意非对映体或对映体或互变形式、包括它们的混合物,或其药学上可接受的盐。 And any diastereomer or enantiomer or tautomeric form thereof including mixtures thereof, or a pharmaceutically acceptable salt thereof.

在一种实施方式中,R1是支链C4-8-烷基、C3-5-环烷基或C3-6-环烷基-C1-3-烷基,它们可以可选地被一个或多个卤素取代基取代。 In one embodiment embodiment, R1 is a branched C4-8- alkyl, C3-5- alkyl or C3-6- cycloalkyl -C1-3- cycloalkyl group, which may optionally be substituted with one or more halogen substituents.

在另一种实施方式中,R1是支链C4-8-烷基、C3-5-环烷基或C3-6-环烷基-C1-3-烷基,例如1,1-(二甲基)丙基、1-乙基丙基、环丙基甲基、环丙基、环丁基或环戊基,例如1-乙基丙基、环丙基甲基或环戊基。 In another embodiment, R1 is a branched C4-8- alkyl, C3-5- alkyl or C3-6- cycloalkyl -C1-3- cycloalkyl group, for example, 1,1- (dimethyl yl) propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl or cyclopentyl, for example, 1-ethylpropyl, cyclopropylmethyl or cyclopentyl.

在另外一种实施方式中,R1是支链C4-8-烷基或C3-5-环烷基,它们可以可选地被一个或多个卤素取代基取代,例如支链C4-8-烷基或C3-5-环烷基,例如1-乙基丙基或环戊基。 In another embodiment embodiment, R1 is a branched alkyl or C3-5- C4-8- cycloalkyl, which may be optionally substituted with one or more halogen substituents, e.g. branched C4-8- alkoxy or C3-5- cycloalkyl group, for example, 1-ethylpropyl or cyclopentyl.

在进一步的实施方式中,A是 In a further embodiment, A is or

其中R2、R3和R4是如式(I”)所定义的。 Wherein R2, R3 and R4 are as defined in formula (I ").

在另一种实施方式中,A是 In another embodiment, A is 其中R2、R3和R4是如式(I”)所定义的。 Wherein R2, R3 and R4 are as defined in formula (I ").

在进一步的实施方式中,A是 In a further embodiment, A is 其中R2、R3和R4是如式(I”)所定义的。 Wherein R2, R3 and R4 are as defined in formula (I ").

在一种实施方式中,R2、R3和R4独立地选自·氢、羟基、卤素、三氟甲基、C2-10-烷酰基或C4-9-环烷酰基,或者·芳基-C1-6-烷基、芳基-C1-6-烷氧基或芳酰基,它们可以可选地如式(I”)所定义被取代。 In one embodiment, R2, R3 and R4 are independently selected from-hydrogen, hydroxy, halo, trifluoromethyl, C2-10- alkanoyl or C4-9- cycloalkyl group, an aryl group or -C1- · 6- alkyl group, an aryl group or an aroyl group -C1-6- alkoxy, which may optionally be of formula (I ") as defined substituted.

在另一种实施方式中,R2、R3和R4独立地选自·氢、羟基、卤素、三氟甲基、C2-10-烷酰基或C4-9-环烷酰基,·苯基-C1-6-烷基、苯基-C1-6-烷氧基或苯甲酰基,它们可以可选地被一个或两个取代基取代,取代基选自卤素和C1-6-烷氧基。 In another embodiment, R2, R3 and R4 are independently selected from-hydrogen, hydroxy, halo, trifluoromethyl, C2-10- alkanoyl or C4-9- cycloalkyl group, a phenyl--C1- 6- alkyl, -C1-6- alkoxy, phenyl or benzoyl, which may be optionally substituted with one or two substituents, substituents selected from halogen and C1-6- alkoxy.

在另外一种实施方式中,R2和R4都是氢,R3不是氢。 In another embodiment, R2 and R4 are hydrogen, R3 is not hydrogen.

在另外一种实施方式中,本发明涉及通式(I1)化合物: In another embodiment, the present invention relates to compounds of the formula (I1): 其中A是如式(I”)或上述实施方式任意一种所定义的。 Wherein A is as defined in formula (I ") or any one of the above-described embodiments as defined herein.

在另外一种实施方式中,本发明涉及通式(I2)化合物: In another embodiment, the present invention relates to compounds of the formula (I2):

其中A是如式(I”)或上述实施方式任意一种所定义的。 Wherein A is as defined in formula (I ") or any one of the above-described embodiments as defined herein.

因此,本发明在另一方面涉及用作药物组合物的通式(I)化合物及其任意非对映体或对映体或互变形式、包括它们的混合物,或其药学上可接受的盐。 Thus, in another aspect it relates to a compound of formula (I) as a pharmaceutical composition and any diastereomer or enantiomer or tautomeric form thereof including mixtures thereof, or a pharmaceutically acceptable salt thereof of the present invention .

本发明还涉及药物组合物,包含至少一种式(I)化合物或其任意非对映体或对映体或互变形式、包括它们的混合物或其药学上可接受的盐作为活性成分,以及一种或多种药学上可接受的载体或稀释剂。 The present invention further relates to pharmaceutical compositions comprising at least one compound of formula (I) or any diastereomer or enantiomer or tautomeric form thereof, including a pharmaceutically acceptable salt thereof, or a mixture thereof as an active ingredient, and one or more pharmaceutically acceptable carrier or diluent.

此外,本发明涉及通式(I')化合物 Further, the present invention relates to compounds of general formula (I ') 其中R1代表·C1-8-烷基、C2-8-烯基或C2-8-炔基,它们可以可选地被一个或多个卤素取代基取代,·C3-5-环烷基、C3-7-环烯基、C3-6-环烷基-C1-3-烷基或C3-6-环烯基-C1-3-烷基,它们可以可选地被一个或多个卤素取代基取代,A代表 Wherein R1 represents · C1-8- alkyl, C2-8- alkenyl or C2-8- alkynyl group which may optionally be substituted with one or more halogen substituents, · C3-5- cycloalkyl, C3 -7-alkenyl, C3-6-cycloalkyl or C3-6-cycloalkenyl group -C1-3- -C1-3- alkyl group, which may optionally be substituted with one or more halogen substituents replace, A representative of or Z和X独立地代表-N=、-CH=、-CF=或-C(CF3)=,W代表-N=或-CR3=, X and Z independently represent -N =, - CH =, - CF = or -C (CF3) =, W representatives -N = or -CR3 =,

Y代表-N=或-CR4=,R2a、R2b、R3和R4独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、芳基-C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-a-环烷氧基、氰基、硝基、C1-6-烷硫基、C1-6-烷基磺酰基或-C(=O)NR4aR4b,其中R4a和R4b独立地是氢、C1-6-烷基或芳基-C1-6-烷基,或·C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基,它们可以可选地在任意位置被一个或多个取代基取代,取代基选自芳基、杂芳基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基和C1-6-烷氧基,芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个取代基取代,取代基选自卤素、羟基、三氟甲基、三氟甲氧基、C1-6-烷氧基、C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、氰基、芳基、杂芳基和C3-8-环 Y represents -N = or -CR4 =, R2a, R2b, R3 and R4 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-10- alkyl, C2-10- alkenyl yl, C3-8-cycloalkyl, C1-6-alkoxy, aryl -C1-6- alkyl, amino, C1-6-alkylamino, di-alkylamino -C1-6-, C3- a- cycloalkoxy, cyano, nitro, C1-6-alkylthio, C1-6-alkylsulfonyl, or -C (= O) NR4aR4b, wherein R4a and R4b are independently hydrogen, C1-6 - -C1-6- alkyl or aryl group, an alkoxy group, or · C2-10-, C4-9- cycloalkyl group, a heterocyclic group or C3-8-heterocycloalkyl C4-9- alkyl group, which may be optionally substituted with one or more substituents, the substituents at any position selected from aryl, heteroaryl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C1-6 - an alkoxy group, an aryl group, an aryl group -C1-6- alkyl, -C1-6- alkoxy, aryl or heteroaryl group, which may optionally be substituted with one or more substituents, the substituents selected from from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylamino, di-alkylamino -C1-6- , cyano, aryl, heteroaryl and cycloalkyl C3-8- 基,或者·芳酰基、杂芳酰基、芳氧基、杂芳氧基、芳基氨基或杂芳基氨基,它们可以可选地被一个或多个取代基取代,取代基选自芳基、杂芳基、C1-10-烷基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基、C1-6-烷氧基、氰基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基和羟基,·或者R2a、R2b、R3和R4中相邻位置的两个一起构成C1-6-亚烷基桥,及其任意非对映体或对映体或互变形式、包括它们的混合物,或其药学上可接受的盐在药物组合物制备中的用途,该药物组合物用于治疗涉及组胺H3受体的障碍和疾病。 Group, or • an aryl group, heteroaryl group, aryl group, heteroaryl group, aryl group or heteroaryl group, which may optionally be substituted with one or more substituents, the substituents selected from aryl, heteroaryl, C1-10- alkyl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, cyano, amino, C1-6-alkyl group, di-alkylamino and hydroxy -C1-6-, * or R2a, R2b, R3 and R4 are two adjacent positions together form a C1-6- alkylene bridge, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures thereof, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition, the pharmaceutical composition for the treatment of diseases and disorders related to the histamine H3 receptor.

本发明在另一方面提供通式(II)化合物: The present invention provides general formula (II), on the other hand: 其中 among them

R2是氢或C1-4-烷基,(i)R1代表·支链C4-6-烷基、支链C4-6-烯基或支链C4-6-炔基,其条件是R1不是异丁基,·C3-5-环烷基、C3-7-环烯基、C3-6-环烷基-C1-3-烷基或C3-6-环烯基-C1-3-烷基,·R1和R2一起构成C3-6-亚烷基桥,和A代表 R2 is hydrogen or C1-4- alkyl, (I) R1 · Representative branched C4-6- alkyl, C4-6- alkenyl group or branched-chain branched C4-6- alkynyl group, with the proviso that R1 is not isobutyl butyl, · C3-5- cycloalkyl, C3_7-cycloalkenyl, C3-6-cycloalkyl or C3-6-cycloalkenyl group -C1-3- -C1-3- alkyl group, · R1 and R2 together form a C3-6- alkylene bridge, and A represents or 或者(ii)R1代表·乙基、正丙基或异丙基,·R1和R2一起构成C3-6-亚烷基桥,和A代表 Or (ii) R1 Representative ethyl, n-propyl or isopropyl, Rl and R2 together form-C3-6- alkylene bridge, and A represents or R3是氢、卤素、羟基、三氟甲基、三氟甲氧基、C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、芳基、芳基-C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷基、C3-8-环烷氧基、氰基、硝基、C1-6-烷硫基或C1-6-烷基磺酰基,Z和X独立地代表-N=、-C(H)=、-C(F)=、-C(Cl)=、-C(CN)=或-C(CF3)=,W代表-N=或-C(R10)=,Y代表-N=或-C(R11)=, R3 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, C1-10- alkyl, C2-10- alkenyl, C3-8-cycloalkyl, C1-6-alkoxy, aryl group, an aryl group -C1-6- alkyl, amino, C1-6-alkylamino, di-alkylamino -C1-6-, C3-8-cycloalkyl, C3-8-cycloalkoxy, cyano , nitro, C1-6-alkylthio or C1-6-alkylsulphonyl group, Z and X independently represent -N =, - C (H) =, - C (F) =, - C (Cl ) =, - C (CN) =, or -C (CF3) =, W representatives -N = or -C (R10) =, Y representative of -N = or -C (R11) =,

R4、R5、R6、R7、R8、R9、R10、R11、R12和R13独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、-SCF3、氨基、氰基、硝基或-C(=O)NR14R15,·C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、C3-8-环烷基-C1-6-烷氧基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷氧基、C1-6-烷硫基、C1-6-烷基磺酰基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基、C4-9-杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基、杂芳酰基、芳氧基、杂芳氧基、芳基氨基或杂芳基氨基,它们可以可选地被一个或多个选自R18的取代基取代,·或者R5、R6、R7、R8、R9、R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥,R14和R15独立地 Independently represent R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 · hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, -SCF3, an amino group, a cyano group, a nitro group or -C (= O) NR14R15, · C1-10- alkyl, C2-10- alkenyl, C3-8- cycloalkyl, C1-6- alkoxy, C3-8- cycloalkyl, -C1- 6-alkoxy, C1-6-alkylamino, di-alkylamino -C1-6-, C3-8-cycloalkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, C2-10- alkyl group, an alkoxy group C4-9- cycloalkyl, C3-8-heterocyclyl or heterocycloalkyl C4-9- alkanoyl, heterocyclic C4-9- alkoxy, which may optionally be substituted with one or a plurality of substituents selected from R16, - aryl, aryl -C1-6- alkyl, -C1-6- alkoxy, aryl or heteroaryl group, which may optionally be substituted with one or more selected from since substituents · aroyl, heteroaroyl, aryloxy, heteroaryloxy group, an aryl group or heteroaryl group, which may optionally be substituted with one or more substituents selected from R18 to R17 substituents , - or R5, R6, R7, R8, R9, R10, R11, R12 and R13 in two adjacent positions together form a C1-6-alkylene bridge or an alkylene group -O -O-C1-6- - bridge, R14 and R15 independently 氢、C1-6-烷基、芳基-C1-6-烷基,或者R14和R15可以一起构成C3-6-亚烷基桥,R16独立地选自芳基、杂芳基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基、NR19R20和C1-6-烷氧基,R17独立地选自卤素、羟基、三氟甲基、三氟甲氧基、C1-6-烷氧基、C1-6-烷基、氨基、C1-6-烷基磺酰基、C1-6-烷基氨基、二-C1-6-烷基氨基、氰基、芳基、杂芳基和C3-8-环烷基,R18独立地选自芳基、杂芳基、C1-10-烷基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基、C1-6-烷氧基、氰基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基和羟基,R19和R20独立地是氢或C1-6-烷基,R19和R20可以一起构成C3-6-亚烷基桥,其条件是该化合物必须不是 Hydrogen, C1-6-alkyl, aryl -C1-6- alkyl group, or R14 and R15 may together form a C3-6- alkylene bridge, R16 are independently selected from aryl, heteroaryl, a C3-8 - cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR19R20 and C1-6- alkoxy, R17 are independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1- 6-alkoxy, C1-6-alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-alkylamino -C1-6-, cyano, aryl, heteroaryl C3-8-cycloalkyl group, and, R18 is independently selected from aryl, heteroaryl, C1-10- alkyl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, cyano, amino, C1-6-alkylamino, di-alkylamino and hydroxy -C1-6-, R19 and R20 are independently hydrogen or C1-6-alkyl, R19, and R20 may together form a C3-6- alkylene bridge, with the proviso that the compound must not be

or 及其任意非对映体或对映体或互变形式、包括它们的混合物,或其药学上可接受的盐。 And any diastereomer or enantiomer or tautomeric form thereof including mixtures thereof, or a pharmaceutically acceptable salt thereof.

在本发明的另一方面,R1是支链C4-6-烷基、C3-5-环烷基或C3-6-环烷基-C1-3-烷基,其条件是R1不是异丁基。 In another aspect, R1 is a branched C4-6- alkyl, C3-5- alkyl or C3-6- cycloalkyl -C1-3- cycloalkyl groups of the present invention, with the proviso that R1 is not isobutyl .

在本发明的另一方面,R1是1,1-(二甲基)丙基、1-乙基丙基、环丙基甲基、环丙基、环丁基、环戊基或1-环丙基-1-甲基乙基。 In another aspect of the present invention, Rl is 1,1- (dimethyl) propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1- propyl-1-methylethyl.

在本发明的另一方面,R1是1-乙基丙基、环丙基甲基、环丙基或环戊基。 In another aspect of the present invention, Rl is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

在本发明的另一方面,R1是支链C4-6-烷基或C3-5-环烷基,其条件是R1不是异丁基。 In another aspect, R1 is a branched C4-6- alkyl or C3-5- cycloalkyl groups of the present invention, with the proviso that R1 is not isobutyl.

在本发明的另一方面,R1是1-乙基丙基、环丙基或环戊基。 In another aspect of the present invention, Rl is 1-ethylpropyl, cyclopropyl or cyclopentyl.

在本发明的另一方面,Z是-C(H)=、-N=或-C(F)=。 In another aspect of the present invention, Z is -C (H) =, - N = or -C (F) =.

在本发明的另一方面,Z是-C(H)=或-N=。 In another aspect of the present invention, Z is -C (H) = or -N =.

在本发明的另一方面,Z是-C(H)=。 In another aspect of the present invention, Z is -C (H) =.

在本发明的另一方面,Z是-N=。 In another aspect of the present invention, Z is -N =.

在本发明的另一方面,X是-C(H)=、-N=或-C(F)=。 In another aspect of the present invention, X is -C (H) =, - N = or -C (F) =.

在本发明的另一方面,Z是-C(H)=或-N=。 In another aspect of the present invention, Z is -C (H) = or -N =.

在本发明的另一方面,Z是-C(H)=。 In another aspect of the present invention, Z is -C (H) =.

在本发明的另一方面,Z是-N=。 In another aspect of the present invention, Z is -N =.

在本发明的另一方面,W是-N=。 In another aspect of the present invention, W is -N =.

在本发明的另一方面,W是-C(R10)=。 In another aspect of the present invention, W is -C (R10) =.

在本发明的另一方面,Y是-N=。 In another aspect of the present invention, Y is -N =.

在本发明的另一方面,Y是-C(R11)=。 In another aspect of the present invention, Y is -C (R11) =.

在本发明的另一方面,R2是氢。 In another aspect of the present invention, R2 is hydrogen.

在本发明的另一方面,R2是C1-4-烷基。 In another aspect of the present invention, R2 of a C1-4- alkyl group.

在本发明的另一方面,R2是甲基或乙基。 In another aspect of the present invention, R2 of is methyl or ethyl.

本发明在另一方面提供通式(III)化合物 The present invention provides formula (III) compound on the other hand 其中A和R3是如通式(II)化合物所定义的。 And wherein R3 is A compound of the general formula (II) as defined above.

在本发明的另一方面,R3是氢、卤素、羟基、三氟甲基、三氟甲氧基、C1-10-烷基、C1-6-烷氧基、芳基、芳基-C1-6-烷基、氨基、C3-8-环烷基、C3-8-环烷氧基、氰基或硝基。 In another aspect of the present invention, R3 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, C1-10- alkyl, C1-6-alkoxy group, an aryl group, an aryl group -C1- 6- alkyl, amino, C3-8-cycloalkyl, C3-8-cycloalkoxy, cyano or nitro.

在本发明的另一方面,R3是氢、卤素、羟基、三氟甲基、C1-10-烷基、C1-6-烷氧基、氰基或硝基。 In another aspect of the present invention, R3 is hydrogen, halo, hydroxy, trifluoromethyl, C1-10- alkyl, C1-6-alkoxy, cyano or nitro.

在本发明的另一方面,R3是氢、卤素、羟基、三氟甲基、C1-6-烷基或氰基。 In another aspect of the present invention, R3 is hydrogen, halo, hydroxy, trifluoromethyl, C1-6-alkyl or cyano.

在本发明的另一方面,R3是氢、卤素或C1-6-烷基。 In another aspect of the present invention, R3 is hydrogen, halo or C1-6- alkyl.

在本发明的另一方面,R3是氢或甲基。 In another aspect of the present invention, R3 is hydrogen or methyl.

在本发明的另一方面,R4、R5、R6、R7、R8和R9独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、-SCF3、氨基或氰基,·C1-10-烷基、C3-8-环烷基、C1-6-烷氧基、C3-8-环烷氧基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基、杂芳酰基、芳氧基、杂芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,·或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥。 In another aspect of the present invention, R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, -SCF3, an amino group or a cyano group, a C1- -10- alkyl, C3-8- cycloalkyl, C1-6- alkoxy, C3-8- cycloalkoxy, C2-10- alkyl group, C4-9- cycloalkyl group, C3-8- C4-9- heterocyclyl or heterocycloalkyl group, which may optionally be substituted with one or more substituents selected from R16, • aryl, aryl -C1-6- alkyl group, an aryl group -C1- 6-alkoxy or heteroaryl group, which may optionally be substituted with one or more substituents selected from R17, - aroyl, heteroaroyl, aryloxy, heteroaryloxy, which may optionally be R18 is selected from one or more substituents, - or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6-alkylene bridge or -O-C1-6- alkylene alkyl -O- bridge.

在本发明的另一方面,R4、R5、R6、R7、R8和R9独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、-SCF3或氰基,·C1-10-烷基、C1-6-烷氧基、C3-8-环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基或芳基-C1-6-烷基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基或芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥。 In another aspect of the present invention, R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, -SCF3, or a cyano group, a C1-10 · - alkyl, C1-6-alkoxy, C3-8-cycloalkoxy group, which may optionally be substituted with one or more substituents selected from the group of R16, an aryl or aryl--C1-6- alkyl group, which may optionally be substituted with one or more substituents selected from R17, - aroyl or aryloxy, which may be optionally substituted with one or more substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6-alkylene bridge or -O-C1-6- alkylene bridge -O-.

在本发明的另一方面,R4、R5、R6、R7、R8和R9独立地代表·氢、卤素或氰基,·C1-10-烷基或C1-6-烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基或芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥。 In another aspect of the present invention, R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen or cyano, · C1-10- alkyl or C1-6- alkoxy, which may optionally substituted with one or more substituents selected from R16, - aryl, optionally substituted with one or more substituents selected from R17, - aroyl or aryloxy, which may optionally be substituted with one or a plurality of substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6-alkylene bridge or an alkylene group -O -O-C1-6- -bridge.

在本发明的另一方面,R4、R5、R6、R7、R8和R9独立地代表·氢、卤素或氰基,·甲基、乙基、丙基、异丙基或C1-6-烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基或芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥。 In another aspect of the present invention, R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen or cyano, methyl, ethyl, propyl, isopropyl or C1-6- alkoxy group which may optionally be substituted with one or more substituents selected from R16, - aryl, optionally substituted with one or more substituents selected from R17, - aroyl or aryloxy, they may optionally substituted with one or more substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6- alkylene bridge, or -O-C1-6 - alkylene bridge -O-.

在本发明的另一方面,R4、R5、R6、R7、R8和R9独立地代表·氢、卤素或氰基,·C1-10-烷基、甲氧基、乙氧基或丙氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基或芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥。 In another aspect of the present invention, R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen or cyano, · C1-10- alkyl, methoxy, ethoxy or propoxy, they may optionally be substituted with one or more substituents selected from R16, - aryl, optionally substituted with one or more substituents selected from R17, - aroyl or aryloxy, which may be optionally substituted with one or more substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6-alkylene bridge or -O-C1-6- alkylene alkyl -O- bridge.

在本发明的另一方面,R4、R5、R6、R7、R8和R9独立地代表·氢、卤素或氰基,·C1-10-烷基或甲氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基或芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥。 In another aspect of the present invention, R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen or cyano, · C1-10- alkyl group or a methoxy group which may optionally be substituted with one or a plurality of substituents selected from R16, - aryl, optionally substituted with one or more substituents selected from R17, - aroyl or aryloxy, which may be optionally substituted with one or more substituents selected from substituents R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6-alkylene bridge or -O-C1-6- alkylene bridge -O-.

在本发明的另一方面,R4、R5、R6、R7、R8和R9独立地代表·氢、卤素或氰基,·C1-10-烷基或C1-6-烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·苯基,可选地被一个或多个选自R17的取代基取代, In another aspect of the present invention, R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen or cyano, · C1-10- alkyl or C1-6- alkoxy, which may optionally substituted with one or more substituents selected from R16, - phenyl optionally substituted with one or more substituents selected from R17,

·芳酰基或芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥。 · Aroyl or aryloxy group, which may optionally be substituted with one or more substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6- alkylene alkyl bridges or -O-C1-6- alkylene bridge -O-.

在本发明的另一方面,R4、R5、R6、R7、R8和R9独立地代表·氢、卤素或氰基,·C1-10-烷基或C1-6-烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·-C(=O)-苯基或芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥。 In another aspect of the present invention, R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen or cyano, · C1-10- alkyl or C1-6- alkoxy, which may optionally substituted with one or more substituents selected from R16, - aryl, optionally substituted with one or more substituents selected from R17, · -C (= O) - phenyl, or aryloxy, they It may be optionally substituted with one or more substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6- alkylene bridge, or -O-C1- 6- alkylene bridge -O-.

在本发明的另一方面,R4、R5、R6、R7、R8和R9独立地代表·氢、卤素或氰基,·C1-10-烷基或C1-6-烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基或-O-苯基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥。 In another aspect of the present invention, R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen or cyano, · C1-10- alkyl or C1-6- alkoxy, which may optionally substituted with one or more substituents selected from R16, - aryl, optionally substituted with one or more substituents selected from R17, or -O- aroyl-phenyl, which may optionally be one or more substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6-alkylene bridge or an alkylene group -O-C1-6- -O- bridge.

在本发明的另一方面,R1是乙基或异丙基。 In another aspect of the present invention, R1 is ethyl or isopropyl.

在本发明的另一方面,R1是异丙基。 In another aspect of the present invention, R1 is isopropyl.

在本发明的另一方面,R1是乙基。 In another aspect of the present invention, R1 is ethyl.

在本发明的另一方面,R1和R2一起构成C3-4-亚烷基桥。 In another aspect of the present invention, R1, and R2 together form a C3-4- alkylene bridge.

在本发明的另一方面,R10、R11、R12和R13独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、氰基或-C(=O)NR14R15,·C1-10-烷基、C3-8-环烷基、C1-6-烷氧基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基、C4-9-杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,·或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 In another aspect of the present invention, R10, R11, R12 and R13 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano or -C (= O) NR14R15, · C1- 10- alkyl, C3-8- cycloalkyl, C1-6- alkoxy, C2-10- alkyl group, C4-9- cycloalkyl group, C3-8- heterocyclyl or heterocyclyl C4-9- alkanoyl, C4-9- alkoxy heterocycle, which may be optionally substituted with one or more substituents selected from R16, - aryl, -C1-6- alkyl group, an aryl group -C1- 6-alkoxy or heteroaryl group, which may optionally be substituted with one or more substituents selected from R17, - aroyl, optionally substituted with one or more substituents selected from R18, or · R10, R11, R12 and R13 in two adjacent positions together form a C1-6- alkylene bridge.

在本发明的另一方面,R10、R11、R12和R13独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、氰基或-C(=O)NR14R15,·C1-10-烷基、C3-8-环烷基、C1-6-烷氧基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基、C4-9-杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 In another aspect of the present invention, R10, R11, R12 and R13 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano or -C (= O) NR14R15, · C1- 10- alkyl, C3-8- cycloalkyl, C1-6- alkoxy, C2-10- alkyl group, C4-9- cycloalkyl group, C3-8- heterocyclyl or heterocyclyl C4-9- alkanoyl, C4-9- alkoxy heterocycle, which may be optionally substituted with one or more substituents selected from R16, - aryl, -C1-6- alkyl group, an aryl group -C1- 6-alkoxy or heteroaryl group, which may optionally be substituted with one or more substituents selected from R17, - aroyl, optionally substituted with one or more substituents selected from R18, or R10 , R11, R12 and R13 in two adjacent positions together form a C1-6- alkylene bridge.

在本发明的另一方面,R10、R11、R12和R13独立地代表·氢、卤素、三氟甲基或-C(=O)NR14R15,·C1-10-烷基、C1-6-烷氧基、C2-10-烷酰基、C4-9-环烷酰基、C4-9-杂环烷酰基或C4-9-杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基、芳基-C1-6-烷基或芳基-C1-6-烷氧基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 In another aspect of the present invention, R10, R11, R12 and R13 independently represent · a hydrogen, halo, trifluoromethyl, or -C (= O) NR14R15, · C1-10- alkyl, C1-6-alkoxy group, C2-10- alkyl group, C4-9- cycloalkyl group, an alkoxy group or a heterocyclic C4-9- alkoxy C4-9- heterocyclyl, which may be optionally substituted with one or more substituents selected from R16 of substituents, - aryl, aryl alkyl or aryl -C1-6- -C1-6- alkoxy, which may optionally be substituted with one or more substituents selected from R17, aroyl · optionally substituted with one or more substituents selected from R18, or R10, R11, R12 and R13 in two adjacent positions together form a C1-6- alkylene bridge.

在本发明的另一方面,R10、R11、R12和R13独立地代表·氢、卤素、三氟甲基或-C(=O)NR14R15,·C1-10-烷基或C4-9-杂环烷酰基,它们可以可选地被一个或多个选自R16的取代基取代, In another aspect of the present invention, R10, R11, R12 and R13 independently represent · a hydrogen, halo, trifluoromethyl, or -C (= O) NR14R15, · C1-10- alkyl or C4-9- heterocyclyl alkyl group, which may optionally be substituted with one or more substituents selected from R16,

·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 · An aryl group, optionally substituted with one or more substituents selected from R17, - aroyl, optionally substituted with one or more substituents selected from R18, or R10, R11, R12 and R13 phase two ortho positions together form a C1-6- alkylene bridge.

在本发明的另一方面,R10、R11、R12和R13独立地代表·氢、卤素、三氟甲基或-C(=O)NR14R15,·甲基、乙基、丙基或C4-9-杂环烷酰基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 In another aspect of the present invention, R10, R11, R12 and R13 independently represent · a hydrogen, halo, trifluoromethyl, or -C (= O) NR14R15, · methyl, ethyl, propyl or C4-9- heterocyclic alkanoyl group, which may optionally be substituted with one or more substituents selected from R16, • aryl, optionally substituted with one or more substituents selected from R17, - aroyl, optionally substituted with one or more substituents selected from R18, or R10, R11, R12 and R13 in two adjacent positions together form a C1-6- alkylene bridge.

在本发明的另一方面,R10、R11、R12和R13独立地代表·氢、卤素、三氟甲基或-C(=O)NR14R15,·C1-10-烷基、哌啶-烷酰基或吡咯烷-烷酰基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 In another aspect of the present invention, R10, R11, R12 and R13 independently represent · a hydrogen, halo, trifluoromethyl, or -C (= O) NR14R15, · C1-10- alkyl, piperidin - alkanoyl or pyrrolidine - alkanoyl, which may be optionally substituted with one or more substituents selected from R16, - aryl, optionally substituted with one or more substituents selected from R17, - aroyl, optionally substituted with one or more substituents selected from R18, or R10, R11, R12 and R13 in two adjacent positions together form a C1-6- alkylene bridge.

在本发明的另一方面,R10、R11、R12和R13独立地代表·氢、卤素、三氟甲基或-C(=O)NR14R15,·C1-10-烷基或C4-9-杂环烷酰基,它们可以可选地被一个或多个选自R16的取代基取代,·苯基,可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 In another aspect of the present invention, R10, R11, R12 and R13 independently represent · a hydrogen, halo, trifluoromethyl, or -C (= O) NR14R15, · C1-10- alkyl or C4-9- heterocyclyl alkyl group, which may optionally be substituted with one or more substituents selected from R16, - phenyl optionally substituted with one or more substituents selected from R17, - aroyl, optionally substituted with a or more substituents selected from the substituent R18 or R10, two R11, R12 and R13 in adjacent positions together form a C1-6- alkylene bridge.

在本发明的另一方面,R14和R15独立地是甲基、乙基或苄基。 In another aspect of the present invention, R14 and R15 are independently methyl, ethyl or benzyl.

在本发明的另一方面,R16是卤素、三氟甲基、三氟甲氧基和C1-6-烷氧基。 In another aspect of the present invention, R16 is halogen, trifluoromethyl, trifluoromethoxy and C1-6- alkoxy.

在本发明的另一方面,R17是卤素、羟基、三氟甲基、C1-6-烷氧基、C1-6-烷基、C1-6-烷基磺酰基或氰基。 In another aspect of the present invention, R17 are halogen, hydroxy, trifluoromethyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl or cyano.

在本发明的另一方面,R17是卤素、三氟甲基、C1-6-烷氧基或C1-6-烷基磺酰基。 In another aspect of the present invention, R17 are halogen, trifluoromethyl, C1-6-alkoxy or C1-6-alkylsulfonyl.

在本发明的另一方面,R18是C1-10-烷基、卤素、三氟甲基、C1-6-烷氧基、氰基、氨基和羟基。 In another aspect of the present invention, R18 is C1-10- alkyl, halo, trifluoromethyl, C1-6-alkoxy, cyano, amino and hydroxy.

在本发明的另一方面,R18是卤素、C1-6-烷氧基和羟基。 In another aspect of the present invention, R18 is halogen, C1-6- alkoxy and hydroxy.

本发明在另一方面提供根据式(II)或(III)的化合物作为药物组合物的用途。 In another aspect the present invention provides a compound according to formula (II) or (III) as a pharmaceutical composition. 在本发明的另一方面,药物组合物可以包含至少一种根据式(II)或(III)的化合物作为活性成分,以及一种或多种药学上可接受的载体或赋形剂。 In another aspect the compounds of the present invention, the pharmaceutical composition may comprise at least one according to formula (II) or (III) as an active ingredient, and one or more pharmaceutically acceptable carrier or excipient. 本发明在另一方面提供单位剂型的这样一种药物组合物,包含约0.05mg至约1000mg、优选约0.1mg至约500mg、尤其优选约0.5mg至约200mg的根据式(II)或(III)的化合物。 In the present invention this aspect provides a pharmaceutical composition in unit dosage form, comprising from about 0.05mg to about lOOOmg, preferably about 0.1mg to about 500mg, especially preferably about 0.5mg to about 200mg according to formula (II) or (III )compound of.

本发明在另一方面提供通式(II')化合物 The present invention provides a compound of formula (II ') In another aspect 其中R2是氢或C1-4-烷基,R1代表·C1-8-烷基、C2-8-烯基或C2-8-炔基,它们可以可选地被一个或多个卤素取代基取代,·C3-5-环烷基、C3-7-环烯基、C3-6-环烷基-C1-3-烷基或C3-6-环烯基-C1-3-烷基,它们可以可选地被一个或多个卤素取代基取代,·R1和R2一起构成C3-6-亚烷基桥,A代表 Wherein R2 is hydrogen or a C1-4- alkyl group, R1 stands · C1-8- alkyl, C2-8- alkenyl or C2-8- alkynyl group which may optionally be substituted with one or more halogen substituents , · C3-5- cycloalkyl, C3_7-cycloalkenyl, C3-6-cycloalkyl or C3-6-cycloalkenyl group -C1-3- -C1-3- alkyl group, which may be optionally substituted with one or more halogen substituents substituted, · R1 and R2 together form a C3-6- alkylene bridge, a representatives or

R3是氢、卤素、羟基、三氟甲基、三氟甲氧基、C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、芳基、芳基-C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷基、C3-8-环烷氧基、氰基、硝基、C1-6-烷硫基或C1-6-烷基磺酰基,Z和X独立地代表-N=、-C(H)=、-C(F)=、-C(Cl)=、-C(CN)=或-C(CF3)=,W代表-N=或-C(R10)=,Y代表-N=或-C(R11)=,R4、R5、R6、R7、R8、R9、R10、R11、R12和R13独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、-SCF3、氨基、氰基、硝基或-C(=O)NR14R15,·C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、C3-8-环烷基-C1-6-烷氧基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷氧基、C1-6-烷硫基、C1-6-烷基磺酰基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基或C4-9-杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,· R3 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, C1-10- alkyl, C2-10- alkenyl, C3-8-cycloalkyl, C1-6-alkoxy, aryl group, an aryl group -C1-6- alkyl, amino, C1-6-alkylamino, di-alkylamino -C1-6-, C3-8-cycloalkyl, C3-8-cycloalkoxy, cyano , nitro, C1-6-alkylthio or C1-6-alkylsulphonyl group, Z and X independently represent -N =, - C (H) =, - C (F) =, - C (Cl ) =, - C (CN) =, or -C (CF3) =, W representatives -N = or -C (R10) =, Y representative of -N = or -C (R11) =, R4, R5, R6, R7 , R8, R9, R10, R11, R12 and R13 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, -SCF3, amino, cyano, nitro or -C (= O) NR14R15, · C1-10- alkyl, C2-10- alkenyl, C3-8- cycloalkyl, C1-6- alkoxy, C3-8- cycloalkyl -C1-6- alkoxy, C1 6-alkyl-amino, di-alkylamino -C1-6-, C3-8-cycloalkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, C2-10- alkyl group, C4-9- cycloalkyl group, a heterocyclic group or C3-8-heterocycloalkyl C4-9- alkanoyl or heterocyclic C4-9- alkoxy, which may optionally be substituted with one or more substituents selected from R16 of substituted, · 基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基、杂芳酰基、芳氧基、杂芳氧基、芳基氨基或杂芳基氨基,它们可以可选地被一个或多个选自R18的取代基取代,·或者R5、R6、R7、R8、R9、R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥,R14和R15独立地是氢、C1-6-烷基、芳基-C1-6-烷基,或者R14和R15可以一起构成C3-6-亚烷基桥,R16独立地选自芳基、杂芳基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基、NR19R20和C1-6-烷氧基,R17独立地选自卤素、羟基、三氟甲基、三氟甲氧基、C1-6-烷氧基、C1-6-烷基、氨基、C1-6-烷基磺酰基、C1-6-烷基氨基、二-C1-6-烷基氨基、氰基、芳基、杂芳基和C3-8-环烷基, Group, an aryl group -C1-6- alkyl, -C1-6- alkoxy, aryl or heteroaryl group, which may optionally be substituted with one or more substituents selected from R17, - aroyl, heteroaryl aroyl, aryloxy, heteroaryloxy group, an aryl group or heteroaryl group, which may optionally be substituted with one or more substituents selected from R18, - or R5, R6, R7, R8, R9 , R10, R11, R12 and R13 in two adjacent positions together form a C1-6-alkylene bridge or -O- -O-C1-6- alkylene bridge, R14 and R15 independently are hydrogen, C1 6-alkyl-aryl group -C1-6- alkyl group, or R14 and R15 may constitute C3-6- alkylene bridge, R16 are independently selected from aryl, heteroaryl, C3-8-cycloalkyl together group, halo, trifluoromethyl, trifluoromethoxy, NR19R20 and C1-6-alkoxy, R17 are independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy alkoxy, C1-6-alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-alkylamino -C1-6-, cyano, aryl, heteroaryl and C3 -8- cycloalkyl,

R18独立地选自芳基、杂芳基、C1-10-烷基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基、C1-6-烷氧基、氰基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基和羟基,R19和R20独立地是氢或C1-6-烷基,R19和R20可以一起构成C3-6-亚烷基桥,及其任意非对映体或对映体或互变形式、包括它们的混合物,或其药学上可接受的盐在药物组合物制备中的用途,该药物组合物用于治疗涉及组胺H3受体的障碍和疾病。 R18 is independently selected from aryl, heteroaryl, C1-10- alkyl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, cyano , amino, C1-6-alkylamino, di-alkylamino and hydroxy -C1-6-, R19 and R20 are independently hydrogen or C1-6-alkyl, R19 and R20 may together constitute a C3-6- alkylene bridge group, and any diastereomer or enantiomer or tautomeric form thereof including mixtures thereof, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition, which relates to a pharmaceutical composition for the treatment group amine H3 receptor disorders and diseases.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于治疗其中抑制H3组胺受体具有有益效果的疾病和障碍。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition for the treatment of diseases and disorders in which inhibition of the histamine H3 receptor has a beneficial effect.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物具有组胺H3拮抗活性或组胺H3反激动活性。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于减少体重。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition for reducing body weight.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于治疗超重或肥胖。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition for the treatment of overweight or obesity.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于抑制食欲或用于诱发饱满感。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition is used for inhibiting appetite or inducing satiety.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于预防和/或治疗涉及超重或肥胖的障碍和疾病。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition for preventing and / or obesity or overweight disorders and therapies involve disease.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于预防和/或治疗进食障碍,例如食欲过盛和过食症。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition for the prevention and / or treatment of eating disorders such as bulimia and bulimia.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于治疗IGT。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition for the treatment of IGT.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于治疗2型糖尿病。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition for the treatment of type 2 diabetes.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于延缓或防止IGT发展为2型糖尿病。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition for delaying or preventing the development of type 2 diabetes, IGT.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于延缓或防止非胰岛素需求型2型糖尿病发展为胰岛素需求型2型糖尿病。 In another aspect the present invention provides the use as defined above of formula (II ') in the manufacture of a compound of the pharmaceutical composition, the pharmaceutical composition for delaying or preventing non-insulin requiring type 2 diabetes to insulin-requiring development of type 2 diabetes.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于治疗其中刺激H3组胺受体具有有益效果的疾病和障碍。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition for treating a histamine H3 receptor stimulation wherein the diseases and disorders having a beneficial effect.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物具有组胺H3激动活性。 The present invention is in the manufacture of a pharmaceutical composition In another aspect provides the use as defined above of formula (II ') compound, the pharmaceutical composition having histamine H3 agonistic activity.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于治疗变应性鼻炎、溃疡或食欲缺乏。 In another aspect the present invention provides the use as defined above of formula (II ') in the manufacture of a compound of the pharmaceutical composition, the pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia.

本发明在另一方面提供如上所定义的通式(II')化合物在药物组合物制备中的用途,该药物组合物用于治疗阿尔茨海默氏病、嗜眠症或注意涣散症。 In another aspect the present invention provides the use as defined above of formula (II ') in the manufacture of a compound of the pharmaceutical composition, the pharmaceutical composition is for treating Alzheimer's disease, narcolepsy or attention deficit disorder.

本发明在另一方面提供治疗涉及H3组胺受体的障碍或疾病的方法,该方法包括在需要时对受治疗者给以有效量的如上所定义的通式(II')化合物或者包含这样一种化合物的药物组合物。 The present invention provides in another aspect relates to a method of treating disorders or diseases of the H3 histamine receptor, the method comprising the formula (II ') a subject in need an effective amount of a given treatment as defined above, or a compound containing such a pharmaceutical composition of a compound.

本发明在另一方面提供治疗涉及H3组胺受体的障碍或疾病的方法,其中如上所定义的通式(II')化合物的有效量为每天约0.05mg至约2000mg、优选约0.1mg至约1000mg、尤其优选约0.5mg至约500mg。 In another aspect the present invention provides methods of treating disorders or diseases involving histamine H3 receptor, wherein the effective amount of the compound of formula (II ') as defined above is about 0.05mg to about 2000mg per day, preferably about 0.1mg to about 1000mg, particularly preferably from about 0.5mg to about 500mg.

本发明在另一方面提供治疗涉及组胺H3受体的疾病和障碍的方法,该方法包括在需要时对受治疗者给以有效量的式(I)化合物或者其任意非对映体或对映体或互变体形式、包括它们的混合物或其药学上可接受的盐或者包含它们的药物组合物。 In another aspect the present invention provides methods of treating diseases and disorders involving the histamine H3 receptor, the method comprising administering a effective amount of a compound of formula (I) or any diastereomer or to a subject when required enantiomers or tautomeric forms including pharmaceutically acceptable salts thereof, or mixtures thereof, or a pharmaceutical composition comprising a.

本发明在一方面涉及具有组胺H3受体拮抗活性或反激动活性的化合物,它们因此可以用于治疗多种其中组胺H3受体阻滞是有益的病症和障碍。 In one aspect of the present invention is a compound of histamine H3 receptor antagonistic activity or inverse agonistic activity relates, therefore they can be used to treat various which histamine H3 receptor blockade is beneficial conditions and disorders.

本发明在另一方面涉及具有组胺H3受体激动活性的化合物,它们因此可以用于治疗多种其中组胺H3受体活化是有益的病症和障碍。 In another aspect the present invention relates to compounds having agonistic activity of the histamine H3 receptor, which can therefore be used to treat various which histamine H3 receptor activation is beneficial conditions and disorders.

在优选的发明实施方式中,本发明化合物用于制备减少体重的药物组合物。 In a preferred embodiment of the invention, the compound of the present invention for reducing the body weight of a pharmaceutical composition.

在优选的发明实施方式中,本发明化合物用于制备治疗超重或肥胖的药物组合物。 In a preferred embodiment of the invention, the compound of the present invention for the treatment of overweight or obesity preparing pharmaceutical compositions.

在另一优选的发明实施方式中,本发明化合物用于制备抑制食欲或诱发饱满感的药物组合物。 In another preferred embodiment of the invention, the compounds of the present invention for the preparation of appetite or induce satiety inhibiting pharmaceutical compositions.

在进一步优选的发明实施方式中,本发明化合物用于制备预防和/或治疗涉及超重或肥胖的障碍和疾病的药物组合物,例如动脉粥样硬化、高血压、IGT(葡萄糖耐量异常)、糖尿病(尤其是2型糖尿病(NIDDM(非胰岛素依赖型糖尿病)))、异常脂肪血症、冠心病、胆囊疾病、骨关节炎和各种类型的癌症(例如子宫内膜、乳腺、前列腺和结肠的癌症)。 In a further preferred embodiment of the invention, the compounds of the present invention for preparing the prophylaxis and / or treatment of disorders related to overweight or obesity, and pharmaceutical compositions of the disease, for example atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes (especially type 2 diabetes (of NIDDM (non-insulin dependent diabetes mellitus))), dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer (e.g., endometrial, breast, prostate and colon cancer).

在进一步优选的发明实施方式中,本发明化合物用于制备预防和/或治疗进食障碍的药物组合物,例如食欲过盛和过食症。 In a further preferred embodiment of the invention, the compounds of the present invention for preparing the prophylaxis and / or treatment of eating disorders, pharmaceutical compositions, e.g. bulimia and bulimia.

