WO2016107603A1 - Substituted nitrogen-containing heterocyclic derivatives and applications thereof - Google Patents

Substituted nitrogen-containing heterocyclic derivatives and applications thereof Download PDF

Info

Publication number
WO2016107603A1
WO2016107603A1 PCT/CN2015/100201 CN2015100201W WO2016107603A1 WO 2016107603 A1 WO2016107603 A1 WO 2016107603A1 CN 2015100201 W CN2015100201 W CN 2015100201W WO 2016107603 A1 WO2016107603 A1 WO 2016107603A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
mmol
alkyl
substituted
Prior art date
Application number
PCT/CN2015/100201
Other languages
French (fr)
Chinese (zh)
Inventor
李德群
Original Assignee
成都贝斯凯瑞生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 成都贝斯凯瑞生物科技有限公司 filed Critical 成都贝斯凯瑞生物科技有限公司
Publication of WO2016107603A1 publication Critical patent/WO2016107603A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings

Definitions

  • the present technology relates to the treatment of hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia), hepatic steatosis, type II diabetes, hyperglycemia, insulin resistance, obesity, metabolic syndrome and Uses, compounds and compositions in anti-tumor.
  • hyperlipidemia including hypertriglyceridemia and hypercholesterolemia
  • hepatic steatosis hepatic steatosis
  • type II diabetes hepatic steatosis
  • hyperglycemia hepatic steatosis
  • insulin resistance obesity
  • metabolic syndrome Uses, compounds and compositions in anti-tumor.
  • Metabolic Syndrome is a pathological state in which a variety of metabolic components are abnormally aggregated. It is a complex metabolic disorder syndrome and is a risk factor for diabetes and cardiovascular and cerebrovascular diseases.
  • Cardio-cerebral vascular disease is the number one killer of human health. Its cause is very complicated. Hyperlipidemia is regarded as a very important risk factor by most people. With the improvement of living standards and the acceleration of aging, hyperlipidemia The incidence and mortality of the disease increased significantly, and there are reports in the literature that dyslipidemia is the main cause of atherosclerosis, coronary heart disease, and myocardial infarction.
  • Hyperlipidemia is often explained by the fact that fat metabolism or abnormal function causes one or more lipids in plasma to be above normal. Hyperlipidemia is a systemic disease, usually referred to as serum total cholesterol (TC), triglyceride (TG) or high density lipoprotein cholesterol (HDL-C) is too low, modern medicine called dyslipidemia . Lipids are insoluble or sparingly soluble in water, so they must bind to proteins to form lipoproteins. Therefore, hyperlipidemia is also commonly referred to as hyperlipoproteinemia.
  • TC serum total cholesterol
  • TG triglyceride
  • HDL-C high density lipoprotein cholesterol
  • Hyperlipidemia and cerebral infarction The increase of cholesterol in the blood is easy to form atherosclerotic plaque. When these plaques accumulate in the arterial wall, the arterial cavity will be narrowed, and the blood will flow into the corresponding part, which will cause kinetic energy defect. When it occurs in the cerebral blood vessels, it can cause cerebral infarction. Medical evidence: long-term lipid-lowering treatment can not only treat cerebral infarction, but also prevent cerebral infarction.
  • Coronary heart disease is also known as coronary atherosclerotic heart disease. Coronary artery is the main artery that supplies blood to the heart. If too much fat is deposited, it will cause arteriosclerosis, which will hinder blood flow, cause heart ischemia, and a series of symptoms, namely coronary heart disease. There are many risk factors for coronary heart disease, such as: high blood lipids, smoking, obesity, high blood pressure, lack of physical activity, diabetes, family history of coronary heart disease, etc. Among them, high blood lipids are one of the important risk factors for coronary heart disease. Therefore, the most basic treatment for coronary heart disease is to regulate blood lipids.
  • Fatty liver refers to the accumulation of fat in the liver, often accompanied by increased blood lipids.
  • the incidence of fatty liver is as high as 5-10%, and about 35% of adult patients with transaminase are fatty liver. Some severe patients can develop cirrhosis. Therefore, fatty liver treatment should also be treated with lipid-lowering.
  • Hyperlipidemia and diabetes Hypertension, hyperlipidemia and hyperglycemia are often referred to as “three highs” and are a major factor threatening the health of people with diabetes. The three are closely related, high blood lipids can aggravate the symptoms of diabetes, most diabetic patients with high blood lipids, more likely to cause stroke, coronary heart disease, limb necrosis, fundus lesions, kidney disease, neuropathy, etc., therefore, in addition to treatment of hyperglycemia in diabetic patients In addition, attention should be paid to regulating blood lipids, which is very important to reduce mortality and disability in diabetic patients.
  • Hyperlipidemia is defined as a dyslipidemia or dyslipidemia. Usually refers to the body's blood lipid concentration is beyond the normal range. Includes triglyceride (TG), serum total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C) or low-density lipoprotein cholesterol (LDL-C) levels and high-density lipoprotein cholesterol (HDL-C) Level reduction With the in-depth study of hyperlipidemia and cardiovascular disease, people began to realize that hypolipidemicemia is very important for reducing the risk of cardiovascular disease.
  • TG triglyceride
  • TC serum total cholesterol
  • VLDL-C very low-density lipoprotein cholesterol
  • LDL-C low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • the blood lipid-lowering drugs commonly used in the market mainly include statins, fibrates, niacins, and bile acid sequestrants.
  • Statins represent drugs: atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, and the like. These drugs are the fastest-developing lipid-lowering drugs in recent years, mainly to inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the serum total cholesterol (TC) synthesis pathway. The activity reduces TC synthesis; increases the number of low-density lipoprotein receptors, accelerates LDL degradation, and increases HDL content, which is beneficial to the clearance and transport of TC.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • statins the side effects are inevitable, such as: rhabdomyolysis, myositis and various enzyme activities in the liver, and some patients are not well adapted to the treatment of statins, more important The single statin treatment often does not achieve the desired results.
  • the fibrates represent drugs: clofibrate, gemfibrozil, fenofibrate, etc. After long-term clinical application, these drugs have been proven to be a class of drugs that are well tolerated and have good lipid-lowering effects.
  • its lipid-lowering pathway increases the activity of lipoprotein lipase, which increases the clearance of triglyceride (TG); lowers blood sugar, which makes the synthesis of glucose and free fatty acids tend to glucose. Lipid synthesis is reduced.
  • Niacin represents a drug: niacin, inositol niacin, acyclovir and the like. These drugs inhibit the synthesis of glycerol by the liver mainly by inhibiting the decomposition of fat and the formation of free fatty acids. Triester (TG) and very low density lipoprotein (VLD-L) to lower blood lipids.
  • TG Triester
  • VLD-L very low density lipoprotein
  • Inadequacies The effect of lowering blood lipids in diabetic patients is not obvious. Side effects such as: liver poisoning, high blood sugar is more obvious, and skin reactions such as skin plague and itching often occur.
  • the bile acid sequestrants represent drugs: Ezetimibe, polyunsaturated fatty acids, and the like. Such lipid-lowering drugs can be classified into two types: cholesterol absorption inhibitors and polyunsaturated fatty acids.
  • Cholesterol absorption inhibitor (Yibei Maibu): combined with bile acid, hinders the reabsorption of bile acid, thereby promoting the conversion of cholesterol into bile acid, which is excreted in the intestine and the drug.
  • LDL low-density lipoprotein
  • LDLR low-density lipoprotein receptor
  • PCSK9 proprotein convertase subtilisin/kexin type 9
  • PCSK9 is a serine protease that is mainly synthesized in the liver, which can reduce the amount of LDLR in hepatocytes. After binding to LDLR located on the cell surface, PCSK9 internalizes into cells and promotes LDLR degradation in lysosomes. Inhibition of PCSK9 activity increases the number of LDLRs and decreases plasma LDL levels.
  • PCSK9 inhibitors are an important direction for large multinational pharmaceutical companies to develop new cardiovascular disease drugs. It is expected that these drugs will surpass statin mature lipid-lowering drugs. Large pharmaceutical companies are working hard to promote the development of PCSK9 inhibitor drugs.
  • the current research work focuses on the development of biologic drugs (including protein drugs and long-chain nucleic acid drugs) (see table below), biologic drugs and small molecules. When the drug is used to treat the same disease, the biopharmaceutical is costly, and only a limited preparation method such as an injection preparation can be used. At present, no small molecule PCSK9 inhibitor has become a clinical drug candidate.
  • a series of patent applications for small molecule compounds of PCSK9 inhibitors are disclosed, including WO2010075469, WO2011006000, WO2011051961, WO2011152508, WO2012090220, JP2013136572, WO2013132509, WO2013137371, WO2014017569, WO2014002105, WO2014002106, WO2014150326, WO2014150395, WO2014139008, and the like.
  • the object of the present invention is to provide a compound of the formula (V), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolism Precursor or prodrug.
  • Compound of formula V is to provide a compound of the formula (V), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolism Precursor or prodrug.
  • Y is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
  • M is a nitrogen atom, or a carbon atom
  • W is a nitrogen atom, or a carbon atom
  • Z is -O-, -S-, -NH-, -CR 5 R 6 -, -C(O)O-, -C(O)NR 5 -, -SO 2 O-, -SO 2 NR 5 - , -P(O)R 5 R 6 or Z is not an atom (ie, the chemical group attached to Z is directly linked by a chemical bond);
  • Ring X is a 3- to 10-membered ring, and the 3- to 10-membered ring X is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
  • R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaryl Alkyl, heterocyclic or heterocyclylalkyl,
  • n 1, 2, 3;
  • the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, including the compound (VI) of the formula
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
  • R 5 , R 6 , R 7 , R 8 , Z, M, q, t, ring X and ring Y are as described above.
  • the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including a compound of the formula (VII),
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxy, sulphur , sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
  • R 5 , R 6 , R 7 , R 8 , R', R", Z, ring X, M, m, n, q, t are as described above.
  • the present invention relates to the compound of the formula (VII) wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently -H, halo, substituted or unsubstituted Substituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocycloalkyl base;
  • R 17 , R 18 , R 19 , R 20 , R 21 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R' , -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", substituted or unsubstituted amino, alkyl, alkane Oxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, also selected from :
  • R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
  • C 1-6 alkyl is optionally substituted by 0 to 13 substituents
  • thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
  • the pyridyl group is optionally substituted with from 0 to 4 substituents.
  • pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
  • the phenyl group is optionally substituted with from 0 to 5 substituents.
  • quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
  • the naphthyl group is optionally substituted with from 0 to 7 substituents.
  • substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring
  • R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
  • the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including a compound of the formula (VIII),
  • the present invention relates to the compound of the formula (VIII), wherein R 22 , R 23 , R 24 , R 25 , R 26 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", Substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hetero A cycloalkyl or heterocyclylalkyl group, also selected from the group consisting of:
  • R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
  • C 1-6 alkyl is optionally substituted by 0 to 13 substituents
  • thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
  • the pyridyl group is optionally substituted with from 0 to 4 substituents.
  • pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
  • the phenyl group is optionally substituted with from 0 to 5 substituents.
  • quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
  • the naphthyl group is optionally substituted with from 0 to 7 substituents.
  • substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring
  • R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
  • the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including the compound (IX) of the formula
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 are as described above;
  • R 22 , R 23 , R 24 , R 25 , R 26 are as described above;
  • R 5 , R 6 , R 7 , R 8 , M, q, t are as described above.
  • the present invention relates to the compound of the formula (IX), wherein R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 are independently -H, halogen, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC( O) OR', -OC(O)NR'R", substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, An aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group, further selected from the group consisting of:
  • R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
  • C 1-6 alkyl is optionally substituted by 0 to 13 substituents
  • thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
  • the pyridyl group is optionally substituted with from 0 to 4 substituents.
  • pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
  • the phenyl group is optionally substituted with from 0 to 5 substituents.
  • quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
  • the naphthyl group is optionally substituted with from 0 to 7 substituents.
  • substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring
  • R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
  • the present invention relates to a compound selected from the following compounds, but is not limited to the following compound ranges:
  • the present invention relates to a compound represented by the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein a preparation method comprises the steps of:
  • X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
  • Another preparation method includes the following steps:
  • X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
  • the present invention relates to a compound of the formula (V), which comprises a pharmaceutical composition comprising a compound of any one and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition consisting of a compound of the formula (V), which comprises a compound which is administered to any one of a therapeutically effective amount of a patient in need of treatment.
  • the present invention relates to the use of any one of the compounds of the formula (V) for the preparation of a medicament for lowering the lipid level of a patient's plasma and/or liver.
  • the present invention relates to a compound of any one of the compounds represented by the general formula (V) for use in the treatment of hyperlipemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, metabolic syndrome, antitumor drugs. the use of.
  • the present invention relates to the use of any one of the compounds of the general formula (V) for the preparation of a medicament for increasing LDLR expression and/or reducing PCSK9 expression.
  • the present invention relates to a compound of the formula (V), and the compounds disclosed herein have the following beneficial effects:
  • the small molecule compound of the general formula (V) disclosed in the present invention is expected to be a new generation of lipid-lowering drug in inhibiting the expression of PCSK9 gene, increasing the expression of LDLR and enhancing the uptake of hepatocytes to LDL.
  • PCSK9 inhibitors as lipid-lowering drugs is an important direction for large multinational pharmaceutical companies to develop new cardiovascular disease drugs. It is expected that these drugs will surpass statin mature lipid-lowering drugs. Large pharmaceutical companies are working hard to promote the development of PCSK9 inhibitor drugs.
  • biologic drugs including protein drugs and long-chain nucleic acid drugs.
  • PCSK9 inhibitors have been developed. Clinical drug candidates. The following table:
  • the biopharmaceutical is expensive, and only a limited preparation method such as an injection preparation can be used, and the small molecule drug has the advantages of low manufacturing cost, various preparation methods, and the like, and the present invention discloses
  • the small molecule compound of the general formula (V) exhibits significant inhibition of PCSK9 gene expression at the cellular level and enhances the significant function of hepatocytes to uptake of LDL, and is expected to have a new generation of lipid-lowering drugs.
  • the formulation of small molecule drugs is more extensive than that of biomacromolecules, which is conducive to the development of a variety of drug formulations for later drug development. Compared to biomacromolecular drugs, it can be provided for a wide range of formulation types. satisfy people's demands.
  • the compound of the general formula (V) disclosed in the present invention has a novel structure and a novel structural feature, and is expected to have a novel effect on PCSK9, compared with a compound disclosed in the prior patent document which is a target of PCSK9.
  • the candidate drug of the mechanism and eventually become a new generation of lipid-lowering drugs with a novel mechanism of action.
  • Patent Application WO2014139008 reports a class of small molecule compounds, some of which are mainly characterized by the inclusion of "borate and boric acid” structural fragments, although multiple bone marrows are currently available.
  • Tumor treatment drug - bortezomib containing “boric acid” structural fragments
  • the application of "boric acid” drugs in non-tumor treatment areas is still limited, mainly because Potential neurotoxic side effects of boron drugs, as well as their potential for "irreversible binding" to biological organisms (Chem. Res. Toxicol., 2013, 26(4), pp 608-615), the chemical properties of the drug
  • the potential “carcinogenicity” that may be caused by molecular design, “reproductive toxicity” has been widely recognized by pharmaceutical chemists.
  • the compound of the formula (V) disclosed in the present invention has novel structure and novel unique structural features, and indicates that the compound disclosed in the present invention
  • the novel molecular structure features may bring unexpected "drug-like characteristics", and it is expected to become a candidate drug with a novel mechanism of action for PCSK9, and eventually become a new generation of lipid-lowering drugs with novel mechanism of action.
  • the compound of the formula (V) disclosed in the invention has the advantages that the raw materials are easy to obtain, the preparation process is simple, and the cost is low.
  • the small molecule compound of the formula (V) disclosed in the present invention is mainly prepared by using a commercially available intermediate, and then subjected to a fragment coupling reaction by a simple chemical reaction.
  • a commercially available starting material having a functional group such as "amine”, “aldehyde” or “halogenated hydrocarbon” can be used to prepare a target compound by one-step chemical reaction. Therefore, the compound of the formula (V) disclosed in the present invention has the advantages that the raw materials are easily available, the preparation process is simple, and the cost is low.
  • the compound of the general formula (V) disclosed in the present invention has the activity of activating AMPK kinase, suggesting that the compound of the present invention can not only be developed into a new generation of lipid-lowering drugs, but also can play a role in controlling blood sugar, and is a comprehensive metabolic synthesis.
  • the comprehensive benefits of patients with lipid-lowering and hypoglycemic agents are more advantageous than the existing single-acting drugs.
  • X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
  • Another preparation method includes the following steps:
  • X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
  • X4 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X4 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VI;
  • Another preparation method includes the following steps:
  • X4 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VI is prepared by reacting X4 and X3 under a certain reaction condition by reductive amination.
  • a compound represented by the formula (VII) of the present invention, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein one of the preparations includes the following steps:
  • X5 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VII;
  • Another preparation method includes the following steps:
  • X5 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VII is obtained by reacting X5 and X3 under a certain reaction condition by reductive amination.
  • X1 and X6 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X6 at a certain reaction temperature, in the presence of a certain alkaline reagent, by coupling to obtain compound VIII;
  • Another preparation method includes the following steps:
  • X1 and X7 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VIII is prepared by reacting X1 and X7 under a certain reaction condition by reductive amination.
  • X5 and X8 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X8 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound IX;
  • Another preparation method includes the following steps:
  • X5 and X9 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X9 are prepared by a reductive amination reaction under certain reaction conditions to obtain IX.
  • Figure 1 shows the effect of the fluorescence intensity observed under the microscope on the ability of the sample to take up LDL by hepatocytes after compound treatment.
  • Fig. 2 is a graph showing the comparison of serum low-density lipoprotein cholesterol (LDL-C) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
  • LDL-C serum low-density lipoprotein cholesterol
  • Fig. 3 shows a comparison of the results of determination of total cholesterol (TC) in serum of a high-fat SD rat after oral administration of a part of the compound of the present invention for four weeks.
  • Figure 4 is a graph showing the comparison of serum alanine aminotransferase (ALT) levels in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
  • Fig. 5 is a graph showing the comparison of the results of serum aspartate aminotransferase (AST) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
  • AST serum aspartate aminotransferase
  • the present technology provides novel compounds, and the use of the compounds in reducing plasma and/or liver lipid levels, as well as in the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Uses in hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome.
  • the compounds provided herein can be formulated into pharmaceutical compositions and medicaments for use in the methods disclosed herein.
  • the invention also provides the use of the compound for the preparation of a pharmaceutical formulation and a medicament, the use of the compound for lowering lipid levels in plasma and/or liver, and the compound in the treatment of hyperlipidemia, hypercholesterolemia Use in disease, hypertriglyceridemia, hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome.
  • an element such as hydrogen or H
  • R group is defined to include hydrogen or H, it also includes ruthenium and osmium.
  • Compound comprises a radioisotope (e.g., tritium, C 14, P 32 and S 35) is therefore also within the scope of the present invention. Means for inserting such markers into the compounds of the invention will be apparent to those skilled in the art based on the disclosure herein.
  • substituted means an organic group (e.g., an alkyl group) as defined below wherein one or more hydrogen-bonded bonds are replaced by a bond to a non-hydrogen atom or a non-carbon atom.
  • Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds (including double or triple bonds) linking the heteroatoms.
  • a substituted group is substituted with one or more substituents. In some embodiments, the substituent is substituted with 1, 2, 3, 4, 5 or 6 substituents.
  • substituents examples include halogen (i.e., F, Cl, Br, and I), a hydroxyl group, an alkoxy group, an alkenyloxy group, an aryloxy group, an aralkyloxy group, a heterocyclic oxygen group, and a heterocyclic alkoxy group.
  • halogen i.e., F, Cl, Br, and I
  • a hydroxyl group an alkoxy group, an alkenyloxy group, an aryloxy group, an aralkyloxy group, a heterocyclic oxygen group, and a heterocyclic alkoxy group.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclic, and heteroaryl, also include ring and ring systems in which a bond to a hydrogen atom is replaced by a bond to a carbon atom.
  • the substituted cycloalkyl, aryl, heterocyclic and heteroaryl groups may also be substituted by substituted or unsubstituted alkyl, alkenyl and alkynyl groups as defined below.
  • the alkyl group includes a linear or branched group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(O)R', -C(O)OR', -S(O) m R', - NR'R", -C(O)NR'R", -NR'C(O)R", -NR'S(O) m R" or -S(O) m NR'R".
  • a cycloalkylalkyl group means an alkyl group substituted with a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 Up to 10 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • Alkenyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R', -C(O)OR', -S(O) m R', -NR'R", -C(O)NR'R", -NR'C (O) R", -NR'S(O) m R" or -S(O) m NR'R".
  • Cycloalkenyl refers to an unsaturated cycloalkyl group as defined above having at least one double bond between two carbon atoms.
  • a cycloalkenyl group can have one, two or three double bonds but does not include an aromatic compound.
  • the cycloalkenyl group contains 4 to 14 carbon atoms or, in some embodiments, 5 to 14 carbon atoms, preferably 5 to 10 carbon atoms, more preferably 5, 6, 7 or 8 carbon atoms.
  • Examples of the cycloalkenyl group include a cyclohexenyl group, a cyclopentenyl group, a cyclohexadienyl group, a butadienyl group, a pentadienyl group, and a hexadienyl group.
  • alkynyl group means an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R', -C(O)OR', -S(O) m R', -NR'R", -C(O)NR'R", -NR'C (O) R", -NR'S(O) m R" or -S(O) m NR'R".
  • the aryl group is a cyclic aromatic hydrocarbon containing no hetero atoms.
  • Aryl groups include monocyclic, bicyclic, and tricyclic systems herein.
  • aryl groups include, but are not limited to, phenyl, methoxyheptyl, diphenyl, indenyl, phenanthryl, anthracenyl, fluorenyl, indanyl, cyclopentadienyl, and naphthyl.
  • the aryl group contains 6-14 carbons, preferably 6 to 12, more preferably 6-10 carbon atoms in the ring portion of the group.
  • the aryl group is phenyl or naphthyl.
  • aryl includes groups containing a fused ring (eg, a fused aromatic-aliphatic ring system) (eg, indanyl, tetrahydronaphthyl, and the like), it does not include having members with rings
  • An aryl group of one of the other groups bonded for example, an alkyl group or a halogenated group.
  • a group such as a tolyl group is referred to as a substituted aryl group.
  • Representative substituted aryl groups can be monosubstituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5- or 6-substituted phenyl or naphthyl groups, which may be substituted, for example, with the substituents listed above.
  • Aralkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above.
  • the aralkyl group contains from 7 to 16 carbon atoms, preferably from 7 to 14 carbon atoms, more preferably from 7 to 10 carbon atoms.
  • the substituted aralkyl group may be substituted at the alkyl group, the aryl group, or both the alkyl group and the aryl moiety.
  • Representative aralkyl groups include, but are not limited to, benzyl and phenethyl and fused (cycloalkylaryl)alkyl (eg, 4-indolylethyl).
  • Representative substituted aralkyl groups can be substituted one or several times with, for example, the substituents listed above.
  • Heterocyclyl includes aromatic (also referred to as heteroaryl) and non-aromatic cyclic compounds containing three or more ring members, wherein one or more of the ring members are heteroatoms such as, but not limited to, N. , O and S.
  • a heterocyclic group contains 1, 2, 3 or 4 heteroatoms.
  • heterocyclyl includes mono, di, and tricyclic rings having from 3 to 16 ring members.
  • Heterocyclyl groups include aromatic, partially unsaturated and saturated ring systems such as imidazolyl, imidazolinyl and imidazolidinyl.
  • heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as benzotriazolyl, 2,3-dihydrobenzo[1,4]. Dioxoalkyl and benzo[1,3]dioxolyl.
  • the phrase also includes bridged polycyclic systems containing heteroatoms such as, but not limited to, quinuclidinyl. However, the phrase does not include heterocyclic groups having other groups (eg, alkyl, oxo or halo groups) bonded to one of the ring members.
  • Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, Furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl , thiazolinyl, isothiazolyl, thiadiazo, oxadiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetra
  • substituted heterocyclic groups may be monosubstituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5- or 6-substituted or substituted by various substituents such as those listed above A disubstituted pyridyl or morpholinyl group.
  • a heteroaryl group is an aromatic ring compound containing five or more ring member atoms, wherein one or more ring members are heteroatoms such as, but not limited to, N, O and S.
  • Heteroaryl groups include, but are not limited to, the following groups, for example, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl , pyrazinyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, fluorenyl, azaindolyl (pyrrolopyridinyl), oxazolyl, benzimidazolyl, Imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzox
  • Heteroaryl groups include fused ring compounds in which all of the rings are aromatic, such as fluorenyl groups, which also include fused ring compounds in which only one ring is aromatic, such as 2,3-dihydroindenyl.
  • heteroaryl includes fused ring compounds, the phrase does not include heteroaryl groups having other groups (eg, alkyl groups) bonded to one of the ring members.
  • a heteroaryl group having such a substitution is referred to as a "substituted heteroaryl group.”
  • Representative substituted heteroaryl groups can be substituted one or several times with, for example, the various substituents listed above.
  • Heterocyclylalkyl is an alkyl group as defined above, but wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclic group as defined above.
  • the substituted heterocyclic alkyl group may be substituted at the alkyl group or the heterocyclic group or at both the alkyl group and the heterocyclic group.
  • Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazole-4- Base-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl and ind-2-yl-propyl.
  • Representative substituted heterocyclylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
  • Heteroarylalkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above.
  • the substituted heteroarylalkyl group may be substituted at the alkyl or heteroaryl portion or at both the alkyl and heteroaryl portions.
  • Representative substituted heteroarylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
  • the groups described herein having two or more points of attachment are designated by the prefix "sub".
  • the divalent alkyl group is an alkylene group
  • the divalent aryl group is an arylene group
  • the divalent heteroaryl group is a heteroarylene group, and the like.
  • Substituted groups having a single point of attachment to a compound of the invention do not use a "sub" designation.
  • chloroethyl is not referred to herein as chloroethylene.
  • An oxo group means a substituent group formed by linking with an oxygen atom, wherein the group bonded to the oxygen atom is a substituted or unsubstituted alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, an alkyl group. , aryl acyl, heteroaryl acyl.
  • the above group may be bonded to an oxygen atom to form an alkoxy group, an aryloxy group, a heteroaryloxy group, a cycloalkyloxy group, an alkyl acyloxy group, an aryl acyloxy group, a heteroaryl acyloxy group, and a ring.
  • Alkyl acyloxy Alkyl acyloxy.
  • the alkoxy group is a substituent in which a bond to a hydrogen atom in a hydroxyl group (-OH) is replaced by a bond to a carbon atom of the substituted or unsubstituted alkyl group defined above.
  • linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.
  • branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy and the like.
  • cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Representative substituted alkoxy groups can be substituted one or several times with, for example, the substituents listed above.
  • alkanoyl and “alkanoyloxy” as used herein mean -C(O)-alkyl and -O-C(O)-alkyl, respectively, each of which contains from 2 to 5 carbon atoms.
  • aryloxy and arylalkoxy mean, respectively, a substituent formed by bonding a substituted or unsubstituted aryl group to an oxygen atom, a substituted or unsubstituted aralkyl group and an oxygen atom.
  • a substituent formed by bonding examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy.
  • Representative substituted aryloxy and arylalkoxy groups can be substituted one or several times with, for example, the substituents listed above.
  • carboxylic acid refers to a -COOH group.
  • Carboxylate refers to a -COOR' group.
  • R' is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic group as defined herein.
  • amide includes both C-amide and N-amide groups, i.e., -C(O)NR'R” and -NR'C(O)R” groups, respectively.
  • R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein.
  • the amide group thus includes, but is not limited to, a carbamoyl group (-C(O)NH 2 ) and a carboxamide group (-NHC(O)H).
  • the amide is -NR'C(O) -(C 1-5 alkyl), this group is referred to as "carbonylamino", in other embodiments, the amide is -NHC(O)-alkyl, the group is referred to as "alkanoylamino" .
  • nitrile or "cyano” as used herein refers to a -CN group.
  • Carbamates include N-carbamate groups and O-carbamate groups, i.e., -NR'C(O)OR” and -OC(O)NR'R” groups, respectively.
  • R' and R" are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group, as defined herein.
  • R' can also be H.
  • amine refers to a radical -NR'R", wherein R' and R" are, independently, hydrogen or substituted or unsubstituted alkyl, as defined herein, Alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic.
  • the amine is an alkylamino, dialkylamino, arylamino or alkylarylamino group.
  • the amine is NH 2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino or benzylamino.
  • sulfonamide includes both S-sulfonamide groups and N-sulfonamide groups, i.e., -SO 2 NR'R" and -NR'SO 2 R” groups, respectively.
  • R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein.
  • the sulfonamide group thus includes, but is not limited to, a sulfonyl group (-SO 2 NH 2 ).
  • the sulfonamide is -NHSO 2 -alkyl, which is referred to as "alkylsulfonylamino" .
  • thiol refers to the -SH group, while the sulfide includes the -SR' group, the sulfoxide includes the -S(O)R' group, the sulfone includes the -SO 2 R' group, and the sulfonyloxy group includes -OSO 2 R', the sulfonic acid oxy group includes -OSO 2 OR'.
  • R' is independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group, as defined herein.
  • the sulfide is an alkyl thiol group, -S-alkyl.
  • urea refers to a -NR'-C(O)-NR'R” group.
  • the R' and R" groups are independently hydrogen or substituted or unsubstituted alkyl, alkenyl as defined herein. , alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl.
  • ⁇ refers to -C(NR')NR'R" and -NR'C(NR')R", wherein R' and R" are each independently hydrogen as defined herein or substituted or not Substituted alkyl, cycloalkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
  • ⁇ refers to -NR'C(NR')NR'R", wherein R' and R" are each independently hydrogen or substituted or unsubstituted alkyl, cycloalkyl, as defined herein, Alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl.
