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CN1404471A - Substituted piperazine compounds - Google Patents

Substituted piperazine compounds Download PDF

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Publication number
CN1404471A
CN1404471A CN01805442A CN01805442A CN1404471A CN 1404471 A CN1404471 A CN 1404471A CN 01805442 A CN01805442 A CN 01805442A CN 01805442 A CN01805442 A CN 01805442A CN 1404471 A CN1404471 A CN 1404471A
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alkyl
hydrogen
halogen
aryl
compound
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杰夫·扎布沃茨基
埃费提·埃尔策英
格雷戈里·努德尔曼
蒂姆·马夸特
瓦布赫沃·瓦尔黑德卡
卜拉布罕·N·易卜拉欣
文卡塔·P·帕列
布伦特·K·布莱克本
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Gilead Palo Alto Inc
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CV Therapeutics Inc
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Abstract

Novel compounds of the general formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein the compounds are useful in therapy to protect skeletal muscles against damage resulting from trauma or to protect skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, in the treatment of cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.

Description

取代的哌嗪化合物Substituted piperazine compounds

发明的背景技术Background Art of the Invention

本申请要求申请日为2000年2月22日的美国专利申请60/184182，60/184457，申请日为2000年2月22日的申请60/184457，申请日为2000年5月23日的申请60/206396，申请日为2000年2月22日的申请60/184306，以及申请日为2000年6月5日的美国专利申请60/209262为优先权，其说明书插入此引作参考。This application claims U.S. Patent Application 60/184,182, filed February 22, 2000, 60/184,457, application 60/184,457, filed February 22, 2000, application, filed May 23, 2000 60/206,396, application 60/184,306, filed February 22, 2000, and US Patent Application 60/209,262, filed June 5, 2000, the specifications of which are incorporated herein by reference.

1.发明领域1. Field of invention

本发明涉及一种取代哌嗪化合物，包含一种或多种化合物的治疗剂，以及治疗哺乳动物疾病的方法，特别是，在人类中进行以下种类疾病的治疗：保护骨骼肌抵抗由创伤导致的损伤，保护肌肉性或全身性疾病如间歇性跛行之后的骨骼肌，治疗休克疾病，保护用于移植中的供体组织和器官，和治疗包括心房和心室心律不齐的心血管疾病，Prinzmetal氏(变异)绞痛，稳定绞痛，和运动导致的绞痛，充血性心脏病，以及心肌梗塞。The present invention relates to a substituted piperazine compound, a therapeutic agent comprising one or more compounds, and a method of treating a disease in a mammal, in particular, in a human being of the type that protects skeletal muscle against damage caused by trauma Injury, protection of skeletal muscle following muscular or systemic disorders such as intermittent claudication, treatment of shock disorders, protection of donor tissues and organs for transplantation, and treatment of cardiovascular disease including atrial and ventricular arrhythmias, Prinzmetal's (Variants) colic, stable colic, and exercise-induced colic, congestive heart disease, and myocardial infarction.

2.现有技术2. Existing technology

美国专利4,567,264，其说明书插入此引作参考，其中公开了一类包括已知化合物雷诺嗪，即(±)-N-(2，6-二甲基苯基)-4-[2-羟基-3-(2-甲氧基苯氧基)-丙基]-1-哌嗪乙酰胺的取代哌嗪化合物，其药用盐，以及它们在治疗心血管疾病，包括心律不齐，变异和运动导致的绞痛，和心肌梗塞中的应用。U.S. Patent No. 4,567,264, the specification of which is hereby incorporated by reference, discloses a class comprising the known compound ranolazine, namely (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy- Substituted piperazine compounds of 3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide, pharmaceutically acceptable salts thereof, and their use in the treatment of cardiovascular diseases, including arrhythmia, variability and exercise Causes of colic, and application in myocardial infarction.

美国专利5,506,229，其说明书插入此引作参考，其中公开了雷诺嗪及其药用盐和酯在治疗经历物理或化学损伤的组织，包括心脏麻醉，氧不足，或再灌注对心脏或骨骼肌或脑组织的损伤，以及在移植的组织中的用途。特别是，通过部分抑制心脏脂肪酸的氧化，雷诺嗪具体可用于治疗心律不齐，变异和运动导致的绞痛和心肌梗塞。该专利还公开了常规的口服和非肠道型雷诺嗪制剂，包括控释制剂。特别地，美国专利5,506,229中实施例7D描述了胶囊形式的控释制剂，该制剂包含雷诺嗪微球和用于控制释放的聚合物的包衣微晶纤维素。U.S. Patent 5,506,229, the specification of which is incorporated herein by reference, discloses that ranolazine and its pharmaceutically acceptable salts and esters are useful in the treatment of tissues undergoing physical or chemical damage, including cardiac anesthesia, hypoxia, or reperfusion to the heart or skeletal muscle or Damage to brain tissue, and use in transplanted tissue. In particular, by partially inhibiting the oxidation of cardiac fatty acids, ranolazine is specifically useful in the treatment of arrhythmias, arrhythmias, and exercise-induced angina and myocardial infarction. The patent also discloses conventional oral and parenteral formulations of ranolazine, including controlled release formulations. In particular, Example 7D of US Pat. No. 5,506,229 describes a controlled release formulation in the form of a capsule comprising ranolazine microspheres and coated microcrystalline cellulose with a polymer for the controlled release.

尽管雷诺嗪作为非常有用的心血管治疗剂是一重大发现，但仍然需要发现具有比雷诺嗪更长的半衰期并且至少具有与雷诺嗪类似活性的，作为部分脂肪酸氧化抑制剂的化合物。Although ranolazine is a significant discovery as a very useful cardiovascular therapeutic agent, there remains a need to find compounds that have a longer half-life than ranolazine and have at least similar activity to ranolazine as partial fatty acid oxidation inhibitors.

发明概述Summary of the invention

本发明包括新的取代哌嗪化合物，该化合物是部分脂肪酸氧化抑制剂且具有很好的治疗半衰期。The present invention encompasses novel substituted piperazine compounds that are partial fatty acid oxidation inhibitors and have a good therapeutic half-life.

本发明也包括新的取代哌嗪化合物，该化合物可以给药于哺乳动物，以保护骨骼肌抵抗创伤导致的损伤，保护肌肉或全身性疾病如间歇性跛行之后的骨骼肌，治疗休克疾病，保护用于移植中的供体组织和器官，和治疗心血管疾病包括心房和心室心律不齐，Prinzmetal氏(变异)绞痛，稳定绞痛，和运动导致的绞痛，充血性心脏病，以及心肌梗塞。The present invention also includes novel substituted piperazine compounds that can be administered to mammals to protect skeletal muscle against trauma-induced damage, to protect skeletal muscle after muscular or systemic diseases such as intermittent claudication, to treat shock disease, to protect For use in donor tissues and organs in transplantation, and in the treatment of cardiovascular disease including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise-induced angina, congestive heart disease, and myocardial infarction.

本发明包括一类具有下列结构式的取代哌嗪化合物：

Figure A0180544200291
其中X选自下列基团：
Figure A0180544200292
和 The present invention includes a class of substituted piperazine compounds having the following structural formula:
Figure A0180544200291
Wherein X is selected from the following groups:
Figure A0180544200292
and

其中m＝1或2或3；where m=1 or 2 or 3;

R1，R2，R3，R4和R5各自独立地选自：氢，卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22，SO2R22，SO2N(R23)2，NR23CO2R22，NR23CON(R23)2，COR23，CO2R23，CON(R23)2，NR23SO2R22，C1-15烷基，C2-15烯基，C2-15炔基，杂环基，芳基，和杂芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22和SO2R22，其中R2和R3可以连接在一起形成具有3至4个碳原子的稠合环系，且R4和R5可以连接在一起形成-CH＝CH-CH＝CH-；R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from: hydrogen, halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one Substituents selected from the following substituents: halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 and SO 2 R 22 , wherein R 2 and R 3 can be linked together to form a fused ring system having 3 to 4 carbon atoms, and R and R may be linked together to form -CH=CH-CH=CH-;

R6，R7和R8各自独立地选自氢和C1-15烷基；R 6 , R 7 and R 8 are each independently selected from hydrogen and C 1-15 alkyl;

R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢，CO2R23，CON(R23)2，C1-4烷基，以及芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，CF3，CN，OR23，N(R23)2，CO2R23，CON(R23)2和芳基，其中R9和R10可以一起形成羰基，或R11和R12可以一起形成羰基，或R13和R14可以一起形成羰基，或R15和R16可以一起形成羰基，其中R11和R13，R9和R15，R9和R11，R11和R15，或R9和R13可以连接在一起形成具有1-4个碳原子的桥环系，且其中R9和R10，R11和R12，R13和R14或R15和R16可以连接在一起形成具有1-5个碳原子的桥环系。R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, CO 2 R 23 , CON(R 23 ) 2 , C 1-4 alkyl, and Aryl, wherein the alkyl and aryl substituents may be optionally substituted with one substituent selected from the group consisting of halogen, CF 3 , CN, OR 23 , N(R 23 ) 2 , CO 2 R 23 , CON(R 23 ) 2 and aryl, wherein R 9 and R 10 can form a carbonyl together, or R 11 and R 12 can form a carbonyl together, or R 13 and R 14 can form a carbonyl together, or R 15 and R 16 can form a carbonyl together, Wherein R 11 and R 13 , R 9 and R 15 , R 9 and R 11 , R 11 and R 15 , or R 9 and R 13 can be joined together to form a bridged ring system with 1-4 carbon atoms, and wherein R 9 and R 10 , R 11 and R 12 , R 13 and R 14 or R 15 and R 16 can be linked together to form a bridged ring system with 1-5 carbon atoms.

R22选自C1-15烷基，芳基，和杂芳基，其中烷基和芳基取代基可任选被1个选自卤素，烷基，单烷基氨基，二烷基氨基，烷基酰氨基，芳基酰氨基，杂芳基酰氨基，CN，O-C1-6烷基，CF3，以及杂芳基的取代基取代；R 22 is selected from C 1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one selected from halogen, alkyl, monoalkylamino, dialkylamino, Alkylamido, arylamido, heteroarylamido, CN, OC 1-6 alkyl, CF 3 , and substituents of heteroaryl;

R23选自H，C1-15烷基，芳基，以及杂芳基，其中烷基和芳基取代基可任选被1个选自卤素，烷基，单烷基氨基，二烷基氨基，烷基，CN，O-C1-6烷基和CF3的取代基取代；且R 23 is selected from H, C 1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one selected from halogen, alkyl, monoalkylamino, dialkyl Amino, alkyl, CN, OC 1-6 alkyl, and CF 3 substituents; and

R24选自烷基，环烷基，和稠合的苯基环烷基，其中连接点在环烷基上，其中烷基，环烷基，和稠合的苯基环烷基可任选被1个至3个选自下列的取代基取代：卤素，CF3，CN，OR20，SR20，S(O)R22，SO2R22，SO2N(R20)2，NR20CO2R22，C1-2烷基，以及芳基，其中芳基取代基可任选被1至3个选自卤素，苯基，CF3，CN，OR20，和C1-6烷基的取代基取代，以及 R is selected from alkyl, cycloalkyl, and fused phenylcycloalkyl, wherein the point of attachment is on the cycloalkyl, wherein alkyl, cycloalkyl, and fused phenylcycloalkyl can be optionally Substituted with 1 to 3 substituents selected from the group consisting of halogen, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , C 1-2 alkyl, and aryl, wherein the aryl substituent can be optionally replaced by 1 to 3 members selected from halogen, phenyl, CF 3 , CN, OR 20 , and C 1-6 alkane Substituent substitution of the group, and

其中R17，R18，R19，R20，和R21独立地选自氢，卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22，SO2R22，SO2N(R23)2，NR23CO2R22，NR23CON(R23)2，COR23，CO2R23，CON(R23)2，NR23SO2R22，C1-15烷基，C2-15烯基，C2-15炔基，杂环基，芳基，和杂芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22和SO2R22。wherein R 17 , R 18 , R 19 , R 20 , and R 21 are independently selected from hydrogen, halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one Substituents selected from the group consisting of: halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 and SO 2 R 22 .

在另外一个方案中，本发明提供了一给哺乳动物服用一种或多种本发明组合物用于下列治疗的方法：保护骨骼肌抵抗创伤导致的损伤，保护肌肉或全身性疾病如间歇性跛行之后的骨骼肌，治疗休克疾病，保护用于移植中的供体组织和器官，和治疗包括心房和心室心律不齐，Prinzmetal氏(变异)绞痛，稳定绞痛，和运动导致的绞痛，充血性心脏病，和心肌梗塞的心血管疾病。本发明的详细说明In another aspect, the present invention provides a method of administering to a mammal one or more compositions of the present invention for the treatment of: protection of skeletal muscle against damage caused by trauma, protection of muscle or systemic diseases such as intermittent claudication subsequent skeletal muscle, treatment of shock disease, protection of donor tissues and organs for transplantation, and treatment including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise-induced angina, Congestive heart disease, and cardiovascular disease of myocardial infarction. Detailed Description of the Invention

本发明包括一类具有下列结构式的取代哌嗪化合物：

Figure A0180544200311
其中X选自：和
Figure A0180544200313
The present invention includes a class of substituted piperazine compounds having the following structural formula:
Figure A0180544200311
where X is selected from: and
Figure A0180544200313

其中m＝1或2或3；where m=1 or 2 or 3;

R1，R2，R3，R4和R5各自独立地选自：氢，卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22，SO2R22，SO2N(R23)2，NR23CO2R22，NR23CON(R23)2，COR23，CO2R23，CON(R23)2，NR23SO2R22，C1-15烷基，C2-15烯基，C2-15炔基，杂环基，芳基，和杂芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22和SO2R22，其中R2和R3可以连接在一起形成具有3至4个碳原子的稠合环系，且其中R4和R5可以连接在一起形成-CH＝CH-CH＝CH-；R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from: hydrogen, halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one Substituents selected from the following substituents: halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 and SO 2 R 22 , wherein R 2 and R 3 can be linked together to form a fused ring system having 3 to 4 carbon atoms, and wherein R and R may be linked together to form -CH=CH-CH=CH-;

R6，R7和R8各自独立地选自氢和C1-15烷基；R 6 , R 7 and R 8 are each independently selected from hydrogen and C 1-15 alkyl;

R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢，CO2R23，CON(R23)2，C1-4烷基，和芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，CF3，CN，OR23，N(R23)2，CO2R23，CON(R23)2和芳基，其中R9和R10可以一起形成羰基，或R11和R12可以一起形成羰基，或R13和R14可以一起形成羰基，或R15和R16可以一起形成羰基，其中R11和R13、R9和R15、R9和R11、R11和R15，或R9和R13可以连接在一起形成具有1-4个碳原子的桥环系，且其中R9和R10、R11和R12、R13和R14，或R15和R16可以连接在一起形成具有1-5个碳原子的桥环系。R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, CO 2 R 23 , CON(R 23 ) 2 , C 1-4 alkyl, and Aryl, wherein the alkyl and aryl substituents may be optionally substituted with one substituent selected from the group consisting of halogen, CF 3 , CN, OR 23 , N(R 23 ) 2 , CO 2 R 23 , CON(R 23 ) 2 and aryl, wherein R 9 and R 10 can form a carbonyl together, or R 11 and R 12 can form a carbonyl together, or R 13 and R 14 can form a carbonyl together, or R 15 and R 16 can form a carbonyl together, wherein R 11 and R 13 , R 9 and R 15 , R 9 and R 11 , R 11 and R 15 , or R 9 and R 13 can be joined together to form a bridged ring system with 1-4 carbon atoms, and wherein R 9 and R 10 , R 11 and R 12 , R 13 and R 14 , or R 15 and R 16 can be linked together to form a bridged ring system with 1-5 carbon atoms.

R22选自C1-15烷基，芳基，和杂芳基，其中烷基和芳基取代基可任选被1个选自卤素，烷基，单烷基氨基，二烷基氨基，烷基酰氨基，芳基酰氨基，杂芳基酰氨基，CN，O-C1-6烷基，CF3，以及杂芳基的取代基取代；R 22 is selected from C 1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one selected from halogen, alkyl, monoalkylamino, dialkylamino, Alkylamido, arylamido, heteroarylamido, CN, OC 1-6 alkyl, CF 3 , and substituents of heteroaryl;

R23选自H，C1-15烷基，芳基，以及杂芳基，其中烷基和芳基取代基可任选被1个选自卤素，烷基，单烷基氨基，二烷基氨基，烷基，CN，O-C1-6烷基和CF3的取代基取代；且R 23 is selected from H, C 1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one selected from halogen, alkyl, monoalkylamino, dialkyl Amino, alkyl, CN, OC 1-6 alkyl, and CF 3 substituents; and

R24选自烷基，环烷基，以及稠合的苯基环烷基，其连接点在环烷基上；其中烷基，环烷基，和稠合的苯基环烷基可任选被1个至3个选自下列的取代基取代：卤素，CF3，CN，OR20，SR20，S(O)R22，SO2R22，SO2N(R20)2，NR20CO2R22，C1-2烷基，以及芳基，该芳基取代基可任选被1至3个选自卤素，苯基，CF3，CN，OR20，以及C1-6烷基的取代基所取代，以及下式的 R 24 is selected from alkyl, cycloalkyl, and fused phenylcycloalkyl, and its point of attachment is on the cycloalkyl; wherein alkyl, cycloalkyl, and fused phenylcycloalkyl can be optionally Substituted with 1 to 3 substituents selected from the group consisting of halogen, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , C 1-2 alkyl, and aryl, the aryl substituent may optionally be 1 to 3 selected from halogen, phenyl, CF 3 , CN, OR 20 , and C 1-6 alkane The substituent of the group is substituted, and the following formula

其中R17，R18，R19，R20，和R21各自独立地选自氢，卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22，SO2R22，SO2N(R23)2，NR23CO2R22，NR23CON(R23)2，COR23，CO2R23，CON(R23)2，NR23SO2R22，C1-15烷基，C2-15烯基，C2-15炔基，杂环基，芳基，以及杂芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22和SO2R22。wherein R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from hydrogen, halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O) R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can optionally be One substituent selected from the group consisting of halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 and SO 2 R 22 .

本发明也包括具有下式(IA)结构式的上述式I中定义的一类取代哌嗪化合物的子集： The present invention also includes a subset of the class of substituted piperazine compounds defined in Formula I above having the following structural formula (IA):

其中m＝1，2；where m=1,2;

R1，R2，R3，R4和R5各自独立地选自：氢，卤素，CF3，OR22和C1-4烷基且其中R22是C1-3烷基；R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from: hydrogen, halogen, CF 3 , OR 22 and C 1-4 alkyl and wherein R 22 is C 1-3 alkyl;

R6，R7和R8各自独立地选自氢和C1-3烷基；R 6 , R 7 and R 8 are each independently selected from hydrogen and C 1-3 alkyl;

R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢，C1-4烷基，或R9和R10可以一起形成羰基，或R11和R12可以一起形成羰基，或R13和R14可以一起形成羰基，或R15和R16可以一起形成羰基，其中R11和R13、R9和R15、R9和R11、R11和R15，或R9和R13可以连接在一起形成桥环系，其中两个R基团一起包含1至4个碳原子，条件是R9，R10，R11，R12，R13，R14，R15和R16不同时为氢。R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, C 1-4 alkyl, or R 9 and R 10 may together form a carbonyl group, or R 11 and R 12 can form a carbonyl group together, or R 13 and R 14 can form a carbonyl group together, or R 15 and R 16 can form a carbonyl group together, wherein R 11 and R 13 , R 9 and R 15 , R 9 and R 11 , R 11 and R 15 , or R 9 and R 13 may be joined together to form a bridged ring system in which the two R groups together contain 1 to 4 carbon atoms, provided that R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are not simultaneously hydrogen.

R17，R18，R19，R20，和R21各自独立地选自氢，卤素，CF3，CN，OR22，S(O)R22，SO2R22，SON(R22)2，CON(R22)2，C1-4烷基，其中R22是C1-3烷基，或R17和R18一起形成-CH＝CH-CH＝CH-，或R18和R19可以一起形成-OCH2O-。R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from hydrogen, halogen, CF 3 , CN, OR 22 , S(O)R 22 , SO 2 R 22 , SON(R 22 ) 2 , CON(R 22 ) 2 , C 1-4 alkyl, wherein R 22 is C 1-3 alkyl, or R 17 and R 18 together form -CH=CH-CH=CH-, or R 18 and R 19 can together form -OCH 2 O-.

在更优选的式IA化合物中，R1，R2，R3，R4和R5各自独立地选自氢，卤素，CF3，OR22和C1-4烷基，其中R22是C1-3烷基；R6选自氢和甲基；R7，R8，R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢和甲基，或R9和R10一起形成羰基，或R13和R14一起形成羰基，条件是R9，R10，R11，R12，R13，R14，R15和R16不同时为氢；R17，R18，R19，R20和R21各自独立地选自氢，卤素，CF3，OR22，C1-3烷基，其中R22是C1-3烷基，或R17和R18一起形成-CH＝CH-CH＝CH-，或R18和R19可以一起形成-OCH2O-。In more preferred compounds of formula IA, R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, halogen, CF 3 , OR 22 and C 1-4 alkyl, wherein R 22 is C 1-3 alkyl; R 6 is selected from hydrogen and methyl; R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and methyl, or R 9 and R 10 together form a carbonyl group, or R 13 and R 14 together form a carbonyl group, provided that R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 do not Simultaneously hydrogen; R 17 , R 18 , R 19 , R 20 and R 21 are each independently selected from hydrogen, halogen, CF 3 , OR 22 , C 1-3 alkyl, wherein R 22 is C 1-3 alkyl , or R 17 and R 18 together form -CH=CH-CH=CH-, or R 18 and R 19 may together form -OCH 2 O-.

在还更优选的式IA化合物中，R1，R2，R3，R4，R5，R6，R7和R8各自独立地选自甲基和氢；R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢和甲基，或R9和R10一起形成羰基，或R13和R14一起形成羰基，条件是R9，R10，R11，R12，R13，R14，R15和R16不同时为氢；R17，R18，R19，R20和R21各自独立地选自氢，卤素，CF3，OR22，其中R22是甲基，甲基，或R17和R18一起形成-CH＝CH-CH＝CH-，或R18和R19可以一起形成-OCH2O-。In still more preferred compounds of formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from methyl and hydrogen; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and methyl, or R 9 and R 10 together form a carbonyl group, or R 13 and R 14 together form a carbonyl group, provided that R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are not simultaneously hydrogen; R 17 , R 18 , R 19 , R 20 and R 21 are each independently selected from hydrogen, halogen, CF 3 , OR 22 , wherein R 22 is methyl, methyl, or R 17 and R 18 together form -CH=CH-CH=CH-, or R 18 and R 19 together form -OCH 2 O-.

在进一步优选的式IA化合物中，R1和R5都为甲基，R2，R3，R4，R6，R7，R8都为氢；R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢和甲基，或R9和R10一起形成羰基，或R13和R14一起形成羰基，条件是R9，R10，R11，R12，R13，R14，R15和R16不同时为氢；R17，R18，R19，R20和R21各自独立地选自氢，卤素，甲基，OR22，其中R22是甲基，或R17和R18一起形成-CH＝CH-CH＝CH-，或R18和R19可以一起形成-OCH2O-。In a further preferred compound of formula IA, R 1 and R 5 are methyl, R 2 , R 3 , R 4 , R 6 , R 7 , R 8 are all hydrogen; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and methyl, or R 9 and R 10 together form a carbonyl group, or R 13 and R 14 together form a carbonyl group, provided that R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are not simultaneously hydrogen; R 17 , R 18 , R 19 , R 20 and R 21 are each independently selected from hydrogen, halogen, methyl, OR 22 , wherein R 22 is methyl, or R 17 and R 18 together form -CH=CH-CH=CH-, or R 18 and R 19 can form together -OCH 2 O-.

在还进一步优选的式IA化合物中，R1和R5都为甲基，R2，R3，R4，R6，R7，R8都为氢；R9，R10选自氢，甲基或一起形成羰基；R11和R12选自氢和甲基；R13和R14选自氢和甲基或一起形成羰基；R15和R16为氢，条件是R9，R10，R11，R12，R13，R14，R15和R16不同时为氢；R17选自氢，氯，氟或甲氧基；R18和R19分别选自氢和甲氧基，或R18和R19可以一起形成-OCH2O-，或R17和R18一起形成-CH＝CH-CH＝CH-；R20是氢；且R21选自氢或氯。In still further preferred compounds of formula IA, R 1 and R 5 are methyl, R 2 , R 3 , R 4 , R 6 , R 7 , R 8 are all hydrogen; R 9 , R 10 are selected from hydrogen, Methyl or together form a carbonyl; R11 and R12 are selected from hydrogen and methyl; R13 and R14 are selected from hydrogen and methyl or together form a carbonyl; R15 and R16 are hydrogen, provided that R9 , R10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are not hydrogen at the same time; R 17 is selected from hydrogen, chlorine, fluorine or methoxy; R 18 and R 19 are respectively selected from hydrogen and methoxy , or R 18 and R 19 may together form -OCH 2 O-, or R 17 and R 18 together form -CH=CH-CH=CH-; R 20 is hydrogen; and R 21 is selected from hydrogen or chlorine.