在进一步优选的发明实施方式中,本发明化合物用于制备治疗IGT的药物组合物。 In a further preferred embodiment of the invention, the compounds of the present invention for preparing a pharmaceutical composition the treatment of IGT.

在进一步优选的发明实施方式中,本发明化合物用于制备治疗2型糖尿病的药物组合物。 In a further preferred embodiment of the invention, the compounds of the present invention for preparing a pharmaceutical composition type 2 diabetes. 这类治疗尤其包括出于延缓或防止IGT发展为2型糖尿病以及延缓或防止非胰岛素需求型2型糖尿病发展为胰岛素需求型2型糖尿病的目的所进行的治疗。 In particular, such treatment includes IGT for delaying or preventing the development of type 2 diabetes, and delaying or preventing non-insulin-requiring type 2 diabetes development for the treatment of insulin-requiring type 2 diabetes purpose carried out.

本发明化合物还可以用于治疗气道障碍,例如气喘,用作抗泻剂,和用于调制胃酸分泌。 The compounds of this invention may also be useful for the treatment of airway disorders such as asthma, as anti-cathartic, and a modulation of gastric acid secretion.

此外,本发明化合物可以用于治疗与睡眠调节和失眠有关的疾病,和用于治疗嗜眠症和注意涣散症。 Furthermore, the compounds of the present invention may be used to treat insomnia and sleep regulation related diseases, and for the treatment of narcolepsy and attention deficit disorder.

而且,本发明化合物可以用作CNS刺激剂或镇静剂。 Furthermore, the compounds of the present invention may be used as CNS stimulants or sedatives.

本发明化合物还可以用于治疗与癫痫有关的病症。 The compounds of this invention may also be useful in the treatment of disorders associated with epilepsy. 另外,本发明化合物可以用于治疗晕动病和眩晕。 Further, the compounds of the present invention may be used for the treatment of motion sickness and vertigo. 此外,它们可以用作下丘脑-垂体分泌调节剂、抗抑郁剂、脑循环调制剂,和用于治疗肠易激综合征。 Further, they can be used hypothalamic - pituitary secretion modulators, antidepressants, modulators of cerebral circulation, and for treatment of irritable bowel syndrome.

此外,本发明化合物可以用于治疗痴呆和阿尔茨海默氏病。 Furthermore, the compounds of the present invention may be useful in the treatment of dementia and Alzheimer's disease.

本发明化合物还可以用于治疗变应性鼻炎、溃疡或食欲缺乏。 The compounds of this invention may also be useful in the treatment of allergic rhinitis, ulcer or anorexia.

本发明化合物此外可以用于治疗偏头痛,参见McLeod et al.,TheJournal of Pharmacology and Experimental Therapeutics 287(1998),43-50,用于治疗心肌梗塞,参见Mackins et al.,Expert Opinion onInvestigational Drugs 9(2000),2537-2542。 Further compounds of the present invention may be used in the treatment of migraine, see McLeod et al., TheJournal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50, for the treatment of myocardial infarction, see Mackins et al., Expert Opinion onInvestigational Drugs 9 ( 2000), 2537-2542.

在进一步的发明方面,用本发明化合物治疗患者是与饮食和/或锻炼相结合的。 In a further aspect of the invention, a patient with diet and / or exercise in combination therapy with the compounds of the present invention.

在进一步的发明方面,本发明化合物是与一种或多种其他活性物质按任意适合比例联合给药的。 In a further aspect of the invention, the compounds of the present invention with one or more further active substances in any suitable ratio of the combined administration. 这类其他活性剂可以选自抗肥胖药、抗糖尿病剂、抗血脂异常剂、抗高血压剂、由糖尿病所致或与之有关的并发症的治疗剂、和由肥胖所致或与之有关的并发症与障碍的治疗剂。 Such other active agents may be selected from antiobesity agents, antidiabetic agents, anti-dyslipidemic agents, anti-hypertensive agent, with or caused by diabetes complications related to therapeutic agents, and relating to or caused by obesity, therapeutic agents complications and disorders.

因而,在进一步的发明方面,本发明化合物是与一种或多种抗肥胖药或食欲调节剂联合给药的。 Accordingly, in a further aspect of the invention, the compounds of the present invention with one or more antiobesity agents or appetite regulating agents administered in combination.

这类药物可以选自下组:CART(可卡因苯丙胺调节的转录)激动剂、NPY(神经肽Y)拮抗剂、MC4(黑皮质素4)激动剂、MC3(黑皮质素3)激动剂、orexin拮抗剂、TNF(肿瘤坏死因子)激动剂、CRF(促皮质素释放因子)激动剂、CRF BP(促皮质素释放因子结合蛋白)拮抗剂、urocortin激动剂、β3肾上腺素能激动剂(例如CL-316243、AJ-9677、GW-0604、LY362884、LY377267或AZ-40140)、MSH(促黑激素)激动剂、MCH(黑素细胞浓缩激素)拮抗剂、CCK(缩胆囊肽)激动剂、血清素再摄取抑制剂(例如氟西汀、帕罗克塞或西酞普兰)、血清素与去甲肾上腺素再摄取抑制剂、混合型血清素与去甲肾上腺素能化合物、5HT(血清素)激动剂、铃蟾肽激动剂、神经节肽拮抗剂、生长激素、生长因子(例如催乳素或胎盘催乳素)、生长激素释放化合物、TRH(促甲状腺素释放激素)激动剂、UCP 2或3(解偶联蛋白2或3)调制剂、瘦素激动剂、DA激 Such drugs may be selected from the group: CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 adrenergic agonists (e.g., CL -316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140), MSH (melanocyte-stimulating hormone) agonists, the MCH (melanocyte-concentrating hormone) antagonists, of CCK (cholecystokinin) agonists, serum reuptake inhibitors (e.g. fluoxetine, paroxetine, or Alexei citalopram), serotonin and norepinephrine reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, ganglion peptide antagonists, growth hormones, growth factors (e.g., prolactin, or placental lactogen), growth hormone releasing compounds, TRH (thyrotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, stimulated the DA 剂(溴隐亭、doprexin)、脂酶/淀粉酶抑制剂、PPAR(过氧化物酶体增殖物活化受体)调制剂、RXR(类视黄酸X受体)调制剂、TRβ激动剂、AGRP(刺豚鼠相关性蛋白)抑制剂、阿片样物质拮抗剂(例如纳曲酮)、exendin-4、GLP-1和睫状神经营养因子。 Agent (bromocriptine, doprexin), lipase / amylase inhibitor, a PPAR (peroxisome proliferator-activated receptor) modulators, a RXR (retinoid X receptor) modulators, TR [beta] agonists, AGRP (agouti related protein) inhibitors, opioid antagonist (e.g. naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.

在一种发明实施方式中,抗肥胖药是瘦素。 In one embodiment of the invention the antiobesity agent is leptin.

在另一种实施方式中,抗肥胖药是右旋苯丙胺或苯丙胺。 In another embodiment, the antiobesity agent is dexamphetamine or amphetamine.

在另一种实施方式中,抗肥胖药是芬氟拉明或右旋芬氟拉明。 In another embodiment, the antiobesity agent is fenfluramine or dexfenfluramine.

在另一种实施方式中,抗肥胖药是西布曲明。 In another embodiment, the antiobesity agent is sibutramine.

在进一步的实施方式中,抗肥胖药是奥利司他。 In further embodiments, the anti-obesity drug orlistat.

在另一种实施方式中,抗肥胖药是马吲哚或芬特明。 In another embodiment, the antiobesity agent is mazindol or phentermine.

在另一种实施方式中,抗肥胖药是苯甲曲秦、安非拉酮、氟西汀、安非他酮、托吡酯或ecopipam。 In another embodiment, the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.

在更进一步的方面,本发明化合物是与一种或多种抗糖尿病剂联合给药的。 In a further aspect, the present invention is a compound with one or more antidiabetic agents administered in combination.

有关的抗糖尿病剂包括胰岛素、胰岛素类似物与衍生物,例如公开在下列文献中的那些:EP 0 792 290(Novo Nordisk A/S),例如NεB29-十四烷酰des(B30)人胰岛素;EP 0 214 826和EP 0 705 275(NovoNordisk A/S),例如AspB28人胰岛素;US 5,504,188(Eli Lilly),例如LysB28ProB29人胰岛素;EP 0 368 187(Aventis),例如Lantus,它们都引用在此作为参考文献;GLP-1衍生物,例如公开在WO 98/08871(Novo Nordisk A/S)中的那些,引用在此作为参考文献,以及口服有效的降血糖剂。 For antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in the following documents: EP 0 792 290 (Novo Nordisk A / S), e.g. NεB29- tetradecanoyl des (B30) human insulin; EP 0 214 826 and EP 0 705 275 (NovoNordisk A / S), for example AspB28 human insulin; US 5,504,188 (Eli Lilly), e.g. LysB28ProB29 human insulin; EP 0 368 187 (Aventis), e.g. Lantus, which are incorporated herein by reference; GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk a / S), those incorporated herein by reference, as well as orally active hypoglycemic agents.

口服有效的降血糖剂优选地包含咪唑啉类;磺酰脲类;双胍类;氯茴苯酸类;噁二唑烷二酮类;噻唑烷二酮类;胰岛素致敏剂;α-葡萄糖苷酶抑制剂;作用于ATP依赖型β-细胞钾通道的药物,例如钾通道开放剂,例如公开在WO 97/26265、WO 99/03861和WO 00/37474(Novo NordiskA/S)中的那些,引用在此作为参考文献;或米格列奈;或钾通道阻滞剂,例如BTS-67582、纳格列奈;高血糖素拮抗剂,例如公开在WO 99/01423和WO 00/39088(Novo Nordisk A/S and Agouron Pharmaceuticals,Inc.)中的那些,引用在此作为参考文献;GLP-1激动剂,例如公开在WO00/42026(Novo Nordisk A/S and Agouron Pharmaceuticals,Inc.)中的那些,引用在此作为参考文献;DPP-IV(二肽基肽酶-IV)抑制剂;PTP酶(蛋白质酪氨酸磷酸酶)抑制剂;参与糖异生和/或糖原分解刺激的肝酶抑制剂;葡萄糖摄取调制剂;GSK-3(糖原合酶激酶-3)抑制剂;改变脂 Orally effective hypoglycemic agents preferably comprise imidazolines; sulfonylureas; biguanides; meglitinides; oxadiazol TZDs; thiazolidine diones; insulin sensitizers; alpha] glucosidase enzyme inhibitors; drugs acting on the ATP-dependent potassium channel β-, for example potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and those of WO 00/37474 (Novo NordiskA / S) is, incorporated herein by reference; or mitiglinide; or potassium channel blockers, such as BTS-67582, nateglinide; glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo those GLP-1 agonists such as those disclosed in WO00 / 42026 (Novo Nordisk a / S and Agouron Pharmaceuticals, Inc) in;. Nordisk a / S and Agouron Pharmaceuticals, Inc) those, incorporated herein by reference. , incorporated herein by reference; DPP-IV (dipeptidyl peptidase -IV) inhibitors; the PTP enzyme (protein tyrosine phosphatase) inhibitors; involved in gluconeogenesis and / or liver enzymes stimulated by glycogenolysis inhibitor; glucose uptake modulators; GSK-3 (glycogen synthase kinase-3) inhibitors; lipid changes 代谢的化合物,例如抗血脂异常剂;降低食物摄取的化合物;PPAR(过氧化物酶体增殖物活化受体);RXR(类视黄酸X受体)激动剂,例如ALRT-268、LG-1268或LG-1069。 Metabolism of the compound, for example anti-dyslipidemic agent; compounds lowering food intake; a PPAR (peroxisome proliferator-activated receptor); a RXR (retinoid X receptor) agonists, such as ALRT-268, LG- 1268 or LG-1069.

在一种发明实施方式中,本发明化合物是与胰岛素或胰岛素类似物或衍生物联合给药的,例如NεB29-十四烷酰des(B30)人胰岛素、AspB28人胰岛素、LysB28ProB29人胰岛素、Lantus或者包含它们中的一种或多种的混合制备物。 In one embodiment of the invention, the compounds of the present invention is insulin or an insulin analogue or derivative administered in combination, e.g. NεB29- tetradecanoyl des (B30) human insulin, of AspB28 human insulin, LysB28ProB29 human insulin, Lantus or contains them in one or more of the mixture was prepared.

在进一步的发明实施方式中,本发明化合物是与一种磺酰脲联合给药的,例如甲苯磺丁脲、氯磺丙脲、妥拉磺脲、格列本脲、格列吡嗪、格列美脲、格列齐特(glicazide)或格列本脲。 In a further embodiment of the invention, the compounds of the present invention is administered in combination with one sulfonylurea, such as tolbutamide, chlorpropamide, tolazamide, glyburide, glipizide, grid glimepiride, gliclazide (glicazide) or glyburide.

在另一种发明实施方式中,本发明化合物是与一种双胍联合给药的,例如甲福明。 In another embodiment of the invention, the compound of the present invention is administered in combination with one biguanide, such as metformin.

在另外一种实施方式中,本发明化合物是与一种美格列奈联合给药的,例如瑞格列奈或纳格列奈。 In another embodiment, the compounds of the present invention is administered in combination with one meglitinide, such as repaglinide or nateglinide.

在另一种发明实施方式中,本发明化合物是与一种噻唑烷二酮胰岛素致敏剂联合给药的,例如曲格列酮、环格列酮、吡格列酮、罗格列酮、伊格列酮(isaglitazone)、达格列酮、恩格列酮、CS-011/CI-1037或T 174或者公开在WO 97/41097、WO 97/41119、WO 97/41120、WO00/41121和WO 98/45292(Dr.Reddy′s Research Foundation)中的化合物,引用在此作为参考文献。 In another embodiment of the invention, the compound of the present invention with one thiazolidinedione insulin sensitizers administered in combination, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone, Ignatius column -one (isaglitazone), darglitazone, englitazone, CS-011 / CI-1037 or T 174 or disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO00 / 41121 and WO 98 / compound (Dr.Reddy's Research Foundation) in 45292, incorporated herein by reference.

在另一种发明实施方式中,本发明化合物可以与一种胰岛素致敏剂联合给药,例如GI 262570、YM-440、MCC-555、JTT-501、AR-H039242、KRP-297、GW-409544、CRE-16336、AR-H049020、LY510929、MBX-102、CLX-0940、GW-501516或者公开在WO 99/19313、WO 00/50414、WO00/63191、WO 00/63192、WO 00/63193(Dr.Reddy′s ResearchFoundation)和WO 00/23425、WO 00/23415、WO 00/23451、WO 00/23445、WO 00/23417、WO 00/23416、WO 00/63153、WO 00/63196、WO 00/63209、WO 00/63190和WO 00/63189(Novo Nordisk A/S)中的化合物,引用在此作为参考文献。 In another embodiment of the invention, the compounds of the present invention may be administered in combination with an insulin sensitizer, e.g. GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW- 409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or disclosed in WO 99/19313, WO 00/50414, WO00 / 63191, WO 00/63192, WO 00/63193 ( Dr.Reddy's ResearchFoundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00 / 63209, the compounds of WO 00/63190 and WO 00/63189 (Novo Nordisk a / S), incorporated herein by reference.

在进一步的发明实施方式中,本发明化合物是与一种α-葡萄糖苷酶抑制剂联合给药的,例如伏格列波糖、乙格列酯、米格列醇或阿卡波糖。 In a further embodiment of the invention, the compounds of the present invention with one α- glucosidase inhibitor administered in combination, for example, voglibose, emiglitate, miglitol or acarbose.

在另一种发明实施方式中,本发明化合物是与一种作用于β-细胞的ATP依赖型钾通道的药物联合给药的,例如甲苯磺丁脲、格列本脲、格列吡嗪、格列齐特、BTS-67582或瑞格列奈。 In another embodiment of the invention, the compound of the present invention is a drug that acts on the ATP-dependent potassium channel of the β- cells administered in combination, for example, tolbutamide, glibenclamide, glipizide, gliclazide, BTS-67582 or repaglinide.

在另外一种发明实施方式中,本发明化合物可以与纳格列奈联合给药。 In another embodiment of the invention, the compounds of the present invention may be administered in combination with nateglinide.

在另外一种实施方式中,本发明化合物是与一种抗高血脂剂或抗血脂剂联合给药的,例如考来烯胺、考来替泊、氯贝特、吉非贝齐、洛伐他汀、普伐他汀、辛伐他汀、普罗布考或右旋甲状腺素。 In another embodiment, the compounds of the present invention is an anti-hyperlipidemia agent or anti-lipid agent administered in combination, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin statins, pravastatin, simvastatin, probucol or right thyroxine.

在另外一种发明实施方式中,本发明化合物是与一种抗血脂剂联合给药的,例如考来烯胺、考来替泊、氯贝特、吉非贝齐、洛伐他汀、普伐他汀、辛伐他汀、普罗布考或右旋甲状腺素。 In another embodiment of the invention, the compounds of the present invention is administered in combination with an anti-hyperlipidemia agent, e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin statin, simvastatin, probucol or right thyroxine.

在发明的另一方面,本发明化合物是与一种以上上述化合物联合给药的,例如甲福明与一种磺酰脲,例如格列本脲;一种磺酰脲与阿卡糖;纳格列奈与甲福明;阿卡波糖与甲福明;一种磺酰脲、甲福明与曲格列酮;胰岛素与一种磺酰脲;胰岛素与甲福明;胰岛素、甲福明与一种磺酰脲;胰岛素与曲格列酮;胰岛素与洛伐他汀;等等。 In another aspect of the invention, the compounds of the present invention is administered in combination one or more of the above compounds, for example, with one sulfonylurea, metformin, e.g. glibenclamide; one kind of sulfonylurea and acarbose; sodium nateglinide and metformin; acarbose and metformin; one kind sulfonylurea, metformin and troglitazone; with one sulfonylurea insulin; insulin and metformin; insulin A-fu out with one sulfonylurea; insulin and troglitazone; insulin and lovastatin; and the like.

此外,本发明化合物可以与一种或多种抗高血压剂联合给药。 Furthermore, the compounds of the present invention may be administered in combination with one or more antihypertensive agents. 抗高血压剂的实例是β-阻滞剂,例如阿普洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、普萘洛尔和美托洛尔;ACE(血管紧张素转化酶)抑制剂,例如贝那普利、卡托普利、依那普利、福辛普利、赖诺普利、喹那普利和雷米普利;钙通道阻滞剂,例如硝苯地平、非洛地平、尼卡地平、伊拉地平、尼莫地平、地尔硫和维拉帕米;和α-阻滞剂,例如多沙唑嗪、乌拉地尔、哌唑嗪和特拉唑嗪。 Examples of antihypertensive agents are β- blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol; the ACE (angiotensin converting enzyme ) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril; calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil ; and α- blockers, e.g. doxazosin, urapidil, prazosin and terazosin triazine. 进一步可以参考Remington:The Scienceand Practice of Pharmacy,19thEdition,Gennaro,Ed.,MackPublishing Co.,Easton,PA,1995。 Further reference may Remington: The Scienceand Practice of Pharmacy, 19thEdition, Gennaro, Ed, MackPublishing Co., Easton, PA, 1995..

应当理解,本发明化合物与饮食和/或锻炼、一种或多种上述化合物和可选的一种或多种其它活性物质的任意适合的组合都被视为属于本发明的范围。 It should be appreciated that the compounds of the present invention with diet and / or exercise, more of the aforementioned compounds and optionally one or one or more other active substances in any suitable combinations are considered within the scope of the present invention.

本发明化合物可以是手性的,意味着,任意所分离的对映体、纯净或部分纯化的对映体或其外消旋混合物都包括在本发明的范围内。 Compounds of the invention may be chiral, meaning, any isolated enantiomers, or pure enantiomer or a racemic mixture of partially purified are included within the scope of the invention.

此外,当在分子中存在双键或者完全或部分饱和的环系或者一个以上不对称中心或者旋转性受限的键时,可以生成非对映体。 Furthermore, when a double bond or a fully or partially saturated ring system or more asymmetric centers or a bond with restricted rotatability in the molecule diastereomers may be generated. 任意所分离的非对映体、纯净或部分纯化的非对映体或其混合物都包括在本发明的范围内。 Any of the diastereomers separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the present invention.

此外,一些本发明化合物可以存在不同的互变形式,任意化合物所能够生成的互变形式都包括在本发明的范围内。 In addition, some of the compounds of the present invention may exist in different tautomeric forms, any compound capable of generating tautomeric forms are included within the scope of the invention.

本发明还涵盖本发明化合物的药学上可接受的盐。 The present invention also encompasses pharmaceutically acceptable salts of the compounds of the present invention. 这类盐包括药学上可接受的酸加成盐、药学上可接受的金属盐、铵与烷基化铵盐。 Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. 酸加成盐包括无机酸以及有机酸的盐。 Acid addition salts include salts of inorganic acids and organic acids. 适合的无机酸的代表性实例包括盐酸、氢溴酸、氢碘酸、磷酸、硫酸、硝酸等。 Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, and nitric acid. 适合的有机酸的代表性实例包括甲酸、乙酸、三氯乙酸、三氟乙酸、丙酸、苯甲酸、肉桂酸、柠檬酸、富马酸、乙醇酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、草酸、苦味酸、丙酮酸、水杨酸、琥珀酸、甲磺酸、乙磺酸、酒石酸、抗坏血酸、扑酸、双亚甲基水杨酸、乙二磺酸、葡糖酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、EDTA、乙醇酸、对-氨基苯甲酸、谷氨酸、苯磺酸、对-甲苯磺酸等。 Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic acid, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, glucosamine sugar acids, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p - aminobenzoic, glutamic, benzenesulfonic, p - toluenesulfonic acid. 药学上可接受的无机或有机酸加成盐的进一步实例包括在J.Pharm.Sci.1977,66,2中所列举的药学上可接受的盐,引用在此作为参考文献。 Pharmaceutically acceptable inorganic or organic acid addition salts Further examples include pharmaceutically on J.Pharm.Sci.1977,66,2 enumerated acceptable salts, incorporated herein by reference. 金属盐的实例包括锂、钠、钾、镁的盐等。 Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. 铵与烷基化铵盐的实例包括铵、甲基铵、二甲基铵、三甲基铵、乙基铵、羟乙基铵、二乙基铵、丁基铵、四甲基铵盐等。 Ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like .

作为药学上可接受的酸加成盐还包括本发明化合物所能够生成的水合物。 As the pharmaceutically acceptable acid addition salts also comprises the hydrates of the compounds of the present invention can be generated.

酸加成盐可以作为化合物合成的直接产物而获得。 Acid addition salts may be obtained as the direct products of compound synthesis. 在替代方式中,可以将游离碱溶于含有适当的酸的适合的溶剂,蒸发溶剂或者分开盐与溶剂,从而分离盐。 In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid and the solvent was evaporated separately or salt with a solvent to separate the salt.

利用本领域技术人员熟知的方法,本发明化合物可以与标准的低分子量溶剂生成溶剂化物。 Using methods well known to those of skill in the compounds of the present invention may be generated solvates with standard low molecular weight solvents. 这类溶剂化物也被涵盖在本发明的范围内。 Such solvates are also encompassed within the scope of the present invention.

本发明还涵盖本发明化合物的前体药物,它们在给药后,在变为活性药理学物质之前经历代谢过程的化学转化。 The present invention also encompasses prodrugs of the compounds of the present invention, which after administration undergo chemical conversion metabolic processes before becomes active pharmacological substances. 一般而言,这类前体药物将是本发明化合物的功能衍生物,它们容易体内转化为所需式(I)化合物。 In general, such prodrugs will be functional derivatives of the compounds of the present invention, it is readily converted in vivo into the required compound of formula (I). 适合的前体药物衍生物的常规选择与制备工艺例如描述在″Designof Prodrugs″,ed.H.Bundgaard,Elsevier,1985中。 Conventional selection and preparation of suitable prodrug derivatives thereof such as described in "Designof Prodrugs", ed.H.Bundgaard, Elsevier, 1985 in the.

本发明还涵盖本发明化合物的活性代谢产物。 The present invention also encompasses active metabolites of the compounds of the present invention.

本发明化合物与组胺H3受体相互作用,因此可用于治疗多种其中组胺H3受体相互作用是有益的病症和障碍。 Compounds of the invention interact with the histamine H3 receptor, and therefore are useful for treating various wherein the histamine H3 receptor interactions are beneficial conditions and disorders.

药物组合物本发明化合物可以单独给药或者与药学上可接受的载体或赋形剂联合给药,分单剂或多剂。 Pharmaceutical compositions of the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients administered in combination, divided single or multiple doses. 根据本发明的药物组合物可以这样配制,按照常规技术,例如公开在Remington:The Science and Practice ofPharmacy,19thEdition,Gennaro,Ed.,Mack Publishing Co.,Easton,PA,1995中的那些,使用药学上可接受的载体或稀释剂以及任意其他已知的助剂和赋形剂。 The pharmaceutical compositions of the invention may be formulated according to conventional techniques, for example, disclosed in Remington:. The Science and Practice ofPharmacy, 19thEdition, Gennaro, Ed, the Mack Publishing Co., Easton, PA, 1995 that the use of a pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients.

药物组合物可以被具体配制成用于借助任意适合途径给药,例如口服、直肠、鼻、肺、局部(包括颊和舌下)、透皮、脑池内、腹膜内、阴道和肠胃外(包括皮下、肌内、鞘内、静脉内和真皮内)途径,口服途径是优选的。 The pharmaceutical compositions may be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. 将被领会的是,优选的途径将依赖于受治疗者的一般条件与年龄、所治疗病症的属性和所选择的活性成分。 It will be appreciated that the preferred route will depend on the general condition and age of the subject, the properties of the active ingredient and the condition of the selected treatment.

用于口服给药的药物组合物包括固体剂型,例如胶囊剂、片剂、糖锭剂、丸剂、锭剂、粉剂和颗粒剂。 Pharmaceutical compositions for oral administration include solid dosage forms, such as capsules, tablets, dragees, pills, lozenges, powders and granules. 在适当时,它们可以带有包衣,例如肠溶衣,或者它们可以按照本领域熟知的方法被这样配制,以提供活性成分的控制释放,例如持续或延长的释放。 Where appropriate, they can be prepared with coatings such as enteric coatings, or they can be formulated according to such methods known in the art, to provide controlled release of the active ingredient, such as sustained or prolonged release.

用于口服给药的液体剂型包括溶液、乳液、混悬液、糖浆剂和酏剂。 Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

用于肠胃外给药的药物组合物包括无菌的水性与非水性可注射溶液、分散体、混悬液或乳液,以及无菌的粉剂,在使用前再生为无菌的可注射溶液或分散体。 The pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions and sterile powders, regenerated prior to use into sterile injectable solutions or dispersions body. 药库注射制剂也被涵盖在本发明的范围内。 Storeroom injectable formulations are also contemplated as being within the scope of the present invention.

其他适合的给药剂型包括栓剂、喷雾剂、软膏剂、霜剂、凝胶剂、吸入剂、皮肤贴剂、植入物等。 Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants and the like.

典型的口服剂量在约0.001至约100mg/kg体重每天的范围内,优选约0.01至约50mg/kg体重每天,更优选约0.05至约10mg/kg体重每天,分一剂或多剂给药,例如1至3剂。 Typical oral dosages in the range of / kg body weight per day, preferably about 0.01 to about 50mg / kg body weight, preferably from about 0.05 to about 10mg / kg body weight, administered one or more doses minutes more per day per day at about 0.001 to about 100mg, e.g. 1-3. 精确的剂量将依赖于给药的频率与方式、受治疗者的性别、年龄、体重与一般条件、所治疗病症和所治疗任何伴发疾病的属性与严重性和本领域技术人员显而易见的其他因素。 The exact dosage will depend upon the frequency and mode of administration, subject gender of the subject, age, weight, and general condition, the condition being treated and any concomitant diseases to other factors and the severity of the properties and apparent to the skilled person to be treated .

借助本领域技术人员已知的方法,制剂可以适宜地呈现单位剂型。 By means of the methods known to the skilled person, suitable formulations may be presented in unit dosage form. 典型的用于口服给药的单位剂型每天一或多次,例如每天1至3次,可以含有0.05至约1000mg、优选约0.1至约500mg、更优选约0.5mg至约200mg。 Typical unit dosage forms for oral administration one or more times per day, for example 1 to 3 times per day may contain from 0.05 to about lOOOmg, preferably about 0.1 to about 500mg, more preferably from about 0.5mg to about 200mg.

就肠胃外途径而言,例如静脉内、鞘内、肌内和相似的给药,典型的剂量是口服给药所采用的剂量的大约一半。 For parenteral routes to, such as intravenous, intrathecal, intramuscular and similar administration, typical dose is about half the dose employed for oral administration of.

本发明化合物一般采用游离物质或其药学上可接受的盐。 The compounds of this invention is generally used as the free substance or a pharmaceutically acceptable salt thereof. 一个实例是具有游离碱实用性的化合物的酸加成盐。 One example is an acid addition salt of a compound having a free base practical. 当式(I)化合物含有游离碱时,这类盐是按照常规方式制备的,将式(I)游离碱的溶液或混悬液用化学当量的药学上可接受的酸处理,例如无机和有机酸。 When the formula (I) compound contains a free base such salts are prepared in a conventional manner, the acceptable free base of formula (I) with a chemical equivalent of a solution or suspension of a pharmaceutically acceptable acid treatment, such as inorganic and organic acid. 代表性实例在上文提到过。 Representative examples mentioned above. 具有羟基的化合物的生理学上可接受的盐包括所述化合物的阴离子与适合阳离子的组合,例如钠或铵离子。 Physiologically acceptable salts of the compounds having a hydroxyl group include the anion of said compound in combination with a suitable cation, such as sodium or ammonium ion.

就肠胃外给药而言,可以采用新颖的式(I)化合物在无菌水溶液、含水丙二醇或者芝麻或花生油中的溶液。 For parenteral administration, solutions of the novel compounds of formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. 如果必要的话,这类水溶液应当被适当缓冲,液体稀释剂首先被足量盐水或葡萄糖赋予等渗性。 If necessary, such aqueous solutions should be suitably buffered and the liquid diluent first rendered isotonic sufficient saline or glucose. 水溶液特别适合于静脉内、肌内、皮下和腹膜内注射。 Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. 所采用的无菌水性介质都是容易为本领域技术人员已知的工艺所获得的。 Sterile aqueous media employed are readily known to those skilled in the art obtained by the process.

适合的药用载体包括惰性固体稀释剂或填充剂、无菌水溶液和各种有机溶剂。 Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. 固体载体的实例有乳糖、白土、蔗糖、环糊精、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸或纤维素的低级烷基醚。 Examples of solid carriers are lactose-lower alkyl ethers, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, or cellulose. 液体载体的实例有糖浆、花生油、橄榄油、磷脂、脂肪酸、脂肪酸胺、聚氧乙烯或水。 Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. 类似地,载体或稀释剂可以包括本领域已知的任何持续释放材料,例如甘油单硬脂酸酯或甘油二硬脂酸酯,单独的或者与一种蜡混合。 Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with one wax. 将新颖的式(I)化合物与药学上可接受的载体结合在一起所构成的药物组合物然后容易以多种适合于所公开的给药途径的剂型给药。 The novel compound of formula (I) and a pharmaceutically acceptable carrier in combination with a pharmaceutical composition consisting of is then readily administered in a dosage form suitable for various administration routes disclosed. 借助药学领域已知的方法,制剂可以适宜地呈现单位剂型。 By methods known in the pharmaceutical art, the formulation can be conveniently presented in unit dosage form.

适合于口服给药的本发明制剂可以呈现离散的单元,例如胶囊或药片,每一单元含有预定量的活性成分,并且可以包括适合的赋形剂。 Formulations of the invention suitable for oral administration may be presented in discrete units, such as capsules or tablets, each unit containing a predetermined amount of the active ingredient, and may comprise suitable excipients. 这些制剂可以是粉剂或颗粒剂、在水性或非水性液体中的溶液或混悬液或者水包油型或油包水型乳剂。 These formulations may be a powder or granules, in an aqueous or nonaqueous liquid solution or suspension or oil-in-water or oil-in-water emulsion.

如果使用固体载体用于口服给药,那么制备物可以被压片、以粉末或颗粒形式置于硬明胶胶囊中或者它可以是糖锭剂或锭剂的形式。 If a solid carrier for oral administration, the preparation may be tableted, placed in the form of powder or granules in hard gelatin capsules or it may be in the form of troches or lozenges. 固体载体的量将在大范围内变化,但是通常将是约25mg至约1g。 The amount of solid carrier will vary over a wide range, but generally will be from about 25mg to about 1g.

如果使用液体载体,那么制备物可以是糖浆剂、乳剂、软明胶胶囊剂或无菌可注射液体的形式,例如水性或非水性液体混悬液或溶液。 If a liquid carrier, the preparation may be in the form of a syrup, emulsion, soft gelatine capsules or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

典型的片剂可以借助常规压片技术制备,可以含有:片心:活性化合物(游离化合物或其盐) 5.0mg乳糖Ph.Eur. 67.8mg微晶纤维素(Avicel) 31.4mgAmberliteIRP88*1.0mg硬脂酸镁Ph.Eur. qs A typical tablet may be prepared by conventional tabletting techniques, may contain: the tablet core: The active compound (free compound or salt thereof) 5.0mg Lactose Ph.Eur 67.8mg Microcrystalline cellulose (Avicel) 31.4mgAmberliteIRP88 * 1.0mg magnesium stearate Ph.Eur. qs

包衣:羟丙基甲基纤维素 约9mgMywacett 9-40T**约0.9mg Coating: Hydroxypropyl methylcellulose from about 0.9mg to about 9mgMywacett 9-40T **

*Polacrillin钾NF,片剂崩解剂,Rohm and Haas**酰化甘油单酯,用作膜衣增塑剂如果需要的话,本发明药物组合物可以包含式(I)化合物与其它的药理活性物质的组合,例如上文所述那些。 * Polacrillin potassium NF, tablet disintegrant, Rohm and Haas ** acylated monoglyceride used as plasticizer, film-coated, if desired, the pharmaceutical compositions of the invention may comprise a compound of formula (I) with other pharmacologically active combination of materials, such as those described above.

实施例实施例中,下列术语打算具有下列通用含义:DIPEA:二异丙基乙胺DMSO:二甲基亚砜THF:四氢呋喃HPLC(方法A)NMR光谱是在Bruker 300MHz和400MHz仪器上记录的。 EXAMPLES Example, the following terms are intended to have the following general meanings: DIPEA: diisopropylethylamine DMSO: dimethyl sulfoxide THF: tetrahydrofuran HPLC (Method A) NMR spectra were recorded on Bruker 300MHz and 400MHz instruments. HPLC-MS是在Perkin Elmer仪器(API 100)上进行的。 HPLC-MS was performed on a Perkin Elmer instrument (API 100). 所用柱子是X-Terra C18,5μm,50×3mm,洗脱是这样进行的,在1.5ml/min下,在室温下,使用5%至90%乙腈/水/0.01%三氟乙酸的梯度,在7.5分钟内。 The column used was X-Terra C18,5μm, 50 × 3mm, elution is carried out at 1.5ml / min, at room temperature, using 5% to 90% acetonitrile / water gradient /0.01% trifluoroacetic acid, within 7.5 minutes.

HPLC(方法B)反相分析是利用214与254nm下的UV检测、在218TP54 4.6mm×150mm C-18二氧化硅柱上进行的,在42℃下以1ml/min洗脱。 (Method B) using reverse phase analytical HPLC with 254nm UV detection at 214 performs the 218TP54 4.6mm × 150mm C-18 silica column, eluted at 1ml / min at 42 ℃. 将柱子用5%乙腈、85%水和10%的0.5%三氟乙酸水溶液平衡,用从5%乙腈、85%水与10%的0.5%三氟乙酸溶液到90%乙腈与10%的0.5%三氟乙酸溶液的线性梯度洗脱,历经15分钟。 The column was washed with 5% acetonitrile, 85% water and 10% 0.5% aqueous trifluoroacetic acid balance, with from 5% acetonitrile, 85% water and 10% of 0.5% trifluoroacetic acid to 90% acetonitrile and 10% 0.5 % trifluoroacetic acid linear gradient over 15 minutes.

HPLC(方法C)RP分析是利用装有Waters 2487双波段检测器的Alliance Waters2695系统进行的。 HPLC (Method C) RP system using Alliance Waters2695 analysis with Waters 2487 dual band detector performed. UV检测是利用Symmetry C18,3.5μm,3.0mm×100mm柱收集的。 UV detection using Symmetry C18,3.5μm, 3.0mm × 100mm column collected. 用5-90%乙腈、90-0%水与5%三氟乙酸(1.0%)水溶液的线性梯度洗脱,历经8分钟,流速1.0mL/min。 With 5-90% acetonitrile, 90-0% water and 5% trifluoroacetic acid (1.0%) with a linear gradient elution of an aqueous solution, after 8 min, flow rate 1.0mL / min.

通用工艺(A)通用工艺(A)可以用于制备通式(Ia)化合物: General procedure (A) General process (A) may be used for the preparation of formula (Ia) compound:

其中-CH(R20R21)代表乙基、异丙基、支链C4-6-烷基、支链C4-6-烯基、支链C4-6-炔基、C3-5-环烷基、C3-7-环烯基、C3-6-环烷基-C1-3-烷基或C3-6-环烯基-C1-3-烷基,它们可以可选地被一个或多个卤素取代基取代。 Wherein the -CH (R20R21) represents an ethyl group, an isopropyl group, a branched C4-6- alkyl, C4-6- branched chain alkenyl, branched C4-6- alkynyl, C3-5- cycloalkyl, C3 -7-alkenyl, C3-6-cycloalkyl or C3-6-cycloalkenyl group -C1-3- -C1-3- alkyl group, which may optionally be substituted with one or more halogen substituents replaced.

向单取代的哌嗪(15.2mmol)在适合的溶剂、例如THF中的混合物加入酮或醛(22.6mmol)、水、乙酸(45.0mmol)、然后是NaCNBH3(18mmol)。 The monosubstituted piperazine (15.2mmol) in a suitable solvent such as THF was added a mixture of ketone or aldehyde (22.6 mmol), water, acetic acid (45.0 mmol), followed by NaCNBH3 (18mmol). 将混合物在55℃下搅拌5.5小时(酮)或者在室温下搅拌过夜(醛),然后在减压下浓缩。 The mixture was stirred at 55 ℃ 5.5 hours (one) or was stirred at room temperature overnight (an aldehyde), then concentrated under reduced pressure. 加入饱和NaHCO3水溶液(100ml),混合物用溶剂萃取,例如乙酸乙酯(3×40ml)。 Saturated aqueous NaHCO3 (100ml), the mixture was extracted with a solvent, such as ethyl acetate (3 × 40ml). 合并萃取液,用盐水洗涤,经硫酸镁干燥,在减压下浓缩。 The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. 可以如下将残余物转化为适当的盐,例如盐酸盐,与一种酸、例如1摩尔含水盐酸、乙醇和甲苯共同蒸发,残余物然后经过重结晶纯化。 As will be residue was converted into an appropriate salt, such as hydrochloride, with an acid, for example, 1 molar aqueous hydrochloric acid, ethanol and toluene co-evaporation, the residue was then purified by recrystallization.

通用工艺(B)通式(I)化合物可以借助通用工艺(B)制备: General procedure (B) a compound of formula (I) can make use of general procedure (B) was prepared: 将单取代的哌嗪(2.00mmol)、DMSO(1.0ml)、适合的芳基或杂芳基卤化物(2.00mmol)与一种碱、例如DIPEA(0.20ml)的混合物在100℃下搅拌1小时,然后在120℃下搅拌18小时。 The mono-substituted piperazine (2.00mmol), DMSO (1.0ml), suitable aryl or heteroaryl halide (2.00 mmol) with a base, for example a mixture of DIPEA (0.20ml) was stirred at 100 ℃ 1 hours, then at 120 ℃ 18 hours. 加入水和碳酸钾,混合物用溶剂萃取,例如乙酸乙酯(3×20ml)。 Water and potassium carbonate were added, and the mixture was extracted with a solvent, such as ethyl acetate (3 × 20ml). 同通用工艺(A)进行分离和纯化。 Isolated and purified the same general procedure (A).

非商业上可得到的取代的2-氯喹啉是如文献所述制备的:F.Effenberger,W.Hartmann,Chemische Berichte 1969,102,3260-3267。 Commercially available non-substituted 2-chloro-quinoline is prepared as in the literature: F.Effenberger, W.Hartmann, Chemische Berichte 1969,102,3260-3267.

通用工艺(C)通式(I)化合物可以借助通用工艺(C)制备: General procedure compound (C) of the general formula (I) may aid in general procedure (C) were prepared: 式I化合物可以这样制备,从适合的单取代的哌嗪和适合的芳基溴开始,在适合的催化剂的存在下,例如三(二亚苄基丙酮)二钯,在适合的溶剂中,例如甲苯,在适合的温度下,例如在0℃与150℃之间。 Compounds of formula I can be prepared starting from a suitable monosubstituted piperazine and a suitable aryl bromide, in the presence of a catalyst suitable, for example tris (dibenzylideneacetone) dipalladium, in a suitable solvent, e.g. toluene, at a suitable temperature, for example at between 0 ℃ and 150 ℃.

实施例14-(4-环戊基哌嗪-1-基)苯酚 Example 14 (4-cyclopentyl-piperazin-1-yl) phenol 向1-(4-羟基苯基)哌嗪(2.70g,15.2mmol)的THF(28ml)悬液加入环戊酮(1.90ml,22.6mmol)、水(0.15ml)、乙酸(2.70ml,45.0mmol)、然后是NaCNBH3(18ml,1M THF溶液,18mmol)。 Was added cyclopentanone (1.90 ml, 22.6 mmol) of 1- (4-hydroxyphenyl) piperazine (2.70g, 15.2mmol) in THF (28ml) suspension, water (0.15 ml), acetic acid (2.70ml, 45.0 mmol), followed by NaCNBH3 (18ml, 1M THF solution, 18mmol). 将混合物在55℃下搅拌5.5小时,然后在减压下浓缩。 The mixture was stirred at 55 ℃ 5.5 hours and then concentrated under reduced pressure. 加入饱和NaHCO3水溶液(100ml)和乙酸乙酯(40ml),将混合物过滤。 Saturated aqueous NaHCO3 (100ml) and ethyl acetate (40ml), the mixture was filtered. 将所得固体重新悬浮在甲醇(30ml)中,加热至回流,在室温下放置过夜。 The resulting solid was re-suspended in methanol (30ml), heated to reflux, allowed to stand at room temperature overnight. 过滤,在减压下干燥,得到标题化合物(1.82g,49%),为固体。 Filtered and dried under reduced pressure to give the title compound (1.82g, 49%), as a solid.

1H NMR(DMSO-d6)δ1.34(m,2H),1.49(m,2H),1.60(m,2H),1.79(m,2H),2.43(m,1H),2.51(m,4H),2.92(m,4H),6.62(d,J=8Hz,2H),6.77(d,J=8Hz,2H),8.78(s,1H);HPLC-MS:m/z 247(MH+);Rf:2.70min. 1H NMR (DMSO-d6) δ1.34 (m, 2H), 1.49 (m, 2H), 1.60 (m, 2H), 1.79 (m, 2H), 2.43 (m, 1H), 2.51 (m, 4H) , 2.92 (m, 4H), 6.62 (d, J = 8Hz, 2H), 6.77 (d, J = 8Hz, 2H), 8.78 (s, 1H); HPLC-MS: m / z 247 (MH +); Rf : 2.70min.

实施例21-环戊基-4-[4-(4-氟苄氧基)苯基]哌嗪 Example 21 Cyclopentyl-4- [4- (4-fluorobenzyloxy) phenyl] piperazine

向氢氧化钾(0.165g,2.95mmol)的乙醇(4ml)悬液加入4-(4-环戊基哌嗪-1-基)苯酚(0.25g,1.02mmol)。 Of potassium hydroxide was added with 4- (0.165g, 2.95mmol) in ethanol (4ml) suspension of (4-cyclopentyl-piperazin-1-yl) phenol (0.25g, 1.02mmol). 10分钟后,加入4-氟苄基氯(0.18ml,0.22g,1.51mmol),将混合物在70℃下搅拌5小时。 After 10 min, was added 4-fluorobenzyl chloride (0.18ml, 0.22g, 1.51mmol), and the mixture was stirred at 70 ℃ 5 hours. 加入饱和NaHCO3水溶液(20ml),混合物用乙酸乙酯萃取(3×20ml)。 Saturated aqueous NaHCO3 (20ml), the mixture was extracted with ethyl acetate (3 × 20ml). 合并萃取液,用盐水洗涤,经硫酸镁干燥,浓缩。 The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated. 从甲醇(4ml)中重结晶,得到0.125g(35%)标题化合物。 Recrystallized from methanol (4ml) to give 0.125g (35%) of the title compound.

1H NMR(DMSO-d6)δ1.34(m,2H),1.50(m,2H),1.62(m,2H),1.81(m,2H),2.45(m,1H),2.51(m,4H),2.99(m,4H),5.00(s,2H),6.87(m,4H),7.19(t,J=8Hz,2H),7.46(m,2H);HPLC-MS:m/z 355(MH+);Rf:4.73min. 1H NMR (DMSO-d6) δ1.34 (m, 2H), 1.50 (m, 2H), 1.62 (m, 2H), 1.81 (m, 2H), 2.45 (m, 1H), 2.51 (m, 4H) , 2.99 (m, 4H), 5.00 (s, 2H), 6.87 (m, 4H), 7.19 (t, J = 8Hz, 2H), 7.46 (m, 2H); HPLC-MS: m / z 355 (MH + ); Rf: 4.73min.