  • halo refers to bromo, chloro, fluoro or iodo. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
  • hydroxy refers to -OH, or may be an ionized form as used herein -O -.
  • imide refers to -C(O)NR'C(O)R", wherein R' and R" are each independently hydrogen or substituted or unsubstituted alkyl, ring, as defined herein. Alkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
  • nitrogen-containing heterocyclic group refers to a ring system containing a nitrogen atom which may "couple” aromatic and non-aromatic ring systems, or link other ring systems through “spirocarbon atoms", such as the following structure:
  • the term "imine” refers to a -CR' (NR") and -N (CR'R”) group, wherein R' and R" are each independently hydrogen or substituted or unsubstituted as defined herein.
  • An alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an arylarylalkyl group, a heterocyclic group or a heterocyclic alkyl group, and satisfies: R' and R" are not hydrogen at the same time.
  • nitro means -NO 2 when used herein.
  • trifluoromethyl refers to a -CF 3.
  • salts of the compounds described herein are within the scope of the invention and include such acid addition or base addition salts which retain the desired pharmacological activity and are not biologically potential Poor effects (eg, salts are not excessively toxic, sensitizing or irritating, and are bioavailable).
  • the compound of the present invention has a basic group (for example, an amino group), it can be combined with a mineral acid (for example, hydrochloric acid, borohydride, nitric acid, sulfuric acid, and phosphoric acid), an organic acid (for example, alginate, formic acid, acetic acid, benzoic acid, Gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid) or acidic amino acids (eg aspartame)
  • a mineral acid for example, hydrochloric acid, borohydride, nitric acid, sulfuric acid, and phosphoric acid
  • an organic acid for example, alginate, formic acid, acetic acid, benzoic acid, Gluconic acid, fumaric
  • the compound of the present invention When the compound of the present invention has an acidic group such as a carboxylic acid group, it can be combined with a metal such as an alkali metal and an alkaline earth metal (for example, Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ) ), ammonia or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (such as arginine, lysine and ornithine) ) form a salt.
  • a metal such as an alkali metal and an alkaline earth metal (for example, Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ )
  • ammonia or organic amines such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, ethanolamine,
  • the compounds of the invention may exhibit tautomerism, conformational isomerism, geometric isomerism and/or stereoisomerism.
  • formulae in the specification and claims represent only one of the possible tautomeric, conformational, stereoisomeric or geometric isomeric forms, it is to be understood that the invention includes a compound having one of the ones described herein or Any tautomeric, conformational, stereoisomeric, and/or geometric isomeric form for a variety of uses, as well as mixtures of these various forms.
  • Stereoisomers of the compounds including all chiral, diastereomeric and racemic forms of the structure, unless explicitly indicated for stereochemistry.
  • compounds useful in the present invention include optical isomers that are enriched or resolved at any or all of the asymmetric atoms. Racemic and diastereomeric mixtures, as well as optical isomers, may be isolated or synthesized to be substantially free of their corresponding isomers or diastereomers, and these stereoisomers are also Within the scope of the invention.
  • the compounds of the invention may exist as solvates, especially as hydrates.
  • the hydrate can be formed during the manufacture of the compound or composition comprising the compound, or the hydrate can be formed over time due to the hygroscopic nature of the compound.
  • the compounds of the invention may also exist as organic solvates, including ethers and alcohol solvates, and the like. Identification and preparation of any particular solvate is known to those of ordinary skill in the art of synthetic organic or pharmaceutical chemistry.
  • Lipids include both synthetic and naturally occurring fat-soluble compounds, including both neutral and amphiphilic molecules.
  • Amphoteric lipids typically comprise a hydrophilic component and a hydrophobic component.
  • Exemplary lipid package include fatty acids, triglycerides, neutral fats, phospholipids, glycolipids, fatty alcohols, waxes, hydrazines, steroids such as cholesterol, and surfactants.
  • Lipid-lowering agent refers to a compound that has one or more of the following effects when administered to a patient: increased liver expression of LDLR; increased half-life of LDLR mRNA in hepatocytes; increased liver to plasma LDL, cholesterol Or uptake of triglycerides; enhance fatty acid oxidation in the liver, reduce triglyceride synthesis and secretion in the liver, and lower total cholesterol, LDL-cholesterol, VLDL-cholesterol or triglyceride levels in plasma and/or liver.
  • the lipid reducing agents disclosed herein include the compounds of the invention.
  • the invention provides the use of a compound of the invention for the manufacture of a medicament for lowering lipid levels in a patient's plasma and/or liver, comprising administering to said patient a reduced effective amount of a compound as described herein or combination.
  • the reduced lipid level may be one or more of total cholesterol, LDL-cholesterol (LDL-C), triglyceride (TG), and unesterified long-chain fatty acids.
  • the compounds and compositions described herein are useful for the prevention or treatment of diseases including, for example, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver (hepatic steatosis), type 2 diabetes, hyperglycemia Disease, obesity or insulin resistance and metabolic syndrome.
  • a method of treatment comprises administering to a subject in need of treatment a therapeutically effective amount of a compound or composition described herein.
  • the compounds of the invention are also useful in the treatment or prevention of disease states or conditions characterized by elevated plasma or hepatic cholesterol or triglycerides or associated with elevated plasma or hepatic cholesterol or triglycerides.
  • the present technology also provides for the treatment or prevention of diseases using the compounds of the invention (eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin)
  • diseases eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin
  • the use of an effective amount of a drug for resistance or metabolic syndrome eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin.
  • the compounds and compositions disclosed herein increase the stability of LDLR mRNA by increasing the LDLR mRNA stability by increasing the transcription of the LDLR gene by inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9). ) mediated degradation of LDLR proteins or all of the above possible cellular mechanisms to reduce lipid levels.
  • Increased levels of LDLR in the liver increase uptake and processing of plasma LDL-C, resulting in decreased plasma levels of cholesterol, LDL-C, and triglycerides.
  • compounds can increase phosphorylation of acetyl CoA carboxylase (ACC) by activating AMP-activated protein kinase (AMPK), a key molecule of bioenergy metabolism regulation.
  • ACC acetyl CoA carboxylase
  • AMPK AMP-activated protein kinase
  • Increased phosphorylation of ACC enhances fatty acid oxidation in the liver, resulting in reduced TG accumulation in the liver and TG secretion in VLDL, which also helps reduce TG, LDL-C, total cholesterol, and unesterified long chains. Plasma levels of fatty acids, thereby preventing or treating diseases associated with hyperlipidemia.
  • AMPK is essential for the body to maintain glucose balance, and that compounds can ultimately treat type 2 diabetes, hyperglycemia, obesity or insulin resistance or metabolism by activating AMPK. Syndrome.
  • the compounds provided herein have the use of increasing LDLR expression comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition described herein, thereby increasing LDLR in said subject expression.
  • the invention provides a use of a compound of the invention to reduce plasma LDL-cholesterol and/or plasma triglycerides, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein or The composition thereby reducing plasma LDL-cholesterol in the patient.
  • the invention provides a lipid lowering agent comprising a compound and a composition thereof.
  • the compounds and compositions are useful in the methods and treatments of reducing lipids described herein.
  • the invention provides a compound of formula V, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and/or a pharmaceutically acceptable salt thereof.
  • the present technology provides pharmaceutical compositions and medicaments comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers.
  • a pharmaceutical composition for treating a condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome is provided.
  • Such compositions include a lipid reducing effective amount of any of the compounds described herein.
  • the pharmaceutical composition is packaged in unit dosage form.
  • the unit dosage form is effective in reducing blood lipids and/or lipid levels in the liver (eg, total cholesterol, LDL-cholesterol, triglycerides, and unesterified long-chain fatty acids) when administered to a subject in need thereof. At least one).
  • blood lipids and/or lipid levels in the liver eg, total cholesterol, LDL-cholesterol, triglycerides, and unesterified long-chain fatty acids
  • compositions By diluting one or more compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, dilutions Agents and the like are mixed to prepare a pharmaceutical composition to prevent or treat a condition associated with increased plasma and/or liver lipid levels.
  • pharmaceutically acceptable carriers eg, hyperlipidemia, hypercholesterolemia, hepatic steatosis, and metabolic syndrome
  • compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the compositions of the present invention may be formulated in a variety of forms for a variety of routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration or by implantation of a reservoir.
  • Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injection.
  • the dosage forms described below are given as examples and should not be construed as limiting the techniques of the present invention.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared by any of the methods known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene
  • a glycol or oil vehicle such as peanut oil, liquid paraffin or olive oil mixed soft gelatin capsules provides an oral formulation.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol , or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or a partial ester of ethylene oxide with a fatty acid and a hexitol anhydride Condensation products such as polyethylene oxide sorbitan
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives such as ethylparaben or n-propylparaben
  • coloring agents such as ethylparaben or n-propylparaben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweeteners, flavoring agents, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • Dosage forms for topical (including buccal and sublingual) or transdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches.
  • the active component can be mixed under sterile conditions with apharmaceutically acceptable carrier or excipient and with any preservative or buffers which may be required.
  • Powders and sprays can be prepared, for example, with excipients such as sugars, mica, silicic acid, sodium hydroxide, calcium silicates and polyamine powders or mixtures of these materials.
  • Ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, waxes, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones. , bentonite, silicic acid, mica and zinc oxide or a mixture thereof.
  • Absorption enhancers can also be used to increase the flow of the compounds of the invention through the skin. The rate of such flow can be controlled by providing a rate controlling membrane (e.g., as part of a transdermal patch) or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the compounds of the invention may also be administered with other conventional therapeutic agents useful in the treatment or prevention of hyperlipemia.
  • exemplary therapeutic agents for combination therapy with one or more compounds of the invention include, but are not limited to, anti-inflammatory drugs, therapeutic antibodies, and cholesterol lowering drugs, for example, statins.
  • Useful additional therapeutic agents useful in combination formulations and co-therapy include, for example, anti-hyperlipidemic agents; anti-dyslipidemic agents; anti-diabetic agents including, but not limited to, cholesterol biosynthesis inhibitors, such as HMG-CoA reductase Inhibitors (also known as statins, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin and atorvastatin); HMG-CoA reduction synthase inhibitors; Squalene epoxidase inhibitor or squalene synthetase inhibitor (also known as squalene synthase inhibitor); microsomal triglyceride transfer protein (MTP) inhibitor; bile acid sequestrant anion exchange resin, These include, but are not limited to, cholestyramine, cholestyramine, colesevelam or dialkylaminoalkyl derivatives of cross-linked dextran; LDL
  • Additional therapies may also include increased exercise, surgery, and changing diets (eg, becoming a low-cholesterol diet).
  • Some botanicals are also effective for combination formulations and collaborative therapies to treat hyperlipidemia, such as curcumin, gum ketone , garlic, soy, soluble fiber, fish oil, green tea, carnitine, chromium, coenzyme Q10, grape seed extract, dimeric pantothenic acid, red yeast rice and royal jelly.
  • Berberine and related compounds can also be used as a second therapeutic agent in combination with the lipid lowering agent of the present invention.
  • berberine sulfate, berberine hydrochloride, berberine chloride, berberine, dihydroberberine, 8-cyanodihydroberberine, tetrahydroberberine N-oxide can be used.
  • Compounds of the invention may also be modified, for example by covalently linking organic structural fragments or conjugates, to improve pharmacokinetic properties, toxicity or bioavailability (e.g., increased in vivo half-life).
  • the conjugate can be a linear or branched hydrophilic polymeric group, a fatty acid group or a fatty acid ester group.
  • the polymeric group can comprise a molecular weight that can be adjusted by one skilled in the art to improve, for example, pharmacokinetic properties, toxicity, or bioavailability.
  • Exemplary conjugates can include polyalkanols (eg, polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymers, amino acid polymers or polyvinylpyrrolidone, and fatty acid or fatty acid ester groups, which Each may independently comprise from about 8 to about 70 carbon atoms.
  • Conjugates for use with the compounds of the invention may also be used as linkers, for example, for any suitable substituent or group, radiolabel (marker or tag), halogen, protein, enzyme, polypeptide, other therapeutic agent (eg drugs or drugs), nucleosides, dyes, oligonucleotides, lipids, phospholipids and/or liposomes.
  • the conjugate can include polyvinylamine (PEI), polyglycine, a hybrid of PEI and polyglycine, polyethylene glycol (PEG), or methoxypolyethylene glycol (mPEG).
  • PI polyvinylamine
  • PEG polyethylene glycol
  • mPEG methoxypolyethylene glycol
  • Conjugates The compounds of the invention may also be linked to, for example, labeled (fluorescing or luminescent) or a label (radioactive, radioisotope and/or isotope) to comprise a probe of the invention. Conjugates for use with the compounds of the invention may improve in vivo half-life in one aspect.
  • linking and/or “binding” may refer to a chemical or physical interaction, such as between a compound of the invention and a target of interest. Examples of linkages or interactions include covalent bonds, ionic bonds, hydrophilic-hydrophobic interactions, hydrophobic-hydrophobic interactions, and complexes. "Links” may also generally be referred to as “binding” or “affinity,” each of which may be used to describe a variety of chemical or physical interactions. Measuring binding or affinity is also a routine technique for those skilled in the art.
  • X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
  • Another preparation method includes the following steps:
  • X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
  • X4 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X4 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VI;
  • Another preparation method includes the following steps:
  • X4 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VI is prepared by reacting X4 and X3 under a certain reaction condition by reductive amination.
  • X5 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VII;
  • Another preparation method includes the following steps:
  • X5 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VII is obtained by reacting X5 and X3 under a certain reaction condition by reductive amination.
  • X1 and X6 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X6 at a certain reaction temperature, in the presence of a certain alkaline reagent, by coupling to obtain compound VIII;
  • Another preparation method includes the following steps:
  • X1 and X7 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VIII is prepared by reacting X1 and X7 under a certain reaction condition by reductive amination.
  • X5 and X8 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X8 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound IX;
  • Another preparation method includes the following steps:
  • X5 and X9 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X9 are prepared by a reductive amination reaction under certain reaction conditions to obtain IX.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS silane
  • chemical shift is given in units of 10 -6 (ppm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5mm silica gel plate.
  • the known starting materials of the present invention may be synthesized by or with reference to methods known in the art, or may be purchased from companies such as GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, TCI Chemicals, Angie Chemicals, and the like.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon balloon or a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction was usually evacuated, charged with hydrogen, and operated three times.
  • reaction temperature is room temperature, and the temperature range is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane And the acetone system, D: n-hexane, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
  • the compound 3C (1.5 g, 5 mmol) was weighed in a round bottom flask, THF was added, dissolved, and then the material was added 3D (0.81 g, 5 mmol), stirred for 10 min, then STAB (1.27 g, 6 mmol) was added and reacted at room temperature for 3 h. After the reaction of the thin layer is completed, the reaction is quenched by the addition of a saturated aqueous solution of ammonium chloride, and the mixture is extracted three times with ethyl acetate. The organic phase is combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate Product 3 (1.6 g, 72%) was obtained.
  • 16D (330 mg, 0.92 mmol) was added to a 50 ml round bottom flask, and ethanol (20 ml) was dissolved. Then, Pd/C (10 mg, 0.09 mmol) was added thereto, and the mixture was purged with H 2 for 5 times (atmospheric pressure), and allowed to react at room temperature overnight. Filtration, washing the filter cake with ethanol, collecting the filtrate, and evaporating the solvent to give a crude product 16E.
  • 46C (126.6 mg, 0.718 mmol) and 46D (200 mg, 0.653 mmol) were dissolved in 1,2-dichloroethane, and sodium triacetoxyborohydride (208 mg, 0.980 mmol) was slowly added in an ice bath.
  • 57A (225mg, 1.5mmol) was added to a 50ml round bottom flask, dissolved in dichloromethane (10ml), then oxalyl chloride (213 ⁇ l, 2.5mmol) and N,N-dimethylformamide (1 drop) were added and reacted at room temperature. overnight. The solvent and an excess of oxalyl chloride were evaporated to give a crude material.
  • the compound 70A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask, which was dissolved in dichloromethane (10 mL), and the mixture was stirred and stirred for 5 min, pyridine (0.5 mL) was added and the mixture was stirred for 10 min. After stirring at room temperature for 30 min, compound acetic anhydride (2 mL) was added and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the layers were separated, and the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography ( petroleum ether: ethyl acetate 5:1).
  • 74A (2g, 24.1mmol) and 74B (400mg, 2.41mmol) were dissolved in 10ml of methanol, stirred at room temperature for 12h, then sodium borohydride (109.4, 2.892mmol) was added slowly, after 15min reaction, filtered by diatomite After the solvent was removed by pressure, the mixture was extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) ).
  • 74C (188.5 mg, 0.798 mmol) and 74D (222 mg, 0.725 mg) were dissolved in 5 ml of 1,2-dichloroethane, and sodium triacetoxyborohydride (230 mg, 1.09 mmol) was slowly added at room temperature under ice bath.
  • 75A (90mg, 0.731mmol), thionyl chloride (1mL) was added to a 50mL round bottom flask, refluxed in an oil bath of 80 ° C for 2h, spin dry to give 75B, then add 75C (200mg, 0.609mmol), THF (20 mL), DMAP (10 mg), EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) The residue was purified by column chromatography (dichloromethane: methanol: 100:1) to afford white solid compound 75 (28 mg, yield: 10.6%).
  • the compound 91A (2000 mg, 10.34 mmol), the compound 91B (2118 mg, 11.37 mmol), potassium carbonate (2140 mg, 15.51 mmol), DMF (5 ml) was added to a 100 ml round bottom flask, and the reaction was cooled after stirring at 70 ° C overnight. The mixture was diluted with EtOAc (3 mL).
  • the compound 16E was obtained according to the preparation of Example 16 and the compound 16E was dissolved in 15 mL of dichloromethane, then 140 ⁇ L (1.01 mmol) of triethylamine was added thereto, and stirred at room temperature, and then compound 148B 223 mg (1.01 mmol) was added portionwise. After the addition, the reaction was carried out overnight at room temperature. The reaction mixture was solid and precipitated. The obtained cake was purified by silica gel column chromatography (dichloromethane: methanol: 10:1) to give a white solid.
  • Compound 16E was prepared according to Example 16 and Compound 16E 300 mg (0.916 mmol) was dissolved in 15 mL of dichloromethane, then, then, triethylamine, 140 ⁇ L (1.01 mmol), and stirred at room temperature, and then added 149B 223 mg (1.01 mmol) ), after the addition, the reaction was carried out overnight at room temperature. The reaction mixture was solid and precipitated. The obtained cake was purified by silica gel column chromatography (dichloromethane: methanol: 10:1) to give a white solid. The methyl chloride was washed, and the cake was collected.
  • 5-formylsalicylic acid 151A (1.66 g, 10.0 mM) was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (4.14 g, 30 mM) and methyl iodide (2.18 mL, 35 mM) , overnight at room temperature. The reaction was completed by TLC. EtOAc was evaporated.
  • Example 151E was obtained as in Example 151.
  • Compound 151E 300 mg (0.879 mmol) was dispersed in 15 mL of water, then 242 mg (1.76 mmol) of potassium carbonate was added, and stirred at room temperature, then danyl chloride 155B 283 mg (1.05 mmol) was added portionwise, and the reaction was carried out overnight at room temperature.
  • the reaction solution was adjusted to pH 3 with 2M HCl, and a solid was precipitated, suction filtered, washed with water, dried, washed with a mixed solvent (dichloromethane:methanol 5:1), and the organic solvent was collected and evaporated to dryness.
  • Example 151E was obtained as in Example 151.
  • Compound 151E 300 mg (0.879 mmol) was dispersed in 15 mL of water, then 242 mg (1.76 mmol) of potassium carbonate was added, and stirred at room temperature, then 2-naphthalenesulfonyl chloride 156B 239 mg (1.05 mmol) was added portionwise, and the reaction was carried out overnight at room temperature. .
  • the reaction solution was adjusted to pH 3 with 2M HCl, and a solid was precipitated, suction filtered, washed with water, dried, washed with a mixed solvent (dichloromethane:methanol 5:1), and the organic solvent was collected and evaporated to dryness.
  • 1-(4-Nitrophenyl)piperazine 157A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC, the solvent was evaporated, and then purified with petroleum ether/ethyl acetate (20/1), filtered and dried to give product 157B.
  • 1-(4-Nitrophenyl)piperazine 158A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC, the solvent was evaporated, and then purified with petroleum ether/ethyl acetate (20/1), filtered and dried to give product 158B.
  • 160F (10 mmol, 1.41 g), 160 g (15 mmol, 1.5 g) and triethylamine (15 mmol, 2.08 ml) were added to a 50 ml round bottom flask, dissolved in DMSO (15 ml), and reacted at 100 ° C for 10 h. After cooling to room temperature, 100 ml of water was added, and a solid was precipitated. Then, 50 ml of ethyl acetate was further added and the mixture was stirred for 10 min, filtered, and washed three times with water to give compound 160H, a yellow solid, 1.67 g, yield 75.6%.
  • 3,4-Dimethoxybenzaldehyde 160A (499 mg, 3.0 mM) was dissolved in methanol (10 mL), sodium borohydride (170 mg, 4.5 mM) was added in portions and stirred at room temperature for 15 min. The mixture was diluted with a saturated aqueous solution of ammonium chloride, and the mixture was evaporated, evaporated, evaporated, evaporated.
  • the above product 160E was dissolved in dichloromethane (15 mL), triethylamine (58 ⁇ L, 0.42 mM) and 4-diphenylsulfonyl chloride (71 mg, 0.28 mM) were added and reacted for 2.5 h, and the reaction was completely monitored by TLC.
  • the aqueous solution of citric acid was extracted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate %).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a compound of formula (V), preparation method therefor and pharmaceutical applications thereof. Specifically, the present invention relates to derivatives represented by the general formula (V), preparation method therefor and the uses thereof as therapeutic agents for preventing and treating hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver, type 2 diabetes, hyperglycemia, obesity or insulin resistance, metabolic syndrome and cancers. The disclosed compounds can also reduce total cholesterol, LDL-cholesterol and triglyceride levels, up regulate liver LDL receptor expression, and down regulate PCSK9 expression.

Description

取代氮杂环衍生物及其应用Substituted nitrogen heterocyclic derivatives and their applications 技术领域Technical field
本发明的技术涉及用于治疗高脂血症(包括高甘油三酯血症和高胆固醇血症)，肝脂肪变性，II型糖尿病，高血糖症，胰岛素抵抗症，肥胖症，代谢综合征和抗肿瘤中的用途、化合物和组合物。The present technology relates to the treatment of hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia), hepatic steatosis, type II diabetes, hyperglycemia, insulin resistance, obesity, metabolic syndrome and Uses, compounds and compositions in anti-tumor.
背景技术Background technique
代谢综合征(Metabolic Syndrome，MS)是多种代谢成分异常聚集的病理状态，是一组复杂的代谢紊乱症候群，是导致糖尿病，心脑血管疾病的危险因素。Metabolic Syndrome (MS) is a pathological state in which a variety of metabolic components are abnormally aggregated. It is a complex metabolic disorder syndrome and is a risk factor for diabetes and cardiovascular and cerebrovascular diseases.
心脑血管疾病是危害人类健康的头号杀手，其病因非常复杂，高血脂又作为其非常关键的危险因子而受到大多数人的关注，而且随着生活水平的改善和老龄化的加速，高血脂症的发生率与死亡率明显提升，更有相关文献报道，血脂异常是引起动脉粥样硬化、冠心病、心肌梗死等的主要原因。Cardio-cerebral vascular disease is the number one killer of human health. Its cause is very complicated. Hyperlipidemia is regarded as a very important risk factor by most people. With the improvement of living standards and the acceleration of aging, hyperlipidemia The incidence and mortality of the disease increased significantly, and there are reports in the literature that dyslipidemia is the main cause of atherosclerosis, coronary heart disease, and myocardial infarction.
高血脂症常被解释为：脂肪的代谢或者运转异常使得血浆中一种或多种脂质高于正常。而且高血脂症是种全身性的疾病，通常指血清中总胆固醇(TC)，甘油三酯(TG)过高或高密度脂蛋白胆固醇(HDL-C)过低，现代医学称之为血脂异常。脂质是不溶或微溶于水，所以必须与蛋白质结合形成脂蛋白，因此，高血脂症通常也称为高脂蛋白血症。Hyperlipidemia is often explained by the fact that fat metabolism or abnormal function causes one or more lipids in plasma to be above normal. Hyperlipidemia is a systemic disease, usually referred to as serum total cholesterol (TC), triglyceride (TG) or high density lipoprotein cholesterol (HDL-C) is too low, modern medicine called dyslipidemia . Lipids are insoluble or sparingly soluble in water, so they must bind to proteins to form lipoproteins. Therefore, hyperlipidemia is also commonly referred to as hyperlipoproteinemia.
高血脂与脑梗塞：血液中胆固醇增高容易形成动脉硬化斑块，当这些斑块在动脉壁内堆积时，会使得动脉官腔狭窄，阻塞血液流入相应的部位，便会引起动能缺损。当它发生在脑血管时就会引起脑梗塞，医学证明：长期调脂治疗不仅能治疗脑梗塞，还能预防脑梗塞。Hyperlipidemia and cerebral infarction: The increase of cholesterol in the blood is easy to form atherosclerotic plaque. When these plaques accumulate in the arterial wall, the arterial cavity will be narrowed, and the blood will flow into the corresponding part, which will cause kinetic energy defect. When it occurs in the cerebral blood vessels, it can cause cerebral infarction. Medical evidence: long-term lipid-lowering treatment can not only treat cerebral infarction, but also prevent cerebral infarction.
高血脂与冠心病：冠心病也叫作冠状动脉粥样硬化性心脏病。冠状动脉是给心脏供血的主要动脉，若过多的脂肪沉积，便会造成动脉硬化，从而使血流受阻，引起心脏缺血，发生一系列的症状，即冠心病。引起冠心病的危险因素很多，如：高血脂、吸烟、肥胖、高血压、缺乏体力活动、糖尿病、冠心病家族史等，其中、高血脂又是引起冠心病的重要危险因素之一。所以防治冠心病最基本的疗法是调节血脂，研究表明血清中总胆固醇水平下降1％，则冠心病发生率下降2％。长期配合调脂治疗能够减少冠心病的心绞痛、心肌梗死等的发生率和死亡率。Hyperlipidemia and coronary heart disease: Coronary heart disease is also known as coronary atherosclerotic heart disease. Coronary artery is the main artery that supplies blood to the heart. If too much fat is deposited, it will cause arteriosclerosis, which will hinder blood flow, cause heart ischemia, and a series of symptoms, namely coronary heart disease. There are many risk factors for coronary heart disease, such as: high blood lipids, smoking, obesity, high blood pressure, lack of physical activity, diabetes, family history of coronary heart disease, etc. Among them, high blood lipids are one of the important risk factors for coronary heart disease. Therefore, the most basic treatment for coronary heart disease is to regulate blood lipids. Studies have shown that serum total cholesterol levels drop by 1%, the incidence of coronary heart disease decreased by 2%. Long-term treatment with lipid-lowering therapy can reduce the incidence and mortality of angina pectoris, myocardial infarction, etc. in coronary heart disease.
高血脂与脂肪肝：脂肪肝是指脂肪在肝内大量积累所致，常伴随血脂增高。脂肪肝发病率高达5-10％，成人体内转氨酸增高者大约35％都是脂肪肝，部分严重患者可发展为肝硬化。因此，脂肪肝治疗也应进行调脂的治疗。Hyperlipidemia and fatty liver: Fatty liver refers to the accumulation of fat in the liver, often accompanied by increased blood lipids. The incidence of fatty liver is as high as 5-10%, and about 35% of adult patients with transaminase are fatty liver. Some severe patients can develop cirrhosis. Therefore, fatty liver treatment should also be treated with lipid-lowering.
高血脂与糖尿病：高血压、高血脂与高血糖常被称为“三高”，是威胁糖尿病患者身体健康的主要因素。三者密切相关，高血脂可以加重糖尿病的症状，大多数糖尿病患者伴有高血脂，更易导致脑中风、冠心病、肢体坏死、眼底病变、肾脏病变、神经病变等，因此糖尿病患者除治疗高血糖外，还应注意调血脂，这对于减少糖尿病患者死亡率和致残率是非常重要。Hyperlipidemia and diabetes: Hypertension, hyperlipidemia and hyperglycemia are often referred to as “three highs” and are a major factor threatening the health of people with diabetes. The three are closely related, high blood lipids can aggravate the symptoms of diabetes, most diabetic patients with high blood lipids, more likely to cause stroke, coronary heart disease, limb necrosis, fundus lesions, kidney disease, neuropathy, etc., therefore, in addition to treatment of hyperglycemia in diabetic patients In addition, attention should be paid to regulating blood lipids, which is very important to reduce mortality and disability in diabetic patients.
高血脂症定义为血脂紊乱或血脂异常。通常指人体内血脂浓度超出了正常范围。包括甘油三酯(TG)、血清总胆固醇(TC)、极低密度脂蛋白胆固醇(VLDL-C)或低密度脂蛋白胆固醇(LDL-C)水平升高和高密度脂蛋白胆固醇(HDL-C)水平降低随着高血脂与心血管疾病的深入研究，人们开始认识到降血脂对减少心血管疾病的风险具有非常重要的意义。Hyperlipidemia is defined as a dyslipidemia or dyslipidemia. Usually refers to the body's blood lipid concentration is beyond the normal range. Includes triglyceride (TG), serum total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C) or low-density lipoprotein cholesterol (LDL-C) levels and high-density lipoprotein cholesterol (HDL-C) Level reduction With the in-depth study of hyperlipidemia and cardiovascular disease, people began to realize that hypolipidemicemia is very important for reducing the risk of cardiovascular disease.