最优选地，式IA的取代哌嗪化合物选自：N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-3-氧哌嗪基}乙酰胺，N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-3，5-二甲基哌嗪基}乙酰胺，2-{(5S，2R)-4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-2，5-二甲基哌嗪基}-N-(2，6-二甲基苯基)乙酰胺，2-{2，5-二氮杂-5-[2-羟基-3-(2-甲氧基苯氧基)丙基]双环[4.4.0]癸-2-基}-N-(2，6-二甲基苯基)乙酰胺，N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-3-氧哌嗪基}乙酰胺，N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-3，3-二甲基哌嗪基}乙酰胺，2-{5-[(2S)-2-羟基-3-(2-甲氧基苯氧基)丙基](1S，4S)-2，5-二氮杂双环[2.2.1]庚-2-基}-N-(2，6-二甲基苯基)乙酰胺，N-(2，6-二甲基苯基)-2-{4-[2-羟基-4-(2-甲氧基苯氧基)丁基]-哌嗪基}乙酰胺，N-(2，6-二甲基苯基)-2-{4-[4-(4-氟苯氧基)-2-羟基丁基]-哌嗪基}乙酰胺，2-(4-{4-[4-(叔丁基)苯氧基)-2-羟基丁基]哌嗪基}-N-(2，6-二甲基苯基)乙酰胺，N-(2，6-二甲基苯基)-2-{4-[2-羟基-4-(4-苯基苯氧基)丁基]哌嗪基}乙酰胺，N-(2，6-二甲基苯基)-2-{4-[2-羟基-4-(4-甲氧基苯氧基)丁基]-哌嗪基}乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(2，6-二甲基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(2，6-二氯苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-氨磺酰基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(5-甲氧基-3-(三氟甲基)苯基]乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-茚满-5-基-乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-萘基乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-氯萘基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(2-吡咯基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-苯基乙酰胺，2-(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(2-氯苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(2-氯-4-甲基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-[2-(1-甲基乙烯基)苯基]乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(2-甲基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(6-甲基-2-(甲基乙基)苯基]乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(3-甲硫基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-氯-2-甲氧基-5-甲基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-[4-(二甲基氨基)苯基]乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(2，4-二甲氧基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(3，4-二氯苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-氯苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(3-氯苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(3，5-二氯苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-甲氧基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-甲基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(3-甲基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-氟苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-氰基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-乙酰基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-3-羟基丙基]-3-甲基哌嗪基}-N-(2-甲氧基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-[4-(三氟甲基)苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-氯-3-(三氟甲基)苯基]乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(3，5-二甲氧基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-吗啉-4-基-苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(3-氟-4-甲氧基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(3，4，5-三甲氧基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(3，4-二甲氧基苯基)乙酰胺，2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-(4-氯-2-氟苯基)乙酰胺，以及2-{(3S)-4-[(2S)-3-(2-氟苯氧基)-2-羟基丙基]-3-甲基哌嗪基}-N-[2-(羟基甲基-6-甲基苯基]乙酰胺。Most preferably, the substituted piperazine compound of formula IA is selected from: N-(2,6-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyphenoxy) Propyl]-3-oxopiperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy) Propyl]-3,5-dimethylpiperazinyl}acetamide, 2-{(5S,2R)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]- 2,5-Dimethylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide, 2-{2,5-diaza-5-[2-hydroxyl-3-(2 -Methoxyphenoxy)propyl]bicyclo[4.4.0]dec-2-yl}-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethyl Phenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-oxopiperazinyl}acetamide, N-(2,6-dimethyl Phenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,3-dimethylpiperazinyl}acetamide, 2-{5-[ (2S)-2-Hydroxy-3-(2-methoxyphenoxy)propyl](1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl}-N -(2,6-Dimethylphenyl)acetamide, N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxyl-4-(2-methoxyphenoxy )Butyl]-piperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(4-fluorophenoxy)-2-hydroxybutyl]- Piperazinyl}acetamide, 2-(4-{4-[4-(tert-butyl)phenoxy)-2-hydroxybutyl]piperazinyl}-N-(2,6-dimethylbenzene base) acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(4-phenylphenoxy)butyl]piperazinyl}acetamide, N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-4-(4-methoxyphenoxy)butyl]-piperazinyl}acetamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2,6-dimethylphenyl ) Acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2, 6-dichlorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4-sulfamoylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methane Basepiperazinyl}-N-(5-methoxy-3-(trifluoromethyl)phenyl]acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorobenzene Oxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-indan-5-yl-acetamide, 2-{(3S)-4-[(2S)-3-(2 -Fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-naphthylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluoro Phenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-chloronaphthyl)acetamide, 2-{(3S)-4-[(2S)-3-( 2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-pyrrolylphenyl)acetamide, 2-{(3S)-4-[(2S) -3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-phenylacetamide, 2-(3S)-4-[(2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-chlorophenyl)acetamide, 2-{(3S)-4-[(2S) -3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-chloro-4-methylphenyl)acetamide, 2-{(3S )-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[2-(1-methylvinyl)benzene Base] acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2 -Methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}- N-(6-methyl-2-(methylethyl)phenyl]acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxy Propyl]-3-methylpiperazinyl}-N-(3-methylthiophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy )-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-chloro-2-methoxy-5-methylphenyl)acetamide, 2-{(3S)-4- [(2S)-3-(2-Fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4-(dimethylamino)phenyl]acetamide, 2 -{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2,4-dimethoxy phenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (3,4-Dichlorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiper Azinyl}-N-(4-chlorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- Methylpiperazinyl}-N-(3-chlorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl}-N-(3,5-dichlorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)- 2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methoxyphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluoro Phenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-methylphenyl)acetamide, 2-{(3S)-4-[(2S )-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-fluorophenyl)acetamide, 2-{(3S)-4- [(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-cyanophenyl)acetamide, 2-{(3S )-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-acetylphenyl)acetamide, 2 -{(3S)-4-[(2S)-3-(2-fluorophenoxy)-3-hydroxypropyl]-3-methylpiperazinyl}-N-(2-methoxyphenyl ) Acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4- (Trifluoromethyl)phenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine Base}-N-(4-chloro-3-(trifluoromethyl)phenyl]acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2 -Hydroxypropyl]-3-methylpiperazinyl}-N-(3,5-dimethoxyphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2 -Fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-morpholin-4-yl-phenyl)acetamide, 2-{(3S)-4- [(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-fluoro-4-methoxyphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,4,5- Trimethoxyphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}- N-(3,4-dimethoxyphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3 -Methylpiperazinyl}-N-(4-chloro-2-fluorophenyl)acetamide, and 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)- 2-hydroxypropyl]-3-methylpiperazinyl}-N-[2-(hydroxymethyl-6-methylphenyl]acetamide.

本发明包括具有结构式IB的式I的取代哌嗪化合物子集：

Figure A0180544200371
The present invention includes a subset of substituted piperazine compounds of formula I having the structural formula IB:
Figure A0180544200371

其中m＝0，1或2或3；where m=0, 1 or 2 or 3;

R1，R2，R3，R4和R5各自独立地选自：氢，卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22，SO2R22，SO2N(R23)2，NR23CO2R22，NR23CON(R23)2，COR23，CO2R23，CON(R23)2，NR23SO2R22，C1-15烷基，C2-15烯基，C2-15炔基，杂环基，芳基，和杂芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22和SO2R22；R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from: hydrogen, halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one Substituents selected from the group consisting of: halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 and SO 2 R 22 ;

R6，R7和R8各自独立地选自氢或C1-15烷基；R 6 , R 7 and R 8 are each independently selected from hydrogen or C 1-15 alkyl;

R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢，CO2R23，CON(R23)2，C1-4烷基，或芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，CF3，CN，OR23，N(R23)2，CO2R23，CON(R23)2或芳基，其中R9和R10可以一起形成羰基，或R11和R12可以一起形成羰基，或R13和R14可以一起形成羰基，或R15和R16可以一起形成羰基，其中R11和R13、R9和R15、R9和R11、R11和R15，或R9和R13可以连接在一起形成桥环系，其中两个R基团一起包含1-4个碳原子，且其中R9和R10、R11和R12、R13和R14，或R15和R16可以连接在一起形成螺环系且其中两个R基团一起包含1-5个碳原子。R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, CO 2 R 23 , CON(R 23 ) 2 , C 1-4 alkyl, or Aryl, wherein the alkyl and aryl substituents may be optionally substituted with one substituent selected from the group consisting of halogen, CF 3 , CN, OR 23 , N(R 23 ) 2 , CO 2 R 23 , CON(R 23 ) 2 or aryl, wherein R 9 and R 10 can form together a carbonyl group, or R 11 and R 12 can form a carbonyl group together, or R 13 and R 14 can form a carbonyl group together, or R 15 and R 16 can form a carbonyl group together, wherein R 11 and R 13 , R 9 and R 15 , R 9 and R 11 , R 11 and R 15 , or R 9 and R 13 can be linked together to form a bridged ring system, wherein the two R groups together comprise 1- 4 carbon atoms, and wherein R 9 and R 10 , R 11 and R 12 , R 13 and R 14 , or R 15 and R 16 can be linked together to form a spiro ring system and wherein the two R groups together comprise 1- 5 carbon atoms.

R17，R18，R19，R20，和R21各自独立地选自氢，卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22，SO2R22，SO2N(R23)2，NR23CO2R22，NR23CON(R23)2，COR23，CO2R23，CON(R23)2，NR23SO2R22，C1-15烷基，C2-15烯基，C2-15炔基，杂环基，芳基，和杂芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22和SO2R22，或其中R17和R18连接在一起形成-CH＝CH-CH＝CH-，或其中R17和R18、R18和R19、R19和R20，或R20和R21结合形成包括3至6个碳原子，其中0至2个碳原子可以被氧原子取代的饱和环系，且该环可任选地被1至3个选自氢，卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22，SO2R22，SO2N(R23)2，NR23CO2R22，NR23CON(R23)2，COR23，CO2R23，CON(R23)2，NR23SO2R22，C1-15烷基，C2-15烯基，C2-15炔基，杂环基，芳基，以及杂芳基的取代基取代，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，NO2，CF3，CN，OR23，SR23，N(R23)2，S(O)R22和SO2R22；R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from hydrogen, halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one Substituents selected from the following substituents: halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 and SO 2 R 22 , or wherein R 17 and R 18 linked together to form -CH=CH-CH=CH-, or wherein R 17 and R 18 , R 18 and R 19 , R 19 and R 20 , or R 20 and R 21 combine to form 3 to 6 carbon atoms, A saturated ring system in which 0 to 2 carbon atoms may be replaced by oxygen atoms, and the ring may optionally be replaced by 1 to 3 members selected from hydrogen, halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N (R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and substituents of heteroaryl Substitution, wherein the alkyl and aryl substituents may optionally be substituted with one substituent selected from the group consisting of halogen, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O) R22 and SO2R22 ;

R22选自C1-15烷基，芳基，或杂芳基，其中烷基和芳基取代基可任选被1个选自卤素，烷基，单烷基氨基，二烷基氨基，烷基酰氨基，芳基酰氨基，杂芳基酰氨基，CN，O-C1-6烷基，CF3，或杂芳基的取代基取代；且R 22 is selected from C 1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one selected from halogen, alkyl, monoalkylamino, dialkylamino, Substituents of alkylamido, arylamido, heteroarylamido, CN, OC1-6alkyl , CF3 , or heteroaryl; and

R23选自H，C1-15烷基，芳基，或杂芳基，其中烷基和芳基取代基可任选被1个选自卤素，烷基，单或二烷基氨基，烷基，CN，O-C1-6烷基或CF3的取代基取代；R 23 is selected from H, C 1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one selected from halogen, alkyl, mono- or dialkylamino, alkyl Substituent group, CN, OC 1-6 alkyl or CF 3 substituent;

在本发明的优选组成中，m＝0，1或2或3；R1，R2，R3，R4和R5各自独立地选自：氢，卤素，CF3，OR22和C1-4烷基；R6，R7和R8各自独立地选自氢或C1-3烷基；R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢和C1-4烷基，或者R9和R10一起形成羰基，或R11和R12一起形成羰基，或R13和R14一起形成羰基，或R15和R16一起形成羰基，或其中R11和R13、R9和R15、R9和R11、R11和R15，或R9和R13可以连接在一起形成包含1-4个碳原子的环，其中R9，R10，R11，R12，R13，R14，R15和R16不全为氢；且R17，R18，R19，R20，和R21各自独立地选自氢，卤素，CF3，CN，OR22，S(O)R22，SO2R22，SON(R22)2，CON(R22)2，C1-4烷基，或R17和R18一起形成-CH＝CH-CH＝CH-，以及苯基。In a preferred composition of the present invention, m=0, 1 or 2 or 3; R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from: hydrogen, halogen, CF 3 , OR 22 and C 1 -4 alkyl; R 6 , R 7 and R 8 are each independently selected from hydrogen or C 1-3 alkyl; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 each independently selected from hydrogen and C 1-4 alkyl, or R 9 and R 10 together form a carbonyl, or R 11 and R 12 together form a carbonyl, or R 13 and R 14 together form a carbonyl, or R 15 and R 16 together form a carbonyl group, or wherein R 11 and R 13 , R 9 and R 15 , R 9 and R 11 , R 11 and R 15 , or R 9 and R 13 can be joined together to form a ring containing 1-4 carbon atoms , wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are not all hydrogen; and R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from hydrogen, halogen, CF 3 , CN, OR 22 , S(O)R 22 , SO 2 R 22 , SON(R 22 ) 2 , CON(R 22 ) 2 , C 1-4 alkyl, or R 17 and R 18 together form -CH=CH-CH=CH-, and phenyl.

在另一些优选化合物中，R1，R2，R3，R4和R5各自独立地选自：氢，卤素，CF3，OR22和C1-2烷基，其中R22是C1-3烷基；R6，R7和R8各自独立地选自氢和甲基；R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢和C1-2烷基，或R9和R10一起形成羰基，或R15和R16一起形成羰基，条件是R9，R10，R11，R12，R13，R14，R15和R16不同时为氢，其中R11和R13、R9和R15、R9和R11、R11和R15，或R9和R13连接在一起形成包含1-4个碳原子的环，以及R17，R18，R19，R20，和R21各自独立地选自氢，卤素，CF3，CN，OR22和C1-4烷基，其中R22是C1-3烷基，且其中R17和R18可以一起形成选自-CH＝CH-CH＝CH-和苯基的取代基。In other preferred compounds, R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from: hydrogen, halogen, CF 3 , OR 22 and C 1-2 alkyl, wherein R 22 is C 1 -3 alkyl; R 6 , R 7 and R 8 are each independently selected from hydrogen and methyl; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from From hydrogen and C 1-2 alkyl, or R 9 and R 10 together form carbonyl, or R 15 and R 16 together form carbonyl, provided that R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are not hydrogen at the same time, wherein R 11 and R 13 , R 9 and R 15 , R 9 and R 11 , R 11 and R 15 , or R 9 and R 13 are joined together to form 1-4 ring of carbon atoms, and R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from hydrogen, halogen, CF 3 , CN, OR 22 and C 1-4 alkyl, wherein R 22 is C 1-3 alkyl, and wherein R 17 and R 18 can form together a substituent selected from -CH=CH-CH=CH- and phenyl.

在更优选的化合物中，m＝1或2；R1，R2，R3，R4和R5各自独立地选自：氢，卤素，CF3，OR22和C1-4烷基，其中R22是C1-3烷基；R6，R7，R8，R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢和甲基；R17，R18，R19，R20，和R21各自独立地选自氢，卤素，CF3，OR22，C1-3烷基，其中R22是甲基；或R17和R18一起形成-CH＝CH-CH＝CH-，或R18和R19一起形成-OCH2O-。In more preferred compounds, m=1 or 2; R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from: hydrogen, halogen, CF 3 , OR 22 and C 1-4 alkyl, Wherein R 22 is C 1-3 alkyl; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and Methyl; R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from hydrogen, halogen, CF 3 , OR 22 , C 1-3 alkyl, wherein R 22 is methyl; or R 17 and R 18 together form -CH=CH-CH=CH-, or R 18 and R 19 together form -OCH 2 O-.

在更优选的化合物中，m＝1或2；R1，R2，R3，R4，R5，R6，R7和R8各自独立地选自甲基和氢；R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢；和R17，R18，R19，R20，和R21各自独立地选自氢，卤素，CF3，OR22，其中R22是甲基，或R17和R18一起形成-CH＝CH-CH＝CH-，或R18和R19一起形成-OCH2O-。In more preferred compounds, m=1 or 2; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from methyl and hydrogen; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen; and R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from hydrogen, halogen , CF 3 , OR 22 , wherein R 22 is methyl, or R 17 and R 18 together form -CH=CH-CH=CH-, or R 18 and R 19 together form -OCH 2 O-.

在另一些优选化合物化合物中，m＝1或2；R1和R5为甲基；R2，R3，R4，R6，R7，R8，R9，R10，R11，R12，R13，R14，R15和R16为氢；R17，R18，R19，R20和R21各自独立地选自氢，卤素，OR22，其中R22是甲基，或R17和R18一起形成-CH＝CH-CH＝CH-，或R18和R19一起形成-OCH2O-。In other preferred compounds, m=1 or 2; R 1 and R 5 are methyl; R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are hydrogen; R 17 , R 18 , R 19 , R 20 and R 21 are each independently selected from hydrogen, halogen, OR 22 , wherein R 22 is methyl, Or R 17 and R 18 together form -CH=CH-CH=CH-, or R 18 and R 19 together form -OCH 2 O-.

在更进一步优选的化合物中，R1和R5为甲基；R2，R3，R4，R6，R7，R8，R9，R10，R11，R12，R13，R14，R15和R16为氢；R17选自氢，氯，氟和甲氧基；R18选自氢和甲氧基；R19选自氢和甲氧基；R20是氢；R21选自氢和氯，或R17和R18一起形成-CH＝CH-CH＝CH-，或R18和R19一起形成-OCH2O-。In further preferred compounds, R 1 and R 5 are methyl; R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are hydrogen; R 17 is selected from hydrogen, chlorine, fluorine and methoxy; R 18 is selected from hydrogen and methoxy; R 19 is selected from hydrogen and methoxy; R 20 is hydrogen; R 21 is selected from hydrogen and chlorine, or R 17 and R 18 together form -CH=CH-CH=CH-, or R 18 and R 19 together form -OCH 2 O-.

最优选地，本发明的取代哌嗪化合物选自N-(2，6-二甲基苯基)-2-[4-(2-羟基-4-苯基丁基)哌嗪基]乙酰胺；N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯基)丙基]哌嗪基}乙酰胺；2-[4-(3-(2H-苯并[d]1，3-二氧杂环戊烯(dioxolen)-5-基)-2-羟基丙基)哌嗪基]-N-(2，6二甲基苯基)乙酰胺；N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(4-甲氧基苯基)丙基]哌嗪基}乙酰胺；N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-苯基丙基]哌嗪基}乙酰胺；N-(2，6-二甲基苯基)-2-{4-[4-(4-甲氧基苯基)-2-羟基丁基]哌嗪基}乙酰胺；2-{4-[4-(2，6-二氟苯基)-2-羟基丁基]哌嗪基}-N-(2，6-二甲基苯基)乙酰胺；N-(2，6-二甲基苯基)-2-{4-[4-(2-氯苯基)-2-羟基丁基]哌嗪基}乙酰胺；2-(4-{4-[4-(叔丁基)苯基-2-羟基丁基}哌嗪基)-N-(2，6-二甲基苯基)乙酰胺；N-(2，6-二甲基苯基)-2-{4-[4-(2-氟苯基)-2-羟基丁基]哌嗪基}乙酰胺；N-(2，6-二甲基苯基)-2-(4-{2-羟基-4-[4-(三氟甲基)苯基]丁基}哌嗪基)乙酰胺；2-[4-(3-(2H-苯并[d]1，3-二氧杂环戊烯-5-基)-2-羟基丙基)哌嗪基]-N-(2，6-二甲基苯基)-2-甲基丙酰胺，N-(2，6-二甲基苯基)-2-[4-(2-羟基-3-苯基丙基)哌嗪基]-2-甲基丙酰胺，N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(3，4，5-三甲氧基苯基)丙基]哌嗪基}-2-甲基丙酰胺，N-(2，6-二甲基苯基)-2-[4-(2-羟基-5-苯基戊基)哌嗪基]乙酰胺，N-(2，6-二甲基苯基)-2-{4-[5-(2-氟苯基)-2-羟基-戊基]哌嗪基}乙酰胺，和N-(2，6-二甲基苯基)-2-{4-[5-(2-氯苯基)-2-羟基-戊基]哌嗪基}乙酰胺。Most preferably, the substituted piperazine compound of the present invention is selected from N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide ; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl}acetamide; 2-[4 -(3-(2H-Benzo[d]1,3-dioxolen (dioxolen)-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6 dimethyl N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}ethyl Amide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-phenylpropyl]piperazinyl}acetamide; N-(2,6-dimethyl Phenyl)-2-{4-[4-(4-methoxyphenyl)-2-hydroxybutyl]piperazinyl}acetamide; 2-{4-[4-(2,6-difluoro Phenyl)-2-hydroxybutyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-{4- [4-(2-Chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide; 2-(4-{4-[4-(tert-butyl)phenyl-2-hydroxybutyl}piperamide Azinyl)-N-(2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)- 2-Hydroxybutyl]piperazinyl}acetamide; N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl) ]butyl}piperazinyl)acetamide; 2-[4-(3-(2H-benzo[d]1,3-dioxol-5-yl)-2-hydroxypropyl)piper Azinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxyl-3 -Phenylpropyl)piperazinyl]-2-methylpropionamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxyl-3-(3,4,5 -Trimethoxyphenyl)propyl]piperazinyl}-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenyl Pentyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-2-hydroxy-pentyl]piperazinyl }acetamide, and N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide.

本发明进一步包括具有结构式IC的上述式I化合物子集：

Figure A0180544200411
The present invention further includes a subset of compounds of formula I above having the structural formula IC:
Figure A0180544200411

其中m＝1，2，或3；where m=1, 2, or 3;

R1，R2，R3，R4和R5各自独立地选自：氢，卤素，NO2，CF3，CN，OR20，SR20，N(R20)2，S(O)R22，SO2R22，SO2N(R20)2，NR20CO2R22，NR20CON(R20)2，COR20，CO2R20，CON(R20)2，NR20SO2R22，C1-15烷基，C2-15烯基，C2-15炔基，杂环基，芳基，以及杂芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，NO2，CF3，CN，OR20，SR20，N(R20)2，S(O)R22和SO2R22；R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from: hydrogen, halogen, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one Substituents selected from the group consisting of halogen, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 and SO 2 R 22 ;

R6，R7和R8各自独立地选自氢或C1-3烷基；R 6 , R 7 and R 8 are each independently selected from hydrogen or C 1-3 alkyl;

R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢，CO2R20，CON(R20)2，C1-4烷基，或芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，CF3，CN，OR20，N(R20)2，CO2R20，CON(R20)2或芳基，其中R9和R10可以一起形成羰基，或R11和R12可以一起形成羰基，或R13和R14可以一起形成羰基，或R15和R16可以一起形成羰基，条件是R11和R13、R9和R15、R9和R11、R11和R15或R9和R13可以连接在一起形成包含1-3个碳原子的环；R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, CO 2 R 20 , CON(R 20 ) 2 , C 1-4 alkyl, or Aryl, wherein the alkyl and aryl substituents may optionally be substituted by one substituent selected from the group consisting of halogen, CF 3 , CN, OR 20 , N(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 or aryl, wherein R 9 and R 10 can form together a carbonyl group, or R 11 and R 12 can form a carbonyl group together, or R 13 and R 14 can form a carbonyl group together, or R 15 and R 16 can form a carbonyl group together, with the proviso that R 11 and R 13 , R 9 and R 15 , R 9 and R 11 , R 11 and R 15 or R 9 and R 13 may be joined together to form a ring comprising 1-3 carbon atoms;

R24选自烷基，环烷基，和稠合的苯基环烷基，其中连接点在环烷基上，其中烷基，环烷基，和稠合的苯基环烷基可任选被1个至3个选自下列的取代基取代：卤素，CF3，CN，OR20，SR20，S(O)R22，SO2R22，SO2N(R20)2，NR20CO2R22，C1-2烷基，和芳基，其中芳基取代基可任选被1至3个选自卤素，苯基，CF3，CN，OR20，以及C1-6烷基的取代基取代； R is selected from alkyl, cycloalkyl, and fused phenylcycloalkyl, wherein the point of attachment is on the cycloalkyl, wherein alkyl, cycloalkyl, and fused phenylcycloalkyl can be optionally Substituted with 1 to 3 substituents selected from the group consisting of halogen, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , C 1-2 alkyl, and aryl, wherein the aryl substituent may optionally be 1 to 3 selected from halogen, phenyl, CF 3 , CN, OR 20 , and C 1-6 alkane The substituent of the group is substituted;

R20选自H，C1-15烷基，芳基，或杂芳基，其中烷基和芳基取代基可任选被1个选自下列的取代基取代：卤素，烷基，单-或二-烷基氨基，烷基，CN，-O-C1-6烷基或CF3；且 R is selected from H, C 1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents may be optionally substituted by one substituent selected from the group consisting of halogen, alkyl, mono- or di-alkylamino, alkyl, CN, -OC 1-6 alkyl or CF 3 ; and

R22选自C1-15烷基，芳基，或杂芳基，其中烷基和芳基取代基可任选被1个选自卤素，烷基，单烷基氨基，二烷基氨基，烷基酰氨基，芳基酰氨基，杂芳基酰氨基，CN，O-C1-6烷基，CF3，或杂芳基的取代基取代。R 22 is selected from C 1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents can be optionally replaced by one selected from halogen, alkyl, monoalkylamino, dialkylamino, Substituents of alkylamido, arylamido, heteroarylamido, CN, OC 1-6 alkyl, CF 3 , or heteroaryl.

在式IC中，优选m＝1或2，最优选为m＝1。In formula IC, m=1 or 2 is preferred, m=1 is most preferred.

在优选的式IC组成中，R1，R2，R3，R4和R5各自独立地选自：氢，卤素，CF3，OR22和C1-4烷基，且其中R22是C1-3烷基。在另一个优选的组成中，R1，R2，R3，R4和R5各自独立地选自氢，CF3，OR20或C1-2烷基。更优选地，R1，R2，R3，R4和R5各自独立地选自氢或甲基，优选地，R2，R3，R4是氢，R1和R5是甲基。In the preferred composition of formula IC, R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from: hydrogen, halogen, CF 3 , OR 22 and C 1-4 alkyl, and wherein R 22 is C 1-3 alkyl. In another preferred composition, R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, CF 3 , OR 20 or C 1-2 alkyl. More preferably, R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen or methyl, preferably, R 2 , R 3 , R 4 are hydrogen, R 1 and R 5 are methyl .

在另一个优选的式IC组成中，R6，R7和R8各自独立地选自氢和C1-3烷基，优选氢或甲基，最优选氢。In another preferred composition of formula IC, R 6 , R 7 and R 8 are each independently selected from hydrogen and C 1-3 alkyl, preferably hydrogen or methyl, most preferably hydrogen.

在另一优选的式IC组成中，R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢，CON(R20)2，C1-4烷基，或芳基，其中烷基和芳基取代基可任选被一个选自下列的取代基取代：卤素，CF3，OR20，N(R20)2，CON(R20)2或芳基，其中R9和R10可以一起形成羰基，或R11和R12可以一起形成羰基，或R13和R14可以一起形成羰基，或R15和R16可以一起形成羰基，条件是R11和R13、R9和R15、R9和R11、R11和R15，或R9和R13可以连接在一起形成环。在另一个优选的组成中，R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢和C1-4烷基，或R9和R10一起形成羰基，或R11和R12一起形成羰基，或R13和R14一起形成羰基，或R15和R16一起形成羰基，R10和R11一起形成-CH2CH2CH2CH2-。在另一个方案中，R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢或C1-2烷基，其中烷基取代基任选被1个选自N(R20)2，或芳基的取代基取代，或其中R9和R10一起形成羰基。更优选地，R9，R10，R11，R12，R13，R14，R15和R16各自独立地选自氢或C1-2烷基，或其中R9和R10一起形成羰基。在另一个方案中，R11和R15各自独立地选自氢或甲基，R9，R10，R12，R13，R14和R16分别为氢，且R9和R10一起形成羰基，或者，R9，R10，R11，R12，R13，R14，R15和R16分别为氢。In another preferred composition of formula IC, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, CON(R 20 ) 2 , C 1- 4 Alkyl, or aryl, wherein the alkyl and aryl substituents may be optionally substituted by one substituent selected from the group consisting of halogen, CF 3 , OR 20 , N(R 20 ) 2 , CON(R 20 ) 2 or aryl, where R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl, provided that R 11 and R 13 , R 9 and R 15 , R 9 and R 11 , R 11 and R 15 , or R 9 and R 13 may be linked together to form a ring. In another preferred composition, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and C 1-4 alkyl, or R 9 and R 10 together form carbonyl, or R 11 and R 12 together form carbonyl, or R 13 and R 14 together form carbonyl, or R 15 and R 16 together form carbonyl , R 10 and R 11 together form -CH2CH2CH2CH 2 -. In another embodiment, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or C 1-2 alkyl, wherein the alkyl substituent is optionally Substituted by 1 substituent selected from N(R 20 ) 2 , or aryl, or wherein R 9 and R 10 together form a carbonyl group. More preferably, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or C 1-2 alkyl, or wherein R 9 and R 10 together form carbonyl. In another embodiment, R 11 and R 15 are each independently selected from hydrogen or methyl, R 9 , R 10 , R 12 , R 13 , R 14 and R 16 are each hydrogen, and R 9 and R 10 together form Carbonyl, or, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each hydrogen.