实施例31-(3-氯苯基)-4-环戊基哌嗪 Example 31- (3-chlorophenyl) -4-cyclopentyl-piperazine 从1-(3-氯苯基)-哌嗪开始,如实施例1所述制备该化合物。 From 1- (3-chlorophenyl) - piperazine, Example 1 This compound was prepared as described.

1H NMR(DMSO-d6)δ1.34(m,2H),1.50(m,2H),1.60(m,2H),1.80(m,2H),2.45(m,1H),2.51(m,4H),3.14(m,4H),6.78(d,J=8Hz,1H),6.88(m,2H),7.19(t,J=8Hz,1H);HPLC-MS:m/z265(MH+);Rf:3.88min. 1H NMR (DMSO-d6) δ1.34 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (m, 2H), 2.45 (m, 1H), 2.51 (m, 4H) , 3.14 (m, 4H), 6.78 (d, J = 8Hz, 1H), 6.88 (m, 2H), 7.19 (t, J = 8Hz, 1H); HPLC-MS: m / z265 (MH +); Rf: 3.88min.

实施例41-[4-(4-环戊基哌嗪-1-基)苯基]乙酮 Example 41- [4- (4-cyclopentyl-piperazin-1-yl) phenyl] ethanone

从1-(4-乙酰基苯基)-哌嗪开始,如实施例1所述制备该化合物。 From 1- (4-acetylphenyl) - piperazine, as in Example 1 This compound was prepared.

1H NMR(DMSO-d6)δ1.30-1.88(m,8H),2.45(s,3H),2.45(m,1H),2.51(m,4H),3.31(m,4H),6.95(d,J=8Hz,2H),7.79(d,J=8Hz,2H);HPLC-MS:m/z 273(MH+);Rf:3.25min. 1H NMR (DMSO-d6) δ1.30-1.88 (m, 8H), 2.45 (s, 3H), 2.45 (m, 1H), 2.51 (m, 4H), 3.31 (m, 4H), 6.95 (d, J = 8Hz, 2H), 7.79 (d, J = 8Hz, 2H); HPLC-MS: m / z 273 (MH +); Rf: 3.25min.

实施例51-(3,4-二氯苯基)-4-(1-乙基丙基)哌嗪 Example 51- (3,4-dichlorophenyl) -4- (1-ethylpropyl) piperazine 从1-(3,4-二氯-苯基)哌嗪和3-戊酮开始,如实施例1所述制备该化合物。 From 1- (3,4-dichloro-phenyl) - piperazine and 3-pentanone starts, Example 1 This compound was prepared as described.

1H NMR(DMSO-d6)δ0.88(t,J=7Hz,6H),1.28(m,2H),1.45(m,2H),2.19(m,1H),2.56(br s,4H),3.12(br s,4H),6.91(m,1H),7.09(br s,1H),7.36(d,J=8Hz,1H);HPLC-MS:m/z 301(MH+);Rf:4.25min. 1H NMR (DMSO-d6) δ0.88 (t, J = 7Hz, 6H), 1.28 (m, 2H), 1.45 (m, 2H), 2.19 (m, 1H), 2.56 (br s, 4H), 3.12 (br s, 4H), 6.91 (m, 1H), 7.09 (br s, 1H), 7.36 (d, J = 8Hz, 1H); HPLC-MS: m / z 301 (MH +); Rf: 4.25min.

实施例6{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}苯基甲酮盐酸盐 Example 6 {4- [4- (1-ethylpropyl) piperazin-1-yl] phenyl} phenyl methanone hydrochloride

将1-(3-戊基)哌嗪(0.31g,2.00mmol)、DMSO(1.0ml)、4-氟二苯酮(0.40g,2.00mmol)与DIPEA(0.20ml)的混合物在100℃下搅拌1小时,然后在120℃下搅拌18小时。 The mixture of 1- (3-pentyl) piperazine (0.31g, 2.00mmol), DMSO (1.0ml), 4- fluoro-benzophenone (0.40g, 2.00mmol) and DIPEA (0.20ml) at 100 ℃ stirred for 1 hour, then at 120 ℃ 18 hours. 加入水(50ml)和碳酸钾(2g),混合物用乙酸乙酯萃取(3×20ml)。 Water was added (50ml) and potassium carbonate (2g), the mixture was extracted with ethyl acetate (3 × 20ml). 合并萃取液,用盐水洗涤,用硫酸镁干燥,在减压下浓缩。 The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. 将粗产物重新溶于乙醇(10ml)和1M含水HCl(4ml),在减压下浓缩溶液。 The crude product was re-dissolved in ethanol (10ml) and 1M aqueous HCl (4ml), the solution was concentrated under reduced pressure. 与乙醇和甲苯共同蒸发后,残余物固化,从乙腈(100ml)中重结晶。 After co-evaporation with ethanol and toluene, and the residue was solidified, was recrystallized from acetonitrile (100ml) in. 得到0.20g(27%)标题化合物。 To give 0.20g (27%) of the title compound.

1H NMR(DMSO-d6)δ0.95(m,6H),1.62(m,2H),1.89(m,2H),3.04-3.27(m,3H),3.48(m,4H),4.05(m,2H),7.08(m,2H),7.51(m,2H),7.65(m,5H),10.75(br s,1H);HPLC-MS:m/z337(MH+);Rf:4.27min. 1H NMR (DMSO-d6) δ0.95 (m, 6H), 1.62 (m, 2H), 1.89 (m, 2H), 3.04-3.27 (m, 3H), 3.48 (m, 4H), 4.05 (m, 2H), 7.08 (m, 2H), 7.51 (m, 2H), 7.65 (m, 5H), 10.75 (br s, 1H); HPLC-MS: m / z337 (MH +); Rf: 4.27min.

实施例71-(4-苄基苯基)-4-(1-乙基丙基)哌嗪盐酸盐 Example 71- (4-benzyl-phenyl) -4- (1-ethylpropyl) piperazine hydrochloride 将{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}苯基甲酮盐酸盐(77mg,0.21mmol)、三氟乙酸(2.0ml)与三乙基甲硅烷(0.5ml)的混合物在60℃下搅拌20小时。 {4- [4- (1-ethylpropyl) piperazin-1-yl] -phenyl} -phenyl-methanone hydrochloride (77mg, 0.21mmol), trifluoroacetic acid (2.0 ml of) triethyl a mixture of silane (0.5ml) was stirred at 60 ℃ 20 hours. 在减压下浓缩混合物,与水和碳酸钾混合。 The mixture was concentrated under reduced pressure, mixed with water and potassium carbonate. 混合物用乙酸乙酯萃取(3×20ml)。 The mixture was extracted with ethyl acetate (3 × 20ml). 合并萃取液,用盐水洗涤,用硫酸镁干燥,在减压下浓缩。 The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. 将粗产物重新溶于乙醇和1M含水HCl,在减压下浓缩溶液。 The crude product was re-dissolved in ethanol and 1M aqueous HCl, the solution was concentrated under reduced pressure. 与乙醇和甲苯共同蒸发后,残余物固化。 After co-evaporation with ethanol and toluene, the residue was solidified. 得到45mg(61%)标题化合物。 To give 45mg (61%) of the title compound.

1H NMR(DMSO-d6)δ0.98(t,J=7Hz,6H),1.64(m,2H),1.89(m,2H),3.04-3.23(m,5H),3.48(m,2H),3.72(m,2H),3.85(s,2H),6.93(d,J=8Hz,2H),7.10-7.30(m,7H),10.05(brs,1H);HPLC-MS:m/z 323(MH+);Rf:4.93min. 1H NMR (DMSO-d6) δ0.98 (t, J = 7Hz, 6H), 1.64 (m, 2H), 1.89 (m, 2H), 3.04-3.23 (m, 5H), 3.48 (m, 2H), 3.72 (m, 2H), 3.85 (s, 2H), 6.93 (d, J = 8Hz, 2H), 7.10-7.30 (m, 7H), 10.05 (brs, 1H); HPLC-MS: m / z 323 ( MH +); Rf: 4.93min.

实施例8 Example 8

环丙基-{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}甲酮盐酸盐 Cyclopropyl - {4- [4- (1-ethylpropyl) piperazin-1-yl] phenyl} methanone hydrochloride 从4-氟苯基(环丙基)酮开始,如实施例6所述制备该化合物。 Starting from 4-fluorophenyl (cyclopropyl) -one, prepared as described in Example 6 of the compound.

1H NMR(DMSO-d6)δ0.98(m,10H),1.64(m,2H),1.89(m,2H),2.82(br s,1H),3.04-3.23(m,3H),3.49(m,4H),4.04(m,2H),7.07(d,J=8Hz,2H),7.96(d,J=8Hz,2H),10.95(brs,1H);HPLC-MS:m/z301(MH+);Rf:4.03min. 1H NMR (DMSO-d6) δ0.98 (m, 10H), 1.64 (m, 2H), 1.89 (m, 2H), 2.82 (br s, 1H), 3.04-3.23 (m, 3H), 3.49 (m , 4H), 4.04 (m, 2H), 7.07 (d, J = 8Hz, 2H), 7.96 (d, J = 8Hz, 2H), 10.95 (brs, 1H); HPLC-MS: m / z301 (MH +) ; Rf: 4.03min.

实施例9(2-氯苯基)-{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}甲酮盐酸盐 Example 9 (2-chlorophenyl) - {4- [4- (1-ethylpropyl) piperazin-1-yl] phenyl} methanone hydrochloride 从4-氟苯基-(2-氯苯基)酮开始,如实施例6所述制备该化合物。 From 4-fluorophenyl - start (2-chlorophenyl) ketone as described in Example 6. This compound was prepared.

1H NMR(DMSO-d6)δ0.98(t,J=7Hz,6H),1.64(m,2H),1.88(m,2H),3.08-3.23(m,3H),3.50(m,4H),4.06(m,2H),7.08(d,J=8Hz,2H),7.31(m,1H),7.48(m,1H),7.50-7.61(m,4H),10.85(br s,1H);HPLC-MS:m/z 371(MH+);Rf:4.43min. 1H NMR (DMSO-d6) δ0.98 (t, J = 7Hz, 6H), 1.64 (m, 2H), 1.88 (m, 2H), 3.08-3.23 (m, 3H), 3.50 (m, 4H), 4.06 (m, 2H), 7.08 (d, J = 8Hz, 2H), 7.31 (m, 1H), 7.48 (m, 1H), 7.50-7.61 (m, 4H), 10.85 (br s, 1H); HPLC -MS: m / z 371 (MH +); Rf: 4.43min.

实施例10{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}-(4-氟苯基)甲酮盐酸盐 10 {4- [4- (1-ethylpropyl) piperazin-1-yl] phenyl} Example - (4-fluorophenyl) methanone hydrochloride

从4,4′-二氟二苯酮开始,如实施例6所述制备该化合物。 Starting from 4,4-difluoro-benzophenone This compound was prepared as described in Example 6.

1H NMR(DMSO-d6)δ0.98(t,J=7Hz,6H),1.66(m,2H),1.89(m,2H),3.08-3.25(m,3H),3.41-3.53(m,4H),4.05(m,2H),7.09(d,J=8Hz,2H),7.38(m,2H),7.69(d,J=8Hz,2H),7.76(m,2H),10.80(br s,1H);HPLC-MS:m/z 355(MH+);Rf:4.37min. 1H NMR (DMSO-d6) δ0.98 (t, J = 7Hz, 6H), 1.66 (m, 2H), 1.89 (m, 2H), 3.08-3.25 (m, 3H), 3.41-3.53 (m, 4H ), 4.05 (m, 2H), 7.09 (d, J = 8Hz, 2H), 7.38 (m, 2H), 7.69 (d, J = 8Hz, 2H), 7.76 (m, 2H), 10.80 (br s, 1H); HPLC-MS: m / z 355 (MH +); Rf: 4.37min.

实施例111-环戊基-4-(6-三氟甲基吡啶-2-基)哌嗪 Example 111--cyclopentyl-4- (6-trifluoromethyl-pyridin-2-yl) piperazine 从1-(6-三氟甲基-吡啶-2-基)哌嗪开始,如实施例1所述制备该化合物。 From 1- (6-trifluoromethyl - pyridin-2-yl) piperazine, Example 1 This compound was prepared as described.

1H NMR(DMSO-d6)δ1.34(m,2H),1.50(m,2H),1.60(m,2H),1.80(m,2H),2.45-2.51(m,5H),3.52(m,4H),7.02(d,J=8Hz,1H),7.11(d,J=8Hz,1H),7.71(t,J=8Hz,1H);HPLC-MS:m/z 300(MH+);Rf:4.10min. 1H NMR (DMSO-d6) δ1.34 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (m, 2H), 2.45-2.51 (m, 5H), 3.52 (m, 4H), 7.02 (d, J = 8Hz, 1H), 7.11 (d, J = 8Hz, 1H), 7.71 (t, J = 8Hz, 1H); HPLC-MS: m / z 300 (MH +); Rf: 4.10min.

实施例121-环戊基-4-(5-三氟甲基吡啶-2-基)哌嗪 Example 121--cyclopentyl-4- (5-trifluoromethyl-pyridin-2-yl) piperazine

从1-(5-三氟甲基-吡啶-2-基)哌嗪开始,如实施例1所述制备该化合物。 From 1- (5-trifluoromethyl - pyridin-2-yl) piperazine, Example 1 This compound was prepared as described.

1H NMR(DMSO-d6)δ1.36(m,2H),1.50(m,2H),1.60(m,2H),1.80(m,2H),2.45-2.52(m,5H),3.58(m,4H),6.92(d,J=8Hz,1H),7.78(br d,J=8Hz,1H),8.39(s,1H);HPLC-MS:m/z 300(MH+);Rf:3.87min. 1H NMR (DMSO-d6) δ1.36 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (m, 2H), 2.45-2.52 (m, 5H), 3.58 (m, 4H), 6.92 (d, J = 8Hz, 1H), 7.78 (br d, J = 8Hz, 1H), 8.39 (s, 1H); HPLC-MS: m / z 300 (MH +); Rf: 3.87min.

实施例131-环戊基-4-(3-三氟甲基吡啶-2-基)哌嗪 Example 131- Cyclopentyl-4- (3-trifluoromethyl-pyridin-2-yl) piperazine 从1-(3-三氟甲基-吡啶-2-基)哌嗪开始,如实施例1所述制备该化合物。 From 1- (3-trifluoromethyl - pyridin-2-yl) piperazine, Example 1 This compound was prepared as described.

1H NMR(DMSO-d6)δ1.29-1.65(m,6H),1.80(m,2H),2.45(m,1H),2.52(m,4H),3.18(m,4H),7.16(m,1H),8.02(m,1H),8.49(m,1H);HPLC-MS:m/z 300(MH+);Rf:3.70min. 1H NMR (DMSO-d6) δ1.29-1.65 (m, 6H), 1.80 (m, 2H), 2.45 (m, 1H), 2.52 (m, 4H), 3.18 (m, 4H), 7.16 (m, 1H), 8.02 (m, 1H), 8.49 (m, 1H); HPLC-MS: m / z 300 (MH +); Rf: 3.70min.

实施例142-[4-(1-乙基丙基)哌嗪-1-基]喹啉盐酸盐 Example 142- [4- (1-ethylpropyl) piperazin-1-yl] quinoline hydrochloride 从2-氯喹啉开始,如实施例6所述制备该化合物。 Starting from 2-chloro-quinoline as described in Example 6. This compound was prepared.

1H NMR(DMSO-d6)δ0.99(t,J=7Hz,6H),1.65(m,2H),1.94(m,2H),3.12(br s,1H),3.33(m,2H),3.57(m,2H),3.93(m,2H), 4.83(m,2H),7.44-7.58(m,2H),7.76(m,1H),7.92(m,1H),8.25(br s,1H),8.42(m,1H),11.20(br s,H);HPLC-MS:m/z 284(MH+);Rf:3.03min. 1H NMR (DMSO-d6) δ0.99 (t, J = 7Hz, 6H), 1.65 (m, 2H), 1.94 (m, 2H), 3.12 (br s, 1H), 3.33 (m, 2H), 3.57 (m, 2H), 3.93 (m, 2H), 4.83 (m, 2H), 7.44-7.58 (m, 2H), 7.76 (m, 1H), 7.92 (m, 1H), 8.25 (br s, 1H) , 8.42 (m, 1H), 11.20 (br s, H); HPLC-MS: m / z 284 (MH +); Rf: 3.03min.

实施例15 Example 15

7-氯-4-[4-(1-乙基丙基)哌嗪-1-基]喹啉盐酸盐 7-Chloro-4- [4- (1-ethylpropyl) piperazin-1-yl] quinoline hydrochloride 从4,7-二氯喹啉开始,如实施例6所述制备该化合物。 Starting from 4,7-dichloro-quinoline This compound was prepared as described in Example 6.

1H NMR(DMSO-d6)δ1.00(t,J=7Hz,6H),1.67(m,2H),1.95(m,2H),3.15(br s,1H),3.30-3.70(m,4H),4.05(m,2H),4.20(m,2H),7.32(m,1H),7.73(m,1H),8.28(m,2H),8.83(m,1H),11.35(br s,H);HPLC-MS:m/z 318(MH+);Rf:3.13min. 1H NMR (DMSO-d6) δ1.00 (t, J = 7Hz, 6H), 1.67 (m, 2H), 1.95 (m, 2H), 3.15 (br s, 1H), 3.30-3.70 (m, 4H) , 4.05 (m, 2H), 4.20 (m, 2H), 7.32 (m, 1H), 7.73 (m, 1H), 8.28 (m, 2H), 8.83 (m, 1H), 11.35 (br s, H) ; HPLC-MS: m / z 318 (MH +); Rf: 3.13min.

实施例16[4-(4-环戊基哌嗪-1-基)苯基]-(3,4-二甲氧基苯基)甲酮盐酸盐 Example 16 [4- (4-cyclopentyl-piperazin-1-yl) phenyl] - (3,4-dimethoxyphenyl) methanone hydrochloride 从4′-氟-3,4-二甲氧基二苯酮开始,如实施例6所述制备该化合物。 Starting from 4'-fluoro-3,4-dimethoxy-benzophenone, as described in Example 6. This compound was prepared.

1H NMR(DMSO-d6)δ1.55(m,2H),1.65-1.90(m,4H),2.02(m,2H),3.05-3.40(m,4H),3.55(m,3H),3.81(s,3H),3.88(s,3H),4.08(m,2H),7.10(m,3H),7.29(m,2H),7.69(d,J=8Hz,2H),10.78(br s,1H);HPLC-MS:m/z 395(MH+);Rf:3.03min. 1H NMR (DMSO-d6) δ1.55 (m, 2H), 1.65-1.90 (m, 4H), 2.02 (m, 2H), 3.05-3.40 (m, 4H), 3.55 (m, 3H), 3.81 ( s, 3H), 3.88 (s, 3H), 4.08 (m, 2H), 7.10 (m, 3H), 7.29 (m, 2H), 7.69 (d, J = 8Hz, 2H), 10.78 (br s, 1H ); HPLC-MS: m / z 395 (MH +); Rf: 3.03min.

实施例17[4-(4-环戊基哌嗪-1-基)-3,5-二氟苯基]苯基甲酮盐酸盐 17 [4- (4-cyclopentyl-piperazin-1-yl) -3,5-difluorophenyl] phenyl methanone hydrochloride Example

从3,4,5-三氟二苯酮开始,如实施例6所述制备该化合物。 Starting from 3,4,5-trifluoro benzophenone This compound was prepared as described in Example 6.

1H NMR(DMSO-d6)δ1.55(m,2H),1.65-1.90(m,4H),2.02(m,2H),3.15(m,2H),3.50-3.71(m,7H),7.42(m,2H),7.58(m,2H),7.68-7.78(m,3H),10.90(br s,1H);HPLC-MS:m/z371(MH+);Rf:2.77min. 1H NMR (DMSO-d6) δ1.55 (m, 2H), 1.65-1.90 (m, 4H), 2.02 (m, 2H), 3.15 (m, 2H), 3.50-3.71 (m, 7H), 7.42 ( m, 2H), 7.58 (m, 2H), 7.68-7.78 (m, 3H), 10.90 (br s, 1H); HPLC-MS: m / z371 (MH +); Rf: 2.77min.

实施例182-(4-环戊基哌嗪-1-基)喹喔啉盐酸盐 Example 182- (4-cyclopentyl-piperazin-1-yl) quinoxaline hydrochloride 从2-氯喹喔啉开始,使用丙腈作为溶剂,如实施例6制备该化合物。 From 2-chloro-quinoxaline started, propionitrile used as a solvent, the compound prepared in Example 6 as described.

1H NMR(DMSO-d6)δ1.55(m,2H),1.64-1.90(m,4H),2.02(m,2H),3.15(m,2H),3.42-3.65(m,5H),4.71(m,2H),7.49(m,1H),7.67(m,2H),7.88(br d,J=8Hz,1H),8.91(s,1H),10.92(br s,1H);HPLC-MS:m/z 283(MH+);Rf:1.70min. 1H NMR (DMSO-d6) δ1.55 (m, 2H), 1.64-1.90 (m, 4H), 2.02 (m, 2H), 3.15 (m, 2H), 3.42-3.65 (m, 5H), 4.71 ( m, 2H), 7.49 (m, 1H), 7.67 (m, 2H), 7.88 (br d, J = 8Hz, 1H), 8.91 (s, 1H), 10.92 (br s, 1H); HPLC-MS: m / z 283 (MH +); Rf: 1.70min.

实施例192-(4-环丙基甲基哌嗪-1-基)喹喔啉盐酸盐 Example 192- (4-cyclopropylmethyl-piperazin-1-yl) quinoxaline hydrochloride 1H NMR(DMSO-d6)δ0.41(m,2H),0.66(m,2H),1.18(m,1H),3.02(m,2H),3.13(m,2H),3.52-3.69(m,4H),4.71(m,2H),7.48(m,1H),7.66(m,2H),7.88(d,J=8Hz,1H),8.90(s,1H),11.17(br s,1H);HPLC-MS:m/z 269(MH+);Rf:1.73min. 1H NMR (DMSO-d6) δ0.41 (m, 2H), 0.66 (m, 2H), 1.18 (m, 1H), 3.02 (m, 2H), 3.13 (m, 2H), 3.52-3.69 (m, 4H), 4.71 (m, 2H), 7.48 (m, 1H), 7.66 (m, 2H), 7.88 (d, J = 8Hz, 1H), 8.90 (s, 1H), 11.17 (br s, 1H); HPLC-MS: m / z 269 (MH +); Rf: 1.73min.

实施例20[6-(4-环戊基哌嗪-1-基)吡啶-3-基]哌啶-1-基甲酮盐酸盐 Example 20 [6- (4-cyclopentyl-piperazin-1-yl) pyridin-3-yl] piperidin-1-yl methanone hydrochloride

1H NMR(DMSO-d6)δ1.45-2.08(m,14H),3.06(m,2H),3.38-3.61(m,9H),4.44(m,2H),7.02(d,J=8Hz,1H),7.70(dd,J=8Hz,1Hz,1H),8.19(d,J=1Hz,1H);HPLC-MS:m/z(MH+). 1H NMR (DMSO-d6) δ1.45-2.08 (m, 14H), 3.06 (m, 2H), 3.38-3.61 (m, 9H), 4.44 (m, 2H), 7.02 (d, J = 8Hz, 1H ), 7.70 (dd, J = 8Hz, 1Hz, 1H), 8.19 (d, J = 1Hz, 1H); HPLC-MS: m / z (MH +).

使用1-(6-氯烟酰基)哌啶(Thunus,Ann.Pharm.Fr.1977,35,197),同实施例6制备该化合物(通用工艺B)。 1- (6-chloro-nicotinoyl) piperidine (Thunus, Ann.Pharm.Fr.1977,35,197), the preparation of the compound (general procedure B) in Example 6.

实施例212-(4-环戊基哌嗪-1-基)喹啉盐酸盐 (4-cyclopentyl-piperazin-1-yl) quinoline hydrochloride Example 212- 1H NMR(DMSO-d6)δ1.62(m,2H),1.82(m,2H),1.96(m,2H),2.09(m,2H),3.25(m,2H),3.55-3.70(m,5H),4.83(m,2H),7.46-7.60(m,2H),7.80(m,1H),7.94(m,1H),8.13(m,1H),8.42(m,1H),11.52(br s,1H);HPLC-MS:m/z282(MH+);Rf:0.34min. 1H NMR (DMSO-d6) δ1.62 (m, 2H), 1.82 (m, 2H), 1.96 (m, 2H), 2.09 (m, 2H), 3.25 (m, 2H), 3.55-3.70 (m, 5H), 4.83 (m, 2H), 7.46-7.60 (m, 2H), 7.80 (m, 1H), 7.94 (m, 1H), 8.13 (m, 1H), 8.42 (m, 1H), 11.52 (br s, 1H); HPLC-MS: m / z282 (MH +); Rf: 0.34min.

从2-氯喹啉开始,同实施例6制备该化合物。 Starting from 2-chloro-quinoline This compound was prepared as in Example 6.

实施例222-(4-环戊基哌嗪-1-基)-7-甲氧基-3-(4-甲氧基苯基)喹啉盐酸盐 Example 222- (4-cyclopentyl-piperazin-1-yl) -7-methoxy-3- (4-methoxyphenyl) quinoline hydrochloride

1H NMR(DMSO-d6)δ1.53(m,2H),1.63-1.86(m,4H),1.98(m,2H),3.05(m,2H),3.33-3.52(m,5H),3.75(m,2H),3.82(s,3H),3.91(s,3H),7.08(d,J=8Hz,2H),7.13(dd,J=8Hz,1Hz,1H),7.49(brs,1H),7.61(d,J=8Hz,2H),7.83(d,J=8Hz,1H),8.15(s,1H),11.29(brs,1H);HPLC-MS:m/z 418(MH+);Rf:3.40min. 1H NMR (DMSO-d6) δ1.53 (m, 2H), 1.63-1.86 (m, 4H), 1.98 (m, 2H), 3.05 (m, 2H), 3.33-3.52 (m, 5H), 3.75 ( m, 2H), 3.82 (s, 3H), 3.91 (s, 3H), 7.08 (d, J = 8Hz, 2H), 7.13 (dd, J = 8Hz, 1Hz, 1H), 7.49 (brs, 1H), 7.61 (d, J = 8Hz, 2H), 7.83 (d, J = 8Hz, 1H), 8.15 (s, 1H), 11.29 (brs, 1H); HPLC-MS: m / z 418 (MH +); Rf: 3.40min.

实施例23{6-[4-(1-环丙基-1-甲基乙基)哌嗪-1-基]吡啶-3-基}苯基甲酮盐酸盐 Example 23 {6- [4- (1-cyclopropyl-1-methylethyl) piperazin-1-yl] pyridin-3-yl} phenyl methanone hydrochloride 1H NMR(DMSO-d6)δ0.48-0.62(m,4H),1.22-1.39(m,7H),3.14(m,2H),3.69(m,4H),4.64(m,2H),7.08(d,J=8Hz,1H),7.55(m,2H),7.61-7.72(m,3H),8.00(dd,J=8Hz,1Hz,1H),8.52(d,J=1Hz,1H),11.27(br s,1H);HPLC-MS:m/z350(MH+);Rf:3.03min. 1H NMR (DMSO-d6) δ0.48-0.62 (m, 4H), 1.22-1.39 (m, 7H), 3.14 (m, 2H), 3.69 (m, 4H), 4.64 (m, 2H), 7.08 ( d, J = 8Hz, 1H), 7.55 (m, 2H), 7.61-7.72 (m, 3H), 8.00 (dd, J = 8Hz, 1Hz, 1H), 8.52 (d, J = 1Hz, 1H), 11.27 (br s, 1H); HPLC-MS: m / z350 (MH +); Rf: 3.03min.

从2-氯-5-苯甲酰基吡啶(TDPenning et al.,J.Med.Chem.2000,43,721-735)开始,同实施例6制备该化合物。 From 2-chloro-5-benzoyl-pyridine (TDPenning et al., J.Med.Chem.2000,43,721-735) begins with the preparation of the compound of Example 6.

实施例24{4-[4-(1-环丙基-1-甲基乙基)哌嗪-1-基]-3,5-二氟苯基}苯基甲酮盐酸盐 24 {4- [4- (1-cyclopropyl-1-methylethyl) piperazin-1-yl] -3,5-difluorophenyl} phenyl methanone hydrochloride Example 1H NMR(DMSO-d6)δ0.48-0.63(m,4H),1.23-1.40(m,7H),3.18(m,2H),3.56(m,2H),3.69(m,2H),3.84(m,2H),7.42(m,2H),7.58(m,2H),7.66-7.76(m,3H),10.90(br s,1H);HPLC-MS:m/z 385(MH+);Rf:3.73min. 1H NMR (DMSO-d6) δ0.48-0.63 (m, 4H), 1.23-1.40 (m, 7H), 3.18 (m, 2H), 3.56 (m, 2H), 3.69 (m, 2H), 3.84 ( m, 2H), 7.42 (m, 2H), 7.58 (m, 2H), 7.66-7.76 (m, 3H), 10.90 (br s, 1H); HPLC-MS: m / z 385 (MH +); Rf: 3.73min.

实施例25{4-[4-(1-环丙基-1-甲基乙基)哌嗪-1-基]-3,5-二氟苯基}苯基甲醇盐酸盐 25 {4- [4- (1-cyclopropyl-1-methylethyl) piperazin-1-yl] -3,5-difluorophenyl} phenyl methanol hydrochloride Example 1H NMR(DMSO-d6)δ0.47-0.61(m,4H),1.23-1.34(m,7H),3.12(m,2H),3.29(m,2H),3.65(m,4H),5.66(m,1H),6.08(m,1H),7.06(m,2H),7.19-7.40(m,5H),10.40(br s,1H);HPLC-MS:m/z 387(MH+);Rf:3.40min. 1H NMR (DMSO-d6) δ0.47-0.61 (m, 4H), 1.23-1.34 (m, 7H), 3.12 (m, 2H), 3.29 (m, 2H), 3.65 (m, 4H), 5.66 ( m, 1H), 6.08 (m, 1H), 7.06 (m, 2H), 7.19-7.40 (m, 5H), 10.40 (br s, 1H); HPLC-MS: m / z 387 (MH +); Rf: 3.40min.

用硼氢化钠还原实施例24,制备该化合物。 Reduction with sodium borohydride in Example 24, to prepare the compound.

实施例26[4-(4-环丙基甲基哌嗪-1-基)-3,5-二氟苯基]-(4-氟苯基)甲酮盐酸盐 Example 26 [3,5-difluorophenyl 4- (4-cyclopropylmethyl-piperazin-1-yl)] - (4-fluorophenyl) methanone hydrochloride 1H NMR(DMSO-d6)δ0.40(m,2H),0.66(m,2H),1.13(m,1H),3.02-3.23(m,5H),3.52-3.68(m,5H),7.40(m,4H),7.82(m,2H),10.55(br s,1H);HPLC-MS:m/z 375(MH+);Rf:2.78min. 1H NMR (DMSO-d6) δ0.40 (m, 2H), 0.66 (m, 2H), 1.13 (m, 1H), 3.02-3.23 (m, 5H), 3.52-3.68 (m, 5H), 7.40 ( m, 4H), 7.82 (m, 2H), 10.55 (br s, 1H); HPLC-MS: m / z 375 (MH +); Rf: 2.78min.

使用3,4,5,4′-四氟二苯酮,同实施例6制备该化合物。 Use 3,4,5,4' tetrafluoroethylene benzophenone This compound was prepared in Example 6 with the embodiment. 原料是借助氟苯与3,4,5-三氟苯甲酰氯的Friedel Crafts酰化作用制备的。 Starting material is acylated by Friedel Crafts-fluorophenyl and 3,4,5-trifluoro-benzoyl chloride prepared in the role.

实施例27{4-[4-(1-乙基丙基)哌嗪-1-基]-3,5-二氟苯基}-(4-氟苯基)甲酮盐酸盐 (4-fluorophenyl) methanone hydrochloride --27 {[(1-ethylpropyl) 4- piperazin-1-yl] -3,5-difluorophenyl} Example 4-

1H NMR(DMSO-d6)δ0.97(t,J=7Hz,6H),1.68(m,2H),1.88(m,2H),3.06-3.26(m,3H),3.52(m,4H),3.75(m,2H),7.41(m,4H),7.82(m,2H),10.31(br s,1H);HPLC-MS:m/z 391(MH+);Rf:3.00min. 1H NMR (DMSO-d6) δ0.97 (t, J = 7Hz, 6H), 1.68 (m, 2H), 1.88 (m, 2H), 3.06-3.26 (m, 3H), 3.52 (m, 4H), 3.75 (m, 2H), 7.41 (m, 4H), 7.82 (m, 2H), 10.31 (br s, 1H); HPLC-MS: m / z 391 (MH +); Rf: 3.00min.

实施例282-[4-(1-乙基丙基)哌嗪-1-基]-6,7-二甲氧基喹啉盐酸盐 Example 282- [4- (1-ethylpropyl) piperazin-1-yl] -6,7-dimethoxy-quinoline hydrochloride 1H NMR(DMSO-d6)δ0.99(t,J=7Hz,6H),1.66(m,2H),1.91(m,2H),3.11(m,1H),3.29(m,2H),3.56(m,4H),3.88(s,3H),3.92(s,3H),4.72(m,2H),7.31-7.43(m,2H),7.82(br s,1H),8.30(br s,1H),10.95(br s,1H);HPLC-MS:m/z 344(MH+);Rf:2.00min. 1H NMR (DMSO-d6) δ0.99 (t, J = 7Hz, 6H), 1.66 (m, 2H), 1.91 (m, 2H), 3.11 (m, 1H), 3.29 (m, 2H), 3.56 ( m, 4H), 3.88 (s, 3H), 3.92 (s, 3H), 4.72 (m, 2H), 7.31-7.43 (m, 2H), 7.82 (br s, 1H), 8.30 (br s, 1H) , 10.95 (br s, 1H); HPLC-MS: m / z 344 (MH +); Rf: 2.00min.

从2-氯-6,7-二甲氧基喹啉(Pettit,Can.J.Chem.1964,42,1764)开始,同实施例6制备该化合物。 Dimethoxy-quinoline (Pettit, Can.J.Chem.1964,42,1764) starting from 2-chloro-6,7, This compound was prepared as in Example 6.

实施例292-[4-(1-乙基丙基)哌嗪-1-基]-4-三氟甲基喹啉盐酸盐 Example 292- [4- (1-ethylpropyl) piperazin-1-yl] -4-trifluoromethyl-quinoline hydrochloride

1H NMR(DMSO-d6)δ0.99(t,J=7Hz,6H),1.65(m,2H),1.91(m,2H),3.08(m,1H),3.19(m,2H),3.52(m,2H),3.75(m,2H),4.77(m,2H),7.48(t,J=7Hz,1H),7.72(m,2H),7.88(m,2H),11.19(br s,1H);HPLC-MS:m/z 352(MH+);Rf:3.70min. 1H NMR (DMSO-d6) δ0.99 (t, J = 7Hz, 6H), 1.65 (m, 2H), 1.91 (m, 2H), 3.08 (m, 1H), 3.19 (m, 2H), 3.52 ( m, 2H), 3.75 (m, 2H), 4.77 (m, 2H), 7.48 (t, J = 7Hz, 1H), 7.72 (m, 2H), 7.88 (m, 2H), 11.19 (br s, 1H ); HPLC-MS: m / z 352 (MH +); Rf: 3.70min.

从2-氯-4-三氟甲基喹啉制备该化合物。 Quinoline This compound was prepared from 2-morpholine-chloro-4-trifluoromethyl. 原料是如文献所述制备的:RDWestland et al.J.Med.Chem.1973,16,319-327。 The starting material is prepared as literature: RDWestland et al.J.Med.Chem.1973,16,319-327.

实施例302-(4-环丙基甲基哌嗪-1-基)-6-甲氧基-4-三氟甲基喹啉盐酸盐 Example 302 (4-cyclopropylmethyl-piperazin-1-yl) -6-methoxy-4-trifluoromethyl quinoline hydrochloride 1H NMR(DMSO-d6)δ0.40(m,2H),0.67(m,2H),1.14(m,1H),3.01-3.16(m,4H),3.46(m,2H),3.64(m,2H),3.87(s,3H),4.66(m,2H),7.16(br s,1H),7.43(dd,J=7Hz,1Hz,1H),7.68(s,1H),7.73(d,J=7Hz,1H),10.70(br s,1H);HPLC-MS:m/z366(MH+);Rf:3.63min. 1H NMR (DMSO-d6) δ0.40 (m, 2H), 0.67 (m, 2H), 1.14 (m, 1H), 3.01-3.16 (m, 4H), 3.46 (m, 2H), 3.64 (m, 2H), 3.87 (s, 3H), 4.66 (m, 2H), 7.16 (br s, 1H), 7.43 (dd, J = 7Hz, 1Hz, 1H), 7.68 (s, 1H), 7.73 (d, J = 7Hz, 1H), 10.70 (br s, 1H); HPLC-MS: m / z366 (MH +); Rf: 3.63min.

实施例31[4-(4-环丙基甲基哌嗪-1-基)-3,5-二氟苯基]苯基甲酮盐酸盐 Example 31 [4- (4-cyclopropylmethyl-piperazin-1-yl) -3,5-difluorophenyl] phenyl methanone hydrochloride 1H NMR(DMSO-d6)δ0.40(m,2H),0.67(m,2H),1.14(m,1H),3.03-3.20(m,4H),3.60(m,6H),7.40(m,2H),7.58(m,2H),7.70(m,3H),10.60(br s,1H);HPLC-MS:m/z 357(MH+);Rf:3.53min. 1H NMR (DMSO-d6) δ0.40 (m, 2H), 0.67 (m, 2H), 1.14 (m, 1H), 3.03-3.20 (m, 4H), 3.60 (m, 6H), 7.40 (m, 2H), 7.58 (m, 2H), 7.70 (m, 3H), 10.60 (br s, 1H); HPLC-MS: m / z 357 (MH +); Rf: 3.53min.

实施例32 Example 32

[4-(4-环丙基甲基哌嗪-1-基)-3,5-二氟苯基]-(3-氟-4-甲氧基苯基)-甲酮盐酸盐 [4- (4-cyclopropylmethyl-piperazin-1-yl) -3,5-difluorophenyl] - (3-fluoro-4-methoxyphenyl) - methanone hydrochloride 1H NMR(DMSO-d6)δ0.41(m,2H),0.65(m,2H),1.15(m,1H),3.06(m,2H),3.18(m,2H),3.50-3.70(m,6H),3.95(s,3H),7.33(t,J=8Hz,1H),7.41(m,2H),7.60(m,2H),10.79(brs,1H);HPLC-MS:m/z 405(MH+);Rf:3.67min. 1H NMR (DMSO-d6) δ0.41 (m, 2H), 0.65 (m, 2H), 1.15 (m, 1H), 3.06 (m, 2H), 3.18 (m, 2H), 3.50-3.70 (m, 6H), 3.95 (s, 3H), 7.33 (t, J = 8Hz, 1H), 7.41 (m, 2H), 7.60 (m, 2H), 10.79 (brs, 1H); HPLC-MS: m / z 405 (MH +); Rf: 3.67min.

实施例33{6-[4-(1-乙基丙基)哌嗪-1-基]吡啶-3-基}苯基甲酮盐酸盐 Example 33 {6- [4- (1-ethylpropyl) piperazin-1-yl] pyridin-3-yl} phenyl methanone hydrochloride 1H NMR(DMSO-d6)δ0.97(t,J=7Hz,6H),1.65(m,2H),1.90(m,2H),3.02-3.22(m,3H),3.49-3.69(m,4H),4.60(m,2H),7.08(d,J=8Hz,1H),7.56(m,2H),7.68(m,3H),7.99(dd,J=8Hz,1Hz,1H),8.50(d,J=1Hz,1H),10.90(brs,1H);HPLC-MS:m/z338(MH+);Rf:3.00min. 1H NMR (DMSO-d6) δ0.97 (t, J = 7Hz, 6H), 1.65 (m, 2H), 1.90 (m, 2H), 3.02-3.22 (m, 3H), 3.49-3.69 (m, 4H ), 4.60 (m, 2H), 7.08 (d, J = 8Hz, 1H), 7.56 (m, 2H), 7.68 (m, 3H), 7.99 (dd, J = 8Hz, 1Hz, 1H), 8.50 (d , J = 1Hz, 1H), 10.90 (brs, 1H); HPLC-MS: m / z338 (MH +); Rf: 3.00min.

实施例34{2-[4-(1-乙基丙基)哌嗪-1-基]吡啶-4-基}苯基甲酮盐酸盐 Example 34 {2- [4- (1-ethylpropyl) piperazin-1-yl] pyridin-4-yl} phenyl methanone hydrochloride

1H NMR(DMSO-d6)δ0.97(t,J=7Hz,6H),1.63(m,2H),1.85(m,2H),3.12(m,3H),3.47(m,4H),4.43(m,2H),6.91(d,J=6Hz,1H),7.14(s,1H),7.58(t,J=8Hz,2H),7.70-7.84(m,3H),8.33(d,J=6Hz,1H),10.43(br s,1H);HPLC-MS:m/z 338(MH+);Rf:2.97min. 1H NMR (DMSO-d6) δ0.97 (t, J = 7Hz, 6H), 1.63 (m, 2H), 1.85 (m, 2H), 3.12 (m, 3H), 3.47 (m, 4H), 4.43 ( m, 2H), 6.91 (d, J = 6Hz, 1H), 7.14 (s, 1H), 7.58 (t, J = 8Hz, 2H), 7.70-7.84 (m, 3H), 8.33 (d, J = 6Hz , 1H), 10.43 (br s, 1H); HPLC-MS: m / z 338 (MH +); Rf: 2.97min.

从2-氯-4-苯甲酰基吡啶制备该化合物,原料是借助苯与2-氯-4-氯代羰基吡啶的Friedel-Crafts酰化作用制备的。 This compound was prepared from 2-chloro-4-benzoyl pyridine starting material by means of Friedel-Crafts acylation of benzene with 2-chloro-4-chlorocarbonyl pyridine prepared.

实施例35{4-[4-(1-乙基丙基)哌嗪-1-基]苯基}-(4-羟基苯基)甲酮盐酸盐 Example 35 {4- [4- (1-ethylpropyl) piperazin-1-yl] phenyl} - (4-hydroxyphenyl) methanone hydrochloride 1H NMR(DMSO-d6)δ0.97(t,J=7Hz,6H),1.65(m,2H),1.92(m,2H),3.05-3.25(m,3H),3.35-3.55(m,4H),4.02(m,2H),6.89(d,J=8Hz,2H),7.08(d,J=8Hz,2H),7.59(d,J=8Hz,2H),7.63(d,J=8Hz,2H),10.36(s,1H),10.60(br s,1H);HPLC-MS:m/z 353(MH+);Rf:2.13min. 1H NMR (DMSO-d6) δ0.97 (t, J = 7Hz, 6H), 1.65 (m, 2H), 1.92 (m, 2H), 3.05-3.25 (m, 3H), 3.35-3.55 (m, 4H ), 4.02 (m, 2H), 6.89 (d, J = 8Hz, 2H), 7.08 (d, J = 8Hz, 2H), 7.59 (d, J = 8Hz, 2H), 7.63 (d, J = 8Hz, 2H), 10.36 (s, 1H), 10.60 (br s, 1H); HPLC-MS: m / z 353 (MH +); Rf: 2.13min.

实施例36{6-[4-(1-乙基丙基)哌嗪-1-基]吡啶-3-基}哌啶-1-基-甲酮盐酸盐 Example 36 {6- [4- (1-ethylpropyl) piperazin-1-yl] pyridin-3-yl piperidin-1-yl} - methanone hydrochloride 1H NMR(DMSO-d6)δ0.97(t,J=7Hz,6H),1.50(m,4H),1.63(m,4H),1.89(m,2H),3.05-3.20(m,3H),3.50(m,8H),4.46(m,2H),7.04(m,1H),7.70(m,1H),8.18(br s,1H),10.90(br s,1H);HPLC-MS:m/z 345(MH+);Rf:2.27min. 1H NMR (DMSO-d6) δ0.97 (t, J = 7Hz, 6H), 1.50 (m, 4H), 1.63 (m, 4H), 1.89 (m, 2H), 3.05-3.20 (m, 3H), 3.50 (m, 8H), 4.46 (m, 2H), 7.04 (m, 1H), 7.70 (m, 1H), 8.18 (br s, 1H), 10.90 (br s, 1H); HPLC-MS: m / z 345 (MH +); Rf: 2.27min.

实施例37N-苄基-6-[4-(1-乙基丙基)哌嗪-1-基]-N-甲基烟酰胺盐酸盐 Example 37N- benzyl-6- [4- (1-ethylpropyl) piperazin-1-yl] -N- methyl-nicotinamide hydrochloride

1H NMR(DMSO-d6)δ0.97(t,J=7Hz,6H),1.63(m,2H),1.88(m,2H),2.89(s,3H),3.09(m,3H),3.50(m,4H),4.45(m,2H),4.62(br s,2H),7.02(d,J=8Hz,1H),7.25-7.41(m,5H),7.78(m,1H),8.28(br s,1H),10.78(br s,1H);HPLC-MS:m/z381(MH+);Rf:3.10min. 1H NMR (DMSO-d6) δ0.97 (t, J = 7Hz, 6H), 1.63 (m, 2H), 1.88 (m, 2H), 2.89 (s, 3H), 3.09 (m, 3H), 3.50 ( m, 4H), 4.45 (m, 2H), 4.62 (br s, 2H), 7.02 (d, J = 8Hz, 1H), 7.25-7.41 (m, 5H), 7.78 (m, 1H), 8.28 (br s, 1H), 10.78 (br s, 1H); HPLC-MS: m / z381 (MH +); Rf: 3.10min.