现在市场上常用的降血脂药物主要有他汀类、贝特类、烟酸类、胆酸螯合剂类等。Currently, the blood lipid-lowering drugs commonly used in the market mainly include statins, fibrates, niacins, and bile acid sequestrants.
他汀类代表药物：阿托伐他汀，辛伐他汀，洛伐他汀，普伐他汀，氟伐他汀等。这类药物是近年来发展比较快的降脂药物，主要是抑制血清总胆固醇(TC)合成途径中的限速酶3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶的活性，降低TC合成；使得低密度脂蛋白受体数量增加，加快LDL降解，同时增加HDL含量，有利于TC的清除和转运。Statins represent drugs: atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, and the like. These drugs are the fastest-developing lipid-lowering drugs in recent years, mainly to inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the serum total cholesterol (TC) synthesis pathway. The activity reduces TC synthesis; increases the number of low-density lipoprotein receptors, accelerates LDL degradation, and increases HDL content, which is beneficial to the clearance and transport of TC.
不足之处：其所带来的副作用是不可避免的，如：横纹肌溶解，肌炎以及肝脏的各种酶活性增强等，另外有一些患者未能很好的适应他汀类药物的治疗，更重要的是单一的他汀类治疗往往还不能达到预期的理想效果。Inadequacies: the side effects are inevitable, such as: rhabdomyolysis, myositis and various enzyme activities in the liver, and some patients are not well adapted to the treatment of statins, more important The single statin treatment often does not achieve the desired results.
贝特类代表药物：氯贝丁酯，吉非罗齐，非诺贝特等。该类药物经过长期的临床应用，已经被证明是一类耐受性好、具有好的调脂作用的药物。其降脂途径除了和他汀类相似外还有增加脂蛋白脂酶的活性，使甘油三酯(TG)的清除增加；降低血糖，从而使得乙醜辅酶A与游离脂肪酸趋向于葡萄糖的合成，使脂质合成减少。The fibrates represent drugs: clofibrate, gemfibrozil, fenofibrate, etc. After long-term clinical application, these drugs have been proven to be a class of drugs that are well tolerated and have good lipid-lowering effects. In addition to similar to statins, its lipid-lowering pathway increases the activity of lipoprotein lipase, which increases the clearance of triglyceride (TG); lowers blood sugar, which makes the synthesis of glucose and free fatty acids tend to glucose. Lipid synthesis is reduced.
不足之处：消化道常出现不良反应，偶尔会出现过敏反应，视力障碍，由于该类药物增加了胆固醇在胆汁中浓度，所以还可能引起胆结石。Inadequacies: Adverse reactions often occur in the digestive tract, occasionally allergic reactions, visual impairment, and because of the increased concentration of cholesterol in the bile, it may also cause gallstones.
烟酸类代表药物：烟酸，烟酸肌醇酯，阿昔莫司等。这类药物主要通过抑制脂肪的分解和游离脂肪酸的形成，抑制肝脏合成甘油 三酯(TG)和极低密度脂蛋白(VLD-L)来降低血脂。Niacin represents a drug: niacin, inositol niacin, acyclovir and the like. These drugs inhibit the synthesis of glycerol by the liver mainly by inhibiting the decomposition of fat and the formation of free fatty acids. Triester (TG) and very low density lipoprotein (VLD-L) to lower blood lipids.
不足之处：对糖尿病患者降血脂作用不明显，副作用如：肝中毒，高血糖较为明显，常出现皮疫，瘙痒等不良反应。Inadequacies: The effect of lowering blood lipids in diabetic patients is not obvious. Side effects such as: liver poisoning, high blood sugar is more obvious, and skin reactions such as skin plague and itching often occur.
胆酸螯合剂类代表药物：依折麦布(Ezetimibe)，多稀不饱和脂肪酸等。这类降脂药物可以分为胆固醇吸收抑制剂和多稀不饱和脂肪酸两类。The bile acid sequestrants represent drugs: Ezetimibe, polyunsaturated fatty acids, and the like. Such lipid-lowering drugs can be classified into two types: cholesterol absorption inhibitors and polyunsaturated fatty acids.
(1)、胆固醇吸收抑制剂(依折麦布)：与胆汁酸结合，阻碍胆汁酸的重吸收，从而促使胆固醇转化为胆汁酸，在肠道和该药物结合排出体外。(1) Cholesterol absorption inhibitor (Yibei Maibu): combined with bile acid, hinders the reabsorption of bile acid, thereby promoting the conversion of cholesterol into bile acid, which is excreted in the intestine and the drug.
(2)、多烯不饱和脂肪酸：与胆固醇结合为酯类，促进胆固醇降解为胆汁酸随胆汁排泄，从而使血柴总胆固醇的浓度降低。(2) Polyunsaturated fatty acids: combined with cholesterol as esters, promotes the degradation of cholesterol to bile acid excretion with bile, thereby lowering the concentration of total cholesterol in the blood.
低密度脂蛋白(LDL)水平过高能致动脉粥样硬化，降低血浆LDL水平对预防和治疗心脑血管等疾病具有重要的意义。血液中大约70％的LDL是通过低密度脂蛋白受体(LDLR)介导的内吞作用完成清除的，LDLR的表达受到前蛋白转化酶枯草杆菌蛋白酶/kexin9型(proprotein convertase subtilisin/kexin type 9)(PCSK9)的影响，PCSK9是一个丝氨酸蛋白酶，主要在肝脏合成，它能够减少肝细胞中LDLR数量。PCSK9与位于细胞表面的LDLR结合后，内化至细胞里，促进溶酶体中LDLR降解。抑制PCSK9的活性可以增加LDLR数量，降低血浆中LDL水平。Low levels of low-density lipoprotein (LDL) can cause atherosclerosis, and lowering plasma LDL levels is important for the prevention and treatment of cardiovascular and cerebrovascular diseases. About 70% of LDL in the blood is cleared by low-density lipoprotein receptor (LDLR)-mediated endocytosis, and the expression of LDLR is regulated by proprotein convertase subtilisin/kexin type 9 (proprotein convertase subtilisin/kexin type 9). (PCSK9), PCSK9 is a serine protease that is mainly synthesized in the liver, which can reduce the amount of LDLR in hepatocytes. After binding to LDLR located on the cell surface, PCSK9 internalizes into cells and promotes LDLR degradation in lysosomes. Inhibition of PCSK9 activity increases the number of LDLRs and decreases plasma LDL levels.
PCSK9抑制剂的开发是当今大型跨国制药公司努力研发新型心血管疾病药物的重要方向，期待这类药物超越他汀类成熟的降脂药物。大型制药公司正密锣紧鼓地推动PCSK9抑制剂药物开发工作，目前的研究工作主要集中在生物制品药物(包括蛋白药物和长链核酸药物)的开发(如下表)，生物制品药物与小分子药物针对治疗同一病症时，生物药具有成本高昂，只能采用注射制剂等有限的制剂方式等缺点，目前，还没有小分子PCSK9抑制剂成为临床候选药物。The development of PCSK9 inhibitors is an important direction for large multinational pharmaceutical companies to develop new cardiovascular disease drugs. It is expected that these drugs will surpass statin mature lipid-lowering drugs. Large pharmaceutical companies are working hard to promote the development of PCSK9 inhibitor drugs. The current research work focuses on the development of biologic drugs (including protein drugs and long-chain nucleic acid drugs) (see table below), biologic drugs and small molecules. When the drug is used to treat the same disease, the biopharmaceutical is costly, and only a limited preparation method such as an injection preparation can be used. At present, no small molecule PCSK9 inhibitor has become a clinical drug candidate.
Figure PCTCN2015100201-appb-000001
Figure PCTCN2015100201-appb-000001
目前公开了一系列PCSK9抑制剂的小分子化合物专利申请，其中包括WO2010075469，WO2011006000，WO2011051961，WO2011152508，WO2012090220，JP2013136572，WO2013132509，WO2013137371，WO2014017569，WO2014002105，WO2014002106，WO2014150326，WO2014150395，WO2014139008等。A series of patent applications for small molecule compounds of PCSK9 inhibitors are disclosed, including WO2010075469, WO2011006000, WO2011051961, WO2011152508, WO2012090220, JP2013136572, WO2013132509, WO2013137371, WO2014017569, WO2014002105, WO2014002106, WO2014150326, WO2014150395, WO2014139008, and the like.
尽管目前已经公开了一系列的具有抑制PCSK9表达和降脂效果的化合物，但是，仍然需要开发新的具有更好药效，药代结果的化合物，经过不断努力，本发明设计具有通式(V)结构的化合物并发现具有此类结构的化合物表现出优异的效果和作用，在更大范围内，更加深入和全面地揭示和阐明了结构和活性效能的关系，具有重要的应用价值。Although a series of compounds having inhibitory effects on PCSK9 expression and lipid-lowering effects have been disclosed, there is still a need to develop new compounds having better pharmacological effects and pharmacological results, and the design of the present invention has a general formula (V) through continuous efforts. The compounds of the structure and the discovery of compounds having such structures exhibit excellent effects and effects, and in a wider range, the relationship between structure and activity efficiency is revealed and elucidated more deeply and comprehensively, and has important application value.
发明内容Summary of the invention
本发明的目的在于提供一种通式(V)所示化合物，以及它们的互变异构体、对映体、非对映体、消旋体和可药用的盐，以及代谢产物和代谢前体或前药。式V的化合物The object of the present invention is to provide a compound of the formula (V), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolism Precursor or prodrug. Compound of formula V
Figure PCTCN2015100201-appb-000002
Figure PCTCN2015100201-appb-000002
其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类；其中： a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof; wherein:
Y选自环烷基、杂环基、芳基、杂芳基，其中，Y is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
所述的环烷基、杂环基、芳基、杂芳基各自独立地被一个或多个选自氢，卤，-OH，-NR′R″，-NO2，-Si(R′)3，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，-S(O)mR′，-S(O)nNR′R″，-OS(O)nR′，-OS(O)nNR′R″，
Figure PCTCN2015100201-appb-000003
Figure PCTCN2015100201-appb-000004
-OS(O)nNH(C＝O)NR′R″，-S(O)nNH(C＝O)NR′R″，-NR′S(O)nR″，-NR′S(O)nNR′R″，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基的取代基所取代；The cycloalkyl, heterocyclic, aryl, heteroaryl groups are each independently selected from one or more selected from the group consisting of hydrogen, halogen, -OH, -NR'R", -NO 2 , -Si(R') 3 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", -S(O) m R', -S(O) n NR'R", -OS(O) n R', -OS(O) n NR'R",
Figure PCTCN2015100201-appb-000003
Figure PCTCN2015100201-appb-000004
-OS(O) n NH(C=O)NR'R", -S(O) n NH(C=O)NR'R", -NR'S(O) n R", -NR'S( O) n NR'R", substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, Substituted by a heteroarylalkyl, heterocyclyl or heterocyclic substituent;
R1，R2，R3，R4，R5，R6，R7，R8独立地是氢，卤，经取代的或未经取代的硅基，氨基，硝基，氧代基，硫基，砜基，氰基，羰基，磺酰氧基，磷酰氧基，烷基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
M为氮原子，或者碳原子；M is a nitrogen atom, or a carbon atom;
W为氮原子，或者碳原子；W is a nitrogen atom, or a carbon atom;
Z为-O-，-S-，-NH-，-CR5R6-，-C(O)O-，-C(O)NR5-，-SO2O-，-SO2NR5-，-P(O)R5R6或者Z不为任何原子(即是，与Z相连的化学基团通过化学键直接连接)；Z is -O-, -S-, -NH-, -CR 5 R 6 -, -C(O)O-, -C(O)NR 5 -, -SO 2 O-, -SO 2 NR 5 - , -P(O)R 5 R 6 or Z is not an atom (ie, the chemical group attached to Z is directly linked by a chemical bond);
环X为3～10元环，所述的3～10元环X选自环烷基、杂环基、芳基、杂芳基，其中，Ring X is a 3- to 10-membered ring, and the 3- to 10-membered ring X is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
所述的环烷基、杂环基、芳基、杂芳基各自独立地被一个或多个选自氢，卤，-OH，-NR′R″，-NO2，-Si(R′)3，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，-S(O)mR′，-S(O)nNR′R″，-OS(O)nR′，-OS(O)nNR′R″，
Figure PCTCN2015100201-appb-000005
Figure PCTCN2015100201-appb-000006
-OS(O)nNR′(C＝O)NR′R″，-S(O)nNR′(C＝O)NR′R″，-NR′S(O)nR″，-NR′S(O)nNR′R″，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基的取代基所取代；The cycloalkyl, heterocyclic, aryl, heteroaryl groups are each independently selected from one or more selected from the group consisting of hydrogen, halogen, -OH, -NR'R", -NO 2 , -Si(R') 3 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", -S(O) m R', -S(O) n NR'R", -OS(O) n R', -OS(O) n NR'R",
Figure PCTCN2015100201-appb-000005
Figure PCTCN2015100201-appb-000006
-OS(O) n NR'(C=O)NR'R", -S(O) n NR'(C=O)NR'R", -NR'S(O) n R", -NR' S(O) n NR'R", substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl Substituted with a substituent of a heteroarylalkyl group, a heterocyclic group or a heterocyclic group;
R′和R″独立的是氢或者经取代的或未经取代的烷基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基，R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaryl Alkyl, heterocyclic or heterocyclylalkyl,
在-NR′R″，-C(O)NR′R″，-OC(O)NR′R″，-OS(O)nNR′R″，-OS(O)nNH(C＝O)NR′R″中，其中NR′R″可以为4至20元含氮杂环基；In -NR'R", -C(O)NR'R", -OC(O)NR'R", -OS(O) n NR'R", -OS(O) n NH(C=O) In NR'R", wherein NR'R" may be a 4 to 20 membered nitrogen-containing heterocyclic group;
m＝0，1，2；m=0,1,2;
n＝1，2，3；n=1, 2, 3;
p＝1，2，3；p=1, 2, 3;
q＝0，1，2，3，4，5，6；q=0,1,2,3,4,5,6;
s＝0，1，2；s=0,1,2;
t＝0，1，2。t=0, 1, 2.
本发明涉及通式化合物化合物(V)，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中包括通式化合物化合物(VI)， The present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, including the compound (VI) of the formula
Figure PCTCN2015100201-appb-000007
Figure PCTCN2015100201-appb-000007
其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中：a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein:
R9，R10，R11，R12，R13，R14，R15，R16独立地是氢，卤，经取代的或未经取代的硅基，氨基，硝基，氧代基，硫基，砜基，氰基，羰基，磺酰氧基，磷酰氧基，烷基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
R5，R6，R7，R8，Z，M，q，t，环X和环Y同前文所述。R 5 , R 6 , R 7 , R 8 , Z, M, q, t, ring X and ring Y are as described above.
本发明涉及通式化合物化合物(V)，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中包括通式化合物化合物(VII)，The present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including a compound of the formula (VII),
Figure PCTCN2015100201-appb-000008
Figure PCTCN2015100201-appb-000008
其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中：a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein:
R9，R10，R11，R12，R13，R14，R15，R16独立地是氢，卤，经取代的或未经取代的硅基，氨基，硝基，氧基，硫基，砜基，氰基，羰基，磺酰氧基，磷酰氧基，烷基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxy, sulphur , sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
R17，R18，R19，R20，R21独立地是氢，卤，-OH，-NR′R″，-NO2，-Si(R′)3，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，-S(O)mR′，-S(O)nNR′R″，-OS(O)nR′，-OS(O)nNR′R″，
Figure PCTCN2015100201-appb-000009
Figure PCTCN2015100201-appb-000010
-OS(O)nNH(C＝O)NR′R″，-S(O)nNH(C＝O)NR′R″，-NR′S(O)nR″，-NR′S(O)nNR′R″，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；R 17 , R 18 , R 19 , R 20 , R 21 are independently hydrogen, halo, -OH, -NR'R", -NO 2 , -Si(R') 3 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", -S(O) m R', -S(O) n NR'R", -OS(O) n R', -OS(O) n NR'R",
Figure PCTCN2015100201-appb-000009
Figure PCTCN2015100201-appb-000010
-OS(O) n NH(C=O)NR'R", -S(O) n NH(C=O)NR'R", -NR'S(O) n R", -NR'S( O) n NR'R", substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
R5，R6，R7，R8，R′，R″，Z，环X，M，m，n，q，t同前文所述。R 5 , R 6 , R 7 , R 8 , R', R", Z, ring X, M, m, n, q, t are as described above.
本发明涉及通式化合物化合物(VII)，其中，R9，R10，R11，R12，R13，R14，R15，R16独立地是-H，卤，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基； The present invention relates to the compound of the formula (VII) wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently -H, halo, substituted or unsubstituted Substituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocycloalkyl base;
R17，R18，R19，R20，R21独立地是-H，卤，-OH，-NO2，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，取代的或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基，还选自包括：R 17 , R 18 , R 19 , R 20 , R 21 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R' , -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", substituted or unsubstituted amino, alkyl, alkane Oxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, also selected from :
Figure PCTCN2015100201-appb-000011
Figure PCTCN2015100201-appb-000011
R27选自苯基，C1-6烷基，环(C3-8)烷基，噻吩基，呋喃基，咪唑基，吡啶基，嘧啶基，哒嗪基，喹啉基，异喹啉基，苯乙炔基，苯甲基，苯乙烯基，萘基，取代氨基，吗啉基，哌啶基，N-甲基哌嗪基，四氢吡咯基，六氢吡啶基，樟脑烷基，对甲苯基，R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
其中，C1-6烷基任选被0至13个取代基取代，Wherein C 1-6 alkyl is optionally substituted by 0 to 13 substituents,
噻吩基，呋喃基和咪唑基任选被0至3个取代基取代，The thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
吡啶基任选被0至4个取代基取代，The pyridyl group is optionally substituted with from 0 to 4 substituents.
嘧啶基和哒嗪基任选被0至3个取代基取代，The pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
苯基任选被0至5个取代基取代，The phenyl group is optionally substituted with from 0 to 5 substituents.
喹啉基和异喹啉基萘基选任选被0至6个取代基取代，The quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
萘基选任选被0至7个取代基取代，The naphthyl group is optionally substituted with from 0 to 7 substituents.
以上的取代基选自：羟基，卤素，氰基，硝基，硅基，-COOH，羧酸酯基，取代或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；The above substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring An alkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
R28选自氢，取代或者未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基。R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
本发明涉及通式化合物化合物(V)，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中包括通式化合物化合物(VIII)，The present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including a compound of the formula (VIII),
Figure PCTCN2015100201-appb-000012
Figure PCTCN2015100201-appb-000012
其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中：a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein:
R22，R23，R24，R25，R26独立地是氢，卤，-OH，-NR′R″，-NO2，-Si(R′)3，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″， -OC(O)OR′，-OC(O)NR′R″，-S(O)mR′，-S(O)nNR′R″，-OS(O)nR′，-OS(O)nNR′R″，
Figure PCTCN2015100201-appb-000013
Figure PCTCN2015100201-appb-000014
-OS(O)nNH(C＝O)NR′R″，-S(O)nNH(C＝O)NR′R″，-NR′S(O)nR″，-NR′S(O)nNR′R″，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基；R 22 , R 23 , R 24 , R 25 , R 26 are independently hydrogen, halo, -OH, -NR'R", -NO 2 , -Si(R') 3 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", -S(O) m R', -S(O) n NR'R", -OS(O) n R', -OS(O) n NR'R",
Figure PCTCN2015100201-appb-000013
Figure PCTCN2015100201-appb-000014
-OS(O) n NH(C=O)NR'R", -S(O) n NH(C=O)NR'R", -NR'S(O) n R", -NR'S( O) n NR'R", substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group or a heterocyclic group;
环Y，R1，R2，R3，R4，R5，R6，R7，R8，R′，R″，M，W，Z，m，n，p，q，s，t同前文所述。Ring Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R′, R′′, M, W, Z, m, n, p, q, s, t As mentioned above.
本发明涉及通式化合物化合物(VIII)，其中，R22，R23，R24，R25，R26独立地是-H，卤，-OH，-NO2，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，取代的或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基，还选自包括：The present invention relates to the compound of the formula (VIII), wherein R 22 , R 23 , R 24 , R 25 , R 26 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", Substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hetero A cycloalkyl or heterocyclylalkyl group, also selected from the group consisting of:
Figure PCTCN2015100201-appb-000015
Figure PCTCN2015100201-appb-000015
R27选自苯基，C1-6烷基，环(C3-8)烷基，噻吩基，呋喃基，咪唑基，吡啶基，嘧啶基，哒嗪基，喹啉基，异喹啉基，苯乙炔基，苯甲基，苯乙烯基，萘基，取代氨基，吗啉基，哌啶基，N-甲基哌嗪基，四氢吡咯基，六氢吡啶基，樟脑烷基，对甲苯基，R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
其中，C1-6烷基任选被0至13个取代基取代，Wherein C 1-6 alkyl is optionally substituted by 0 to 13 substituents,
噻吩基，呋喃基和咪唑基任选被0至3个取代基取代，The thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
吡啶基任选被0至4个取代基取代，The pyridyl group is optionally substituted with from 0 to 4 substituents.
嘧啶基和哒嗪基任选被0至3个取代基取代，The pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
苯基任选被0至5个取代基取代，The phenyl group is optionally substituted with from 0 to 5 substituents.
喹啉基和异喹啉基萘基选任选被0至6个取代基取代，The quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
萘基选任选被0至7个取代基取代，The naphthyl group is optionally substituted with from 0 to 7 substituents.
以上的取代基选自：羟基，卤素，氰基，硝基，硅基，-COOH，羧酸酯基，取代或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；The above substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring An alkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
R28选自氢，取代或者未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基。R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
本发明涉及通式化合物化合物(V)，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中包括通式化合物化合物(IX)， The present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including the compound (IX) of the formula
Figure PCTCN2015100201-appb-000016
Figure PCTCN2015100201-appb-000016
其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中：a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein:
R9，R10，R11，R12，R13，R14，R15，R16，R17，R18，R19，R20，R21同前文所述；R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 are as described above;
R22，R23，R24，R25，R26同前文所述；R 22 , R 23 , R 24 , R 25 , R 26 are as described above;
R5，R6，R7，R8，M，q，t同前文所述。R 5 , R 6 , R 7 , R 8 , M, q, t are as described above.
本发明涉及通式化合物化合物(IX)，其中，R17，R18，R19，R20，R21，R22，R23，R24，R25，R26独立地是-H，卤，-OH，-NO2，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，取代的或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基，还选自包括：The present invention relates to the compound of the formula (IX), wherein R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 are independently -H, halogen, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC( O) OR', -OC(O)NR'R", substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, An aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group, further selected from the group consisting of:
Figure PCTCN2015100201-appb-000017
Figure PCTCN2015100201-appb-000017
R27选自苯基，C1-6烷基，环(C3-8)烷基，噻吩基，呋喃基，咪唑基，吡啶基，嘧啶基，哒嗪基，喹啉基，异喹啉基，苯乙炔基，苯甲基，苯乙烯基，萘基，取代氨基，吗啉基，哌啶基，N-甲基哌嗪基，四氢吡咯基，六氢吡啶基，樟脑烷基，对甲苯基，R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
其中，C1-6烷基任选被0至13个取代基取代，Wherein C 1-6 alkyl is optionally substituted by 0 to 13 substituents,
噻吩基，呋喃基和咪唑基任选被0至3个取代基取代，The thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
吡啶基任选被0至4个取代基取代，The pyridyl group is optionally substituted with from 0 to 4 substituents.
嘧啶基和哒嗪基任选被0至3个取代基取代，The pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
苯基任选被0至5个取代基取代，The phenyl group is optionally substituted with from 0 to 5 substituents.
喹啉基和异喹啉基萘基选任选被0至6个取代基取代，The quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
萘基选任选被0至7个取代基取代，The naphthyl group is optionally substituted with from 0 to 7 substituents.
以上的取代基选自：羟基，卤素，氰基，硝基，硅基，-COOH，羧酸酯基，取代或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；The above substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring An alkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
R28选自氢，取代或者未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基。 R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
本发明涉及的化合物，该化合物选自以下化合物，但不局限于以下化合物范围：The present invention relates to a compound selected from the following compounds, but is not limited to the following compound ranges:
Figure PCTCN2015100201-appb-000018
Figure PCTCN2015100201-appb-000018
Figure PCTCN2015100201-appb-000019
Figure PCTCN2015100201-appb-000019
Figure PCTCN2015100201-appb-000020
Figure PCTCN2015100201-appb-000020
Figure PCTCN2015100201-appb-000021
Figure PCTCN2015100201-appb-000021
Figure PCTCN2015100201-appb-000022
Figure PCTCN2015100201-appb-000022
Figure PCTCN2015100201-appb-000023
Figure PCTCN2015100201-appb-000024
或其药用可接受的盐。
Figure PCTCN2015100201-appb-000023
Figure PCTCN2015100201-appb-000024
Or a pharmaceutically acceptable salt thereof.
本发明涉及通式(V)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：The present invention relates to a compound represented by the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein a preparation method comprises the steps of:
Figure PCTCN2015100201-appb-000025
Figure PCTCN2015100201-appb-000025
X1和X2为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X1和X2在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物V；X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
另一种制备方法包括以下步骤：Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000026
Figure PCTCN2015100201-appb-000026
X1和X3为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X1和X3在一定的反应条件下，通过还原氨化的反应制备得到V。X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
本发明涉及通式(V)所示化合物，制备一种药物组合物，其包含任意一项的化合物和药学上可以接受的载体。The present invention relates to a compound of the formula (V), which comprises a pharmaceutical composition comprising a compound of any one and a pharmaceutically acceptable carrier.
本发明涉及通式(V)所示化合物组成的一种药物组合物，所述组合物包括给予需要治疗的患者有效治疗量的任意一项的化合物。The present invention relates to a pharmaceutical composition consisting of a compound of the formula (V), which comprises a compound which is administered to any one of a therapeutically effective amount of a patient in need of treatment.
本发明涉及通式(V)所示化合物中任意一项化合物在制备用于降低患者血浆和/或肝的脂类水平的药物中的用途。The present invention relates to the use of any one of the compounds of the formula (V) for the preparation of a medicament for lowering the lipid level of a patient's plasma and/or liver.
本发明涉及通式(V)所示化合物中任意一项化合物在制备用于治疗高脂血症，高胆固醇血症，高甘油三酯血症，肝脂肪变性，代谢综合征，抗肿瘤药物中的用途。The present invention relates to a compound of any one of the compounds represented by the general formula (V) for use in the treatment of hyperlipemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, metabolic syndrome, antitumor drugs. the use of.
本发明涉及通式(V)所示化合物中任意一项化合物在制备用于增加LDLR表达和/或降低PCSK9表达的药物中的用途。The present invention relates to the use of any one of the compounds of the general formula (V) for the preparation of a medicament for increasing LDLR expression and/or reducing PCSK9 expression.
本发明涉及通式(V)所示化合物，本发明公开的化合物具有以下有益效果： The present invention relates to a compound of the formula (V), and the compounds disclosed herein have the following beneficial effects:
Figure PCTCN2015100201-appb-000027
Figure PCTCN2015100201-appb-000027
1、本发明公开的具有通式(V)小分子化合物，在抑制PCSK9基因表达，增加细胞LDLR的表达，增强肝细胞对LDL的摄取能力中的显著作用，有望成为新一代降脂药。1. The small molecule compound of the general formula (V) disclosed in the present invention is expected to be a new generation of lipid-lowering drug in inhibiting the expression of PCSK9 gene, increasing the expression of LDLR and enhancing the uptake of hepatocytes to LDL.
PCSK9抑制剂作为降脂药物的开发是当今大型跨国制药公司努力研发新型心血管疾病药物的重要方向，期待这类药物超越他汀类成熟的降脂药物。大型制药公司正密锣紧鼓地推动PCSK9抑制剂药物开发工作，目前的研究工作主要集中在生物制品药物(包括蛋白药物和长链核酸药物)的开发，目前，还没有小分子PCSK9抑制剂成为临床候选药物。如下表：The development of PCSK9 inhibitors as lipid-lowering drugs is an important direction for large multinational pharmaceutical companies to develop new cardiovascular disease drugs. It is expected that these drugs will surpass statin mature lipid-lowering drugs. Large pharmaceutical companies are working hard to promote the development of PCSK9 inhibitor drugs. The current research work focuses on the development of biologic drugs (including protein drugs and long-chain nucleic acid drugs). Currently, no small molecule PCSK9 inhibitors have been developed. Clinical drug candidates. The following table:
Figure PCTCN2015100201-appb-000028
Figure PCTCN2015100201-appb-000028
生物制品药物与小分子药物针对治疗同一病症时，生物药具有成本高昂，只能采用注射制剂等有限的制剂方式等缺点，而小分子药物具有制造成本低廉，制剂方法多样等优点，本发明公开的有通式(V)小分子化合物，在细胞水平表现出显著的抑制PCSK9基因表达，增强肝细胞对LDL的摄取能力中的显著作用，有望成为具有新一代降脂药。另一方面，小分子药物的制剂方案比生物大分子药物选择面更加广泛，有利于后期药物开发多种剂型药物的开发，相比生物大分子药物而言，可以提供给为广泛的制剂类型，满足人们的需求。When a biologic drug and a small molecule drug are used to treat the same disease, the biopharmaceutical is expensive, and only a limited preparation method such as an injection preparation can be used, and the small molecule drug has the advantages of low manufacturing cost, various preparation methods, and the like, and the present invention discloses The small molecule compound of the general formula (V) exhibits significant inhibition of PCSK9 gene expression at the cellular level and enhances the significant function of hepatocytes to uptake of LDL, and is expected to have a new generation of lipid-lowering drugs. On the other hand, the formulation of small molecule drugs is more extensive than that of biomacromolecules, which is conducive to the development of a variety of drug formulations for later drug development. Compared to biomacromolecular drugs, it can be provided for a wide range of formulation types. satisfy people's demands.