在式IC化合物中，R24选自烷基，环烷基，和稠合的苯基环烷基，其中连接点在环烷基上，其中烷基，环烷基，和稠合的苯基环烷基可任选被1个至3个选自下列的取代基取代：卤素，CF3，CN，OR20，SR20，S(O)R22，SO2R22，SO2N(R20)2，NR20CO2R22，C1-2烷基，以及芳基，其中任选的芳基取代基又可任选被1至3个选自卤素，苯基，CF3，CN，OR20和C1-6烷基的取代基取代。在某些优选的式IC化合物中，R24选自烷基，环烷基，和稠合的苯基环烷基，其中连接点在环烷基上，其中烷基，环烷基，和稠合的苯基环烷基可任选被1个至2个选自下列的取代基取代：卤素，CF3，CN，OR20，SR20，S(O)R22，SO2R22，C1-2烷基和芳基，其中任选的芳基取代基可任选被1至3个选自卤素，苯基，CF3，CN，OR20，以及C1-6烷基的取代基取代。在另一个优选的式IC化合物中，R24选自烷基，环烷基，和稠合的苯基环烷基，其中连接点在环烷基上，其中烷基，环烷基，和稠合的苯基环烷基可任选被1个至2个选自下列的取代基取代：卤素，CF3，OR20和芳基，其中任选的芳基取代基可任选被1至3个选自卤素，苯基，CF3，CN，OR20，以及C1-6烷基的取代基取代。在另一个优选的式IC化合物中，R24选自具有1至6个碳原子的烷基，具有4至6个碳原子的环烷基，稠合的苯基环烷基，其中的苯基任选被1至2个选自卤素，CF3，OH，甲基和芳基的取代基取代，该芳基任选被1至2个选自卤素，CF3，OH，C1-2烷基和芳基的取代基取代。在另一些优选的式IC化合物中，R24是具有1至6个碳原子的烷基和环烷基，或R24是稠合的苯基环烷基，该苯基环烷基任选被1至2个选自卤素，CF3，OR20，C1-2烷基和芳基的取代基取代，或R24是任选被1至2个选自卤素，CF3，OR20，C1-4烷基和芳基取代的苯基甲基。In the compound of formula IC, R 24 is selected from alkyl, cycloalkyl, and fused phenylcycloalkyl, wherein the point of attachment is on cycloalkyl, wherein alkyl, cycloalkyl, and fused phenyl Cycloalkyl can be optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , C 1-2 alkyl, and aryl, wherein the optional aryl substituent can be optionally replaced by 1 to 3 selected from halogen, phenyl, CF 3 , CN , OR 20 and substituents of C 1-6 alkyl are substituted. In certain preferred compounds of formula IC, R is selected from alkyl, cycloalkyl, and fused phenylcycloalkyl, wherein the point of attachment is on cycloalkyl, wherein alkyl, cycloalkyl, and fused The combined phenylcycloalkyl group may be optionally substituted by 1 to 2 substituents selected from the group consisting of halogen, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , C 1-2 alkyl and aryl, wherein the optional aryl substituent can be optionally substituted by 1 to 3 substituents selected from halogen, phenyl, CF 3 , CN, OR 20 , and C 1-6 alkyl replace. In another preferred compound of formula IC, R 24 is selected from alkyl, cycloalkyl, and fused phenylcycloalkyl, wherein the point of attachment is on cycloalkyl, wherein alkyl, cycloalkyl, and fused The combined phenylcycloalkyl group may be optionally substituted by 1 to 2 substituents selected from the group consisting of halogen, CF 3 , OR 20 and aryl, wherein the optional aryl substituent may be optionally substituted by 1 to 3 Substituents selected from halogen, phenyl, CF 3 , CN, OR 20 , and C 1-6 alkyl. In another preferred compound of formula IC, R is selected from alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 6 carbon atoms, fused phenylcycloalkyl, wherein phenyl optionally substituted with 1 to 2 substituents selected from halogen, CF 3 , OH, methyl and aryl optionally substituted with 1 to 2 substituents selected from halogen, CF 3 , OH, C 1-2 alkane Substituents of radicals and aryls are substituted. In other preferred compounds of formula IC, R 24 is an alkyl and cycloalkyl group having 1 to 6 carbon atoms, or R 24 is a fused phenylcycloalkyl group optionally replaced by 1 to 2 substituents selected from halogen, CF 3 , OR 20 , C 1-2 alkyl and aryl, or R 24 is optionally substituted by 1 to 2 substituents selected from halogen, CF 3 , OR 20 , C 1-4 Alkyl and aryl substituted phenylmethyl groups.

在式IC化合物中，R20选自H，C1-3烷基或芳基，其中烷基和芳基取代基可任选被1个选自下列的取代基取代：卤素，-OMe，和CF3。更优选地，R20选自H或C1-3烷基，最优选地，R20是甲基或H。In the compound of formula IC, R is selected from H, C 1-3 alkyl or aryl, wherein the alkyl and aryl substituents may be optionally substituted by one substituent selected from the group consisting of halogen, -OMe, and CF 3 . More preferably, R 20 is selected from H or C 1-3 alkyl, most preferably, R 20 is methyl or H.

最优选地，式IC的取代哌嗪化合物选自：2-({2-[4-(3-异丙氧基-2-羟基丙基)哌嗪基]-N-({2，6-二甲基苯基)乙酰胺；N-(2，6-二甲基苯基)-2-[4-(2-羟基-3-茚满-2-基-氧丙基)哌嗪基]乙酰胺；N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(苯基甲氧基)丙基]哌嗪基}乙酰胺，2-[4-(3{[4-(叔丁基)苯基]甲氧基}2-羟基丙基)哌嗪基]-N-(2，6二甲基丙基)乙酰胺，N-(2，6-二甲基苯基)-2-(4-{3-[(2-氟苯基)甲氧基]-2-羟基丙基}哌嗪基)乙酰胺，2-(4-{3-[(2，4-二氟苯基)甲氧基]-2-羟基丙基}哌嗪基)-N-(2，6二甲基丙基)乙酰胺，N-(2，6-二甲基苯基)-2-[4-(2-羟基-3-{[4-(三氟甲基)苯基]甲氧基}丙基)哌嗪基]乙酰胺，N-(2，6-二甲基苯基)-2-(4-{2-羟基-3-[(2-甲氧基苯基)甲氧基]丙基}哌嗪基)乙酰胺，2-(4-{3[(2，4-二甲氧基苯基)甲氧基]-2-羟基丙基}哌嗪基)-N-(2，6二甲基苯基)乙酰胺，N-(2，6-二甲基苯基)-2-(4-{2-羟基-3-[(4-甲氧基苯基)甲氧基]丙基}哌嗪基)乙酰胺，N-(2，6-二甲基苯基)-2-(4-{3-[(4-氟苯基)甲氧基]-2-羟基丙基}哌嗪基)乙酰胺，N-(2，6-二甲基苯基)-2-(4-{2-羟基-3-[(4-甲基苯基)甲氧基]丙基}哌嗪基)乙酰胺，N-(2，6-二甲基苯基)-2-(4-{2-羟基-3-[(4-苯基苯基)甲氧基]丙基}哌嗪基)乙酰胺，N-(2，6-二甲基苯基)-2-(4-{3-[(4-丁基苯基)甲氧基]-2-羟基丙基}哌嗪基)乙酰胺，N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-萘基甲氧基)丙基]哌嗪基}乙酰胺，N-(2，6-二甲基苯基)-2-{4-[3-(环己基甲氧基)-2-羟基丙基]哌嗪基}乙酰胺，和N-(2，6-二甲基苯基)-2-(4-{3-[(4-氟苯基)甲氧基]-2-羟基丙基}-3，3-二甲基哌嗪基)乙酰胺。Most preferably, the substituted piperazine compound of formula IC is selected from: 2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6- Dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yl-oxypropyl)piperazinyl] Acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(phenylmethoxy)propyl]piperazinyl}acetamide, 2-[4 -(3{[4-(tert-butyl)phenyl]methoxy}2-hydroxypropyl)piperazinyl]-N-(2,6 dimethylpropyl)acetamide, N-(2, 6-Dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, 2-(4-{3 -[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6 dimethylpropyl)acetamide, N-(2,6- Dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide, N-(2 , 6-dimethylphenyl)-2-(4-{2-hydroxyl-3-[(2-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, 2-(4 -{3[(2,4-dimethoxyphenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-( 2,6-Dimethylphenyl)-2-(4-{2-hydroxyl-3-[(4-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, N-( 2,6-Dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, N-(2, 6-Dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6 -Dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6- Dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, N-(2,6-di Methylphenyl)-2-{4-[2-hydroxy-3-(2-naphthylmethoxy)propyl]piperazinyl}acetamide, N-(2,6-dimethylphenyl) -2-{4-[3-(cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl}acetamide, and N-(2,6-dimethylphenyl)-2-(4- {3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide.

此处所用术语具有下列定义。The terms used herein have the following definitions.

“卤”或“卤素”——单独或结合是指卤素，即氯(Cl)，氟(F)，溴(Br)，碘(I)。"Halo" or "halogen" - alone or in combination refers to halogen, ie chlorine (Cl), fluorine (F), bromine (Br), iodine (I).

“羟基“是指基团-OH。"Hydroxy" refers to the group -OH.

“硫醇”或“巯基”是指基团-SH。"Thiol" or "mercapto" refers to the group -SH.

“烷基”——单独或结合是指烷烃衍生的基团，含有1至20个碳原子，优选1至15个碳原子(除非特别定义)。其是直链烷基，支链烷基或环烷基。优选地，直链或支链烷基含有1-15，更优选1至8，进一步优选1-6，还更优选1-4和最优选1-2个碳原子，如甲基，乙基，丙基，异丙基，丁基，叔丁基等等。此处所用术语“低级烷基”直接是指上述的直链烷基。优选地，环烷基是指单环，双环，或三环系且每个环为3-8员环，优选3-6员环，如环丙基，环丁基，环戊基，环己基，金钢烷基等等。烷基也包括直链或支链含有或被环烷基部分间隔的烷基。直链或支链烷基连接在任意可产生稳定化合物的有效点上。其实例包括，但不限于，4-(异丙基)-环己基乙基或2-甲基-环丙基戊基。取代的烷基是指前述定义的直链烷基，支链烷基，或环烷基，其独立地被1至3个下列基团或取代基取代：卤素，羟基，烷氧基，烷硫基，烷基亚磺酰基，烷基磺酰基，酰氧基，芳氧基，杂芳氧基，任选被烷基，芳基或杂芳基单或二取代的氨基，脒基，任选被烷基，芳基或杂芳基或杂环基取代的脲，任选被N-单-或N，N-二-烷基，芳基或杂芳基取代的氨基磺酰基，烷基磺酰基氨基，芳基磺酰基氨基，杂芳基磺酰基氨基，烷基羰基氨基，芳基羰基氨基，杂芳基羰基氨基等等。"Alkyl" - alone or in combination means an alkane-derived group containing 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms (unless otherwise specified). It is straight chain alkyl, branched chain alkyl or cycloalkyl. Preferably, the linear or branched chain alkyl group contains 1-15, more preferably 1-8, further preferably 1-6, still more preferably 1-4 and most preferably 1-2 carbon atoms, such as methyl, ethyl, Propyl, isopropyl, butyl, t-butyl, etc. The term "lower alkyl" as used herein directly refers to the above-mentioned straight-chain alkyl. Preferably, cycloalkyl refers to a monocyclic, bicyclic, or tricyclic ring system and each ring is a 3-8-membered ring, preferably a 3-6-membered ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , adamantyl, etc. Alkyl also includes straight or branched chains containing or interrupted by cycloalkyl moieties. Straight or branched chain alkyl groups are attached at any effective point to yield a stable compound. Examples include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl. Substituted alkyl refers to straight chain alkyl, branched chain alkyl, or cycloalkyl as defined above, which are independently substituted by 1 to 3 of the following groups or substituents: halogen, hydroxyl, alkoxy, alkylthio radical, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or disubstituted by alkyl, aryl or heteroaryl, amidino, optionally Urea substituted by alkyl, aryl or heteroaryl or heterocyclic group, aminosulfonyl optionally substituted by N-mono- or N,N-di-alkyl, aryl or heteroaryl, alkylsulfonyl Acylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and the like.

“烯基”——单独或结合是指含有2-20，优选2-17，更优选2-10，再优选2-8，最优选2至4个碳原子，具有至少一个，优选1-3个，更优选1-2个，最优选1个碳-碳双键的直链，支链，或环烃基。在环烷基的情况下，多个碳碳双键共轭并不因此给环带来芳香性。碳碳双键可以被包括在一个除环丙基外的环烷基部分，或被包括在直链或支链部分。烯基的实例包括乙烯基，丙烯基，异丙烯基，丁烯基，环己烯基，环己烯基烷基等等。取代的烯基是指前述定义的直链烯基，支链烯基或环烯基，独立地被1至3个下列基团或取代基取代：卤素，羟基，烷氧基，烷硫基，烷基亚磺酰基，烷基磺酰基，酰氧基，芳氧基，杂芳氧基，任选被烷基，芳基或杂芳基单或二取代的氨基，脒基，任选被烷基，芳基或杂芳基或杂环基取代的脲，任选被烷基，芳基或杂芳基N-单或N，N-二取代的氨基磺酰基，烷基磺酰基氨基，芳基磺酰基氨基，杂芳基磺酰基氨基，烷基羰基氨基，芳基羰基氨基，杂芳基羰基氨基，羧基，烷氧基羰基，芳氧基羰基，杂芳氧基羰基等等并且连接在任意可以产生稳定化合物的有效点上。"Alkenyl" - alone or in combination means containing 2-20, preferably 2-17, more preferably 2-10, more preferably 2-8, most preferably 2 to 4 carbon atoms, with at least one, preferably 1-3 1, more preferably 1-2, most preferably 1 straight-chain, branched-chain, or cyclic hydrocarbon group with a carbon-carbon double bond. In the case of cycloalkyl groups, multiple carbon-carbon double bond conjugations do not thereby impart aromaticity to the ring. Carbon-carbon double bonds may be included in a cycloalkyl moiety other than cyclopropyl, or in straight or branched chain moieties. Examples of alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl and the like. Substituted alkenyl refers to straight chain alkenyl, branched alkenyl or cycloalkenyl as defined above, independently substituted by 1 to 3 of the following groups or substituents: halogen, hydroxyl, alkoxy, alkylthio, Alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or disubstituted by alkyl, aryl or heteroaryl, amidino, optionally alkyl radical, aryl or heteroaryl or heterocyclic substituted urea, optionally alkyl, aryl or heteroaryl N-mono- or N,N-disubstituted aminosulfonyl, alkylsulfonylamino, aryl Sulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, etc. Any effective point where a stable compound can be produced.

“炔基”——单独或结合是指含有2-20，优选2-17，更优选2-10，再优选2-8，最优选2-4个碳原子，具有至少一个，优选1个碳-碳三键的直链或支链烃。炔基的实例包括乙炔基，丙炔基，丁炔基等等。取代的炔基是指前述定义的直链炔基或支链炔基，其独立地被1至3个下列基团或取代基取代：卤素，羟基，烷氧基，烷硫基，烷基亚磺酰基，烷基磺酰基，酰氧基，芳氧基，杂芳氧基，任选被烷基，芳基或杂芳基单或二取代的氨基，脒基，任选被烷基，芳基或杂芳基或杂环基取代的脲，任选被烷基，芳基或杂芳基N-单或N，N-二取代的氨基磺酰基，烷基磺酰基氨基，芳基磺酰基氨基，杂芳基磺酰基氨基，烷基羰基氨基，芳基羰基氨基，杂芳基羰基氨基等等并且连接在任意可以产生稳定化合物的有效点上。"Alkynyl" - alone or in combination means containing 2-20, preferably 2-17, more preferably 2-10, more preferably 2-8, most preferably 2-4 carbon atoms, with at least one, preferably 1 carbon - Straight chain or branched chain hydrocarbons with carbon triple bonds. Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Substituted alkynyl means a straight-chain or branched-chain alkynyl as defined above, which is independently substituted by 1 to 3 of the following groups or substituents: halogen, hydroxy, alkoxy, alkylthio, alkylene Sulfonyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or disubstituted by alkyl, aryl or heteroaryl, amidino, optionally alkyl, aryl radical or heteroaryl or heterocyclyl substituted urea, optionally alkyl, aryl or heteroaryl N-mono- or N,N-disubstituted aminosulfonyl, alkylsulfonylamino, arylsulfonyl Amino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, etc. and are attached at any effective point to produce a stable compound.

“烷基烯基”是指基团-R-CR’＝CR”’R””，其中R是低级烷基或取代的低级烷基，R’，R”’，R””分别为氢，卤素，低级烷基，取代的低级烷基，酰基，芳基，取代的芳基，杂芳基，或取代杂芳基，如下面所定义。"Alkylalkenyl" means the group -R-CR'=CR"'R"", wherein R is lower alkyl or substituted lower alkyl, R', R"', R"" are independently hydrogen, Halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, as defined below.

“烷基炔基”是指-RC≡CR’其中R是低级烷基或取代的低级烷基，R’是氢，低级烷基，取代的低级烷基，酰基，芳基，取代的芳基，杂芳基，或取代的杂芳基，如下面所定义。"Alkylalkynyl" means -RC≡CR' where R is lower alkyl or substituted lower alkyl, R' is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl , heteroaryl, or substituted heteroaryl, as defined below.

“烷氧基”是指基团-OR，其中R是指低级烷基，取代的低级烷基，酰基，取代的芳基，芳烷基，取代的芳烷基，杂烷基，杂芳基烷基，环烷基，取代的环烷基，环杂烷基，或取代的环杂烷基，如下面所定义。"Alkoxy" means the group -OR, where R means lower alkyl, substituted lower alkyl, acyl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroaryl Alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl, as defined below.

“烷硫基”是指基团-SR，-S(O)n＝1-2-R，其中R是低级烷基，取代的低级烷基，芳基，取代的芳基，芳烷基或取代的芳烷基，如此处所定义。"Alkylthio" refers to the group -SR, -S(O) n=1-2 -R, wherein R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or Substituted aralkyl, as defined herein.

“酰基”是指基团-C(O)R，其中R是氢，低级烷基，取代的低级烷基，芳基，取代的芳基等等，如此处所定义。"Acyl" means a group -C(O)R where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, and the like, as defined herein.

“芳氧基”是指基团-OAr，其中Ar是芳基，取代的芳基，杂芳基，或取代的杂芳基，如此处所定义。"Aryloxy" means the group -OAr, where Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, as defined herein.

“氨基”是指基团NRR’，其中R和R’分别为氢，低级烷基，取代的低级烷基，芳基，取代的芳基，杂芳基，或如此处定义的取代杂芳基，或酰基。"Amino" means the group NRR', where R and R' are independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl as defined herein , or acyl.

“酰氨基”是指基团-C(O)NRR’，其中R和R’分别是氢，低级烷基，取代的低级烷基，芳基，取代的芳基，杂芳基，取代的杂芳基，如此处所定义。"Acylamino" means the group -C(O)NRR', where R and R' are independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted hetero Aryl, as defined herein.

“羧基”是指基团-C(O)OR，其中R是氢，低级烷基，取代的低级烷基，芳基，取代的芳基，杂芳基，和取代的杂芳基，如此处所定义。"Carboxy" means the group -C(O)OR, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, as used herein definition.

“芳基”——单独或结合是指苯基或萘基，任选与5-7，优选5-6员环烷基稠合和/或任选被1至3个选自下列的取代基取代：卤素，羟基，烷氧基，烷硫基，烷基亚磺酰基，烷基磺酰基，酰氧基，芳氧基，杂芳氧基，任选被烷基，芳基或杂芳基单或二取代的氨基，脒基，任选被烷基，芳基或杂芳基或杂环基取代的脲，任选被烷基，芳基或杂芳基N-单或N，N-二取代的氨基磺酰基，烷基磺酰基氨基，芳基磺酰基氨基，杂芳基磺酰基氨基，烷基羰基氨基，芳基羰基氨基，杂芳基羰基氨基等等。"Aryl" - alone or in combination means phenyl or naphthyl, optionally fused with 5-7, preferably 5-6 membered cycloalkyl and/or optionally substituted by 1 to 3 substituents selected from Substitution: halogen, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, optionally replaced by alkyl, aryl or heteroaryl Mono- or disubstituted amino, amidino, urea optionally substituted by alkyl, aryl or heteroaryl or heterocyclyl, optionally alkyl, aryl or heteroaryl N-mono or N,N- Disubstituted aminosulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino and the like.

“取代的芳基”是指任选被1至多个功能基取代的芳基，如卤素，低级烷基，低级烷氧基，烷硫基，乙炔基，氨基，酰氨基，羧基，羟基，芳基，芳氧基，杂环基，杂芳基，取代的杂芳基，硝基，氰基，硫醇基，磺酰氨基等等。"Substituted aryl" means aryl optionally substituted by 1 to more functional groups, such as halogen, lower alkyl, lower alkoxy, alkylthio, ethynyl, amino, amido, carboxyl, hydroxy, aryl radical, aryloxy, heterocyclyl, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfonylamino, etc.

“杂环基”-单独或结合是指饱和，不饱和或芳香碳环基，具有单环(如吗啉基，吡啶基或呋喃基)或多个稠合环(如萘啶基(naphthpyridyl)，喹啉基，中氮茚基或苯并[b]噻吩基)和环中具有至少一个杂原子，如N，O或S，，并可任选未取代或被下列基团取代：卤素，低级烷基，低级烷氧基，烷硫基，乙炔基，氨基，酰氨基，羧基，羟基，芳基，芳氧基，杂环基，杂芳基，取代的杂芳基，硝基，氰基，硫醇基，磺酰氨基等等。"Heterocyclyl" - alone or in combination means a saturated, unsaturated or aromatic carbocyclic group having a single ring (such as morpholinyl, pyridyl or furyl) or multiple fused rings (such as naphthpyridyl) , quinolinyl, indolizinyl or benzo[b]thienyl) and have at least one heteroatom in the ring, such as N, O or S, and may be optionally unsubstituted or substituted by: halogen, Lower alkyl, lower alkoxy, alkylthio, ethynyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocyclyl, heteroaryl, substituted heteroaryl, nitro, cyano group, thiol group, sulfonylamino group, etc.

“杂芳基”-单独或结合是指具有5-6个环原子的单环芳香环结构，或具有8至10个原子的双环结构，含有一个或多个，优选1-4个，更优选1-3，最优选1-2个独立地选自O，S，和N的杂原子，并任选被1至3个选自下列的基团取代：卤素，羟基，烷氧基，烷硫基，烷基亚磺酰基，烷基磺酰基，酰氧基，芳氧基，杂芳氧基，任选被烷基，芳基或杂芳基单或二取代的氨基，脒基，任选被烷基，芳基，杂芳基或杂环基取代的脲，任选被烷基，芳基或杂芳基N-单或N，N-二取代的氨基磺酰基，烷基磺酰基氨基，芳基磺酰基氨基，杂芳基磺酰基氨基，烷基羰基氨基，芳基羰基氨基，杂芳基羰基氨基等等。杂芳基也包括被氧化的S或N，如亚磺酰基，磺酰基，和四级环氮原子的N-氧化物。碳或氮原子是杂芳基环结构的连接点以保持稳定芳香环结构。杂芳基的实例包括吡啶基，哒嗪基，吡嗪基，喹唑啉基，嘌呤基，喹啉基，异喹啉基，嘧啶基，吡咯基，噁唑基，噻唑基，噻吩基，异噁唑基，氧杂噻二唑基，异噻唑基，四唑基，咪唑基，三嗪基，呋喃基，苯并呋喃基，吲哚基，苯并噻唑基，苯并噁唑基等等。取代的杂芳基包含连接在可产生稳定化合物的碳或氮上的取代基。"Heteroaryl" - alone or in combination means a monocyclic aromatic ring structure having 5-6 ring atoms, or a bicyclic structure having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, most preferably 1-2 heteroatoms independently selected from O, S, and N, and optionally substituted with 1 to 3 groups selected from: halogen, hydroxy, alkoxy, alkylthio radical, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or disubstituted by alkyl, aryl or heteroaryl, amidino, optionally Urea substituted by alkyl, aryl, heteroaryl or heterocyclyl, aminosulfonyl optionally N-mono- or N,N-disubstituted by alkyl, aryl or heteroaryl, alkylsulfonylamino , arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino and the like. Heteroaryl also includes oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of quaternary ring nitrogen atoms. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure to maintain a stable aromatic ring structure. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl, quinolinyl, isoquinolyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, Isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furyl, benzofuryl, indolyl, benzothiazolyl, benzoxazolyl, etc. wait. Substituted heteroaryls contain substituents attached to carbon or nitrogen which result in stable compounds.

“杂环基”-单独或结合是指非-芳香环烷基，具有5-10个原子其中环上的1至3个碳原子被O，S或N的杂原子置换，并任选苯并稠合或稠合5-6员杂芳基和/或任选如在环烷基情况下被取代。杂环基也包括氧化的S或N，如亚磺酰基，磺酰基和四级环氮的N-氧化物。连接点在碳原子或氮原子上。杂环基的实例是四氢呋喃基，二氢吡啶基，哌啶基，吡咯烷基，哌嗪基，二氢苯并呋喃基，二氢吲哚基，等等。取代的杂环基含有连接在可产生稳定化合物的碳或氮原子上的取代基氮。"Heterocyclyl" - alone or in combination means a non-aromatic cycloalkyl group, having 5-10 atoms in which 1 to 3 ring carbon atoms are replaced by O, S or N heteroatoms, and optionally benzo Fused or fused 5-6 membered heteroaryl and/or optionally substituted as in the case of cycloalkyl. Heterocyclyl also includes oxidized S or N, such as sulfinyl, sulfonyl and N-oxides of quaternary ring nitrogens. The point of attachment is on a carbon or nitrogen atom. Examples of heterocyclic groups are tetrahydrofuryl, dihydropyridyl, piperidyl, pyrrolidinyl, piperazinyl, dihydrobenzofuranyl, indolinyl, and the like. Substituted heterocyclyl groups contain a substituent nitrogen attached to a carbon or nitrogen atom which results in a stable compound.