实施例382-[4-(1-乙基丙基)哌嗪-1-基]-6-甲氧基喹啉盐酸盐 Example 382- [4- (1-ethylpropyl) piperazin-1-yl] -6-methoxy-quinoline hydrochloride 1H NMR(DMSO-d6)δ0.98(t,J=7Hz,6H),1.66(m,2H),1.92(m,2H),3.11(m,1H),3.31(m,2H),3.57(m,2H),3.82(m,2H),3.88(s,3H),4.74(m,2H),7.41(br s,2H),7.53(m,1H),8.12(br s,1H),8.34(br s,1H),10.95(br s,1H);HPLC-MS:m/z314(MH+);Rf:2.17min. 1H NMR (DMSO-d6) δ0.98 (t, J = 7Hz, 6H), 1.66 (m, 2H), 1.92 (m, 2H), 3.11 (m, 1H), 3.31 (m, 2H), 3.57 ( m, 2H), 3.82 (m, 2H), 3.88 (s, 3H), 4.74 (m, 2H), 7.41 (br s, 2H), 7.53 (m, 1H), 8.12 (br s, 1H), 8.34 (br s, 1H), 10.95 (br s, 1H); HPLC-MS: m / z314 (MH +); Rf: 2.17min.

实施例396-[4-(1-乙基丙基)哌嗪-1-基]-N-甲基-N-苯基烟酰胺盐酸盐 Example 396- [4- (1-ethylpropyl) piperazin-1-yl] -N- methyl-nicotinamide hydrochloride -N- phenyl 1H NMR(DMSO-d6)δ0.95(t,J=7Hz,6H),1.62(m,2H),1.83(m,2H),3.05(m,3H),3.34(s,3H),3.43(m,4H),4.35(m,2H),6.76(d,J=8Hz,1H),7.21(m,3H),7.31(m,2H),7.42(dd,J=8Hz,1Hz,1H),8.01(d,J=1Hz,1H),10.54(br s,1H);HPLC-MS:m/z 367(MH+);Rf:2.90min. 1H NMR (DMSO-d6) δ0.95 (t, J = 7Hz, 6H), 1.62 (m, 2H), 1.83 (m, 2H), 3.05 (m, 3H), 3.34 (s, 3H), 3.43 ( m, 4H), 4.35 (m, 2H), 6.76 (d, J = 8Hz, 1H), 7.21 (m, 3H), 7.31 (m, 2H), 7.42 (dd, J = 8Hz, 1Hz, 1H), 8.01 (d, J = 1Hz, 1H), 10.54 (br s, 1H); HPLC-MS: m / z 367 (MH +); Rf: 2.90min.

实施例40{6-[4-(1-乙基丙基)哌嗪-1-基]吡啶-3-基}-(4-氟苯基)甲酮盐酸盐 40 {6- [4- (1-ethylpropyl) piperazin-1-yl] pyridin-3-yl} Example - (4-fluorophenyl) methanone hydrochloride 1H NMR(DMSO-d6)δ0.95(t,J=7Hz,6H),1.62(m,2H),1.83(m,2H),3.10(m,3H),3.45-3.65(m,4H),4.55(m,2H),7.05(d,J=8Hz,1H),7.38(d,J=8Hz,2H),7.78(dd,J=8Hz,4Hz,2H),7.96(dd,J=8Hz,1Hz,1H),8.48(d,J=1Hz,1H),10.85(br s,1H);HPLC-MS:m/z 356(MH+);Rf:2.40min. 1H NMR (DMSO-d6) δ0.95 (t, J = 7Hz, 6H), 1.62 (m, 2H), 1.83 (m, 2H), 3.10 (m, 3H), 3.45-3.65 (m, 4H), 4.55 (m, 2H), 7.05 (d, J = 8Hz, 1H), 7.38 (d, J = 8Hz, 2H), 7.78 (dd, J = 8Hz, 4Hz, 2H), 7.96 (dd, J = 8Hz, 1Hz, 1H), 8.48 (d, J = 1Hz, 1H), 10.85 (br s, 1H); HPLC-MS: m / z 356 (MH +); Rf: 2.40min.

实施例412-[4-(1-乙基丙基)哌嗪-1-基]-4-甲基喹啉盐酸盐 Example 412- [4- (1-ethylpropyl) piperazin-1-yl] -4-methyl-quinoline hydrochloride 1H NMR(DMSO-d6)δ0.98(t,J=7Hz,6H),1.64(m,2H),1.92(m,2H),2.69(s,3H),3.12(m,1H),3.32(m,2H),3.57(m,2H),3.94(m,2H),4.86(m,2H),7.53(br s,2H),7.80(m,1H),8.01(m,1H),8.32(br s,1H),11.20(br s,1H);HPLC-MS:m/z 298(MH+);Rf:1.26min. 1H NMR (DMSO-d6) δ0.98 (t, J = 7Hz, 6H), 1.64 (m, 2H), 1.92 (m, 2H), 2.69 (s, 3H), 3.12 (m, 1H), 3.32 ( m, 2H), 3.57 (m, 2H), 3.94 (m, 2H), 4.86 (m, 2H), 7.53 (br s, 2H), 7.80 (m, 1H), 8.01 (m, 1H), 8.32 ( br s, 1H), 11.20 (br s, 1H); HPLC-MS: m / z 298 (MH +); Rf: 1.26min.

实施例422-[4-(1-乙基丙基)哌嗪-1-基]-5,6,7,8-四氢喹啉盐酸盐 Example 422- [4- (1-ethylpropyl) piperazin-1-yl] -5,6,7,8-tetrahydroquinoline hydrochloride

1H NMR(DMSO-d6)δ0.98(t,J=7Hz,6H),1.50-2.03(m,8H),2.63(m,2H),2.90(m,2H),3.00-3.33(m,3H),3.50(m,2H),3.75(m,2H),4.48(m,2H),7.13(br s,1H),7.75(br s,1H),11.10(br s,1H);HPLC-MS:m/z 288(MH+);Rf:1.83min. 1H NMR (DMSO-d6) δ0.98 (t, J = 7Hz, 6H), 1.50-2.03 (m, 8H), 2.63 (m, 2H), 2.90 (m, 2H), 3.00-3.33 (m, 3H ), 3.50 (m, 2H), 3.75 (m, 2H), 4.48 (m, 2H), 7.13 (br s, 1H), 7.75 (br s, 1H), 11.10 (br s, 1H); HPLC-MS : m / z 288 (MH +); Rf: 1.83min.

从2-氯-5,6,7,8-四氢喹啉(SCZimmerman,Z.Zeng,J.Org.Chem.1990,55,4789-5791)制备该化合物。 5,6,7,8-tetrahydroquinoline (SCZimmerman, Z.Zeng, J.Org.Chem.1990,55,4789-5791) This compound was prepared from 2-chloro.

实施例432-(4-环丙基甲基哌嗪-1-基)-6-甲氧基喹啉盐酸盐 Example 432- (4-cyclopropylmethyl-piperazin-1-yl) -6-methoxy-quinoline hydrochloride 1H NMR(DMSO-d6)δ0.41(m,2H),0.66(m,2H),1.18(m,1H),3.02(m,2H),3.13(m,2H),3.52-3.69(m,4H),3.85(s,3H),4.71(m,2H),7.41(br s,2H),7.53(m,1H),8.12(br s,1H),8.34(br s,1H),11.38(br s,1H);HPLC-MS:m/z 298(MH+);Rf:1.87min. 1H NMR (DMSO-d6) δ0.41 (m, 2H), 0.66 (m, 2H), 1.18 (m, 1H), 3.02 (m, 2H), 3.13 (m, 2H), 3.52-3.69 (m, 4H), 3.85 (s, 3H), 4.71 (m, 2H), 7.41 (br s, 2H), 7.53 (m, 1H), 8.12 (br s, 1H), 8.34 (br s, 1H), 11.38 ( br s, 1H); HPLC-MS: m / z 298 (MH +); Rf: 1.87min.

实施例442-(4-异丙基哌嗪-1-基)-6-甲氧基喹啉盐酸盐 EXAMPLE 442- (4-isopropyl-piperazin-1-yl) -6-methoxy-quinoline hydrochloride embodiment 1H NMR(DMSO-d6)δ1.32(d,J=7Hz,6H),3.28(m,2H),3.53(m,3H),3.80(m,1H),3.85(s,3H),4.85(m,2H),7.43(br s,2H),7.59(d,J=8Hz,1H),8.27(br s,1H),8.34(br s,1H),8.40(d,J=8Hz,1H),11.60(br s,1H);HPLC-MS:m/z 286(MH+);Rf:1.77min. 1H NMR (DMSO-d6) δ1.32 (d, J = 7Hz, 6H), 3.28 (m, 2H), 3.53 (m, 3H), 3.80 (m, 1H), 3.85 (s, 3H), 4.85 ( m, 2H), 7.43 (br s, 2H), 7.59 (d, J = 8Hz, 1H), 8.27 (br s, 1H), 8.34 (br s, 1H), 8.40 (d, J = 8Hz, 1H) , 11.60 (br s, 1H); HPLC-MS: m / z 286 (MH +); Rf: 1.77min.

实施例452-[4-(1-乙基丙基)哌嗪-1-基]-6-氟-4-甲基喹啉盐酸盐 Example 452- [4- (1-ethylpropyl) piperazin-1-yl] -6-fluoro-4-methyl-quinoline hydrochloride 1H NMR(DMSO-d6)δ0.98(t,J=7Hz,6H),1.64(m,2H),1.92(m,2H),2.67(s,3H),3.12(m,1H),3.32(m,2H),3.57-4.00(m,4H),4.85(m,2H),7.57(br s,2H),7.68(m,1H),7.82(m,1H),8.33(br s,1H),11.10(br s,1H);HPLC-MS:m/z 316(MH+);Rf:1.92min. 1H NMR (DMSO-d6) δ0.98 (t, J = 7Hz, 6H), 1.64 (m, 2H), 1.92 (m, 2H), 2.67 (s, 3H), 3.12 (m, 1H), 3.32 ( m, 2H), 3.57-4.00 (m, 4H), 4.85 (m, 2H), 7.57 (br s, 2H), 7.68 (m, 1H), 7.82 (m, 1H), 8.33 (br s, 1H) , 11.10 (br s, 1H); HPLC-MS: m / z 316 (MH +); Rf: 1.92min.

从2-氯-6-氟-4-甲基喹啉制备该化合物,原料是这样制备的:4-氟苯胺的乙酰乙酰化,继之以酸介导的环闭合和借助磷酰氯处理将所得喹诺酮转化为氯喹啉。 From 2-chloro-6-fluoro-4-methyl-quinoline This compound was prepared, starting material is prepared: The resulting 4-fluoroaniline phosphorus oxychloride acetoacetylated, followed by the acid mediated ring closure and the means of quinolone into chloroquinoline.

实施例462-(4-异丙基哌嗪-1-基)喹啉盐酸盐 Example 462- (4-isopropyl-piperazin-1-yl) quinoline hydrochloride 1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.19(m,2H),3.52(m,3H),3.72(m,2H),4.79(m,2H),7.45(m,2H),7.68(m,1H),7.86(m,1H),8.03(m,1H),8.31(m,1H),11.45(br s,1H);HPLC-MS:m/z 256(MH+);Rf:1.47min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.19 (m, 2H), 3.52 (m, 3H), 3.72 (m, 2H), 4.79 (m, 2H), 7.45 ( m, 2H), 7.68 (m, 1H), 7.86 (m, 1H), 8.03 (m, 1H), 8.31 (m, 1H), 11.45 (br s, 1H); HPLC-MS: m / z 256 ( MH +); Rf: 1.47min.

实施例472-(4-环丙基哌嗪-1-基)-6-甲氧基喹啉盐酸盐 Example 472- (4-cyclopropyl-piperazin-1-yl) -6-methoxy-quinoline hydrochloride

1H NMR(DMSO-d6)δ0.81(m,2H),1.20(br s,2H),2.86(br s,1H),3.25-3.75(m,4H),3.85(s,3H),4.09(m,2H),4.73(m,2H),7.41(m,2H),7.55(m,1H),8.14(m,1H),8.37(m,1H),11.51(br s,1H);HPLC-MS:m/z284(MH+);Rf:1.80min. 1H NMR (DMSO-d6) δ0.81 (m, 2H), 1.20 (br s, 2H), 2.86 (br s, 1H), 3.25-3.75 (m, 4H), 3.85 (s, 3H), 4.09 ( m, 2H), 4.73 (m, 2H), 7.41 (m, 2H), 7.55 (m, 1H), 8.14 (m, 1H), 8.37 (m, 1H), 11.51 (br s, 1H); HPLC- MS: m / z284 (MH +); Rf: 1.80min.

实施例482-(4-异丙基-哌嗪-1-基)-6-三氟甲氧基喹啉盐酸盐 Example 482- (4-isopropyl - piperazine-1-yl) -6-trifluoromethoxy-quinoline hydrochloride 1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.17(m,2H),3.52(m,3H),3.68(m,2H),4.79(m,2H),7.56(d,J=8Hz,1H),7.68(br d,J=7Hz,1H),7.91(br s,1H),8.04(br s,1H),8.35(br d,J=7Hz,1H),11.28(br s,1H);HPLC-MS:m/z 340(MH+);Rf:3.04min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.17 (m, 2H), 3.52 (m, 3H), 3.68 (m, 2H), 4.79 (m, 2H), 7.56 ( d, J = 8Hz, 1H), 7.68 (br d, J = 7Hz, 1H), 7.91 (br s, 1H), 8.04 (br s, 1H), 8.35 (br d, J = 7Hz, 1H), 11.28 (br s, 1H); HPLC-MS: m / z 340 (MH +); Rf: 3.04min.

实施例496-氯-2-(4-环丙基-哌嗪-1-基)-喹啉盐酸盐 Quinoline hydrochloride - Example 496--chloro-2- (- piperazin-1-yl 4-cyclopropyl) embodiment 1H NMR(DMSO-d6)δ0.81(m,2H),1.14(br s,2H),2.88(br s,1H),3.25-3.70(m,6H),4.67(m,2H),7.44(d,J=8Hz,1H),7.61(d,J=8Hz,1H),7.72(m,1H),7.91(br s,1H),8.18(brd,J=8Hz,1H),10.75(br s,1H);HPLC-MS:m/z 288(MH+);Rf:1.77min. 1H NMR (DMSO-d6) δ0.81 (m, 2H), 1.14 (br s, 2H), 2.88 (br s, 1H), 3.25-3.70 (m, 6H), 4.67 (m, 2H), 7.44 ( d, J = 8Hz, 1H), 7.61 (d, J = 8Hz, 1H), 7.72 (m, 1H), 7.91 (br s, 1H), 8.18 (brd, J = 8Hz, 1H), 10.75 (br s , 1H); HPLC-MS: m / z 288 (MH +); Rf: 1.77min.

实施例502-(4-环丙基-哌嗪-1-基)-6-三氟甲氧基喹啉盐酸盐 Example 502- (4-cyclopropyl - piperazin-1-yl) -6-trifluoromethoxy-quinoline hydrochloride

1H NMR(DMSO-d6)δ0.81(m,2H),1.15(br s,2H),2.88(br s,1H),3.20-3.70(m,6H),4.68(m,2H),7.49(d,J=8Hz,1H),7.59(br d,J=8Hz,1H),7.82(m,2H),8.27(d,J=8Hz,1H),10.89(br s,1H);HPLC-MS:m/z 338(MH+);Rf:2.24min. 1H NMR (DMSO-d6) δ0.81 (m, 2H), 1.15 (br s, 2H), 2.88 (br s, 1H), 3.20-3.70 (m, 6H), 4.68 (m, 2H), 7.49 ( d, J = 8Hz, 1H), 7.59 (br d, J = 8Hz, 1H), 7.82 (m, 2H), 8.27 (d, J = 8Hz, 1H), 10.89 (br s, 1H); HPLC-MS : m / z 338 (MH +); Rf: 2.24min.

实施例512-(4-异丙基-哌嗪-1-基)-8-三氟甲基喹啉盐酸盐 Example 512- (4-isopropyl - piperazine-1-yl) -8-trifluoromethyl-quinoline hydrochloride 1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.10(m,2H),3.51(m,5H),4.72(m,2H),7.38(t,J=8Hz,1H),7.46(d,J=8Hz,1H),7.95(br d,J=7Hz,1H),8.05(br d,J=7Hz,1H),8.26(d,J=8Hz,1H),10.66(br s,1H);HPLC-MS:m/z 324(MH+);Rf:3.08min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.10 (m, 2H), 3.51 (m, 5H), 4.72 (m, 2H), 7.38 (t, J = 8Hz, 1H ), 7.46 (d, J = 8Hz, 1H), 7.95 (br d, J = 7Hz, 1H), 8.05 (br d, J = 7Hz, 1H), 8.26 (d, J = 8Hz, 1H), 10.66 ( br s, 1H); HPLC-MS: m / z 324 (MH +); Rf: 3.08min.

实施例522-(4-异丙基-哌嗪-1-基)-6-三氟甲基喹啉盐酸盐 Example 522- (4-isopropyl - piperazine-1-yl) -6-trifluoromethyl-quinoline hydrochloride 1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.12(m,2H),3.50-3.68(m,5H),4.78(m,2H),7.52(d,J=7Hz,1H),7.88(m,2H),8.26(br s,1H),8.36(d,J=7Hz,1H),10.95(br s,1H);HPLC-MS:m/z 324(MH+);Rf:2.11min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.12 (m, 2H), 3.50-3.68 (m, 5H), 4.78 (m, 2H), 7.52 (d, J = 7Hz , 1H), 7.88 (m, 2H), 8.26 (br s, 1H), 8.36 (d, J = 7Hz, 1H), 10.95 (br s, 1H); HPLC-MS: m / z 324 (MH +); Rf: 2.11min.

实施例532-(4-异丙基-哌嗪-1-基)-6-丙基喹啉盐酸盐 Example 532- (4-isopropyl - piperazine-1-yl) -6-propyl-quinoline hydrochloride

1H NMR(DMSO-d6)δ0.91(t,J=7Hz,3H),1.31(d,J=7Hz,6H),1.66(sext,J=7Hz,2H),2.70(t,J=7Hz,2H),3.23(m,2H),3.48-3.90(m,5H),4.81(m,2H),7.52(m,1H),7.63(m,1H),7.70(br s,1H),8.09(br s,1H),8.34(br s,1H),11.35(br s,1H);HPLC-MS:m/z 298(MH+);Rf:1.97min. 1H NMR (DMSO-d6) δ0.91 (t, J = 7Hz, 3H), 1.31 (d, J = 7Hz, 6H), 1.66 (sext, J = 7Hz, 2H), 2.70 (t, J = 7Hz, 2H), 3.23 (m, 2H), 3.48-3.90 (m, 5H), 4.81 (m, 2H), 7.52 (m, 1H), 7.63 (m, 1H), 7.70 (br s, 1H), 8.09 ( br s, 1H), 8.34 (br s, 1H), 11.35 (br s, 1H); HPLC-MS: m / z 298 (MH +); Rf: 1.97min.

实施例546,8-二氟-2-(4-异丙基哌嗪-1-基)喹啉盐酸盐 2- (4-isopropyl-piperazin-1-yl) quinoline hydrochloride Example 546,8- difluoromethyl 1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.09(m,2H),3.51(m,5H),4.66(m,2H),7.45-7.58(m,3H),8.18(d,J=7Hz,1H),10.92(br s,1H). 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.09 (m, 2H), 3.51 (m, 5H), 4.66 (m, 2H), 7.45-7.58 (m, 3H), 8.18 (d, J = 7Hz, 1H), 10.92 (br s, 1H).

实施例558-氟-2-(4-异丙基哌嗪-1-基)喹啉盐酸盐 Example 558- fluoro-2- (4-isopropyl-piperazin-1-yl) quinoline hydrochloride 1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.09(m,2H),3.52(m,5H),4.70(m,2H),7.24(m,1H),7.40(m,2H),7.59(d,J=7Hz,1H),8.20(d,J=7Hz,1H),10.84(br s,1H). 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.09 (m, 2H), 3.52 (m, 5H), 4.70 (m, 2H), 7.24 (m, 1H), 7.40 ( m, 2H), 7.59 (d, J = 7Hz, 1H), 8.20 (d, J = 7Hz, 1H), 10.84 (br s, 1H).

实施例562-(4-环丙基哌嗪-1-基)-6-三氟甲基喹啉盐酸盐 Example 562- (4-cyclopropyl-piperazin-1-yl) -6-trifluoromethyl-quinoline hydrochloride

1H NMR(DMSO-d6)δ0.81(m,2H),1.19(br s,2H),2.88(br s,1H),3.20-3.70(m,6H),4.73(m,2H),7.52(d,J=8Hz,1H),7.88(m,2H),8.26(br s,1H),8.33(d,J=8Hz,1H),11.12(brs,1H);HPLC-MS:m/z 322(MH+);Rf:2.41min. 1H NMR (DMSO-d6) δ0.81 (m, 2H), 1.19 (br s, 2H), 2.88 (br s, 1H), 3.20-3.70 (m, 6H), 4.73 (m, 2H), 7.52 ( d, J = 8Hz, 1H), 7.88 (m, 2H), 8.26 (br s, 1H), 8.33 (d, J = 8Hz, 1H), 11.12 (brs, 1H); HPLC-MS: m / z 322 (MH +); Rf: 2.41min.

实施例572-(4-环丙基哌嗪-1-基)-6-丙基喹啉盐酸盐 Example 572- (4-cyclopropyl-piperazin-1-yl) -6-propyl-quinoline hydrochloride 1H NMR(DMSO-d6)δ0.82(m,2H),0.91(t,J=7Hz,3H),1.18(br s,2H),1.66(sext,J=7Hz,2H),2.69(t,J=7Hz,2H),2.85(br s,1H),3.30-3.75(m,6H),4.72(m,2H),7.51(m,1H),7.62(m,1H),7.69(br s,1H),7.97(br s,1H),8.33(br s,1H),11.20(br s,1H);HPLC-MS:m/z296(MH+);Rf:1.97min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 0.91 (t, J = 7Hz, 3H), 1.18 (br s, 2H), 1.66 (sext, J = 7Hz, 2H), 2.69 (t, J = 7Hz, 2H), 2.85 (br s, 1H), 3.30-3.75 (m, 6H), 4.72 (m, 2H), 7.51 (m, 1H), 7.62 (m, 1H), 7.69 (br s, 1H), 7.97 (br s, 1H), 8.33 (br s, 1H), 11.20 (br s, 1H); HPLC-MS: m / z296 (MH +); Rf: 1.97min.

实施例582-(4-乙基哌嗪-1-基)喹啉盐酸盐 Example 582- (4-ethyl-piperazin-1-yl) quinoline hydrochloride 也可以参照S.Cacchi et al.,SynLett 1997,1400-1402。 You may also refer to S.Cacchi et al., SynLett 1997,1400-1402.

1H NMR(DMSO-d6)δ1.30(t,J=7Hz,3H),3.15(m,4H),3.55-3.85(m,4H),4.81(m,2H),7.47(m,1H),7.53(m,1H),7.74(m,1H),7.89(d,J=8Hz,1H),8.13(br s,1H),8.40(br s,1H),11.34(brs,1H);HPLC-MS:m/z 242(MH+);Rf:1.04min. 1H NMR (DMSO-d6) δ1.30 (t, J = 7Hz, 3H), 3.15 (m, 4H), 3.55-3.85 (m, 4H), 4.81 (m, 2H), 7.47 (m, 1H), 7.53 (m, 1H), 7.74 (m, 1H), 7.89 (d, J = 8Hz, 1H), 8.13 (br s, 1H), 8.40 (br s, 1H), 11.34 (brs, 1H); HPLC- MS: m / z 242 (MH +); Rf: 1.04min.

实施例59(通用工艺(B))3-(4-异丙基-哌嗪-1-基)-6-苯基-哒嗪,盐酸盐 Example 59 (General procedure (B)) 3- (4- isopropyl - piperazin-1-yl) -6-phenyl - pyridazine, hydrochloride

从1-异丙基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-苯基哒嗪开始,按照通用工艺(B)制备该化合物。 From 1-isopropyl-piperazine and such J.Heterocycl.Chem., 15,881 (1978) 3- chloro-6-phenyl pyridazine prepared starting with the general procedure (B) This compound was prepared.

1H NMR(D2O):δ1.46(d,6H);3.28(m,2H);3.48(m,2H);3.64-3.84(m,3H);4.57(m,2H);7.63-7.72(m,4H);7.90(m,2H);8.12(d,1H);HPLC-MS:m/z=283.2(M+1);Rt=1.52min. 1H NMR (D2O): δ1.46 (d, 6H); 3.28 (m, 2H); 3.48 (m, 2H); 3.64-3.84 (m, 3H); 4.57 (m, 2H); 7.63-7.72 (m , 4H); 7.90 (m, 2H); 8.12 (d, 1H); HPLC-MS: m / z = 283.2 (m + 1); Rt = 1.52min.

实施例60(通用工艺(B))3-(4-环戊基-哌嗪-1-基)-6-(4-甲磺酰基-苯基)-哒嗪 Example 60 (General procedure (B)) 3- (4-Cyclopentyl - piperazin-1-yl) -6- (4-methanesulfonyl-phenyl) - - pyridazine 从1-环戊基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(4-甲磺酰基-苯基)-哒嗪开始,按照通用工艺(B)制备该化合物。 ., 15,881 (1978) prepared 3-chloro-6- (4-methanesulfonyl-phenyl) - - from 1-cyclopentyl-piperazine and as J.Heterocycl.Chem pyridazine starting with the general process (B) this compound was prepared.

1H NMR(CDCl3):δ1.38-1.80(m,6H),1.92(m,2H);2.56(quint,1H);2.66(dd,4H);3.10(s,3H);3.97(dd,4H);6.99(d,1H);7.69(d,1H);8.03(d,2H);8.20(d,2H);HPLC-MS:m/z=387.0(M+1);Rt=2.20min. 1H NMR (CDCl3): δ1.38-1.80 (m, 6H), 1.92 (m, 2H); 2.56 (quint, 1H); 2.66 (dd, 4H); 3.10 (s, 3H); 3.97 (dd, 4H ); 6.99 (d, 1H); 7.69 (d, 1H); 8.03 (d, 2H); 8.20 (d, 2H); HPLC-MS: m / z = 387.0 (m + 1); Rt = 2.20min.

实施例61(通用工艺(B))3-(4-环丙基甲基-哌嗪-1-基)-6-(4-甲磺酰基-苯基)-哒嗪 Example 61 (General procedure (B)) 3- (4- cyclopropylmethyl - piperazin-1-yl) -6- (4-methanesulfonyl-phenyl) - - pyridazine 从1-环戊基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(4-甲磺酰基-苯基)-哒嗪开始,按照通用工艺(B)制备该化合物。 ., 15,881 (1978) prepared 3-chloro-6- (4-methanesulfonyl-phenyl) - - from 1-cyclopentyl-piperazine and as J.Heterocycl.Chem pyridazine starting with the general process (B) this compound was prepared.

1H NMR(CDCl3):δ0.15(q,2H);0.57(m,2H);0.92(m,1H);2.34(d,2H);2.69(dd,4H);3.10(s,3H);3.80(dd,4H);7.01(d,1H);7.70(d,1H);8.03(d,2H);8.21(d,2H);HPLC-MS:m/z=373.4(M+1);Rt=2.04min. 1H NMR (CDCl3): δ0.15 (q, 2H); 0.57 (m, 2H); 0.92 (m, 1H); 2.34 (d, 2H); 2.69 (dd, 4H); 3.10 (s, 3H); 3.80 (dd, 4H); 7.01 (d, 1H); 7.70 (d, 1H); 8.03 (d, 2H); 8.21 (d, 2H); HPLC-MS: m / z = 373.4 (m + 1); Rt = 2.04min.

实施例62(通用工艺(B))3-(4-异丙基-哌嗪-1-基)-6-(4-甲磺酰基-苯基)-哒嗪 62 (General procedure (B)) Example 3- (4-isopropyl - piperazine-1-yl) -6- (4-methanesulfonyl-phenyl) - - pyridazine 从1-异丙基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(4-甲磺酰基-苯基)-哒嗪开始,按照通用工艺(B)制备该化合物。 ., And 1-isopropyl-piperazine e.g., 15,881 (1978) prepared 6-chloro-3- (- 4-methanesulfonyl-phenyl) - pyridazine J. Heterocycl. Chem from the beginning, according to general process (B) this compound was prepared.

1H NMR(DMSO-d6):δ1.01(d,6H);2.57(m,4H);2.71(m,1H);3.26(s,3H);3.67(m,4H);7.39(d,1H);8.02(d,2H);8.06(d,1H);8.30(d,2H);HPLC-MS:m/z=360.8(M+1);Rt=1.43min. 1H NMR (DMSO-d6): δ1.01 (d, 6H); 2.57 (m, 4H); 2.71 (m, 1H); 3.26 (s, 3H); 3.67 (m, 4H); 7.39 (d, 1H ); 8.02 (d, 2H); 8.06 (d, 1H); 8.30 (d, 2H); HPLC-MS: m / z = 360.8 (m + 1); Rt = 1.43min.

实施例63(通用工艺(B))3-(4-氯-苯基)-6-(4-异丙基-哌嗪-1-基)-4-甲基-哒嗪,二盐酸盐 Example 63 (General procedure (B)) 3- (4- chloro - phenyl) -6- (4-isopropyl - piperazine-1-yl) -4-methyl - pyridazine dihydrochloride 从1-异丙基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的6-氯-3-(4-氯-苯基)-4-甲基-哒嗪开始,按照通用工艺(B)制备该化合物。 From 1-isopropyl-piperazine and e.g., 15,881 (1978) prepared 6-chloro -3- J.Heterocycl.Chem. (4- chloro - phenyl) -4-methyl - pyridazine Start , the compound according to general procedure (B) was prepared.

1H NMR(D2O):δ1.08(d,6H);2.10(s,1H);3.01(m,2H);3.23(m,2H);3.28-3.44(m,3H);4.31(broad d,2H);7.27(d,2H);7.34(d,2H);7.58(s,1H);HPLC-MS:m/z=331.1(M+1);Rt=3.1min. 1H NMR (D2O): δ1.08 (d, 6H); 2.10 (s, 1H); 3.01 (m, 2H); 3.23 (m, 2H); 3.28-3.44 (m, 3H); 4.31 (broad d, 2H); 7.27 (d, 2H); 7.34 (d, 2H); 7.58 (s, 1H); HPLC-MS: m / z = 331.1 (m + 1); Rt = 3.1min.

C18H23N4Cl,2HCl C18H23N4Cl, 2HCl

计算值C53.54 H6.24 N13.88实测值C53.34 H6.31 N13.70. Calcd C53.54 H6.24 N13.88 found C53.34 H6.31 N13.70.

实施例64(通用工艺(B))3-(4-氯-苯基)-6-(4-环戊基-哌嗪-1-基)-4-甲基-哒嗪,盐酸盐 Example 64 (General procedure (B)) 3- (4- chloro - phenyl) -6- (4-Cyclopentyl - piperazin-1-yl) -4-methyl - pyridazine, hydrochloride 从1-环戊基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的6-氯-3-(4-氯-苯基)-4-甲基-哒嗪开始,按照通用工艺(B)制备该化合物。 From 1-cyclopentyl-piperazine and as J.Heterocycl.Chem, 15,881 (1978) 6- chloro-prepared 3- (4-chloro-phenyl) -. 4-methyl - pyridazine Start , the compound according to general procedure (B) was prepared.

1H NMR(D2O):δ1.29-1.60(m,6H);1.91(m,2H);2.12(s,3H);3.00(m,2H);3.24(m,2H);3.36(m,1H);3.51(broad d,2H);4.29(broad d,2H);7.29(d,2H);7.36(d,2H);7.60(s,1H);HPLC-MS:m/z=357.1(M+1);Rt=3.25min. 1H NMR (D2O): δ1.29-1.60 (m, 6H); 1.91 (m, 2H); 2.12 (s, 3H); 3.00 (m, 2H); 3.24 (m, 2H); 3.36 (m, 1H ); 3.51 (broad d, 2H); 4.29 (broad d, 2H); 7.29 (d, 2H); 7.36 (d, 2H); 7.60 (s, 1H); HPLC-MS: m / z = 357.1 (m +1); Rt = 3.25min.

C20H25N4Cl,2HCl计算值C55.89 H6.33 N13.04实测值C55.83 H6.47 N12.93. C20H25N4Cl, 2HCl calcd C55.89 H6.33 N13.04 found C55.83 H6.47 N12.93.

实施例65(通用工艺(B))3-(4-氯苯基)-6-(4-环戊基哌嗪-1-基)-哒嗪 65 (General procedure (B)) Example 3- (4-Chlorophenyl) -6- (4-cyclopentyl-piperazin-1-yl) - pyridazine 从1-环戊基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(4-氯-苯基)-哒嗪开始,如实施例6所述制备该化合物。 From 1-cyclopentyl-piperazine and as J.Heterocycl.Chem, 15,881 (1978) 3- chloro prepared 6- (4-chloro - phenyl) - pyridazine started, as in Example 6 this compound was prepared. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(CDCl3):δ1.39-1.81(m,6H),1.91(m,2H),2.56(q,1H),2.66(dd,4H),3.74(dd,4H),6.96(d,J=9.5Hz,1H),7.43(d,J=8.7Hz,2H),7.61(d,J=9.5Hz,1H),7.93(d,J=8.7Hz,2H);HPLC-MS(Method #):m/z=343(M+1);Rt=2.93min. 1H NMR (CDCl3): δ1.39-1.81 (m, 6H), 1.91 (m, 2H), 2.56 (q, 1H), 2.66 (dd, 4H), 3.74 (dd, 4H), 6.96 (d, J = 9.5Hz, 1H), 7.43 (d, J = 8.7Hz, 2H), 7.61 (d, J = 9.5Hz, 1H), 7.93 (d, J = 8.7Hz, 2H); HPLC-MS (Method #) : m / z = 343 (m + 1); Rt = 2.93min.

实施例66(通用工艺(B))3-(4-环戊基哌嗪-1-基)-6-(3-氟-4-甲氧基苯基)-哒嗪,二盐酸盐 66 (General procedure (B)) Example 3- (4-cyclopentyl-piperazin-1-yl) -6- (3-fluoro-4-methoxyphenyl) - pyridazine dihydrochloride 从1-环戊基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(3-氟-4-甲氧基苯基)-哒嗪开始,如实施例6所述制备该化合物。 Prepared from 3-chloro-1-cyclopentyl-piperazine and as J.Heterocycl.Chem, 15,881 (1978) -6- (3- fluoro-4-methoxyphenyl) - pyridazine start as described in Example 6. this compound was prepared.

1H NMR(DMSO-d6):δ1.45-2.15(m,8H),3.17(m,2H),3.40-3.77(m,5H),3.92(s,3H),7.34(t,J=8.7Hz,1H),7.80(d,J=9.8Hz,1H),7.85-8.05(m,2H),8.29(d,J=9.8Hz,1H),11.75(bs,1H);HPLC-MS:m/z=357(M+1);Rt=2.47min. 1H NMR (DMSO-d6): δ1.45-2.15 (m, 8H), 3.17 (m, 2H), 3.40-3.77 (m, 5H), 3.92 (s, 3H), 7.34 (t, J = 8.7Hz , 1H), 7.80 (d, J = 9.8Hz, 1H), 7.85-8.05 (m, 2H), 8.29 (d, J = 9.8Hz, 1H), 11.75 (bs, 1H); HPLC-MS: m / z = 357 (M + 1); Rt = 2.47min.

实施例67(通用工艺(B))3-(4-环戊基哌嗪-1-基)-6-(3,4-二甲氧基苯基)-哒嗪 67 (General procedure (B)) Example 3- (4-cyclopentyl-piperazin-1-yl) -6- (3,4-dimethoxyphenyl) - pyridazine 从1-环戊基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(3,4-二甲氧基苯基)-哒嗪开始,如实施例6所述制备该化合物。 . Pyridazine Start - 1-cyclopentyl-piperazine and e.g., 15,881 (1978) prepared 3-chloro-6- (3,4-dimethoxyphenyl) from J. Heterocycl. Chem as described in Example 6 to prepare the compound. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(CDCl3):δ1.40-1.65(m,4H),1.73(m,2H),1.91(m,2H),2.55(q,1H),2.66(t,4H),3.72(t,4H),3.93(s,3H),3.98(s,3H),6.93(d,1H),6.97(d,1H),7.36(dd,1H),7.64(d,1H),7.86(d,1H);HPLC-MS:m/z=370(M+1);Rt=1.90min. 1H NMR (CDCl3): δ1.40-1.65 (m, 4H), 1.73 (m, 2H), 1.91 (m, 2H), 2.55 (q, 1H), 2.66 (t, 4H), 3.72 (t, 4H ), 3.93 (s, 3H), 3.98 (s, 3H), 6.93 (d, 1H), 6.97 (d, 1H), 7.36 (dd, 1H), 7.64 (d, 1H), 7.86 (d, 1H) ; HPLC-MS: m / z = 370 (m + 1); Rt = 1.90min.

实施例68(通用工艺(B))3-(4-氯苯基)-6-(4-环丙基甲基哌嗪-1-基)-哒嗪 Example 68 (General procedure (B)) 3- (4- chlorophenyl) -6- (4-cyclopropylmethyl-piperazin-1-yl) - pyridazine

从1-环丙基甲基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(4-氯苯基)-哒嗪开始,如实施例6所述制备该化合物。 From 1-cyclopropyl-methylpiperazine and as J.Heterocycl.Chem, 15,881 (1978) 3- chloro prepared 6- (4-chlorophenyl) - pyridazin-start, as described in Example 6 this compound was prepared. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(CDCl3):δδ0.46(m,2H),0.88(m,2H),1.33(m,1H),2.90(d,2H),3.1-3.5(m,4H),4.1-4.35(m,4H),7.05(d,1H),7.46(d,2H),7.72(d,1H),7.95(d,2H);HPLC-MS:m/z=329(M+1);Rt=2.11min. 1H NMR (CDCl3): δδ0.46 (m, 2H), 0.88 (m, 2H), 1.33 (m, 1H), 2.90 (d, 2H), 3.1-3.5 (m, 4H), 4.1-4.35 (m , 4H), 7.05 (d, 1H), 7.46 (d, 2H), 7.72 (d, 1H), 7.95 (d, 2H); HPLC-MS: m / z = 329 (m + 1); Rt = 2.11 min.

实施例69(通用工艺(B))[名称] 69 (General procedure (B)) [Name] Example embodiments 从1-环戊基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(4-三氟甲基苯基)-哒嗪开始,如实施例6所述制备该化合物。 Prepared from 3-chloro-1-cyclopentyl-piperazine and as J.Heterocycl.Chem, 15,881 (1978) -6- (4- trifluoromethyl-phenyl) - pyridazine started, as described the compound prepared in Example 6. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(CDCl3):δ1.40-1.65(m,4H),1.65-1.80(m,2H),1.92(m,2H),2.55(q,1H),2.65(t,4H),3.76(t,4H),6.99(d,1H),7.67(d,1H),7.72(d,2H),8.12(d,2H);HPLC-MS):m/z=377(M+1);Rt=2.68min. 1H NMR (CDCl3): δ1.40-1.65 (m, 4H), 1.65-1.80 (m, 2H), 1.92 (m, 2H), 2.55 (q, 1H), 2.65 (t, 4H), 3.76 (t , 4H), 6.99 (d, 1H), 7.67 (d, 1H), 7.72 (d, 2H), 8.12 (d, 2H); HPLC-MS): m / z = 377 (m + 1); Rt = 2.68min.

实施例70(通用工艺(B))3-(4-异丙基哌嗪-1-基)-6-(4-三氟甲基苯基)-哒嗪 70 (General procedure (B)) Example 3- (4-isopropyl-piperazin-1-yl) -6- (4-trifluoromethylphenyl) - pyridazine 从1-异丙基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(4-三氟甲基苯基)-哒嗪开始,如实施例6所述制备该化合物。 Prepared from 3-chloro-1-isopropyl-piperazine and as J.Heterocycl.Chem, 15,881 (1978) -6- (4- trifluoromethyl-phenyl) - pyridazine started, as described the compound prepared in Example 6. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(DMSO-d6):δ1.20(d,6H),2.8-4.2(m,9H),7.47(d,1H),7.85(d,2H),8.12(d,1H),8.28(d,2H);HPLC-MS:m/z=351(M+1);Rt=2.51min. 1H NMR (DMSO-d6): δ1.20 (d, 6H), 2.8-4.2 (m, 9H), 7.47 (d, 1H), 7.85 (d, 2H), 8.12 (d, 1H), 8.28 (d , 2H); HPLC-MS: m / z = 351 (m + 1); Rt = 2.51min.

实施例71(通用工艺(B))3-(4-环丙基甲基哌嗪-1-基)-6-(4-三氟甲基苯基)-哒嗪 Example 71 (General procedure (B)) 3- (4- cyclopropylmethyl-piperazin-1-yl) -6- (4-trifluoromethylphenyl) - pyridazine 从1-环丙基甲基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(4-三氟甲基苯基)-哒嗪开始,如实施例6所述制备该化合物。 . Pyridazine Start - 1-cyclopropyl-methylpiperazine and such, (1978) prepared 3-chloro-6- (4-trifluoromethylphenyl) J.Heterocycl.Chem 15,881 from as described in Example 6 to prepare the compound. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(CDCl3):δ0.15(m,2H),0.57(m,2H),0.92(m,1H),2.33(d,2H),2.69(t,4H),3.79(t,4H),7.00(d,1H),7.67(d,1H),7.72(d,2H),8.12(d,2H);HPLC-MS:m/z=363(M+1);Rt=2.65min. 1H NMR (CDCl3): δ0.15 (m, 2H), 0.57 (m, 2H), 0.92 (m, 1H), 2.33 (d, 2H), 2.69 (t, 4H), 3.79 (t, 4H), 7.00 (d, 1H), 7.67 (d, 1H), 7.72 (d, 2H), 8.12 (d, 2H); HPLC-MS: m / z = 363 (m + 1); Rt = 2.65min.

实施例72(通用工艺(B))3-(4-氯苯基)-6-(4-异丙基哌嗪-1-基)-哒嗪 Example 72 (General procedure (B)) 3- (4- chlorophenyl) -6- (4-isopropyl-piperazin-1-yl) - pyridazine 从1-异丙基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(4-氯苯基)-哒嗪开始,如实施例6所述制备该化合物。 From 1-isopropyl-piperazine and as J.Heterocycl.Chem, 15,881 (1978) 3- chloro prepared 6- (4-chlorophenyl) - pyridazin-start, as described in Example 6 the above compound was prepared. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(CDCl3):δ1.10(d,6H),2.68(t,4H),2.75(q,1H),3.73(t,4H),6.97(d,1H),7.43(d,2H),7.61(d,1H),7.94(d,2H);HPLC-MS:m/z=317(M+1);Rt=2.03min. 1H NMR (CDCl3): δ1.10 (d, 6H), 2.68 (t, 4H), 2.75 (q, 1H), 3.73 (t, 4H), 6.97 (d, 1H), 7.43 (d, 2H), 7.61 (d, 1H), 7.94 (d, 2H); HPLC-MS: m / z = 317 (m + 1); Rt = 2.03min.

实施例73(通用工艺(B))3-(4-环丙基甲基哌嗪-1-基)-6-(3-氟-4-甲氧基苯基)-哒嗪 Example 73 (General procedure (B)) 3- (4- cyclopropylmethyl-piperazin-1-yl) -6- (3-fluoro-4-methoxyphenyl) - pyridazine

从1-环丙基甲基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(3-氟-4-甲氧基苯基)-哒嗪开始,如实施例6所述制备该化合物。 Prepared from 3-chloro-1-cyclopropyl-methylpiperazine and as J.Heterocycl.Chem, 15,881 (1978) -6- (3- fluoro-4-methoxyphenyl) - pyridazin triazine starts, Example 6 this compound was prepared as described. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(DMSO-d6):δ0.40(m,2H),0.65(m,2H),1.15(m,1H),2.8-3.7(m,10H),3.90(s,3H),7.29(t,1H),7.47(d,1H),7.88(d,1H),7.93(d,1H),8.06(d,1H);HPLC-MS:m/z=343(M+1);Rt=1.90min,实施例74(通用工艺(B))3-(3-氟-4-甲氧基苯基)-6-(4-异丙基哌嗪-1-基)-哒嗪 1H NMR (DMSO-d6): δ0.40 (m, 2H), 0.65 (m, 2H), 1.15 (m, 1H), 2.8-3.7 (m, 10H), 3.90 (s, 3H), 7.29 (t , 1H), 7.47 (d, 1H), 7.88 (d, 1H), 7.93 (d, 1H), 8.06 (d, 1H); HPLC-MS: m / z = 343 (m + 1); Rt = 1.90 min, Example 74 (General procedure (B)) 3- (3- fluoro-4-methoxyphenyl) -6- (4-isopropyl-piperazin-1-yl) - pyridazine 从1-异丙基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(3-氟-4-甲氧基苯基)-哒嗪开始,如实施例6所述制备该化合物。 Prepared from 3-chloro-1-isopropyl-piperazine and as J.Heterocycl.Chem, 15,881 (1978) -6- (3- fluoro-4-methoxyphenyl) - pyridazine start as described in Example 6. this compound was prepared. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(CDCl3):δ1.11(d,6H),2.70(m,4H),2.80(q,1H),3.74(m,4H),3.94(s,3H),6.96(d,1H),7.04(t,1H),7.57(d,1H),7.72(d,1H),7.78(m,1H);HPLC-MS:m/z=331(M+1);Rt=1.57min. 1H NMR (CDCl3): δ1.11 (d, 6H), 2.70 (m, 4H), 2.80 (q, 1H), 3.74 (m, 4H), 3.94 (s, 3H), 6.96 (d, 1H), 7.04 (t, 1H), 7.57 (d, 1H), 7.72 (d, 1H), 7.78 (m, 1H); HPLC-MS: m / z = 331 (m + 1); Rt = 1.57min.