2、与现有的专利文献公开的以PCSK9为作用的靶点的化合物相比，本发明公开的具有通式(V)化合物，结构新颖，具有崭新的结构特征，有望成为对PCSK9具有新颖作用机理的候选药物，并最终成为新一代具有新颖作用机制的降脂药物。2. The compound of the general formula (V) disclosed in the present invention has a novel structure and a novel structural feature, and is expected to have a novel effect on PCSK9, compared with a compound disclosed in the prior patent document which is a target of PCSK9. The candidate drug of the mechanism, and eventually become a new generation of lipid-lowering drugs with a novel mechanism of action.
现有公开专利文献报道了几类作用于PCSK9靶点的小分子化合物，以专利申请人分类总结如下：The existing published patent documents report several types of small molecule compounds that act on the PCSK9 target, and the patent applicants are summarized as follows:
a、CVI Pharmaceutical Limited的申请专利WO2010075469，WO2011006000中报道了基于天然产物紫堇碱结构改造得到的小分子化合物，该类基于天然产物结构的小分子化合物，其制造工艺较为复杂，部分合成方法需要使用剧毒的化学试剂，会给操作工人和自然环境带来巨大的危害。a, CVI Pharmaceutical Limited application patent WO2010075469, WO2011006000 reported a small molecule compound based on the structural transformation of the natural product purpurine, which is based on the small molecular compound of the natural product structure, the manufacturing process is more complicated, and some synthetic methods need to be used. Very toxic chemical agents can cause great harm to operators and the natural environment.
b、Cadila Healthcare Limited的申请专利WO2011051961，WO2012090220，WO2013132509，WO2014002105，WO2014002106中报道了几类小分子化合物，这几类小分子化合物在分子结构特点上主要含有一个共同的化学结构片段——六氢吡喃甲基氨基结构片段。该结构片段可能在化合物结构与生物活性中扮演着重要的角色。b. Several types of small molecule compounds are reported in the application patents WO2011051961, WO2012090220, WO2013132509, WO2014002105, WO2014002106, which are mainly composed of a common chemical structure fragment, hexahydropyridyl. A methylamino structure fragment. This structural fragment may play an important role in the structure and biological activity of the compound.
c、Kowa Company Limited申请专利WO2011152508，JP2013136572，WO2013137371，WO2014017569中报道了几类小分子化合物，这类小分子化合物分子结构相对复杂，一般的实施例化合物还含有三个手性中心，其制造难度相对较大，实施例化合物一般需要六步化学反应(不包括含有手性中心的结构片段的构建)才能制备得到目标化合物。c. Several types of small molecule compounds are reported in the Kowa Company Limited application patents WO2011152508, JP2013136572, WO2013137371, WO2014017569. The molecular structure of such small molecule compounds is relatively complicated, and the general example compounds also contain three chiral centers, which are relatively difficult to manufacture. Larger, the example compounds generally require a six-step chemical reaction (excluding the construction of a structural fragment containing a chiral center) to produce the target compound.
d、Amorchem Holdings INC.申请专利WO2014139008中报道了一类小分子化合物，该类小分子化合物的部分实施例化合物主要结构特点在于含有“硼酸酯和硼酸”结构片段，尽管目前已经上市多发性骨髓瘤治疗药物——硼替佐米(含有“硼酸”结构片段)，但是“硼酸类”药物在非肿瘤治疗领域(例如：糖尿病，高脂血症等等)的应用仍然受到限制，主要原因在于含硼药物的潜在的神经毒性副作用，以及其潜在的与生物机体“不可逆结合”的化学特性(Chem.Res.Toxicol.,2013,26(4),pp 608–615)，该化学特性的在药物分子设计中可能造成的潜在的“致癌性”，“生殖毒性”已经广泛受到药物化学家的重视。 d. Amorchem Holdings INC. Patent Application WO2014139008 reports a class of small molecule compounds, some of which are mainly characterized by the inclusion of "borate and boric acid" structural fragments, although multiple bone marrows are currently available. Tumor treatment drug - bortezomib (containing "boric acid" structural fragments), but the application of "boric acid" drugs in non-tumor treatment areas (eg diabetes, hyperlipidemia, etc.) is still limited, mainly because Potential neurotoxic side effects of boron drugs, as well as their potential for "irreversible binding" to biological organisms (Chem. Res. Toxicol., 2013, 26(4), pp 608-615), the chemical properties of the drug The potential "carcinogenicity" that may be caused by molecular design, "reproductive toxicity" has been widely recognized by pharmaceutical chemists.
e、Shifa Biomedical Corporation申请专利WO2014150326，WO2014150395中报道了两类小分子化合物，这些小分子化合物的制备方法相对复杂，某些活性比较优秀的化合物的制备需要使用重金属催化反应，并且使用异氰酸酯化合物。e. The two types of small molecule compounds are reported in the patent application WO2014150326, WO2014150395. These small molecule compounds are relatively complicated to prepare, and the preparation of some compounds with relatively good activity requires the use of heavy metal catalyzed reactions and the use of isocyanate compounds.
以上总结的就是目前公开的文献中以PCSK9为作用靶点的小分子化合物。本发明公开的化合物同样以PCSK9为作用靶点，该类化合物与上述总结的几类小分子化合物均可能成为未来基于PCSK9作用靶点的新型药物。The above summarizes the small molecule compounds targeting PCSK9 in the currently published literature. The compounds disclosed in the present invention also target PCSK9, and such compounds and the above-mentioned several types of small molecule compounds may become novel drugs based on the target of PCSK9 in the future.
与现有的专利文献公开的以PCSK9为作用的靶点的化合物相比，本发明公开的具有通式(V)化合物，结构新颖，具有崭新的独特结构特征，预示着本发明公开的化合物其新颖的分子结构特点，有可能带来意想不到“类药性特点”，有望成为对PCSK9具有新颖作用机理的候选药物，并最终成为新一代具有新颖作用机制的降脂药物。Compared with the compound disclosed in the prior patent document, which has a target of PCSK9, the compound of the formula (V) disclosed in the present invention has novel structure and novel unique structural features, and indicates that the compound disclosed in the present invention The novel molecular structure features may bring unexpected "drug-like characteristics", and it is expected to become a candidate drug with a novel mechanism of action for PCSK9, and eventually become a new generation of lipid-lowering drugs with novel mechanism of action.
3、本发明公开的具有通式(V)化合物，具有原料易得，制备过程操作简单，成本低廉优势。3. The compound of the formula (V) disclosed in the invention has the advantages that the raw materials are easy to obtain, the preparation process is simple, and the cost is low.
本发明公开的具有通式(V)的小分子化合物，主要采用市售中间体，然后采用简单的化学反应进行片段偶联反应制备得到。例如采用市售的具有“胺”，“醛”，“卤代烃”等官能团的起始物料，然后进行一步化学反应即可以制备得到目标化合物。因此，本发明公开的具有通式(V)化合物，具有原料易得，制备过程操作简单，成本低廉的优势。The small molecule compound of the formula (V) disclosed in the present invention is mainly prepared by using a commercially available intermediate, and then subjected to a fragment coupling reaction by a simple chemical reaction. For example, a commercially available starting material having a functional group such as "amine", "aldehyde" or "halogenated hydrocarbon" can be used to prepare a target compound by one-step chemical reaction. Therefore, the compound of the formula (V) disclosed in the present invention has the advantages that the raw materials are easily available, the preparation process is simple, and the cost is low.
4、本发明公开的具有通式(V)化合物具有活化AMPK激酶的活性，提示本发明化合物不但可以开发成为新一代降脂药，而且可以起到较好控制血糖的作用，为广大的代谢综合征患者在降脂和降糖方面获得综合的收益比现有单一作用药物更具优势。4. The compound of the general formula (V) disclosed in the present invention has the activity of activating AMPK kinase, suggesting that the compound of the present invention can not only be developed into a new generation of lipid-lowering drugs, but also can play a role in controlling blood sugar, and is a comprehensive metabolic synthesis. The comprehensive benefits of patients with lipid-lowering and hypoglycemic agents are more advantageous than the existing single-acting drugs.
本发明公开的通式化合物(V)制备主要参照以下的方案进行制备，The preparation of the compound of the general formula (V) disclosed in the present invention is mainly prepared by referring to the following scheme,
Figure PCTCN2015100201-appb-000029
Figure PCTCN2015100201-appb-000029
本发明所述通式(V)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：A compound represented by the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein the preparation method comprises the following steps :
Figure PCTCN2015100201-appb-000030
Figure PCTCN2015100201-appb-000030
X1和X2为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X1和X2在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物V；X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
另一种制备方法包括以下步骤：Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000031
Figure PCTCN2015100201-appb-000031
X1和X3为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X1和X3在一定的反应条件下，通过还原氨化的反应制备得到V。X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
更进一步地，通式(VI)： Further, the general formula (VI):
Figure PCTCN2015100201-appb-000032
Figure PCTCN2015100201-appb-000032
本发明所述通式(VI)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：A compound represented by the formula (VI), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein the preparation method comprises the following steps :
Figure PCTCN2015100201-appb-000033
Figure PCTCN2015100201-appb-000033
X4和X2为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X4和X2在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物VI；X4 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X4 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VI;
另一种制备方法包括以下步骤：Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000034
Figure PCTCN2015100201-appb-000034
X4和X3为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X4和X3在一定的反应条件下，通过还原氨化的反应制备得到VI。X4 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VI is prepared by reacting X4 and X3 under a certain reaction condition by reductive amination.
更进一步地，通式(VII)：Further, the general formula (VII):
Figure PCTCN2015100201-appb-000035
Figure PCTCN2015100201-appb-000035
本发明所述通式(VII)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方 法包括以下步骤：A compound represented by the formula (VII) of the present invention, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein one of the preparations The method includes the following steps:
Figure PCTCN2015100201-appb-000036
Figure PCTCN2015100201-appb-000036
X5和X2为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X5和X2在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物VII；X5 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VII;
另一种制备方法包括以下步骤：Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000037
Figure PCTCN2015100201-appb-000037
X5和X3为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X5和X3在一定的反应条件下，通过还原氨化的反应制备得到VII。X5 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VII is obtained by reacting X5 and X3 under a certain reaction condition by reductive amination.
更进一步地，通式(VIII)：Further, the general formula (VIII):
Figure PCTCN2015100201-appb-000038
Figure PCTCN2015100201-appb-000038
本发明所述通式(VIII)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：A compound represented by the formula (VIII), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein the preparation method comprises the following steps :
Figure PCTCN2015100201-appb-000039
Figure PCTCN2015100201-appb-000039
X1和X6为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X1和X6在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物VIII；X1 and X6 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X6 at a certain reaction temperature, in the presence of a certain alkaline reagent, by coupling to obtain compound VIII;
另一种制备方法包括以下步骤： Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000040
Figure PCTCN2015100201-appb-000040
X1和X7为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X1和X7在一定的反应条件下，通过还原氨化的反应制备得到VIII。X1 and X7 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VIII is prepared by reacting X1 and X7 under a certain reaction condition by reductive amination.
更进一步地，通式(IX)：Further, the general formula (IX):
Figure PCTCN2015100201-appb-000041
Figure PCTCN2015100201-appb-000041
本发明所述通式(IX)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：A compound represented by the formula (IX), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein the preparation method comprises the following steps :
Figure PCTCN2015100201-appb-000042
Figure PCTCN2015100201-appb-000042
X5和X8为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X5和X8在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物IX；X5 and X8 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X8 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound IX;
另一种制备方法包括以下步骤：Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000043
Figure PCTCN2015100201-appb-000043
X5和X9为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X5和X9在一定的反应条件下，通过还原氨化的反应制备得到IX。 X5 and X9 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X9 are prepared by a reductive amination reaction under certain reaction conditions to obtain IX.
附图说明：BRIEF DESCRIPTION OF THE DRAWINGS:
图1显示了化合物处理后，显微镜下观察到的荧光强度评价样品对肝细胞摄取LDL能力的影响。Figure 1 shows the effect of the fluorescence intensity observed under the microscope on the ability of the sample to take up LDL by hepatocytes after compound treatment.
图2显示了高脂SD大鼠，经本发明部分化合物口服灌胃给药四周后，血清中低密度脂蛋白胆固醇(LDL-C)的测定结果比较。Fig. 2 is a graph showing the comparison of serum low-density lipoprotein cholesterol (LDL-C) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
图3显示了高脂SD大鼠，经本发明部分化合物口服灌胃给药四周后，血清中总胆固醇(TC)的测定结果比较。Fig. 3 shows a comparison of the results of determination of total cholesterol (TC) in serum of a high-fat SD rat after oral administration of a part of the compound of the present invention for four weeks.
图4显示了高脂SD大鼠，经本发明部分化合物口服灌胃给药四周后，血清中谷丙转氨酶(ALT)的测定结果比较。Figure 4 is a graph showing the comparison of serum alanine aminotransferase (ALT) levels in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
图5显示了高脂SD大鼠，经本发明部分化合物口服灌胃给药四周后，血清中谷草转氨酶(AST)的测定结果比较。Fig. 5 is a graph showing the comparison of the results of serum aspartate aminotransferase (AST) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
发明详述Detailed description of the invention
在多个方面，本发明的技术提供了新颖的化合物，以及该化合物在降低血浆和/或肝的脂类水平的用途以及治疗高脂血症、高胆固醇血症、高甘油三酯血症、肝脂肪变性、II型糖尿病、高血糖症、胰岛素抵抗症、肥胖症和代谢综合征中的用途。本文提供的化合物可被配制用于本文公开的方法中的药物组合物和药剂。本发明还提供了所述化合物用于制备药物配制物和药剂的用途，所述化合物在降低血浆和/或肝的脂类水平中的用途以及所述化合物在治疗高脂血症、高胆固醇血症、高甘油三酯血症、肝脂肪变性、II型糖尿病、高血糖症，胰岛素抵抗症、肥胖症和代谢综合征中的用途。In various aspects, the present technology provides novel compounds, and the use of the compounds in reducing plasma and/or liver lipid levels, as well as in the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Uses in hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome. The compounds provided herein can be formulated into pharmaceutical compositions and medicaments for use in the methods disclosed herein. The invention also provides the use of the compound for the preparation of a pharmaceutical formulation and a medicament, the use of the compound for lowering lipid levels in plasma and/or liver, and the compound in the treatment of hyperlipidemia, hypercholesterolemia Use in disease, hypertriglyceridemia, hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome.
下述术语在本文通篇中参照下述定义来使用。The following terms are used throughout the text with reference to the following definitions.
通常，提到某个元素，例如氢或H，表示包括该元素的所有同位素。例如，如果R基团被定义为包括氢或H，其还包括氘和氚。包含放射性同位素(例如氚、C14、P32和S35)的化合物因此也在本发明的范围。用于将此类标记插入本发明的化合物中的手段是本领域技术人员基于本文公开的内容显而易见的。Generally, reference to an element, such as hydrogen or H, is meant to include all isotopes of that element. For example, if the R group is defined to include hydrogen or H, it also includes ruthenium and osmium. Compound comprises a radioisotope (e.g., tritium, C 14, P 32 and S 35) is therefore also within the scope of the present invention. Means for inserting such markers into the compounds of the invention will be apparent to those skilled in the art based on the disclosure herein.
通常，“经取代的”表示这样的如下文定义的有机基团(例如烷基)，其中含有的一个或多个连接氢的键被连接非氢原子或非碳原子的键替换。经取代的基团还包括这样的基团：其中一个或多个连接碳原子或氢原子的键被一个或多个连接杂原子的键(包括双键或三键)替换。由此，除非另有指明，被取代的基团被一个或多个取代基取代。在一些实施方式中，取代基被1、2、3、4、5或6个取代基取代。取代基的例子包括卤(即，F，Cl，Br和I)、羟基、烷氧基、烯氧基、芳基氧基、芳烷基氧基、杂环基氧和杂环基烷氧基、羰基、羧基、酯、氨基甲酸盐/酯、肟、羟基胺、烷氧基胺、芳烷氧基胺、硫醇、硫化物、亚砜、砜、磺酰基、磺酰胺、胺、N-氧化物、肼、酰肼、腙、叠氮化物、酰胺、脲、脒、胍、烯胺、酰亚胺、异氰酸盐/酯、异硫代氰酸盐/酯、氰酸盐/酯、硫代氰酸盐/酯、亚胺、硝基、腈等等。Generally, "substituted" means an organic group (e.g., an alkyl group) as defined below wherein one or more hydrogen-bonded bonds are replaced by a bond to a non-hydrogen atom or a non-carbon atom. Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds (including double or triple bonds) linking the heteroatoms. Thus, unless otherwise indicated, a substituted group is substituted with one or more substituents. In some embodiments, the substituent is substituted with 1, 2, 3, 4, 5 or 6 substituents. Examples of the substituent include halogen (i.e., F, Cl, Br, and I), a hydroxyl group, an alkoxy group, an alkenyloxy group, an aryloxy group, an aralkyloxy group, a heterocyclic oxygen group, and a heterocyclic alkoxy group. , carbonyl, carboxyl, ester, carbamate, hydrazine, hydroxylamine, alkoxyamine, aralkyloxyamine, thiol, sulfide, sulfoxide, sulfone, sulfonyl, sulfonamide, amine, N -oxides, hydrazines, hydrazides, hydrazines, azides, amides, ureas, hydrazines, hydrazines, enamines, imides, isocyanates, isothiocyanates, cyanates / Esters, thiocyanates, imines, nitro, nitriles, and the like.
经取代的环基，例如经取代的环烷基、芳基、杂环基和杂芳基，还包括其中连接氢原子的键被连接碳原子的键替换的环和环系统。经取代的环烷基、芳基、杂环基和杂芳基还可被下文定义的经取代的或未经取代的烷基、烯基和炔基取代。Substituted ring groups, such as substituted cycloalkyl, aryl, heterocyclic, and heteroaryl, also include ring and ring systems in which a bond to a hydrogen atom is replaced by a bond to a carbon atom. The substituted cycloalkyl, aryl, heterocyclic and heteroaryl groups may also be substituted by substituted or unsubstituted alkyl, alkenyl and alkynyl groups as defined below.
烷基包括包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基、正癸基、3，3-二乙基己基、2，2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代、-C(O)R′、-C(O)OR′、-S(O)mR′、-NR′R″、-C(O)NR′R″、-NR′C(O)R″、-NR′S(O)mR″或-S(O)mNR′R″。The alkyl group includes a linear or branched group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-B Hexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branches thereof Chain isomers, etc. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(O)R', -C(O)OR', -S(O) m R', - NR'R", -C(O)NR'R", -NR'C(O)R", -NR'S(O) m R" or -S(O) m NR'R".
环烷基烷基是指饱和或部分不饱和单环或多环环状烃取代的烷基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至10个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。A cycloalkylalkyl group means an alkyl group substituted with a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 Up to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
烯基指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的不饱和烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧 基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-C(O)R′、-C(O)OR′、-S(O)mR′、-NR′R″、-C(O)NR′R″、-NR′C(O)R″、-NR′S(O)mR″或-S(O)mNR′R″。Alkenyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R', -C(O)OR', -S(O) m R', -NR'R", -C(O)NR'R", -NR'C (O) R", -NR'S(O) m R" or -S(O) m NR'R".
环烯基指包括具有至少一个处于两个碳原子之间的双键的，如上文定义的不饱和环烷基。在一些实施方式中，环烯基可具有一个、两个或三个双键但是不包括芳香族化合物。环烯基包含4至14个碳原子，或在一些实施方式中，包含5至14个碳原子，优选包含5至10个碳原子,更优选包含5、6、7或8个碳原子。环烯基的例子包括环己烯基、环戊烯基、环己二烯基、丁二烯基、戊二烯基和己二烯基。Cycloalkenyl refers to an unsaturated cycloalkyl group as defined above having at least one double bond between two carbon atoms. In some embodiments, a cycloalkenyl group can have one, two or three double bonds but does not include an aromatic compound. The cycloalkenyl group contains 4 to 14 carbon atoms or, in some embodiments, 5 to 14 carbon atoms, preferably 5 to 10 carbon atoms, more preferably 5, 6, 7 or 8 carbon atoms. Examples of the cycloalkenyl group include a cyclohexenyl group, a cyclopentenyl group, a cyclohexadienyl group, a butadienyl group, a pentadienyl group, and a hexadienyl group.
炔基指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的不饱和烷基，例如乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-C(O)R′、-C(O)OR′、-S(O)mR′、-NR′R″、-C(O)NR′R″、-NR′C(O)R″、-NR′S(O)mR″或-S(O)mNR′R″。An alkynyl group means an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R', -C(O)OR', -S(O) m R', -NR'R", -C(O)NR'R", -NR'C (O) R", -NR'S(O) m R" or -S(O) m NR'R".
芳基是不含杂原子的环状芳香烃。芳基在本文中包括单环、二环和三环系统。因此，芳基包括但不限于苯基、茂并芳庚基、二苯基、芴基、菲基、蒽基、茚基、茚满基、并环戊二烯基和萘基。在一些实施方式中，芳基在基团的环的部分中含有6-14个碳，优选6至12个，更优选6-10个碳原子。在一些实施方式中，芳基是苯基或萘基。虽然词组“芳基”包括含有稠合的环(例如稠合的芳香族-脂肪族环系统)的基团(例如茚满基、四氢萘基等等)，但其不包括具有与环成员之一键合的其它基团(例如烷基或卤代基团)的芳基。甲苯基等基团被称为经取代的芳基。代表性的经取代的芳基可以是经单取代的或被取代超过一次的。例如，经单取代的芳基包括但不限于2-、3-、4-、5-或6-取代的苯基或萘基，其可被例如上文列出的取代基取代。The aryl group is a cyclic aromatic hydrocarbon containing no hetero atoms. Aryl groups include monocyclic, bicyclic, and tricyclic systems herein. Thus, aryl groups include, but are not limited to, phenyl, methoxyheptyl, diphenyl, indenyl, phenanthryl, anthracenyl, fluorenyl, indanyl, cyclopentadienyl, and naphthyl. In some embodiments, the aryl group contains 6-14 carbons, preferably 6 to 12, more preferably 6-10 carbon atoms in the ring portion of the group. In some embodiments, the aryl group is phenyl or naphthyl. Although the phrase "aryl" includes groups containing a fused ring (eg, a fused aromatic-aliphatic ring system) (eg, indanyl, tetrahydronaphthyl, and the like), it does not include having members with rings An aryl group of one of the other groups bonded (for example, an alkyl group or a halogenated group). A group such as a tolyl group is referred to as a substituted aryl group. Representative substituted aryl groups can be monosubstituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5- or 6-substituted phenyl or naphthyl groups, which may be substituted, for example, with the substituents listed above.
芳烷基是如上文定义的烷基，其中，烷基的氢或碳键被连接上文定义的芳基的键所替换。在一些实施方式中，芳烷基含有7至16个碳原子，优选7至14个碳原子，更优选7至10个碳原子。经取代的芳烷基可在烷基、芳基的部分被取代，或在烷基和芳基部分均被取代。代表性的芳烷基包括但不限于苄基和苯乙基和稠合的(环烷基芳基)烷基(例如4-茚满基乙基)。代表性的经取代的芳烷基可被例如上文列出的取代基取代一次或数次。Aralkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above. In some embodiments, the aralkyl group contains from 7 to 16 carbon atoms, preferably from 7 to 14 carbon atoms, more preferably from 7 to 10 carbon atoms. The substituted aralkyl group may be substituted at the alkyl group, the aryl group, or both the alkyl group and the aryl moiety. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl and fused (cycloalkylaryl)alkyl (eg, 4-indolylethyl). Representative substituted aralkyl groups can be substituted one or several times with, for example, the substituents listed above.
杂环基包括含有3个或多个环成员的芳香族(也被称为杂芳基)和非芳香族环状化合物，其中环成员中的一个或多个是杂原子，例如但不限于N、O和S。在一些实施方式中，杂环基含有1、2、3或4个杂原子。在一些例子中，杂环基包括具有3至16个环成员的单、二和三环。杂环基包括芳香族的、部分未饱和的和饱和的环系统，例如，咪唑基、咪唑啉基和咪唑烷基。词组“杂环基”包括稠合的环种类，这包括包含稠合的芳香族和非芳香族基团的那些，例如苯并三唑基、2,3-二氢苯并[1,4]二噁烷基和苯并[1,3]二氧杂环戊烯基。该词组还包括桥联的含有杂原子的多环系统，例如但不限于奎宁环基。但是，该词组不包括具有与环成员之一键合的其它基团(例如烷基、氧代或卤代基团)的杂环基。相反，这些被称为“经取代的杂环基”。杂环基包括但不限于吖丙啶基、吖丁啶基、吡咯烷基、咪唑烷基、吡唑烷基、噻唑烷基、四氢硫代苯基、四氢呋喃基、二氧杂环戊烯基、呋喃基、硫代苯基、吡咯基、吡咯啉基、咪唑基、咪唑啉基、吡唑基、吡唑啉基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、噻唑啉基、异噻唑基、噻重氮基、噁二唑基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、四氢吡喃基、四氢硫代吡喃基、氧硫杂环己烷、二氧六环基、二噻烷基、吡喃基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、二氢吡啶基、二氢二噻嗯基、二氢二硫酮基、高哌嗪基、奎宁环基、吲哚基、吲哚啉基、异吲哚基、氮杂吲哚基(吡咯并吡啶基)、吲唑基、吲哚嗪基、苯并三唑基、苯并咪唑基、苯并呋喃基、苯并硫代苯基、苯并噻唑基、苯并噁二唑基、苯并噁嗪基、苯并二噻嗯基、苯并噁噻嗯基、苯并噻嗪基、苯并噁唑基、苯并噻唑基、苯并噻重氮基、苯并[1,3]二氧杂环戊烯基、吡唑并吡啶基、咪唑并吡啶基(氮杂苯并咪唑基)、三唑并吡啶基、异噁唑并吡啶基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、喹嗪基、喹喔啉基、喹唑啉基、酞嗪基、萘啶基、硫杂萘基、二氢苯并噻嗪基、二氢苯并呋喃基、二氢吲哚基、二氢苯并二噁烷基、四氢吲哚基、四氢吲唑基、四苯并咪唑基、四氢苯并三唑基、四氢吡咯并吡啶基、四氢吡唑并吡啶基、四氢咪唑并吡啶基、四氢三唑并吡啶基和四氢喹啉基。代表性的经取代的杂环基可经单取代或被取代超过一次，例如但不限于2-、3-、4-、5-或6-取代的或被例如上文列出的多种取代基二取代的吡啶基或吗啉基。Heterocyclyl includes aromatic (also referred to as heteroaryl) and non-aromatic cyclic compounds containing three or more ring members, wherein one or more of the ring members are heteroatoms such as, but not limited to, N. , O and S. In some embodiments, a heterocyclic group contains 1, 2, 3 or 4 heteroatoms. In some examples, heterocyclyl includes mono, di, and tricyclic rings having from 3 to 16 ring members. Heterocyclyl groups include aromatic, partially unsaturated and saturated ring systems such as imidazolyl, imidazolinyl and imidazolidinyl. The phrase "heterocyclyl" includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as benzotriazolyl, 2,3-dihydrobenzo[1,4]. Dioxoalkyl and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic systems containing heteroatoms such as, but not limited to, quinuclidinyl. However, the phrase does not include heterocyclic groups having other groups (eg, alkyl, oxo or halo groups) bonded to one of the ring members. Instead, these are referred to as "substituted heterocyclic groups." Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, Furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl , thiazolinyl, isothiazolyl, thiadiazo, oxadiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl , oxathiane, dioxolane, dithiaalkyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiazide 、, dihydrodithione, homopiperazinyl, quinuclidinyl, fluorenyl, porphyrin, isodecyl, azaindolyl (pyrrolopyridyl), carbazolyl, Pyridazinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxadiazolyl, benzoxazinyl, benzodithiazide Um, benzophenidate , benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazo, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, indenyl, xanthyl, adenyl, guanyl, quinolinyl, isoquinolinyl, quinazolidyl, Quinoxalinyl, quinazolinyl, pyridazinyl, naphthyridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, indanyl, dihydrobenzo diox Alkyl, tetrahydroindenyl, tetrahydrocarbazolyl, tetrabenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridinyl, tetrahydropyrazolopyridinyl, tetrahydroimidazopyridinyl , tetrahydrotriazolopyridinyl and tetrahydroquinolyl. Representative substituted heterocyclic groups may be monosubstituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5- or 6-substituted or substituted by various substituents such as those listed above A disubstituted pyridyl or morpholinyl group.
杂芳基是含有5个或更多个环成员原子的芳香族环化合物，其中一个或多个环成员是杂原子，例如但不限于N、O和S。杂芳基包括但不限于下述基团，例如，吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、硫代苯基、苯并硫代苯基、呋喃基、苯并呋喃基、吲哚基、氮杂吲哚基(吡咯并吡啶基)、吲唑基、苯并咪唑基、咪唑并吡啶基(氮杂苯并咪唑基)、吡唑并吡啶基、三唑并吡啶基、苯并三唑基、苯并噁唑基、苯并噻唑基、苯并噻重氮基、咪唑并吡啶基、异噁唑并吡啶基、硫杂萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基。杂芳基包括其中所有环都是芳香族的稠合环化合物，例如吲哚基，其还包括其中仅一个环是芳香族的稠合环化合物，例如2，3-二氢吲哚基。虽然词组“杂芳基”包括稠合的环化合物，但该词组不包括具有与环成员之一键合的其它基团(例如烷基)的杂芳基。相反，具有此类取代的杂芳基被称为“经取代的杂芳基”。代表性的经取代的杂芳基可被例如上文列出的多种取代基取代一次或数次。A heteroaryl group is an aromatic ring compound containing five or more ring member atoms, wherein one or more ring members are heteroatoms such as, but not limited to, N, O and S. Heteroaryl groups include, but are not limited to, the following groups, for example, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl , pyrazinyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, fluorenyl, azaindolyl (pyrrolopyridinyl), oxazolyl, benzimidazolyl, Imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazo, imidazole And pyridyl, isoxazolopyridinyl, thionaphthyl, anthracenyl, xanthyl, adenyl, guanyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, quinoxalinyl And quinazolinyl. Heteroaryl groups include fused ring compounds in which all of the rings are aromatic, such as fluorenyl groups, which also include fused ring compounds in which only one ring is aromatic, such as 2,3-dihydroindenyl. Although the phrase "heteroaryl" includes fused ring compounds, the phrase does not include heteroaryl groups having other groups (eg, alkyl groups) bonded to one of the ring members. In contrast, a heteroaryl group having such a substitution is referred to as a "substituted heteroaryl group." Representative substituted heteroaryl groups can be substituted one or several times with, for example, the various substituents listed above.