“取代的杂芳基”是指任选被1个或多个功能基单或多取代的杂环基，功能基为如卤素，低级烷基，低级烷氧基，烷硫基，乙炔基，氨基，酰氨基，羧基，羟基，芳基，芳氧基，杂环基，取代的杂环基，杂芳基，取代的杂芳基，硝基，氰基，硫醇基，磺酰氨基等等。"Substituted heteroaryl" refers to a heterocyclic group optionally mono- or multi-substituted by one or more functional groups such as halogen, lower alkyl, lower alkoxy, alkylthio, ethynyl, Amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfonylamino, etc. wait.

“芳烷基”是指基团-R-Ar，其中Ar是芳基，R是低级烷基或取代的低级烷基。芳基任选未取代或被如下基团取代：卤素，低级烷基，烷氧基，烷硫基，乙炔基，氨基，酰氨基，羧基，羟基，芳基，芳氧基，杂环基，取代的杂环基，杂芳基，取代的杂芳基，硝基，氰基，硫醇基，磺酰氨基等等。"Aralkyl" means the group -R-Ar where Ar is aryl and R is lower alkyl or substituted lower alkyl. Aryl is optionally unsubstituted or substituted by: halogen, lower alkyl, alkoxy, alkylthio, ethynyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocyclyl, Substituted heterocyclyl, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfonylamino, etc.

“杂芳基烷基”是指基团-R-HetAr，其中HetAr是杂芳基且R是低级烷基或取代的低级烷基。杂芳基烷基可以任选未取代或被如下基团取代：卤素，低级烷基，取代的低级烷基，烷氧基，烷硫基，乙炔基，芳基，芳氧基，杂环基，取代的杂环基，杂芳基，取代的杂芳基，硝基，氰基，硫醇基，磺酰氨基等等。"Heteroarylalkyl" refers to the group -R-HetAr where HetAr is heteroaryl and R is lower alkyl or substituted lower alkyl. Heteroarylalkyl can be optionally unsubstituted or substituted by: halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, ethynyl, aryl, aryloxy, heterocyclyl , substituted heterocyclyl, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfonylamino, etc.

“环烷基”是指含有3-15个碳原子的二价(divalent)环或多环烷基。"Cycloalkyl" refers to a divalent ring or polycyclic alkyl group containing 3 to 15 carbon atoms.

“取代的环烷基”是指含有一个或多个下列取代基的环烷基：卤素，低级烷基，取代的低级烷基，烷氧基，烷硫基，乙炔基，芳基，芳氧基，杂环基，取代的杂环基，杂芳基，取代的杂芳基，硝基，氰基，硫醇基，磺酰氨基等等。"Substituted cycloalkyl" means a cycloalkyl group containing one or more of the following substituents: halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, ethynyl, aryl, aryloxy radical, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfonylamino and the like.

“烷基环烷基”是指基团-R-环烷基，其中环烷基是环烷基且R是低级烷基或取代的低级烷基。环烷基可任选未取代或被下列基团取代：卤素，低级烷基，低级烷氧基，烷硫基，乙炔基，氨基，酰氨基，羧基，羟基，芳基，芳氧基，杂环基，取代的杂环基，杂芳基，取代的杂芳基，硝基，氰基，硫醇基，磺酰氨基等等。"Alkylcycloalkyl" refers to the group -R-cycloalkyl where cycloalkyl is cycloalkyl and R is lower alkyl or substituted lower alkyl. Cycloalkyl can be optionally unsubstituted or substituted by the following groups: halogen, lower alkyl, lower alkoxy, alkylthio, ethynyl, amino, amido, carboxyl, hydroxy, aryl, aryloxy, hetero Cyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfonylamino, and more.

“任选的”或“任选地”是指随后描述的事件或情况可以出现或不出现。且描述包括其中事件或条件出现的情况和其中不出现的情况。例如，“任选的药用赋形剂”是指所述制剂可以包括，也可以不包括赋形剂，而不是特指所述情况出现。并且所述制剂包括其中任选的赋形剂存在的情况和它们不存在的情况。"Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur. And the description includes instances where the event or condition occurs and instances where it does not. For example, "optional pharmaceutical excipients" means that the preparation may or may not include excipients, but does not specifically mean that the above situation occurs. And said formulations include both cases where optional excipients are present and cases where they are absent.

“治疗”和“疗法”是指治疗哺乳动物，特别是人的疾病，包括："Treatment" and "therapy" refer to the treatment of diseases in mammals, especially humans, including:

(i)预防患者出现疾病，其中患者有疾病的倾向，但还未被诊断出疾病；(i) preventing disease in a patient who is predisposed to the disease but has not been diagnosed;

(ii)抑制疾病，如阻止疾病发展；或(ii) inhibiting the disease, such as arresting the development of the disease; or

(iii)减轻疾病，即导致疾病消退。(iii) Alleviating the disease, ie causing regression of the disease.

本发明组合物用于在下列疗法中治疗哺乳动物：保护骨骼肌抵抗创伤导致的损伤，保护肌肉或全身性疾病如间歇性跛行之后的骨骼肌，治疗休克疾病，保护用于移植中的供体组织和器官，和治疗心血管疾病包括心房和心室心律不齐，Prinzmetal氏(变异)绞痛，稳定绞痛，和运动导致的绞痛，充血性心脏病，和心肌梗塞。治疗是用治疗有效量的至少一种的本发明化合物和/或其药用的酸加成盐与药用赋形剂混合来实现的。Compositions of the invention are useful in the treatment of mammals in the following therapies: protection of skeletal muscle against damage caused by trauma, protection of skeletal muscle following muscular or systemic disease such as intermittent claudication, treatment of shock disease, protection of a donor for use in transplantation Tissues and organs, and treatment of cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise-induced angina, congestive heart disease, and myocardial infarction. Treatment is effected with a therapeutically effective amount of at least one compound of the invention and/or a pharmaceutically acceptable acid addition salt thereof in admixture with pharmaceutically acceptable excipients.

落入本发明范围内的化合物包括上述定义的化合物(+)和(-)的旋光异构体和R-和S-异构体和其混合物。本发明包括单个的异构体和其可能的混合物。Compounds falling within the scope of the present invention include optical isomers and R- and S-isomers of the compounds (+) and (-) defined above and mixtures thereof. The present invention includes both individual isomers and possible mixtures thereof.

所有的上述方案包括其药用酸加成盐，特别是单和二盐酸盐，以及其混合物。All of the aforementioned regimens include their pharmaceutically acceptable acid addition salts, especially the mono and dihydrochlorides, and mixtures thereof.

具有通式I和IA的化合物可以用反应式1A-7A的方案制备。本发明化合物的常规合成是化学式1A的方案。化合物IV可以通过取代的苯胺II与2-取代的氯代乙酰氯III的N-酰化而制备。化合物II可以商购或通过相应的硝基苯衍生物(酸/SnCl2或催化氢化，见高等有机化学，Ed.J.March(1992)A。Wileyinterscience)的还原容易地制备。某些可商购的相应于通式结构II的取代苯胺包括2，6-二甲基苯胺，2，3-二甲基苯胺，2-甲基苯胺，4-甲基苯胺，4-甲基苯胺，2，4-二氯苯胺，3，4-二氯苯胺，2，5-二氯苯胺，2，4-二氯苯胺，2-氯苯胺，3-氯苯胺，2，6-二氟苯胺，2，5-二氟苯胺，3，4-二氟苯胺，2-氟苯胺，4-氟苯胺，3-氟苯胺，2-氟-6-氯苯胺，4-氟-3-氯苯胺。Compounds of general formulas I and IA can be prepared using the schemes of Schemes 1A-7A. A general synthesis of compounds of the invention is the scheme of Formula 1A. Compound IV can be prepared by N-acylation of substituted aniline II with 2-substituted chloroacetyl chloride III. Compound II is commercially available or readily prepared by reduction of the corresponding nitrobenzene derivatives (acid/ SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March (1992) A. Wiley interscience). Certain commercially available substituted anilines corresponding to general structure II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4-methylaniline, 4-methylaniline Aniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2,6-difluoro Aniline, 2,5-difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline .

反应式1

Figure A0180544200501
Reaction 1
Figure A0180544200501

化合物VI可以通过将化合物IV与N-保护的取代哌嗪V在适宜的溶剂(如DMF，EtOH)中加热反应而得到。化合物V氮原子的保护是仅当其用于控制化合物V与化合物IV加成时的区域化学时才需要。在某些情况下，化合物V可以从商业途径获得。可商购的与通式V结构相应的化合物实例包括2-甲基哌嗪，2，5-二甲基哌嗪，2，6-二甲基哌嗪。式VI化合物的脱保护可以在标准条件下进行(如Boc用TFA，CBz和苄基用氢化)。化合物I可以通过将式VII化合物与环氧化物VIII在适宜的溶剂(乙醇，DMF)中加热反应而制备。Compound VI can be obtained by reacting compound IV with N-protected substituted piperazine V in a suitable solvent (such as DMF, EtOH) under heating. Protection of the nitrogen atom of compound V is only necessary if it is used to control the regiochemistry of the addition of compound V to compound IV. In some cases, Compound V can be obtained from commercial sources. Examples of commercially available compounds corresponding to the structure of general formula V include 2-methylpiperazine, 2,5-dimethylpiperazine, 2,6-dimethylpiperazine. Deprotection of compounds of formula VI can be performed under standard conditions (eg TFA for Boc, hydrogenation for CBz and benzyl). Compound I can be prepared by heating the compound of formula VII and epoxide VIII in a suitable solvent (ethanol, DMF).

反应式2A

Figure A0180544200511
Reaction 2A
Figure A0180544200511

环氧化物VIII(其中m＝1或2)可以按反应式2A所述制备。将取代的苯酚IX与表氯醇，环氧溴丙烷，或4-溴-1，2-环氧丁烷和碳酸钾在丙酮中加热可以得到环氧化物VIII。化合物IX可通过商业途径得到。可以商购的式XI化合物包括2-氯苯酚，2-氟苯酚，2-甲氧基苯酚，2-甲基苯酚，芝麻酚，2，6-二氯苯酚，3，5-二氯苯酚，2，6-二氟苯酚，2，4-二氟苯酚-5-二氢茚醇，3-氯-4-氟苯酚，2-氯-4-氟苯酚和5，6，7，8-四氢-2-萘醇。在某些情况下，式VIII化合物可以通过商业途径获得。可商购的相应与通式结构VIII的化合物包括苄基缩水甘油醚，缩水甘油2-甲基苯基醚，缩水甘油4-甲氧基苯基醚，缩水甘油4-氯苯基醚，缩水甘油2-氯苯基醚，缩水甘油2-甲氧基苯基醚，缩水甘油4-甲基苯基醚，缩水甘油3，4-二氯苯基醚，缩水甘油4-氟苯基醚。Epoxides VIII (where m = 1 or 2) can be prepared as described in Scheme 2A. Epoxide VIII can be obtained by heating substituted phenol IX with epichlorohydrin, epibromohydrin, or 4-bromo-1,2-epoxybutane and potassium carbonate in acetone. Compound IX is commercially available. Commercially available compounds of formula XI include 2-chlorophenol, 2-fluorophenol, 2-methoxyphenol, 2-methylphenol, sesamol, 2,6-dichlorophenol, 3,5-dichlorophenol, 2,6-difluorophenol, 2,4-difluorophenol-5-indanol, 3-chloro-4-fluorophenol, 2-chloro-4-fluorophenol and 5,6,7,8-tetra Hydrogen-2-naphthol. In some instances, compounds of Formula VIII are commercially available. Commercially available compounds corresponding to the general structure VIII include benzyl glycidyl ether, glycidyl 2-methylphenyl ether, glycidyl 4-methoxyphenyl ether, glycidyl 4-chlorophenyl ether, glycidyl Glycerol 2-chlorophenyl ether, glycidyl 2-methoxyphenyl ether, glycidyl 4-methylphenyl ether, glycidyl 3,4-dichlorophenyl ether, glycidyl 4-fluorophenyl ether.

反应式3A

Figure A0180544200521
Reaction 3A
Figure A0180544200521

化合物可以按反应式3A所述制备。用叔丁基锂作为碱，化合物XII与烷基卤化物的通过烷基化可以得到化合物XIII，如Pohlman等(J.Org.Chem.(1977)，62，1016-1022)所述。XIV用乙硼烷还原可以得到N-苄基保护的化合物V的改型，随后将N-Boc用三氟乙酸(TFA)脱保护[乙硼烷还原见Jacobson等J.Med.Chem.(1992)，42，1123-1144]。Compounds can be prepared as described in Scheme 3A. Compounds XIII can be obtained by alkylation of compounds XII with alkyl halides using tert-butyllithium as base, as described by Pohlman et al. (J. Org. Chem. (1977), 62, 1016-1022). The N-benzyl protected modification of compound V can be obtained by reducing XIV with diborane followed by deprotection of N-Boc with trifluoroacetic acid (TFA) [see Jacobson et al. J. Med. Chem. (1992 for diborane reduction). ), 42, 1123-1144].

反应式4A

Figure A0180544200522
Reaction 4A
Figure A0180544200522

化合物V也可以通过D或L氨基酸的标准偶合(如EDC或PyBrop)和标准的脱保护而制备，如反应式4A所述[制备二酮哌嗪见-P.Cledera等，Tetrahedron，(1998)p.12349-12360和R.A.Smith等Bioorg.Med.Chem.Lett(1998)p2369-2374]。二酮哌嗪用乙硼烷环原得到N-苄基保护的化合物V的改型。Compound V can also be prepared by standard coupling of D or L amino acids (such as EDC or PyBrop) and standard deprotection, as described in Reaction Scheme 4A [Preparation of diketopiperazines see - P. Cledera et al., Tetrahedron, (1998) p.12349-12360 and R.A. Smith et al. Bioorg. Med. Chem. Lett (1998) p2369-2374]. Modification of diketopiperazine to N-benzyl protected compound V with diborane ring.

化合物V也包括哌嗪的双环同系物(1S，4S)-(+)-2，5-二氮杂双环[2.2.1]庚烷83，3，8-二氮杂双环[3.2.1]辛烷84，和2，5-二氮杂双环[2.2.2]辛烷85。

Figure A0180544200531
Compound V also includes the bicyclic homologue of piperazine (1S, 4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83,3,8-diazabicyclo[3.2.1] Octane 84, and 2,5-diazabicyclo[2.2.2]octane 85.
Figure A0180544200531

可商购的双环同系物包括(1S，4S)-(+)-2，5-二氮杂双环[2.2.1]庚烷83，化合物84，85和83的(1R，4R)异构体可以通过已公开的方法制备(对于84和85见Sturm，P.A.等J，Med.Chem.1974，17，481-487；对于83见Barish，T.F.和Fox，D.E.J.Org.Chem.，1990，55，1684-1687)。Commercially available bicyclic homologues include (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83, the (1R,4R) isomer of compounds 84, 85 and 83 Can be prepared by published methods (for 84 and 85 see Sturm, P.A. et al. J, Med.Chem.1974,17,481-487; for 83 see Barish, T.F. and Fox, D.E.J.Org.Chem., 1990,55, 1684-1687).

制备式IA化合物的具体实例公开于反应式5A，6A，和7A中以进一步说明怎样制备本发明化合物。特别地，以饱和的碳酸氢盐和乙醚(1∶1)作为碱和助溶剂，将2，6-二氯苯胺和2-氯代乙酰氯2进行酰化反应，分别得到氯代乙酰胺衍生物3。进一步将化合物3与2，6-二甲基哌嗪通过在乙醇中加热反应得到化合物5。将化合物5与环氧化物6在乙醇中加热回流反应得到2，6-二甲基哌嗪衍生物7。化合物6可通过依次将表氯醇和2-甲氧基苯酚在丙酮中在K2CO3存在下加热而制备，如反应式6A所示。Specific examples of preparing compounds of Formula IA are disclosed in Schemes 5A, 6A, and 7A to further illustrate how to prepare compounds of the present invention. Specifically, 2,6-dichloroaniline and 2-chloroacetyl chloride 2 were acylated with saturated bicarbonate and diethyl ether (1:1) as base and cosolvent to obtain chloroacetamide derivatives, respectively Object 3. Compound 5 was obtained by further reacting compound 3 with 2,6-dimethylpiperazine by heating in ethanol. Compound 5 and epoxide 6 were heated under reflux in ethanol to obtain 2,6-dimethylpiperazine derivative 7. Compound 6 can be prepared by sequentially heating epichlorohydrin and 2-methoxyphenol in acetone in the presence of K2CO3 , as shown in Scheme 6A.

反应式5A

Figure A0180544200532
Reaction 5A
Figure A0180544200532

反应式6A Reaction 6A

化合物14的具体合成如反应式7A所述。化合物11通过将环氧化物6用Boc-亚乙基二胺在EtOH中加热开环而制备。化合物11的酰化用氯代乙酰氯在二氯甲烷中用二异丙基乙基胺为碱进行。用TFA除去Boc基团随后通过将环在EtOH中加热打开得到化合物13。使化合物13与6按上述方法反应得到化合物14。

Figure A0180544200551
The specific synthesis of compound 14 is described in Reaction Scheme 7A. Compound 11 was prepared by heating ring opening of epoxide 6 with Boc-ethylenediamine in EtOH. Acylation of compound 11 was carried out with chloroacetyl chloride in dichloromethane using diisopropylethylamine as base. Removal of the Boc group with TFA followed by opening of the ring by heating in EtOH gave compound 13. Compound 13 was reacted with 6 to obtain compound 14 as described above.
Figure A0180544200551

具有通式I和IB的化合物可以在反应式1B-7B的方案中制备。本发明化合物的一般合成列于反应式1B中。化合物IV可以通过将通式II的取代苯胺与2-取代氯代乙酰氯III的N-酰化而制备。化合物II可商购或通过相应的硝基苯衍生物还原而容易地制备(酸/SnCl2或催化氢化，见高等有机化学，Ed.J.March，(1992)A。Wiley-Interscience)。可商购的通式II取代苯胺包括2，6-二甲基苯胺，2，3-二甲基苯胺，2-甲基苯胺，4-甲基苯胺，2，4-二氯苯胺，3，4-二氯苯胺，2，5-二氯苯胺，2，4-二氯苯胺，2-氯苯胺，3-氯苯胺，2，6-二氟苯胺，2，5-二氟苯胺，3，4-二氟苯胺，2-氟苯胺，4-氟苯胺，3-氟苯胺，2-氟-6-氯苯胺，4-氟-3-氯苯胺。化合物VI可以通过使化合物IV与N-保护的取代哌嗪V在适宜的溶剂(如DMF，EtOH)中加热反应而制备。化合物V氮原子的保护是仅在其用于控制化合物V与化合物IV加成的区域化学时才需要的。在某些情况下，化合物V可以从商业途径获得。可商购的与通式V结构相应的化合物实例包括2-甲基哌嗪，2，5-二甲基哌嗪，2，6-二甲基哌嗪。式VI化合物的脱保护可以在标准条件下进行(如Boc用TFA，CBz和苄基用氢化)。化合物I可以通过将式VII化合物与环氧化物VIII在适宜的溶剂(乙醇，DMF)中加热反应而制备。Compounds of general formulas I and IB can be prepared in the schemes of Schemes 1B-7B. The general synthesis of compounds of the invention is set forth in Scheme 1B. Compound IV can be prepared by N-acylation of substituted anilines of general formula II with 2-substituted chloroacetyl chlorides III. Compound II is commercially available or readily prepared by reduction of the corresponding nitrobenzene derivatives (acid/ SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Commercially available substituted anilines of general formula II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3, 4-dichloroaniline, 2,5-dichloroaniline, 2,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2,6-difluoroaniline, 2,5-difluoroaniline, 3, 4-Difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline. Compound VI can be prepared by heating reaction of compound IV with N-protected substituted piperazine V in a suitable solvent (such as DMF, EtOH). Protection of the compound V nitrogen atom is only necessary if it is used to control the regiochemistry of the addition of compound V to compound IV. In some cases, Compound V can be obtained from commercial sources. Examples of commercially available compounds corresponding to the structure of general formula V include 2-methylpiperazine, 2,5-dimethylpiperazine, 2,6-dimethylpiperazine. Deprotection of compounds of formula VI can be performed under standard conditions (eg TFA for Boc, hydrogenation for CBz and benzyl). Compound I can be prepared by heating the compound of formula VII and epoxide VIII in a suitable solvent (ethanol, DMF).

反应式2B Reaction 2B

环氧化物VIII可用反应式2B制备。将取代的烯丙基苯XI用mCPBA或过氧化氢进行环氧化得到环氧化物VIII(G.Majetich，R.Hicks，G.Sun和P.McGill，(1998)，63，2564-2573)。化合物XI可以依次通过使醛IX与亚甲基三苯基正膦在维悌希条件或Homer Emmons条件下[高等有机化学，EdS.J.March(1992)Wiley-Intersxience出版和S.Pine，G.Shen和H.Hoang，Synthesis(1991)，1]反应而制备。化合物XI也可以通过使通式X的卤化物与溴化烯丙基镁偶合而方便地制备。在某些情况下，化合物XI可以从商业途径获得。可商购的相应于通式结构XI的化合物包括(其中m＝0)3-氟苯乙烯，4-氟苯乙烯，2-氯苯乙烯，3-氯苯乙烯，4-氯苯乙烯，2，6-二氯苯乙烯，3，4-二氯苯乙烯，3，4-二甲氧基苯乙烯。其它的可商购的将有通式XI的化合物包括(其中m＝1)4-甲氧基烯丙基苯，2-羟基烯丙基苯，4，5-二甲氧基烯丙基苯，2-甲基烯丙基苯黄樟素和1-烯丙基萘。Epoxide VIII can be prepared using Equation 2B. Epoxidation of substituted allylbenzenes XI with mCPBA or hydrogen peroxide affords epoxides VIII (G. Majetich, R. Hicks, G. Sun and P. McGill, (1998), 63, 2564-2573) . Compound XI can be obtained successively by making aldehyde IX and methylene triphenylphosphorane under Wittig conditions or Homer Emmons conditions [Advanced Organic Chemistry, EdS.J.March (1992) Wiley-Intersxience Publishing and S.Pine, G .Shen and H.Hoang, Synthesis (1991), 1] reaction and preparation. Compound XI can also be conveniently prepared by coupling a halide of general formula X with allylmagnesium bromide. In some cases, Compound XI can be obtained from commercial sources. Commercially available compounds corresponding to general structure XI include (where m=0) 3-fluorostyrene, 4-fluorostyrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2 , 6-dichlorostyrene, 3,4-dichlorostyrene, 3,4-dimethoxystyrene. Other commercially available compounds of general formula XI include (where m=1) 4-methoxyallylbenzene, 2-hydroxyallylbenzene, 4,5-dimethoxyallylbenzene , 2-methylallyl benzene safrole and 1-allyl naphthalene.

反应式3B

Figure A0180544200581
Reaction 3B
Figure A0180544200581

化合物V可按反应式3B所述制备。化合物XII与烷基卤化物用叔丁基锂作为碱进行烷基化可得到化合物XIII，如Pohlmam等(J.Org.Chem.，(1997)，62，1016-1022)。用三氟乙酸对N-Boc脱保护后，将XIII用乙硼烷还原可以得到N-苄基保护的化合物V改型(TFA，对于乙硼烷还原见Jacobson等J.Med.Chem，(1999)，42，1123-1144)。Compound V can be prepared as described in Scheme 3B. Alkylation of compound XII with alkyl halides using tert-butyllithium as a base can give compound XIII, such as Pohlmam et al. (J. Org. Chem., (1997), 62, 1016-1022). After deprotection of N-Boc with trifluoroacetic acid, reduction of XIII with diborane can give N-benzyl protected compound V modification (TFA, for diborane reduction see Jacobson et al. J. Med. Chem, (1999 ), 42, 1123-1144).

反应式4B Reaction 4B

化合物V也可以通过D或L氨基酸标准的偶合(如EDC或PyBrop)和标准的脱保护(如Boc用TFA处理)而制备，如反应式4B所述[制备二酮哌嗪见-P.Cledera等，Tetrahedron，(1998)p.12349-12360和R.A.Smith等Bioorg.Med.Chem.Lett(1998)p2369-2374]。二酮哌嗪用乙硼烷还原得到N-苄基保护的化合物V的改型。Compound V can also be prepared by standard coupling of D or L amino acids (such as EDC or PyBrop) and standard deprotection (such as treatment of Boc with TFA), as described in Reaction Scheme 4B [Preparation of diketopiperazine see-P.Cledera et al., Tetrahedron, (1998) p.12349-12360 and R.A. Smith et al. Bioorg. Med. Chem. Lett (1998) p2369-2374]. Reduction of diketopiperazine with diborane affords a modification of the N-benzyl protected compound V.

化合物V也包括哌嗪的双环同系物(1S，4S)-(+)-2，5-二氮杂双环[2.2.1]庚烷83，3，8-二氮杂双环[3.2.1]辛烷84，和2，5-二氮杂双环[2.2.2]辛烷85。

Figure A0180544200591
Compound V also includes the bicyclic homologue of piperazine (1S, 4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83,3,8-diazabicyclo[3.2.1] Octane 84, and 2,5-diazabicyclo[2.2.2]octane 85.
Figure A0180544200591

可商购的双环同系物包括(1S，4S)-(+)-2，5-二氮杂双环[2.2.1]庚烷83，化合物84，85和83的(1R，4R)异构体可以通过已公开的方法制备(对于84和85见Sturm，P.A.等J，Med.Chem.1974，17，481-487；对于86见Barish，T.F.和Fox，D.E.J.Org.Chem.，1990，55，1684-1687)。Commercially available bicyclic homologues include (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83, the (1R,4R) isomer of compounds 84, 85 and 83 Can be prepared by published methods (for 84 and 85 see Sturm, P.A. et al. J, Med.Chem.1974,17,481-487; for 86 see Barish, T.F. and Fox, D.E.J.Org.Chem., 1990,55, 1684-1687).

本发明化合物的制备的具体实例公开于反应式5B以进一步举例说明怎样制备本发明化合物。特别是将2，6-二氯苯胺与2-氯代乙酰氯2用饱和的碳酸氢盐和乙醚(1∶1)作为碱和助溶剂酰化，分别得到氯代乙酰胺衍生物3。进一步将化合物3与哌嗪通过在乙醇中加热反应得到化合物5。将化合物5与环氧化物6均在乙醇中加热回流反应得到哌嗪衍生物7。Specific examples of the preparation of compounds of the present invention are disclosed in Scheme 5B to further illustrate how to prepare compounds of the present invention. In particular, acylation of 2,6-dichloroaniline and 2-chloroacetyl chloride 2 with saturated bicarbonate and diethyl ether (1:1) as a base and a cosolvent can give chloroacetamide derivative 3, respectively. Compound 5 was obtained by further reacting compound 3 with piperazine by heating in ethanol. Both compound 5 and epoxide 6 were reacted under reflux in ethanol to obtain piperazine derivative 7.