实施例75(通用工艺(B))3-(3,4-二甲氧基苯基)-6-(4-异丙基哌嗪-1-基)-哒嗪,二盐酸盐 75 (General procedure (B)) Example 3 (3,4-dimethoxyphenyl) -6- (4-isopropyl-piperazin-1-yl) - pyridazine dihydrochloride 从1-异丙基哌嗪和如J.Heterocycl.Chem.,15,881(1978)所述制备的3-氯-6-(3,4-二甲氧基苯基)-哒嗪开始,如实施例6所述制备该化合物。 . Pyridazine Start - 1-isopropyl-piperazine and e.g., 15,881 (1978) prepared 3-chloro (3,4-dimethoxyphenyl) J.Heterocycl.Chem -6- from as described in Example 6 to prepare the compound. 得到标题化合物的游离碱。 To give the free base of the title compound.

1H NMR(DMSO-d6):δ1.32(d,6H),3.17(q,1H),3.3-4.1(m,6H),3.84(s,3H),3.87(s,3H),4.56(d,2H),7.09(d,1H),7.62(d,1H),7.68-7.73(m,2H),8.23(d,1H),11.35(s,1H);HPLC-MS:m/z=343(M+1);Rt=1.50min. 1H NMR (DMSO-d6): δ1.32 (d, 6H), 3.17 (q, 1H), 3.3-4.1 (m, 6H), 3.84 (s, 3H), 3.87 (s, 3H), 4.56 (d , 2H), 7.09 (d, 1H), 7.62 (d, 1H), 7.68-7.73 (m, 2H), 8.23 ​​(d, 1H), 11.35 (s, 1H); HPLC-MS: m / z = 343 (M + 1); Rt = 1.50min.

实施例76(通用工艺(B))(9a-R)-2-(6-三氟甲氧基喹啉-2-基)八氢吡啶并[1,2-a]吡嗪盐酸盐 Example 76 (General procedure (B)) (9a-R) -2- (6- trifluoromethoxy-quinolin-2-yl) octahydro-pyrido [1,2-a] pyrazine hydrochloride 利用通用工艺(B),从(9a-R)-八氢吡啶并[1,2-a]吡嗪和2-氯-6-三氟甲氧基喹啉制备该化合物。 Using general procedure (B), from (9a-R) - octahydro-pyrido [1,2-a] pyrazine and 2-chloro-6-trifluoromethoxy-quinoline This compound was prepared.

1H NMR(DMSO-d6)δ1.40-1.65(m,1H),1.65-2.08(m,5H),2.93(m,1H),3.18(m,1H),3.25-3.55(m,4H),3.71(m,1H),4.85(m,2H),7.61(d,J=8Hz,1H),7.70(d,J=8Hz,1H),7.93(s,1H),8.19(br s,1H),8.39(d,J=8Hz,1H),11.60(br s,1H);HPLC-MS:m/z 352(MH+);Rt=2.67min. 1H NMR (DMSO-d6) δ1.40-1.65 (m, 1H), 1.65-2.08 (m, 5H), 2.93 (m, 1H), 3.18 (m, 1H), 3.25-3.55 (m, 4H), 3.71 (m, 1H), 4.85 (m, 2H), 7.61 (d, J = 8Hz, 1H), 7.70 (d, J = 8Hz, 1H), 7.93 (s, 1H), 8.19 (br s, 1H) , 8.39 (d, J = 8Hz, 1H), 11.60 (br s, 1H); HPLC-MS: m / z 352 (MH +); Rt = 2.67min.

实施例77(通用工艺(B))7-氟-2-(4-异丙基哌嗪-1-基)-6-甲基喹啉盐酸盐 Example 77 (General procedure (B)) 7- fluoro-2- (4-isopropyl-piperazin-1-yl) -6-methyl-quinoline hydrochloride 利用通用工艺(B),从1-异丙基哌嗪和2-氯-7-氟-6-甲基喹啉制备该化合物。 Using general procedure (B), from 1-isopropyl-piperazine and 2-chloro-6-methyl-7-fluoro-quinoline This compound was prepared.

1H NMR(DMSO-d6)δ1.32(d,J=7Hz,6H),2.38(s,3H),3.26(m,2H),3.54(m,3H),3.83(m,2H),4.88(br s,2H),7.49(d,J=8Hz,1H),7.85(d,J=8Hz,H),8.09(br s,1H),8.35(d,J=8Hz,1H),11.57(br s,1H);HPLC-MS:m/z287(MH+);Rt=1.47min. 1H NMR (DMSO-d6) δ1.32 (d, J = 7Hz, 6H), 2.38 (s, 3H), 3.26 (m, 2H), 3.54 (m, 3H), 3.83 (m, 2H), 4.88 ( br s, 2H), 7.49 (d, J = 8Hz, 1H), 7.85 (d, J = 8Hz, H), 8.09 (br s, 1H), 8.35 (d, J = 8Hz, 1H), 11.57 (br s, 1H); HPLC-MS: m / z287 (MH +); Rt = 1.47min.

实施例78(通用工艺(B))7-氯-2-(4-异丙基哌嗪-1-基)喹啉盐酸盐 7-chloro-2- (4-isopropyl-piperazin-1-yl) quinoline hydrochloride 78 ((B) General procedure) Example 利用通用工艺(B),从1-异丙基哌嗪和2,7-二氯喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-isopropyl-piperazine and 2,7-dichloro-quinoline.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3,23(m,2H),3.53(m,3H),3.79(m,2H),4.87(br s,2H),7.48(d,J=8Hz,1H),7.54(d,J=8Hz,1H),7.92(d,J=8Hz,1H),8.26(br s,1H),8.38(d,J=8Hz,1H),11.50(br s,1H);HPLC-MS:m/z289(MH+);Rt=1.61min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3,23 (m, 2H), 3.53 (m, 3H), 3.79 (m, 2H), 4.87 (br s, 2H) , 7.48 (d, J = 8Hz, 1H), 7.54 (d, J = 8Hz, 1H), 7.92 (d, J = 8Hz, 1H), 8.26 (br s, 1H), 8.38 (d, J = 8Hz, 1H), 11.50 (br s, 1H); HPLC-MS: m / z289 (MH +); Rt = 1.61min.

实施例79(通用工艺(B))6-氟-2-(4-异丙基哌嗪-1-基)喹啉盐酸盐 Example 79 (General procedure (B)) 6- fluoro-2- (4-isopropyl-piperazin-1-yl) quinoline hydrochloride 利用通用工艺(B),从1-异丙基哌嗪和2-氯-6-氟喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-isopropyl-piperazine and 2-chloro-6-fluoro quinoline.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.22(m,2H),3.53(m,3H),3.79(m,2H),4.85(br s,2H),7.55-7.70(m,2H),7.45(d,J=8Hz,1H),8.26(br s,1H),8.36(d,J=8Hz,1H),11.52(br s,1H);HPLC-MS:m/z 274(MH+);Rt=1.21min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.22 (m, 2H), 3.53 (m, 3H), 3.79 (m, 2H), 4.85 (br s, 2H), 7.55 -7.70 (m, 2H), 7.45 (d, J = 8Hz, 1H), 8.26 (br s, 1H), 8.36 (d, J = 8Hz, 1H), 11.52 (br s, 1H); HPLC-MS: m / z 274 (MH +); Rt = 1.21min.

实施例80(通用工艺(B))2-(4-环丙基哌嗪-1-基)-7-氟-6-甲基喹啉盐酸盐 Example 80 (General procedure (B)) 2- (4- cyclopropyl-piperazin-1-yl) -7-fluoro-6-methyl-quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-7-氟-6-甲基喹啉制备该化合物。 Using general procedure (B), from 1-cyclopropyl-piperazine and 2-chloro-6-methyl-7-fluoro-quinoline This compound was prepared.

1H NMR(DMSO-d6)δ0.82(m,2H),1.20(m,2H),2.36(s,3H),2.87(m,1H);3.25-4.15(m,6H),4.74(br s,2H),7.43(d,J=8Hz,1H),7.80(m,2H),8.28(d,J=8Hz,1H),11.36(br s,1H);HPLC-MS:m/z 287(MH+);Rt=1.47min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.20 (m, 2H), 2.36 (s, 3H), 2.87 (m, 1H); 3.25-4.15 (m, 6H), 4.74 (br s , 2H), 7.43 (d, J = 8Hz, 1H), 7.80 (m, 2H), 8.28 (d, J = 8Hz, 1H), 11.36 (br s, 1H); HPLC-MS: m / z 287 ( MH +); Rt = 1.47min.

实施例81(通用工艺(B))2-(4-环丙基哌嗪-1-基)-7-氟-6-甲氧基喹啉盐酸盐 Example 81 (General procedure (B)) of 2- (4-cyclopropyl piperazin-1-yl) -7-fluoro-6-methoxy-quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-7-氟-6-甲氧基喹啉制备该化合物。 Using general procedure (B), -6- methoxy-quinoline This compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-7-fluoro.

1H NMR(DMSO-d6)δ0.82(m,2H),1.18(m,2H),2.88(m,1H),3.25-4.10(m,6H),3.93(s,3H),4.64(br s,2H),7.40(d,J=8Hz,1H),7.55(d,J=8Hz,1H),7.73(br s,1H),8.24(d,J=8Hz,1H),11.11(br s,1H);HPLC-MS:m/z 301(MH+);Rt=1.37min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.18 (m, 2H), 2.88 (m, 1H), 3.25-4.10 (m, 6H), 3.93 (s, 3H), 4.64 (br s , 2H), 7.40 (d, J = 8Hz, 1H), 7.55 (d, J = 8Hz, 1H), 7.73 (br s, 1H), 8.24 (d, J = 8Hz, 1H), 11.11 (br s, 1H); HPLC-MS: m / z 301 (MH +); Rt = 1.37min.

实施例82(通用工艺(B))7-氟-2-(4-异丙基哌嗪-1-基)-6-甲氧基喹啉盐酸盐 82 (General procedure (B)) Example 7-fluoro-2- (4-isopropyl-piperazin-1-yl) -6-methoxy-quinoline hydrochloride 利用通用工艺(B),从1-异丙基哌嗪和2-氯-7-氟-6-甲氧基喹啉制备该化合物。 Using general procedure (B), -6- methoxy-quinoline This compound was prepared from 1-isopropyl-piperazine and 2-chloro-7-fluoro.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.16(m,2H),3.45-4.05(m,5H),3.93(s,3H),4.72(m,2H),7.42(d,J=8Hz,1H),7.56(d,J=8Hz,1H),7.83(br s,1H),8.25(d,J=8Hz,1H),11.13(br s,1H);HPLC-MS:m/z 303(MH+);Rt=1.41min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.16 (m, 2H), 3.45-4.05 (m, 5H), 3.93 (s, 3H), 4.72 (m, 2H), 7.42 (d, J = 8Hz, 1H), 7.56 (d, J = 8Hz, 1H), 7.83 (br s, 1H), 8.25 (d, J = 8Hz, 1H), 11.13 (br s, 1H); HPLC -MS: m / z 303 (MH +); Rt = 1.41min.

实施例83(通用工艺(B))(9a-R)-2-(7-氟-6-甲氧基喹啉-2-基)八氢吡啶并[1,2-a]吡嗪盐酸盐 Example 83 (General procedure (B)) (9a-R) -2- (7- fluoro-6-methoxy-quinolin-2-yl) octahydro-pyrido [1,2-a] pyrazine hydrochloride salt

利用通用工艺(B),从(9a-R)八氢吡啶并[1,2-a]吡嗪和2-氯-7-氟-6-甲氧基喹啉制备该化合物。 Using general procedure (B), from (9a-R) octahydro-pyrido [1,2-a] pyrazine and 2-chloro-7-fluoro-6-methoxy-quinoline This compound was prepared.

1H NMR(DMSO-d6)δ1.40-1.55(m,1H),1.65-2.08(m,5H),2.93(m,1H),3.20(m,1H),3.25-3.55(m,4H),3.73(m,1H),4.81(m,2H),7.50(d,J=8Hz,1H),7.62(d,J=8Hz,1H),8.13(br s,1H),8.34(d,J=8Hz,1H),11.59(br s,1H);HPLC-MS:m/z 315(MH+);Rt=1.41min. 1H NMR (DMSO-d6) δ1.40-1.55 (m, 1H), 1.65-2.08 (m, 5H), 2.93 (m, 1H), 3.20 (m, 1H), 3.25-3.55 (m, 4H), 3.73 (m, 1H), 4.81 (m, 2H), 7.50 (d, J = 8Hz, 1H), 7.62 (d, J = 8Hz, 1H), 8.13 (br s, 1H), 8.34 (d, J = 8Hz, 1H), 11.59 (br s, 1H); HPLC-MS: m / z 315 (MH +); Rt = 1.41min.

实施例84(通用工艺(B))(9a-R)-2-(6-三氟甲基喹啉-2-基)八氢吡啶并[1,2-]吡嗪盐酸盐 84 (General procedure (B)) (9a-R) -2- (6- trifluoromethyl-quinolin-2-yl) and Example octahydropyrido [1,2] pyrazine hydrochloride 利用通用工艺(B),从(9a-R)-八氢吡啶并[1,2-a]吡嗪和2-氯-6-三氟甲基喹啉制备该化合物。 Using general procedure (B), from (9a-R) - octahydro-pyrido [1,2-a] pyrazine and 2-chloro-6-trifluoromethyl-quinoline This compound was prepared.

1H NMR(DMSO-d6)δ1.40-1.55(m,1H),1.65-2.05(m,5H),2.92(m,1H),3.20(m,1H),3.30-3.55(m,4H),3.70(m,1H),4.88(m,2H),7.61(d,J=8Hz,1H),7.93(d,J=8Hz,1H),8.15(br s,1H),8.31(s,1H),8.43(d,J=8Hz,1H),11.60(br s,1H);HPLC-MS:m/z 335(MH+);Rt=2.27min. 1H NMR (DMSO-d6) δ1.40-1.55 (m, 1H), 1.65-2.05 (m, 5H), 2.92 (m, 1H), 3.20 (m, 1H), 3.30-3.55 (m, 4H), 3.70 (m, 1H), 4.88 (m, 2H), 7.61 (d, J = 8Hz, 1H), 7.93 (d, J = 8Hz, 1H), 8.15 (br s, 1H), 8.31 (s, 1H) , 8.43 (d, J = 8Hz, 1H), 11.60 (br s, 1H); HPLC-MS: m / z 335 (MH +); Rt = 2.27min.

实施例85(通用工艺(B))7-氟-2-(4-异丙基哌嗪-1-基)喹啉盐酸盐 Quinoline hydrochloride Example 85 (General procedure (B)) 7- fluoro-2- (4-isopropyl-piperazin-1-yl) 利用通用工艺(B),从1-异丙基哌嗪和2-氯-7-氟喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-isopropyl-piperazine and 2-chloro-7-fluoro-quinoline.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.19(m,2H),3.45-4.20(m,5H),4.84(m,2H),7.32(m,1H),7.45(d,J=8Hz,1H),7.83(br s,1H),7.95(m,1H),8.35(m,1H),11.35(br s,1H);HPLC-MS:m/z274(MH+);Rt=1.31min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.19 (m, 2H), 3.45-4.20 (m, 5H), 4.84 (m, 2H), 7.32 (m, 1H), 7.45 (d, J = 8Hz, 1H), 7.83 (br s, 1H), 7.95 (m, 1H), 8.35 (m, 1H), 11.35 (br s, 1H); HPLC-MS: m / z274 (MH + ); Rt = 1.31min.

实施例86(通用工艺(B))6-氯-2-(4-异丙基哌嗪-1-基)喹啉盐酸盐 6-chloro-2- (4-isopropyl-piperazin-1-yl) quinoline hydrochloride 86 ((B) General procedure) Example 利用通用工艺(B),从1-异丙基哌嗪和2,6-二氯喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-isopropyl-piperazine and 2,6-dichloro-quinoline.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.19(m,2H),3.45-3.80(m,5H),4.82(m,2H),7.55(d,J=8Hz,1H),7.72(d,J=8Hz,1H),7.99(s,1H),8.07(br s,1H),8.29(d,J=8Hz,1H),11.38(br s,1H);HPLC-MS:m/z290(MH+);Rt=1.64min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.19 (m, 2H), 3.45-3.80 (m, 5H), 4.82 (m, 2H), 7.55 (d, J = 8Hz , 1H), 7.72 (d, J = 8Hz, 1H), 7.99 (s, 1H), 8.07 (br s, 1H), 8.29 (d, J = 8Hz, 1H), 11.38 (br s, 1H); HPLC -MS: m / z290 (MH +); Rt = 1.64min.

实施例87(通用工艺(B))6-异丙基-2-(4-异丙基哌嗪-1-基)喹啉盐酸盐 87 (General procedure (B)) Example 6-isopropyl-2- (4-isopropyl-piperazin-1-yl) quinoline hydrochloride embodiment 利用通用工艺(B),从1-异丙基哌嗪和2-氯-6-异丙基喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-isopropyl-piperazine and 2-chloro-6-isopropyl-quinoline.

1H NMR(DMSO-d6)δ1.27(d,J=7Hz,6H),1.32(d,J=7Hz,6H),3.05(sept,J=7Hz,1H),3.26(m,2H),3.40-3.95(m,5H),4.86(m,2H),7.55(d,J=8Hz,1H),7.72(d,J=8Hz,1H),7.77(s,1H),8.21(br s,1H),8.42(d,J=8Hz,1H),11.55(br s,1H);HPLC-MS:m/z 298(MH+);Rt=1.87min. 1H NMR (DMSO-d6) δ1.27 (d, J = 7Hz, 6H), 1.32 (d, J = 7Hz, 6H), 3.05 (sept, J = 7Hz, 1H), 3.26 (m, 2H), 3.40 -3.95 (m, 5H), 4.86 (m, 2H), 7.55 (d, J = 8Hz, 1H), 7.72 (d, J = 8Hz, 1H), 7.77 (s, 1H), 8.21 (br s, 1H ), 8.42 (d, J = 8Hz, 1H), 11.55 (br s, 1H); HPLC-MS: m / z 298 (MH +); Rt = 1.87min.

实施例88(通用工艺(B))2-(4-环丙基哌嗪-1-基)-6-异丙基喹啉盐酸盐 88 (General procedure (B)) Example 2- (4-cyclopropyl-piperazin-1-yl) -6-isopropyl-quinoline hydrochloride

利用通用工艺(B),从1-环丙基哌嗪和2-氯-6-异丙基喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-6-isopropyl-quinoline.

1H NMR(DMSO-d6)δ0.83(m,2H),1.20(m,2H),1.27(d,J=7Hz,6H),2.86(br s,1H),3.04(sept,J=7Hz,1H),3.25-3.85(m,5H),4.15(brs,1H),4.74(m,2H),7.53(m,1H),7.70(d,J=8Hz,1H),7.75(s,1H),8.06(br s,1H),8.38(m,1H),11.41(br s,1H);HPLC-MS:m/z(MH+);Rt=min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.20 (m, 2H), 1.27 (d, J = 7Hz, 6H), 2.86 (br s, 1H), 3.04 (sept, J = 7Hz, 1H), 3.25-3.85 (m, 5H), 4.15 (brs, 1H), 4.74 (m, 2H), 7.53 (m, 1H), 7.70 (d, J = 8Hz, 1H), 7.75 (s, 1H) , 8.06 (br s, 1H), 8.38 (m, 1H), 11.41 (br s, 1H); HPLC-MS: m / z (MH +); Rt = min.

实施例89(通用工艺(B))2-(4-环丙基哌嗪-1-基)喹啉盐酸盐 2- (4-cyclopropyl-piperazin-1-yl) quinoline hydrochloride 89 ((B) General procedure) Example 利用通用工艺(B),从1-环丙基哌嗪和2-氯喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-quinoline.

1H NMR(DMSO-d6)δ0.83(m,2H),1.19(m,2H),2.87(br s,1H),3.30-3.80(m,6H),4.74(m,2H),7.45(m,1H),7.52(d,J=8Hz,1H),7.73(m,1H),7.89(d,J=8Hz,1H),8.02(br s,1H),8.38(m,1H),11.22(br s,1H);HPLC-MS:m/z(MH+);Rt=min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.19 (m, 2H), 2.87 (br s, 1H), 3.30-3.80 (m, 6H), 4.74 (m, 2H), 7.45 (m , 1H), 7.52 (d, J = 8Hz, 1H), 7.73 (m, 1H), 7.89 (d, J = 8Hz, 1H), 8.02 (br s, 1H), 8.38 (m, 1H), 11.22 ( br s, 1H); HPLC-MS: m / z (MH +); Rt = min.

实施例90(通用工艺(B))2-(4-环丙基哌嗪-1-基)-6,7-二甲氧基喹啉盐酸盐 Example 90 (General procedure (B)) 2- (4- cyclopropyl-piperazin-1-yl) -6,7-dimethoxy-quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-6,7-二甲氧基喹啉制备该化合物。 Using general procedure (B), morpholine quinoline This compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-6,7-dimethoxy.

1H NMR(DMSO-d6)δ0.82(m,2H),1.20(m,2H),2.87(br s,1H),3.25-3.75(m,6H),3.86(s,3H),3.90(s,3H),4.66(m,2H),7.25-7.50(m,3H),8.24(br s,1H),11.38(br s,1H);HPLC-MS:m/z 314(MH+);Rt=1.27min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.20 (m, 2H), 2.87 (br s, 1H), 3.25-3.75 (m, 6H), 3.86 (s, 3H), 3.90 (s , 3H), 4.66 (m, 2H), 7.25-7.50 (m, 3H), 8.24 (br s, 1H), 11.38 (br s, 1H); HPLC-MS: m / z 314 (MH +); Rt = 1.27min.

实施例91(通用工艺(B)) Example 91 (General procedure (B))

2-(4-异丙基哌嗪-1-基)-6,7-二甲氧基喹啉盐酸盐 2- (4-isopropyl-piperazin-1-yl) -6,7-dimethoxy-quinoline hydrochloride 利用通用工艺(B),从1-异丙基哌嗪和2-氯-6,7-二甲氧基喹啉制备该化合物。 Using general procedure (B), morpholine quinoline This compound was prepared from 1-isopropyl-piperazine and 2-chloro-6,7-dimethoxy.

1H NMR(DMSO-d6)δ1.32(d,J=7Hz,6H),3.25(m,2H),3.45-4.00(m,5H),3.87(s,3H),3.91(s,3H),4.80(m,2H),7.39(m,2H),7.96(br s,1H),8.34(br s,1H),11.50(br s,1H);HPLC-MS:m/z 316(MH+);Rt=1.27min. 1H NMR (DMSO-d6) δ1.32 (d, J = 7Hz, 6H), 3.25 (m, 2H), 3.45-4.00 (m, 5H), 3.87 (s, 3H), 3.91 (s, 3H), 4.80 (m, 2H), 7.39 (m, 2H), 7.96 (br s, 1H), 8.34 (br s, 1H), 11.50 (br s, 1H); HPLC-MS: m / z 316 (MH +); Rt = 1.27min.

实施例92(通用工艺(B))2-(4-环丙基哌嗪-1-基)-7-氟喹啉盐酸盐 Example 92 (General procedure (B)) 2- (4- cyclopropyl-piperazin-1-yl) -7-fluoro-quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-7-氟喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-7-fluoro-quinoline.

1H NMR(DMSO-d6)δ0.82(m,2H),1.22(m,2H),2.87(br s,1H),3.30-3.80(m,6H),4.79(m,2H),7.34(m,1H),7.47(d,J=8Hz,1H),7.85(br s,1H),7.96(m,1H),8.37(m,1H),11.55(br s,1H);HPLC-MS:m/z 271(MH+);Rt=1.24min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.22 (m, 2H), 2.87 (br s, 1H), 3.30-3.80 (m, 6H), 4.79 (m, 2H), 7.34 (m , 1H), 7.47 (d, J = 8Hz, 1H), 7.85 (br s, 1H), 7.96 (m, 1H), 8.37 (m, 1H), 11.55 (br s, 1H); HPLC-MS: m / z 271 (MH +); Rt = 1.24min.

实施例93(通用工艺(B))2-(4-环丙基哌嗪-1-基)-6,8-二氟喹啉盐酸盐 93 (General procedure (B)) Example 2- (4-cyclopropyl-piperazin-1-yl) -6,8-difluoro-quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-6,8-二氟喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-6,8-difluoro-quinoline.

1H NMR(DMSO-d6)δ0.82(m,2H),1.19(m,2H),2.87(brs,1H),3.20-3.70(m,6H),4.63(m,2H),7.48(m,3H),8.19(d,J=8Hz,1H),11.11(br s,1H);HPLC-MS:m/z290(MH+);Rt=2.27min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.19 (m, 2H), 2.87 (brs, 1H), 3.20-3.70 (m, 6H), 4.63 (m, 2H), 7.48 (m, 3H), 8.19 (d, J = 8Hz, 1H), 11.11 (br s, 1H); HPLC-MS: m / z290 (MH +); Rt = 2.27min.

实施例94(通用工艺(B))2-(4-环丙基哌嗪-1-基)-6-氟喹啉盐酸盐 Example 94 (General procedure (B)) 2- (4- cyclopropyl-piperazin-1-yl) -6-fluoro quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-6-氟喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-6-fluoro quinoline.

1H NMR(DMSO-d6)δ0.82(m,2H),1.21(m,2H),2.87(br s,1H),3.30-3.80(m,6H),4.73(m,2H),7.56(d,J=8Hz,1H),7.62(m,1H),7.71(d,J=8Hz,1H),8.09(br s,1H),8.33(d,J=8Hz,1H),11.42(br s,1H);HPLC-MS:m/z 272(MH+);Rt=1.27min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.21 (m, 2H), 2.87 (br s, 1H), 3.30-3.80 (m, 6H), 4.73 (m, 2H), 7.56 (d , J = 8Hz, 1H), 7.62 (m, 1H), 7.71 (d, J = 8Hz, 1H), 8.09 (br s, 1H), 8.33 (d, J = 8Hz, 1H), 11.42 (br s, 1H); HPLC-MS: m / z 272 (MH +); Rt = 1.27min.

实施例95(通用工艺(B))7-氯-2-(4-环丙基哌嗪-1-基)喹啉盐酸盐 Quinoline hydrochloride Example 95 (General procedure (B)) 7- Chloro-2- (4-cyclopropyl-piperazin-1-yl) 利用通用工艺(B),从1-环丙基哌嗪和2,7-二氯喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2,7-dichloro-quinoline.

1H NMR(DMSO-d6)δ0.82(m,2H),1.20(m,2H),2.87(br s,1H),3.25-3.75(m,6H),4.72(m,2H),7.40(d,J=8Hz,1H),7.46(d,J=8Hz,1H),7.87(d,J=8Hz,1H),7.94(br s,1H),8.29(d,J=8Hz,1H),11.29(br s,1H);HPLC-MS:m/z288(MH+);Rt=1.71min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.20 (m, 2H), 2.87 (br s, 1H), 3.25-3.75 (m, 6H), 4.72 (m, 2H), 7.40 (d , J = 8Hz, 1H), 7.46 (d, J = 8Hz, 1H), 7.87 (d, J = 8Hz, 1H), 7.94 (br s, 1H), 8.29 (d, J = 8Hz, 1H), 11.29 (br s, 1H); HPLC-MS: m / z288 (MH +); Rt = 1.71min.

实施例96(通用工艺(B))(9a-R)-2-喹啉-2-基-八氢吡啶并[1,2-a]吡嗪盐酸盐 96 (General procedure (B)) (9a-R) -2- quinolin-2-yl Example - octahydro-pyrido [1,2-a] pyrazine hydrochloride

利用通用工艺(B),从(9a-R)-八氢吡啶并[1,2-a]吡嗪和2-氯喹啉制备该化合物。 Using general procedure (B), from (9a-R) - This compound was prepared octahydro-pyrido [1,2-a] pyrazine and 2-chloro-quinoline.

1H NMR(DMSO-d6)δ1.40-1.55(m,1H),1.65-2.10(m,5H),2.92(m,1H),3.25(m,1H),3.35-3.90(m,5H),4.90(m,2H),7.49(m,1H),7.59(d,J=8Hz,1H),7.77(m,1H),7.92(d,J=8Hz,1H),8.32(br s,1H),8.46(m,1H),11.69(br s,1H);HPLC-MS:m/z 268(MH+);Rt=1.07min. 1H NMR (DMSO-d6) δ1.40-1.55 (m, 1H), 1.65-2.10 (m, 5H), 2.92 (m, 1H), 3.25 (m, 1H), 3.35-3.90 (m, 5H), 4.90 (m, 2H), 7.49 (m, 1H), 7.59 (d, J = 8Hz, 1H), 7.77 (m, 1H), 7.92 (d, J = 8Hz, 1H), 8.32 (br s, 1H) , 8.46 (m, 1H), 11.69 (br s, 1H); HPLC-MS: m / z 268 (MH +); Rt = 1.07min.

实施例97(通用工艺(B))(9a-R)-2-(6-氯喹啉-2-基)八氢吡啶并[1,2-a]吡嗪盐酸盐 97 (General procedure (B)) (9a-R) -2- (6- chloro-quinolin-2-yl) and Example octahydropyrido [1,2-a] pyrazine hydrochloride 利用通用工艺(B),从(9a-R)-八氢吡啶并[1,2-a]吡嗪和2,6-二氯喹啉制备该化合物。 Using general procedure (B), from (9a-R) - This compound was prepared octahydro-pyrido [1,2-a] pyrazine and 2,6-dichloro-quinoline.

1H NMR(DMSO-d6)δ1.40-1.55(m,1H),1.65-2.05(m,5H),2.93(m,1H),3.18(m,1H),3.25-3.55(m,4H),3.68(m,1H),4.90(m,2H),7.56(d,J=8Hz,1H),7.71(d,J=8Hz,1H),7.98(s,1H),8.07(br s,1H),8.29(d,J=8Hz,1H),11.47(br s,1H);HPLC-MS:m/z302(MH+);Rt=1.81min. 1H NMR (DMSO-d6) δ1.40-1.55 (m, 1H), 1.65-2.05 (m, 5H), 2.93 (m, 1H), 3.18 (m, 1H), 3.25-3.55 (m, 4H), 3.68 (m, 1H), 4.90 (m, 2H), 7.56 (d, J = 8Hz, 1H), 7.71 (d, J = 8Hz, 1H), 7.98 (s, 1H), 8.07 (br s, 1H) , 8.29 (d, J = 8Hz, 1H), 11.47 (br s, 1H); HPLC-MS: m / z302 (MH +); Rt = 1.81min.

实施例98(通用工艺(B))(9a-R)-2-(7-氟-6-甲基喹啉-2-基)八氢吡啶并[1,2-a]吡嗪盐酸盐 98 (General procedure (B)) (9a-R) -2- (7- fluoro-6-methyl-quinolin-2-yl) and Example octahydropyrido [1,2-a] pyrazine hydrochloride 利用通用工艺(B),从(9a-R)-八氢吡啶并[1,2-a]吡嗪和2-氯-7-氟-6-甲基喹啉制备该化合物。 Using general procedure (B), from (9a-R) - octahydro-pyrido [1,2-a] pyrazine and 2-chloro-7-fluoro-6-methyl-quinoline This compound was prepared.

1H NMR(DMSO-d6)δ1.40-1.55(m,1H),1.65-2.10(m,5H),2.36(s,3H),2.92(m,1H),3.23(m,1H),3.30-3.60(m,4H),3.80(m,1H),4.87(m,2H),7.51(d,J=8Hz,1H),7.84(d,J=8Hz,1H),8.13(br s,1H),8.36(d,J=8Hz,1H),11.77(br s,1H);HPLC-MS:m/z300(MH+);Rt=1.54min. 1H NMR (DMSO-d6) δ1.40-1.55 (m, 1H), 1.65-2.10 (m, 5H), 2.36 (s, 3H), 2.92 (m, 1H), 3.23 (m, 1H), 3.30- 3.60 (m, 4H), 3.80 (m, 1H), 4.87 (m, 2H), 7.51 (d, J = 8Hz, 1H), 7.84 (d, J = 8Hz, 1H), 8.13 (br s, 1H) , 8.36 (d, J = 8Hz, 1H), 11.77 (br s, 1H); HPLC-MS: m / z300 (MH +); Rt = 1.54min.

实施例99(通用工艺(B))(9a-R)-2-(6-丙基喹啉-2-基)八氢吡啶并[1,2-a]吡嗪盐酸盐 99 (General procedure (B)) (9a-R) -2- (6- propyl-quinolin-2-yl) and Example octahydropyrido [1,2-a] pyrazine hydrochloride 利用通用工艺(B),从(9a-R)-八氢吡啶并[1,2-a]吡嗪和2-氯-6-丙基喹啉制备该化合物。 Using general procedure (B), from (9a-R) - octahydro-pyrido [1,2-a] pyrazine and 2-chloro-6-propyl-quinoline This compound was prepared.

1H NMR(DMSO-d6)δ0.91(t,J=7Hz,3H),1.40-1.55(m,1H),1.60-2.10(m;7H),2.70(t,J=7Hz,2H),2.92(m,1H),3.24(m,1H),3.30-3.85(m,5H),4.88(m,2H),7.57(d,J=8Hz,1H),7.65(d,J=8Hz,1H),7.72(s,1H),8.28(br s,1H),8.41(m,1H),11.69(br s,1H);HPLC-MS:m/z 309(MH+);Rt=2.27min. 1H NMR (DMSO-d6) δ0.91 (t, J = 7Hz, 3H), 1.40-1.55 (m, 1H), 1.60-2.10 (m; 7H), 2.70 (t, J = 7Hz, 2H), 2.92 (m, 1H), 3.24 (m, 1H), 3.30-3.85 (m, 5H), 4.88 (m, 2H), 7.57 (d, J = 8Hz, 1H), 7.65 (d, J = 8Hz, 1H) , 7.72 (s, 1H), 8.28 (br s, 1H), 8.41 (m, 1H), 11.69 (br s, 1H); HPLC-MS: m / z 309 (MH +); Rt = 2.27min.

实施例100(通用工艺(B))2-(4-异丙基哌嗪-1-基)喹喔啉盐酸盐 Quinoxaline hydrochloride 100 (general procedure (B)) 2- (4- isopropyl-piperazin-1-yl) Example 利用通用工艺(B),从1-异丙基哌嗪和2-氯喹喔啉制备该化合物。 Using general procedure (B), from 1-isopropyl-piperazine and 2-chloro-quinoxaline This compound was prepared.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.13(m,2H),3.45-3.65(m,5H),4.75(m,2H),7.48(m,1H),7.66(m,2H),7.88(d,J=8Hz,1H),8.91(s,1H),11.15(br s,1H);HPLC-MS:m/z257(MH+);Rt=1.25min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.13 (m, 2H), 3.45-3.65 (m, 5H), 4.75 (m, 2H), 7.48 (m, 1H), 7.66 (m, 2H), 7.88 (d, J = 8Hz, 1H), 8.91 (s, 1H), 11.15 (br s, 1H); HPLC-MS: m / z257 (MH +); Rt = 1.25min.

实施例101(通用工艺(B))[4-(4-环丙基哌嗪-1-基)苯基]苯基甲酮盐酸盐 101 (General procedure (B)) Example [4- (4-cyclopropyl-piperazin-1-yl) phenyl] phenyl methanone hydrochloride

利用通用工艺(B),从1-环丙基哌嗪和4-氟二苯酮制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 4-fluoro benzophenone.

1H NMR(DMSO-d6)δ0.82(m,2H),1.16(m,2H),2.92(br s,1H),3.30-3.40(m,4H),3.56(brs,2H),4.09(m,2H),7.12(d,J=8Hz,2H),7.54(m,2H),7.60-7.75(m,5H),10.82(br s,1H);HPLC-MS:m/z307(MH+);Rt=2.00min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.16 (m, 2H), 2.92 (br s, 1H), 3.30-3.40 (m, 4H), 3.56 (brs, 2H), 4.09 (m , 2H), 7.12 (d, J = 8Hz, 2H), 7.54 (m, 2H), 7.60-7.75 (m, 5H), 10.82 (br s, 1H); HPLC-MS: m / z307 (MH +); Rt = 2.00min.

实施例102(通用工艺(B))[4-(4-环丙基哌嗪-1-基)-3,5-二氟苯基]苯基甲酮盐酸盐 102 (General procedure (B)) Example [4- (4-cyclopropyl-piperazin-1-yl) -3,5-difluorophenyl] phenyl methanone hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和3,4,5-三氟二苯酮制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 3,4,5-trifluoro benzophenone.

1H NMR(DMSO-d6)δ0.82(m,2H),1.16(m,2H),2.96(br s,1H),3.30-3.75(m,8H),7.43(d,J=8Hz,2H),7.58(t,J=8Hz,2H),7.65-7.78(m,3H),10.90(br s,1H);HPLC-MS:m/z 343(MH+);Rt=2.29min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.16 (m, 2H), 2.96 (br s, 1H), 3.30-3.75 (m, 8H), 7.43 (d, J = 8Hz, 2H) , 7.58 (t, J = 8Hz, 2H), 7.65-7.78 (m, 3H), 10.90 (br s, 1H); HPLC-MS: m / z 343 (MH +); Rt = 2.29min.

实施例103(通用工艺(B))2-(4-异丙基哌嗪-1-基)-5,6,7-三甲氧基喹啉盐酸盐 Example 103 (General procedure (B)) 2- (4- isopropyl-piperazin-1-yl) 5,6,7-trimethoxy-quinoline hydrochloride 利用通用工艺(B),从1-异丙基哌嗪和2-氯-5,6,7-三甲氧基喹啉制备该化合物。 Using general procedure (B), morpholine quinoline This compound was prepared from 1-isopropyl-piperazine and 2-chloro-5,6,7-trimethoxy.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.21(m,2H),3.45-3.85(m,5H),3.82(s,3H),3.93(s,3H),3.99(s,3H),4.78(m,2H),7.31(m,1H),7.56(m,1H),8.31(m,1H),11.36(br s,1H);HPLC-MS:m/z 346(MH+);Rt=1.22min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.21 (m, 2H), 3.45-3.85 (m, 5H), 3.82 (s, 3H), 3.93 (s, 3H), 3.99 (s, 3H), 4.78 (m, 2H), 7.31 (m, 1H), 7.56 (m, 1H), 8.31 (m, 1H), 11.36 (br s, 1H); HPLC-MS: m / z 346 (MH +); Rt = 1.22min.

实施例104(通用工艺(B)) Example 104 (General procedure (B))

2-(4-环丙基哌嗪-1-基)-5,6,7-三甲氧基喹啉盐酸盐 2- (4-cyclopropyl-piperazin-1-yl) 5,6,7-trimethoxy-quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-5,6,7-三甲氧基喹啉制备该化合物。 Using general procedure (B), morpholine quinoline This compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-5,6,7-trimethoxy.

1H NMR(DMSO-d6)δ0.82(m,2H),1.22(m,2H),2.87(br s,1H),3.30-4.10(m,6H),3.83(s,3H),3.93(s,3H),4.00(s,3H),4.76(m,2H),7.33(m,1H),7.65(br s,1H),8.34(m,1H),11.62(br s,1H);HPLC-MS:m/z344(MH+);Rt=1.46min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.22 (m, 2H), 2.87 (br s, 1H), 3.30-4.10 (m, 6H), 3.83 (s, 3H), 3.93 (s , 3H), 4.00 (s, 3H), 4.76 (m, 2H), 7.33 (m, 1H), 7.65 (br s, 1H), 8.34 (m, 1H), 11.62 (br s, 1H); HPLC- MS: m / z344 (MH +); Rt = 1.46min.

实施例105(通用工艺(B))2-(4-环丙基哌嗪-1-基)-6-三氟甲硫基喹啉盐酸盐 Example 105 (General procedure (B)) 2- (4- cyclopropyl-piperazin-1-yl) -6-trifluoromethyl-methylthio-quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-6-三氟甲硫基喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-6-trifluoromethylthio quinoline.

1H NMR(DMSO-d6)δ0.82(m,2H),1.20(m,2H),2.86(br s,1H),3.20-3.70(m,6H),4.75(m,2H),7.53(m,1H),7.86(m,2H),8.20-8.40(m,2H),11.28(br s,1H);HPLC-MS:m/z 354(MH+);Rt=2.61min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.20 (m, 2H), 2.86 (br s, 1H), 3.20-3.70 (m, 6H), 4.75 (m, 2H), 7.53 (m , 1H), 7.86 (m, 2H), 8.20-8.40 (m, 2H), 11.28 (br s, 1H); HPLC-MS: m / z 354 (MH +); Rt = 2.61min.

实施例106(通用工艺(B))7-氯-2-(4-环丙基哌嗪-1-基)-6-甲氧基喹啉盐酸盐 106 (General procedure (B)) Example 7-chloro-2- (4-cyclopropyl-piperazin-1-yl) -6-methoxy-quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2,7-二氯-6-甲氧基喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2,7-dichloro-6-methoxy-quinoline.

1H NMR(DMSO-d6)δ0.82(m,2H),1.16(m,2H),2.88(m,1H),3.25-3.70(m,6H),3.94(s,3H),4.62(m,2H),7.45(d,J=8Hz,1H),7.51(s,1H),7.96(br s,1H),8.23(d,J=8Hz,1H),10.98(br s,1H);HPLC-MS:m/z 318(MH+);Rt=1.80min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.16 (m, 2H), 2.88 (m, 1H), 3.25-3.70 (m, 6H), 3.94 (s, 3H), 4.62 (m, 2H), 7.45 (d, J = 8Hz, 1H), 7.51 (s, 1H), 7.96 (br s, 1H), 8.23 ​​(d, J = 8Hz, 1H), 10.98 (br s, 1H); HPLC- MS: m / z 318 (MH +); Rt = 1.80min.

实施例107(通用工艺(B))5,7-二氯-2-(4-环丙基哌嗪-1-基)喹啉盐酸盐 5,7-dichloro-2- (4-cyclopropyl-piperazin-1-yl) quinoline hydrochloride 107 ((B) General procedure) Example 利用通用工艺(B),从1-环丙基哌嗪和2,5,7-三氯喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2,5,7-trichloro-quinoline.

1H NMR(DMSO-d6)δ0.82(m,2H),1.19(m,2H),2.86(m,1H),3.20-3.65(m,6H),4.69(m,2H),7.51(d,J=8Hz,1H),7.56(s,1H),7.68(s,1H),8.30(d,J=8Hz,1H),11.24(br s,1H);HPLC-MS:m/z 322(MH+);Rt=2.78min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.19 (m, 2H), 2.86 (m, 1H), 3.20-3.65 (m, 6H), 4.69 (m, 2H), 7.51 (d, J = 8Hz, 1H), 7.56 (s, 1H), 7.68 (s, 1H), 8.30 (d, J = 8Hz, 1H), 11.24 (br s, 1H); HPLC-MS: m / z 322 (MH + ); Rt = 2.78min.

实施例108(通用工艺(B))1-环丙基-4-[5-(4-三氟甲基苯基)吡啶-2-基]哌嗪盐酸盐 108 (General procedure (B)) Example 1-cyclopropyl-4- [5- (4-trifluoromethylphenyl) pyridin-2-yl] piperazine hydrochloride 所需的2-氯-5-(4-三氟苯基)吡啶是如R.Church,R.Trust,JDAlbright,and D.Powell,J.Org.Chem.1995,60,3750-3758所述制备的,按照下列方式:在10℃下,向从二甲基甲酰胺(5.98g,0.082mol)和磷酰氯(22.5g,0.146mol)制备的Vilsmeier试剂溶液加入4-(三氟甲基)苯基乙酸(6.64g,0.033mol)。 The desired 2-chloro-5- (4-trifluorophenyl) pyridine are as R.Church, R.Trust, JDAlbright, and D.Powell, the J.Org.Chem.1995,60,3750-3758 prepared in the following manner: at 10 ℃, was added 4- (trifluoromethyl) was added to a solution of Vilsmeier reagent prepared from dimethylformamide (5.98 g, 0.082 mol) and phosphorus oxychloride (22.5g, 0.146mol) phenylacetic acid (6.64g, 0.033mol). 将混合物在70℃下搅拌8小时。 The mixture was stirred at 70 ℃ 8 hours. 冷却至环境温度后,将混合物缓慢加入到冰水混合物中(温度<10℃),然后缓慢加入Na2CO3溶液直至达到pH11。 After cooling to ambient temperature, the mixture was slowly added to ice-water mixture (temperature <10 ℃), followed by slow addition of Na2CO3 solution until pH11. 向碱性混合物加入甲苯(125ml),将所得混合物回流1.5小时。 Toluene was added (125ml) to the basic mixture, the resulting mixture was refluxed for 1.5 hours. 冷却至环境温度后,分离水层,用甲苯(100ml)萃取。 After cooling to ambient temperature, the aqueous layer was separated and extracted with toluene (100ml). 合并有机层,用水洗涤,干燥(Na2SO4),在减压下浓缩。 The organic layers were combined, washed with water, dried (Na2SO4), and concentrated under reduced pressure. 使所得固体从二氯甲烷与庚烷的混合物中重结晶,得到6.98g(87%)3-二甲氨基-2-(4-三氟甲基苯基)丙烯醛,为黄色晶体,mp.97℃。 The resulting solid was recrystallized from a mixture of dichloromethane and heptane to give 6.98g (87%) 3- dimethylamino-2- (4-trifluoromethylphenyl) propenal as yellow crystals, mp. 97 ℃.