杂环基烷基是如上文定义的烷基，但其中，烷基的氢或碳键被连接上文定义的杂环基的键所替换。经取代的杂环基烷基可在烷基、杂环基的部分被取代，或在烷基和杂环基部分均被取代。代表性的杂环基烷基包括但不限于吗啉-4-基-乙基、呋喃-2-基-甲基、咪唑-4- 基-甲基、吡啶-3-基-甲基、四氢呋喃-2-基-乙基和吲哚-2-基-丙基。代表性的经取代的杂环基烷基可被例如上文列出的取代基取代一次或数次。Heterocyclylalkyl is an alkyl group as defined above, but wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclic group as defined above. The substituted heterocyclic alkyl group may be substituted at the alkyl group or the heterocyclic group or at both the alkyl group and the heterocyclic group. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazole-4- Base-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl and ind-2-yl-propyl. Representative substituted heterocyclylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
杂芳烷基是如上文定义的烷基，其中，烷基的氢或碳键被连接上文定义的杂芳基的键所替换。经取代的杂芳烷基可在烷基、杂芳基的部分被取代，或在烷基和杂芳基部分均被取代。代表性的经取代的杂芳烷基可被例如上文列出的取代基取代一次或数次。Heteroarylalkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above. The substituted heteroarylalkyl group may be substituted at the alkyl or heteroaryl portion or at both the alkyl and heteroaryl portions. Representative substituted heteroarylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
本发明的化合物中，具有两个或多个连接点(即二价、三价或多价)的本文描述的基团被用前缀“亚”来命名。例如，二价烷基是亚烷基，二价芳基是亚芳基，二价杂芳基是杂亚芳基，等等。与本发明的化合物具有单个连接点的经取代的基团不使用“亚”命名。因此，例如，氯乙基在本文中不被称为氯亚乙基。In the compounds of the invention, the groups described herein having two or more points of attachment (ie, divalent, trivalent or multivalent) are designated by the prefix "sub". For example, the divalent alkyl group is an alkylene group, the divalent aryl group is an arylene group, the divalent heteroaryl group is a heteroarylene group, and the like. Substituted groups having a single point of attachment to a compound of the invention do not use a "sub" designation. Thus, for example, chloroethyl is not referred to herein as chloroethylene.
氧代基是指通过与氧原子相连构成的取代基团，其中与氧原子相连接的基团为经取代或者未经取代的烷基，芳基，杂芳基，环烷基，烷基酰基，芳基酰基，杂芳基酰基。以上的基团与氧原子连接即可以构成烷氧基，芳氧基，杂芳氧基，环烷基氧基，烷基酰氧基，芳基酰氧基，杂芳基酰氧基，环烷基酰氧基。An oxo group means a substituent group formed by linking with an oxygen atom, wherein the group bonded to the oxygen atom is a substituted or unsubstituted alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, an alkyl group. , aryl acyl, heteroaryl acyl. The above group may be bonded to an oxygen atom to form an alkoxy group, an aryloxy group, a heteroaryloxy group, a cycloalkyloxy group, an alkyl acyloxy group, an aryl acyloxy group, a heteroaryl acyloxy group, and a ring. Alkyl acyloxy.
烷氧基是羟基(-OH)中连接氢原子的键被连接上文定义的经取代的或未经取代的烷基的碳原子的键替换的取代基。线性烷氧基的例子包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等等。带支链的烷氧基的例子包括但不限于异丙氧基、仲丁氧基、叔丁氧基、异戊氧基、异己氧基等等。环烷氧基的例子包括但不限于环丙基氧、环丁基氧、环戊基氧、环己基氧等等。代表性的经取代的烷氧基可被例如上文列出的取代基取代一次或数次。The alkoxy group is a substituent in which a bond to a hydrogen atom in a hydroxyl group (-OH) is replaced by a bond to a carbon atom of the substituted or unsubstituted alkyl group defined above. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy and the like. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups can be substituted one or several times with, for example, the substituents listed above.
术语“烷酰基”和“烷酰基氧”在本文中使用时分别指-C(O)-烷基和-O-C(O)-烷基，它们每个含有2-5碳原子。The terms "alkanoyl" and "alkanoyloxy" as used herein mean -C(O)-alkyl and -O-C(O)-alkyl, respectively, each of which contains from 2 to 5 carbon atoms.
术语“芳基氧”和“芳基烷氧基”分别指经取代的或未经取代的芳基与氧原子键合构成的取代基，经取代的或未经取代的芳烷基与氧原子键合构成的取代基。例子包括但不限于苯氧基、萘基氧和苄氧基。代表性的经取代的芳基氧和芳基烷氧基可被例如上文列出的取代基取代一次或数次。The terms "aryloxy" and "arylalkoxy" mean, respectively, a substituent formed by bonding a substituted or unsubstituted aryl group to an oxygen atom, a substituted or unsubstituted aralkyl group and an oxygen atom. A substituent formed by bonding. Examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups can be substituted one or several times with, for example, the substituents listed above.
术语“羧酸”在本文中使用时指-COOH基团。The term "carboxylic acid" as used herein refers to a -COOH group.
术语“羧酸酯”在本文中使用时指-COOR′基团。R′是如本文定义的经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基、芳烷基、杂环基烷基或杂环基。The term "carboxylate" as used herein refers to a -COOR' group. R' is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic group as defined herein.
术语“酰胺”(或“酰胺基”)包括C-酰胺基团和N-酰胺基团，即分别是-C(O)NR′R″和-NR′C(O)R″基团。R′和R″独立地是如本文定义的氢或者经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基烷基或杂环基。酰胺基因此包括但不限于氨基甲酰基(-C(O)NH2)和甲酰胺基团(-NHC(O)H)。在一些实施方式中，酰胺是-NR′C(O)-(C1-5烷基)，该基团被称为“羰基氨基”，在另一些实施方式中，酰胺是-NHC(O)-烷基，该基团被称为“烷酰基氨基”。The term "amide" (or "amido") includes both C-amide and N-amide groups, i.e., -C(O)NR'R" and -NR'C(O)R" groups, respectively. R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein. The amide group thus includes, but is not limited to, a carbamoyl group (-C(O)NH 2 ) and a carboxamide group (-NHC(O)H). In some embodiments, the amide is -NR'C(O) -(C 1-5 alkyl), this group is referred to as "carbonylamino", in other embodiments, the amide is -NHC(O)-alkyl, the group is referred to as "alkanoylamino" .
术语“腈”或“氰基”在本文中使用时指-CN基团。The term "nitrile" or "cyano" as used herein refers to a -CN group.
氨基甲酸盐/酯包括N-氨基甲酸盐基团和O-氨基甲酸盐基团，即分别是-NR′C(O)OR″和-OC(O)NR′R″基团。R′和R″独立地是如本文定义的经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基烷基或杂环基。R′还可以是H。Carbamates include N-carbamate groups and O-carbamate groups, i.e., -NR'C(O)OR" and -OC(O)NR'R" groups, respectively. R' and R" are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group, as defined herein. R' can also be H.
术语“胺”(或“氨基”)在本文中使用时指-NR′R″基团，其中R′和R″独立地是如本文定义的氢或者经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基烷基或杂环基。在一些实施方式中，胺是烷基氨基、二烷基氨基、芳基氨基或烷基芳基氨基。在其它一些实施方式中，胺是NH2、甲基氨基、二甲基氨基、乙基氨基、二乙基氨基、丙基氨基、异丙基氨基、苯基氨基或苄基氨基。The term "amine" (or "amino") as used herein, refers to a radical -NR'R", wherein R' and R" are, independently, hydrogen or substituted or unsubstituted alkyl, as defined herein, Alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic. In some embodiments, the amine is an alkylamino, dialkylamino, arylamino or alkylarylamino group. In some other embodiments, the amine is NH 2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino or benzylamino.
术语“磺酰胺”包括S-磺酰胺基团和N-磺酰胺基团，即分别是-SO2NR′R″和-NR′SO2R″基团。R′和R″独立地是如本文定义的氢或者经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基烷基或杂环基。磺酰胺基团因此包括但不限于磺酰基(-SO2NH2)。在本文的一些实施方式中，磺酰胺是-NHSO2-烷基，其被称为“烷基磺酰基氨基”。The term "sulfonamide" includes both S-sulfonamide groups and N-sulfonamide groups, i.e., -SO 2 NR'R" and -NR'SO 2 R" groups, respectively. R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein. The sulfonamide group thus includes, but is not limited to, a sulfonyl group (-SO 2 NH 2 ). In some embodiments herein, the sulfonamide is -NHSO 2 -alkyl, which is referred to as "alkylsulfonylamino" .
术语“硫醇”指-SH基团，而硫化物包括-SR′基团，亚砜包括-S(O)R′基团，砜包括-SO2R′基团，以及磺酰氧基包括-OSO2R′，磺酸氧基包括-OSO2OR′。R′独立地是如本文定义的经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。在一些实施方式中，硫化物是烷基硫醇基团，-S-烷基。The term "thiol" refers to the -SH group, while the sulfide includes the -SR' group, the sulfoxide includes the -S(O)R' group, the sulfone includes the -SO 2 R' group, and the sulfonyloxy group includes -OSO 2 R', the sulfonic acid oxy group includes -OSO 2 OR'. R' is independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group, as defined herein. In some embodiments, the sulfide is an alkyl thiol group, -S-alkyl.
术语“脲”指-NR′-C(O)-NR′R″基团。R′和R″基团独立地是如本文定义的氢或者经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基或杂环基烷基。The term "urea" refers to a -NR'-C(O)-NR'R" group. The R' and R" groups are independently hydrogen or substituted or unsubstituted alkyl, alkenyl as defined herein. , alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl.
术语“脒”指-C(NR′)NR′R″和-NR′C(NR′)R″，其中，R′和R″每个独立地是如本文定义的氢或者经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。The term "脒" refers to -C(NR')NR'R" and -NR'C(NR')R", wherein R' and R" are each independently hydrogen as defined herein or substituted or not Substituted alkyl, cycloalkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
术语“胍”指-NR′C(NR′)NR′R″，其中R′和R″每个独立地是如本文定义的氢或者经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。The term "胍" refers to -NR'C(NR')NR'R", wherein R' and R" are each independently hydrogen or substituted or unsubstituted alkyl, cycloalkyl, as defined herein, Alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl.
术语“烯胺”指-C(R′)＝C(R′)NR′R″和-NR′C(R′)＝C(R′)R″，其中R′和R″每个独立地是如本文定义的氢、经取代的或未经取代的烷基、 环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。The term "enamine" means -C(R')=C(R')NR'R" and -NR'C(R')=C(R')R", wherein R' and R" are each independently Is a hydrogen, substituted or unsubstituted alkyl group as defined herein, Cycloalkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
术语“卤”或“卤代”在本文中使用时指溴、氯、氟或碘。在一些实施方式中，卤是氟。在其它一些实施方式中，卤是氯或溴。The term "halo" or "halo" as used herein, refers to bromo, chloro, fluoro or iodo. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
术语“羟基”在本文中使用时可以指-OH或其离子化形式-O-。The term "hydroxy" refers to -OH, or may be an ionized form as used herein -O -.
术语“酰亚胺”指-C(O)NR′C(O)R″，其中R′和R″每个独立地是如本文定义的氢或者经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。The term "imide" refers to -C(O)NR'C(O)R", wherein R' and R" are each independently hydrogen or substituted or unsubstituted alkyl, ring, as defined herein. Alkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
术语“含氮杂环基”指含有氮原子的环系，该环系可以“骈合”芳香和非芳香环系，或者通过“螺碳原子”链接其他环系，例如以下结构：The term "nitrogen-containing heterocyclic group" refers to a ring system containing a nitrogen atom which may "couple" aromatic and non-aromatic ring systems, or link other ring systems through "spirocarbon atoms", such as the following structure:
Figure PCTCN2015100201-appb-000044
等等。
Figure PCTCN2015100201-appb-000044
and many more.
术语“亚胺”指-CR′(NR″)和-N(CR′R″)基团，其中R′和R″每个独立地是如本文定义的氢或经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基、并且满足：R′和R″不同时是氢。The term "imine" refers to a -CR' (NR") and -N (CR'R") group, wherein R' and R" are each independently hydrogen or substituted or unsubstituted as defined herein. An alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an arylarylalkyl group, a heterocyclic group or a heterocyclic alkyl group, and satisfies: R' and R" are not hydrogen at the same time.
术语“硝基”在本文中使用时指-NO2。The term "nitro" means -NO 2 when used herein.
术语“三氟甲基”在本文中使用时指-CF3。The term "trifluoromethyl" as used herein refers to a -CF 3.
术语“三氟甲氧基”在本文中使用时指-OCF3。-OCF 3 refers to as used herein, the term "trifluoromethoxy."
本文描述的化合物的可药用盐在本发明的范围内，其包括这样的酸加成盐或碱加成盐，所述盐保持了预期的药理学活性并且从生物学角度而言不是具有潜在不良效果的(例如盐没有过分的毒性、致敏性或刺激性，并且是生物可利用的)。当本发明的化合物具有碱性基团(例如，氨基)时，可与无机酸(例如盐酸、氢硼酸、硝酸、硫酸和磷酸)、有机酸(例如藻酸盐、甲酸、乙酸、苯甲酸、葡糖酸、延胡索酸、草酸、酒石酸、乳酸、马来酸、柠檬酸、琥珀酸、苹果酸、甲磺酸、苯磺酸、萘磺酸和对甲苯磺酸)或酸性氨基酸(例如天冬氨酸和谷氨酸)形成可药用盐。当本发明的化合物具有酸性基团，例如羧酸基团时，其可与金属，例如碱金属和碱土金属(例如Na+、Li+、K+、Ca2+、Mg2+、Zn2+)、氨或有机胺(例如二环己基胺、三甲基胺、三乙基胺、吡啶、乙醇胺、二乙醇胺、三乙醇胺)或碱性氨基酸(例如精氨酸、赖氨酸和鸟氨酸)形成盐。此类盐可在对化合物的分离和纯化期间“一锅法”制备，或者可通过将游离碱或游离酸经纯化后化合物分别与合适的酸或碱单独反应并且分离由此形成的盐来制备此类盐。Pharmaceutically acceptable salts of the compounds described herein are within the scope of the invention and include such acid addition or base addition salts which retain the desired pharmacological activity and are not biologically potential Poor effects (eg, salts are not excessively toxic, sensitizing or irritating, and are bioavailable). When the compound of the present invention has a basic group (for example, an amino group), it can be combined with a mineral acid (for example, hydrochloric acid, borohydride, nitric acid, sulfuric acid, and phosphoric acid), an organic acid (for example, alginate, formic acid, acetic acid, benzoic acid, Gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid) or acidic amino acids (eg aspartame) The acid and glutamic acid) form a pharmaceutically acceptable salt. When the compound of the present invention has an acidic group such as a carboxylic acid group, it can be combined with a metal such as an alkali metal and an alkaline earth metal (for example, Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ) ), ammonia or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (such as arginine, lysine and ornithine) ) form a salt. Such salts may be prepared "one-pot" during the isolation and purification of the compound, or may be prepared by separately reacting the free base or the free acid with the appropriate acid or base and isolating the salt thus formed. Such salts.
本领域技术人员已知的，本发明的化合物可展示出互变异构、构象异构、几何异构和/或立体异构的现象。虽然本说明书和权利要求中的式图仅代表可能的互变异构、构象异构、立体异构或几何异构形式之一，但是应当理解，本发明包括化合物的具有本文描述的一种或多种用途的任何互变异构、构象异构、立体异构和/或几何异构形式以及这些多种不同形式的混合物。As known to those skilled in the art, the compounds of the invention may exhibit tautomerism, conformational isomerism, geometric isomerism and/or stereoisomerism. Although the formulae in the specification and claims represent only one of the possible tautomeric, conformational, stereoisomeric or geometric isomeric forms, it is to be understood that the invention includes a compound having one of the ones described herein or Any tautomeric, conformational, stereoisomeric, and/or geometric isomeric form for a variety of uses, as well as mixtures of these various forms.
本领域技术人员易于理解的，大范围的官能团和其它结构可展示出互变异构体，本文描述的化合物的所有互变异构体都在本发明的范围内。It will be readily understood by those skilled in the art that a wide range of functional groups and other structures can exhibit tautomers, and all tautomers of the compounds described herein are within the scope of the invention.
除非明确指示了立体化学，化合物的立体异构体，包括结构的所有手性、非对映异构和外消旋形式。因此，用于本发明中的化合物包括在任何或所有非对称原子处富集或拆分的光学异构体。外消旋和非对映异构混合物，以及各光学异构体，均可被分离或合成，以基本上不含其对应异构体或非对映异构体，这些立体异构体也在本发明的范围内。Stereoisomers of the compounds, including all chiral, diastereomeric and racemic forms of the structure, unless explicitly indicated for stereochemistry. Thus, compounds useful in the present invention include optical isomers that are enriched or resolved at any or all of the asymmetric atoms. Racemic and diastereomeric mixtures, as well as optical isomers, may be isolated or synthesized to be substantially free of their corresponding isomers or diastereomers, and these stereoisomers are also Within the scope of the invention.
本发明的化合物可作为溶剂化物存在，尤其是作为水合物。水合物可在化合物或包含化合物的组合物的制造期间形成，或者水合物可随着时间由于化合物的吸湿性质而形成。本发明的化合物还可作为有机溶剂化物存在，包括醚和醇溶剂化物等等。对任何特定的溶剂化物的鉴定和制备都是合成有机或药物化学领域普通技术人员已知的。The compounds of the invention may exist as solvates, especially as hydrates. The hydrate can be formed during the manufacture of the compound or composition comprising the compound, or the hydrate can be formed over time due to the hygroscopic nature of the compound. The compounds of the invention may also exist as organic solvates, including ethers and alcohol solvates, and the like. Identification and preparation of any particular solvate is known to those of ordinary skill in the art of synthetic organic or pharmaceutical chemistry.
脂类包括合成的和天然存在的脂溶性化合物，其包括中性和两性分子。两性脂类典型地包含亲水组分和疏水组分。示例性脂类包 括脂肪酸、甘油三酯、中性脂肪、磷脂、醣脂、脂肪醇、蜡、萜、类固醇(例如胆固醇)和表面活性剂。Lipids include both synthetic and naturally occurring fat-soluble compounds, including both neutral and amphiphilic molecules. Amphoteric lipids typically comprise a hydrophilic component and a hydrophobic component. Exemplary lipid package These include fatty acids, triglycerides, neutral fats, phospholipids, glycolipids, fatty alcohols, waxes, hydrazines, steroids such as cholesterol, and surfactants.
“脂类降低试剂”在本文中使用时指施用给患者时具有一种或多种下述作用的化合物：增加LDLR的肝表达；增加LDLRmRNA在肝细胞中的半衰期；增加肝对血浆LDL、胆固醇或甘油三酯的摄取；增强肝的脂肪酸氧化，降低肝的甘油三酯合成和分泌，以及降低血浆和/或肝的总胆固醇、LDL-胆固醇、VLDL-胆固醇或甘油三酯水平。本文公开的脂类降低试剂包括本发明中的化合物。"Lipid-lowering agent" as used herein, refers to a compound that has one or more of the following effects when administered to a patient: increased liver expression of LDLR; increased half-life of LDLR mRNA in hepatocytes; increased liver to plasma LDL, cholesterol Or uptake of triglycerides; enhance fatty acid oxidation in the liver, reduce triglyceride synthesis and secretion in the liver, and lower total cholesterol, LDL-cholesterol, VLDL-cholesterol or triglyceride levels in plasma and/or liver. The lipid reducing agents disclosed herein include the compounds of the invention.
在一个方面，本发明提供了利用本发明化合物制造在降低患者血浆和/或肝的脂类水平的药物中的用途，包括向所述患者施用脂类降低有效量的如本文所述的化合物或组合物。降低的脂类水平可以是总胆固醇、LDL-胆固醇(LDL-C)、甘油三酯(TG)和未酯化的长链脂肪酸中的一种或多种。In one aspect, the invention provides the use of a compound of the invention for the manufacture of a medicament for lowering lipid levels in a patient's plasma and/or liver, comprising administering to said patient a reduced effective amount of a compound as described herein or combination. The reduced lipid level may be one or more of total cholesterol, LDL-cholesterol (LDL-C), triglyceride (TG), and unesterified long-chain fatty acids.
本文描述的化合物和组合物可用于预防或治疗下述疾病，包括例如，高脂血症，高胆固醇血症，高甘油三酯血症，脂肪肝(肝脂肪变性)，II型糖尿病，高血糖症，肥胖症或胰岛素抵抗症和代谢综合征。治疗的方法包括向需要治疗的受试者施用治疗有效量的本文所述的化合物或组合物。本发明的化合物还可用于治疗或预防特征在于升高的血浆或肝胆固醇或甘油三酯或与升高的血浆或肝胆固醇或甘油三酯相关的疾病状态或病态。本发明的技术还提供使用本发明化合物制造治疗或预防疾病(例如，高脂血症、高胆固醇血症、高甘油三酯血症、脂肪肝、II型糖尿病，高血糖症，肥胖症或胰岛素抵抗症或代谢综合征)的有效量药物的用途。The compounds and compositions described herein are useful for the prevention or treatment of diseases including, for example, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver (hepatic steatosis), type 2 diabetes, hyperglycemia Disease, obesity or insulin resistance and metabolic syndrome. A method of treatment comprises administering to a subject in need of treatment a therapeutically effective amount of a compound or composition described herein. The compounds of the invention are also useful in the treatment or prevention of disease states or conditions characterized by elevated plasma or hepatic cholesterol or triglycerides or associated with elevated plasma or hepatic cholesterol or triglycerides. The present technology also provides for the treatment or prevention of diseases using the compounds of the invention (eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin) The use of an effective amount of a drug for resistance or metabolic syndrome.
本文公开的化合物和组合物通过增加LDLR的肝表达，通过增加LDLRmRNA的稳定性，通过增加LDLR基因转录，通过抑制前蛋白转化酶枯草杆菌蛋白酶/kexin9型(proprotein convertase subtilisin/kexin type 9)(PCSK9)介导的LDLR蛋白的降解或上述可能的细胞机制的全部，来降低脂类水平。肝中增加的LDLR水平增加了血浆LDL-C的摄取和加工，从而导致胆固醇、LDL-C和甘油三酯的血浆水平降低。此外，化合物可通过活化AMP活化的蛋白激酶(AMPK)(生物能量代谢调节的关键分子)来增加乙酰CoA羧化酶(ACC)的磷酸化。ACC的增加的磷酸化增强了肝中的脂肪酸氧化，导致肝的TG积累降低，以及导致TG以VLDL形式分泌，这还有助于减少TG、LDL-C、总胆固醇和未酯化的长链脂肪酸的血浆水平，从而防止或治疗与高脂血症相关的疾病。另一方面，我们相信，遗传学和药理学研究表明，AMPK是机体保持葡萄糖平衡所必需的，化合物通过活化AMPK，最终起到治疗II型糖尿病，高血糖症，肥胖症或胰岛素抵抗症或代谢综合征。The compounds and compositions disclosed herein increase the stability of LDLR mRNA by increasing the LDLR mRNA stability by increasing the transcription of the LDLR gene by inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9). ) mediated degradation of LDLR proteins or all of the above possible cellular mechanisms to reduce lipid levels. Increased levels of LDLR in the liver increase uptake and processing of plasma LDL-C, resulting in decreased plasma levels of cholesterol, LDL-C, and triglycerides. In addition, compounds can increase phosphorylation of acetyl CoA carboxylase (ACC) by activating AMP-activated protein kinase (AMPK), a key molecule of bioenergy metabolism regulation. Increased phosphorylation of ACC enhances fatty acid oxidation in the liver, resulting in reduced TG accumulation in the liver and TG secretion in VLDL, which also helps reduce TG, LDL-C, total cholesterol, and unesterified long chains. Plasma levels of fatty acids, thereby preventing or treating diseases associated with hyperlipidemia. On the other hand, we believe that genetic and pharmacological studies have shown that AMPK is essential for the body to maintain glucose balance, and that compounds can ultimately treat type 2 diabetes, hyperglycemia, obesity or insulin resistance or metabolism by activating AMPK. Syndrome.
在另一个方面，本发明提供的化合物具有增加LDLR表达的用途，包括向需要其的受试者施用治疗有效量的本文所述的化合物或组合物，由此增加所述受试者中的LDLR表达。在本发明的另一方面，本发明提供了一种利用本发明化合物减少血浆LDL-胆固醇和/或血浆甘油三酯的用途，包括向需要其的患者施用治疗有效量的本文所述的化合物或组合物，由此减少所述患者的血浆LDL-胆固醇。In another aspect, the compounds provided herein have the use of increasing LDLR expression comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition described herein, thereby increasing LDLR in said subject expression. In another aspect of the invention, the invention provides a use of a compound of the invention to reduce plasma LDL-cholesterol and/or plasma triglycerides, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein or The composition thereby reducing plasma LDL-cholesterol in the patient.
在另一个方面，本发明提供了包括化合物及其组合物的脂类降低试剂。化合物和组合物可用于本文所述的降低脂类的方法和治疗中。在一种实施方式中，本发明提供了式V化合物，其立体异构体、其互变异构体、其溶剂化物和/或其可药用盐。In another aspect, the invention provides a lipid lowering agent comprising a compound and a composition thereof. The compounds and compositions are useful in the methods and treatments of reducing lipids described herein. In one embodiment, the invention provides a compound of formula V, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and/or a pharmaceutically acceptable salt thereof.
在另一个方面，本发明的技术提供了包含本文公开的任何化合物和可药用载体或一种或多种赋形剂或填料的药物组合物和药剂。在一些实施方式中，提供了治疗选自由高脂血症、高胆固醇血症、高甘油三酯血症、肝脂肪变性和代谢综合征构成的组的病况的药物组合物。此类组合物包括脂类降低有效量的本文所述的任何化合物。在一种实施方式中，将药物组合物包装成单位剂量形式。在施用给需要其的受试者时，单位剂量形式能有效降低血流和/或肝中的脂类水平(例如总胆固醇、LDL-胆固醇、甘油三酯和未酯化的长链脂肪酸中的至少一种)。In another aspect, the present technology provides pharmaceutical compositions and medicaments comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers. In some embodiments, a pharmaceutical composition for treating a condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome is provided. Such compositions include a lipid reducing effective amount of any of the compounds described herein. In one embodiment, the pharmaceutical composition is packaged in unit dosage form. The unit dosage form is effective in reducing blood lipids and/or lipid levels in the liver (eg, total cholesterol, LDL-cholesterol, triglycerides, and unesterified long-chain fatty acids) when administered to a subject in need thereof. At least one).
可通过将本发明的一种或多种化合物、其可药用盐、其立体异构体、其互变异构体或其溶剂化物与可药用载体、赋形剂、粘合剂、稀释剂等等混合，来制备药物组合物，以防止或治疗与增加的血浆和/或肝的脂类水平相关的病症。本文所述的化合物和组合物可用于制备防止或治疗与增加的血浆和/或肝脂类水平相关的多种病症(例如高脂血症、高胆固醇血症、肝脂肪变性和代谢综合征)的配制物和药剂。此类组合物可以是例如颗粒、粉末、片剂、胶囊、糖浆、栓剂、注射剂、乳液、酏剂、悬浮液或溶液的形式。本发明的组合物可被配制成用于多种施用途径的各种形式，例如，通过口服、肠胃外、局部、直肠、经鼻、阴道施用或者通过植入的贮器来施用。肠胃外或全身性施用包括但不限于皮下、静脉内、腹膜内和肌内、注射。下述剂量形式作为例子给出，其不应被解释为限制本发明的技术。By diluting one or more compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, dilutions Agents and the like are mixed to prepare a pharmaceutical composition to prevent or treat a condition associated with increased plasma and/or liver lipid levels. The compounds and compositions described herein are useful in the preparation of a variety of conditions (eg, hyperlipidemia, hypercholesterolemia, hepatic steatosis, and metabolic syndrome) that prevent or treat elevated plasma and/or hepatic lipid levels. Formulations and medicaments. Such compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The compositions of the present invention may be formulated in a variety of forms for a variety of routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration or by implantation of a reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injection. The dosage forms described below are given as examples and should not be construed as limiting the techniques of the present invention.
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可参照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。The active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared by any of the methods known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙 二醇或油溶媒例如花生油、液体石蜡或橄榄油混合软明胶胶囊提供口服制剂。Hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient with a water-soluble carrier such as polyethylene A glycol or oil vehicle such as peanut oil, liquid paraffin or olive oil mixed soft gelatin capsules provides an oral formulation.
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种娇味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol , or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or a partial ester of ethylene oxide with a fatty acid and a hexitol anhydride Condensation products such as polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agents such as sucrose, saccharin or aspartame.