反应式5B Reaction 5B

化合物8可以商购并用3-氯代过氧苯甲酸在二氯甲烷中环氧化，如反应式6B所述。Compound 8 is commercially available and epoxidized with 3-chloroperoxybenzoic acid in dichloromethane as described in Scheme 6B.

反应式6B

Figure A0180544200602
Reaction 6B
Figure A0180544200602

四碳环氧化物15可以通过可商购的4-甲氧基苄基氯与烯丙基溴化镁偶合然后用mCPBA氧化而制备，如反应式7B所述。The four-carbon epoxide 15 can be prepared by coupling commercially available 4-methoxybenzyl chloride with allylmagnesium bromide followed by oxidation with mCPBA, as described in Scheme 7B.

反应式7B Reaction 7B

具有通式I和IC的化合物可以如反应式1C-6C所述制备。本发明化合物的一般合成列于反应式1C中。

Figure A0180544200612
Compounds of general formulas I and IC can be prepared as described in Schemes 1C-6C. The general synthesis of compounds of the invention is set forth in Scheme 1C.
Figure A0180544200612

化合物IV可通过取代苯胺II与2-取代氯代乙酰氯III进行N-酰化而制备。化合物II可以商购或通过相应的硝基苯衍生物还原(酸/SnCl2或催化氢化，见高等有机化学，Ed.J.March，(1992)A.Wiley-Interscience)容易地制备。可商购的取代苯胺II的某些实例包括2，6二甲基苯胺，2，3-二甲基苯胺，2-甲基苯胺，4-甲基苯胺，4-甲基苯胺，2，4-二氯苯胺，3，4-二氯苯胺，2，5-二氯苯胺，2，4-二氯苯胺，2-氯苯胺，3-氯苯胺，2，6-二氟苯氨，2，5-二氟苯氨，3，4-二氟苯氨，2-氟苯氨，4-氟苯氨，3-氟苯氨，2-氟-6-氯苯胺，4-氟-3-氯苯胺。Compound IV can be prepared by N-acylation of substituted aniline II with 2-substituted chloroacetyl chloride III. Compound II is commercially available or readily prepared by reduction of the corresponding nitrobenzene derivative (acid/SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available substituted anilines II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4-methylaniline, 4-methylaniline, 2,4 -Dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2,6-difluoroaniline, 2, 5-Difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloro aniline.

化合物VI可以通过使化合物IV与N-保护的取代哌嗪V通过在适宜的溶剂(如DMF，EtOH)中加热反应而制备。化合物V氮原子的保护是仅在其用于控制化合物V与化合物IV加成的区域化学时才需要。在某些情况下，化合物V可以从商业途径获得。可商购的与通式V结构相应的化合物实例包括2-甲基哌嗪，2，5-二甲基哌嗪，2，6-二甲基哌嗪和4-苄氧基羰基哌嗪-2-酮。式VI化合物的脱保护可以在标准条件下进行(如Boc用TFA，CBz和苄基用氢化)。化合物I可以通过将式VII化合物与环氧化物VIII在适宜的溶剂(乙醇，DMF)中加热反应而制备。Compound VI can be prepared by reacting compound IV with N-protected substituted piperazine V by heating in a suitable solvent (eg DMF, EtOH). Protection of the nitrogen atom of compound V is only necessary if it is used to control the regiochemistry of the addition of compound V to compound IV. In some cases, Compound V can be obtained from commercial sources. Examples of commercially available compounds corresponding to the structure of general formula V include 2-methylpiperazine, 2,5-dimethylpiperazine, 2,6-dimethylpiperazine and 4-benzyloxycarbonylpiperazine- 2-keto. Deprotection of compounds of formula VI can be performed under standard conditions (eg TFA for Boc, hydrogenation for CBz and benzyl). Compound I can be prepared by heating the compound of formula VII and epoxide VIII in a suitable solvent (ethanol, DMF).

反应式2C

Figure A0180544200622
Reaction 2C
Figure A0180544200622

环氧化物VIII可以通过反应式2C所述制备。将烷基醇IX与表氯醇或环氧溴丙烷和氢化钠在DMF中加热可以得到环氧化物VIII。某些化合物VIII可以从商业途径获得。可商购的通式结构VIII化合物包括缩水甘油异丙醚，N丁基缩水甘油醚和T丁基缩水甘油醚。Epoxide VIII can be prepared as described in Equation 2C. Epoxides VIII can be obtained by heating alkyl alcohol IX with epichlorohydrin or epibromohydrin and sodium hydride in DMF. Certain compounds VIII are commercially available. Commercially available compounds of general structure VIII include glycidyl isopropyl ether, N butyl glycidyl ether and T butyl glycidyl ether.

化合物V可以如反应式3C制备。化合物XII与烷基卤化物用叔丁基锂为碱进行烷基化可以得到化合物XIII，如Pohlman等(J.Org.Chem，(1997)，62，1016-1022)所述。用三氟乙酸将N-Boc脱保护后，XIV用乙硼烷进行还原可以得到N-苄基保护的化合物V变型(TFA，乙硼烷的还原见Jacobson等，J.Med.Chem.，(1999)，42，1123-1144)。Compound V can be prepared as shown in Reaction Scheme 3C. Alkylation of compound XII with alkyl halides using tert-butyllithium as a base can give compound XIII as described by Pohlman et al. (J. Org. Chem, (1997), 62, 1016-1022). After deprotecting N-Boc with trifluoroacetic acid, XIV can be reduced with diborane to obtain N-benzyl protected compound V modification (TFA, see Jacobson et al., J.Med.Chem., for the reduction of diborane 1999), 42, 1123-1144).

反应式3C Reaction 3C

化合物V也可以通过D或L氨基酸标准的偶合(如EDC或PyBrop)而制备，如反应式4C所述[制备二酮哌嗪见-P.Cledera等，Tetrahedron，(1998)p.12349-12360和R.A.Smith等Bioorg.Med.Chem.Lett(1998)p2369-2374]。二酮哌嗪用乙硼烷还原得到N-苄基保护的化合物V的改型。Compound V can also be prepared by standard coupling of D or L amino acids (such as EDC or PyBrop), as described in Reaction Scheme 4C [Preparation of diketopiperazine see-P.Cledera et al., Tetrahedron, (1998) p.12349-12360 and R.A. Smith et al Bioorg. Med. Chem. Lett (1998) p2369-2374]. Reduction of diketopiperazine with diborane affords a modification of the N-benzyl protected compound V.

反应式4C

Figure A0180544200641
Reaction 4C
Figure A0180544200641

本发明化合物制备的具体实例公开于反应式5C和6C中以进一步说明怎样制备本发明化合物。

Figure A0180544200642
Specific examples of the preparation of the compounds of the present invention are disclosed in Schemes 5C and 6C to further illustrate how the compounds of the present invention can be prepared.
Figure A0180544200642

特别地，将2，6-二氯苯胺与2-氯代乙酰氯2用饱和的碳酸氢盐和乙醚(1∶1)作为碱和助溶剂酰化，分别得到氯代乙酰胺衍生物3。进一步将化合物3与哌嗪通过在乙醇中加热反应得到化合物5。将化合物5与环氧化物6均在乙醇中加热回流反应得到哌嗪衍生物7。化合物6可通过依次将表氯醇和2-茚满醇在DMF中，在NaH存在下加热反应而制备，如反应式6C所示。Specifically, 2,6-dichloroaniline and 2-chloroacetyl chloride 2 were acylated with saturated bicarbonate and diethyl ether (1:1) as base and cosolvent to give chloroacetamide derivative 3, respectively. Compound 5 was obtained by further reacting compound 3 with piperazine by heating in ethanol. Both compound 5 and epoxide 6 were reacted under reflux in ethanol to obtain piperazine derivative 7. Compound 6 can be prepared by sequentially heating epichlorohydrin and 2-indanol in DMF in the presence of NaH, as shown in Reaction Scheme 6C.

反应式6C Reaction 6C

可以将本发明化合物的酸加成盐用适宜的碱，如碳酸钾或氢氧化钠，典型地在水溶剂存在下，在约0至100℃的温度下处理而转化成相应的游离碱。游离碱可以通过常规方法分离，如用有机溶剂萃取。Acid addition salts of compounds of the invention can be converted to the corresponding free bases by treatment with a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of an aqueous solvent at a temperature of from about 0 to 100°C. The free base can be isolated by conventional methods, such as extraction with an organic solvent.

本发明的盐可以利用不同的溶解性和挥发性，或用适宜承载的离子交换树脂而互换。这种转换在约0℃至溶剂沸点之间的温度进行，其中溶剂是用于生产的的介质。活性化合物和此处所述的盐的给药可以通过任意治疗剂可接受的给药方式进行。该方法包括口服，肠道外，经皮，皮下和其它系统模式。除了在患者自己不能摄取任何药物的情况外，优选的给药方式是口服。在此情况下，需要进行肠道外给药。The salts of the present invention can be interchanged by taking advantage of different solubility and volatility, or by using suitably loaded ion exchange resins. This transformation takes place at a temperature between about 0°C and the boiling point of the solvent which is the medium used for the production. Administration of the active compounds and salts described herein may be by any of the therapeutically acceptable modes of administration. The methods include oral, parenteral, transdermal, subcutaneous and other systemic modes. The preferred mode of administration is oral, except in cases where the patient is unable to ingest any drug on his own. In such cases, parenteral administration is required.

根据所需模式，组合物可以是固体形式，半固体形式或液体制剂形式，如片剂，栓剂，丸剂，胶囊，粉末，液体，悬浮液等等，优选地以适宜单独服用精确剂量的单位剂量形式。组合物可以包括一种或多种常规的药物赋形剂和至少一种本发明的活性化合物或其药用盐，并且另外可以包括其它医药剂，药剂，载体，辅料，稀释剂等等。Depending on the desired mode, the composition may be in the form of solid, semi-solid or liquid preparations such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, etc., preferably in unit dosages suitable for individual administration of precise doses form. The composition may include one or more conventional pharmaceutical excipients and at least one active compound of the present invention or a pharmaceutically acceptable salt thereof, and may additionally include other pharmaceutical agents, medicaments, carriers, adjuvants, diluents and the like.

活性化合物的给药量当然根据所治疗的患者，患者的体重，疾病的严重程度，给药方式和处方医生的判断来决定。但是，有效的剂量范围在0.1-30mg/kg/天，优选0.5-2-mg/kg/天。对于平均70kg的人来说，服用量为每天7-2100mg，优选35-1400mg/天。由于本发明化合物的许多作用(保护骨骼肌抵抗由创伤导致的损伤，保护肌肉或全身性疾病如间歇性跛行之后的骨骼肌，治疗休克疾病，保护用于移植中的供体组织和器官，和治疗心血管疾病包括心房和心室心律不齐，Prinzmetal(变异)氏绞痛，稳定绞痛，和运动导致的绞痛，充血性心脏病，和心肌梗塞)是通过相似的机制(部分脂肪酸氧化抑制)取得，剂量(和给药方式)通常是相同的且优选在所有这些用途范围中。The amount of active compound administered will of course depend on the patient being treated, the patient's weight, the severity of the disease, the mode of administration and the judgment of the prescribing physician. However, an effective dosage range is 0.1-30 mg/kg/day, preferably 0.5-2-mg/kg/day. For an average 70 kg person, the dose is 7-2100 mg per day, preferably 35-1400 mg per day. Due to the many actions of the compounds of the present invention (protection of skeletal muscle against damage caused by trauma, protection of skeletal muscle after muscular or systemic diseases such as intermittent claudication, treatment of shock diseases, protection of donor tissues and organs used in transplantation, and Treatment of cardiovascular disease including atrial and ventricular arrhythmias, Prinzmetal (variant) angina, stable angina, and exercise-induced angina, congestive heart disease, and myocardial infarction) by a similar mechanism (partial fatty acid oxidation inhibition ), the dosage (and mode of administration) is generally the same and preferably in all these uses.

对于固体组合物，常规的无毒固体包括，可以使用例如药物级的甘露糖醇，乳糖，淀粉，硬脂酸镁，糖精钠，滑石粉，纤维素，葡萄糖，蔗糖，碳酸镁，等等。上述定义的活性化合物可以用例如聚亚烷基二醇，如丙二醇作为载体配制成栓剂。液体给药形式的药物组合物可以通过例如将上述定义的活性化合物和任选的药物辅料溶解，分散在赋形剂，例如水，盐水，葡萄糖水溶液，甘油，乙醇等中，以形成溶液或悬浮液。如果需要，给药的药物组合物可以含有少量无毒辅助物质，如润湿剂或乳化剂，pH缓冲剂等，如乙酸钠，脱水山梨糖醇单月桂酸酯，三乙醇胺乙酸钠，三乙醇胺油酸酯等。制备这类剂量形式的实际方法是已知的，或对本领域技术人员来说是显而易见的；例如，见Remington的药物科学，Mack PublishingCompany，Easton，Pennsylvania，第15版，1975。给药的组合物或制剂无论如何，含有的活性化合物的量是治疗有效量，即以有效地减轻所治疗患者的症状。对于口服给药，药用无毒组合物通过加入任何常用的赋形剂而制成，如，药物级的甘露糖醇，乳糖，淀粉，硬脂酸镁，糖精钠，滑石粉，纤维素，葡萄糖，蔗糖，碳酸镁，等等。这种组合物可以是溶液，悬浮液，片剂，丸剂，胶囊，粉末，缓释制剂等等。这种组合物可以含有10％-95％，优选1-70％的活性成分。For solid compositions, conventional nontoxic solids include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like can be used. The active compounds as defined above may be formulated as suppositories with carriers such as polyalkylene glycols, such as propylene glycol. Pharmaceutical compositions in the form of liquid administration can be obtained by, for example, dissolving and dispersing the above-defined active compound and optional pharmaceutical excipients in an excipient such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form a solution or suspension liquid. Pharmaceutical compositions for administration may, if desired, contain small amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, etc., such as sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine Oleate etc. Actual methods of preparing such dosage forms are known, or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th ed., 1975. The compositions or formulations to be administered will however contain the active compound in an amount which is therapeutically effective, ie effective to alleviate the symptoms of the patient being treated. For oral administration, pharmaceutical nontoxic compositions are prepared by adding any commonly used excipients, such as, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, Glucose, sucrose, magnesium carbonate, etc. Such compositions may be solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Such compositions may contain 10%-95%, preferably 1-70%, active ingredient.

肠道外给药一般是以注射为特征的，或者皮下，肌肉或者静脉。注射剂可以以常规形式制备，或者为液体溶液或悬浮液，适宜在注射前制成液体溶液或悬浮液的固体形式，或乳液。适宜的赋形剂是，例如水，盐水，葡萄糖，甘油，乙醇等等。此外，如果需要，给药的药物组合物也可以含有少量无毒辅助物质，如润湿剂或乳化剂，pH缓冲剂等，如乙酸钠，脱水山梨糖醇单月桂酸酯，三乙醇胺油酸酯等。Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injections can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like. In addition, the pharmaceutical composition for administration may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, etc., if desired, such as sodium acetate, sorbitan monolaurate, triethanolamine oleic acid Esters etc.

最近发明的非肠道给药途径是用缓释或控释系统的植入，以保持剂量的恒定水平。见美国专利3,710,795，插入此引作参考。在另一种最近的方式中，本发明组合物可以用美国专利申请09/321,522，申请日1999年5月27日公开的组合物和/或方法以控释的剂量形式给药，该专利的说明书插入此引作参考。A recently invented route of parenteral administration is the implantation of sustained or controlled release systems to maintain a constant level of dosage. See US Patent 3,710,795, which is incorporated herein by reference. In another more recent form, the compositions of the present invention may be administered in controlled release dosage form using the compositions and/or methods disclosed in U.S. Patent Application 09/321,522, filed May 27, 1999, which The specification is hereby incorporated by reference.

给哺乳动物，优选人通过其它已知的药物剂量形式服用一种或多种本发明化合物是在本发明范围内的，包括但不限于通过大丸剂，静脉注射，经皮给药，通过吸入，皮下给药，或其它的本领域技术人员已知的治疗剂给药方法或途径。It is within the scope of the present invention to administer one or more compounds of the present invention to a mammal, preferably a human, by other known pharmaceutical dosage forms including, but not limited to, by bolus, intravenously, transdermally, by inhalation, Subcutaneous administration, or other methods or routes of administration of therapeutic agents known to those skilled in the art.

下列实施例是本发明的代表，但不能被理解为是对权利要求范围的限定。The following examples are representative of the invention and should not be construed as limiting the scope of the claims.

                          实施例1Example 1

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基)丙基]-3，5-二甲基哌嗪基}乙酰胺(7)

Figure A0180544200671
N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxy)propyl]-3,5-dimethylpiperazinyl}acetamide (7)
Figure A0180544200671

A部分Part A

N-(2，6-二甲基苯基)-2-氯乙酰胺(3)的合成Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3)

将2，6-二甲基苯胺(9.8g，81.2mmol)溶解在乙醚(100mL)和饱和NaHCO3(100mL)水溶液中并将混合物在冰/水浴中冷却。用2小时在该冷却溶液中滴加氯代乙酰氯2(9.17g，81.2mmol)。将混合物加热至室温，维持14小时。用乙酸乙酯(3×50)萃取该混合物。将化合的有机层用硫酸镁干燥，过滤并浓缩。将残余物在乙醚中磨碎并过滤，得到化合物3，为白色固体。2,6-Dimethylaniline (9.8 g, 81.2 mmol) was dissolved in diethyl ether (100 mL) and saturated aqueous NaHCO 3 (100 mL) and the mixture was cooled in an ice/water bath. Chloroacetyl chloride 2 (9.17 g, 81.2 mmol) was added dropwise to the cooled solution over 2 hours. The mixture was warmed to room temperature for 14 hours. The mixture was extracted with ethyl acetate (3 x 50). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was triturated in ether and filtered to afford compound 3 as a white solid.

B部分Part B

N-(2，6-二甲基苯基)-2-(3，5-二甲基哌嗪基)乙酰胺(5)的合成Synthesis of N-(2,6-dimethylphenyl)-2-(3,5-dimethylpiperazinyl)acetamide (5)

在化合物3(5g，25.2mmol)的乙醇(100mL)溶液中加入2，6-二甲基哌嗪4(2.1g，25.0mmol)和N，N-二异丙基胺(3.2g，25.2mmol)。将反应混合物加热回流24小时。将混合物真空浓缩后，通过柱色谱(10∶1，DCM∶MeOH)纯化残余物，得到化合物5。

Figure A0180544200681
Add 2,6-dimethylpiperazine 4 (2.1 g, 25.0 mmol) and N, N-diisopropylamine (3.2 g, 25.2 mmol) to a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) ). The reaction mixture was heated to reflux for 24 hours. After the mixture was concentrated in vacuo, the residue was purified by column chromatography (10:1, DCM:MeOH) to afford compound 5.
Figure A0180544200681

C部分Part C

缩水甘油4-甲氧基苯基醚(6)的合成Synthesis of Glycidyl 4-Methoxyphenyl Ether (6)

将2-甲氧基苯酚(1.0g，8.0mmol)和表氯醇(3.7g，40.0mmol)溶解在丙酮(20mL)中。加入K2CO3(2.2g，16.0mmol)并将混合物加热至70℃，维持24小时。将反应混合物真空浓缩。将残余物溶解在100mL乙酸乙酯中，用100mL水洗涤，硫酸镁干燥。将混合物蒸发至干并用柱色谱(2∶1，己烷∶乙酸乙酯)将残余物纯化，得到化合物6。2-Methoxyphenol (1.0 g, 8.0 mmol) and epichlorohydrin (3.7 g, 40.0 mmol) were dissolved in acetone (20 mL). K 2 CO 3 (2.2 g, 16.0 mmol) was added and the mixture was heated to 70° C. for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate, washed with 100 mL of water, and dried over magnesium sulfate. The mixture was evaporated to dryness and the residue was purified by column chromatography (2:1, hexane:ethyl acetate) to give compound 6.

D部分Part D

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基)丙基]-3，5二甲基哌嗪基}乙酰胺(7)的合成N-(2,6-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxy)propyl]-3,5 dimethylpiperazinyl}acetamide ( 7) Synthesis of

在化合物5的10mL乙醇(0.4g，1.4mmol)溶液中加入化合物6(0.27g，1.5mmol)。将反应混合物加热回流24小时。将混合物真空浓缩并用Prep.TLC(10∶1，DCM∶MeOH)纯化残余物，得到化合物7。

Figure A0180544200691
Compound 6 (0.27 g, 1.5 mmol) was added to a solution of compound 5 in 10 mL of ethanol (0.4 g, 1.4 mmol). The reaction mixture was heated to reflux for 24 hours. The mixture was concentrated in vacuo and the residue was purified by Prep. TLC (10:1, DCM:MeOH) to give compound 7.
Figure A0180544200691

2-{(5S，2R)-4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-2，5-二甲基哌嗪基}-N-(2，6-二甲基苯基)乙酰胺(15)2-{(5S,2R)-4-[2-Hydroxy-3-(2-methoxyphenoxy)propyl]-2,5-dimethylpiperazinyl}-N-(2,6 -Dimethylphenyl)acetamide (15)

化合物15用化合物7的方法制备，但在B部分用(2R，5S)-二甲基哌嗪代替2，6-二甲基哌嗪4，得到化合物15；质谱(M+1)＝456.4。

Figure A0180544200692
Compound 15 was prepared by the method of compound 7, but substituting (2R,5S)-dimethylpiperazine for 2,6-dimethylpiperazine 4 in Part B to give compound 15; mass spectrum (M+1)=456.4.
Figure A0180544200692

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-2-氧代哌嗪基}乙酰胺(16)N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-2-oxopiperazinyl}acetamide (16)

化合物16用化合物7的方法制备，但在化合物7的B部分用4-苄氧基羰基-2-氧-哌嗪代替2，6-二甲基哌嗪4，在除去CBZ保护基(氢化-20psi，10％钯炭)后进行到最终目标，得到化合物16；质谱(M+1)＝442.41。

Figure A0180544200701
Compound 16 was prepared by the method of compound 7, but 2,6-dimethylpiperazine 4 was replaced with 4-benzyloxycarbonyl-2-oxo-piperazine in part B of compound 7, and after removing the CBZ protecting group (hydrogenation- 20 psi, 10% palladium on carbon) to the final target to obtain compound 16; mass spectrum (M+1) = 442.41.
Figure A0180544200701

2，5-二氮杂-5-[2-羟基-3-(2-甲氧基苯氧基)丙基]双环[4.4.0]癸-2-基}-N-(2，6-二甲基苯基)乙酰胺(17)2,5-diaza-5-[2-hydroxy-3-(2-methoxyphenoxy)propyl]bicyclo[4.4.0]dec-2-yl}-N-(2,6- Dimethylphenyl)acetamide (17)

化合物17用化合物7的方法制备，但在B部分用全氢喹啉代替2，6-二甲基哌嗪4，得到化合物15；质谱(M+1)＝482.4。

Figure A0180544200702
Compound 17 was prepared by the method of compound 7, but in Part B, perhydroquinoline was used instead of 2,6-dimethylpiperazine 4 to obtain compound 15; mass spectrum (M+1)=482.4.
Figure A0180544200702

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-3，3-二甲基哌嗪基}乙酰胺(18)N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,3-dimethylpiperazinyl } Acetamide (18)

化合物18用化合物7的方法制备，但在B部分用2，2-二甲基哌嗪代替2，6-二甲基哌嗪4得到化合物18；质谱(M+1)＝456.51。 Compound 18 was prepared by the method of compound 7, except that 2,6-dimethylpiperazine 4 was replaced by 2,2-dimethylpiperazine in part B to give compound 18; mass spectrum (M+1)=456.51.

2-{5-[(2S)-2-羟基-3-(2-甲氧基苯氧基)丙基](1S，4S)-2，5-二氮杂双环[2.2.1]庚-2-基}-N-(2，6二甲基苯基)乙酰胺(19)2-{5-[(2S)-2-Hydroxy-3-(2-methoxyphenoxy)propyl](1S,4S)-2,5-diazabicyclo[2.2.1]heptyl- 2-yl}-N-(2,6-dimethylphenyl)acetamide (19)

化合物19用化合物7的方法制备，但在B部分用(1S，4S)-(+)-2，5-二氮杂双环[2.2.1]庚烷代替2，6-二甲基哌嗪4，得到化合物19；质谱(M+1)＝481.5。

Figure A0180544200711
Compound 19 was prepared by the method of compound 7, but substituting (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane for 2,6-dimethylpiperazine in part B 4 , to obtain compound 19; mass spectrum (M+1)=481.5.
Figure A0180544200711

N-(2，6-二甲基苯基)-2-{4-[2-羟基-4-(2-甲氧基苯氧基)丁基]哌嗪基}乙酰胺(20)N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-4-(2-methoxyphenoxy)butyl]piperazinyl}acetamide (20)

化合物20用化合物7的方法制备，但在B部分用4-溴-1，2-环氧丁烷6b代替表氯醇6a得到化合物20；质谱(M+1)＝442.37。 Compound 20 was prepared by the method of compound 7, but 4-bromo-1,2-epoxybutane 6b was used instead of epichlorohydrin 6a in part B to give compound 20; mass spectrum (M+1)=442.37.

N-(2，6-二甲基苯基)-2-{4-[4-(4-氟苯氧基)-2-羟基丁基]哌嗪基}乙酰胺(21)N-(2,6-Dimethylphenyl)-2-{4-[4-(4-fluorophenoxy)-2-hydroxybutyl]piperazinyl}acetamide (21)

化合物21用化合物7的方法制备，但在B部分用4-溴-1，2-环氧丁烷6b代替表氯醇6a得到化合物21；质谱(M+1)＝430.35。

Figure A0180544200721
Compound 21 was prepared by the method of compound 7, but substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to give compound 21; mass spectrum (M+1)=430.35.
Figure A0180544200721

2-(4-{4-[4-(叔丁基)苯氧基]-2-羟基丁基}哌嗪基)-N-(2，6-二甲基苯基)乙酰胺(22)2-(4-{4-[4-(tert-butyl)phenoxy]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide (22)

化合物22用化合物7的方法制备，但在B部分用4-溴-1，2-环氧丁烷6b代替表氯醇6a得到化合物22；质谱(M+1)＝468.32。

Figure A0180544200722
Compound 22 was prepared by the method of compound 7, but substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to give compound 22; mass spectrum (M+1)=468.32.
Figure A0180544200722

N-(2，6-二甲基苯基)-2-{4-[2-羟基-4-(4-苯基苯氧基)丁基]哌嗪基}乙酰胺(23)N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-4-(4-phenylphenoxy)butyl]piperazinyl}acetamide (23)

化合物23用化合物7的方法制备，但在B部分用4-溴-1，2-环氧丁烷6b代替表氯醇6a得到化合物23；质谱(M+1)＝488.41。 Compound 23 was prepared by the method of compound 7, but substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to give compound 23; mass spectrum (M+1)=488.41.