1H NMR光谱(CDCl3)δ9.10(s,1H),7.57(m,2H),7.32(m,2H),6.95(s,1H),2.85(s,6H);RF(SiO2,氯仿/甲醇95∶5)0.34. 1H NMR spectrum (CDCl3) δ9.10 (s, 1H), 7.57 (m, 2H), 7.32 (m, 2H), 6.95 (s, 1H), 2.85 (s, 6H); RF (SiO2, chloroform / methanol 95:5) 0.34.

向甲醇钠(3.64g,0.068mol)的甲醇(68ml)溶液加入氰基乙酰胺(6.95g,0.082mol)和前述产物(6.98g,0.029mol)。 Was added cyanoacetamide (6.95g, 0.082mol) and the product (6.98g, 0.029mol) of sodium methoxide (3.64g, 0.068mol) in methanol (68ml). 将混合物在环境温度下搅拌1.5小时,然后回流8小时。 The mixture was stirred at ambient temperature for 1.5 hours and then refluxed for 8 hours. 在此期间沉淀出黄色固体。 During this time a yellow solid precipitated. 将反应混合物用水(75ml)稀释,用10%含水盐酸酸化。 The reaction mixture was washed with water (75ml), acidified with 10% aqueous hydrochloric acid. 滤出黄色固体,用水、乙醇、二乙醚、然后用己烷洗涤。 The yellow solid was filtered off, washed with water, ethanol, diethyl ether, and then washed with hexane. 得到2-羟基-5-(4-三氟甲基苯基)烟腈(6.66g,87%),为黄色固体,mp.235-242℃。 To give 2-hydroxy-5- (4-trifluoromethylphenyl) nicotinonitrile (6.66g, 87%), as a yellow solid, mp.235-242 ℃.

1H NMR(DMSO-d6)δ8.42(m,1H),7.91(m,1H),7.66(m,4H);RF(SiO2,氯仿/甲醇95∶5)0.18. 1H NMR (DMSO-d6) δ8.42 (m, 1H), 7.91 (m, 1H), 7.66 (m, 4H); RF (SiO2, chloroform / methanol 95:5) 0.18.

向乙酸(100ml)与浓盐酸(70ml)的混合物加入前述产物(6.66g,0.025mol)。 And concentrated hydrochloric acid (70ml) was added the product (6.66g, 0.025mol) to acetic acid (100ml). 将反应混合物回流18小时,用水(200ml)稀释,冷却至室温,同时搅拌。 The reaction mixture was refluxed for 18 hours, diluted with water (200ml), cooled to room temperature while stirring. 滤出固体,用水、然后用50%含水乙醇洗涤,得到5.42g(77%)2-羟基-5-(4-三氟甲基苯基)烟酸,为浅灰色固体,mp.305-315℃。 The solid was filtered off, washed with water, then washed with 50% aqueous ethanol to give 5.42g (77%) 2- hydroxy-5- (4-trifluoromethylphenyl) nicotinic acid as a light gray solid, mp.305-315 ℃.

1H NMR(DMSO-d6)δ8.71(d,1H),8.43(d,1H),7.96(m,2H),7.81(m,2H);RF(SiO2,氯仿/甲醇95∶5)0.13. 1H NMR (DMSO-d6) δ8.71 (d, 1H), 8.43 (d, 1H), 7.96 (m, 2H), 7.81 (m, 2H); RF (SiO2, chloroform / methanol 95:5) 0.13.

将前述产物(5.42g,0.019mol)与新鲜蒸馏的喹啉(50ml)的混合物在215℃下搅拌12小时。 The mixture of the previous product (5.42g, 0.019mol) and freshly distilled quinoline (50ml) was stirred at 215 ℃ 12 hours. 将反应混合物冷却至环境温度,加入庚烷(250ml)。 The reaction mixture was cooled to ambient temperature, heptane (250ml). 滤出固体,用庚烷洗涤,从二氯甲烷与庚烷的混合物中重结晶,得到3.92g(86%)2-羟基-5-(4-三氟甲基苯基)吡啶,mp.178-182℃。 The solid was filtered off, washed with heptane, and recrystallized from a mixture of dichloromethane and heptane to give 3.92g (86%) 2- hydroxy-5- (4-trifluoromethylphenyl) pyridine, mp.178 -182 ℃.

1H NMR(CDCl3)δ7.79(dd,2H),7.68(d,3H),7.52(d,2H),6.73(d,1H);RF(SiO2,氯仿/甲醇95∶5)0.23. 1H NMR (CDCl3) δ7.79 (dd, 2H), 7.68 (d, 3H), 7.52 (d, 2H), 6.73 (d, 1H); RF (SiO2, chloroform / methanol 95:5) 0.23.

将磷酰氯(27.6g,0.18mol)与前述产物(3.92g,0.016mol)的混合物在105℃下搅拌10小时。 The mixture of phosphorus oxychloride (27.6g, 0.18mol) and the product (3.92g, 0.016mol) was stirred at 105 ℃ 10 hours. 在减压下蒸发过量磷酰氯,残余物用甲苯(75ml)汽提一次。 Excess phosphorus oxychloride was evaporated under reduced pressure, the residue was treated with toluene (75ml) steam stripping. 向残余物加入水(75ml)和二氯甲烷(75ml),分离二氯甲烷层,水相用二氯甲烷(75ml)萃取。 Water (75ml) and dichloromethane (75ml) was added to the residue, dichloromethane layer was separated, the aqueous phase was extracted with dichloromethane (75ml). 合并萃取液,用水、然后用碳酸氢钠溶液洗涤,干燥(MgSO4),在减压下浓缩,得到2.95g(72%)2-氯-5-(4-三氟甲基苯基)吡啶,为浅褐色晶体,mp.98-101℃。 The combined extracts were washed with water, then washed with sodium bicarbonate solution, dried (MgSO4), and concentrated under reduced pressure to give 2.95g (72%) 2- chloro-5- (4-trifluoromethylphenyl) pyridine, light brown crystals, mp.98-101 ℃.

1H NMR(CDCl3)δ8.62(dd,1H),7.86(dd,1H),7.44(dd,1H),7.66(m,2H),7.75(m,2H);RF(SiO2,氯仿/甲醇95∶5)0.94. 1H NMR (CDCl3) δ8.62 (dd, 1H), 7.86 (dd, 1H), 7.44 (dd, 1H), 7.66 (m, 2H), 7.75 (m, 2H); RF (SiO2, chloroform / methanol 95 :5) 0.94.

如通用工艺(B)所述,将该产物用1-环丙基哌嗪处理,得到标题化合物。 The general procedure (B) said, the product was treated with 1-cyclopropyl-piperazine, to give the title compound.

1H NMR(DMSO-d6)δ0.83(m,2H),1.13(m,2H),2.85(m,1H),3.25-3.75(m,6H),4.51(m,2H),7.12(d,J=8Hz,1H),7.79(d,J=8Hz,2H),7.89(d,J=8Hz,2H),8.05(m,1H),8.59(m,1H),10.56(br s,1H);HPLC-MS:m/z348(MH+);Rt=2.77min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.13 (m, 2H), 2.85 (m, 1H), 3.25-3.75 (m, 6H), 4.51 (m, 2H), 7.12 (d, J = 8Hz, 1H), 7.79 (d, J = 8Hz, 2H), 7.89 (d, J = 8Hz, 2H), 8.05 (m, 1H), 8.59 (m, 1H), 10.56 (br s, 1H) ; HPLC-MS: m / z348 (MH +); Rt = 2.77min.

实施例109(通用工艺(B))3-(4-环丙基哌嗪-1-基)-6-(4-三氟甲基苯基)哒嗪盐酸盐 Example 109 (General procedure (B)) 3- (4- cyclopropyl-piperazin-1-yl) -6- (4-trifluoromethylphenyl) pyridazine hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和3-氯-6-(4-三氟甲基苯基)哒嗪制备该化合物。 Using general procedure (B), from 1-cyclopropyl-piperazine and 3-chloro-6- (4-trifluoromethylphenyl) pyridazine This compound was prepared triazine.

1H NMR(DMSO-d6)δ0.83(m,2H),1.19(m,2H),2.89(m,1H),3.30-3.70(m,6H),4.61(m,2H),7.61(d,J=8Hz,1H),7.88(d,J=8Hz,2H),8.22(d,J=8Hz,1H),8.29(d,J=8Hz,2H),11.11(br s,1H);HPLC-MS:m/z349(MH+);Rt=2.40min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.19 (m, 2H), 2.89 (m, 1H), 3.30-3.70 (m, 6H), 4.61 (m, 2H), 7.61 (d, J = 8Hz, 1H), 7.88 (d, J = 8Hz, 2H), 8.22 (d, J = 8Hz, 1H), 8.29 (d, J = 8Hz, 2H), 11.11 (br s, 1H); HPLC- MS: m / z349 (MH +); Rt = 2.40min.

实施例110(通用工艺(B)) Example 110 (General procedure (B))

6-(4-环丙基哌嗪-1-基)-[1,3]二氧戊环并[4,5-g]喹啉盐酸盐 6- (4-cyclopropyl-piperazin-1-yl) - [1,3] dioxolo [4,5-g] quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和6-氯[1,3]二氧戊环并[4,5-g]喹啉制备该化合物。 Using general procedure (B), morpholine quinoline This compound was prepared from 1-cyclopropyl-piperazine and 6-chloro [l, 3] dioxolo [4,5-g].

1H NMR(DMSO-d6)δ0.83(m,2H),1.15(m,2H),2.88(m,1H),3.20-3.70(m,6H),4.59(m,2H),6.17(s,2H),7.29(m,3H),8.13(m,1H),10.80(br s,1H);HPLC-MS:m/z 298(MH+);Rt=0.68min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.15 (m, 2H), 2.88 (m, 1H), 3.20-3.70 (m, 6H), 4.59 (m, 2H), 6.17 (s, 2H), 7.29 (m, 3H), 8.13 (m, 1H), 10.80 (br s, 1H); HPLC-MS: m / z 298 (MH +); Rt = 0.68min.

实施例111(通用工艺(B))6-环己基-2-(4-环丙基哌嗪-1-基)喹啉盐酸盐 Example 111 (General procedure (B)) of 6-cyclohexyl-2- (4-cyclopropyl-piperazin-1-yl) quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-6-环己基喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-6-cyclohexyl-quinoline.

1H NMR(DMSO-d6)δ0.83(m,2H),1.10-1.55(m,8H),1.70-1.93(m,4H),2.65(m,1H),2.86(m,1H),3.30-3.70(m,6H),4.72(m,2H),7.50(m,1H),7.66(m,1H),7.72(m,1H),7.99(br s,1H),8.35(br s,1H),11.29(br s,1H);HPLC-MS:m/z 336(MH+);Rt=2.55min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.10-1.55 (m, 8H), 1.70-1.93 (m, 4H), 2.65 (m, 1H), 2.86 (m, 1H), 3.30- 3.70 (m, 6H), 4.72 (m, 2H), 7.50 (m, 1H), 7.66 (m, 1H), 7.72 (m, 1H), 7.99 (br s, 1H), 8.35 (br s, 1H) , 11.29 (br s, 1H); HPLC-MS: m / z 336 (MH +); Rt = 2.55min.

实施例112(通用工艺(B))6-环己基-2-(4-异丙基哌嗪-1-基)喹啉盐酸盐 112 (General procedure (B)) Example 6-cyclohexyl-2- (4-isopropyl-piperazin-1-yl) quinoline hydrochloride embodiment 利用通用工艺(B),从1-异丙基哌嗪和2-氯-6-环己基喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-isopropyl-piperazine and 2-chloro-6-cyclohexyl-quinoline.

1H NMR(DMSO-d6)δ1.10-1.55(m,8H),1.31(d,J=7Hz,6H),1.70-1.93(m,4H),2.65(m,1H),3.23(m,2H),3.50-3.85(m,3H),4.80(m,2H),7.51(m,1H),7.67(m,1H),7.73(m,1H),8.08(br s,1H),8.36(br s,1H),11.31(br s,1H);HPLC-MS:m/z 338(MH+);Rt=2.50min. 1H NMR (DMSO-d6) δ1.10-1.55 (m, 8H), 1.31 (d, J = 7Hz, 6H), 1.70-1.93 (m, 4H), 2.65 (m, 1H), 3.23 (m, 2H ), 3.50-3.85 (m, 3H), 4.80 (m, 2H), 7.51 (m, 1H), 7.67 (m, 1H), 7.73 (m, 1H), 8.08 (br s, 1H), 8.36 (br s, 1H), 11.31 (br s, 1H); HPLC-MS: m / z 338 (MH +); Rt = 2.50min.

实施例113(通用工艺(B))2-(4-环丙基哌嗪-1-基)-6,7-二甲氧基-3-甲基喹啉盐酸盐 Example 113 (General procedure (B)) 2- (4- cyclopropyl-piperazin-1-yl) -6,7-dimethoxy-3-methyl-quinoline hydrochloride 所需的2-氯-6,7-二甲氧基-3-甲基喹啉是按照TetrahedronLetters 1979,4885所公开的工艺制备的,按照下列方式:向3,4-二甲氧基苯胺(4.70g,30.7mmol)的二氯甲烷(50ml)溶液加入吡啶(8.0ml,3当量),然后滴加丙酰氯(3.5ml,40.5mmol)。 The desired 2-chloro-6,7-dimethoxy-3-methyl-quinoline was prepared according to the process disclosed TetrahedronLetters 1979,4885, the following manner: a solution of 3,4-dimethoxyaniline ( 4.70g, 30.7mmol) in dichloromethane (50ml) was added pyridine (8.0ml, 3 eq) was then added dropwise propionyl chloride (3.5ml, 40.5mmol). 在室温下搅拌1小时又50分钟后,将混合物倒入水(200ml)与浓盐酸(8ml)的混合物中。 After stirring at room temperature for 1 hour and 50 minutes, the mixture was poured into water (200ml) and concentrated hydrochloric acid (8ml) mixture. 分离各相,水相用二氯甲烷萃取一次。 The phases were separated, the aqueous phase was extracted once with dichloromethane. 合并有机相,用盐水洗涤,用硫酸镁干燥,浓缩,得到6.89g油,几分钟后结晶。 The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated to give an oil 6.89g, crystallized after a few minutes. 从乙酸乙酯与庚烷的混合物中重结晶,得到3.60g(49%)N-(3,4-二甲氧基苯基)丙酰胺,为深色晶体。 From a mixture of ethyl acetate and heptane recrystallized to give 3.60g (49%) N- (3,4- dimethoxyphenyl) propanamide as a dark crystals.

将该酰基苯胺(2.1g,10.0mmol)与DMF(1.1ml,15mmol)混合,在室温下向该混合物滴加POCl3(6.5ml,70mmol)。 The anilide (2.1g, 10.0mmol) and DMF (1.1ml, 15mmol) were mixed to the mixture was added dropwise at room temperature POCl3 (6.5ml, 70mmol). 当加入结束时,将混合物在75℃下搅拌2小时。 When the addition was complete, the mixture was stirred at 75 ℃ 2 hours. 将混合物倒入冰水(100ml)中,搅拌30分钟,过滤。 The mixture was poured into ice water (100ml), stirred for 30 minutes and filtered. 固体用甲苯和乙腈汽提,得到1.60g(67%)2-氯-6,7-二甲氧基-3-甲基喹啉,为固体。 Toluene and acetonitrile solid was stripped to give 1.60g (67%) 2- chloro-6,7-dimethoxy-3-methyl-quinoline as a solid. 如通用工艺(B)所述,将该产物用1-环丙基哌嗪处理,得到标题化合物。 The general procedure (B) said, the product was treated with 1-cyclopropyl-piperazine, to give the title compound.

1H NMR(DMSO-d6)δ0.83(m,2H),1.23(m,2H),2.42(s,3H),2.94(m,1H),3.40-4.50(m,8H),3.88(s,3H),3.91(s,3H),7.29(s,1H),7.48(br s,1H),8.12(br s,1H),11.24(br s,1H);HPLC-MS:m/z 328(MH+);Rt=1.63min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.23 (m, 2H), 2.42 (s, 3H), 2.94 (m, 1H), 3.40-4.50 (m, 8H), 3.88 (s, 3H), 3.91 (s, 3H), 7.29 (s, 1H), 7.48 (br s, 1H), 8.12 (br s, 1H), 11.24 (br s, 1H); HPLC-MS: m / z 328 ( MH +); Rt = 1.63min.

实施例114(通用工艺(B))6-(4-异丙基哌嗪-1-基)-[1,3]二氧戊环并[4,5-g]喹啉盐酸盐 114 (General procedure (B)) Example 6- (4-isopropyl-piperazin-1-yl) - [1,3] dioxolo [4,5-g] quinoline hydrochloride 利用通用工艺(B),从1-异丙基哌嗪和6-氯[1,3]二氧戊环并[4,5-g]喹啉制备该化合物。 Using general procedure (B), from 1-isopropyl-piperazine and 6-chloro [l, 3] dioxolo [4,5-g] quinoline This compound was prepared.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.40(m,2H),3.45-4.00(m,5H),4.72(m,2H),6.21(s,2H),7.34(m,2H),7.62(br s,1H),8.21(m,1H),11.12(br s,1H);HPLC-MS:m/z 300(MH+);Rt=0.65min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.40 (m, 2H), 3.45-4.00 (m, 5H), 4.72 (m, 2H), 6.21 (s, 2H), 7.34 (m, 2H), 7.62 (br s, 1H), 8.21 (m, 1H), 11.12 (br s, 1H); HPLC-MS: m / z 300 (MH +); Rt = 0.65min.

实施例115(通用工艺(B))[3,5-二氟-4-(4-异丙基-哌嗪-1-基)-苯基]-哌啶-1-基-甲酮盐酸盐 Example 115 (General procedure (B)) [3,5- difluoro-4- (4-isopropyl - piperazin-1-yl) - phenyl] - piperidin-1-yl - methanone hydrochloride salt 利用通用工艺(B),借助1-异丙基哌嗪与3,4,5-三氟苯甲酸胡椒脂的反应制备该化合物。 Using general procedure (B), This compound was prepared by reaction of 1-isopropyl-piperazine and 3,4,5-trifluorobenzoic acid pepper butter. 该反应得到两种产物,即本实施例和实施例121。 The reaction yielded two products, i.e., the present embodiment and Example 121.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),1.40-1.62(m,6H),3.09(m,2H),3.20-3.65(m,11H),7.12(m,2H),10.42(br s,1H);HPLC-MS:m/z 352(MH+);Rt=3.75min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 1.40-1.62 (m, 6H), 3.09 (m, 2H), 3.20-3.65 (m, 11H), 7.12 (m, 2H ), 10.42 (br s, 1H); HPLC-MS: m / z 352 (MH +); Rt = 3.75min.

实施例116(通用工艺(B))(9a-R)-2-(6,7-二甲氧基喹啉-2-基)八氢吡啶并[1,2-a]吡嗪盐酸盐 Example 116 (General procedure (B)) (9a-R) -2- (6,7-dimethoxy-quinolin-2-yl) octahydro-pyrido [1,2-a] pyrazine hydrochloride

利用通用工艺(B),从(9a-R)八氢吡啶并[1,2-a]吡嗪和2-氯-6,7-二甲氧基喹啉制备该化合物。 Using general procedure (B), from (9a-R) octahydro-pyrido [1,2-a] pyrazine and 2-chloro-6,7-dimethoxy quinoline This compound was prepared.

1H NMR(DMSO-d6)δ1.40-1.55(m,1H),1.65-2.05(m,5H),2.93(m,1H),3.22(m,1H),3.25-3.60(m,4H),3.65-4.20(m,1H),3.87(s,3H),3.90(s,3H),4.79(m,2H),7.40(m,2H),8.00(br s,1H),8.33(br s,1H),11.55(br s,1H);HPLC-MS:m/z 328(MH+);Rt=0.97min. 1H NMR (DMSO-d6) δ1.40-1.55 (m, 1H), 1.65-2.05 (m, 5H), 2.93 (m, 1H), 3.22 (m, 1H), 3.25-3.60 (m, 4H), 3.65-4.20 (m, 1H), 3.87 (s, 3H), 3.90 (s, 3H), 4.79 (m, 2H), 7.40 (m, 2H), 8.00 (br s, 1H), 8.33 (br s, 1H), 11.55 (br s, 1H); HPLC-MS: m / z 328 (MH +); Rt = 0.97min.

实施例117(通用工艺(B))2-(4-环丙基哌嗪-1-基)-5,6,7,8-四氢喹啉盐酸盐 117 (General procedure (B)) Example 2- (4-cyclopropyl-piperazin-1-yl) -5,6,7,8-tetrahydroquinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-5,6,7,8-四氢喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-5,6,7,8-tetrahydroquinoline.

1H NMR(DMSO-d6)δ0.81(m,2H),1.17(m,2H),1.67-1.82(m,4H),2.62(m,2H),2.75-2.95(m,3H),3.20-3.65(m,6H),4.37(m,2H),7.02(br s,1H),7.63(br s,1H),11.10(br s,1H);HPLC-MS:m/z 258(MH+);Rt=0.62min. 1H NMR (DMSO-d6) δ0.81 (m, 2H), 1.17 (m, 2H), 1.67-1.82 (m, 4H), 2.62 (m, 2H), 2.75-2.95 (m, 3H), 3.20- 3.65 (m, 6H), 4.37 (m, 2H), 7.02 (br s, 1H), 7.63 (br s, 1H), 11.10 (br s, 1H); HPLC-MS: m / z 258 (MH +); Rt = 0.62min.

实施例118(通用工艺(B))[5-氯-6-(4-环丙基哌嗪-1-基)吡啶-3-基]哌啶-1-基甲酮盐酸盐 118 (General procedure (B)) Example [5-chloro-6- (4-cyclopropyl-piperazin-1-yl) pyridin-3-yl] piperidin-1-yl methanone hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和5,6-二氯烟酸胡椒脂制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 5,6-dichloro-nicotinic acid aliphatic pepper.

1H NMR(DMSO-d6)δ0.82(m,2H),1.12(m,2H),1.45-1.65(m,6H),2.96(m,1H),3.30-3.60(m,10H),3.96(m,2H),7.89(s,1H),8.27(s,1H),10.68(br s,1H);HPLC-MS:m/z 349(MH+);Rt=1.50min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.12 (m, 2H), 1.45-1.65 (m, 6H), 2.96 (m, 1H), 3.30-3.60 (m, 10H), 3.96 ( m, 2H), 7.89 (s, 1H), 8.27 (s, 1H), 10.68 (br s, 1H); HPLC-MS: m / z 349 (MH +); Rt = 1.50min.

实施例119(通用工艺(B)) Example 119 (General procedure (B))

(9a-R)-[6-(八氢吡啶并[1,2-a]吡嗪-2-基)吡啶-3-基]哌啶-1-基甲酮盐酸盐 (9a-R) - [6- (octahydro-pyrido [1,2-a] pyrazin-2-yl) pyridin-3-yl] piperidin-1-yl methanone hydrochloride 利用通用工艺(B),从(9a-R)-八氢吡啶并[1,2-a]吡嗪和6-氯烟酸胡椒脂制备该化合物。 Using general procedure (B), from (9a-R) - octahydro-pyrido [1,2-a] pyrazine and 6-chloro pepper aliphatic acid This compound was prepared.

1H NMR(DMSO-d6)δ1.51(m,3H),1.60(m,2H),1.78-1.98(m,3H),2.90-3.25(m,4H),3.30-3.50(m,5H),3.74(m,6H),4.50(m,2H),7.02(d,J=7Hz,1H),7.66(d,J=7Hz,1H),8.19(s,1H),10.86(br s,1H);HPLC-MS:m/z329(MH+);Rt=1.31min. 1H NMR (DMSO-d6) δ1.51 (m, 3H), 1.60 (m, 2H), 1.78-1.98 (m, 3H), 2.90-3.25 (m, 4H), 3.30-3.50 (m, 5H), 3.74 (m, 6H), 4.50 (m, 2H), 7.02 (d, J = 7Hz, 1H), 7.66 (d, J = 7Hz, 1H), 8.19 (s, 1H), 10.86 (br s, 1H) ; HPLC-MS: m / z329 (MH +); Rt = 1.31min.

实施例120(通用工艺(B))[6-(4-环丙基哌嗪-1-基)吡啶-3-基]哌啶-1-基甲酮盐酸盐 Example 120 (General procedure (B)) [6- (4- cyclopropyl-piperazin-1-yl) pyridin-3-yl] piperidin-1-yl methanone hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和6-氯烟酸胡椒脂制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 6-chloro pepper aliphatic acid.

1H NMR(DMSO-d6)δ0.81(m,2H),1.17(m,2H),1.51(m,4H),1.60(m,2H),2.87(m,1H),3.20-3.60(m,10H),4.47(m,2H),7.01(d,J=7Hz,1H),7.67(d,J=7Hz,1H),8.21(s,1H),11.04(br s,1H);HPLC-MS:m/z315(MH+);Rt=1.22min. 1H NMR (DMSO-d6) δ0.81 (m, 2H), 1.17 (m, 2H), 1.51 (m, 4H), 1.60 (m, 2H), 2.87 (m, 1H), 3.20-3.60 (m, 10H), 4.47 (m, 2H), 7.01 (d, J = 7Hz, 1H), 7.67 (d, J = 7Hz, 1H), 8.21 (s, 1H), 11.04 (br s, 1H); HPLC-MS : m / z315 (MH +); Rt = 1.22min.

实施例121(通用工艺(B))[3,4-二氟-5-(4-异丙基-哌嗪-1-基)-苯基]-哌啶-1-基-甲酮盐酸盐 Example 121 (General procedure (B)) [3,4- difluoro-5- (4-isopropyl - piperazin-1-yl) - phenyl] - piperidin-1-yl - methanone hydrochloride salt

利用通用工艺(B),借助1-异丙基哌嗪与3,4,5-三氟苯甲酸胡椒脂的反应制备该化合物。 Using general procedure (B), This compound was prepared by reaction of 1-isopropyl-piperazine and 3,4,5-trifluorobenzoic acid pepper butter. 该反应得到两种产物,即本实施例和实施例115。 The reaction yielded two products, i.e., the present embodiment and Example 115.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),1.40-1.65(m,6H),3.12-3.62(m,13H),6.89(d,J=8Hz,1H),7.09(m,1H),11.09(br s,1H);HPLC-MS:m/z 352(MH+);Rt=3.95min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 1.40-1.65 (m, 6H), 3.12-3.62 (m, 13H), 6.89 (d, J = 8Hz, 1H), 7.09 (m, 1H), 11.09 (br s, 1H); HPLC-MS: m / z 352 (MH +); Rt = 3.95min.

实施例122(通用工艺(B))[4-(4-异丙基-哌嗪-1-基)-3-三氟甲基-苯基]-哌啶-1-基-甲酮盐酸盐 122 (General procedure (B)) Example [4- (4-isopropyl - piperazine-1-yl) -3-trifluoromethyl - phenyl] - piperidin-1-yl - methanone hydrochloride salt 利用通用工艺(B),借助1-异丙基哌嗪与4-氟-3-三氟甲基苯甲酸胡椒脂制备该化合物。 Using general procedure (B), means of preparing the compound 1-isopropyl-piperazine with 4-fluoro-3-trifluoromethylbenzoic acid pepper fat.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),1.40-1.65(m,6H),3.05(m,1H),3.15(m,1H),3.28(m,8H),3.52(m,3H),7.57(br d,J=8Hz,1H),7.68(br s,1H),7.71(br d,J=8Hz,1H),10.39(br s,1H);HPLC-MS:m/z 384(MH+);Rt=4.21min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 1.40-1.65 (m, 6H), 3.05 (m, 1H), 3.15 (m, 1H), 3.28 (m, 8H), 3.52 (m, 3H), 7.57 (br d, J = 8Hz, 1H), 7.68 (br s, 1H), 7.71 (br d, J = 8Hz, 1H), 10.39 (br s, 1H); HPLC-MS : m / z 384 (MH +); Rt = 4.21min.

实施例1232-(4-环丙基-3-甲基-哌嗪-1-基)-6,7-二甲氧基-喹啉盐酸盐 Example 1232- (4-cyclopropyl-3-methyl - piperazin-1-yl) -6,7-dimethoxy - quinoline hydrochloride 如Gillaspy,ML;Lefker,BA;Hada,WA;and Hoover,DJin Tetrahedron Lett.1995,36(41),7399-7402所述,借助6,7-二甲氧基-2-(3-甲基哌嗪-1-基)喹啉的还原性环丙基化作用制备该化合物。 As Gillaspy, ML; Lefker, BA; Hada, WA; and Hoover, DJin Tetrahedron Lett.1995,36 (41), said 7399-7402, by means of 6,7-dimethoxy-2- (3- piperazin-1-yl) cyclopropyl reductive action of quinoline this compound was prepared.

1H NMR(DMSO-d6)δ0.82(m,1H),0.99(m,2H),1.40(m,1H),1.55(d,J=7Hz,3H),2.76(m,1H),3.30-3.80(m,5H),3.87(s,3H),3.90(s,3H),4.65-4.83(m,2H),7.38(br s,2H),7.82(br s,1H),8.31(br s,1H),11.30(br s,1H);HPLC-MS:m/z328(MH+);Rt=3.09min. 1H NMR (DMSO-d6) δ0.82 (m, 1H), 0.99 (m, 2H), 1.40 (m, 1H), 1.55 (d, J = 7Hz, 3H), 2.76 (m, 1H), 3.30- 3.80 (m, 5H), 3.87 (s, 3H), 3.90 (s, 3H), 4.65-4.83 (m, 2H), 7.38 (br s, 2H), 7.82 (br s, 1H), 8.31 (br s , 1H), 11.30 (br s, 1H); HPLC-MS: m / z328 (MH +); Rt = 3.09min.

实施例124(通用工艺(B))[6-(4-环丙基哌嗪-1-基)吡啶-3-基]吡咯烷-1-基-甲酮盐酸盐 124 (General procedure (B)) Example [6- (4-cyclopropyl-piperazin-1-yl) pyridin-3-yl] pyrrolidin-1-yl - methanone hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和6-氯烟酸pyrrolidide制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 6-chloronicotinic acid pyrrolidide.

1H NMR(DMSO-d6)δ0.81(m,2H),1.15(m,2H),1.84(m,4H),2.88(m,1H),3.15-3.60(m,10H),4.49(m,2H),7.00(d,J=7Hz,1H),7.83(d,J=7Hz,1H),8.38(s,1H),10.91(br s,1H);HPLC-MS:m/z301(MH+);Rt=1.22min. 1H NMR (DMSO-d6) δ0.81 (m, 2H), 1.15 (m, 2H), 1.84 (m, 4H), 2.88 (m, 1H), 3.15-3.60 (m, 10H), 4.49 (m, 2H), 7.00 (d, J = 7Hz, 1H), 7.83 (d, J = 7Hz, 1H), 8.38 (s, 1H), 10.91 (br s, 1H); HPLC-MS: m / z301 (MH +) ; Rt = 1.22min.

实施例125(通用工艺(B))2-(4-异丙基哌嗪-1-基)喹啉-6-甲腈盐酸盐 Example 125 (General procedure (B)) 2- (4- isopropyl-piperazin-1-yl) quinoline-6-carbonitrile hydrochloride 向3,3-二乙氧基丙酸乙酯(62g,326mmol)与水(100ml)的混合物加入NaOH(16.0g),同时搅拌。 3,3-diethoxy-propionate (62g, 326mmol) and a mixture of water (100ml) was added NaOH (16.0g), while stirring. 在110℃下搅拌(打开烧瓶)。 Deg.] C with stirring at 110 (open flask). 40分钟后,混合物是均匀的,中断加热,使混合物冷却至室温。 After 40 minutes, the mixture is uniform, heating was discontinued, the mixture was cooled to room temperature. 将混合物酸化(大约35ml浓HCl,pH3-2),萃取(4×二氯甲烷)。 The mixture was acidified (approximately 35ml of concentrated HCl, pH3-2), and extracted (4 × dichloromethane). 合并萃取液,用盐水洗涤(1×50ml),干燥(硫酸镁),浓缩。 The combined extracts were washed with brine (1 × 50ml), dried (magnesium sulfate), and concentrated. 得到48g油。 Get 48g oil.

向该油滴加亚硫酰氯(80ml)。 To the oil droplets thionyl chloride (80ml). 将混合物在回流(80℃)下搅拌1小时30分钟。 The mixture was stirred at reflux (80 ℃) 1 hour and 30 minutes. 小心地浓缩后,残余物称重为48g(理论重量应为43g)。 After careful concentration, the residue weighed 48g (theoretical weight should 43g). 使酰氯保持在-20℃下过夜。 Acid chloride kept overnight at -20 ℃.

将该产物与二氯甲烷(70ml)混合,将该溶液的5/7(大约230mmol)加入到4-溴苯胺(34.5g,201mmol)与吡啶(50ml)的二氯甲烷(150ml)溶液中,将混合物在室温下摇动过夜。 The product with dichloromethane (70ml) were mixed and the 5/7 (about 230 mmol) was added to a solution of 4-bromoaniline (34.5g, 201mmol) and pyridine (50ml) in dichloromethane (150ml) solution of the mixture was shaken at room temperature overnight. 将混合物过滤,所得固体用二氯甲烷洗涤,干燥,得到21g N-(4-溴苯基)-3-乙氧基丙烯酰胺,为无色固体。 The mixture was filtered, the resulting solid was washed with dichloromethane and dried to give 21g N- (4- bromophenyl) -3-ethoxy-acrylamide as a colorless solid. 向滤液加入水(700ml)与浓盐酸(50ml)的混合物。 A mixture of water (700 ml of) and concentrated hydrochloric acid (50ml) was added to the filtrate. 摇动后沉淀出固体,滤出,用二氯甲烷和AcOEt洗涤,干燥。 After shaking precipitated solid was filtered off, washed with dichloromethane and AcOEt, and dried. 得到另外14.4g产物。 An additional 14.4g of product. 将滤液萃取(3×二氯甲烷),用盐水洗涤一次,干燥,浓缩。 The filtrate was extracted (3 × dichloromethane), washed once with brine, dried, and concentrated. 得到另外18g产物。 An additional 18g of product. 总收率:53.4g。 The total yield: 53.4g.

将该产物(58.8g,218mmol)与冰冷的浓硫酸(390ml)混合,将混合物先在0℃下搅拌15分钟(直至几乎全部丙烯酰胺溶解),再在室温下搅拌4小时。 The product (58.8 g, 218 mmol) with ice-cold concentrated sulfuric acid (390ml), and the mixture was stirred first at 0 ℃ 15 min (until almost all dissolved acrylamide), stirred at room temperature for 4 hours. 然后将混合物倒入冰水(3L)中,放置过夜。 The mixture was then poured into ice water (3L) and allowed to stand overnight. 将混合物过滤,固体用水洗涤。 The mixture was filtered, the solid washed with water. 借助乙腈、乙醇和二氯甲烷,将固体转移至烧瓶中,在减压下浓缩悬液。 Means acetonitrile, ethanol and dichloromethane, the solid was transferred to a flask, the suspension was concentrated under reduced pressure. 将残余物重新悬浮在乙腈(300ml)中,加热至回流,在室温下放置过夜。 The residue was resuspended in acetonitrile (300ml), heated to reflux, allowed to stand overnight at room temperature. 过滤,在减压下干燥固体,得到31.3g(64%)6-溴-2-喹诺酮,为黄色固体。 Filtered and the solid was dried under reduced pressure to give 31.3g (64%) 6- bromo-2-quinolone as a yellow solid.

将该喹诺酮(6.28g,28.0mmol)与氰化铜(I)(5.02g,56.1mmol)和NMP(15ml)混合,将混合物在回流(202℃)下搅拌6小时,然后在室温下搅拌过夜。 The quinolone (6.28g, 28.0mmol) and copper cyanide (I) (5.02g, 56.1mmol) and NMP (15ml), and the mixture was stirred at reflux (202 ℃) 6 hours and then stirred overnight at room temperature . 加入水(150ml),将混合物过滤,固体用水洗涤。 Water was added (150ml), the mixture was filtered, the solid washed with water. 将固体重新悬浮在1N盐酸(200ml)中,加入氯化铁(III)六水合物(17.8g)。 The solid was re-suspended in 1N hydrochloric acid (200ml) was added iron (III) chloride hexahydrate (17.8g). 将所得混合物在室温下搅拌3天,过滤,将固体用水洗涤一次,用乙醇汽提,在减压下干燥,得到4.33g(91%)6-氰基-2-喹诺铜,为灰色固体。 The resulting mixture was stirred at room temperature for 3 days, filtered and the solid was washed once with water, stripped with ethanol, and dried under reduced pressure to give 4.33g (91%) 6- cyano-2-quinolone copper as a gray solid . 如通用工艺(B)所述,将该产物用POCl3、再用1-异丙基哌嗪处理,得到标题化合物。 The general procedure (B) said, the product was POCI3, then 1-isopropyl-piperazine to give the title compound.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.10(m,2H),3.52(m,5H),4.79(m,2H),7.49(d,J=8Hz,1H),7.71(d,J=8Hz,1H),7.86(d,J=8Hz,1H),8.23(d,J=8Hz,1H),8.35(s,1H),10.73(br s,1H);HPLC-MS:m/z 281(MH+);Rt=1.62min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.10 (m, 2H), 3.52 (m, 5H), 4.79 (m, 2H), 7.49 (d, J = 8Hz, 1H ), 7.71 (d, J = 8Hz, 1H), 7.86 (d, J = 8Hz, 1H), 8.23 ​​(d, J = 8Hz, 1H), 8.35 (s, 1H), 10.73 (br s, 1H); HPLC-MS: m / z 281 (MH +); Rt = 1.62min.

实施例126(通用工艺(B))3-(4-环丙基哌嗪-1-基)-6-苯基哒嗪盐酸盐 126 (General procedure (B)) Example 3- (4-cyclopropyl-piperazin-1-yl) -6-phenyl-pyridazine hydrochloride

利用通用工艺(B),从1-环丙基哌嗪和3-氯-6-苯基哒嗪制备该化合物。 Using general procedure (B), the triazine compound was prepared from 1-cyclopropyl-piperazine and 3-chloro-6-phenyl pyridazine.

1H NMR(DMSO-d6)δ0.82(m,2H),1.22(m,2H),2.88(br s,1H),3.37(m,2H),3.59(m,4H),4.57(m,2H),7.53(m,3H),7.80(d,J=8Hz,1H),8.06(m,2H),8.29(d,J=8Hz,1H),11.47(br s,1H);HPLC-MS:m/z281(MH+);Rt=1.43min. 1H NMR (DMSO-d6) δ0.82 (m, 2H), 1.22 (m, 2H), 2.88 (br s, 1H), 3.37 (m, 2H), 3.59 (m, 4H), 4.57 (m, 2H ), 7.53 (m, 3H), 7.80 (d, J = 8Hz, 1H), 8.06 (m, 2H), 8.29 (d, J = 8Hz, 1H), 11.47 (br s, 1H); HPLC-MS: m / z281 (MH +); Rt = 1.43min.

实施例127(通用工艺(B))3-(4-环丙基哌嗪-1-基)-6-(3,4-二甲氧基苯基)哒嗪盐酸盐 127 (General procedure (B)) Example 3- (4-cyclopropyl-piperazin-1-yl) -6- (3,4-dimethoxyphenyl) pyridazine hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和3-氯-6-(3,4-二甲氧基苯基)哒嗪制备该化合物。 Using general procedure (B), from 1-cyclopropyl-piperazine and 3-chloro-6- (3,4-dimethoxyphenyl) piperazine pyridazine This compound was prepared.

1H NMR(DMSO-d6)δ0.83(m,2H),1.22(m,2H),2.88(br s,1H)3.36(m,2H),3.60(m,4H),3.84(s,3H),3.87(s,3H),4.53(m,2H),7.14(d,J=8Hz,1H),7.66(m,2H),7.86(d,J=8Hz,1H),8.37(d,J=8Hz,1H),11.43(br s,1H);HPLC-MS:m/z341(MH+);Rt=1.45min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.22 (m, 2H), 2.88 (br s, 1H) 3.36 (m, 2H), 3.60 (m, 4H), 3.84 (s, 3H) , 3.87 (s, 3H), 4.53 (m, 2H), 7.14 (d, J = 8Hz, 1H), 7.66 (m, 2H), 7.86 (d, J = 8Hz, 1H), 8.37 (d, J = 8Hz, 1H), 11.43 (br s, 1H); HPLC-MS: m / z341 (MH +); Rt = 1.45min.

实施例128(通用工艺(B))7-(4-异丙基哌嗪-1-基)-2,3-二氢-[1,4]二氧杂环己烯并[2,3-g]喹啉 128 (General procedure (B)) Example 7- (4-isopropyl-piperazin-1-yl) -2,3-dihydro - [l, 4] dioxino [2,3- g] quinoline 利用通用工艺(B),从1-异丙基哌嗪和7-氯-2,3-二氢[1,4,]二氧杂环己烯并[2,3-g]喹啉制备该化合物。 [2,3-g] quinoline was prepared morpholine using the general procedure (B), from 1-isopropyl-piperazine and 7-chloro-2,3-dihydro [1, 4] dioxine and compound.

1H NMR(DMSO-d6)δ1.00(d,J=7Hz,6H),2.67(hept,J=7Hz,1H),3.33(s,4H),3.56(m,4H),4.29(m,4H),6.95(s,1H),7.02(d,J=8Hz,1H),7.13(s,1H),7.84(d,J=8Hz,1H);HPLC-MS:m/z 314(MH+);Rt=1.14min. 1H NMR (DMSO-d6) δ1.00 (d, J = 7Hz, 6H), 2.67 (hept, J = 7Hz, 1H), 3.33 (s, 4H), 3.56 (m, 4H), 4.29 (m, 4H ), 6.95 (s, 1H), 7.02 (d, J = 8Hz, 1H), 7.13 (s, 1H), 7.84 (d, J = 8Hz, 1H); HPLC-MS: m / z 314 (MH +); Rt = 1.14min.

实施例1292-(4-环丙基-3-甲基哌嗪-1-基)喹啉盐酸盐 1292- (4-cyclopropyl-3-methyl-piperazin-1-yl) quinoline hydrochloride Example 如Gillaspy,ML;Lefker,BA;Hada,WA;and Hoover,DJin Tetrahedron Lett.1995,36(41),7399-7402所述,借助2-(3-甲基哌嗪-1-基)喹啉的还原性环丙基化作用制备该化合物。 As Gillaspy, ML; Lefker, BA; Hada, WA; and Hoover, DJin Tetrahedron Lett.1995,36 (41), said 7399-7402, by means of 2- (3-methyl-piperazin-1-yl) quinoline cyclopropyl reductive action of the compound was prepared.

1H NMR(DMSO-d6)δ0.82(m,1H),1.00(m,2H),1.41(m,1H),1.56(d,J=7Hz,3H),2.76(m,1H),3.25-3.80(m,5H),4.81(m,2H),7.44(br s,1H),7.55(m,1H),7.72(m,1H),7.88(m,1H),8.11(br s,1H),8.37(br s,1H),11.40(br s,1H);HPLC-MS:m/z268(MH+);Rt=1.18min. 1H NMR (DMSO-d6) δ0.82 (m, 1H), 1.00 (m, 2H), 1.41 (m, 1H), 1.56 (d, J = 7Hz, 3H), 2.76 (m, 1H), 3.25- 3.80 (m, 5H), 4.81 (m, 2H), 7.44 (br s, 1H), 7.55 (m, 1H), 7.72 (m, 1H), 7.88 (m, 1H), 8.11 (br s, 1H) , 8.37 (br s, 1H), 11.40 (br s, 1H); HPLC-MS: m / z268 (MH +); Rt = 1.18min.

实施例130(通用工艺(B))6-环丙基甲氧基-2-(4-环丙基哌嗪-1-基)喹啉盐酸盐 130 (General procedure (B)) Example 6-cyclopropyl-methoxy-2- (4-cyclopropyl-piperazin-1-yl) quinoline hydrochloride embodiment 利用通用工艺(B),从1-异丙基哌嗪和2-氯-6-(环丙基甲氧基)喹啉制备该化合物。 Using general procedure (B), (cyclopropylmethoxy) quinoline was prepared from 1-isopropyl-piperazine and 2-chloro-6 This compound. 所需的2-氯-6-(环丙基甲氧基)喹啉是用POCl3处理6-(环丙基甲氧基)-2-喹诺酮所制备的。 The desired 2-chloro-6- (cyclopropylmethoxy) quinoline is treated with POCl3 6- (cyclopropylmethoxy) -2-quinolone is prepared. 6-(环丙基甲氧基)-2-喹诺酮是从对应的6-羟基喹诺酮制备的,在二甲基甲酰胺中,在催化量碘化钠的存在下,用(溴甲基)环丙烷和碳酸钾处理。 6- (cyclopropylmethoxy) -2-quinolone is prepared from 6-hydroxy quinolone corresponding, in dimethylformamide, in the presence of a catalytic amount of sodium iodide, with (bromomethyl) cycloalkyl propane and potassium carbonate.