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油悬浮液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和娇味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
通过加入水可使适用于制备水混悬也的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、娇味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。The dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweeteners, flavoring agents, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂和由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、娇味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
药物组合物可以是无菌注射水溶液形式。可在使用的可接受的溶媒和溶剂中有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the bloodstream of the patient by a local injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be prepared as an injection.
用于局部(包括经颊和舌下)或透皮施用本发明的化合物的剂量形式包括粉末、喷雾、油膏、糊剂、乳膏、洗液、凝胶、溶液和贴片。活性组分可在无菌条件下与可药用载体或赋形剂以及与可能需要的任何防腐剂或缓冲剂混合。粉末和喷雾可例如用赋形剂(例如糖、云母、硅酸、氢氧化钠、硅酸钙和聚胺粉末或这些物质的混合物)来制备。油膏、糊剂、乳膏和凝胶还可含有下述赋形剂，例如，动物和植物脂肪、油、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、硅酮、斑脱土、硅酸、云母和氧化锌或其混合物。还可使用吸收增强剂，来增加本发明的化合物穿透皮肤的流动。可通过提供速率控制膜(例如作为透皮贴片的一部分)或将化合物分散于聚合物基质或凝胶中来控制此类流动的速率。Dosage forms for topical (including buccal and sublingual) or transdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active component can be mixed under sterile conditions with apharmaceutically acceptable carrier or excipient and with any preservative or buffers which may be required. Powders and sprays can be prepared, for example, with excipients such as sugars, mica, silicic acid, sodium hydroxide, calcium silicates and polyamine powders or mixtures of these materials. Ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, waxes, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones. , bentonite, silicic acid, mica and zinc oxide or a mixture thereof. Absorption enhancers can also be used to increase the flow of the compounds of the invention through the skin. The rate of such flow can be controlled by providing a rate controlling membrane (e.g., as part of a transdermal patch) or by dispersing the compound in a polymer matrix or gel.
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。The compounds of the invention may be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
本发明的化合物还可与可用于治疗或预防高脂血性疾病的其它传统治疗剂一起施用。用于与本发明的一种或多种化合物的组合疗法的示例性治疗试剂包括但不限于抗炎性药、治疗性抗体和胆固醇降低药，例如，他汀。可用于组合配制物和协作治疗的有用的附加治疗试剂包括，例如，抗高脂血症试剂；抗血脂异常试剂；抗糖尿病试剂，包括但不限于胆固醇生物合成抑制剂，例如HMG-CoA还原酶抑制剂(也被称为他汀，洛伐他汀，辛伐他汀，普伐他汀，氟伐他汀，瑞舒伐他汀，匹伐他汀和阿托伐他汀)；HMG-CoA还原合酶抑制剂；角鲨烯环氧酶抑制剂或角鲨烯合成酶抑制剂(还被称为角鲨烯合酶抑制剂)；微粒体甘油三酯转移蛋白(MTP)抑制剂；胆酸螯合剂阴离子交换树脂，包括但不限于消胆胺，降胆宁，考来维仑或经交联葡聚糖的二烷基氨基烷基衍生物；LDL受体诱导剂；贝特类，包括但不限于安妥明，苯扎贝特，非诺贝特和吉非贝齐；二甲双胍，罗格列酮，血浆HDL-升高试剂，包括但不限于烟酸，贝特类；抗高胆固醇血症试剂，包括但不限于胆固醇-摄取抑制剂；酰基辅酶A胆固醇酰基转移酶(ACAT)抑制剂，包括但不限于美林那胺；普罗布考；烟酸及其盐；烟酰胺；胆固醇吸收抑制剂，包括但不限于β-谷甾醇或依替米贝；维生素B6(吡哆醇)及其可药用盐，例如HCl盐；维生素B12(氰钴胺)；维生素B3(烟酸和烟酰胺)；抗氧化剂维生素，包括但不限于维生素C和维生素E和β胡萝卜素；β阻断剂；血管紧张素II受体(AT1)拮抗剂；血管紧张素转化酶抑制剂，肾素抑制剂；血小板聚集抑制剂，包括但不限于纤维蛋白原受体拮抗剂，即，糖蛋白IIb/IIIa纤维蛋白原受体拮抗剂；激素，包括但不限于雌激素；胰岛素；离子交换树脂；Ω-3油；苯氟雷司；廿六碳五烯酸 乙酯和氨氯地平。附加疗法还可包括增加锻炼、手术和改变膳食(例如变为低胆固醇膳食)一些植物药品也可有效用于组合配制物和协作疗法，以治疗高脂血症，例如姜黄素，香胶甾酮，大蒜，大豆，可溶纤维，鱼油，绿茶，肉毒碱，铬，辅酶Q10，葡萄籽提取物，二聚泛酸，红曲米和蜂王浆。The compounds of the invention may also be administered with other conventional therapeutic agents useful in the treatment or prevention of hyperlipemia. Exemplary therapeutic agents for combination therapy with one or more compounds of the invention include, but are not limited to, anti-inflammatory drugs, therapeutic antibodies, and cholesterol lowering drugs, for example, statins. Useful additional therapeutic agents useful in combination formulations and co-therapy include, for example, anti-hyperlipidemic agents; anti-dyslipidemic agents; anti-diabetic agents including, but not limited to, cholesterol biosynthesis inhibitors, such as HMG-CoA reductase Inhibitors (also known as statins, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin and atorvastatin); HMG-CoA reduction synthase inhibitors; Squalene epoxidase inhibitor or squalene synthetase inhibitor (also known as squalene synthase inhibitor); microsomal triglyceride transfer protein (MTP) inhibitor; bile acid sequestrant anion exchange resin, These include, but are not limited to, cholestyramine, cholestyramine, colesevelam or dialkylaminoalkyl derivatives of cross-linked dextran; LDL receptor inducers; fibrates, including but not limited to clofibrate, Bezafibrate, fenofibrate and gemfibrozil; metformin, rosiglitazone, plasma HDL-elevation reagents, including but not limited to niacin, fibrates; anti-hypercholesterolemia agents, including but not Limited to cholesterol-uptake inhibitors; acyl-CoA cholesterol Acyltransferase (ACAT) inhibitors, including but not limited to, melinamide; probucol; niacin and its salts; nicotinamide; cholesterol absorption inhibitors including, but not limited to, beta-sitosterol or ezetimibe; Vitamin B6 (pyridoxine) and its pharmaceutically acceptable salts, such as HCl salts; vitamin B 12 (cyanocobalamin); vitamin B 3 (nicotinic acid and niacinamide); antioxidant vitamins, including but not limited to vitamin C and vitamins E and beta carotene; beta blocker; angiotensin II receptor (AT1) antagonist; angiotensin converting enzyme inhibitor, renin inhibitor; platelet aggregation inhibitor, including but not limited to fibrinogen receptor Antagonists, ie, glycoprotein IIb/IIIa fibrinogen receptor antagonists; hormones including, but not limited to, estrogen; insulin; ion exchange resins; omega-3 oil; phenylfluoros; Ester and amlodipine. Additional therapies may also include increased exercise, surgery, and changing diets (eg, becoming a low-cholesterol diet). Some botanicals are also effective for combination formulations and collaborative therapies to treat hyperlipidemia, such as curcumin, gum ketone , garlic, soy, soluble fiber, fish oil, green tea, carnitine, chromium, coenzyme Q10, grape seed extract, dimeric pantothenic acid, red yeast rice and royal jelly.
小檗碱和相关化合物也可作为第二治疗试剂，与本发明的脂类降低试剂一起使用。例如，可使用硫酸小檗碱、盐酸小檗碱、氯化小檗碱、氧小檗碱、二氢小檗碱、8-氰基二氢小檗碱、四氢小檗碱N-氧化物、四氢小檗碱、原小檗碱、9-乙氧基羰基小檗碱、9-N,N-二甲基氨基甲酰基小檗碱和12-溴代小檗碱、小檗碱叠氮化物和小檗碱甜菜碱。Berberine and related compounds can also be used as a second therapeutic agent in combination with the lipid lowering agent of the present invention. For example, berberine sulfate, berberine hydrochloride, berberine chloride, berberine, dihydroberberine, 8-cyanodihydroberberine, tetrahydroberberine N-oxide can be used. , tetrahydroberberine, protoberberine, 9-ethoxycarbonyl berberine, 9-N,N-dimethylcarbamoyl berberine and 12-bromo berberine, berberine Nitride and berberine betaine.
还可修饰本发明的化合物，例如通过共价联接有机结构片段或缀合物来进行，以改善药代动力学性质、毒性或生物利用性(例如增加的体内半衰期)。缀合物可以是线性的或带支链的亲水性聚合基团、脂肪酸基团或脂肪酸酯基团。聚合基团可包含可被本领域技术人员调节的分子量，以改善，例如药代动力学性质、毒性或生物利用性。示例性的缀合物可包括聚烷醇(例如聚乙二醇(PEG)、聚丙二醇(PPG))，碳水化合物聚合物，氨基酸聚合物或聚乙烯吡咯烷酮和脂肪酸或脂肪酸酯基团，它们每个均可独立包含大约8至大约70个碳原子。用于与本发明的化合物一起使用的缀合物还可用作为接头，例如用于任何合适的取代基或基团、放射性标记(标志物或标签)、卤、蛋白、酶、多肽、其它治疗试剂(例如药物或药品)、核苷、染料、寡核苷酸、脂类、磷脂和/或脂质体。在一个方面，缀合物可包括聚乙烯胺(PEI)、多聚甘氨酸、PEI和多聚甘氨酸的杂交体、聚乙二醇(PEG)或甲氧基聚乙二醇(mPEG)。缀合物还可将本发明的化合物连接至，例如，标记(发荧光的或发光的)或标志物(放射性素、放射性同位素和/或同位素)，以包含本发明的探针。与本发明的化合物一起使用的缀合物在一个方面可改善体内半衰期。Compounds of the invention may also be modified, for example by covalently linking organic structural fragments or conjugates, to improve pharmacokinetic properties, toxicity or bioavailability (e.g., increased in vivo half-life). The conjugate can be a linear or branched hydrophilic polymeric group, a fatty acid group or a fatty acid ester group. The polymeric group can comprise a molecular weight that can be adjusted by one skilled in the art to improve, for example, pharmacokinetic properties, toxicity, or bioavailability. Exemplary conjugates can include polyalkanols (eg, polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymers, amino acid polymers or polyvinylpyrrolidone, and fatty acid or fatty acid ester groups, which Each may independently comprise from about 8 to about 70 carbon atoms. Conjugates for use with the compounds of the invention may also be used as linkers, for example, for any suitable substituent or group, radiolabel (marker or tag), halogen, protein, enzyme, polypeptide, other therapeutic agent (eg drugs or drugs), nucleosides, dyes, oligonucleotides, lipids, phospholipids and/or liposomes. In one aspect, the conjugate can include polyvinylamine (PEI), polyglycine, a hybrid of PEI and polyglycine, polyethylene glycol (PEG), or methoxypolyethylene glycol (mPEG). Conjugates The compounds of the invention may also be linked to, for example, labeled (fluorescing or luminescent) or a label (radioactive, radioisotope and/or isotope) to comprise a probe of the invention. Conjugates for use with the compounds of the invention may improve in vivo half-life in one aspect.
术语“连结”和/或“结合”可表示化学或物理相互作用，例如本发明的化合物和感兴趣的目标之间的。连结或相互作用的例子包括共价键、离子键、亲水-疏水相互作用、疏水-疏水相互作用和复合体。“连结”一般还可称作“结合”或“亲和性”，它们每个均可用于描述多种化学或物理相互作用。测量结合或亲和性也是本领域技术人员的常规技术。The term "linking" and/or "binding" may refer to a chemical or physical interaction, such as between a compound of the invention and a target of interest. Examples of linkages or interactions include covalent bonds, ionic bonds, hydrophilic-hydrophobic interactions, hydrophobic-hydrophobic interactions, and complexes. "Links" may also generally be referred to as "binding" or "affinity," each of which may be used to describe a variety of chemical or physical interactions. Measuring binding or affinity is also a routine technique for those skilled in the art.
本文提供下面的实施例来阐述本发明的优点，以及进一步协助本领域普通技术人员制备或使用本发明的化合物或其盐、药物组合物、衍生物、代谢产物、前药、外消旋混合物或互变异构形式。本文的实施例还用于阐述本发明优选方面。实施例不应以任何方式被解释为限制由所附权利要求定义的本发明的范围。The following examples are provided to illustrate the advantages of the present invention, and further assist those of ordinary skill in the art in preparing or using the compounds of the present invention or salts, pharmaceutical compositions, derivatives, metabolites, prodrugs, racemic mixtures thereof or Tautomeric form. The embodiments herein are also used to illustrate preferred aspects of the invention. The examples are not to be construed as limiting the scope of the invention as defined by the appended claims.
具体实施方式detailed description
以下进一步解释本发明的一般方法，本发明的化合物可以通过本领域中公知的方法来制备，下面以本发明的优选化合物的制备流程为例详细进行说明但本发明化合物的制备方法不局限于此。The general method of the present invention is further explained below, and the compound of the present invention can be produced by a method known in the art, and the preparation process of the preferred compound of the present invention is exemplified in detail below, but the preparation method of the compound of the present invention is not limited thereto. .
本发明公开的通式化合物(V)制备主要参照以下的方案进行制备，The preparation of the compound of the general formula (V) disclosed in the present invention is mainly prepared by referring to the following scheme,
Figure PCTCN2015100201-appb-000045
Figure PCTCN2015100201-appb-000045
本发明所述通式(V)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：A compound represented by the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein the preparation method comprises the following steps :
Figure PCTCN2015100201-appb-000046
Figure PCTCN2015100201-appb-000046
X1和X2为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X1和X2在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物V；X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
另一种制备方法包括以下步骤： Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000047
Figure PCTCN2015100201-appb-000047
X1和X3为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X1和X3在一定的反应条件下，通过还原氨化的反应制备得到V。X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
更进一步地，通式(VI)：Further, the general formula (VI):
Figure PCTCN2015100201-appb-000048
Figure PCTCN2015100201-appb-000048
本发明所述通式(VI)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：A compound represented by the formula (VI), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein the preparation method comprises the following steps :
Figure PCTCN2015100201-appb-000049
Figure PCTCN2015100201-appb-000049
X4和X2为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X4和X2在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物VI；X4 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X4 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VI;
另一种制备方法包括以下步骤：Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000050
Figure PCTCN2015100201-appb-000050
X4和X3为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X4和X3在一定的反应条件下，通过还原氨化的反应制备得到VI。X4 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VI is prepared by reacting X4 and X3 under a certain reaction condition by reductive amination.
更进一步地，通式(VII)： Further, the general formula (VII):
Figure PCTCN2015100201-appb-000051
Figure PCTCN2015100201-appb-000051
本发明所述通式(VII)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：A compound represented by the formula (VII), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein the preparation method comprises the following steps :
Figure PCTCN2015100201-appb-000052
Figure PCTCN2015100201-appb-000052
X5和X2为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X5和X2在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物VII；X5 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VII;
另一种制备方法包括以下步骤：Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000053
Figure PCTCN2015100201-appb-000053
X5和X3为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X5和X3在一定的反应条件下，通过还原氨化的反应制备得到VII。X5 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VII is obtained by reacting X5 and X3 under a certain reaction condition by reductive amination.
更进一步地，通式(VIII)：Further, the general formula (VIII):
Figure PCTCN2015100201-appb-000054
Figure PCTCN2015100201-appb-000054
本发明所述通式(VIII)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤： A compound represented by the formula (VIII), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein the preparation method comprises the following steps :
Figure PCTCN2015100201-appb-000055
Figure PCTCN2015100201-appb-000055
X1和X6为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X1和X6在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物VIII；X1 and X6 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X6 at a certain reaction temperature, in the presence of a certain alkaline reagent, by coupling to obtain compound VIII;
另一种制备方法包括以下步骤：Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000056
Figure PCTCN2015100201-appb-000056
X1和X7为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X1和X7在一定的反应条件下，通过还原氨化的反应制备得到VIII。X1 and X7 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VIII is prepared by reacting X1 and X7 under a certain reaction condition by reductive amination.
更进一步地，通式(IX)：Further, the general formula (IX):
Figure PCTCN2015100201-appb-000057
Figure PCTCN2015100201-appb-000057
本发明所述通式(IX)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：A compound represented by the formula (IX), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein the preparation method comprises the following steps :
Figure PCTCN2015100201-appb-000058
Figure PCTCN2015100201-appb-000058
X5和X8为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X5和X8在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物IX；X5 and X8 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X8 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound IX;
另一种制备方法包括以下步骤： Another preparation method includes the following steps:
Figure PCTCN2015100201-appb-000059
Figure PCTCN2015100201-appb-000059
X5和X9为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X5和X9在一定的反应条件下，通过还原氨化的反应制备得到IX。X5 and X9 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X9 are prepared by a reductive amination reaction under certain reaction conditions to obtain IX.
下面通过具体的实施例来进一步说明本发明，但本领域技术人员应知，本发明并不仅限于这些实施例。The invention is further illustrated by the following examples, but those skilled in the art should understand that the invention is not limited thereto.
化合物的结构是通过核磁共振(NMR)或质谱(MS)确定的。NMR的测定是用BrukerAVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出。The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl. Silane (TMS), chemical shift is given in units of 10 -6 (ppm).
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thremo型号：Finnigan LCQ advantage MAX)The measurement of MS was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thremo model: Finnigan LCQ advantage MAX)
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm硅胶板。Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm~ 0.5mm silica gel plate.
柱层析一般使用烟台黄海200～300目硅胶为载体。Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
本发明的已知的起始原料可以采用或参照本领域已知的方法来合成，或可购买自GmbH&Co.KG，Acros Organnics，Aldrich Chemical Company，TCI Chemicals，安耐吉化学等公司。The known starting materials of the present invention may be synthesized by or with reference to methods known in the art, or may be purchased from companies such as GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, TCI Chemicals, Angie Chemicals, and the like.
实施例中如无特殊说明，反应均在氩气氛或氮气氛下进行。In the examples, unless otherwise specified, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气球或氮气球。An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon balloon or a nitrogen balloon having a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气球。The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
氢化反应常抽真空，充入氢气，反复操作3次。The hydrogenation reaction was usually evacuated, charged with hydrogen, and operated three times.
实施例中如无特殊说明，反应的温度为室温，温度范围是20℃～30℃In the examples, unless otherwise specified, the reaction temperature is room temperature, and the temperature range is 20 ° C to 30 ° C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A:二氯甲烷和甲醇体系，B:正己烷和乙酸乙酯体系，C:正己烷和丙酮体系，D:正己烷，E:乙酸乙酯，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane And the acetone system, D: n-hexane, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括：A:二氯甲烷和甲醇体系，B:正己烷和乙酸乙酯体系，C:正己烷和丙酮体系，D:正己烷，E:乙酸乙酯，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。The system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone The system, D: n-hexane, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
实施例1Example 1
Figure PCTCN2015100201-appb-000060
Figure PCTCN2015100201-appb-000060
在25ml圆底烧瓶中加入化合物1A(200mg,1.23mmol),化合物1B(327mg,1.12mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(285mg,1.34mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得淡黄色固体产物化合物1(227mg,产率：46.3％)。1H NMR(400MHz,CDCl3)δ7.93–7.79(m,3H),7.75–7.64(m,2H),7.27–7.16(m,2H),6.94(dd,J＝15.1,3.0Hz,2H),6.86–6.70(m,4H),3.83(s,3H),3.71(s,2H),3.19(t,J＝10.3Hz,4H),2.62(t,J＝10.3Hz,4H)；MS(ESI)m/z[M+H]+：439.24。 Compound 1A (200 mg, 1.23 mmol), Compound 1B (327 mg, 1.12 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (285 mg, 1.34 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The compound was obtained as a pale yellow solid (yield: 46.3%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 - 7.79 (m, 3H), 7.75 - 7.64 (m, 2H), 7.27 - 7.16 (m, 2H), 6.94 (dd, J = 15.1, 3.0 Hz, 2H ), 6.86–6.70 (m, 4H), 3.83 (s, 3H), 3.71 (s, 2H), 3.19 (t, J = 10.3 Hz, 4H), 2.62 (t, J = 10.3 Hz, 4H); (ESI) m/z [M+H] + : 437.24.
实施例2Example 2
Figure PCTCN2015100201-appb-000061
Figure PCTCN2015100201-appb-000061
在25ml圆底烧瓶中加入化合物2A(208mg,1.3mmol),化合物2B(250mg,1.67mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(249mg,1.40mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(8:1)为洗脱剂，得白色固体产物2(152mg,产率：32.5％)。1H NMR(400MHz,CDCl3)δ7.53(d,J＝7.4Hz,1H),7.34–7.26(m,8H),7.23(d,J＝6.7Hz,1H),7.01–6.84(m,3H),3.75(s,2H),3.28–3.13(m,4H),2.76–2.60(m,4H)；MS(ESI)m/z[M+H]+：360.17。Compound 2A (208 mg, 1.3 mmol), compound 2B (250 mg, 1.67 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (249 mg, 1.40 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc EtOAc (EtOAc) To a white solid product 2 (152 mg, yield: 32.5%). 1 H NMR (400MHz, CDCl 3 ) δ7.53 (d, J = 7.4Hz, 1H), 7.34-7.26 (m, 8H), 7.23 (d, J = 6.7Hz, 1H), 7.01-6.84 (m, 3H), 3.75 (s, 2H), 3.28 - 3.13 (m, 4H), 2.76 - 2.60 (m, 4H); MS (ESI) m/z [M+H] + : 360.17.
实施例3Example 3
Figure PCTCN2015100201-appb-000062
Figure PCTCN2015100201-appb-000062
圆底烧瓶中加入3A(2.9g,20mmol)，再加入CH2Cl2，搅拌溶解后加入3B(4.2g,22mmol)和Et3N(3.3ml,24mmol)，室温下搅拌12h，薄层检测反应完全后加入水搅拌30min，然后加入乙酸乙酯稀释反应液，分层后收集有机相，水相再用乙酸乙酯萃取两次，合并有机相，依次用饱和食盐水洗涤，无水硫酸钠干燥，最后浓缩得到粗产物3C(5.5g)。3A (2.9 g, 20 mmol) was added to a round bottom flask, and then CH 2 Cl 2 was added. After stirring, 3B (4.2 g, 22 mmol) and Et 3 N (3.3 ml, 24 mmol) were added, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, the mixture was stirred with water for 30 min, then the mixture was diluted with ethyl acetate. The organic layer was separated and the organic phase was separated, and then the mixture was combined with ethyl acetate. Drying and finally concentrating to give the crude product 3C (5.5 g).
称取化合物3C(1.5g,5mmol)置于圆底烧瓶中，加入THF，溶解后加入原料3D(0.81g,5mmol)，搅拌10min，然后加入STAB(1.27g,6mmol)，于室温下反应3h，薄层检测反应完全后加入饱和氯化铵溶液淬灭反应，反应液用乙酸乙酯萃取三次，合并有机相，依次用饱和食盐水洗涤，无水硫酸钠干燥，最后浓缩柱层析纯化，得到产物3(1.6g,72％)。1H NMR(400MHz,CDCl3)δ8.00(d,J＝8.3Hz,1H),7.79(d,J＝8.4Hz,2H),7.73(d,J＝7.8Hz,1H),7.52(s,1H),7.38–7.31(m,1H),7.27(dt,J＝10.9,6.8Hz,4H),6.94(d,J＝7.9Hz,2H),6.87(t,J＝7.3Hz,1H),3.69(s,2H),3.27–3.12(m,4H),2.70–2.56(m,4H),2.37(s,3H)；MS(ESI)m/z[M+H]+：445.58。The compound 3C (1.5 g, 5 mmol) was weighed in a round bottom flask, THF was added, dissolved, and then the material was added 3D (0.81 g, 5 mmol), stirred for 10 min, then STAB (1.27 g, 6 mmol) was added and reacted at room temperature for 3 h. After the reaction of the thin layer is completed, the reaction is quenched by the addition of a saturated aqueous solution of ammonium chloride, and the mixture is extracted three times with ethyl acetate. The organic phase is combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate Product 3 (1.6 g, 72%) was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (s) , 1H), 7.38 - 7.31 (m, 1H), 7.27 (dt, J = 10.9, 6.8 Hz, 4H), 6.94 (d, J = 7.9 Hz, 2H), 6.87 (t, J = 7.3 Hz, 1H) , 3.69 (s, 2H), 3.27 - 3.12 (m, 4H), 2.70 - 2.56 (m, 4H), 2.37 (s, 3H); MS (ESI) m/z [M+H] + : 445.58.
实施例4Example 4
Figure PCTCN2015100201-appb-000063
Figure PCTCN2015100201-appb-000063
在25ml圆底烧瓶中加入化合物4A(300mg,1.86mmol),化合物4B(494mg,1.69mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(430mg,2.03mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(3:1)为洗脱剂，得白色固体产物4(196mg,产率：42.2％)。1H NMR(400MHz,CDCl3)δ7.91(d,J＝7.8Hz,2H),7.67(t,J＝7.4Hz,1H),7.53(t,J＝7.7Hz,2H),7.33(t,J＝7.5Hz,2H),7.29–7.19(m,3H),7.14(d,J＝8.1Hz,1H),6.96–6.85(m,2H),3.57(s,3H),3.51(s,2H),2.99(d,J＝11.3Hz,2H),2.11(td,J＝11.2,3.3Hz,2H),1.91–1.77(m,4H)；MS(ESI)m/z[M+H]+：439.41。Compound 4A (300 mg, 1.86 mmol), compound 4B (494 mg, 1.69 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (430 mg, 2.03 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. To a white solid product 4 (196 mg, yield: 42.2%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (d, J = 7.8 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.33 (t , J = 7.5 Hz, 2H), 7.29 - 7.19 (m, 3H), 7.14 (d, J = 8.1 Hz, 1H), 6.96 - 6.85 (m, 2H), 3.57 (s, 3H), 3.51 (s, 2H), 2.99 (d, J = 11.3 Hz, 2H), 2.11 (td, J = 11.2, 3.3 Hz, 2H), 1.91 - 1.77 (m, 4H); MS (ESI) m/z [M+H] + : 439.41.
实施例5Example 5
Figure PCTCN2015100201-appb-000064
Figure PCTCN2015100201-appb-000064
在50ml圆底烧瓶中加入化合物5A(980mg,5.5mmol),化合物5B(831mg,5.0mmol),乙酸乙酯(5ml)，搅拌下加入三乙酰氧基硼氢 化钠(1272mg,6mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得淡黄色油状产物5C。Compound 5A (980 mg, 5.5 mmol), compound 5B (831 mg, 5.0 mmol), ethyl acetate (5 ml) was added to a 50 ml round bottom flask, and triacetoxyborohydride was added with stirring. Sodium (1272 mg, 6 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a pale yellow oil.
在25ml圆底烧瓶中加入化合物5C(413mg,1.26mmol),化合物5D(264mg,1.38mmol)，三乙胺(255mg,2.52mmol)与二氯甲烷(5ml),在室温下搅拌4h,TLC检测原料5C消耗完全。将反应体系浓缩，经制备TLC纯化，(二氯甲烷：甲醇(15:1)为展开剂)，得白色固体产物5(426mg,产率：70.1％)。1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.3Hz,2H),7.26(d,J＝8.0Hz,2H),6.91(s,1H),6.88–6.77(m,4H),6.76–6.69(m,2H),3.87(s,3H),3.85(s,3H),3.47(s,2H),3.18–3.08(m,4H),2.60–2.51(m,4H),2.41(s,3H)；MS(ESI)m/z[M+H]+：483.05。The compound 5C (413 mg, 1.26 mmol), mp. The raw material 5C is completely consumed. The reaction was concentrated and purified by EtOAc EtOAc (EtOAc:EtOAc: 1 H NMR (400MHz, CDCl 3 ) δ7.66 (d, J = 8.3Hz, 2H), 7.26 (d, J = 8.0Hz, 2H), 6.91 (s, 1H), 6.88-6.77 (m, 4H) , 6.76–6.69 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.47 (s, 2H), 3.18–3.08 (m, 4H), 2.60–2.51 (m, 4H), 2.41 (s, 3H); MS ( ESI) m / z [m + H] +: 483.05.
实施例6Example 6
Figure PCTCN2015100201-appb-000065
Figure PCTCN2015100201-appb-000065
在50ml圆底烧瓶中加入化合物6A(980mg,5.5mmol),化合物6B(831mg,5.0mmol),乙酸乙酯(5ml)，搅拌下加入三乙酰氧基硼氢化钠(1272mg,6mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得淡黄色油状产物6C。Compound 6A (980 mg, 5.5 mmol), compound 6B (831 mg, 5.0 mmol), ethyl acetate (5 ml) was added to a 50 ml round bottom flask, and sodium triacetoxyborohydride (1272 mg, 6 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a pale yellow oil.
在25ml圆底烧瓶中加入化合物6C(615mg,1.88mmol),化合物6D(258mg,2.25mmol)，三乙胺(380mg,3.76mmol)与二氯甲烷(5ml),在室温下搅拌4h,TLC检测原料6C消耗完全。将反应体系浓缩，经制备TLC纯化，(二氯甲烷：甲醇(20:1)为展开剂)，得白色固体产物6(574mg,产率：75.2％)。1H NMR(400MHz,CDCl3)δ7.20–7.12(m,2H),6.93(d,J＝1.7Hz,1H),6.91(d,J＝2.2Hz,1H),6.90–6.85(m,2H),6.83(d,J＝8.1Hz,1H),3.90(s,3H),3.88(s,3H),3.51(s,2H),3.23–3.16(m,4H),3.09(s,3H),2.63–2.55(m,4H)；MS(ESI)m/z[M+Na]+：439.08。The compound 6C (615 mg, 1.88 mmol), mp. The raw material 6C is completely consumed. The reaction was concentrated and purified by EtOAc EtOAc (EtOAc:EtOAc: 1 H NMR (400MHz, CDCl 3 ) δ7.20-7.12 (m, 2H), 6.93 (d, J = 1.7Hz, 1H), 6.91 (d, J = 2.2Hz, 1H), 6.90-6.85 (m, 2H), 6.83 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.51 (s, 2H), 3.23 - 3.16 (m, 4H), 3.09 (s, 3H) ), 2.63 - 2.55 (m, 4H); MS (ESI) m/z [M+Na] + : 439.08.