N-(2，6-二甲基苯基)-2-{4-[2-羟基-4-(4-甲氧基苯氧基)丁基]哌嗪基}乙酰胺(24)N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-4-(4-methoxyphenoxy)butyl]piperazinyl}acetamide (24)

化合物24用化合物7的方法制备，但在B部分用4-溴-1，2-环氧丁烷6b代替表氯醇6a得到化合物24；质谱(M+1)＝442.37。Compound 24 was prepared by the method of compound 7, but substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to give compound 24; mass spectrum (M+1)=442.37.

                        实施例2Example 2

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-3-氧代哌嗪基}乙酰胺(14)N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-oxopiperazinyl}acetamide (14)

E部分Part E

(叔丁氧基)-N-(2-{[2-羟基-3-(2-甲氧基苯氧基)丙基]氨基}乙基)碳酰胺(11)的合成Synthesis of (tert-butoxy)-N-(2-{[2-hydroxy-3-(2-methoxyphenoxy)propyl]amino}ethyl)carboxamide (11)

将环氧化物6(1.0g，5.5mmol)和Boc-乙二胺(0.88g，5.5mmol)溶解在20mL乙醇中并将混合物加热回流24小时。将溶剂蒸发并用柱色谱(1∶1己烷∶乙酸乙酯)纯化残余物，得到化合物11。Epoxide 6 (1.0 g, 5.5 mmol) and Boc-ethylenediamine (0.88 g, 5.5 mmol) were dissolved in 20 mL of ethanol and the mixture was heated to reflux for 24 hours. The solvent was evaporated and the residue was purified by column chromatography (1:1 hexane:ethyl acetate) to give compound 11.

N-{2-[(叔丁氧基)羰基氨基]乙基}-2-氯-N-[2-羟基-3-(2-甲氧基苯氧基)丙基]乙酰胺(12)的合成N-{2-[(tert-butoxy)carbonylamino]ethyl}-2-chloro-N-[2-hydroxy-3-(2-methoxyphenoxy)propyl]acetamide (12) Synthesis

将化合物11(1.0g，3.0mmol)溶解在20mL DCM中并用二异丙基乙胺(0.76g，4.5mmol)处理。将混合物冷却至℃。在冷却的混合物中滴加氯代乙酰氯的5mL DCM溶液。将反应混合物室温搅拌24小时。将混合物用50mL DCM稀释并用50mL水和10％柠檬酸洗涤。将有机层用硫酸镁干燥并过滤。减压蒸发溶剂并用乙醚结晶残余物，得到化合物12。Compound 11 (1.0 g, 3.0 mmol) was dissolved in 20 mL of DCM and treated with diisopropylethylamine (0.76 g, 4.5 mmol). The mixture was cooled to °C. A solution of chloroacetyl chloride in 5 mL of DCM was added dropwise to the cooled mixture. The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with 50 mL DCM and washed with 50 mL water and 10% citric acid. The organic layer was dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was crystallized from diethyl ether to give compound 12.

1-[2-羟基-3-(2-甲氧基苯氧基)丙基]哌嗪-2-酮(13)的合成。Synthesis of 1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-2-one (13).

将化合物12(0.5g，1.5mmol)溶解在10mL TFA中。将混合物在室温搅拌2小时。减压除去TFA。将残余物溶解在20mL乙醇中并用二异丙基乙胺(0.76g，4.5mmol)处理。将混合物加热回流24小时。减压除去溶剂得到化合物13，不需纯化直接使用。Compound 12 (0.5 g, 1.5 mmol) was dissolved in 10 mL TFA. The mixture was stirred at room temperature for 2 hours. TFA was removed under reduced pressure. The residue was dissolved in 20 mL of ethanol and treated with diisopropylethylamine (0.76 g, 4.5 mmol). The mixture was heated to reflux for 24 hours. The solvent was removed under reduced pressure to obtain compound 13, which was used directly without purification.

F部分Part F

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-3-氧代哌嗪基}乙酰胺(14)的合成N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-oxopiperazinyl}acetamide Synthesis of (14)

在化合物13的10mL乙醇(0.1g，0.30mmol)溶液中加入化合物3(0.7g，0.36mmol)和二异丙基乙胺(0.76g，0.36mmol)。将反应混合物加热回流24小时。将混合物真空浓缩并用Prep.TLC(10∶1，DCM∶MeOH)纯化残余物，得到化合物14：质谱(M+1)＝442.34。Compound 3 (0.7 g, 0.36 mmol) and diisopropylethylamine (0.76 g, 0.36 mmol) were added to a solution of compound 13 in 10 mL of ethanol (0.1 g, 0.30 mmol). The reaction mixture was heated to reflux for 24 hours. The mixture was concentrated in vacuo and the residue was purified by Prep. TLC (10:1, DCM:MeOH) to give compound 14: mass spectrum (M+1)=442.34.

                    实施例3

Figure A0180544200741
Example 3
Figure A0180544200741

列于下面表1中的化合物用实施例2中化合物14的方法制备。The compounds listed in Table 1 below were prepared by the method of compound 14 in Example 2.

                      表1  R MH+  25  2，6-二甲基苯基 430.3  26  2，6-二氯苯基 471  27  4-氨基磺酰基苯基 481.2  28  3-三氟甲基-5-甲氧基苯基 500.2  29  5-茚满基 442.2  30  1-萘基 452.3  31  1-(4-氯萘基) 486.3  32  2-N-吡咯基-苯基 467.3  33  苯基 402.2  34  2-氯苯基 436.2  35  2-氯-4-甲基苯基 450.2  36  2-(1-甲基乙烯基)苯基 442.3  37  2-甲基苯基 416.2  38  2-异丙基-6-甲基苯基 458.4  39  3-甲硫基苯基 448.2  40  2-甲氧基-4-氯-5-甲基苯基 480.2  41  4-二甲基氨基苯基 445.3  42  2，4-二甲氧基苯基 462.3  43  3，4-二氯苯基 471.1  44  4-氯苯基 436.3  45  3-氯苯基 436.2  46  3，5-二氯苯基 471.1  47  4-甲氧基苯基 432.3  48  4-甲基苯基 416.2  49  3-甲基苯基 416.2  50  4-氟苯基 420.2  51  4-氰基苯基 427.3  52  4-乙酰基苯基 444  53  2-甲氧基苯基 432.4  54  4-三氟甲基苯基 470.2  55  3-三氟甲基-4-氯苯基 504.1  56  3，5-二甲氧基苯基 462.3  57  4-N-吗啉基苯基 487.4  58  3-氟-4-甲氧基苯基 450.2  59  3，4，5-三甲氧基苯基 492.3  60  3，4-二甲氧基苯基 490  61  2-氟-4-氯苯基 454.2  62  2-羟基甲基-6-甲基苯基 446 Table 1 R MH + 25 2,6-Dimethylphenyl 430.3 26 2,6-Dichlorophenyl 471 27 4-aminosulfonylphenyl 481.2 28 3-trifluoromethyl-5-methoxyphenyl 500.2 29 5-indanyl 442.2 30 1-Naphthyl 452.3 31 1-(4-Chloronaphthyl) 486.3 32 2-N-Pyrrolyl-phenyl 467.3 33 Phenyl 402.2 34 2-Chlorophenyl 436.2 35 2-Chloro-4-methylphenyl 450.2 36 2-(1-Methylvinyl)phenyl 442.3 37 2-Methylphenyl 416.2 38 2-isopropyl-6-methylphenyl 458.4 39 3-Methylthiophenyl 448.2 40 2-methoxy-4-chloro-5-methylphenyl 480.2 41 4-Dimethylaminophenyl 445.3 42 2,4-Dimethoxyphenyl 462.3 43 3,4-Dichlorophenyl 471.1 44 4-Chlorophenyl 436.3 45 3-Chlorophenyl 436.2 46 3,5-Dichlorophenyl 471.1 47 4-methoxyphenyl 432.3 48 4-Methylphenyl 416.2 49 3-Methylphenyl 416.2 50 4-fluorophenyl 420.2 51 4-cyanophenyl 427.3 52 4-Acetylphenyl 444 53 2-methoxyphenyl 432.4 54 4-Trifluoromethylphenyl 470.2 55 3-Trifluoromethyl-4-chlorophenyl 504.1 56 3,5-dimethoxyphenyl 462.3 57 4-N-morpholinophenyl 487.4 58 3-fluoro-4-methoxyphenyl 450.2 59 3,4,5-trimethoxyphenyl 492.3 60 3,4-Dimethoxyphenyl 490 61 2-fluoro-4-chlorophenyl 454.2 62 2-Hydroxymethyl-6-methylphenyl 446

                     实施例4Example 4

2-[4-(3-(2H-苯并[d]1，3-二氧杂环戊烯-5-基)-2-羟基丙基)哌嗪基]-N-(2，6二甲基苯基)乙酰胺(7B) 2-[4-(3-(2H-Benzo[d]1,3-dioxol-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6 di Methylphenyl)acetamide (7B)

A部分Part A

N-(2，6二甲基苯基)-2-氯乙酰胺(3B)的合成Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3B)

将2，6二甲基苯胺(9.8g，81.2mmol)溶解在乙醚(100mL)和饱和碳酸氢钠(100mL)中并将反应混合物在冰/水浴中冷却。用2小时在冷却的溶液中滴加氯代乙酰氯2B(9.17g，81.2mmol)。在14小时以上将混合物加热至室温。用乙酸乙酯(3×50)萃取混合物。用硫酸镁干燥化合的有机层，过滤并浓缩。用乙醚磨碎残余物并过滤，得到化合物3B，为白色固体。2,6 Dimethylaniline (9.8 g, 81.2 mmol) was dissolved in diethyl ether (100 mL) and saturated sodium bicarbonate (100 mL) and the reaction mixture was cooled in an ice/water bath. Chloroacetyl chloride 2B (9.17 g, 81.2 mmol) was added dropwise to the cooled solution over 2 hours. The mixture was warmed to room temperature over 14 hours. The mixture was extracted with ethyl acetate (3 x 50). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was triturated with ether and filtered to afford compound 3B as a white solid.

B部分Part B

N-(2，6二甲基苯基)-2-哌嗪基乙酰胺(5B)的合成Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5B)

在化合物3(5g，25.2mmol)的乙醇(100mL)溶液中加入化合物4B(2.1g，25.0mmol)和N，N-二异丙基胺(3.2g，25.2mmol)。将反应混合物加热回流24小时。将混合物真空浓缩并用柱色谱(10∶1，二氯甲烷∶甲醇)纯化残余物，得到化合物5B。Compound 4B (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25.2 mmol) were added to a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL). The reaction mixture was heated to reflux for 24 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, dichloromethane:methanol) to give compound 5B.

C部分Part C

5-(环氧乙烷-2-基甲基)-2H-苯并[d]1，3-二1噁烷(6B)的合成Synthesis of 5-(oxiran-2-ylmethyl)-2H-benzo[d]1,3-dioxane (6B)

在1小时内在冰冷却的8(1.0g，6.17mmol)的二氯甲烷溶液中滴加3-氯过氧苯甲酸(1.8g，10.43mmol)的20mL二氯甲烷溶液。将反应混合物室温搅拌12小时。将反应混合物过滤除去固体并真空浓缩。在残余物中加入二乙醚(200ml)，并用饱和碳酸氢钠(3×100ml)洗涤。有机层用硫酸镁干燥，真空浓缩。用Prep.TLC(2∶1己烷∶乙酸乙酯)纯化残余物，得到6B。To an ice-cooled solution of 8 (1.0 g, 6.17 mmol) in dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (1.8 g, 10.43 mmol) in 20 mL of dichloromethane over 1 hour. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered to remove solids and concentrated in vacuo. Diethyl ether (200ml) was added to the residue and washed with saturated sodium bicarbonate (3 x 100ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by Prep. TLC (2:1 hexane:ethyl acetate) to afford 6B.

D部分Part D

2-[4-(3-2H-苯并[d]1，3-二氧杂环戊烯-5-基)-2-羟基丙基]哌嗪基]-N-(2，6-二甲基苯基)乙酰胺(7B)2-[4-(3-2H-Benzo[d]1,3-dioxol-5-yl)-2-hydroxypropyl]piperazinyl]-N-(2,6-di Methylphenyl)acetamide (7B)

在化合物5B(0.4g，1.64mmol)的乙醇(100mL)溶液中加入化合物6B(0.38g，2.14mmol)的10mL乙醇溶液。将反应混合物回流24小时。将混合物真空浓缩，用Prep.TLC(10∶1二氯甲烷∶甲醇)纯化残余物，得到7B：质谱(MH+1)＝426.34。

Figure A0180544200771
To a solution of compound 5B (0.4 g, 1.64 mmol) in ethanol (100 mL) was added a solution of compound 6B (0.38 g, 2.14 mmol) in 10 mL of ethanol. The reaction mixture was refluxed for 24 hours. The mixture was concentrated in vacuo and the residue was purified by Prep. TLC (10:1 dichloromethane:methanol) to give 7B: mass spectrum (MH+1)=426.34.
Figure A0180544200771

N-(2，6-二甲基苯基)-2-[4-(2-羟基-4-苯基丁基)哌嗪基]乙酰胺(9B)N-(2,6-Dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide (9B)

化合物9B用化合物7B的方法制备，但在C部分用4-苯基-丁烯替换3-(3，4-亚甲基二氧基苯基)-1-丙烯，得到化合物9B：质谱(MH+1)＝396.32。

Figure A0180544200772
Compound 9B was prepared using the method of compound 7B, but substituting 4-phenyl-butene for 3-(3,4-methylenedioxyphenyl)-1-propene in part C to give compound 9B: mass spectrum (MH +1) = 396.32.
Figure A0180544200772

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲氧基苯基)丙基]哌嗪基}乙酰胺(10B)N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl}acetamide (10B)

化合物10B用化合物7B的方法制备，但在C部分用3-(2-甲氧基苯基)-1-丙烯替换3-(3，4-亚甲二氧基苯基)-1-丙烯得到化合物10B：质谱(MH+1)＝412.35。 Compound 10B was prepared by the method of compound 7B but substituting 3-(2-methoxyphenyl)-1-propene for 3-(3,4-methylenedioxyphenyl)-1-propene in Part C to give Compound 10B: mass spectrum (MH+1) = 412.35.

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(4-甲氧基苯基)丙基]哌嗪基}乙酰胺(11B)N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide (11B)

化合物11B用化合物7B的方法制备，但在C部分用3-(4-甲氧基苯基)-1-丙烯替换3-(3，4-亚甲二氧基苯基)-1-丙烯得到化合物11B：质谱(MH+1)＝412.35。

Figure A0180544200781
Compound 11B was prepared by the method of compound 7B but substituting 3-(4-methoxyphenyl)-1-propene for 3-(3,4-methylenedioxyphenyl)-1-propene in Part C to give Compound 11B: mass spectrum (MH+1) = 412.35.
Figure A0180544200781

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-苯基丙基]哌嗪基}乙酰胺(12B)N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-3-phenylpropyl]piperazinyl}acetamide (12B)

化合物12B用化合物7B的方法制备，但在C部分用3-苯基-1-丙烯替换3-(3，4-亚甲二氧基苯基)-1-丙烯得到化合物12B：质谱(MH+1)＝382。

Figure A0180544200782
Compound 12B was prepared by the method of compound 7B, but substituting 3-phenyl-1-propene for 3-(3,4-methylenedioxyphenyl)-1-propene in part C to give compound 12B: mass spectrum (MH+ 1) = 382.
Figure A0180544200782

N-(2，6-二甲基苯基)-2-[4-(2-羟基-3-萘基丙基]哌嗪基}乙酰胺(13B)N-(2,6-Dimethylphenyl)-2-[4-(2-hydroxy-3-naphthylpropyl]piperazinyl}acetamide (13B)

化合物13B用化合物7B的方法制备，但在C部分用3-(1-萘基)-1-丙烯替换3-(3，4-亚甲二氧基苯基)-1-丙烯得到化合物13：质谱(MH+1)＝432.55。Compound 13B was prepared by the method of compound 7B, but substituting 3-(1-naphthyl)-1-propene for 3-(3,4-methylenedioxyphenyl)-1-propene in part C to give compound 13: Mass spectrum (MH+1) = 432.55.

                     实施例5Example 5

A部分Part A

中间体(14B)：在4-甲氧基苄基氯(2mmol)的无水乙醚(10mL)溶液中，加入烯丙基溴化镁(4M1，1M THF溶液)并将反应混合物室温搅拌16小时。加入饱和氯化铵溶液(91mL)分离乙醚层，用水洗涤并干燥。碱压蒸发乙醚得到油状物烯烃14B。不需纯化用于下一步反应中。Intermediate (14B): To a solution of 4-methoxybenzyl chloride (2 mmol) in anhydrous ether (10 mL) was added allylmagnesium bromide (4M1, 1M in THF) and the reaction mixture was stirred at room temperature for 16 hours . A saturated ammonium chloride solution (91 mL) was added to separate the ether layer, washed with water and dried. Alkaline evaporation of ether afforded olefin 14B as an oil. It was used in the next reaction without purification.

B部分Part B

中间体(15B)：在1小时内，在冰冷却的15B的二氯甲烷溶液(2mmol)中滴加3-氯过氧苯甲酸(4mmol)的20mL二氯甲烷溶液。将反应混合物室温搅拌12小时。将反应混合物过滤除去任何固体并真空浓缩。在残余物中加入乙醚(200mL)，用饱和碳酸氢钠(3×100mL)洗涤。有机层用硫酸镁干燥，真空浓缩。用Prep.TLC(2∶1己烷∶乙酸乙酯)纯化残余物，得到15B。Intermediate (15B): To an ice-cooled solution of 15B in dichloromethane (2 mmol) was added dropwise a solution of 3-chloroperoxybenzoic acid (4 mmol) in 20 mL of dichloromethane. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered to remove any solids and concentrated in vacuo. Diethyl ether (200 mL) was added to the residue, washed with saturated sodium bicarbonate (3×100 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by Prep. TLC (2:1 hexane:ethyl acetate) to afford 15B.

C部分Part C

N-(2，6-二甲基苯基)-2-{4-[4-(4-甲氧基苯基)-2-羟基丁基]哌嗪基}乙酰胺(16B)N-(2,6-Dimethylphenyl)-2-{4-[4-(4-methoxyphenyl)-2-hydroxybutyl]piperazinyl}acetamide (16B)

在化合物5B(0.4g，1.64mmol)的乙醇(100mL)溶液中加入化合物15B(2.14mmol)的10mL乙醇溶液。将反应混合物回流24小时。将混合物真空浓缩，用Prep.TLC(10∶1二氯甲烷∶甲醇)纯化残余物，得到化合物16B。(M+1)＝426.3。

Figure A0180544200791
To a solution of compound 5B (0.4 g, 1.64 mmol) in ethanol (100 mL) was added a solution of compound 15B (2.14 mmol) in 10 mL of ethanol. The reaction mixture was refluxed for 24 hours. The mixture was concentrated in vacuo and the residue was purified by Prep. TLC (10:1 dichloromethane:methanol) to give compound 16B. (M+1)=426.3.
Figure A0180544200791

2-{4-[4-(2，6-二甲基苯基)-2-羟基丁基]哌嗪基}-N-(2，6-二甲基苯基)乙酰胺(17B)2-{4-[4-(2,6-Dimethylphenyl)-2-hydroxybutyl]piperazinyl}-N-(2,6-Dimethylphenyl)acetamide (17B)

化合物17B按照与化合物16B相似的方法制备，但用2，6-二氟苄基氯代替4-甲氧基苄基氯。(M+1)＝432.2。 Compound 17B was prepared in a similar manner to compound 16B, substituting 2,6-difluorobenzyl chloride for 4-methoxybenzyl chloride. (M+1)=432.2.

N-(2，6-二甲基苯基)-2-{4-[4-(2-氯苯基)-2-羟基丁基]哌嗪基}乙酰胺(18B)N-(2,6-Dimethylphenyl)-2-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide (18B)

化合物18B按照与化合物16B相似的方法制备，但用2-氯苄基氯代替4-甲氧基苄基氯。(M+1)＝430.2。 Compound 18B was prepared in a similar manner to compound 16B, substituting 2-chlorobenzyl chloride for 4-methoxybenzyl chloride. (M+1)=430.2.

2-(4-{4-[4-(叔丁基)苯基]-2-羟基丁基}哌嗪基)-N-(2，6-二甲基苯基)乙酰胺(19B)2-(4-{4-[4-(tert-butyl)phenyl]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide (19B)

化合物19B按照与化合物16B相似的方法制备，但用4-叔丁基苄基氯代替4-甲氧基苄基氯。(M+1)＝452.3。

Figure A0180544200811
Compound 19B was prepared in a similar manner to compound 16B, substituting 4-tert-butylbenzyl chloride for 4-methoxybenzyl chloride. (M+1)=452.3.
Figure A0180544200811

N-(2，6-二甲基苯基)-2-{4-[4-(2-氟苯基)-2-羟基丁基]哌嗪基}乙酰胺(20B)N-(2,6-Dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl}acetamide (20B)

化合物20B按照与化合物16B相似的方法制备，但用2-氟苄基氯代替4-甲氧基苄基氯。(M+1)＝414.2。 Compound 20B was prepared in a similar manner to compound 16B, substituting 2-fluorobenzyl chloride for 4-methoxybenzyl chloride. (M+1)=414.2.

N-(2，6-二甲基苯基)-2-(4-{2-羟基-4-[4-(三氟甲基)苯基]丁基}哌嗪基)乙酰胺(21B)N-(2,6-Dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide (21B)

化合物21B按照与化合物16B相似的方法制备，但用4-三氟甲基苄基氯代替4-甲氧基苄基氯。(M+1)＝464.2。 Compound 21B was prepared in a similar manner to compound 16B, substituting 4-trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M+1)=464.2.

2-[4-(3-(2H-苯并[d]1，3-二氧杂环戊烯-5-基)-2-羟基丙基)哌嗪基]-N-(2，6-二甲基苯基)-2-甲基丙酰胺(22B)2-[4-(3-(2H-Benzo[d]1,3-dioxol-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6- Dimethylphenyl)-2-methylpropanamide (22B)

该化合物用与化合物7B类似的方法制备，但在A部分用2-氯-2-甲基丙酰氯代替氯代乙酰氯。(M+1)＝454.54。

Figure A0180544200821
This compound was prepared in a similar manner to compound 7B, except that 2-chloro-2-methylpropionyl chloride was used instead of chloroacetyl chloride in Part A. (M+1)=454.54.
Figure A0180544200821

N-(2，6-二甲基苯基)-2-[4-(2-羟基-3-苯基丙基)哌嗪基]-2-甲基丙酰胺(23B)N-(2,6-Dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropionamide (23B)

该化合物用与化合物7B类似的方法制备，但在A部分用2-氯-2-甲基丙酰氯代替氯代乙酰氯，用烯丙基苯代替8B。(M+1)＝410.34。

Figure A0180544200822
This compound was prepared in a similar manner to compound 7B, except that in part A 2-chloro-2-methylpropionyl chloride was used instead of chloroacetyl chloride and allylbenzene was used instead of 8B. (M+1)=410.34.
Figure A0180544200822

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(3，4，5-三甲基苯基)丙基]哌嗪基}-2-甲基丙酰胺(24B)N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethylphenyl)propyl]piperazinyl}-2-methyl Propionamide (24B)

该化合物用与化合物7B类似的方法制备，但在A部分用2-氯-2-甲基丙酰氯代替氯代乙酰氯，和3，4，5-三甲氧基烷基苯代替8B。(M+1)＝472.54。 This compound was prepared in a similar manner to compound 7B, but substituting 2-chloro-2-methylpropanoyl chloride for chloroacetyl chloride and 3,4,5-trimethoxyalkylbenzene for 8B in part A. (M+1)=472.54.

N-(2，6-二甲基苯基)-2-[4-(2-羟基-5-苯基戊基)哌嗪基]乙酰胺(25B)N-(2,6-Dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide (25B)

该化合物用与化合物16B类似的方法制备，但在A部分用苯乙基氯代替-甲氧基苄基氯。(M+1)＝410.4。 This compound was prepared in a similar manner to compound 16B, but substituting phenethyl chloride for -methoxybenzyl chloride in part A. (M+1)=410.4.

N-(2，6-二甲基苯基)-2-{4-[5-(2-氟苯基)-戊基]哌嗪基}乙酰胺(26B)N-(2,6-Dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-pentyl]piperazinyl}acetamide (26B)

该化合物用与化合物16B类似的方法制备，但在A部分用2-氟苯乙基氯代替4-甲氧基苄基氯。(M+1)＝428.1。

Figure A0180544200832
This compound was prepared in a similar manner to compound 16B, but substituting 2-fluorophenethyl chloride for 4-methoxybenzyl chloride in part A. (M+1)=428.1.
Figure A0180544200832

N-(2，6-二甲基苯基)-2-{4-[5-(2-氯苯基)-戊基]哌嗪基}乙酰胺(27B)N-(2,6-Dimethylphenyl)-2-{4-[5-(2-chlorophenyl)-pentyl]piperazinyl}acetamide (27B)

该化合物用与化合物16B类似的方法制备，但在A部分用2-氯苯乙基氯代替4-甲氧基苄基氯。(M+1)＝444.3。This compound was prepared in a similar manner to compound 16B, but substituting 2-chlorophenethyl chloride for 4-methoxybenzyl chloride in Part A. (M+1)=444.3.

                        实施例6Example 6

N-(2，6-二甲基苯基)-2-[4-(2-羟基-3-茚满-2-基氧丙基)哌嗪基乙酰胺(7C)N-(2,6-Dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinylacetamide (7C)

A部分Part A

N-(2，6-二甲基苯基)-2-氯乙酰胺(3C)的合成Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3C)

2，6-二甲基苯胺(9.8g，81.2mmol)溶解在乙醚(100mL)和饱和碳酸氢钠(100mL)中，并将反应混合物在冰/水浴中冷却。用2小时向该冷却溶液中滴加氯代乙酰氯2C(9.17g，81.2mmol)。将反应混合物加热到室温，维持14小时。将混合物用100mL乙醚稀释并将有机层用硫酸镁干燥，过滤并浓缩得到化合物3C，为白色固体。2,6-Dimethylaniline (9.8 g, 81.2 mmol) was dissolved in diethyl ether (100 mL) and saturated sodium bicarbonate (100 mL), and the reaction mixture was cooled in an ice/water bath. To this cooled solution was added dropwise chloroacetyl chloride 2C (9.17 g, 81.2 mmol) over 2 hours. The reaction mixture was warmed to room temperature for 14 hours. The mixture was diluted with 100 mL of ether and the organic layer was dried over magnesium sulfate, filtered and concentrated to afford compound 3C as a white solid.