1H NMR(DMSO-d6)δ0.35(m,2H),0.60(m,2H),0.82(m,2H),1.20(m,2H),1.28(m,1H),2.87(br s,1H), 3.25-4.20(m,6H),3.92(d,J=7Hz,2H),4.70(m,2H),7.30-7.60(m,3H),8.08(br s,1H),8.32(br s,1H),11.37(br s,1H);HPLC-MS:m/z324(MH+);Rt=1.94min. 1H NMR (DMSO-d6) δ0.35 (m, 2H), 0.60 (m, 2H), 0.82 (m, 2H), 1.20 (m, 2H), 1.28 (m, 1H), 2.87 (br s, 1H ), 3.25-4.20 (m, 6H), 3.92 (d, J = 7Hz, 2H), 4.70 (m, 2H), 7.30-7.60 (m, 3H), 8.08 (br s, 1H), 8.32 (br s , 1H), 11.37 (br s, 1H); HPLC-MS: m / z324 (MH +); Rt = 1.94min.

实施例131(通用工艺(B))2-(4-异丙基哌嗪-1-基)-6-吡唑-1-基喹啉盐酸盐 131 (General procedure (B)) Example 2- (4-isopropyl-piperazin-1-yl) -6-pyrazol-1-yl quinoline hydrochloride 利用通用工艺(B),从1-异丙基哌嗪和2-氯-6-(1-吡唑基)喹啉制备该化合物。 Using general procedure (B), (1- pyrazolyl) quinoline was prepared from 1-isopropyl-piperazine and 2-chloro-6 This compound. 所需的2-氯-6-(1-吡唑基)喹啉是用POCl3处理6-(1-吡唑基)-2-喹诺酮所制备的。 The desired 2-chloro-6- (1-pyrazolyl) quinoline was treated with POCl3 6- (1- pyrazolyl) -2-quinolone is prepared. 6-(1-吡唑基)-2-喹诺酮是按照下列方式制备的:将6-溴-2-喹诺酮(3.58g,16.0mmol)、DMF(15ml)、吡唑(1.66g,24.4mmol)、碳酸钾(3.33g,24.1mmol)与碘化铜(I)(0.76g,3.99mmol)的混合物在160℃下搅拌22小时。 6- (1-pyrazolyl) -2-quinolone is prepared in the following manner: A mixture of 6-bromo-2-quinolone (3.58g, 16.0mmol), DMF (15ml), pyrazole (1.66g, 24.4mmol) , potassium carbonate (3.33g, 24.1mmol) with a mixture of copper (I) (0.76g, 3.99mmol) iodide was stirred at 160 ℃ 22 hours. 加入水(300ml),充分研制后,将混合物过滤,固体用水洗涤。 Water was added (300ml), was sufficiently developed, the mixture was filtered, the solid washed with water. 将固体用EtOH汽提,重新悬浮在乙腈与乙醇的混合物(100ml,1∶1)中,加热至回流,保持在室温下过夜。 The solid was stripped with EtOH, resuspended in a mixture of acetonitrile and ethanol (100ml, 1:1), heated to reflux, kept at room temperature overnight. 过滤,用一点乙腈洗涤,在减压下干燥,得到1.7g(50%)6-(1-吡唑基)-2-喹诺酮,为金属绿色固体。 Filtered, washed with a little acetonitrile, and dried under reduced pressure to give 1.7g (50%) 6- (1- pyrazolyl) -2-quinolone as a metallic green solid.

1H NMR(DMSO-d6)δ1.32(d,J=7Hz,6H),3.10-3.70(m,7H),4.81(m,2H),6.60(m,1H),7.56(d,J=8Hz,1H),7.81(s,1H),8.09(m,1H),8.22(d,J=8Hz,1H),8.32(s,1H),8.38(d,J=8Hz,1H),8.58(m,1H),11.11(br s,1H);HPLC-MS:m/z322(MH+);Rt=1.67min. 1H NMR (DMSO-d6) δ1.32 (d, J = 7Hz, 6H), 3.10-3.70 (m, 7H), 4.81 (m, 2H), 6.60 (m, 1H), 7.56 (d, J = 8Hz , 1H), 7.81 (s, 1H), 8.09 (m, 1H), 8.22 (d, J = 8Hz, 1H), 8.32 (s, 1H), 8.38 (d, J = 8Hz, 1H), 8.58 (m , 1H), 11.11 (br s, 1H); HPLC-MS: m / z322 (MH +); Rt = 1.67min.

实施例132(通用工艺(B))2-(4-异丙基哌嗪-1-基)喹啉-6-醇盐酸盐 2- (4-isopropyl-piperazin-1-yl) quinolin-6-ol hydrochloride 132 ((B) General procedure) Example 利用通用工艺(B),从1-异丙基哌嗪和2-氯-6-羟基喹啉制备该化合物。 Using general procedure (B), morpholine quinoline This compound was prepared from 1-isopropyl-piperazine and 2-chloro-6-hydroxy.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.15-3.90(m,7H),4.79(m,2H),7.22(m,1H),7.33(d,J=8Hz,1H),7.53(d,J=8Hz,1H),8.13(br s,1H),8.35(d,J=8Hz,1H),10.17(brs,1H),11.41(br s,1H);HPLC-MS:m/z 272(MH+);Rt=0.40min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.15-3.90 (m, 7H), 4.79 (m, 2H), 7.22 (m, 1H), 7.33 (d, J = 8Hz , 1H), 7.53 (d, J = 8Hz, 1H), 8.13 (br s, 1H), 8.35 (d, J = 8Hz, 1H), 10.17 (brs, 1H), 11.41 (br s, 1H); HPLC -MS: m / z 272 (MH +); Rt = 0.40min.

实施例133(通用工艺(B))2-(4-环丙基哌嗪-1-基)喹啉-6-甲腈盐酸盐 Example 133 (General procedure (B)) 2- (4- cyclopropyl-piperazin-1-yl) quinoline-6-carbonitrile hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-6-氰基喹啉制备该化合物。 Using general procedure (B), morpholine quinoline This compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-6-cyano.

1H NMR(DMSO-d6)δ0.83(m,2H),1.15(m,2H),2.87(brs,1H),3.20-3.65(m,6H),4.74(m,2H),7.49(d,J=8Hz,1H),7.72(d,J=8Hz,1H),7.86(d,J=8Hz,1H),8.24(d,J=8Hz,1H),8.35(s,1H),10.88(brs,1H);HPLC-MS:m/z279(MH+);Rt=1.43min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.15 (m, 2H), 2.87 (brs, 1H), 3.20-3.65 (m, 6H), 4.74 (m, 2H), 7.49 (d, J = 8Hz, 1H), 7.72 (d, J = 8Hz, 1H), 7.86 (d, J = 8Hz, 1H), 8.24 (d, J = 8Hz, 1H), 8.35 (s, 1H), 10.88 (brs , 1H); HPLC-MS: m / z279 (MH +); Rt = 1.43min.

实施例134(通用工艺(B))(9a-R)-2-(八氢吡啶并[1,2-a]吡嗪-2-基)喹啉-6-甲腈盐酸盐 Example 134 (General procedure (B)) (9a-R) -2- (octahydro-pyrido [1,2-a] pyrazin-2-yl) quinoline-6-carbonitrile hydrochloride 利用通用工艺(B),从(9a-R)-八氢吡啶并[1,2-a]吡嗪和2-氯-6-氰基喹啉制备该化合物。 Using general procedure (B), from (9a-R) - octahydro-pyrido [1,2-a] pyrazine and 2-chloro-6-cyano-quinoline This compound was prepared.

1H NMR(DMSO-d6)δ1.40-1.60(m,1H),1.65-2.00(m,5H),2.85-3.65(m,7H),4.80(m,2H),7.53(d,J=8Hz,1H),7.79(d,J=8Hz,1H),7.89(d,J=8Hz,1H),8.26(d,J=8Hz,1H),8.37(s,1H),11.31(br s,1H);HPLC-MS:m/z293(MH+);Rt=1.72min. 1H NMR (DMSO-d6) δ1.40-1.60 (m, 1H), 1.65-2.00 (m, 5H), 2.85-3.65 (m, 7H), 4.80 (m, 2H), 7.53 (d, J = 8Hz , 1H), 7.79 (d, J = 8Hz, 1H), 7.89 (d, J = 8Hz, 1H), 8.26 (d, J = 8Hz, 1H), 8.37 (s, 1H), 11.31 (br s, 1H ); HPLC-MS: m / z293 (MH +); Rt = 1.72min.

实施例135(通用工艺(B)) Example 135 (General procedure (B))

4-氯-6-(4-异丙基哌嗪-1-基)-3-苯基哒嗪盐酸盐 4-chloro-6- (4-isopropyl-piperazin-1-yl) -3-phenyl-pyridazine hydrochloride 利用通用工艺(B),从1-异丙基哌嗪和4,6-二氯-3-苯基哒嗪制备该化合物。 Using general procedure (B), the triazine compound was prepared from 1-isopropyl-piperazine and 4,6-dichloro-pyridazin-3-phenyl.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),3.13(m,2H),3.40-3.65(m,5H),4.63(m,2H),7.50(m,3H),7.63(m,2H),7.78(s,1H),11.01(br s,1H);HPLC-MS:m/z317(MH+);Rt=2.11min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 3.13 (m, 2H), 3.40-3.65 (m, 5H), 4.63 (m, 2H), 7.50 (m, 3H), 7.63 (m, 2H), 7.78 (s, 1H), 11.01 (br s, 1H); HPLC-MS: m / z317 (MH +); Rt = 2.11min.

实施例136(通用工艺(B))3-(4-环丙基哌嗪-1-基)-6-(3-三氟甲基苯基)哒嗪盐酸盐 136 (General procedure (B)) Example 3- (4-cyclopropyl-piperazin-1-yl) -6- (3-trifluoromethylphenyl) pyridazine hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和3-氯-6-(3-三氟甲基苯基)哒嗪制备该化合物。 Using general procedure (B), from 1-cyclopropyl-piperazine and 3-chloro-6- (3-trifluoromethylphenyl) piperazine pyridazine This compound was prepared.

1H NMR(DMSO-d6)δ0.83(m,2H),1.22(m,2H),2.89(br s,1H),3.35(m,2H),3.59(m,4H),4.63(m,2H),7.68(d,J=8Hz,1H),7.77(m,1H),7.84(m,1H),8.32(d,J=8Hz,1H),8.40(m,2H),11.40(br s,1H);HPLC-MS:m/z 349(MH+);Rt=2.43min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.22 (m, 2H), 2.89 (br s, 1H), 3.35 (m, 2H), 3.59 (m, 4H), 4.63 (m, 2H ), 7.68 (d, J = 8Hz, 1H), 7.77 (m, 1H), 7.84 (m, 1H), 8.32 (d, J = 8Hz, 1H), 8.40 (m, 2H), 11.40 (br s, 1H); HPLC-MS: m / z 349 (MH +); Rt = 2.43min.

实施例1371-[2-(4-异丙基哌嗪-1-基)喹啉-6-基]乙酮盐酸盐 Example 1371- [2- (4-isopropyl-piperazin-1-yl) quinolin-6-yl] ethanone hydrochloride

在四氢呋喃中将2-(4-异丙基哌嗪-1-基)喹啉-6-甲腈用过量溴化甲基镁处理,制备该化合物。 Quinoline-6-carbonitrile with an excess of methyl magnesium bromide in tetrahydrofuran in the process of 2- (4-isopropyl-piperazin-1-yl) This compound was prepared.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),2.65(s,3H),3.18(m,2H),3.40-3.80(m,5H),4.82(m,2H),7.52(d,J=8Hz,1H),7.91(br s,1H),8.15(d,J=8Hz,1H),8.40(d,J=8Hz,1H),8.54(s,1H),11.16(br s,1H);HPLC-MS:m/z298(MH+);Rt=1.47min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 2.65 (s, 3H), 3.18 (m, 2H), 3.40-3.80 (m, 5H), 4.82 (m, 2H), 7.52 (d, J = 8Hz, 1H), 7.91 (br s, 1H), 8.15 (d, J = 8Hz, 1H), 8.40 (d, J = 8Hz, 1H), 8.54 (s, 1H), 11.16 ( br s, 1H); HPLC-MS: m / z298 (MH +); Rt = 1.47min.

实施例138(通用工艺(B))3-(4-异丙基哌嗪-1-基)-6-苯基哒嗪-4-甲腈盐酸盐 138 (General procedure (B)) 3- (4- isopropyl-piperazin-1-yl) -6-phenyl Example pyridazin-4-carbonitrile hydrochloride 利用通用工艺(B),从1-异丙基哌嗪和3-氯-6-苯基哒嗪-4-甲腈制备该化合物。 Using general procedure (B), the compound was prepared from 1-isopropyl-piperazine and 3-chloro-6-phenyl-pyridazin-4-carbonitrile.

1H NMR(DMSO-d6)δ1.32(d,J=7Hz,6H),3.23(m,2H),3.50-3.75(m,5H),4.46(m,2H),7.55(m,3H),8.13(d,J=7Hz,2H),8.72(s,1H),10.67(br s,1H);HPLC-MS:m/z 308(MH+);Rt=2.16min. 1H NMR (DMSO-d6) δ1.32 (d, J = 7Hz, 6H), 3.23 (m, 2H), 3.50-3.75 (m, 5H), 4.46 (m, 2H), 7.55 (m, 3H), 8.13 (d, J = 7Hz, 2H), 8.72 (s, 1H), 10.67 (br s, 1H); HPLC-MS: m / z 308 (MH +); Rt = 2.16min.

实施例139(通用工艺(B))6-溴-2-(4-异丙基哌嗪-1-基)喹啉 Bromo-2- (4-isopropyl-piperazin-1-yl) quinoline 139 ((B) General procedure) Example 利用通用工艺(B),从1-异丙基哌嗪和6-溴-2-氯喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-isopropyl-piperazine and 6-bromo-2-chloroquinoline.

1H NMR(DMSO-d6)δ1.00(d,J=7Hz,6H),2.52(m,4H),2.69(sept,J=7Hz,1H),3.68(m,4H),7.28(d,J=8Hz,1H),7.48(d,J=8Hz,1H),7.60(dd,J=1Hz,8Hz,1H),7.93(d,J=1Hz,1H),8.00(d,J=8Hz,1H). 1H NMR (DMSO-d6) δ1.00 (d, J = 7Hz, 6H), 2.52 (m, 4H), 2.69 (sept, J = 7Hz, 1H), 3.68 (m, 4H), 7.28 (d, J = 8Hz, 1H), 7.48 (d, J = 8Hz, 1H), 7.60 (dd, J = 1Hz, 8Hz, 1H), 7.93 (d, J = 1Hz, 1H), 8.00 (d, J = 8Hz, 1H ).

实施例140(通用工艺(B))2-(4-环丙基哌嗪-1-基)-6-吡唑-1-基喹啉盐酸盐 Example 140 (General procedure (B)) 2- (4- cyclopropyl-piperazin-1-yl) -6-pyrazol-1-yl quinoline hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2-氯-6-吡唑-1-基喹啉制备该化合物。 Using general procedure (B), the compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-6-pyrazol-1-yl quinoline.

1H NMR(DMSO-d6)δ0.83(m,2H),1.22(m,2H),2.88(m,1H),3.30-3.80(m,6H),4.79(m,2H),6.61(m,1H),7.59(d,J=6Hz,1H),7.81(s,1H),8.10-8.30(m,2H),8.34(s,1H),8.41(d,J=6Hz,1H),8.59(s,1H),11.47(br s,1H);HPLC-MS:m/z320(MH+);Rt=1.64min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.22 (m, 2H), 2.88 (m, 1H), 3.30-3.80 (m, 6H), 4.79 (m, 2H), 6.61 (m, 1H), 7.59 (d, J = 6Hz, 1H), 7.81 (s, 1H), 8.10-8.30 (m, 2H), 8.34 (s, 1H), 8.41 (d, J = 6Hz, 1H), 8.59 ( s, 1H), 11.47 (br s, 1H); HPLC-MS: m / z320 (MH +); Rt = 1.64min.

实施例141(通用工艺(B))7-氯-2-(4-环丙基哌嗪-1-基)喹啉-6-醇盐酸盐 Example 141 (General procedure (B)) 7- Chloro-2- (4-cyclopropyl-piperazin-1-yl) quinolin-6-ol hydrochloride 利用通用工艺(B),从1-环丙基哌嗪和2,7-二氯-6-羟基喹啉制备该化合物。 Using general procedure (B), morpholine quinoline This compound was prepared from 1-cyclopropyl-piperazine and 2,7-dichloro-6-hydroxy. 所需的2,7-二氯-6-羟基喹啉是这样制备的,在二氯甲烷中用三溴化硼进行2,7-二氯-6-甲氧基喹啉的脱甲基作用,后者是从3-氯-4-甲氧基苯胺制备的,如F.Effenberger and W.Hartmann inChemische Berichte 1969,102,3260-3267所述。 Desired 2,7-dichloro-6-hydroxy-quinoline is prepared, 2,7-dichloro-6-methoxy-demethylation quinoline boron tribromide in methylene chloride. , which is from the 3-chloro-4-methoxyaniline as F.Effenberger and W.Hartmann inChemische Berichte 1969,102,3260-3267.

1H NMR(DMSO-d6)δ0.83(m,2H),1.14(m,2H),2.88(m,1H),3.20-3.80(m,6H),4.61(m,2H),7.32(s,1H),7.42(m,1H),7.96(m,1H),8.21(m,1H),10.65(br s,1H),10.84(br s,1H);HPLC-MS:m/z304(MH+);Rt=1.06min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.14 (m, 2H), 2.88 (m, 1H), 3.20-3.80 (m, 6H), 4.61 (m, 2H), 7.32 (s, 1H), 7.42 (m, 1H), 7.96 (m, 1H), 8.21 (m, 1H), 10.65 (br s, 1H), 10.84 (br s, 1H); HPLC-MS: m / z304 (MH +) ; Rt = 1.06min.

实施例142[2-(4-环丙基哌嗪-1-基)喹啉-6-基]-(4-氟苯基)甲酮盐酸盐 142 [2- (4-cyclopropyl-piperazin-1-yl) quinolin-6-yl] Example - (4-fluorophenyl) methanone hydrochloride 在四氢呋喃中将2-(4-环丙基哌嗪-1-基)喹啉-6-甲腈用过量溴化(4-氟苯基)镁处理,制备该产物。 Tetrahydrofuran in the 2- (4-cyclopropyl-piperazin-1-yl) quinoline-6-carbonitrile with an excess of bromide (4-fluorophenyl) magnesium treatment, the product was prepared.

1H NMR(DMSO-d6)δ0.84(m,2H),1.14(m,2H),2.89(m,1H),3.25-3.90(m,6H),4.77(m,2H),7.44(m,3H),7.76(m,1H),7.86(m,2H),7.98(m,1H),8.21(s,1H),8.34(d,J=8Hz,1H),10.65(br s,1H);HPLC-MS:m/z376(MH+);Rt=2.61min. 1H NMR (DMSO-d6) δ0.84 (m, 2H), 1.14 (m, 2H), 2.89 (m, 1H), 3.25-3.90 (m, 6H), 4.77 (m, 2H), 7.44 (m, 3H), 7.76 (m, 1H), 7.86 (m, 2H), 7.98 (m, 1H), 8.21 (s, 1H), 8.34 (d, J = 8Hz, 1H), 10.65 (br s, 1H); HPLC-MS: m / z376 (MH +); Rt = 2.61min.

实施例143(通用工艺(B))环丙基-[2-(4-环丙基哌嗪-1-基)喹啉-6-基]甲酮盐酸盐 [2- (4-cyclopropyl-piperazin-1-yl) quinolin-6-yl] methanone hydrochloride - Example 143 (General procedure (B)) cyclopropyl 在四氢呋喃中将2-(4-环丙基哌嗪-1-基)喹啉-6-甲腈用过量溴化环丙基镁处理,制备该产物。 Tetrahydrofuran in the 2- (4-cyclopropyl-piperazin-1-yl) quinoline-6-carbonitrile with an excess of cyclopropyl magnesium bromide treatment, the product was prepared.

1H NMR(DMSO-d6)δ0.83(m,2H),1.07(m,4H),1.18(m,2H),2.88(m,1H),3.00(quint,J=7Hz,1H),3.30-3.70(m,6H),4.76(m,2H),7.50(d,J=8Hz,1H),7.82(br s,1H),8.18(d,J=8Hz,1H),8.37(d,J=8Hz,1H),8.66(s,1H),11.05(br s,1H);HPLC-MS:m/z322(MH+);Rt=1.98min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.07 (m, 4H), 1.18 (m, 2H), 2.88 (m, 1H), 3.00 (quint, J = 7Hz, 1H), 3.30- 3.70 (m, 6H), 4.76 (m, 2H), 7.50 (d, J = 8Hz, 1H), 7.82 (br s, 1H), 8.18 (d, J = 8Hz, 1H), 8.37 (d, J = 8Hz, 1H), 8.66 (s, 1H), 11.05 (br s, 1H); HPLC-MS: m / z322 (MH +); Rt = 1.98min.

实施例144(通用工艺(B))2-(4-环丙基哌嗪-1-基)-6-(4-氟苄氧基)喹啉盐酸盐 Quinoline 144 (general procedure (B)) Example 2- (4-cyclopropyl-piperazin-1-yl) -6- (4-fluorobenzyloxy) hydrochloride

利用通用工艺(B),从1-环丙基哌嗪和2-氯-6-(4-氟苄氧基)喹啉制备该化合物。 Using general procedure (B), This compound was prepared from 1-cyclopropyl-piperazine and 2-chloro-6- (4-fluoro-benzyloxy) quinoline.

1H NMR(DMSO-d6)δ0.83(m,2H),1.20(m,2H),2.87(m,1H),3.30-3.80(m,6H),4.70(m,2H),5.18(s,2H),7.25(t,J=8Hz,2H),7.54(m,5H),8.08(br s,1H),8.33(m,1H),11.34(brs,1H);HPLC-MS:m/z 378(MH+);Rt=2.53min. 1H NMR (DMSO-d6) δ0.83 (m, 2H), 1.20 (m, 2H), 2.87 (m, 1H), 3.30-3.80 (m, 6H), 4.70 (m, 2H), 5.18 (s, 2H), 7.25 (t, J = 8Hz, 2H), 7.54 (m, 5H), 8.08 (br s, 1H), 8.33 (m, 1H), 11.34 (brs, 1H); HPLC-MS: m / z 378 (MH +); Rt = 2.53min.

实施例1456-环己-1-烯基-2-(4-异丙基哌嗪-1-基)喹啉盐酸盐 Example 1456- -en--2- (4-isopropyl-piperazin-1-yl) quinoline hydrochloride 将6-溴-2-(4-异丙基哌嗪-1-基)喹啉用丁基锂、再用环己酮处理,制备该产物。 6-bromo-2- (4-isopropyl-piperazin-1-yl) quinoline-butyllithium, and then cyclohexanone process, the product was prepared. 酸处理后,叔醇经历消去作用,得到标题化合物。 After the acid treatment, the role of tertiary alcohol undergoes elimination to give the title compound.

1H NMR(DMSO-d6)δ1.31(d,J=7Hz,6H),1.60-1.80(m,4H),2.22(m,2H),2.45(m,2H),3.23(m,2H),3.45-4.00(m,5H),4.78(m,2H),6.34(m,1H),7.50(m,1H),7.86(m,2H),7.98(br s,1H),8.34(m,1H),11.06(br s,1H);HPLC-MS:m/z336(MH+);Rt=2.50min. 1H NMR (DMSO-d6) δ1.31 (d, J = 7Hz, 6H), 1.60-1.80 (m, 4H), 2.22 (m, 2H), 2.45 (m, 2H), 3.23 (m, 2H), 3.45-4.00 (m, 5H), 4.78 (m, 2H), 6.34 (m, 1H), 7.50 (m, 1H), 7.86 (m, 2H), 7.98 (br s, 1H), 8.34 (m, 1H ), 11.06 (br s, 1H); HPLC-MS: m / z336 (MH +); Rt = 2.50min.

实施例146(通用工艺(C))1-(联苯-3-基)-4-(环戊基)哌嗪 EXAMPLE 146 (general procedure (C)) 1- (biphenyl-3-yl) -4- (cyclopentyl) -piperazine embodiment 将3-溴联苯(300mg,1.28mmol)、1-环戊基哌嗪(238mg,1.54mmol)、叔丁醇钠(173mg,1.8mmol)、三(二亚苄基丙酮)二钯(12mg,0.01mmol)与外消旋2,2'-双(二苯膦基)-1,1'-联萘(24mg,0.04mmol)在甲苯(11ml)中的混合物在氮下混合在密封的反应容器中。 3-bromo biphenyl (300mg, 1.28mmol), 1- cyclopentyl-piperazine (238mg, 1.54mmol), sodium tert-butoxide (173mg, 1.8mmol), tris (dibenzylideneacetone) dipalladium (12 mg of , 0.01mmol) and rac-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (24mg, 0.04mmol) in toluene (11 ml of) mixed under nitrogen in a sealed reaction container. 在密封的反应容器中,将反应混合物在80℃下搅拌3天。 In a sealed reaction vessel, the reaction mixture was stirred at 80 ℃ 3 days. 将其冷却至室温,用水洗涤(2×10ml)。 It was cooled to room temperature, washed with water (2 × 10ml). 合并有机层,用1N盐酸萃取(2×20ml)。 The organic layers were combined and extracted with 1N hydrochloric acid (2 × 20ml). 合并水性萃取液,用1N氢氧化钠水溶液调至碱性,用叔丁基甲基醚萃取(3×20ml)。 The combined aqueous extracts were made basic with 1N aqueous sodium hydroxide solution, extracted with tert-butyl methyl ether (3 × 20ml) with. 叔丁基甲基醚层经过硫酸镁干燥。 Tert-butyl methyl ether layer was dried over magnesium sulfate. 在真空中除去溶剂,得到220mg标题化合物。 The solvent was removed in vacuo to give 220mg of the title compound.

1H-NMR(CDCl3,两组信号,宽信号)δ1.35-1.85(m,6H);1.95(m,2H);2.55(m,1H);2.70(m,4H);3.30(m,4H);6.95(d,1H);7.05(d,1H);7.15(s,1H);7.35(t,2H);7.45(t,2H);7.60(d,2H).HPLC方法B:在10.45分钟时洗脱如下将标题化合物转化为它的盐酸盐:将其溶于乙酸乙酯(5ml)。 1H-NMR (CDCl3, two sets of signals, broad signals) δ1.35-1.85 (m, 6H); 1.95 (m, 2H); 2.55 (m, 1H); 2.70 (m, 4H); 3.30 (m, 4H ); 6.95 (d, 1H); 7.05 (d, 1H); 7.15 (s, 1H); 7.35 (t, 2H); 7.45 (t, 2H); 7.60 (d, 2H) .HPLC method B: 10.45 min elution title compound as converted to its hydrochloride: which is dissolved in ethyl acetate (5ml). 加入3.2M氯化氢的乙酸乙酯溶液(5ml)。 Was added 3.2M hydrogen chloride in ethyl acetate (5ml). 在真空中除去溶剂。 The solvent was removed in vacuo. 将残余物溶于乙醇(50ml)。 The residue was dissolved in ethanol (50ml). 在真空中除去溶剂。 The solvent was removed in vacuo.

实施例147(通用工艺(C))1-环戊基-4-[4-(2-(吡咯烷-1-基)乙氧基)苯基]哌嗪 EXAMPLE 147 (general procedure (C)) 1- cyclopentyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] piperazine embodiment 如关于1-(联苯-3-基)-4-(环戊基)哌嗪所述,使用1-(2-(4-溴苯氧基)乙基)吡咯烷代替3-溴联苯,合成86mg标题化合物。 As described for l- (biphenyl-3-yl) -4- (cyclopentyl) piperazine said, using 1- (2- (4-bromophenoxy) ethyl) pyrrolidine in place of 3-bromobiphenyl synthesis of the title compound 86mg.

1H-NMR(DMSO-d6)δ1.55(m,2H);1.75(m,2H);1.85(m,4H);2.00(m,4H);3.10(m,6H);3.40-3.70(m,9H);4.30(t,2H);7.00(AB,4H);10.80(br,1H);11.10(br,1H).HPLC方法C:在2.24分钟时洗脱。 1H-NMR (DMSO-d6) δ1.55 (m, 2H); 1.75 (m, 2H); 1.85 (m, 4H); 2.00 (m, 4H); 3.10 (m, 6H); 3.40-3.70 (m , 9H); 4.30 (t, 2H); 7.00 (AB, 4H); 10.80 (br, 1H); 11.10 (br, 1H) .HPLC method C: eluted at 2.24 minutes. MS:计算值[M+H]+:344;实测值:344。 MS: Calcd [M + H] +: 344; Found: 344.

如下将标题化合物转化为它的盐酸盐,将其溶于乙酸乙酯(5ml)。 As will be converted to the title compound as its hydrochloride salt, which was dissolved in ethyl acetate (5ml). 加入3.2M氯化氢的乙酸乙酯溶液(5ml)。 Was added 3.2M hydrogen chloride in ethyl acetate (5ml). 在真空中除去溶剂。 The solvent was removed in vacuo. 将残余物溶于乙醇(50ml)。 The residue was dissolved in ethanol (50ml). 在真空中除去溶剂。 The solvent was removed in vacuo.

实施例148(通用工艺(C))1-(联苯-4-基)-4-(环戊基)哌嗪 Example 148 (General procedure (C)) 1- (biphenyl-4-yl) -4- (cyclopentyl) -piperazine embodiment 如关于1-(联苯-3-基)-4-(环戊基)哌嗪所述,使用4-溴联苯代替3-溴联苯,合成180mg标题化合物。 As described for l- (biphenyl-3-yl) -4- (cyclopentyl) piperazine said, using 4-bromobiphenyl instead of 3-bromobiphenyl, the title compound 180mg synthesized.

1H-NMR(CDCl3)δ1.80-2.00(m,8H);2.55(m,1H);2.70(m,4H);3.20(m,4H);7.00(d,2H);7.30(m,1H);7.40(t,2H);and 7.55(m,together 4H),HPLC方法C:在4.52分钟时洗脱。 1H-NMR (CDCl3) δ1.80-2.00 (m, 8H); 2.55 (m, 1H); 2.70 (m, 4H); 3.20 (m, 4H); 7.00 (d, 2H); 7.30 (m, 1H ); 7.40 (t, 2H); and 7.55 (m, together 4H), HPLC method C: eluted at 4.52 minutes.

如下将标题化合物转化为它的盐酸盐,将其溶于乙酸乙酯(5ml)。 As will be converted to the title compound as its hydrochloride salt, which was dissolved in ethyl acetate (5ml). 加入3.2M氯化氢的乙酸乙酯溶液(5ml)。 Was added 3.2M hydrogen chloride in ethyl acetate (5ml). 在真空中除去溶剂。 The solvent was removed in vacuo. 将残余物溶于乙醇(50ml)。 The residue was dissolved in ethanol (50ml). 在真空中除去溶剂。 The solvent was removed in vacuo.

实施例149(通用工艺(C))[3-(4-(环戊基)哌嗪-1-基)苯基]-(4-氟苯基)甲酮 Example 149 (General procedure (C)) [3- (4- (cyclopentyl) piperazin-1-yl) phenyl] - (4-fluorophenyl) methanone 如关于1-(联苯-3-基)-4-(环戊基)哌嗪所述,使用3-溴-4'-氟二苯酮代替3-溴联苯,合成300mg标题化合物。 As described for l- (biphenyl-3-yl) -4- (cyclopentyl) piperazine said, using 3-bromo-4'-fluoro-benzophenone instead of 3-bromobiphenyl, the title compound 300mg synthesized.

1H-NMR(CDCl3)δ1.45(m,2H);1.60(m,2H);1.75(m,2H);1.90(m,2H);2.55(quintet,1H);2.70(m,4H);3.30(m,4H);7.15(m,4H);7.35(m,2H);7.85(m,2H).HPLC方法C:在4.22分钟时洗脱。 1H-NMR (CDCl3) δ1.45 (m, 2H); 1.60 (m, 2H); 1.75 (m, 2H); 1.90 (m, 2H); 2.55 (quintet, 1H); 2.70 (m, 4H); 3.30 (m, 4H); 7.15 (m, 4H); 7.35 (m, 2H); 7.85 (m, 2H) .HPLC method C: eluted at 4.22 minutes. MS:计算值[M+H]+:353;实测值:353。 MS: Calcd [M + H] +: 353; Found: 353.

如下将标题化合物转化为它的盐酸盐,将其溶于乙酸乙酯(5ml)。 As will be converted to the title compound as its hydrochloride salt, which was dissolved in ethyl acetate (5ml). 加入3.2M氯化氢的乙酸乙酯溶液(5ml)。 Was added 3.2M hydrogen chloride in ethyl acetate (5ml). 在真空中除去溶剂。 The solvent was removed in vacuo. 将残余物溶于乙醇(50ml)。 The residue was dissolved in ethanol (50ml). 在真空中除去溶剂。 The solvent was removed in vacuo.

下列化合物也属于本发明的范围: The following compounds are also within the scope of the present invention:

药理学方法下列体外结合测定法能够测定化合物与组胺H3受体相互作用的能力。 The following pharmacological in vitro method of determining the ability of a compound capable of binding to the histamine H3 receptor interaction assays.

结合测定法I将大鼠大脑皮质在冰冷的K-Hepes,5mM MgCl2pH7.1缓冲液中均质化。 The binding assay I Rat cerebral cortex in ice cold K-Hepes, 5mM MgCl2pH7.1 homogenization buffer. 两次差速离心后,将后一吐弃块重新悬浮在含有1mg/ml杆菌肽的新鲜Hepes缓冲液中。 After centrifugation difference between the two, the latter spurn block resuspended in fresh Hepes buffer containing 1mg / ml of bacitracin. 将膜悬液的等分试样(400μg/ml)在25℃下与30pM[125I]-iodoproxifan(一种已知的组胺H3受体拮抗剂)和不同浓度供试化合物培育60分钟。 Aliquots of the membrane suspension (400μg / ml) at 25 deg.] C and 30pM [125I] -iodoproxifan (a known histamine H3 receptor antagonist) and incubated with different concentrations of test compound for 60 minutes. 培育是这样终止的,用冰冷的培养基稀释,继之以迅速通过用0.5%聚乙烯亚胺预处理1小时的Whatman GF/B滤器过滤。 Cultivation is terminated, diluted with ice-cold medium, followed by rapidly pretreated one hour with 0.5% polyethyleneimine Whatman GF / B filter. 利用Cobra II自动γ计数器计数滤器上所保留的放射性。 Radioactivity retained on the filters counted using a Cobra II auto γ counter. 滤器的放射性与供试化合物的结合亲和性间接成比例。 Filter radioactivity binding affinity of the test compound is indirectly proportional. 借助非线性回归分析,分析结果。 With non-linear regression analysis and the results.

结合测定法II将H3受体激动剂配体R-α-甲基[3H]组胺(RAMHA)与离体大鼠皮质细胞膜在25℃下培育1小时,继之以通过Whatman GF/B滤器过滤培育物。 Binding assay II The H3 R-α- methyl [3H] histamine (RAMHA) and isolated rat cortex membranes incubated for 1 hour at 25 ℃, followed by a Whatman GF / B filters receptor agonist ligand cultivation was filtered. 利用β计数器测量滤器上所保留的放射性。 The radioactivity was measured using β counter retained on the filters.

将雄性Wistar大鼠(150-200g)斩首,快速切取大脑皮质,立即冷冻在干冰上。 Male Wistar rats (150-200g) decapitated, the cerebral cortex was cut out quickly, immediately frozen on dry ice. 将组织保存在-80℃下直至膜制备。 The tissue was stored at -80 ℃ until membrane preparation. 在膜制备期间,将组织一直保存在冰上。 During the membrane preparation the tissue has been stored on ice. 利用Ultra-Turrax均质化器将大鼠大脑皮质在10体积(w/w)冰冷的Hepes缓冲液(20mM Hepes,5mM MgCl2pH7.1(KOH)+1mg/ml杆菌肽)中均质化30秒。 Using Ultra-Turrax homogenizer the rat cerebral cortex in 10 volumes (w / w) ice-cold Hepes buffer (20mM Hepes, 5mM MgCl2pH7.1 (KOH) + 1mg / ml bacitracin) homogenized for 30 sec . 将组织匀浆在140g下离心10分钟。 The tissue homogenate was centrifuged for 10 minutes at 140g. 将上清液转移至新的试管,在23000g下离心30分钟。 The supernatant was transferred to a new tube, centrifuged at 23000g for 30 min. 将吐弃块重新悬浮在5-10ml Hepes缓冲液中,均质化,在23000g下离心10分钟。 The block is discarded spit resuspended in 5-10ml Hepes buffer, homogenized, centrifuged for 10 minutes at 23000g. 这种短离心步骤重复两次。 This short centrifugation step is repeated twice. 最后一次离心后,将吐弃块重新悬浮在2-4mlHepes缓冲液中,测定蛋白质浓度。 After the last centrifugation, resuspended in spurn 2-4mlHepes block buffer, protein concentration was determined. 将膜用Hepes缓冲液稀释至蛋白质浓度为5mg/ml,等分,贮存在-80℃下备用。 Membranes was diluted with Hepes buffer to a protein concentration of 5mg / ml, aliquoted and stored at -80 ℃ standby.

在试管中混合50μl供试化合物、100μl膜(200μg/ml)、300μl Hepes缓冲液和50μl R-α-甲基[3H]组胺(1nM)。 In a test tube mixing 50 l of the test compound, 100μl membrane (200μg / ml), 300μl Hepes buffer and 50μl R-α- methyl [3H] histamine (1 nM). 将所要测试的化合物溶于DMSO,进一步在H2O中稀释至所需浓度。 The compound to be tested were dissolved in DMSO, further diluted in H2O to the desired concentration. 将放射性配体和膜稀释在Hepes缓冲液+1mg/ml杆菌肽中。 The radioligand and the membrane are diluted in Hepes buffer + 1mg / ml of bacitracin. 将混合物在25℃下培育60分钟。 The mixture was incubated at 25 ℃ 60 minutes. 培育是这样终止的,加入5ml冰冷的0.9%NaCl,继之以迅速通过用0.5%聚乙烯亚胺预处理1小时的Whatman GF/B滤器过滤。 Cultivation is terminated by adding 5ml of ice-cold 0.9% NaCl, followed by rapid pretreated one hour with 0.5% polyethyleneimine Whatman GF / B filter. 将滤器用2×5ml冰冷的NaCl洗涤。 The filters were washed with ice-cold NaCl with 2 × 5ml. 向每只滤器加入3ml闪烁鸡尾酒试剂,利用PackardTri-Carb β计数器测量所保留的放射性。 Scintillation cocktail was added to 3ml of each filter, using a radioactive PackardTri-Carb β counter measures reserved. 利用Windows程序GraphPadPrism,GraphPad Software,USA,借助结合曲线(最少6个点)的非线性回归分析计算IC50值。 Windows program using GraphPadPrism, GraphPad Software, USA, Analysis IC50 values ​​were calculated by nonlinear regression binding curves (6 points minimum) a.

结合测定法III借助PCR克隆人H3受体,亚克隆至pcDNA3表达载体中。 III binding assays cloned human H3 receptor by PCR, subcloned into the pcDNA3 expression vector. 通过转染H3表达载体至HEK 293细胞,并且使用G418选择H3克隆体,生成稳定表达H3受体的细胞。 Into HEK 293 cells transfected with the expression vector by H3, and H3 clones were selected using G418 to generate cells stably expressing the H3 receptor. 在37℃和5%CO2下,将人H3-HEK 293克隆体培养在含有glutamax、10%胎牛血清、1%青霉素/链霉抗生物素和1mg/mlG418的DMEM(GIBCO-BRL)中。 At 37 [deg.] C and 5% CO2, the human H3-HEK 293 clones cultured in glutamax, 10% fetal calf serum, 1% penicillin / streptavidin and biotin 1mg / ml G418 in DMEM (GIBCO-BRL) medium. 在收获前,将融合细胞用PBS清洗,与Versene(蛋白酶,GIBCO-BRL)培育大约5分钟。 Before harvesting, the fused cells were washed with PBS, and incubated with Versene (proteinase, GIBCO-BRL) for approximately 5 minutes. 将细胞用PBS和DMEM冲洗,将细胞悬液收集在试管中,在Heraeus Sepatech Megafuge 1.0中、在1500rpm下离心5-10分钟。 The cells were washed with PBS and DMEM, the cell suspension collected in a tube, in the Heraeus Sepatech Megafuge 1.0, centrifuged for 5-10 minutes at 1500rpm. 将吐弃块重新悬浮在10-20体积Hepes缓冲液(20mM Hepes,5mM MgCl2,pH7.1(KOH))中,利用Ultra-Turrax均质化器均质化10-20秒。 The block is discarded spit resuspended in 10-20 volumes Hepes buffer (20mM Hepes, 5mM MgCl2, pH7.1 (KOH)), the use of Ultra-Turrax homogenizer homogenized for 10-20 seconds. 将组织匀浆在23000g下离心30分钟。 The homogenate was centrifuged at 23000g for 30 min. 将吐弃块重新悬浮在5-10ml Hepes缓冲液中,利用Ultra-Turrax均质化5-10秒,在23000g下离心10分钟。 The block is discarded spit resuspended in 5-10ml Hepes buffer, homogenized using Ultra-Turrax 5-10 seconds, centrifuged for 10 minutes at 23000g. 在该离心步骤之后,将膜吐弃块重新悬浮在2-4ml Hepes缓冲液中,利用注射器或特氟隆均质化器均质化,测定蛋白质浓度。 After this centrifugation step, the membrane was discarded blocks spit resuspended in 2-4ml Hepes buffer, using a syringe or Teflon homogenizer homogenization, protein concentration was determined. 将膜用Hepes缓冲液稀释至蛋白质浓度为1-5mg/ml,等分,保存在-80℃下备用。 Membranes was diluted with Hepes buffer to a protein concentration of 1-5mg / ml, aliquoted and stored at -80 ℃ standby.

将膜悬液的等分试样在25℃下与30pM[125I]-iodoproxifan(一种对H3受体具有高亲和性的已知化合物)和不同浓度供试化合物培育60分钟。 Aliquots of the membrane suspension at 25 deg.] C and 30pM [125I] -iodoproxifan (a kind of H3 receptor having a high affinity for known compounds) and incubated at different concentrations of test compound for 60 minutes. 培育是这样终止的,用冰冷的培养基稀释,继之以迅速通过用0.5%聚乙烯亚胺预处理1小时的Whatman GF/B滤器过滤。 Cultivation is terminated, diluted with ice-cold medium, followed by rapidly pretreated one hour with 0.5% polyethyleneimine Whatman GF / B filter. 利用Cobra II自动γ计数器计数滤器上所保留的放射性。 Radioactivity retained on the filters counted using a Cobra II auto γ counter. 滤器的放射性与供试化合物的结合亲和性间接成比例。 Filter radioactivity binding affinity of the test compound is indirectly proportional. 借助非线性回归分析,分析结果。 With non-linear regression analysis and the results.

在测试时,本发明式(I)化合物一般对组胺H3受体显示高结合亲和性。 In testing, the compound of the invention of formula (I) according to the general histamine H3 receptor shows a high binding affinity.

优选地,正如一项或多项测定法所测定的,根据本发明的化合物的IC50值小于10μM,更优选小于1μM,进而更优选小于500nM,例如小于100nM。 Preferably, one or more assays, as measured, according to the present invention are compounds of the IC50 value of less than 10 M, more preferably less than [mu] M, and even more preferably less than 500 nM, such as less than 100nM.

功能测定法I采用表达人H3受体的HEK 293细胞的膜,借助体外功能测定法测定化合物与组胺H3受体相互作用、充当激动剂、反激动剂和/或拮抗剂的能力。 I functional assay using HEK 293 cells expressing the human H3 receptor membrane, of a compound to interact by means of the histamine H3 receptor in vitro functional assay, act as agonists, inverse agonists and / or antagonists capabilities.

借助PCR克隆H3受体,亚克隆至pcDNA3表达载体中。 H3 receptor was cloned by PCR and subcloned into pcDNA3 expression vector. 通过转染H3表达载体至HEK 293细胞中,并且使用G418选择H3克隆体,生成稳定表达H3受体的细胞。 H3 expression vectors into HEK 293 cells by transfection, using G418 selection and H3 clones were generated cells stably expressing the H3 receptor. 在37℃和5%CO2下,将人H3-HEK 293克隆体培养在含有glutamax、10%胎牛血清、1%青霉素/链霉抗生物素和1mg/mlG418的DMEM中。 At 37 [deg.] C and 5% CO2, the human H3-HEK 293 clones were cultured in 10% fetal calf serum, 1% penicillin / streptavidin and biotin DMEM containing glutamax 1mg / mlG418 in.