实施例7Example 7
Figure PCTCN2015100201-appb-000066
Figure PCTCN2015100201-appb-000066
在25ml圆底烧瓶中加入化合物7A(196mg,1.1mmol),化合物7B(306mg,1.0mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(254mg,1.2mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物7(189mg,产率：40.3％)。1H NMR(400MHz,CDCl3)δ7.80–7.71(m,2H),7.52–7.45(m,2H),6.81(dd,J＝8.9,6.0Hz,2H),6.67–6.60(m,3H),6.59–6.53(m,2H),3.83(s,3H),3.66(s,2H),3.19(t,J＝10.3Hz,4H),2.62(t,J＝10.3Hz,4H),2.43(s,3H)；MS(ESI)m/z[M+H]+：469.11。To a 25 ml round bottom flask was added compound 7A (196 mg, 1.1 mmol), Compound 7B (306 mg, 1.0 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (254 mg, 1.2 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 7 (189 mg, yield: 40.3%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 - 7.71 (m, 2H), 7.52 - 7.45 (m, 2H), 6.81 (dd, J = 8.9, 6.0 Hz, 2H), 6.67 - 6.60 (m, 3H) ), 6.59 - 6.53 (m, 2H), 3.83 (s, 3H), 3.66 (s, 2H), 3.19 (t, J = 10.3 Hz, 4H), 2.62 (t, J = 10.3 Hz, 4H), 2.43 (s, 3H); MS ( ESI) m / z [m + H] +: 469.11.
实施例8Example 8
Figure PCTCN2015100201-appb-000067
Figure PCTCN2015100201-appb-000067
在25ml圆底烧瓶中加入化合物8A(400mg,1.2mmol),化合物8B(213mg,1.1mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(276mg,1.3mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物8(191mg,产率：34.3％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.32(d,J＝8.1Hz,2H),6.92–6.75(m,5H),6.26–6.14(m,2H),3.67(s,2H),3.34(q,J＝7.0Hz,4H),3.28–3.08(m,4H),2.85–2.55(m,4H),2.47(s,3H),1.17(t,J＝7.0Hz,6H)；MS(ESI)m/z[M+Na]+：532.21。Compound 8A (400 mg, 1.2 mmol), compound 8B (213 mg, 1.1 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 8 (191 mg, yield: 34.3%). 1 H NMR (400MHz, CDCl 3 ) δ7.71 (d, J = 8.3Hz, 2H), 7.32 (d, J = 8.1Hz, 2H), 6.92-6.75 (m, 5H), 6.26-6.14 (m, 2H), 3.67 (s, 2H), 3.34 (q, J = 7.0 Hz, 4H), 3.28 - 3.08 (m, 4H), 2.85 - 2.55 (m, 4H), 2.47 (s, 3H), 1.17 (t , J = 7.0 Hz, 6H); MS (ESI) m/z [M+Na] + : 532.21.
实施例9Example 9
Figure PCTCN2015100201-appb-000068
Figure PCTCN2015100201-appb-000068
在25ml圆底烧瓶中加入化合物9A(400mg,1.2mmol),化合物9B(184mg,1.1mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(276mg,1.3mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得淡黄色固体产物9(205mg,产率：38.5％)。1H NMR(400MHz,CDCl3)δ7.94(d,J＝8.9Hz,1H),7.70(d,J＝8.3Hz,2H),7.31(d,J＝8.1Hz,2H),7.19(d,J＝2.6Hz,1H),6.88–6.79(m,2H),6.79–6.70(m,3H),3.89(s,2H),3.20–3.05(m,4H),2.74–2.58(m,4H),2.46(s,3H)；MS(ESI)m/z[M+H]+：484.21。To a 25 ml round bottom flask was added compound 9A (400 mg, 1.2 mmol), Compound 9B (184 mg, 1.1 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (276 mg, 1.3 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The pale yellow solid product 9 (205 mg, yield: 38.5%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.19 (d) , J=2.6Hz, 1H), 6.88–6.79 (m, 2H), 6.79–6.70 (m, 3H), 3.89 (s, 2H), 3.20–3.05 (m, 4H), 2.74–2.58 (m, 4H) ), 2.46 (s, 3H); MS (ESI) m/z [M+H] + : 484.21.
实施例10Example 10
Figure PCTCN2015100201-appb-000069
Figure PCTCN2015100201-appb-000069
在25ml圆底烧瓶中加入化合物10A(400mg,1.2mmol),化合物10B(214mg,1.1mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(276mg,1.3mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得淡黄色固体产物10(238mg,产率：42.5％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.31(d,J＝8.1Hz,2H),7.21(dd,J＝5.1,1.1Hz,1H),7.15(dd,J＝3.6,1.1Hz,1H),7.07–7.00(m,2H),6.85(dt,J＝6.6,2.8Hz,3H),6.81–6.76(m,2H),3.75(s,2H),3.25–3.13(m,4H),2.72–2.62(m,4H),2.46(s,3H)；MS(ESI)m/z[M+Na]+：533.82。Compound 10A (400 mg, 1.2 mmol), compound 10B (214 mg, 1.1 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a pale yellow solid (yield: 238 mg, yield: 42.5%). 1 H NMR (400MHz, CDCl 3 ) δ7.71 (d, J = 8.3Hz, 2H), 7.31 (d, J = 8.1Hz, 2H), 7.21 (dd, J = 5.1,1.1Hz, 1H), 7.15 (dd, J=3.6, 1.1 Hz, 1H), 7.07–7.00 (m, 2H), 6.85 (dt, J=6.6, 2.8 Hz, 3H), 6.81–6.76 (m, 2H), 3.75 (s, 2H) ), 3.25 - 3.13 (m, 4H), 2.72 - 2.62 (m, 4H), 2.46 (s, 3H); MS (ESI) m/z [M+Na] + : 533.82.
实施例11Example 11
Figure PCTCN2015100201-appb-000070
Figure PCTCN2015100201-appb-000070
在25ml圆底烧瓶中加入化合物11A(400mg,1.2mmol),化合物11B(160mg,1.1mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(276mg,1.3mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物11(178mg,产率：35.1％)。1H NMR(400MHz,CDCl3)δ7.72(dd,J＝12.5,8.1Hz,3H),7.40(d,J＝8.1Hz,1H),7.30(d,J＝8.1Hz,2H),7.26(d,J＝2.1Hz,1H),7.19(dt,J＝25.8,7.1Hz,2H),6.83(d,J＝9.1Hz,2H),6.72(d,J＝9.1Hz,2H),3.90(s,2H),3.22–3.14(m,4H),2.82–2.70(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：462.22。Compound 11A (400 mg, 1.2 mmol), compound 11B (160 mg, 1.1 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 11 (178 mg, yield: 35.1%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (dd, J = 12.5, 8.1 Hz, 3H), 7.40 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 2.1 Hz, 1H), 7.19 (dt, J = 25.8, 7.1 Hz, 2H), 6.83 (d, J = 9.1 Hz, 2H), 6.72 (d, J = 9.1 Hz, 2H), 3.90 (s, 2H), 3.22 - 3.14 (m, 4H), 2.82 - 2.70 (m, 4H), 2.45 (s, 3H); MS (ESI) m/z [M+H] + : 462.22.
实施例12Example 12
Figure PCTCN2015100201-appb-000071
Figure PCTCN2015100201-appb-000071
在25ml圆底烧瓶中加入化合物12A(400mg,1.2mmol),化合物12B(276mg,1.1mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(276mg,1.3mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物12(200mg,产率：32.1％)。1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.3Hz,2H),7.49(dd,J＝12.3,7.2Hz,3H),7.42(dd,J＝5.0,1.9Hz,2H),7.38–7.30(m,5H),7.17(d,J＝2.0Hz,1H),6.85–6.79(m,2H),6.65(d,J＝9.1Hz,2H),5.13(s,2H),4.04(s,2H),3.22–3.10(m,4H),2.94–2.80(m,4H),2.44(s,3H)；MS(ESI)m/z[M+H]+：568.30。 To a 25 ml round bottom flask was added compound 12A (400 mg, 1.2 mmol), Compound 12B (276 mg, 1.1 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (276 mg, 1.3 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 12 (200 mg, yield: 32.1%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (d, J = 8.3 Hz, 2H), 7.49 (dd, J = 12.3, 7.2 Hz, 3H), 7.42 (dd, J = 5.0, 1.9 Hz, 2H) , 7.38 - 7.30 (m, 5H), 7.17 (d, J = 2.0 Hz, 1H), 6.85 - 6.79 (m, 2H), 6.65 (d, J = 9.1 Hz, 2H), 5.13 (s, 2H), 4.04 (s, 2H), 3.22 - 3.10 (m, 4H), 2.94 - 2.80 (m, 4H), 2.44 (s, 3H); MS (ESI) m/z [M+H] + : 568.30.
实施例13Example 13
Figure PCTCN2015100201-appb-000072
Figure PCTCN2015100201-appb-000072
在25ml圆底烧瓶中加入化合物13A(400mg,1.2mmol),化合物13B(189mg,1.1mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(276mg,1.3mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物13(164mg,产率：30.6％)。1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.6Hz,1H),7.80(d,J＝7.9Hz,1H),7.73(dd,J＝8.6,4.5Hz,3H),7.52–7.44(m,1H),7.33(t,J＝6.9Hz,3H),7.13(d,J＝8.8Hz,1H),6.92–6.86(m,2H),6.83–6.77(m,2H),4.24(s,2H),3.40–3.10(m,4H),2.97–2.62(m,4H),,2.47(s,3H)；MS(ESI)m/z[M+H]+：489.29。Compound 13A (400 mg, 1.2 mmol), compound 13B (189 mg, 1.1 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 13 (164 mg, yield: 30.6%). 1 H NMR (400MHz, CDCl 3 ) δ7.86 (d, J = 8.6Hz, 1H), 7.80 (d, J = 7.9Hz, 1H), 7.73 (dd, J = 8.6,4.5Hz, 3H), 7.52 –7.44(m,1H), 7.33(t,J=6.9Hz,3H), 7.13(d,J=8.8Hz,1H), 6.92–6.86(m,2H),6.83–6.77(m,2H), 4.24 (s, 2H), 3.40 - 3.10 (m, 4H), 2.97 - 2.62 (m, 4H), 2.47 (s, 3H); MS (ESI) m/z [M+H] + : 489.29.
实施例14Example 14
Figure PCTCN2015100201-appb-000073
Figure PCTCN2015100201-appb-000073
在25ml圆底烧瓶中加入化合物14A(400mg,1.2mmol),化合物14B(183mg,1.1mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(276mg,1.3mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(2:1)为洗脱剂，得白色固体产物14(218mg,产率：41.1％)。1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.3Hz,2H),7.36–7.27(m,2H),7.07–6.97(m,2H),6.87(dd,J＝7.9,1.7Hz,1H),6.86–6.82(m,2H),6.79–6.74(m,2H),3.88(s,3H),3.86(s,3H),3.64(s,2H),3.23–3.09(m,4H),2.73–2.61(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：483.23。To a 25 ml round bottom flask was added compound 14A (400 mg, 1.2 mmol), Compound 14B (183 mg, 1.1 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (276 mg, 1.3 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a white solid (yield: 218 mg, yield: 41.1%). 1 H NMR (400MHz, CDCl 3 ) δ7.70 (d, J = 8.3Hz, 2H), 7.36-7.27 (m, 2H), 7.07-6.97 (m, 2H), 6.87 (dd, J = 7.9,1.7 Hz, 1H), 6.86–6.82 (m, 2H), 6.79–6.74 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.64 (s, 2H), 3.23–3.09 (m, 4H), 2.73 - 2.61 (m, 4H), 2.45 (s, 3H); MS (ESI) m/z [M+H] + : 483.23.
实施例15Example 15
Figure PCTCN2015100201-appb-000074
Figure PCTCN2015100201-appb-000074
50ml圆底烧瓶中加入15A(249mg，1.5mmol)，二氯甲烷(10ml)溶解，再加入草酰氯(213μl，2.5mmol)以及N,N-二甲基甲酰胺(1滴)，室温下反应过夜。蒸干溶剂和过量的草酰氯，得到粗品15B。15A (249mg, 1.5mmol) was added to a 50ml round bottom flask, dissolved in dichloromethane (10ml), then oxalyl chloride (213μl, 2.5mmol) and N,N-dimethylformamide (1 drop) were added and reacted at room temperature. overnight. The solvent and excess oxalyl chloride were evaporated to give a crude material 15B.
在50ml圆底烧瓶中加入15C(332mg，1.0mmol)，二氯甲烷(10ml)溶解，再加入三乙胺(278μl，2.0mmol)。将粗品15B用二氯甲烷(5ml)溶解，缓慢滴入，室温反应过夜，TLC检测原料反应完全。浓缩后经硅胶柱层析(二氯甲烷：甲醇＝50:1)为洗脱剂，得产物15D(353mg，产率73.4％)。Into a 50 ml round bottom flask was added 15 C (332 mg, 1.0 mmol), dichloromethane (10 ml), and then triethylamine (278 μl, 2.0 mmol). The crude product 15B was dissolved in dichloromethane (5 ml), and the mixture was slowly added dropwise and allowed to react overnight at room temperature. After concentration, the residue was purified byjjjjjjjjjjjj
在50ml圆底烧瓶中加入15D(353mg，0.735mmol)，四氢呋喃(10ml)溶解，于0℃缓慢加入LiAlH4(112mg，2.94mmol)，70℃下反应1h。冷却到室温后，用甲醇淬灭反应，最后加入饱和NaHCO3(1ml),过滤，甲醇洗涤滤饼，浓缩后经硅胶柱层析(石油醚：乙酸乙酯＝1:1)得产物15(113mg，产率32.9％)。1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.3Hz,2H),7.32(d,J＝8.1Hz,2H),7.16(d,J＝8.6Hz,2H),6.88–6.85(m,4H),6.81–6.78(m,2H),3.81(s,3H),3.21–3.18(m,4H),2.82-2.78(m,2H),2.69–2.61(m,6H),2.46(s,3H)；MS(ESI)m/z[M+H]+：467.08。 15D (353 mg, 0.735 mmol) was added to a 50 ml round bottom flask, and tetrahydrofuran (10 ml) was dissolved. LiAlH 4 (112 mg, 2.94 mmol) was slowly added at 0 ° C, and reacted at 70 ° C for 1 h. After cooling to room temperature, the reaction was quenched with methanol and finally with saturated NaHCO 3 (1ml), filtered, and the filter cake was washed with methanol, concentrated in vacuo purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to give product 15 ( 113 mg, yield 32.9%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 6.88 - 6.85 (m, 4H), 6.81–6.78 (m, 2H), 3.81 (s, 3H), 3.21–3.18 (m, 4H), 2.82–2.78 (m, 2H), 2.69–2.61 (m, 6H), 2.46 (s, 3H); MS ( ESI) m / z [m + H] +: 467.08.
实施例16Example 16
Figure PCTCN2015100201-appb-000075
Figure PCTCN2015100201-appb-000075
在100ml圆底烧瓶中加入16A(2.02g，10mmol)，DMSO(20ml)溶解，搅拌下加入哌嗪(1.12g，13mmol)、K2CO3(2.07g,15mmol)以及TBAI(37mg,0.1mmol)，120℃下反应6h。冷却至室温后，水洗，乙酸乙酯萃取，合并有机层，饱和NaCl洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(先石油醚：乙酸乙酯＝5:1；后二氯甲烷：甲醇＝10:1)得黄色固体产物16B(1.14g，产率55.1％)。Was added 16A (2.02g, 10mmol) in 100ml round bottom flask, DMSO (20ml) was dissolved with stirring was added piperazine (1.12g, 13mmol), K 2 CO 3 (2.07g, 15mmol) and TBAI (37mg, 0.1mmol ), reacted at 120 ° C for 6 h. After cooling to room temperature, the mixture was washed with EtOAc EtOAc EtOAc. :Methanol = 10:1) yielded yellow solid product 16B (1.14 g, yield 55.1%).
在50ml圆底烧瓶中加入16B(622mg，3.0mmol)，二氯甲烷(15ml)溶解，搅拌下加入16C(548mg，3.3mmol)以及NaBH(OAc)3(954mg，4.5mmol)，室温下反应过夜。饱和NaHCO3淬灭反应，分液，乙酸乙酯萃取，合并有机相，浓缩后经硅胶柱层析(石油醚：乙酸乙酯＝1:1)得黄色固体产物16D(330mg，产率30.8％)。16B (622 mg, 3.0 mmol) was added to a 50 ml round bottom flask, and dichloromethane (15 ml) was dissolved, and 16 C (548 mg, 3.3 mmol) and NaBH(OAc) 3 (954 mg, 4.5 mmol) were added under stirring, and allowed to react at room temperature overnight. . The reaction was quenched with saturated NaHCO 3, partitioned, extracted with ethyl acetate, the organic phases were combined, concentrated in vacuo purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to give a yellow solid 16D (330mg, yield 30.8% ).
50ml圆底烧瓶中加入16D(330mg，0.92mmol)，乙醇(20ml)溶解，然后加入Pd/C(10mg，0.09mmol)，用H2换气5次(常压)，室温下反应过夜。过滤，乙醇洗涤滤饼，收集滤液，蒸干溶剂，得粗品16E。16D (330 mg, 0.92 mmol) was added to a 50 ml round bottom flask, and ethanol (20 ml) was dissolved. Then, Pd/C (10 mg, 0.09 mmol) was added thereto, and the mixture was purged with H 2 for 5 times (atmospheric pressure), and allowed to react at room temperature overnight. Filtration, washing the filter cake with ethanol, collecting the filtrate, and evaporating the solvent to give a crude product 16E.
在50ml圆底烧瓶中加入粗品16E，二氯甲烷(10mL)溶解，搅拌下加入三乙胺(208μl,1.5mmol)以及TsCl(228mg，1.2mmol)，室温下反应过夜。浓缩后经硅胶柱层析(二氯甲烷：甲醇＝50:1)得产物16(103mg，产率23.3％)。1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.3Hz,2H),7.22(d,J＝8.1Hz,2H),6.96–6.92(m,3H),6.88-6.82(m,2H),6.80–6.77(m,2H),3.91(s,3H),3.90(s,3H),3.51(s,2H),3.17–3.15(m,4H),2.60–2.58(m,4H),2.40(s,3H)；MS(ESI)m/z[M+Na]+：504.09。The crude product was dissolved in dichloromethane (10 mL), and then triethylamine (208 μl, 1.5 mmol) and TsCl (228 mg, 1.2 mmol) were added to a 50 ml round bottom flask and allowed to react at room temperature overnight. After concentration, the residue was purified byjjjjjjjjjjjj 1 H NMR (400MHz, CDCl 3 ) δ7.59 (d, J = 8.3Hz, 2H), 7.22 (d, J = 8.1Hz, 2H), 6.96-6.92 (m, 3H), 6.88-6.82 (m, 2H), 6.80–6.77 (m, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.51 (s, 2H), 3.17–3.15 (m, 4H), 2.60–2.58 (m, 4H) , 2.40 (s, 3H); MS (ESI) m/z [M+Na] + : 504.09.
实施例17Example 17
Figure PCTCN2015100201-appb-000076
Figure PCTCN2015100201-appb-000076
在25ml圆底烧瓶中加入化合物17A(292mg,1.79mmol)，化合物17B(400mg,1.63mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(416mg,1.96mmol)。室温下搅拌过夜，TLC检测原料反应完全。饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得白色固体产物17(239mg,产率：37.5％)。1H NMR(400MHz,CDCl3)δ8.31–8.22(m,1H),7.98–7.89(m,2H),7.83(d,J＝7.6Hz,1H),7.62(dd,J＝14.6,7.3Hz,2H),7.57–7.45(m,3H),7.33(t,J＝7.4Hz,2H),7.21(dd,J＝9.4,8.4Hz,3H),3.83(s,2H),2.80(d,J＝11.4Hz,2H),2.44(qd,J＝12.0,3.6Hz,1H),2.06–1.89(m,2H),1.71(d,J＝11.8Hz,2H),1.58(qd,J＝12.5,3.5Hz,2H)；MS(ESI)m/z[M+H]+：392.22。To a 25 ml round bottom flask was added compound 17A (292 mg, 1.79 mmol), Compound 17B (400 mg, 1.63 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (416 mg, 1.96 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) White solid product 17 (239 mg, yield: 37.5%). 1 H NMR (400MHz, CDCl 3 ) δ8.31-8.22 (m, 1H), 7.98-7.89 (m, 2H), 7.83 (d, J = 7.6Hz, 1H), 7.62 (dd, J = 14.6,7.3 Hz, 2H), 7.57–7.45 (m, 3H), 7.33 (t, J=7.4 Hz, 2H), 7.21 (dd, J=9.4, 8.4 Hz, 3H), 3.83 (s, 2H), 2.80 (d) , J = 11.4 Hz, 2H), 2.44 (qd, J = 12.0, 3.6 Hz, 1H), 2.06 - 1.89 (m, 2H), 1.71 (d, J = 11.8 Hz, 2H), 1.58 (qd, J = 12.5,3.5Hz, 2H); MS (ESI ) m / z [m + H] +: 392.22.
实施例18Example 18
Figure PCTCN2015100201-appb-000077
Figure PCTCN2015100201-appb-000077
在25ml圆底烧瓶中加入化合物18A(200mg,0.6mmol),化合物18B(109mg,0.55mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(140mg,0.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得白色固体产物18(115mg,产率：40.7％)。1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.3Hz,2H),7.42–7.27(m,5H),7.18–7.07(m,3H),7.07–7.02(m,2H),6.94(dd,J＝8.1,1.7Hz, 1H),6.90–6.84(m,2H),6.82–6.74(m,2H),3.56(s,2H),3.21–3.11(m,4H),2.65–2.55(m,4H),2.46(s,3H)；MS(ESI)m/z[M+H]+：515.11。To a 25 ml round bottom flask was added compound 18A (200 mg, 0.6 mmol), Compound 18B (109 mg, 0.55 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (140 mg, 0.66 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a white solid (18 mg, yield: 40.7%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (d, J = 8.3 Hz, 2H), 7.42 - 7.27 (m, 5H), 7.18 - 7.07 (m, 3H), 7.07 - 7.02 (m, 2H), 6.94 (dd, J=8.1, 1.7 Hz, 1H), 6.90–6.84 (m, 2H), 6.82–6.74 (m, 2H), 3.56 (s, 2H), 3.21–3.11 (m, 4H), 2.65– 2.55 (m, 4H), 2.46 (s, 3H); MS (ESI) m / z [m + H] +: 515.11.
实施例19Example 19
Figure PCTCN2015100201-appb-000078
Figure PCTCN2015100201-appb-000078
在25ml圆底烧瓶中加入化合物19A(200mg,0.6mmol),化合物19B(135mg,0.55mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(140mg,0.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得白色固体产物19(121mg,产率：39.1％)。1H NMR(400MHz,CDCl3)δ7.88(d,J＝7.5Hz,2H),7.78(d,J＝7.6Hz,1H),7.70(d,J＝8.2Hz,2H),7.63–7.58(m,2H),7.56–7.52(m,2H),7.48(t,J＝7.5Hz,3H),7.31(d,J＝8.1Hz,2H),6.84(d,J＝9.1Hz,2H),6.71(d,J＝9.1Hz,2H),3.84(s,2H),3.03–2.93(m,4H),2.45(s,3H),2.43–2.33(m,4H)；MS(ESI)m/z[M+H]+：563.08。Compound 19A (200 mg, 0.6 mmol), compound 19B (135 mg, 0.55 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask and sodium triacetoxyborohydride (140 mg, 0.66 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) White solid product 19 (121 mg, yield: 39.1%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 7.5 Hz, 2H), 7.78 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.63 - 7.58 (m, 2H), 7.56–7.52 (m, 2H), 7.48 (t, J = 7.5 Hz, 3H), 7.31 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 9.1 Hz, 2H) , 6.71 (d, J = 9.1 Hz, 2H), 3.84 (s, 2H), 3.03 - 2.93 (m, 4H), 2.45 (s, 3H), 2.43 - 2.33 (m, 4H); MS (ESI) m /z[M+H] + :563.08.
实施例20Example 20
Figure PCTCN2015100201-appb-000079
Figure PCTCN2015100201-appb-000079
在25ml圆底烧瓶中加入化合物20A(319mg,1.79mmol),化合物20B(400mg,1.63mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(416mg,1.96mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(10:1)为洗脱剂，得白色固体产物20(194mg,产率：29.1％)。1H NMR(400MHz,CDCl3)δ8.24(dd,J＝7.9,1.1Hz,1H),7.89(dd,J＝5.3,3.4Hz,2H),7.77(d,J＝7.6Hz,1H),7.64–7.57(m,1H),7.56–7.46(m,4H),6.78(d,J＝9.0Hz,2H),6.72(d,J＝9.0Hz,2H),3.85(s,2H),2.93–2.86(m,4H),2.48–2.39(m,4H)；MS(ESI)m/z[M+H]+：409.15。To a 25 ml round bottom flask was added compound 20A (319 mg, 1.79 mmol), Compound 20B (400 mg, 1.63 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (416 mg, 1.96 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The white solid product 20 (194 mg, yield: 29.1%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.24 (dd, J = 7.9, 1.1 Hz, 1H), 7.89 (dd, J = 5.3, 3.4 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H) , 7.64 - 7.57 (m, 1H), 7.56 - 7.46 (m, 4H), 6.78 (d, J = 9.0 Hz, 2H), 6.72 (d, J = 9.0 Hz, 2H), 3.85 (s, 2H), 2.93 - 2.86 (m, 4H), 2.48 - 2.39 (m, 4H); MS (ESI) m/z [M+H] + : 409.15.
实施例21Example 21
Figure PCTCN2015100201-appb-000080
Figure PCTCN2015100201-appb-000080
在25ml圆底烧瓶中加入化合物21A(300mg,0.90mmol),化合物21B(88mg,0.82mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(209mg,0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物21(137mg,产率：39.4％)。1H NMR(400MHz,CDCl3)δ8.58(d,J＝1.8Hz,1H),8.54(dd,J＝4.8,1.6Hz,1H),7.75–7.66(m,3H),7.30(dd,J＝7.4,5.0Hz,3H),6.89–6.82(m,2H),6.80–6.73(m,2H),3.58(s,2H),3.22–3.10(m,4H),2.67–2.54(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：424.17。Compound 21A (300 mg, 0.90 mmol), Compound 21B (88 mg, 0.82 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (209 mg, 0.98 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Solid product 21 (137 mg, yield: 39.4%). 1 H NMR (400MHz, CDCl 3 ) δ8.58 (d, J = 1.8Hz, 1H), 8.54 (dd, J = 4.8,1.6Hz, 1H), 7.75-7.66 (m, 3H), 7.30 (dd, J=7.4, 5.0 Hz, 3H), 6.89–6.82 (m, 2H), 6.80–6.73 (m, 2H), 3.58 (s, 2H), 3.22–3.10 (m, 4H), 2.67–2.54 (m, 4H), 2.45 (s, 3H ); MS (ESI) m / z [m + H] +: 424.17.
实施例22Example 22
Figure PCTCN2015100201-appb-000081
Figure PCTCN2015100201-appb-000081
在25ml圆底烧瓶中加入化合物22A(300mg,0.90mmol),化合物22B(88mg,0.82mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(209mg,0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物22(128mg,产率：36.9％)。1H NMR(400MHz,CDCl3)δ8.57(dd,J＝4.5,1.5Hz,2H),7.74–7.67(m,2H),7.32–7.30(m,3H),6.92–6.83(m,2H),6.82–6.75(m,2H),3.57(s,2H),3.23–3.13(m,4H),2.65–2.54(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：424.15。Compound 22A (300 mg, 0.90 mmol), Compound 22B (88 mg, 0.82 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (209 mg, 0.98 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Solid product 22 (128 mg, yield: 36.9%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (dd, J = 4.5, 1.5 Hz, 2H), 7.74 - 7.67 (m, 2H), 7.32 - 7.30 (m, 3H), 6.92 - 6.83 (m, 2H) ), 6.82–6.75 (m, 2H), 3.57 (s, 2H), 3.23–3.13 (m, 4H), 2.65–2.54 (m, 4H), 2.45 (s, 3H); MS (ESI) m/z [M+H] + : 424.15.
实施例23Example 23
Figure PCTCN2015100201-appb-000082
Figure PCTCN2015100201-appb-000082
在25ml圆底烧瓶中加入化合物23A(300mg,0.90mmol),化合物23B(88mg,0.82mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(209mg,0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物23(124mg,产率：35.6％)。1H NMR(400MHz,CDCl3)δ8.60(dd,J＝4.9,0.8Hz,1H),7.74–7.66(m,3H),7.44(d,J＝7.8Hz,1H),7.31(d,J＝8.1Hz,2H),7.24–7.17(m,1H),6.89–6.82(m,2H),6.81–6.75(m,2H),3.73(s,2H),3.24–3.14(m,4H),2.72–2.63(m,4H),2.46(s,3H)；MS(ESI)m/z[M+H]+：424.07。Compound 23A (300 mg, 0.90 mmol), compound 23B (88 mg, 0.82 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (209 mg, 0.98 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 23 (124 mg, yield: 35.6%). 1 H NMR (400MHz, CDCl 3 ) δ8.60 (dd, J = 4.9,0.8Hz, 1H), 7.74-7.66 (m, 3H), 7.44 (d, J = 7.8Hz, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.24–7.17 (m, 1H), 6.89–6.82 (m, 2H), 6.81–6.75 (m, 2H), 3.73 (s, 2H), 3.24–3.14 (m, 4H) , 2.72 - 2.63 (m, 4H), 2.46 (s, 3H); MS (ESI) m/z [M+H] + : 424.07.