B部分Part B

N-(2，6-二甲基苯基)-2-哌嗪基乙酰胺(5C)的合成Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5C)

在化合物3C的100mL乙醇溶液(5g，25.2mmol)中加入化合物4C(2.1g，25.0mmol)和N，N-二异丙基乙胺(3.2g，25.2mmol)。将反应混合物回流24小时。将反应混合物真空浓缩并用柱色谱(10∶1，DCM∶MeOH)纯化残余物，得到化合物5C。Compound 4C (2.1 g, 25.0 mmol) and N,N-diisopropylethylamine (3.2 g, 25.2 mmol) were added to compound 3C in 100 mL ethanol solution (5 g, 25.2 mmol). The reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM:MeOH) to give compound 5C.

C部分Part C

2-(环氧乙烷-2-基甲氧基)丙烷(6C)的合成Synthesis of 2-(oxiran-2-ylmethoxy)propane(6C)

在冷却到0度的60％NaH(0.18g，4.5mmol)的DMF(10mL)溶液中滴加2-丙醇(0.5g，3.73mmol)的DMF(2mL)溶液。搅拌30分钟后滴加环氧溴丙烷(1.11g，8.18mmol)的DMF(1ml)溶液。将反应物加热至室温搅拌48小时。真空除去溶剂并用Prep.TLC(30∶1，DCM∶MeOH)纯化残余物，得到化合物6C。A solution of 2-propanol (0.5 g, 3.73 mmol) in DMF (2 mL) was added dropwise to a solution of 60% NaH (0.18 g, 4.5 mmol) in DMF (10 mL) cooled to 0°C. After stirring for 30 minutes, a solution of epibromohydrin (1.11 g, 8.18 mmol) in DMF (1 mL) was added dropwise. The reaction was warmed to room temperature and stirred for 48 hours. The solvent was removed in vacuo and the residue was purified by Prep. TLC (30:1, DCM:MeOH) to give compound 6C.

D部分Part D

N-(2，6-二甲基苯基)-2-[4-(2-羟基-3-茚满-2-基氧丙基)哌嗪基]乙酰胺(7C)的合成Synthesis of N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]acetamide (7C)

在6C(0.43g，2.3mmol)的乙醇(4ml)溶液中加入5C(0.405g，1.64mmol)。将该溶液加热回流搅拌24小时。完成后将溶液真空浓缩并用Prep.TLC(10∶1，DCM∶MeOH)纯化，得到7C。质谱(M+1)＝438.36。

Figure A0180544200841
To a solution of 6C (0.43g, 2.3mmol) in ethanol (4ml) was added 5C (0.405g, 1.64mmol). The solution was stirred at reflux for 24 hours. Upon completion the solution was concentrated in vacuo and purified by Prep. TLC (10:1, DCM:MeOH) to afford 7C. Mass spectrum (M+1) = 438.36.
Figure A0180544200841

2-({2-[4-(3-异丙氧基-2-羟基丙基)哌嗪基]-N-({2，6-二甲基苯基)乙酰胺(10C)2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide (10C)

化合物10C用与化合物7 C类似的方法制备，但在D部分用商购的缩水甘油异丙醚代替2-(环氧乙烷-2-基甲氧基)茚满得到10C：质谱(M+1)＝364.37。

Figure A0180544200851
Compound 10C was prepared in a similar manner to compound 7C, but substituting commercially available glycidyl isopropyl ether for 2-(oxiran-2-ylmethoxy)indan in part D to give 10C: mass spectrum (M+ 1) = 364.37.
Figure A0180544200851

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(苯基甲氧基)丙基]哌嗪基}乙酰胺(11C)N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-3-(phenylmethoxy)propyl]piperazinyl}acetamide (11C)

化合物11C用与化合物7C类似的方法制备，但在D部分用商购的苄基缩水甘油醚代替2-(环氧乙烷-2-基甲氧基)茚满得到11C：质谱(M+1)＝412.36。 Compound 11C was prepared in a similar manner to compound 7C, but substituting commercially available benzyl glycidyl ether for 2-(oxiran-2-ylmethoxy)indan in Part D to give 11C: mass spectrum (M+1 ) = 412.36.

2-({2-[4-(3-环戊氧基-2-羟基丙基)哌嗪基]-N-({2，6-二甲基苯基)乙酰胺(12C)2-({2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide (12C)

化合物12C用与化合物7C类似的方法制备，但在C部分用商购的环戊醇代替2-二氢茚醇得到12C：MS(MH+1)＝390。Compound 12C was prepared in a similar manner to compound 7C, but substituting commercially available cyclopentanol for 2-indanol in Part C to give 12C: MS(MH+1)=390.

2-({2-[4-(3-环己氧基-2-羟基丙基)哌嗪基]-N-({2，6-二甲基苯基)乙酰胺(13C)2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide (13C)

化合物13C用与化合物7C类似的方法制备，但在C部分用商购的环己醇代替2-二氢茚醇得到13C：MS(MH+1)＝404。 Compound 13C was prepared in a similar manner to compound 7C, but substituting commercially available cyclohexanol for 2-indanol in Part C to give 13C: MS(MH+1)=404.

2-[4-(3-{[4-(叔丁基)苯基]甲氧基}-2-羟基丙基)哌嗪基]-N-(2，6-二甲基苯基)乙酰胺(14C)：2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)ethyl Amide (14C):

化合物14C用与化合物7C类似的方法制备，但在C部分用商购的4-叔丁基苄基醇代替2-丙醇得到13C：MS(M+1)＝468.44。 Compound 14C was prepared in a similar manner to compound 7C, but substituting commercially available 4-tert-butylbenzyl alcohol for 2-propanol in Part C to give 13C: MS (M+1) = 468.44.

N-(2，6-二甲基苯基)-2-(4-{3-[(2-氟苯基)甲氧基]-2-羟基丙基}哌嗪基)乙酰胺(15C)：N-(2,6-Dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide (15C) :

化合物15C用与化合物7C类似的方法制备，但在C部分用商购的2-氟苄基醇代替2-丙醇：MS(M+1)＝430.39。 Compound 15C was prepared in a similar manner to compound 7C, but substituting commercially available 2-fluorobenzyl alcohol for 2-propanol in part C: MS (M+1) = 430.39.

2-(4-{3-[(2，4-二氟苯基)甲氧基]-2-羟基丙基}哌嗪基)-N-(2，6-二甲基苯基)乙酰胺(16C)：2-(4-{3-[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide (16C):

化合物16C用与化合物7类似的方法制备，但在C部分用商购的2，4-二氟苄基醇代替2-丙醇：MS(M+1)＝448.38。 Compound 16C was prepared in a similar manner to compound 7, but substituting commercially available 2,4-difluorobenzyl alcohol for 2-propanol in part C: MS (M+1) = 448.38.

N-(2，6-二甲基苯基)-2-[4-(2-羟基-3-{[4-(三氟甲基)苯基]甲氧基}丙基)哌嗪基]乙酰胺(17C)：N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl] Acetamide (17C):

化合物17C用与化合物7C类似的方法制备，但在C部分用商购的4-三氟甲基-苄基醇代替2-丙醇：MS(M+1)＝480.37。

Figure A0180544200872
Compound 17C was prepared in a similar manner to compound 7C, but substituting commercially available 4-trifluoromethyl-benzyl alcohol for 2-propanol in part C: MS (M+1) = 480.37.
Figure A0180544200872

N-(2，6-二甲基苯基)-2-(4-{2-羟基-3-[(2-甲氧基苯基)甲氧基]丙基}哌嗪基)乙酰胺(18C)：N-(2,6-dimethylphenyl)-2-(4-{2-hydroxyl-3-[(2-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide ( 18C):

化合物18C用与化合物7C类似的方法制备，但在C部分用商购的2-甲氧基-苄基醇代替2-丙醇：MS(M+1)＝442.41。

Figure A0180544200873
Compound 18C was prepared in a similar manner to compound 7C, but substituting commercial 2-methoxy-benzyl alcohol for 2-propanol in part C: MS (M+1) = 442.41.
Figure A0180544200873

2-(4-{3-[(2，4-甲氧基苯基)甲氧基]-2-羟基丙基}哌嗪基)-N-(2，6-二甲基苯基)乙酰胺(19C)：2-(4-{3-[(2,4-methoxyphenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)ethyl Amide (19C):

化合物19C用与化合物7C类似的方法制备，但在C部分用商购的2，4-二甲氧基-苄基醇代替代替2-丙醇：MS(M+1)＝472.42。

Figure A0180544200881
Compound 19C was prepared in a similar manner to compound 7C, but in part C, commercially available 2,4-dimethoxy-benzyl alcohol was used instead of 2-propanol: MS (M+1) = 472.42.
Figure A0180544200881

N-(2，6-二甲基苯基)-2-(4-{2-羟基-3-[(4-甲氧基苯基)甲氧基]丙基}哌嗪基)乙酰胺(20C)：N-(2,6-dimethylphenyl)-2-(4-{2-hydroxyl-3-[(4-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide ( 20C):

化合物20C用与化合物7C类似的方法制备，但在C部分用商购的4-甲氧基-苄基醇代替2-丙醇：MS(M+1)＝442.42。 Compound 20C was prepared in a similar manner to compound 7C, but substituting commercially available 4-methoxy-benzyl alcohol for 2-propanol in part C: MS (M+1) = 442.42.

N-(2，6-二甲基苯基)-2-(4-{3-[(4-氟苯基)甲氧基]-2-羟基丙基}哌嗪基)乙酰胺(21C)：N-(2,6-Dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide (21C) :

化合物21C用与化合物7C类似的方法制备，但在C部分用商购的4-氟-苄基醇代替2-丙醇：MS(M+1)＝430.40。 Compound 21C was prepared in a similar manner to compound 7C, but substituting commercially available 4-fluoro-benzyl alcohol for 2-propanol in part C: MS (M+1) = 430.40.

N-(2，6-二甲基苯基)-2-(4-{2-羟基-3-[(4-甲基苯基)甲氧基]丙基}哌嗪基)乙酰胺(22C)：N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}piperazinyl)acetamide (22C ):

化合物22C用与化合物7C类似的方法制备，但在C部分用商购的4-甲基-苄基醇代替2-丙醇：MS(M+1)＝426.41。

Figure A0180544200891
Compound 22C was prepared in a similar manner to compound 7C, but substituting commercially available 4-methyl-benzyl alcohol for 2-propanol in part C: MS (M+1) = 426.41.
Figure A0180544200891

N-(2，6-二甲基苯基)-2-(4-{2-羟基-3-[(4-苯基苯基)甲氧基]丙基}哌嗪基)乙酰胺(23C)：N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}piperazinyl)acetamide (23C ):

化合物23C用与化合物7C类似的方法制备，但在C部分用商购的4-苯基-苄基醇代替2-丙醇：MS(M+1)＝488.42。

Figure A0180544200892
Compound 23C was prepared in a similar manner to compound 7C, but substituting commercially available 4-phenyl-benzyl alcohol for 2-propanol in part C: MS (M+1) = 488.42.
Figure A0180544200892

N-(2，6-二甲基苯基)-2-(4-{3-[(4-丁基苯基)甲氧基]-2-羟基丙基}哌嗪基)乙酰胺(24C)：N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide (24C ):

化合物24C用与化合物7C类似的方法制备，但在C部分用商购的4-正丁基-苄基醇代替2-丙醇：MS(M+1)＝468.45。 Compound 24C was prepared in a similar manner to compound 7C, but substituting commercial 4-n-butyl-benzyl alcohol for 2-propanol in Part C: MS (M+1) = 468.45.

N-(2，6-二甲基苯基)-2-{4-[2-羟基-3-(2-萘基甲氧基)丙基]哌嗪基}乙酰胺(25C)：N-(2,6-Dimethylphenyl)-2-{4-[2-hydroxy-3-(2-naphthylmethoxy)propyl]piperazinyl}acetamide (25C):

化合物25C用与化合物7C类似的方法制备，但在C部分用商购的2-萘基甲醇代替2-丙醇：MS(M+1)＝462.41。

Figure A0180544200901
Compound 25C was prepared in a similar manner to compound 7C, but substituting commercial 2-naphthylmethanol for 2-propanol in part C: MS (M+1) = 462.41.
Figure A0180544200901

N-(2，6-二甲基苯基)-2-{4-[3-(环己基甲氧基)-2-羟基丙基]哌嗪基}乙酰胺(26C)：N-(2,6-Dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl}acetamide (26C):

化合物26C用与化合物7C类似的方法制备，但在C部分用商购的环己基甲醇代替2-丙醇：MS(M+1)＝418.55。

Figure A0180544200902
Compound 26C was prepared in a similar manner to compound 7C, but substituting commercially available cyclohexylmethanol for 2-propanol in Part C: MS (M+1) = 418.55.
Figure A0180544200902

N-(2，6-二甲基苯基)-2-(4-{3-[(4-氟苯基)甲氧基]-2-羟基丙基}-3，3-二甲基哌嗪基)乙酰胺(27C)：N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperene Azinyl)acetamide (27C):

化合物27C用与化合物7C类似的方法制备，但在C部分用商购的4-氟苄基醇代替2-丙醇和在B部分用2，2-二甲基哌嗪代替化合物4。MS(M+1)＝458.5。Compound 27C was prepared in a similar manner to compound 7C, but substituting commercial 4-fluorobenzyl alcohol for 2-propanol in part C and 2,2-dimethylpiperazine for compound 4 in part B. MS (M+1) = 458.5.

                     实施例7Example 7

线粒体试验Mitochondrial test

用Nedergard和Cannon(Methods in Enzymol，55，3，1979)等分离大鼠心脏线粒体。Rat heart mitochondria were isolated by Nedergard and Cannon (Methods in Enzymol, 55, 3, 1979).

棕榈酰基辅酶A氧化——棕榈酰基辅酶A氧化是在总体积100毫升含有下列的试剂中进行：110mM KCl，pH8的33mM Tris缓冲液，2mM Kpi，2mM MgCl2，0.1mM EDTA，14.7mM脱脂BSA，0.5mM苹果酸，13mM肉碱，1mM ADP，52mg线粒体蛋白质，和16mM 1-C14棕榈酰基辅酶A(Sp.活性60mCi/mmol；20mCi/ml，每一试验用5毫升)。将本发明化合物以下列浓度加入DMSO中：100mM，30mM，和3mM。在每个试验中，使用DMSO作对照。在30℃15分钟后，将酶反应物离心(20,000g，1分钟)，并将70毫升上清液加入活化的反相硅酸柱上(约0.5ml硅酸)。用2ml水洗脱该柱，并用0.5ml洗脱液作为闪烁计数以捕获的C14碳酸氢盐离子测定C14的量。Palmitoyl-CoA Oxidation - Palmitoyl-CoA oxidation was performed in a total volume of 100 ml containing the following reagents: 110 mM KCl, 33 mM Tris buffer pH 8, 2 mM Kpi, 2 mM MgCl 2 , 0.1 mM EDTA, 14.7 mM defatted BSA , 0.5 mM malic acid, 13 mM carnitine, 1 mM ADP, 52 mg mitochondrial protein, and 16 mM 1-C14 palmitoyl-CoA (Sp. activity 60 mCi/mmol; 20 mCi/ml, 5 ml per assay). Compounds of the invention were added in DMSO at the following concentrations: 100 mM, 30 mM, and 3 mM. In each experiment, DMSO was used as a control. After 15 minutes at 30° C., the enzyme reaction was centrifuged (20,000 g, 1 minute) and 70 ml of the supernatant was applied to an activated reverse-phase silicic acid column (approximately 0.5 ml silicic acid). The column was eluted with 2 ml of water and 0.5 ml of the eluate was used as scintillation counting to determine the amount of C14 from the captured C14 bicarbonate ion.

                  表1棕榈酰基肉碱作为底物对线粒体脂肪酸氧化的抑制Table 1 Inhibition of mitochondrial fatty acid oxidation by palmitoylcarnitine as a substrate

       ——在3种浓度下的对照％ 化合物#  100μM 30μM 3μM 雷诺嗪  75％ 90％ -- 14  -- -- -- 7  85％ 98％ 107％ 15  78％ 97％ 103％ 17  89％ 98％ 100％ 16  100％ 96％ -- 18  17％ 19  - 22  25％ 23  - 9B  84％ 84％ -- 10B  -- -- -- 7B  -- -- -- 11B  83％ 92％ -- 12B  42％ 95％ 13B  -- --  -- 16B  37％ 17B  78％ 18B  78％ 19B  35％ 20B  56％ 21B  56％ 23B  70％ 24B  72％ 10C  100％ 97％ -- 7C  68％ -- -- 11C  79％ -- -- 12C  41％ -- -- 13C  30％ -- -- 14C  21％ - - 15C  100％ - - 16C  97％ - - 17C  35％ - - 18C  96％ - - 19C  97％ - - 20C  100％ - - 21C  87％ - - 22C  45％ - - 23C  12％ - - 24C  15％ - - 25C  38％ - - 26C  70％ - - 27C  73％ - - ——Contrast % at 3 concentrations compound# 100μM 30μM 3μM ranolazine 75% 90% -- 14 -- -- -- 7 85% 98% 107% 15 78% 97% 103% 17 89% 98% 100% 16 100% 96% -- 18 17% 19 - twenty two 25% twenty three - 9B 84% 84% -- 10B -- -- -- 7B -- -- -- 11B 83% 92% -- 12B 42% 95% 13B -- -- -- 16B 37% 17B 78% 18B 78% 19B 35% 20B 56% 21B 56% 23B 70% 24B 72% 10C 100% 97% -- 7C 68% -- -- 11C 79% -- -- 12C 41% -- -- 13C 30% -- -- 14C twenty one% - - 15C 100% - - 16C 97% - - 17C 35% - - 18C 96% - - 19C 97% - - 20C 100% - - 21C 87% - - 22C 45% - - 23C 12% - - 24C 15% - - 25C 38% - - 26C 70% - - 27C 73% - -

                         实施例8Example 8

棕榈酰基肉碱的氧化Oxidation of palmitoylcarnitine

棕榈酰基肉碱的氧化在总体积100毫升含有下列的试剂中进行：110mM KCl，Ph8的33Mm Tris缓冲液，2mM Kpi，2mM MgCl2，0.1mMEDTA，0.1mg/ml脱脂BSA，0.5mM苹果酸，3mM ADP，52毫克线粒体蛋白质，和43mM 1-C14棕榈酰基肉碱(Sp.活性60mCi/mmol；20mCi/ml，每一试验用5毫升)。将本发明化合物以下列浓度加入DMSO溶液中：100mM，30mM，和3mM。在每个试验中，使用DMSO作对照。在30℃，15分钟后，将酶反应物离心分离(20,000g，1分钟)，并将70毫升上清液加入活化的反相硅酸柱上(约0.5ml硅酸)。用2ml水洗脱该柱，并用0.5ml洗脱液作闪烁计数以捕获的C14碳酸氢盐离子测定C14的量。数据表示为对照的％活性。Oxidation of palmitoylcarnitine was carried out in a total volume of 100 ml containing the following reagents: 110 mM KCl, 33 Mm Tris buffer Ph8, 2 mM Kpi, 2 mM MgCl 2 , 0.1 mM EDTA, 0.1 mg/ml defatted BSA, 0.5 mM malic acid, 3 mM ADP, 52 mg mitochondrial protein, and 43 mM 1-C14 palmitoylcarnitine (Sp. activity 60 mCi/mmol; 20 mCi/ml, 5 mL per assay). Compounds of the present invention were added to DMSO solutions at the following concentrations: 100 mM, 30 mM, and 3 mM. In each experiment, DMSO was used as a control. After 15 minutes at 30° C., the enzyme reaction was centrifuged (20,000 g, 1 minute), and 70 ml of the supernatant was added to an activated reverse-phase silicic acid column (approximately 0.5 ml silicic acid). The column was eluted with 2 ml of water and the amount of C14 was determined by scintillation counting of the captured C14 bicarbonate ion with 0.5 ml of the eluate. Data are expressed as % activity of control.

                  表2棕榈酰基肉碱作为底物对线粒体脂肪酸氧化的抑制              Table 2 Inhibition of mitochondrial fatty acid oxidation by palmitoylcarnitine as a substrate

     ——在3种浓度下的对照％ 化合物# 100μM  30μM  3μM 雷诺嗪 63％  98％  -- 14 --  --  -- 7 95％  102％  109％ 15 82％  98％  106％ 17 80％  88％  103％ 16 64％  --  -- 9B --  --  -- 10B --  --  -- 7B --  --  -- 11B --  --  -- 12B 56％  --  -- 13B --  --  -- 10C 80％  --  -- 7C --  --  -- 11C --  --  -- 12C --  --  -- 13C --  --  -- ——Contrast % at 3 concentrations compound# 100μM 30μM 3μM ranolazine 63% 98% -- 14 -- -- -- 7 95% 102% 109% 15 82% 98% 106% 17 80% 88% 103% 16 64% -- -- 9B -- -- -- 10B -- -- -- 7B -- -- -- 11B -- -- -- 12B 56% -- -- 13B -- -- -- 10C 80% -- -- 7C -- -- -- 11C -- -- -- 12C -- -- -- 13C -- -- --

                        实施例9Example 9

代谢稳定性：为了测定本发明化合物的代谢稳定性，用人肝S-9微粒体部分保温培养。在37℃，30分钟后，用LC质谱测定保留的母体药物的量。每个化合物的响应因子通过建立标准曲线并在样品分析期间使用内标而测定。5个试验中在30分钟的时间点保留的雷诺嗪百分数的平均值是57％。本发明化合物在如下方案中测定并且用保留的母体百分数除以保留的雷诺嗪的平均值(57％)得到代谢稳定因子。化合物的稳定性数大于1.2的，在肝S-9测定中比雷诺嗪稳定。化合物的稳定性数在1.2h和0.8之间的，在肝S-9测定中与雷诺嗪具有相同的稳定性。化合物的稳定性数小于0.8，在肝S-9测定中比雷诺嗪的稳定性差。Metabolic Stability: To determine the metabolic stability of the compounds of the present invention, human liver S-9 microsomal fractions were incubated. After 30 min at 37°C, the amount of parent drug retained was determined by LC mass spectrometry. Response factors for each compound were determined by establishing a standard curve and using an internal standard during sample analysis. The mean of the percent ranolazine retained at the 30 minute time point over the 5 trials was 57%. Compounds of the invention were assayed in the following protocol and the metabolic stability factor was obtained by dividing the percent parent retained by the mean value of ranolazine retained (57%). Compounds with a stability number greater than 1.2 are more stable than ranolazine in the liver S-9 assay. Compounds with stability numbers between 1.2h and 0.8 have the same stability as ranolazine in the liver S-9 assay. The compound has a stability number less than 0.8, which is less stable than ranolazine in the liver S-9 assay.

该试验的目的是为了在人肝S9部分保温培养30分钟后，对本发明化合物的保留百分数与雷诺嗪的保留百分数进行比较。The purpose of this test is to compare the percent retention of the compounds of the invention with that of ranolazine after incubation of human liver S9 fractions for 30 minutes.

试剂：Reagent:

使用下列试剂：磷酸钾，0.5M pH7.4(保温缓冲液)，保持在室温；保持在4℃的0.05M MgCl2；β-烟酰胺腺嘌呤二核苷酸磷酸酯，四钠盐，还原形式(NADPH)，在使用当天从Sigma Lot#79H7044制备的0.02M在水中的溶液(～16.6mg/mL)。1mM雷诺嗪或化合物43，45，47，52，70，74，76，78，和80在ACN中进一步稀释得到100μM在10％的ACN中的溶液；从Gentest得到的人S9原料：20mg/mL。The following reagents were used: potassium phosphate, 0.5M pH 7.4 (incubation buffer), kept at room temperature; 0.05M MgCl 2 kept at 4°C; β-nicotinamide adenine dinucleotide phosphate, tetrasodium salt, reduced Form (NADPH), a 0.02M solution in water (-16.6 mg/mL) prepared on the day of use from Sigma Lot #79H7044. 1 mM ranolazine or compounds 43, 45, 47, 52, 70, 74, 76, 78, and 80 were further diluted in ACN to give a 100 μM solution in 10% ACN; human S9 stock from Gentest: 20 mg/mL .

方法：method:

保温培养的混合物制备如下：The incubation mixture was prepared as follows:

                   表3  成分 每0.25mL保温混合物的体积  最终浓度  10μM CMT化合物 25μL  10μM  MgCl2 25μL  0.005M  NADPH 25μL  0.002M  S9 25μL  2mg/mL  保温缓冲液 25μL  0.05M  水 125μL  ---- table 3 Element Volume per 0.25mL incubation mixture final concentration 10 μM CMT compound 25 μL 10μM MgCl2 25 μL 0.005M NADPH 25 μL 0.002M S9 25 μL 2mg/mL Incubation buffer 25 μL 0.05M water 125μL ----

*保温混合物中使用1％有机溶剂(乙腈)。通常，通过预先混合0.75mLMgCl2，0.75mL保温缓冲液，0.75mLNADPH，3.75mL水一次制备30个培养物。然后吸移200μL/保温液，加入25μL试验化合物，混合，并通过加入S-9开始反应。 * 1% organic solvent (acetonitrile) was used in the incubation mixture. Typically, 30 cultures were prepared at once by premixing 0.75 mL MgCl 2 , 0.75 mL incubation buffer, 0.75 mL NADPH, 3.75 mL water. Then 200 μL/incubation was pipetted, 25 μL of test compound was added, mixed, and the reaction was started by adding S-9.

将所有成分用保温缓冲液混合，并再吸移200μL/管+25μL试验化合物以及25μLS-9。All components were mixed with incubation buffer and an additional 200 μL/tube + 25 μL test compound plus 25 μL S-9 was pipetted.

在37℃预保温5分钟后，在0和30分钟搅拌反应液，除去50μl保温混合物的等分试样并加入100μL含有内标的9∶1乙腈∶甲醇。After a 5 minute pre-incubation at 37°C, the reaction was stirred at 0 and 30 minutes, a 50 μl aliquot of the incubation mixture was removed and 100 μL of 9:1 acetonitrile:methanol containing an internal standard was added.

将混合物离心并将100μL上清液的等分试样在1mL溶剂C中(0.1％甲酸水溶液)稀释。变化化合物与内标的比例并在时间0和30分钟通过LC/MS(注射10μL)分析样品。The mixture was centrifuged and a 100 [mu]L aliquot of the supernatant was diluted in 1 mL of solvent C (0.1% formic acid in water). The ratio of compound to internal standard was varied and samples were analyzed by LC/MS (10 μL injection) at time 0 and 30 minutes.