将H3受体表达细胞用磷酸盐缓冲盐水(PBS)洗涤一次,用Versene(GIBCO-BRL)收获。 The H3 receptor expressing cells are washed once with phosphate buffered saline (PBS), with Versene (GIBCO-BRL) were harvested. 加入PBS,将细胞在188g下离心5分钟。 Addition of PBS, the cells were centrifuged for 5 minutes at 188g. 将细胞吐弃块重新悬浮在刺激缓冲液中至浓度为1×106细胞/ml。 The discharge cells resuspended to a concentration of discarded blocks to 1 × 106 cells / ml in stimulation buffer. 利用FlashPlatecAMP测定法(NENTMLife Science Products)测量cAMP的蓄积。 By measuring cAMP accumulation assay FlashPlatecAMP (NENTMLife Science Products). 测定一般是如厂商所述进行的。 The assay is generally performed by the manufacturer. 简而言之,向Flashplate每孔加入50μl细胞悬液,其中还含有25μl 40μM异丙肾上腺素以刺激cAMP的生成,和25μl供试化合物(单独的激动剂或反激动剂,或者激动剂与拮抗剂的组合)。 Briefly, 50μl of cell suspension was added to each well Flashplate which also contained 25μl 40μM isoproterenol to stimulate cAMP generation, and 25 l of test compound (agonist or inverse agonists alone, or agonist and antagonist combination of agents). 测定可以按照“激动剂模式”进行,这意味着向细胞加入单独的递增浓度的供试化合物,测量cAMP。 It can be measured according to the "agonist mode", which means added to the cells in increasing concentrations of a single test compound, measuring cAMP. 如果cAMP上升,那么它是一种反激动剂;如果cAMP没有改变,那么它是一种中性拮抗剂;如果cAMP下降,那么它是一种激动剂。 If cAMP increase, it is an inverse agonist; if cAMP does not change, it is a neutral antagonist; if cAMP decreased, it is an agonist. 测定也可以按照“拮抗剂模式”进行,这意味着加入递增浓度的供试化合物以及递增浓度的已知H3激动剂(例如RAMHA)。 May be measured according to the "antagonist mode", which means that addition of increasing concentrations of the test compound, and increasing concentrations of a known H3 agonist (e.g. RAMHA). 如果化合物是一种拮抗剂,那么它的递增浓度导致H3激动剂剂量响应曲线向右偏移。 If the compound is an antagonist, increasing concentrations of it cause H3 agonist's dose-response curve shifted to the right. 每孔中的最终体积为100μl。 The final volume in each well was 100μl. 将供试化合物溶于DMSO,用H2O稀释。 Test compounds were dissolved in DMSO, and diluted with H2O. 将混合物摇动5分钟,在室温下放置25分钟。 The mixture was shaken for 5 minutes, and left at room temperature for 25 minutes. 用每孔100μl“检测混合物”终止反应。 100 l per well, "Detection Mix" the reaction was terminated. 然后将平板用塑料密封,摇动30分钟,放置过夜,最后在Cobra II自动γTop计数器中计数放射性。 The plate was then sealed with plastic, shaken for 30 minutes, allowed to stand overnight, and finally the radioactivity was counted in the Cobra II auto γTop counter. 利用GraphPad Prism,借助剂量响应曲线(最少6个点)的非线性回归分析计算EC50值。 Using GraphPad Prism, by means of dose response and EC50 values ​​calculated by nonlinear regression analysis curves (6 points minimum) a. 借助Schild图分析计算Kb值。 FIG. Analysis calculated by Schild value Kb.

功能测定法II借助名为[35S]GTPγS测定法的功能测定法测定化合物与人H3受体结合和相互作用、充当激动剂、反激动剂和/或拮抗剂的能力。 [35S] functional assay GTPγS assay of a compound to human H3 receptor binding interactions and act as agonists, inverse agonists and / or antagonist capability by functional assay II named. 该测定法通过催化α-亚单位上鸟苷5'-二磷酸(GDP)被鸟苷5'-三磷酸(GTP)置换,测量G蛋白的活化。 The assay is guanosine 5'-triphosphate (GTP) by guanosine substitution catalytic subunit of α- 5'-diphosphate (GDP), the measurement of G protein activation. 与GTP结合的G蛋白离解为两个亚单位,GαGTP和Gβγ,它们继而调节细胞内酶和离子通道。 GTP G protein binding to dissociate into two subunits, GαGTP and Gβγ, which in turn modulation of intracellular enzymes and ion channels. GTP被Gα亚单位(GTP酶)迅速水解,G蛋白失活,准备进入新的GTP置换周期。 The Gα subunit GTP (GTP enzyme) rapid hydrolysis, G protein inactivation, ready to enter a new GTP replacement cycle.

为了研究配体诱导的G蛋白偶联受体(GPCR)因G蛋白的鸟嘌呤核苷酸置换增加而活化的功能,测定了[35S]-鸟苷-5 '-O-(3-硫代)三磷酸[35S]GTPγS的结合,它是GTP的非水解类似物。 In order to study ligand-induced G protein coupled receptor (GPCR) due to the G protein guanine nucleotide substitutions increasing activation function, measured [35S] - guanosine -5 '-O- (3- thioxo ) triphosphate [35S] GTPγS binding, which is a non-hydrolyzable analog of GTP. 如下可以体外监测该过程,将含有G蛋白偶联受体H3的细胞膜与GDP和[35S]GTPγS培育。 The following procedure can be monitored in vitro, containing the G protein coupled receptor H3 with GDP and the cell membrane [35S] GTPγS cultivation. 细胞膜是从稳定表达人H3受体的CHO细胞获得的。 Cell membranes are obtained from CHO cells stably expressing the human H3 receptor. 将细胞用PBS洗涤两次,用PBS+1mM EDTA,pH7.4收获,在1000rpm下离心5分钟。 The cells were washed twice with PBS, with PBS + 1mM EDTA, pH7.4 were harvested, centrifuged for 5 minutes at 1000rpm. 利用Ultra-Turrax均质化器将细胞吐弃块在10ml冰冷的Hepes缓冲液(20mMHepes,10mM EDTA pH7.4(NaOH))中均质化30秒,在20,000rpm下离心15分钟。 Using Ultra-Turrax homogenizer Cells spurn block 10ml ice cold Hepes buffer (20mMHepes, 10mM EDTA pH7.4 (NaOH)) homogenized for 30 seconds, centrifuged for 15 minutes at 20,000rpm. 在该离心步骤之后,将膜吐弃块重新悬浮在10ml冰冷的Hepes缓冲液(20mM Hepes,0.1mM EDTA pH7.4(NaOH))中,如上所述均质化。 After this centrifugation step, the membrane was discarded blocks spit resuspended in 10ml of ice-cold Hepes buffer (20mM Hepes, 0.1mM EDTA pH7.4 (NaOH)), as described above homogenized. 该工艺重复两次,最后一次均质化步骤除外,测定蛋白质浓度,将膜稀释至蛋白质浓度为2mg/ml,等分,保存在-80℃下备用。 This process was repeated twice, except for the last homogenization step, the protein concentration was measured, the membrane was diluted to a protein concentration 2mg / ml, aliquoted and stored at -80 ℃ standby.

为了研究反激动剂/拮抗剂的存在和效力,加入H3受体激动剂配体R-α-甲基组胺(RAMHA)。 In order to study the presence and efficacy of inverse agonists / antagonists, H3 receptor agonist ligand was added R-α- methyl histamine (RAMHA). 测量供试化合物抵消RAMHA作用的能力。 RAMHA canceling ability of the test compound effect measurements. 在研究激动剂的作用时,不向测定介质加入RAMHA。 In studying the role of an agonist, RAMHA is not added to the assay medium. 将供试化合物在测定缓冲液(20mM HEPES,120mM NaCl,10mM MgCl2pH 7.4(NaOH))中稀释至不同浓度,继之以加入10-8nM RAMHA(仅在检查反激动剂/拮抗剂的情况下)、3μM GDP、2.5μg膜、0.5mg SPA珠粒和0.1nM[35S]GTPγS,在室温下轻微摇动培育2小时。 The test compounds in assay buffer (20mM HEPES, 120mM NaCl, 10mM MgCl2pH 7.4 (NaOH)) diluted to different concentrations, followed by (only in the inspection inverse agonist / antagonist the case) were added to 10-8nM RAMHA , 3μM GDP, 2.5μg film, 0.5mg SPA beads and 0.1nM [35S] GTPγS, incubated with gentle shaking at room temperature for 2 hours. 将平板在1500rpm下离心10分钟,利用Top计数器测量放射性。 The plates were centrifuged at 1500rpm for 10 minutes and radioactivity was measured using a Top counter. 借助非线性回归分析结果,测定IC50值。 By non-linear regression analysis, IC50 values ​​are determined.

RAMHA和其他H3激动剂刺激[35S]GTPγS与表达H3受体的膜的结合。 RAMHA and other H3 agonists stimulate [35S] GTPγS binding to membranes expressing the H3 receptor. 在拮抗剂/反激动剂试验中,测量递增量供试化合物抑制通过10-8MRAMHA增加[35S]GTPγS结合的能力,表现为放射性信号的减少。 In the antagonist / inverse agonist test, the measurement of increasing amounts of the test compound 10-8MRAMHA suppressed by increasing the [35S] GTPγS binding ability, reduce the performance of the radioactive signal. 所测定的拮抗剂IC50值是这种化合物抑制10-8M RAMHA作用达50%的能力。 Antagonist IC50 values ​​are determined such compounds inhibit the ability of 10-8M RAMHA by 50% effect. 在激动剂试验中,测量递增量供试化合物的能力,表现为放射性信号的增加。 In the agonist test, the ability to measure the increments of the test compound, manifested as an increase in radioactivity signal. 所测定的激动剂EC50值是这种化合物增加信号达10-5M RAMHA所得最大信号的50%的能力。 Agonist EC50 value measured is the ability of 10-5M RAMHA resultant signal maximum signal to 50% of such compounds increases.

优选地,正如一项或多项测定法所测定的,根据本发明的拮抗剂和激动剂的IC50/EC50值小于10μM,优选小于1μM,进而更优选小于500nM,例如小于100nM。 Preferably, one or more assays, as measured according to antagonists and agonists of the present invention, IC50 / EC50 value of less than 10 M, preferably less than [mu] M, and even more preferably less than 500 nM, such as less than 100nM.

开放笼子的计划饲喂大鼠模型利用体内开放笼子的计划饲喂大鼠模型测定本发明化合物减少体重的能力。 Determination of compounds of the invention ability to reduce the weight of the cage open plan model using rats fed vivo open cage plan fed rat model.

从Mφllegrd Breeding and Research Centre A/S(Denmark)购买Sprague-Dawley(SD)雄性大鼠,大小约1.5至2月龄,体重约200-250g。 Later Sprague-Dawley (SD) from Mφllegrd Breeding and Research Centre A / S (Denmark) male rats, a size of about 1.5 to 2 months of age, weighing about 200-250g. 在到达后,允许它们适应几天,然后放置在单独的开放的塑料笼子中。 After arrival, allowing them to adapt to a few days, and then placed in individual open plastic cages. 使它们习惯于每天食物(Altromin pelleted rat chow)在笼子中仅存在7个小时,从07.30至14.30,历时一周。 They are accustomed to the daily food (Altromin pelleted rat chow) there is only seven hours in the cage, from 07.30 to 14.30, which lasted a week. 水是自由获取的。 Water is freely available. 随着食物的消耗在7至9天后达到稳定,动物准备投入使用。 With the food consumed in 7-9 days to stabilize the animals ready for use.

每只动物仅用一次,以避免处置之间的延时效应。 Each animal only once, in order to avoid delay effect between disposal. 在试验期间,在开始前30分钟将化合物腹膜内或口服给药。 During the test, 30 minutes before the start of the compounds intraperitoneally or orally. 向一组动物给以不同剂量的供试化合物,向对照组动物给以载体。 Given different doses of test compounds to one group of animals, given vehicle to the control animals. 在给药后1、2和3小时监测食物和水的摄取。 Monitoring in food and water intake 1, 2 and 3 hours after dosing.

任何副作用都可以被迅速发现(桶状滚动、浓密的毛等),因为动物被限制在透明的塑料笼子中,能够进行连续的监测。 Any side effects can be quickly found (barrel-rolling, bushy hair, etc.), because the animal is confined in a transparent plastic cage, capable of continuous monitoring.

Claims (74)

1.通式(II)化合物: 1. Formula (II) compound: 其中R2是氢或C1-4-烷基,(i)R1代表·支链C4-6-烷基、支链C4-6-烯基或支链C4-6-炔基,其条件是R1不是异丁基,·C3-5-环烷基、C3-7-环烯基、C3-6-环烷基-C1-3-烷基或C3-6-环烯基-C1-3-烷基,·R1和R2一起构成C3-6-亚烷基桥,和A代表 Wherein R2 is hydrogen or C1-4- alkyl, (I) R1 · Representative branched C4-6- alkyl, C4-6- alkenyl group or branched-chain branched C4-6- alkynyl group, with the proviso that R1 is not isobutyl, · C3-5- cycloalkyl, C3-7- cycloalkenyl, C3-6- cycloalkyl or C3-6-cycloalkenyl group -C1-3- -C1-3- alkyl group , · R1 and R2 together form a C3-6- alkylene bridge, and A represents or 或者(ii)R1代表·乙基、正丙基或异丙基,·R1和R2一起构成C3-6-亚烷基桥,和A代表 Or (ii) R1 Representative ethyl, n-propyl or isopropyl, Rl and R2 together form-C3-6- alkylene bridge, and A represents or R3是氢、卤素、羟基、三氟甲基、三氟甲氧基、C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、芳基、芳基-C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷基、C3-8-环烷氧基、氰基、硝基、C1-6-烷硫基或C1-6-烷基磺酰基,Z和X独立地代表-N=、-C(H)=、-C(F)=、-C(Cl)=、-C(CN)=或-C(CF3)=,W代表-N=或-C(R10)=,Y代表-N=或-C(R11)=,R4、R5、R6、R7、R8、R9、R10、R11、R12和R13独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、-SCF3、氨基、氰基、硝基或-C(=O)NR14R15,·C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、C3-8-环烷基-C1-6-烷氧基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷氧基、C1-6-烷硫基、C1-6-烷基磺酰基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基、C4-9杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,· R3 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, C1-10- alkyl, C2-10- alkenyl, C3-8-cycloalkyl, C1-6-alkoxy, aryl group, an aryl group -C1-6- alkyl, amino, C1-6-alkylamino, di-alkylamino -C1-6-, C3-8-cycloalkyl, C3-8-cycloalkoxy, cyano , nitro, C1-6-alkylthio or C1-6-alkylsulphonyl group, Z and X independently represent -N =, - C (H) =, - C (F) =, - C (Cl ) =, - C (CN) =, or -C (CF3) =, W representatives -N = or -C (R10) =, Y representative of -N = or -C (R11) =, R4, R5, R6, R7 , R8, R9, R10, R11, R12 and R13 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, -SCF3, amino, cyano, nitro or -C (= O) NR14R15, · C1-10- alkyl, C2-10- alkenyl, C3-8- cycloalkyl, C1-6- alkoxy, C3-8- cycloalkyl -C1-6- alkoxy, C1 6-alkyl-amino, di-alkylamino -C1-6-, C3-8-cycloalkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, C2-10- alkyl group, C4-9- cycloalkyl group, a heterocyclic group or C3-8-heterocycloalkyl C4-9- alkanoyl, heterocyclic c4-9 alkoxy, which may optionally be substituted with one or more substituents selected from R16 substitution, · 基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基、杂芳酰基、芳氧基、杂芳氧基、芳基氨基或杂芳基氨基,它们可以可选地被一个或多个选自R18的取代基取代,·或者R5、R6、R7、R8、R9、R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥,R14和R15独立地是氢、C1-6-烷基、芳基-C1-6-烷基,或者R14和R15可以一起构成C3-6-亚烷基桥,R16独立地选自芳基、杂芳基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基、NR19R20和C1-6-烷氧基,R17独立地选自卤素、羟基、三氟甲基、三氟甲氧基、C1-6-烷氧基、C1-6-烷基、氨基、C1-6-烷基磺酰基、C1-6-烷基氨基、二-C1-6-烷基氨基、氰基、芳基、杂芳基和C3-8-环烷基,R18独立地选自芳基、杂芳基、C1-10-烷基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基 Group, an aryl group -C1-6- alkyl, -C1-6- alkoxy, aryl or heteroaryl group, which may optionally be substituted with one or more substituents selected from R17, - aroyl, heteroaryl aroyl, aryloxy, heteroaryloxy group, an aryl group or heteroaryl group, which may optionally be substituted with one or more substituents selected from R18, - or R5, R6, R7, R8, R9 , R10, R11, R12 and R13 in two adjacent positions together form a C1-6-alkylene bridge or -O- -O-C1-6- alkylene bridge, R14 and R15 independently are hydrogen, C1 6-alkyl-aryl group -C1-6- alkyl group, or R14 and R15 may constitute C3-6- alkylene bridge, R16 are independently selected from aryl, heteroaryl, C3-8-cycloalkyl together group, halo, trifluoromethyl, trifluoromethoxy, NR19R20 and C1-6-alkoxy, R17 are independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy alkoxy, C1-6-alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-alkylamino -C1-6-, cyano, aryl, heteroaryl and C3 -8-alkyl, R18 is independently selected from aryl, heteroaryl, C1-10- alkyl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy 、C1-6-烷氧基、氰基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基和羟基,R19和R20独立地是氢或C1-6-烷基,R19和R20可以一起构成C3-6-亚烷基桥,其条件是该化合物必须不是 , C1-6-alkoxy, cyano, amino, C1-6-alkylamino, di-alkylamino and hydroxy -C1-6-, R19 and R20 are independently hydrogen or C1-6-alkyl, R19 and R20 together constitute a C3-6- alkylene bridge, with the proviso that the compound must not be or 及其任意非对映体或对映体或互变形式、包括它们的混合物,或其药学上可接受的盐。 And any diastereomer or enantiomer or tautomeric form thereof including mixtures thereof, or a pharmaceutically acceptable salt thereof.
2.根据权利要求1的化合物,其中R1是支链C4-6-烷基、C3-5-环烷基或C3-6-环烷基-C1-3-烷基,其条件是R1不是异丁基。 2. A compound according to claim 1, wherein R1 is a branched C4-6- alkyl, C3-5- alkyl or C3-6- cycloalkyl -C1-3- cycloalkyl group, with the proviso that R1 is not isobutyl butyl.
3.根据权利要求2的化合物,其中R1是1,1-(二甲基)丙基、1-乙基丙基、环丙基甲基、环丙基、环丁基、环戊基或1-环丙基-1-甲基乙基。 3. A compound according to claim 2, wherein R1 is 1,1- (dimethyl) propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1 - cyclopropyl-1-methylethyl.
4.根据权利要求3的化合物,其中R1是1-乙基丙基、环丙基甲基、环丙基或环戊基。 4. A compound according to claim 3, wherein R1 is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.
5.根据权利要求1的化合物,其中R1是支链C4-6-烷基或C3-5-环烷基,其条件是R1不是异丁基。 5. A compound according to claim 1, wherein R1 is a branched C4-6- alkyl or C3-5- cycloalkyl, with the proviso that R1 is not isobutyl.
6.根据权利要求5的化合物,其中R1是1-乙基丙基、环丙基或环戊基。 6. A compound according to claim 5, wherein R1 is 1-ethylpropyl, cyclopropyl or cyclopentyl.
7.根据权利要求1至6任意一项的化合物,其中Z是-C(H)=、-N=或-C(F)=。 7. A compound according to any one of 1 to 6 claims, wherein Z is -C (H) =, - N = or -C (F) =.
8.根据权利要求7的化合物,其中Z是-C(H)=或-N=。 8. A compound according to claim 7, wherein Z is -C (H) = or -N =.
9.根据权利要求8的化合物,其中Z是-C(H)=。 9. A compound according to claim 8, wherein Z is -C (H) =.
10.根据权利要求8的化合物,其中Z是-N=。 10. The compound according to claim 8, wherein Z is -N =.
11.根据权利要求1至10任意一项的化合物,其中X是-C(H)=、-N=或-C(F)=。 11. A compound of any one of claims 1 to 10, wherein X is -C (H) =, - N = or -C (F) =.
12.根据权利要求11的化合物,其中Z是-C(H)=或-N=。 12. The compound according to claim 11, wherein Z is -C (H) = or -N =.
13.根据权利要求12的化合物,其中Z是-C(H)=。 13. The compound according to claim 12, wherein Z is -C (H) =.
14.根据权利要求12的化合物,其中Z是-N=。 14. The compound according to claim 12, wherein Z is -N =.
15.根据权利要求1至14任意一项的化合物,其中W是-N=。 15. A compound according to any one of claims 1 to 14, wherein W is -N =.
16.根据权利要求1至14任意一项的化合物,其中W是-C(R10)=。 16. A compound according to any one of claims 1 to 14, wherein W is -C (R10) =.
17.根据权利要求1至16任意一项的化合物,其中Y是-N=。 17. A compound according to any one of claims 1 to 16, wherein Y is -N =.
18.根据权利要求1至16任意一项的化合物,其中Y是-C(R11)=。 18. A compound according to any one of claims 1 to 16, wherein Y is -C (R11) =.
19.根据权利要求1至18任意一项的化合物,其中R2是氢。 19. The compound of any one of 1 to 18 claim, wherein R2 is hydrogen.
20.根据权利要求1至18任意一项的化合物,其中R2是C1-4-烷基。 20. The compound of any one of 1 to 18 claim, wherein R2 is C1-4- alkyl.
21.根据权利要求20的化合物,其中R2是甲基或乙基。 21. The compound according to claim 20, wherein R2 is methyl or ethyl.
22.根据权利要求1的通式(III)化合物 22. Formula according to claim 1, (III) a compound of claim 其中A和R3是如权利要求1所定义的。 Wherein A and R3 are as defined in claim.
23.根据权利要求1至22任意一项的化合物,其中R3是氢、卤素、羟基、三氟甲基、三氟甲氧基、C1-10-烷基、C1-6-烷氧基、芳基、芳基-C1-6-烷基、氨基、C3-8-环烷基、C3-8-环烷氧基、氰基或硝基。 22 23. A compound according to any one of claims, wherein R3 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, C1-10- alkyl, C1-6-alkoxy, aryl group, an aryl group -C1-6- alkyl, amino, C3-8-cycloalkyl, C3-8-cycloalkoxy, cyano or nitro.
24.根据权利要求2 3的化合物,其中R3是氢、卤素、羟基、三氟甲基、C1-10-烷基、C1-6-烷氧基、氰基或硝基。 24. A compound according to claim 23, wherein R3 is hydrogen, halo, hydroxy, trifluoromethyl, C1-10- alkyl, C1-6-alkoxy, cyano or nitro.
25.根据权利要求24的化合物,其中R3是氢、卤素、羟基、三氟甲基、C1-6-烷基或氰基。 25. The compound according to claim 24, wherein R3 is hydrogen, halo, hydroxy, trifluoromethyl, C1-6-alkyl or cyano.
26.根据权利要求25的化合物,其中R3是氢、卤素或C1-6-烷基。 26. The compound according to claim 25, wherein R3 is hydrogen, halo or C1-6- alkyl.
27.根据权利要求25的化合物,其中R3是氢或甲基。 27. The compound according to claim 25, wherein R3 is hydrogen or methyl.
28.根据权利要求1至27任意一项的化合物,其中R4、R5、R6、R7、R8和R9独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、-SCF3、氨基或氰基,·C1-10-烷基、C3-8-环烷基、C1-6-烷氧基、C3-8-环烷氧基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基、杂芳酰基、芳氧基、杂芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-烷基-O-桥。 28. A compound according to any one of claims 1 to 27, wherein R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, -SCF3, an amino group or a cyano group, · C1-10- alkyl, C3-8- cycloalkyl, C1-6- alkoxy, C3-8- cycloalkoxy, C2-10- alkyl group, C4-9- cycloalkyl alkanoyl, C3-8-C4-9- heterocyclyl or heterocycloalkyl group, which may optionally be substituted with one or more substituents selected from R16, - aryl, aryl alkyl -C1-6- group, aryl group or heteroaryl -C1-6- alkoxy group which may optionally be substituted with one or more substituents selected from R17, - aroyl, heteroaroyl, aryloxy, heteroaryloxy group which may optionally be substituted with one or more substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6- alkylene bridge or -O -C1-6- alkyl bridge -O-.
29.根据权利要求28的化合物,其中R4、R5、R6、R7、R8和R9独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、-SCF3或氰基,·C1-10-烷基、C1-6-烷氧基、C3-8-环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基或芳基-C1-6-烷基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基或芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-烷基-O-桥。 29. A compound according to claim 28, wherein R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, -SCF3, or a cyano group, a C1- -10- alkyl, C1-6-alkoxy, C3-8-cycloalkoxy group, which may optionally be substituted with one or more substituents selected from R16, aryl or aryl--C1- 6- alkyl, which may be optionally substituted with one or more substituents selected from R17, - aroyl or aryloxy, which may be optionally substituted with one or more substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6-alkylene bridge -O- or -O-C1-6- alkyl bridge.
30.根据权利要求28的化合物,其中R4、R5、R6、R7、R8和R9独立地代表·氢、卤素或氰基,·C1-10-烷基或C1-6-烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基或芳氧基,它们可以可选地被一个或多个选自R18的取代基取代,或者R5、R6、R7、R8、R9中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-烷基-O-桥。 30. The compound according to claim 28, wherein R4, R5, R6, R7, R8 and R9 independently represent · a hydrogen, halogen or cyano, · C1-10- alkyl or C1-6- alkoxy group, they may be optionally substituted with one or more substituents selected from R16, - aryl, optionally substituted with one or more substituents selected from R17, - aroyl or aryloxy, which may optionally be one or more substituents selected from R18, or R5, R6, R7, R8, R9 in two adjacent positions together form a C1-6-alkylene bridge or -O-C1-6- alkyl - O- bridge.
31.根据权利要求30的化合物,其中C1-10-烷基代表甲基、乙基、丙基或异丙基。 31. The compound according to claim 30, wherein C1-10- alkyl represents methyl, ethyl, propyl or isopropyl.
32.根据权利要求30的化合物,其中C1-6-烷氧基代表甲氧基、乙氧基或丙氧基。 32. A compound according to claim 30, wherein C1-6- alkoxy represents methoxy, ethoxy or propoxy.
33.根据权利要求32的化合物,其中C1-6-烷氧基代表甲氧基。 33. A compound according to claim 32, wherein C1-6- alkoxy represents methoxy.
34.根据权利要求30的化合物,其中芳基代表苯基。 34. A compound according to claim 30, wherein aryl represents phenyl.
35.根据权利要求30的化合物,其中芳酰基代表-C(=O)-苯基。 35. A compound according to claim 30, wherein aroyl Representative -C (= O) - phenyl.
36.根据权利要求30的化合物,其中芳氧基代表-O-苯基。 36. A compound according to claim 30, wherein the aryloxy group represents -O- phenyl.
37.根据权利要求1的化合物,其中R1是乙基或异丙基。 37. The compound according to claim 1, wherein R1 is ethyl or isopropyl.
38.根据权利要求37的化合物,其中R1是异丙基。 38. The compound according to claim 37, wherein R1 is isopropyl.
39.根据权利要求37的化合物,其中R1是乙基。 39. A compound according to claim 37, wherein R1 is ethyl.
40.根据权利要求39的化合物,其中R1和R2一起构成C3-4-亚烷基桥。 40. A compound according to claim 39, wherein R1 and R2 together form a C3-4- alkylene bridge.
41.根据权利要求37至40任意一项的化合物,其中R10、R11、R12和R13独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、氰基或-C(=O)NR14R15,·C1-10-烷基、C3-8-环烷基、C1-6-烷氧基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基、C4-9-杂环烷酰基、C4-9-杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 41.37-40 compound according to any one of claims, wherein R10, R11, R12 and R13 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano or -C (= O) NR14R15, · C1-10- alkyl, C3-8- cycloalkyl, C1-6- alkoxy, C2-10- alkyl group, C4-9- cycloalkyl group, C3-8- heterocyclyl , C4-9- heterocycloalkyl group, C4-9- alkoxy heterocycle, which may be optionally substituted with one or more substituents selected from R16, - aryl, aryl alkyl -C1-6- group, aryl group or heteroaryl -C1-6- alkoxy group which may optionally be substituted with one or more substituents selected from R17, - aroyl, optionally substituted with one or more substituents selected from R18 substituents, or R10, R11, R12 and R13 in two adjacent positions together form a C1-6- alkylene bridge.
42.根据权利要求41的化合物,其中R10、R11、R12和R13独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、氰基或-C(=O)NR14R15,·C1-10-烷基、C3-8-环烷基、C1-6-烷氧基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基、C4-9-杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 42. A compound according to claim 41, wherein R10, R11, R12 and R13 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano or -C (= O) NR14R15, · C1-10- alkyl, C3-8- cycloalkyl, C1-6- alkoxy, C2-10- alkyl group, C4-9- cycloalkyl group, C3-8- heterocyclyl or C4-9- heterocyclic alkanoyl, C4-9- alkoxy heterocycle, which may be optionally substituted with one or more substituents selected from R16, - aryl, -C1-6- alkyl group, an aryl group - C1-6- alkoxy, aryl or heteroaryl group, which may optionally be substituted with one or more substituents selected from R17, - aroyl, optionally substituted with one or more substituents selected from R18, or R10, R11, R12 and R13 in two adjacent positions together form a C1-6- alkylene bridge.
43.根据权利要求42的化合物,其中10、R11、R12和R13独立地代表·氢、卤素、三氟甲基或-C(=O)NR14R15,·C1-10-烷基、C1-6-烷氧基、C2-10-烷酰基、C4-9-环烷酰基、C4-9-杂环烷酰基或C4-9-杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基、芳基-C1-6-烷基或芳基-C1-6-烷氧基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 43. A compound according to claim 42, wherein 10, R11, R12 and R13 independently represent · a hydrogen, halo, trifluoromethyl, or -C (= O) NR14R15, · C1-10- alkyl, C1-6- alkoxy, C2-10- alkyl group, C4-9- cycloalkyl group, an alkoxy group or a heterocyclic C4-9- alkoxy C4-9- heterocyclyl, which may be optionally substituted with one or more substituents selected from substituents R16, - aryl, aryl alkyl or aryl -C1-6- -C1-6- alkoxy, which may optionally be substituted with one or more substituents selected from R17, - aroyl, optionally substituted with one or more substituents selected from R18, or R10, two R11, R12 and R13 in adjacent positions together form a C1-6- alkylene bridge.
44.根据权利要求43的化合物,其中R10、R11、R12和R13独立地代表·氢、卤素、三氟甲基或-C(=O)NR14R15,·C1-10-烷基或C4-9-杂环烷酰基,它们可以可选地被一个或多个选自R16的取代基取代,·芳基,可选地被一个或多个选自R17的取代基取代,·芳酰基,可选地被一个或多个选自R18的取代基取代,或者R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥。 44. The compound according to claim 43, wherein R10, R11, R12 and R13 independently represent · a hydrogen, halo, trifluoromethyl, or -C (= O) NR14R15, · C1-10- alkyl or C4-9- heterocyclic alkanoyl group, which may optionally be substituted with one or more substituents selected from R16, • aryl, optionally substituted with one or more substituents selected from R17, - aroyl, optionally substituted with one or more substituents selected from R18, or R10, R11, R12 and R13 in two adjacent positions together form a C1-6- alkylene bridge.
45.根据权利要求44的化合物,其中C1-10-烷基代表甲基、乙基或丙基。 45. The compound according to claim 44, wherein C1-10- alkyl represents methyl, ethyl or propyl.
46.根据权利要求44的化合物,其中C4-9-杂环烷酰基代表哌啶-烷酰基或吡咯烷-烷酰基。 46. ​​The compound according to claim 44, wherein the heterocyclic C4-9- alkanoyl piperidine Representative - alkanoyl or pyrrolidine - alkanoyl.
47.根据权利要求44的化合物,其中芳基代表苯基。 47. The compound according to claim 44, wherein aryl represents phenyl.
48.根据权利要求1至47任意一项的化合物,其中R14和R15独立地是甲基、乙基或苄基。 48. A compound according to any one of claims 1 to 47, wherein R14 and R15 are independently methyl, ethyl or benzyl.
49.根据权利要求1至48任意一项的化合物,其中R16是卤素、三氟甲基、三氟甲氧基和C1-6-烷氧基。 49. A compound according to any one of claims 1 to 48, wherein R16 is halo, trifluoromethyl, trifluoromethoxy and C1-6- alkoxy.
50.根据权利要求1至49任意一项的化合物,其中R17是卤素、羟基、三氟甲基、C1-6-烷氧基、C1-6-烷基、C1-6-烷基磺酰基或氰基。 50. A compound according to any one of claims 1 to 49, wherein R17 is halogen, hydroxy, trifluoromethyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl or cyano.
51.根据权利要求50的化合物,其中R17是卤素、三氟甲基、C1-6-烷氧基或C1-6烷基磺酰基。 51. A compound according to claim 50, wherein R17 is halo, trifluoromethyl, C1-6-alkoxy or C1-6 alkylsulfonyl.
52.根据权利要求1至51任意一项的化合物,其中R18是C1-10-烷基、卤素、三氟甲基、C1-6-烷氧基、氰基、氨基和羟基。 52. A compound according to any one of claims 1 to 51, wherein R18 is C1-10- alkyl, halo, trifluoromethyl, C1-6-alkoxy, cyano, amino and hydroxy.
53.根据权利要求52的化合物,其中R18是卤素、C1-6-烷氧基和羟基。 53. A compound according to claim 52, wherein R18 is halogen, C1-6-alkoxy and hydroxy.
54.根据在先权利要求1至53任意一项的化合物作为药物组合物的用途。 54. A compound according to any one of claims 1 to 53 the preceding claims as a pharmaceutical composition.
55.药物组合物,包含至少一种根据权利要求1至53任意一项的化合物作为活性成分、以及一种或多种药学上可接受的载体或赋形剂。 55. A pharmaceutical composition, comprising at least one compound of any one of claims 1 to 53 as an active ingredient, and one or more pharmaceutically acceptable carrier or excipient.
56.根据权利要求55的药物组合物,为单位剂型,包含约0.05mg至约1000mg、优选约0.1mg至约500mg、尤其优选约0.5mg至约200mg根据权利要求1至53任意一项的化合物。 56. A pharmaceutical composition according to claim 55, in unit dosage form, comprising from about 0.05mg to about lOOOmg, preferably about 0.1mg to about 500mg, especially preferably about 0.5mg to about 200mg 1 to 53 is a compound according to any one of claims .
57.通式(II')化合物 (II ') 57. A compound of formula 其中R2是氢或C1-4-烷基,R1代表·C1-8-烷基、C2-8-烯基或C2-8-炔基,它们可以可选地被一个或多个卤素取代基取代,·C3-5-环烷基、C3-7-环烯基、C3-6-环烷基-C1-3-烷基或C3-6-环烯基-C1-3-烷基,它们可以可选地被一个或多个卤素取代基取代,·R1和R2一起构成C3-6-亚烷基桥,A代表 Wherein R2 is hydrogen or a C1-4- alkyl group, R1 stands · C1-8- alkyl, C2-8- alkenyl or C2-8- alkynyl group which may optionally be substituted with one or more halogen substituents , · C3-5- cycloalkyl, C3_7-cycloalkenyl, C3-6-cycloalkyl or C3-6-cycloalkenyl group -C1-3- -C1-3- alkyl group, which may be optionally substituted with one or more halogen substituents substituted, · R1 and R2 together form a C3-6- alkylene bridge, a representatives or R3是氢、卤素、羟基、三氟甲基、三氟甲氧基、C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、芳基、芳基-C1-6-烷基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷基、C3-8-环烷氧基、氰基、硝基、C1-6-烷硫基或C1-6-烷基磺酰基,Z和X独立地代表-N=、-C(H)=、-C(F)=、-C(Cl)=、-C(CN)=或-C(CF3)=,W代表-N=或-C(R10)=,Y代表-N=或-C(R11)=,R4、R5、R6、R7、R8、R9、R10、R11、R12和R13独立地代表·氢、卤素、羟基、三氟甲基、三氟甲氧基、-SCF3、氨基、氰基、硝基或-C(=O)NR14R15,·C1-10-烷基、C2-10-烯基、C3-8-环烷基、C1-6-烷氧基、C3-8-环烷基-C1-6-烷氧基、C1-6-烷基氨基、二-C1-6-烷基氨基、C3-8-环烷氧基、C1-6-烷硫基、C1-6-烷基磺酰基、C2-10-烷酰基、C4-9-环烷酰基、C3-8-杂环基或C4-9-杂环烷酰基、C4-9-杂环烷氧基,它们可以可选地被一个或多个选自R16的取代基取代,· R3 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, C1-10- alkyl, C2-10- alkenyl, C3-8-cycloalkyl, C1-6-alkoxy, aryl group, an aryl group -C1-6- alkyl, amino, C1-6-alkylamino, di-alkylamino -C1-6-, C3-8-cycloalkyl, C3-8-cycloalkoxy, cyano , nitro, C1-6-alkylthio or C1-6-alkylsulphonyl group, Z and X independently represent -N =, - C (H) =, - C (F) =, - C (Cl ) =, - C (CN) =, or -C (CF3) =, W representatives -N = or -C (R10) =, Y representative of -N = or -C (R11) =, R4, R5, R6, R7 , R8, R9, R10, R11, R12 and R13 independently represent · a hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, -SCF3, amino, cyano, nitro or -C (= O) NR14R15, · C1-10- alkyl, C2-10- alkenyl, C3-8- cycloalkyl, C1-6- alkoxy, C3-8- cycloalkyl -C1-6- alkoxy, C1 6-alkyl-amino, di-alkylamino -C1-6-, C3-8-cycloalkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, C2-10- alkyl group, C4-9- cycloalkyl group, a heterocyclic group or C3-8-heterocycloalkyl C4-9- alkanoyl, heterocyclic C4-9- alkoxy, which may optionally be substituted with one or more substituents selected from R16 to substituted, · 基、芳基-C1-6-烷基、芳基-C1-6-烷氧基或杂芳基,它们可以可选地被一个或多个选自R17的取代基取代,·芳酰基、杂芳酰基、芳氧基、杂芳氧基、芳基氨基或杂芳基氨基,它们可以可选地被一个或多个选自R18的取代基取代,·或者R5、R6、R7、R8、R9、R10、R11、R12和R13中相邻位置的两个一起构成C1-6-亚烷基桥或-O-C1-6-亚烷基-O-桥,R14和R15独立地是氢、C1-6-烷基、芳基-C1-6-烷基,或者R14和R15可以一起构成C3-6-亚烷基桥,R16独立地选自芳基、杂芳基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧基、NR19R20和C1-6-烷氧基,R17独立地选自卤素、羟基、三氟甲基、三氟甲氧基、C1-6-烷氧基、C1-6-烷基、氨基、C1-6-烷基磺酰基、C1-6-烷基氨基、二-C1-6-烷基氨基、氰基、芳基、杂芳基和C3-8-环烷基,R18独立地选自芳基、杂芳基、C1-10-烷基、C3-8-环烷基、卤素、三氟甲基、三氟甲氧 Group, an aryl group -C1-6- alkyl, -C1-6- alkoxy, aryl or heteroaryl group, which may optionally be substituted with one or more substituents selected from R17, - aroyl, heteroaryl aroyl, aryloxy, heteroaryloxy group, an aryl group or heteroaryl group, which may optionally be substituted with one or more substituents selected from R18, - or R5, R6, R7, R8, R9 , R10, R11, R12 and R13 in two adjacent positions together form a C1-6-alkylene bridge or -O- -O-C1-6- alkylene bridge, R14 and R15 independently are hydrogen, C1 6-alkyl-aryl group -C1-6- alkyl group, or R14 and R15 may constitute C3-6- alkylene bridge, R16 are independently selected from aryl, heteroaryl, C3-8-cycloalkyl together group, halo, trifluoromethyl, trifluoromethoxy, NR19R20 and C1-6-alkoxy, R17 are independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy alkoxy, C1-6-alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-alkylamino -C1-6-, cyano, aryl, heteroaryl and C3 -8-alkyl, R18 is independently selected from aryl, heteroaryl, C1-10- alkyl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy 、C1-6-烷氧基、氰基、氨基、C1-6-烷基氨基、二-C1-6-烷基氨基和羟基,R19和R20独立地是氢或C1-6-烷基,R19和R20可以一起构成C3-6-亚烷基桥,及其任意非对映体或对映体或互变形式、包括它们的混合物,或其药学上可接受的盐在药物组合物制备中的用途,该药物组合物用于治疗涉及组胺H3受体的障碍和疾病。 , C1-6-alkoxy, cyano, amino, C1-6-alkylamino, di-alkylamino and hydroxy -C1-6-, R19 and R20 are independently hydrogen or C1-6-alkyl, R19 and R20 may together form a C3-6- alkylene bridge, and any non-enantiomeric forms or enantiomers or tautomers, pharmaceutically including mixtures thereof, or a pharmaceutically acceptable salt thereof in the manufacture of pharmaceutical compositions uses, the pharmaceutical compositions for the treatment of diseases and disorders related to the histamine H3 receptor.
58.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于治疗其中抑制H3组胺受体具有有益效果的疾病和障碍。 57 58. The use of a compound as defined in claim in the manufacture of a pharmaceutical composition, the pharmaceutical composition for treating a histamine H3 receptor inhibiting wherein the diseases and disorders having a beneficial effect.
59.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物具有组胺H3拮抗活性或组胺H3反激动活性。 59. The use of a compound as defined in claim 57 for the preparation of pharmaceutical compositions, the pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.
60.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于减少体重。 57 60. The use of a compound as defined in claim in the manufacture of a pharmaceutical composition, the pharmaceutical composition for reducing body weight.
61.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于治疗超重或肥胖。 61. The compound of claim 57 defined in the preparation of a pharmaceutical composition claims, the pharmaceutical composition for the treatment of overweight or obesity.
62.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于抑制食欲或诱发饱满感。 57 62. The use of a compound as defined in claim in the manufacture of a pharmaceutical composition, the pharmaceutical composition for suppressing appetite or inducing satiety.
63.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于预防和/或治疗涉及超重或肥胖的障碍和疾病。 57 63. The use of a compound as defined in claim in the manufacture of a pharmaceutical composition, the pharmaceutical composition for the prevention and / or treatment of overweight or obesity and diseases involving disorders.
64.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于预防和/或治疗进食障碍,例如食欲过盛和过食症。 57 64. The use of a compound as defined in claim in the manufacture of a pharmaceutical composition, the pharmaceutical composition for the prevention and / or treatment of eating disorders such as bulimia and bulimia.
65.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于治疗IGT。 57 65. The use of a compound as defined in claim in the manufacture of a pharmaceutical composition, the pharmaceutical composition for the treatment of IGT.
66.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于治疗2型糖尿病。 57 66. The use of a compound as defined in claim in the manufacture of a pharmaceutical composition, the pharmaceutical composition for the treatment of type 2 diabetes.
67.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于延缓或防止IGT发展为2型糖尿病。 57 67. The use of a compound as defined in claim in the manufacture of a pharmaceutical composition, the pharmaceutical composition for delaying or preventing the development of type 2 diabetes, IGT.
68.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于延缓或防止非胰岛素需求型2型糖尿病发展为胰岛素需求型2型糖尿病。 68. The compound of claim 57 defined in the preparation of a pharmaceutical composition claims, the pharmaceutical composition for delaying or preventing non-insulin requiring type 2 diabetes to insulin-requiring development of type 2 diabetes.
69.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于治疗其中刺激H3组胺受体具有有益效果的疾病和障碍。 57 69. The use of a compound as defined in claim in the manufacture of a pharmaceutical composition, the pharmaceutical composition for treating a histamine H3 receptor stimulation wherein the diseases and disorders having a beneficial effect.
70.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物具有组胺H3激动活性。 70. The use of a compound as defined in 57 the preparation of a pharmaceutical composition as claimed in claim, the pharmaceutical composition having histamine H3 agonistic activity.
71.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于治疗变应性鼻炎、溃疡或食欲缺乏。 71. The use of a compound as defined in 57 the preparation of a pharmaceutical composition as claimed in claim, the pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia.
72.如权利要求57所定义的化合物在药物组合物制备中的用途,该药物组合物用于治疗阿尔茨海默氏病、嗜眠症或注意涣散症。 72. The compound of claim 57 defined in the preparation of a pharmaceutical composition claims, the pharmaceutical composition for treating Alzheimer's disease, narcolepsy or attention deficit disorder.
73.治疗涉及H3组胺受体的障碍或疾病的方法,该方法包括在需要时对受治疗者给以有效量的如权利要求57所定义的化合物或者根据权利要求55或56的药物组合物。 73. A method of treating a disease or disorder involving H3 histamine receptor, the method comprising when desired compound 57 as defined in the claimed subject given effective amount of a composition or a medicament according to claim 55 or claim 56, .
74.根据权利要求73的方法,其中化合物的有效量为每天约0.05mg至约2000mg、优选约0.1mg至约1000mg、尤其优选约0.5mg至约500mg。 74. The method according to claim 73, wherein the effective amount of the compound is from about 0.05mg to about 2000mg per day, preferably about 0.1mg to about lOOOmg, especially preferably from about 0.5mg to about 500mg.
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