分析和数据计算：Analysis and data calculation:

用内标和ODS-C18柱以0.25ml/分钟的流速，通过LC/MS对用于开始化合物和有效的代谢物的样品进行分析。下面将上述方法所得的雷诺嗪与本发明化合物比较的相对稳定性因子列于表4中。如果化合物在肝S9测定中比雷诺嗪更稳定，则稳定性因子大于1.0。如果化合物没有雷诺嗪稳定，则稳定性因子小于1.0。Samples for starting compounds and effective metabolites were analyzed by LC/MS with internal standard and ODS-C18 column at a flow rate of 0.25 ml/min. The relative stability factors of the ranolazine obtained by the above method compared with the compound of the present invention are listed in Table 4 below. If the compound is more stable than ranolazine in the liver S9 assay, the stability factor is greater than 1.0. If the compound is less stable than ranolazine, the stability factor is less than 1.0.

        表4  化合物#  肝S9稳定性因子  雷诺嗪  1.0  5  0.45  7  1.51  15  1.20  16  0.15  17  0.45  9B  1.18  10B  1.03  7B  1.46  11B  1.33  12B  1.38  13B  0.10  16B  0.99  17B  0.71  18B  0.68  19B  -  20B  -  21B  -  22B  1.49  23B  0.5  24B  1.05  25B  -  26B  -  27B  -  21C  --  22C  0.61  23C  0.05  24C  0.02  25C  0.01  26C  --  27C  -- Table 4 compound# hepatic S9 stability factor ranolazine 1.0 5 0.45 7 1.51 15 1.20 16 0.15 17 0.45 9B 1.18 10B 1.03 7B 1.46 11B 1.33 12B 1.38 13B 0.10 16B 0.99 17B 0.71 18B 0.68 19B - 20B - 21B - 22B 1.49 23B 0.5 24B 1.05 25B - 26B - 27B - 21C -- 22C 0.61 23C 0.05 24C 0.02 25C 0.01 26C -- 27C --

Claims (95)

1. the substituted piperazine like compound that has following structural: Wherein X is selected from following groups:
Figure A0180544200022
With
Figure A0180544200023
M=1 or 2 or 3 wherein;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22, R wherein 2And R 3Can be joined together to form have 3 to 4 carbon atoms condense ring system and R 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-15Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, and aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system with 1-4 carbon atom, and R wherein 9And R 10, R 11And R 12, R 13And R 14Or R 15And R 16Can be joined together to form the bridged ring system with 1-5 carbon atom, condition is to work as R 24Be phenyl and as X be The time, R 9, R 10, R 11, R 12, R 13, R 15And R 16Be not hydrogen entirely;
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces;
R 23Be selected from H, C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl, CN, O-C 1-6Alkyl and CF 3Substituting group replace; And
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 3 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, C 1-2Alkyl, and aryl, this aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, and C 1-6The substituting group of alkyl replaces, and
R wherein 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
2. the substituted piperazine like compound that has the claim of following structural:
Figure A0180544200041
M=1 or 2 or 3 wherein;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22, R wherein 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-15Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, and aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system with 1-4 carbon atom, and R wherein 9And R 10, R 11And R 12, R 13And R 14Or R 15And R 16Can be joined together to form the bridged ring system with 1-5 carbon atom, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen entirely;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces; And
R 23Be selected from H, C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl, CN ,-O-C 1-6Alkyl and CF 3Substituting group replace.
3. the compound of claim 2, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-8Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, SR 23And N (R 23) 2, R wherein 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-8Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-4Alkyl, and aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the bridged ring system that comprises 1 to 4 carbon atom;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
4. the compound of claim 2, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-6Alkyl, C 2-6Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by one and be selected from CF 3And OR 23Substituting group replace R wherein 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1 to 4 carbon atom;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, COR 23, CO 2R 23, CON (R 23) 2, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces; And
R 23Be selected from H, C 1-8Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen ,-O-C 1-3Alkyl and CF 3Substituting group replace.
5. the compound of claim 2, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-6Alkyl, C 2-6Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by OR 23Replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, COR 23, CO 2R 23, CON (R 23) 2, C 1-8Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3And OR 23
R 22Be selected from C 1-4Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, O-C 1-3Alkyl and CF 3Substituting group replaces; And
R 23Be selected from H, C 1-5Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen ,-OMe and CF 3Substituting group replace.
6. the compound of claim 5, wherein m=1 or 2.
7. the compound of claim 5, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-3Alkyl, C 2-6Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by OR 23Replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, COR 23, CO 2R 23, CON (R 23) 2, C 1-8Alkyl;
R 22Be C 1-4Alkyl; With
R 23Be selected from H and C 1-5Alkyl.
8. the compound of claim 5, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-3Alkyl, C 2-6Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by OR 23Replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, COR 23, CO 2R 23, CON (R 23) 2And C 1-8Alkyl;
R 22Be C 1-2Alkyl; With
R 23Be selected from H and C 1-2Alkyl.
9. the compound of claim 5, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-3Alkyl, C 2-3Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by OR 23Replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another, wherein R 9And R 10Can form carbonyl or R together 13And R 14Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23And C 1-2Alkyl;
R 22It is methyl; With
R 23Be selected from H and methyl.
10. the compound of claim 5, wherein R 18, R 19, R 20, and R 21Be respectively hydrogen, and R 17Be selected from halogen and OR 2
11. the compound of claim 10, wherein R 12Be (S)-methyl and R 9, R 10, R 11, R 13, R 14, R 15And R 16Dividing is hydrogen.
12. the compound of claim 10, wherein R 9And R 10Form carbonyl together, R 11, R 12, R 13, R 14, R 15And R 16Dividing is hydrogen.
13. the compound of claim 10, wherein R 9, R 10, R 11, R 12, R 15And R 16Dividing is hydrogen and R 13And R 14Form carbonyl together.
14. the compound that claim 3 to 13 is any, wherein m=1.
15. the compound of claim 10, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-3Alkyl, C 2-3Thiazolinyl, N-morpholinyl, and pyrryl, wherein alkyl substituent can be chosen wantonly by OH and replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-.
16. the compound of claim 2, wherein m=1 or 2;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22, and C 1-2Alkyl, wherein R 22Be C 1-2Alkyl;
R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, or R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen simultaneously, and R wherein 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1 to 4 carbon atom;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, OR 23, C 1-4Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3And OR 23R wherein 23Be C 1-2Alkyl.
17. the compound of claim 16, wherein R 1, R 2, R 3, R 4And R 5Be selected from hydrogen independently of one another, and methyl.
18. the compound of claim 16, wherein R 6, R 7And R 8Be respectively hydrogen.
19. the compound of claim 16, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, or R 9And R 10Form carbonyl together, or R 15And R 16Can form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen and R wherein simultaneously 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be connected to form the ring that comprises 1 to 2 carbon atom.
20. the compound of claim 16, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, or R 9And R 10Form carbonyl together, or R 11And R 12Can form carbonyl, R together 13Or R 14Can form carbonyl or R together 15And R 16Can form carbonyl together.
21. the compound of claim 16, wherein R 9And R 10Form carbonyl together, R 15And R 16Form carbonyl together, perhaps R 9And R 10Form carbonyl R simultaneously together 15And R 16Form carbonyl together.
22. the compound of claim 16, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, C 1-4Alkyl and OR 22R wherein 22Be C 1-2Alkyl.
23. the compound of claim 2 wherein
m＝1；
R 1, R 2, R 3, R 4And R 5Be selected from hydrogen independently of one another, and methyl;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, or R 9And R 10Form carbonyl together, or R 11And R 12Form carbonyl together, or R 13And R 14Form carbonyl together, or R 15And R 16Can form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen simultaneously, and R wherein 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 11Can be connected to form the ring that comprises 1 to 4 carbon atom.
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, C 1-4Alkyl and OR 22With
R 22Be C 1-2Alkyl;
24. the compound of claim 23, wherein R 1And R 5Be respectively methyl and R 2, R 3, and R 4Be respectively hydrogen.
25. the compound of claim 23, wherein R 11, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen and R 9And R 10Form carbonyl together.
26. the compound of claim 23, wherein R 9, R 10, R 11, R 12, R 15And R 16Be respectively hydrogen and R 13And R 14Form carbonyl together.
27. the compound of claim 23, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen and methyl.
28. the compound of claim 23, wherein R 9, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen and R 10And R 11Form ring together with 1 to 4 carbon atom.
29. the compound of claim 23, wherein R 9, R 10, R 12, R 13, R 14And R 16Be respectively hydrogen and R 11And R 15Form ring together with 1 to 3 carbon atom.
30. the compound of claim 23, wherein R 18, R 19, and R 21Be respectively hydrogen and R 17And R 18Be respectively methyl.
31. the compound of claim 23, wherein R 17Be-OCH 3, and R 18, R 19, R 20And R 21Be respectively hydrogen.
32. the compound of claim 23, wherein R 17, R 18, R 20And R 21Be respectively hydrogen and R 19Be selected from-OCH 3,-F, C 1-4Alkyl and unsubstituted aryl.
33. the compound of claim 2; be selected from N-(2; the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3-oxygen piperazinyl } ethanamide; N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3; 5-lupetazin base } ethanamide; 2-{ (5S; 2R)-and 4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-2; 5-lupetazin base }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; 2-{2; 5-diaza-5-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] dicyclo [4.4.0] last of the ten Heavenly stems-2-yl }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; N-(2; the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3-oxygen piperazinyl } ethanamide; N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3; 3-lupetazin base } ethanamide; 2-{5-[(2 S)-and 2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] (1S; 4S)-2; 5-diazabicyclo [2.2.1] heptan-2-yl }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-4-(2-methoxyl group phenoxy group) butyl] piperazinyl } ethanamide, N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[4-(4-fluorophenoxy)-2-hydroxybutyl] piperazinyl } ethanamide; 2-(4-{4-[4-(tertiary butyl) phenoxy group]-the 2-hydroxybutyl } piperazinyl)-N-(2, the 6-3,5-dimethylphenyl) ethanamide, N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-4-(4-phenyl phenoxy group) butyl] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-4-(4-methoxyl group phenoxy group) butyl] piperazinyl } ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2, the 6-dichlorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-sulfamyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(5-methoxyl group-3-(trifluoromethyl) phenyl] ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-indane-5-yl acetamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-the N-naphthyl acetamide, 2-{ (3S)-4-[(2 S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloronaphthyl, methylnaphthyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-pyrryl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-phenyl acetanilide,Phenacetylaniline, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-chloro-phenyl-) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-chloro-4-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[2-(1-methyl ethylene) phenyl] ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-aminomethyl phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(6-methyl-2-(methylethyl) phenyl] ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-methylthio group phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-2-methoxyl group-5-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[4-(dimethylamino) phenyl] ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2, the 4-Dimethoxyphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; the 4-dichlorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-phenyl-) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-chloro-phenyl-) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; the 5-dichlorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-p-methoxy-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-fluorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-cyano-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-acetylphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-p-methoxy-phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[4-(trifluoromethyl) phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-3-(trifluoromethyl) phenyl] ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; the 5-Dimethoxyphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-morpholine-4-base phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-fluoro-4-p-methoxy-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; 4; the 5-trimethoxyphenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3, the 4-Dimethoxyphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-2-fluorophenyl) ethanamide, and 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[2-(hydroxymethyl-6-aminomethyl phenyl] ethanamide.
34. have the substituted piperazine like compound of following structural:
M=or 1 or 2 or 3 wherein;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-15Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2Or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, and wherein two R groups comprise 1-4 carbon atom together, and R wherein 9And R 10, R 11And R 12, R 13And R 14Or R 15And R 16Can be joined together to form spiro system, and wherein two R groups comprise 1-5 carbon atom together.
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22And R 17And R 18, R 18And R 19, R 19And R 20Or R 20And R 21Comprise 5 to 6 carbon atoms in conjunction with forming, wherein 0 to 2 carbon atom saturated rings that can be replaced by Sauerstoffatom and wherein R 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces; And
R 23Be selected from H, C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, list or dialkyl amido, alkyl, CN, O-C 1-6Alkyl and CF 3Substituting group replace.
35. the compound of claim 34, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, heterocyclic radical, aryl, and heteroaryl;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-8Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1-4 carbon atom together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-15Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23And R wherein 17And R 18, R 18And R 19, R 19And R 20Or R 20And R 21Comprise 5 to 6 carbon atoms in conjunction with forming, 0 to 2 carbon atom saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from C 1-8Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, CN, CF 3Substituting group replace; And
R 23Be selected from H, C 1-8Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl, CN, or CF 3Substituting group replace.
36. the compound of claim 34, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, C 1-8Alkyl, aryl, and heteroaryl;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-5Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-4Alkyl, or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1-2 carbon atom together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, C 1-8Alkyl, aryl, and heteroaryl, and R 19And R 20Can comprise 5 carbon atoms in conjunction with formation, 2 carbon atoms saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from C 1-6Alkyl, aryl; And
R 23Be selected from H, C 1-6Alkyl, aryl.
37. the compound of claim 34, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, C 1-6Alkyl;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-3Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1-2 carbon atom together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, C 1-6Alkyl, and R 19And R 20Comprise 5 carbon atoms in conjunction with forming, 2 carbon atoms saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from C 1-3Alkyl; And
R 23Be selected from H, C 1-3Alkyl.
38. the compound of claim 37, wherein m=1 or 2 or 3.
39. the compound of claim 37, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, methyl, wherein R 9And R 10Can form carbonyl, R together 13And R 14Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1-2 carbon atom together.
40. the compound of claim 37, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another.
41. the compound of claim 39 or 40, wherein R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another.
42. the compound of claim 37, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be hydrogen.
43. the compound of claim 37, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, C 1-2Alkyl;
R 6It is hydrogen atom; And
R 7And R 8Be selected from hydrogen or methyl independently of one another; And
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-3Alkyl, wherein R 9And R 10Can form carbonyl or R together 13And R 14Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, C 1-6Alkyl, and R 19And R 20Can comprise 5 carbon atoms in conjunction with formation, 2 carbon atoms saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from methyl; With
R 23Be selected from H, methyl.
44. the compound of claim 43, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, and methyl.
45. the compound of claim 43, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another.
46. the compound of claim 43, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, OR 23, C 1-4Alkyl, and R 19And R 20Can comprise 5 carbon atoms in conjunction with formation, 2 carbon atoms saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-.
47. the compound of claim 43, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, OR 23, C 1-4Alkyl, and R 19And R 20In conjunction with formation-O-CH 2-O-or-OCH 2CH 2O-and R wherein 17And R 18Can form together-CH=CH-CH=CH-.
48. the compound of claim 34, wherein m=1 or 2;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22, C 1-2Alkyl, wherein R 22Be C 1-2Alkyl;
R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, or R 9And R 10Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1-4 carbon atom; And
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, OR 23, C 1-3Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein R 23Be C 1-2Alkyl, and R wherein 17And R 18Or R 18And R 19Can form together to be selected from and comprise-CH=CH-CH=CH--O-CH 2-O and-O-CH 2-CH 2The ring of-O-.
49. the compound of claim 48, wherein R 1, R 2, R 3, R 4And R 5Be selected from hydrogen and methyl independently of one another.
50. the compound of claim 48, wherein R 6, R 7And R 8Be respectively hydrogen.
51. the compound of claim 48, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-3Alkyl.
52. the compound of claim 48, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another.
53. the compound of claim 15, wherein R 9And R 10Form carbonyl together, R 15And R 16Form carbonyl or R together 9And R 10Form carbonyl and R together 15And R 16Also form carbonyl together.
54. the compound of claim 48, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, C 1-4Alkyl, OR 22, R wherein 22Be C 1-2Alkyl.
55. the compound of claim 48, wherein R 17And R 18Or R 18And R 19Form to be selected from together and comprise-CH=CH-CH=CH--O-CH 2The ring of-O-.
56. the compound of claim 34, wherein
M=1 or 2;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen and methyl;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, or R 9And R 10Can form carbonyl, R together 11And R 12Can form carbonyl, R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1-4 carbon atom;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, C 1-4Alkyl, CF 3And OR 22And
R 22Be C 1-2Alkyl.
57. the compound of claim 56, wherein R 1And R 5Be respectively methyl and R 2, R 3And R 4Be respectively hydrogen.
58. the compound of claim 56, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another.
59. the compound of claim 56, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen.
60. the compound of claim 56, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen respectively, Cl, F ,-OCH 3,-CF 3And C 1-4Alkyl.
61. the compound of claim 60, wherein R 18, and R 20Be respectively hydrogen.
62. the compound of claim 60, wherein R 19Be-OCH 3
63. the compound of claim 56, wherein R 17Be-OCH 3, and R 18, R 19, R 20, and R 21Be respectively hydrogen.
64. the compound of claim 56, wherein R 17, R 18, R 20And R 21Be respectively hydrogen and R 19Be selected from-OCH 3,-F ,-CF 3, C 1-4
65. the compound of claim 34 is selected from N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxy-4-phenyl butyl) piperazinyl] ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-p-methoxy-phenyl) propyl group] piperazinyl } ethanamide; 2-[4-(3-(2H-benzo [d] 1,3-dioxole (dioxolen)-5-yl)-2-hydroxypropyl) piperazinyl]-N-(2,6 3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(4-p-methoxy-phenyl) propyl group] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-phenyl propyl] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(4-p-methoxy-phenyl)-2-hydroxybutyl] piperazinyl } ethanamide; 2-{4-[4-(2, the 6-difluorophenyl)-2-hydroxybutyl] piperazinyl }-N-(2, the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(2-chloro-phenyl-)-2-hydroxybutyl] piperazinyl } ethanamide; 2-(4-{4-[4-(tertiary butyl) phenyl-2-hydroxybutyl } piperazinyl)-N-(2, the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-(4-{2-hydroxyl-4-[4-(trifluoromethyl) phenyl] butyl } piperazinyl) ethanamide; 2-[4-(3-(2H-benzo [d] 1,3-dioxole-5-yl)-and the 2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl)-the 2-methyl propanamide, N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-phenyl propyl) piperazinyl]-the 2-methyl propanamide, N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(3,4, the 5-trimethoxyphenyl) propyl group] piperazinyl }-the 2-methyl propanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-[4-(2-hydroxyl-5-phenylpentyl) piperazinyl] ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-2-hydroxyl-amyl group] piperazinyl } ethanamide, and N-(2, the 6-3,5-dimethylphenyl)-2-{4-[5-(2-chloro-phenyl-)-2-hydroxyl-amyl group] piperazinyl } ethanamide.
66. have the substituted piperazine like compound of following structural:
M=1 wherein, 2, or 3;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 20, SR 20, N (R 20) 2, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, NR 20CON (R 20) 2, COR 20, CO 2R 20, CON (R 20) 2, NR 20SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 20, SR 20, N (R 20) 2, S (O) R 22And SO 2R 22
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 20, CON (R 20) 2, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 20, N (R 20) 2, CO 2R 20, CON (R 20) 2Or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together, condition is R 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1-3 carbon atom;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 3 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, C 1-2Alkyl, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, C 1-6The substituting group of alkyl replaces,
R 20Be selected from H, C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen, alkyl, single-or two-alkylamino, alkyl, CN ,-O-C 1-6Alkyl or CF 3And
R 22Be selected from C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces;
67. the compound of claim 66, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 20, SR 20, N (R 20) 2, SO 2N (R 20) 2, CO 2R 20, CON (R 20) 2, C 1-8Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 20, SR 20, N (R 20) 2, S (O) R 22And SO 2R 22
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CON (R 20) 2, C 1-4Alkyl, or R wherein 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together; And
R 20Be selected from H, C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen, alkyl, single-or two-alkylamino, alkyl cyano group ,-O-C 1-6Alkyl or CF 3
68. the compound of claim 66, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 20, C 1-5Alkyl, C 2-3Thiazolinyl, or C 2-3Alkynyl, wherein alkyl can be chosen wantonly by CF 3Replace;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CON (R 20) 2, or C 1-4Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, C 1-2Alkyl, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, C 1-6The substituting group of alkyl replaces; And
R 20Be selected from H, C 1-8Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen ,-O-C 1-3Alkyl or CF 3
69. the compound of claim 66, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 20, C 1-3Alkyl, C 2-3Thiazolinyl, or C 2-3Alkynyl, wherein alkyl can be chosen wantonly by CF 3Replace;
R 6, R 7And R 8Be selected from hydrogen or methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen or C independently of one another 1-2Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, OR 20, S (O) R 22, C 1-2Alkyl, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, C 1-6The substituting group of alkyl replaces; And
R 20Be selected from H, C 1-5Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen ,-O-Me or CF 3
70. the compound of claim 66, wherein m=1 or 2;
R wherein 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22And C 1-4Alkyl, and R wherein 22Be C 1-3Alkyl;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CON (R 20) 2, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen, CF 3, OR 20, N (R 20) 2, CON (R 20) 2Or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together; Condition is R 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form ring;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, and C 1-6The substituting group of alkyl replaces; And
R 20Be selected from H, C 1-3Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen ,-O-Me and CF 3
71. the compound of claim 70, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, or R 9And R 10Form carbonyl together, or R 11And R 12Form carbonyl together, or R 13And R 14Form carbonyl together, or R 15And R 16Form carbonyl together, R 10And R 11Formation-CH together 2CH 2CH 2CH 2-.
72. the compound of claim 70, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CON (R 20) 2, C 1-3Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen, N (R 20) 2, and aryl, or R wherein 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl together, condition is R 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form ring.
73. the compound of claim 70, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, or C 1-2Alkyl, wherein alkyl substituent can be chosen wantonly by 1 and be selected from N (R 20) 2, or the substituting group of aryl replaces, or R wherein 9And R 10Form carbonyl together.
74. the compound of claim 66, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 20Or C 1-3Alkyl, wherein alkyl substituent can be chosen wantonly by CF 3Replace.
75. the compound of claim 66, wherein R 6, R 7And R 8Be selected from hydrogen or methyl independently of one another.
76. the compound of claim 66, wherein m=1;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, CF 3, OR 20Or C 1-2Alkyl;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen or C independently of one another 1-2Alkyl, or R wherein 9And R 10Can form carbonyl together;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 2 and be selected from halogen, phenyl, CF 3, OR 20, and C 1-4The substituting group of alkyl replaces; And
R 20Be selected from H or C 1-3Alkyl.
77. the compound of claim 76, wherein R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 2 and be selected from halogen, phenyl, CF 3, OR 20, and C 1-4The substituting group of alkyl replaces.
78. the compound of claim 66, wherein R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 2 and be selected from halogen, phenyl, CF 3, OR 20, and C 1-4The substituting group of alkyl replaces.
79. the compound of claim 76, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OCH 3Or methyl.
80. the compound of claim 76, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen or methyl.
81. the compound of claim 76, wherein R 11And R 15Be selected from hydrogen or methyl respectively, R 9, R 10, R 12, R 13, R 14And R 16Be respectively hydrogen, and R 9And R 10Can form carbonyl together.
82. the compound of claim 66, wherein m=1;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, or methyl;
R 6, R 7And R 8Be respectively hydrogen;
R 11And R 15Be respectively hydrogen or methyl, R 9, R 10, R 12, R 13, R 14And R 16Be respectively hydrogen, and R 9And R 10Can form carbonyl together;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 2 and be selected from halogen, phenyl, CF 3, OR 20, and C 1-4The substituting group of alkyl replaces; And
R 20Be methyl or hydrogen.
83. the compound of claim 82, wherein R 24Be alkyl and cycloalkyl with 1 to 6 carbon atom.
84. the compound of claim 82, wherein R 24Be to choose wantonly to be selected from halogen, CF by 1 to 2 3, OR 20, C 1-2The condensed benzyl ring alkyl that alkyl and aryl replace.
85. the compound of claim 82, wherein R 24Be to choose wantonly to be selected from halogen, CF by 1 to 2 3, OR 20, C 1-4The condensed phenyl methyl that alkyl and aryl replace.
86. the compound of claim 82, wherein R 2, R 3, and R 4Be respectively hydrogen and R 1And R 5Be respectively methyl.
87. the compound of claim 66, wherein m=1;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen or methyl;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen; And
R 24Be selected from alkyl, have the cycloalkyl of 4 to 6 carbon atoms, and wherein phenyl is optional is selected from halogen, CF by 1 to 2 with 1 to 6 carbon atom 3, OH, the condensed benzyl ring alkyl that the substituting group of methyl and aryl replaces, and aryl is optional is selected from halogen, CF by 1 to 2 3, OH, C 1-2The substituting group of alkyl and aryl replaces.
88. the compound of claim 66 is selected from: 2-{2-[4-(3-isopropoxy-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-indane-2-base oxygen propyl group) piperazinyl] ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(phenyl methoxyl group) propyl group] piperazinyl } ethanamide, 2-(2-[4-(3-cyclopentyloxy-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide; 2-(2-[4-(3-cyclohexyl oxygen base-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide; 2-[4-(3-{[4-(tertiary butyl) phenyl] methoxyl group } the 2-hydroxypropyl) piperazinyl]-N-(2,6 dimethyl propyls) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide, 2-(4-{3[(2, the 4-difluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl)-N-(2,6 dimethyl propyls) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-[4-(2-hydroxyl-3-{[4-(trifluoromethyl) phenyl] methoxyl group } propyl group) piperazinyl] ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(2-p-methoxy-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, 2-(4-{3[(2, the 4-p-methoxy-phenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl)-N-(2,6 dimethyl propyls) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(4-p-methoxy-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(4-aminomethyl phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(4-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-butyl phenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(2-naphthyl methoxyl group) propyl group] piperazinyl } ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-{4-[3-(cyclohexyl methoxyl group)-2-hydroxypropyl] piperazinyl } ethanamide, and N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl) methoxyl group]-the 2-hydroxypropyl }-3,3-lupetazin base) ethanamide.
89. methods of treatment; comprise claim 1 compound of taking the treatment significant quantity to the Mammals of the following treatment of needs: the damage that the opposing of protection skeletal muscle is caused by wound; skeletal muscle after protection muscle or systemic disease such as the intermittent claudication; treatment shock disease; donor tissue that protection is used for transplanting and organ and treatment cardiovascular disorder.
90. the method for claim 89, wherein cardiovascular disorder is selected from atrium and ventricle arrhythmia, and PrinzmetalShi (variation) angina is stablized the angina that angina and motion cause, congestive heart disease, or myocardial infarction.
91. the method for claim 89, the scope of wherein treating significant quantity about 0.01 to about 100mg/kg weight of mammal.
92. the compound of claim 89, wherein Mammals is the people.
93. comprise the pharmaceutical composition of claim 1 compound and one or more drug excipients.
94. the pharmaceutical composition of claim 93, wherein pharmaceutical composition is the solution form.
95. the pharmaceutical composition of claim 93, wherein pharmaceutical composition is tablet or capsule form.
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CN107043361A (en) * 2017-05-25 2017-08-15 合肥医工医药有限公司 Treat anginal compound, Preparation method and use

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CN107043361A (en) * 2017-05-25 2017-08-15 合肥医工医药有限公司 Treat anginal compound, Preparation method and use
CN107043361B (en) * 2017-05-25 2019-07-02 合肥医工医药股份有限公司 Compound for treating angina pectoris, preparation method and use

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