实施例24Example 24
Figure PCTCN2015100201-appb-000083
Figure PCTCN2015100201-appb-000083
在25ml圆底烧瓶中加入化合物24A(300mg,0.90mmol),化合物24B(121mg,0.90mmol)碳酸钾(187mg,1.36mmol),N,N-二甲基甲酰胺(2ml)，60℃下搅拌过夜，TLC检测原料反应完全。向反应体系中加入2倍体积的水，再用二氯甲烷萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(10:1)为洗脱剂，得白色固体产物24(194mg,产率：50.1％)。1H NMR(400MHz,DMSO)δ11.35(s,1H),11.27(s,1H),7.71(d,J＝8.3Hz,2H),7.46(d,J＝8.3Hz,2H),6.91–6.84(m,2H),6.83–6.78(m,2H),3.32(s,2H),3.16–3.06(m,4H),2.58–2.48(m,4H),2.42(s,3H)；MS(ESI)m/z[M-H]-：428.24。Compound 24A (300 mg, 0.90 mmol), compound 24B (121 mg, 0.90 mmol), potassium carbonate (187 mg, 1.36 mmol), N,N-dimethylformamide (2 ml), and stirred at 60 ° C. Overnight, TLC detected the reaction of the starting material completely. To the reaction system, 2 times by volume of water was added, and the mixture was extracted with methylene chloride. The organic layer was combined, dried over anhydrous sodium sulfate, concentrated, then purified by silica gel column chromatography eluting with dichloromethane: methanol (10:1) The product was obtained as a white solid (24 mg, yield: 50.1%). 1 H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 11.27 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 6.91 - 6.84 (m, 2H), 6.83–6.78 (m, 2H), 3.32 (s, 2H), 3.16–3.06 (m, 4H), 2.58–2.48 (m, 4H), 2.42 (s, 3H); ESI) m/z [MH] - : 428.24.
实施例25Example 25
Figure PCTCN2015100201-appb-000084
Figure PCTCN2015100201-appb-000084
在25ml圆底烧瓶中加入化合物25A(200mg,0.60mmol),化合物25B(53mg,0.55mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(139mg,0.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物25(85mg,产率：37.7％)。1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.3Hz,2H),7.30(d,J＝8.1Hz,2H),7.03(s,2H),6.89–6.80(m,2H),6.79–6.72(m,2H),3.71(s,2H),3.17–3.08(m,4H),2.69–2.57(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：413.04。To a 25 ml round bottom flask was added compound 25A (200 mg, 0.60 mmol), Compound 25B (53 mg, 0.55 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (139 mg, 0.66 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Solid product 25 (85 mg, yield: 37.7%). 1 H NMR (400MHz, CDCl 3 ) δ7.70 (d, J = 8.3Hz, 2H), 7.30 (d, J = 8.1Hz, 2H), 7.03 (s, 2H), 6.89-6.80 (m, 2H) , 6.79–6.72 (m, 2H), 3.71 (s, 2H), 3.17–3.08 (m, 4H), 2.69–2.57 (m, 4H), 2.45 (s, 3H); MS (ESI) m/z [ M+H] + : 413.04.
实施例26Example 26
Figure PCTCN2015100201-appb-000085
Figure PCTCN2015100201-appb-000085
在25ml圆底烧瓶中加入化合物26A(200mg,0.60mmol),化合物26B(53mg,0.55mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基 硼氢化钠(139mg,0.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物26(100mg,产率：43.9％)。1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.3Hz,2H),7.62(d,J＝0.8Hz,1H),7.31(d,J＝8.0Hz,2H),6.97(s,1H),6.89–6.81(m,2H),6.79–6.73(m,2H),3.60(s,2H),3.18–3.12(m,4H),2.66–2.60(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：413.08。To a 25 ml round bottom flask was added compound 26A (200 mg, 0.60 mmol), Compound 26B (53 mg, 0.55 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (139 mg, 0.66 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Solid product 26 (100 mg, yield: 43.9%). 1 H NMR (400MHz, CDCl 3 ) δ7.70 (d, J = 8.3Hz, 2H), 7.62 (d, J = 0.8Hz, 1H), 7.31 (d, J = 8.0Hz, 2H), 6.97 (s , 1H), 6.89–6.81 (m, 2H), 6.79–6.73 (m, 2H), 3.60 (s, 2H), 3.18–3.12 (m, 4H), 2.66–2.60 (m, 4H), 2.45 (s) , MS (ESI) m/z [M+H] + : 413.08.
实施例27Example 27
Figure PCTCN2015100201-appb-000086
Figure PCTCN2015100201-appb-000086
在25ml圆底烧瓶中加入化合物27A(200mg,0.60mmol),化合物27B(60mg,0.55mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(139mg,0.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(2:1)为洗脱剂，得白色固体产物27(98mg,产率：41.7％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.32(d,J＝8.0Hz,2H),6.90–6.83(m,2H),6.81–6.74(m,2H),6.66–6.62(m,1H),6.10–6.02(m,2H),3.68(s,3H),3.50(s,2H),3.19–3.07(m,4H),2.63–2.52(m,4H),2.47(s,3H)；MS(ESI)m/z[M]+：426.07。To a 25 ml round bottom flask was added compound 27A (200 mg, 0.60 mmol), Compound 27B (60 mg, 0.55 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (139 mg, 0.66 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a white solid (yield: (yield: 41.7%). 1 H NMR (400MHz, CDCl 3 ) δ7.71 (d, J = 8.3Hz, 2H), 7.32 (d, J = 8.0Hz, 2H), 6.90-6.83 (m, 2H), 6.81-6.74 (m, 2H), 6.66–6.62 (m, 1H), 6.10–6.02 (m, 2H), 3.68 (s, 3H), 3.50 (s, 2H), 3.19–3.07 (m, 4H), 2.63–2.52 (m, 4H), 2.47 (s, 3H); MS (ESI) m/z [M] + : 426.07.
实施例28Example 28
Figure PCTCN2015100201-appb-000087
Figure PCTCN2015100201-appb-000087
在25ml圆底烧瓶中加入化合物28A(300mg,0.90mmol),化合物28B(90mg,0.82mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(212mg,1.00mmol)。室温下搅拌过夜，TLC检测原料反应完全。饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(15:1)为洗脱剂，得白色固体产物28(142mg,产率：40.5％)。1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.3Hz,2H),7.33–7.27(m,2H),6.93(d,J＝1.1Hz,1H),6.87(d,J＝0.8Hz,1H),6.82(t,J＝6.2Hz,2H),6.75(d,J＝9.2Hz,2H),3.71(s,3H),3.65(s,2H),3.18–3.06(m,4H),2.62–2.56(m,4H),2.44(s,3H；MS(ESI)m/z[M+H]+：427.68。Compound 28A (300 mg, 0.90 mmol), Compound 28B (90 mg, 0.82 mmol), ethyl acetate (2 ml), EtOAc. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Solid product 28 (142 mg, yield: 40.5%). 1H NMR (400MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.33 - 7.27 (m, 2H), 6.93 (d, J = 1.1 Hz, 1H), 6.87 (d, J = 0.8 Hz) , 1H), 6.82 (t, J = 6.2 Hz, 2H), 6.75 (d, J = 9.2 Hz, 2H), 3.71 (s, 3H), 3.65 (s, 2H), 3.18 - 3.06 (m, 4H) , 2.62 - 2.56 (m, 4H), 2.44 (s, 3H; MS (ESI) m/z [M+H] + : 427.68.
实施例29Example 29
Figure PCTCN2015100201-appb-000088
Figure PCTCN2015100201-appb-000088
在25ml圆底烧瓶中加入化合物29A(200mg,0.60mmol),化合物29B(52mg,0.55mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(139mg,0.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(30:1)为洗脱剂，得黄色油状产物29(90mg,产率：39.6％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.32(d,J＝8.1Hz,2H),6.89–6.83(m,2H),6.81–6.74(m,3H),6.16(dd,J＝5.8,2.8Hz,1H),6.08(s,1H),3.57(s,2H),3.22–3.08(m,4H),2.63–2.54(m,4H),2.46(s,3H)；MS(ESI)m/z[M]+：411.95。Compound 29A (200 mg, 0.60 mmol), Compound 29B (52 mg, 0.55 mmol), ethyl acetate (2 ml), EtOAc. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Oily product 29 (90 mg, yield: 39.6%). 1 H NMR (400MHz, CDCl 3 ) δ7.71 (d, J = 8.3Hz, 2H), 7.32 (d, J = 8.1Hz, 2H), 6.89-6.83 (m, 2H), 6.81-6.74 (m, 3H), 6.16 (dd, J=5.8, 2.8 Hz, 1H), 6.08 (s, 1H), 3.57 (s, 2H), 3.22–3.08 (m, 4H), 2.63–2.54 (m, 4H), 2.46 (s, 3H); MS (ESI) m/z [M] + : 411.95.
实施例30Example 30
Figure PCTCN2015100201-appb-000089
Figure PCTCN2015100201-appb-000089
在25ml圆底烧瓶中加入化合物30A(300mg,0.90mmol),化合物30B(129mg,0.82mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基 硼氢化钠(209mg,0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物30(121mg,产率：31.2％)。1H NMR(400MHz,CDCl3)δ8.88(d,J＝4.3Hz,1H),8.27(d,J＝8.4Hz,1H),8.15(d,J＝8.4Hz,1H),7.79–7.64(m,3H),7.58(ddd,J＝8.2,6.9,1.2Hz,1H),7.46(d,J＝4.4Hz,1H),7.30(d,J＝8.0Hz,2H),6.90–6.82(m,2H),6.82–6.74(m,2H),4.00(s,2H),3.23–3.13(m,4H),2.76–2.64(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：474.09。To a 25 ml round bottom flask was added compound 30A (300 mg, 0.90 mmol), Compound 30B (129 mg, 0.82 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (209 mg, 0.98 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 30 (121 mg, yield: 31.2%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (d, J = 4.3 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.79 - 7.64 (m, 3H), 7.58 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 6.90 - 6.82 ( m, 2H), 6.82–6.74 (m, 2H), 4.00 (s, 2H), 3.23–3.13 (m, 4H), 2.76–2.64 (m, 4H), 2.45 (s, 3H); MS (ESI) m/z [M+H] + : 474.09.
实施例31Example 31
Figure PCTCN2015100201-appb-000090
Figure PCTCN2015100201-appb-000090
在50mL圆底烧瓶中加入化合物31A(200mg，0.609mmol)，氯仿(6mL)，间氟苯磺酰氯31B(324μL，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)得到无色膏状产物31(257mg，产率86.7％)。1H NMR(400MHz,CDCl3)δ7.64–7.59(m,1H),7.56–7.46(m,2H),7.35(tdd,J＝8.3,2.5,0.9Hz,1H),6.91(d,J＝1.6Hz,1H),6.87–6.73(m,6H),3.89(s,3H),3.87(s,3H),3.49(s,2H),3.20–3.09(m,4H),2.63–2.50(m,4H)；MS(ESI)m/z[M+H]+：487.03。Compound 31A (200 mg, 0.609 mmol), chloroform (6 mL), m-fluorobenzenesulfonyl chloride 31B (324 μL, 2.44 mmol), pyridine (0.5 mL) was reacted in a 50 mL round bottom flask, and reacted in an oil bath at 65 ° C for 4 h. The solvent was evaporated to dryness. EtOAc EtOAc m. Colorless cream product 31 (257 mg, yield 86.7%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.64 - 7.59 (m, 1H), 7.56 - 7.46 (m, 2H), 7.35 (tdd, J = 8.3, 2.5, 0.9 Hz, 1H), 6.91 (d, J) =1.6 Hz, 1H), 6.87–6.73 (m, 6H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.20–3.09 (m, 4H), 2.63–2.50 ( m, 4H); MS (ESI ) m / z [m + H] +: 487.03.
实施例32Example 32
Figure PCTCN2015100201-appb-000091
Figure PCTCN2015100201-appb-000091
50mL圆底烧瓶中加入化合物32A(200mg，0.609mmol)，氯仿(6mL)，化合物32B(494mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)得到无色膏状产物32(175mg，产率58.1％)。1H NMR(400MHz,CDCl3)δ7.54–7.38(m,6H),7.15–7.09(m,2H),6.91(d,J＝1.5Hz,1H),6.88–6.79(m,5H),3.89(s,3H),3.87(s,3H),3.49(s,2H),3.21–3.12(m,4H),2.63–2.51(m,4H)；MS(ESI)m/z[M+H]+：495.05。In a 50 mL round bottom flask, compound 32A (200 mg, 0.609 mmol), chloroform (6 mL), Compound 32B (494 mg, 2.44 mmol), pyridine (0.5 mL) was reacted in an oil bath at 65 ° C for 4 h. The residue was added with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjjj 32 (175 mg, yield 58.1%). 1 H NMR (400MHz, CDCl 3 ) δ7.54-7.38 (m, 6H), 7.15-7.09 (m, 2H), 6.91 (d, J = 1.5Hz, 1H), 6.88-6.79 (m, 5H), 3.89(s,3H), 3.87(s,3H), 3.49(s,2H), 3.21–3.12(m,4H),2.63–2.51(m,4H);MS(ESI)m/z[M+H ] + :495.05.
实施例33Example 33
Figure PCTCN2015100201-appb-000092
Figure PCTCN2015100201-appb-000092
50mL圆底烧瓶中加入化合物33A(200mg，0.609mmol)，氯仿(6mL)，化合物33B(464mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)得到浅黄色膏状产物33(156mg，产率53.1％)。1H NMR(400MHz,CDCl3)δ7.48–7.38(m,5H),7.04–6.98(m,2H),6.92(d,J＝1.5Hz,1H),6.88–6.80(m,4H),4.47(s,2H),3.89(s,3H),3.88(s,3H),3.50(s,2H),3.22–3.12(m,4H),2.63–2.53(m,4H)；MS(ESI)m/z[M+H]+：483.11。In a 50 mL round bottom flask, compound 33A (200 mg, 0.609 mmol), chloroform (6 mL), Compound 33B (464 mg, 2.44 mmol), pyridine (0.5 mL) was reacted in an oil bath at 65 ° C for 4 h, and the solvent was evaporated. The residue was added with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjjj 33 (156 mg, yield 53.1%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 - 7.38 (m, 5H), 7.04 - 6.98 (m, 2H), 6.92 (d, J = 1.5 Hz, 1H), 6.88 - 6.80 (m, 4H), 4.47 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.50 (s, 2H), 3.22 - 3.12 (m, 4H), 2.63 - 2.53 (m, 4H); MS (ESI) m/z [M+H] + : 483.1.
实施例34Example 34
Figure PCTCN2015100201-appb-000093
Figure PCTCN2015100201-appb-000093
50mL圆底烧瓶中加入化合物34A(200mg，0.609mmol)，N,N二甲基甲酰胺(3mL)溶解，冰浴中搅拌5min，加入氢化钠(22mg，0.913mmol)，冰浴中搅拌10min后，升至室温搅拌30min，加入化合物34B(206μL，1.22mmol)，室温下搅拌过夜。加水，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇70:1)得到白色固体产物34(170mg，产率58.5％)。1H NMR(400MHz,CDCl3)δ7.18–7.12(m,2H),6.92(d,J＝1.6Hz,1H),6.91–6.80(m,4H),3.89(s,3H),3.88(s,3H),3.78–3.71(m,4H),3.50(s,2H),3.40–3.35(m,4H),3.21–3.15(m,4H),2.63–2.55(m,4H)；MS(ESI)m/z[M+H]+：478.18。Compound 34A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask, and N,N dimethylformamide (3 mL) was dissolved. The mixture was stirred for 5 min in ice-bath, and sodium hydride (22 mg, 0.913 mmol) was added, and the mixture was stirred for 10 min. After stirring to room temperature for 30 min, compound 34B (206 μL, 1.22 mmol) was added and stirred at room temperature overnight. The mixture was combined with EtOAc EtOAc. . 1 H NMR (400MHz, CDCl 3 ) δ7.18-7.12 (m, 2H), 6.92 (d, J = 1.6Hz, 1H), 6.91-6.80 (m, 4H), 3.89 (s, 3H), 3.88 ( s, 3H), 3.78–3.71 (m, 4H), 3.50 (s, 2H), 3.40–3.35 (m, 4H), 3.21–3.15 (m, 4H), 2.63–2.55 (m, 4H); ESI) m/z [M+H] + : 478.18.
实施例35Example 35
Figure PCTCN2015100201-appb-000094
Figure PCTCN2015100201-appb-000094
50mL圆底烧瓶中加入化合物35A(200mg，0.609mmol)，N,N二甲基甲酰胺(3mL)溶解，冰浴中搅拌5min，加入氢化钠(22mg，0.913mmol)，冰浴中搅拌10min，升至室温搅拌30min，加入化合物35B(131μL，1.22mmol)，室温下搅拌过夜。加水，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)分离纯化得到白色固体产物35(156mg，产率58.8％)。1H NMR(400MHz,CDCl3)δ7.19–7.12(m,2H),6.92(d,J＝1.5Hz,1H),6.90–6.80(m,4H),3.89(s,3H),3.88(s,3H),3.50(s,2H),3.22–3.14(m,4H),2.94(s,6H),2.63–2.54(m,4H)；MS(ESI)m/z[M+H]+：436.15。Compound 35A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask. N,N-dimethylformamide (3 mL) was dissolved, and stirred for 5 min in ice-bath, and sodium hydride (22 mg, 0.913 mmol) was added and stirred for 10 min. After stirring to room temperature for 30 min, compound 35B (131 uL, 1.22 mmol). The mixture was combined with EtOAc. EtOAc. %). 1 H NMR (400MHz, CDCl 3 ) δ7.19-7.12 (m, 2H), 6.92 (d, J = 1.5Hz, 1H), 6.90-6.80 (m, 4H), 3.89 (s, 3H), 3.88 ( s,3H), 3.50 (s, 2H), 3.22–3.14 (m, 4H), 2.94 (s, 6H), 2.63–2.54 (m, 4H); MS (ESI) m/z [M+H] + :436.15.
实施例36Example 36
Figure PCTCN2015100201-appb-000095
Figure PCTCN2015100201-appb-000095
50mL圆底烧瓶中加入化合物36A(200mg，0.609mmol)，N,N二甲基甲酰胺(3mL)溶解，冰浴中搅拌5min，加入氢化钠(22mg，0.913mmol)，冰浴中搅拌10min，升至室温搅拌30min，加入化合物36B(305mg，1.22mmol)，室温下搅拌过夜。加水，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)和制备TLC(二氯甲烷：甲醇50:1)分离纯化得到无色油状产物36(25mg，产率7.6％)。1H NMR(400MHz,CDCl3)δ7.21–7.15(m,2H),6.94–6.80(m,5H),3.90(s,3H),3.88(s,3H),3.77(d,J＝15.0Hz,1H),3.50(s,2H),3.24–3.11(m,5H),2.64–2.50(m,5H),2.46–2.35(m,1H),2.16–2.02(m,2H),1.96(d,J＝18.5Hz,1H),1.75–1.65(m,1H),1.49–1.40(m,1H),1.16(s,3H),0.90(s,3H)；MS(ESI)m/z[M+H]+：543.37。Compound 36A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask. N,N-dimethylformamide (3 mL) was dissolved, and stirred for 5 min in ice-cooled, sodium hydride (22 mg, 0.913 mmol). After stirring to room temperature for 30 min, compound 36B (305 mg, 1.22 mmol). The mixture was combined with EtOAc. Purification afforded the product 36 (25 mg, yield: 7. 1 H NMR (400MHz, CDCl 3 ) δ7.21-7.15 (m, 2H), 6.94-6.80 (m, 5H), 3.90 (s, 3H), 3.88 (s, 3H), 3.77 (d, J = 15.0 Hz, 1H), 3.50 (s, 2H), 3.24 - 3.11 (m, 5H), 2.64 - 2.50 (m, 5H), 2.46 - 2.35 (m, 1H), 2.16 - 2.02 (m, 2H), 1.96 ( d, J = 18.5 Hz, 1H), 1.75 - 1.65 (m, 1H), 1.49 - 1.40 (m, 1H), 1.16 (s, 3H), 0.90 (s, 3H); MS (ESI) m/z [ M+H] + : 543.37.
实施例37Example 37
Figure PCTCN2015100201-appb-000096
Figure PCTCN2015100201-appb-000096
50mL圆底烧瓶中加入化合物37A(200mg，0.609mmol)，溶于二氯甲烷(5mL)，再加入化合物37B(174μL，0.913mmol)， 三乙胺(127μL，0.913mmol)，室温下搅拌过夜。减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)分离纯化得到白色固体产物37(151mg，产率46.9％)。1H NMR(400MHz,CDCl3)δ7.92–7.83(m,4H),7.56–7.49(m,2H),7.49–7.41(m,4H),7.09–7.03(m,2H),6.90(d,J＝1.5Hz,1H),6.87–6.73(m,4H),3.88(s,3H),3.87(s,3H),3.48(s,2H),3.13–3.03(m,4H),2.60–2.50(m,4H)；MS(ESI)m/z[M+H]+：29.15。Compound 37A (200 mg, 0.609 mmol) was added to a 50 mL round-brown flask, and then dissolved in dichloromethane (5 mL), and then Compound 37B (174 μL, 0.913 mmol), triethylamine (127 μL, 0.913 mmol) was stirred at room temperature overnight. The solvent was evaporated to drynesshhhhhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Isolation and purification gave the product as a white solid (yield: 151 mg, 46.9%). 1 H NMR (400MHz, CDCl 3 ) δ 7.92–7.83 (m, 4H), 7.56–7.49 (m, 2H), 7.49–7.41 (m, 4H), 7.09–7.03 (m, 2H), 6.90 (d) , J=1.5 Hz, 1H), 6.87–6.73 (m, 4H), 3.88 (s, 3H), 3.87 (s, 3H), 3.48 (s, 2H), 3.13–3.03 (m, 4H), 2.60– 2.50 (m, 4H); MS (ESI) m / z [m + H] +: 29.15.
实施例38Example 38
Figure PCTCN2015100201-appb-000097
Figure PCTCN2015100201-appb-000097
50mL圆底烧瓶中加入化合物38A(200mg，0.609mmol)，氯仿(6mL)，化合物38B(616mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)分离纯化得到无色膏状产物38(244mg，产率73.6％)。1H NMR(400MHz,CDCl3)δ7.90–7.83(m,2H),7.75–7.68(m,2H),7.65–7.58(m,2H),7.53–7.40(m,3H),6.94–6.73(m,7H),3.88(s,3H),3.87(s,3H),3.49(s,2H),3.19–3.10(m,4H),2.62–2.50(m,4H)；MS(ESI)m/z[M+H]+：545.09。In a 50 mL round bottom flask, compound 38A (200 mg, 0.609 mmol), chloroform (6 mL), Compound 38B (616 mg, 2.44 mmol), pyridine (0.5 mL), A saturated aqueous solution of sodium hydrogencarbonate was added to the residue, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjj Product 38 (244 mg, yield 73.6%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.90–7.83 (m, 2H), 7.75–7.68 (m, 2H), 7.65–7.58 (m, 2H), 7.53–7.40 (m, 3H), 6.94–6.73 (m, 7H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.19 - 3.10 (m, 4H), 2.62 - 2.50 (m, 4H); MS (ESI) m /z[M+H] + :545.09.
实施例39Example 39
Figure PCTCN2015100201-appb-000098
Figure PCTCN2015100201-appb-000098
50mL圆底烧瓶中加入化合物39A(200mg，0.609mmol)，氯仿(6mL)，化合物39B(569mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇70:1)分离纯化得到类白色固体产物39(127mg，产率39.7％)。1H NMR(400MHz,CDCl3)δ7.76–7.70(m,2H),7.68–7.62(m,2H),7.55(brs,1H),6.91(d,J＝1.5Hz,1H),6.88–6.79(m,4H),6.78–6.71(m,2H),3.88(s,3H),3.87(s,3H),3.49(s,2H),3.19–3.09(m,4H),2.61–2.51(m,4H),2.22(s,3H)；MS(ESI)m/z[M+H]+：526.08。In a 50 mL round bottom flask, compound 39A (200 mg, 0.609 mmol), chloroform (6 mL), Compound 39B (569 mg, 2.44 mmol), pyridine (0.5 mL) was reacted in an oil bath at 65 ° C for 4 h. The residue was added with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjjjj Product 39 (127 mg, yield 39.7%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 - 7.70 (m, 2H), 7.68 - 7.62 (m, 2H), 7.55 (brs, 1H), 6.91 (d, J = 1.5 Hz, 1H), 6.88 - 6.79 (m, 4H), 6.78–6.71 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.19–3.09 (m, 4H), 2.61–2.51 ( m, 4H), 2.22 (s , 3H); MS (ESI) m / z [m + H] +: 526.08.
实施例40Example 40
Figure PCTCN2015100201-appb-000099
Figure PCTCN2015100201-appb-000099
50mL圆底烧瓶中加入化合物40A(200mg，0.609mmol)，氯仿(6mL)，化合物40A(572mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)分离纯化得到白色固体产物40(178mg，产率55.5％)。1H NMR(400MHz,CDCl3)δ7.36(d,J＝2.2Hz,1H),7.29–7.25(m,1H),6.95–6.74(m,8H),4.36–4.25(m,4H),3.89(s,3H),3.88(s,3H),3.49(s,2H),3.19–3.09(m,4H),2.61–2.51(m,4H)；MS(ESI)m/z[M+H]+：527.29。To a 50 mL round bottom flask was added compound 40A (200 mg, 0.609 mmol), chloroform (6 mL), Compound 40A (572 mg, 2.44 mmol), pyridine (0.5 mL), and reacted in a 65 ° C oil bath for 4 h. The residue was added with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated 40 (178 mg, yield 55.5%). 1 H NMR (400MHz, CDCl 3 ) δ7.36 (d, J = 2.2Hz, 1H), 7.29-7.25 (m, 1H), 6.95-6.74 (m, 8H), 4.36-4.25 (m, 4H), 3.89(s,3H), 3.88(s,3H), 3.49(s,2H), 3.19–3.09(m,4H),2.61–2.51(m,4H);MS(ESI)m/z[M+H ] + : 527.29.
实施例41Example 41
Figure PCTCN2015100201-appb-000100
Figure PCTCN2015100201-appb-000100
50mL圆底烧瓶中加入化合物41A(200mg，0.609mmol)，氯仿(6mL)，化合物41B(491mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)分离纯化得到浅黄色膏状产物41(220mg，产率73.2％)。1H NMR(400MHz,CDCl3)δ7.96–7.89(m,2H),7.84–7.77(m,2H),6.90(d,J＝1.6Hz,1H),6.87–6.73(m,6H),3.88(s,3H),3.87(s,3H),3.49(s,2H),3.20–3.11(m,4H),2.61–2.51(m,4H)；MS(ESI)m/z[M+H]+：494.09。In a 50 mL round bottom flask, compound 41A (200 mg, 0.609 mmol), chloroform (6 mL), Compound 41B (491 mg, 2.44 mmol), pyridine (0.5 mL), and reacted in an oil bath at 65 ° C for 4 h. The residue was added with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate was evaporated. The organic phase was combined, washed with water, dried over anhydrous sodium sulfate, and concentrated, then purified by silica gel column chromatography (dichloromethane: methanol 100:1) Product 41 (220 mg, yield 73.2%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 - 7.89 (m, 2H), 7.84 - 7.77 (m, 2H), 6.90 (d, J = 1.6 Hz, 1H), 6.87 - 6.73 (m, 6H), 3.88(s,3H), 3.87(s,3H), 3.49(s,2H), 3.20–3.11(m,4H),2.61–2.51(m,4H);MS(ESI)m/z[M+H ] + :494.09.
实施例42Example 42
Figure PCTCN2015100201-appb-000101
Figure PCTCN2015100201-appb-000101
50mL圆底烧瓶中加入化合物42A(200mg，0.609mmol)，氯仿(6mL)，化合物42B(635mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)分离纯化得到无色膏状产物42(263mg，产率78.2％)。1H NMR(400MHz,CDCl3)δ7.90–7.82(m,2H),7.36–7.29(m,2H),6.91(d,J＝1.6Hz,1H),6.88–6.73(m,6H),3.89(s,3H),3.87(s,3H),3.49(s,2H),3.19–3.11(m,4H),2.61–2.52(m,4H)；MS(ESI)m/z[M+H]+：553.13。To a 50 mL round bottom flask was added Compound 42A (200 mg, 0.609 mmol), chloroform (6 mL), Compound 42B (635 mg, 2.44 mmol), pyridine (0.5 mL), and reacted in an oil bath at 65 ° C for 4 h. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjj Product 42 (263 mg, yield 78.2%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 - 7.82 (m, 2H), 7.36 - 7.29 (m, 2H), 6.91 (d, J = 1.6 Hz, 1H), 6.88 - 6.73 (m, 6H), 3.89(s,3H), 3.87(s,3H), 3.49(s,2H), 3.19–3.11(m,4H),2.61–2.52(m,4H);MS(ESI)m/z[M+H ] + :553.13.
实施例43Example 43
Figure PCTCN2015100201-appb-000102
Figure PCTCN2015100201-appb-000102
50mL圆底烧瓶中加入化合物43A(200mg，0.609mmol)，氯仿(6mL)，化合物43B(657mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)分离纯化得到浅黄色固体产物43(80mg，产率23.4％)。1H NMR(400MHz,CDCl3)δ8.57(d,J＝8.5Hz,1H),8.47(d,J＝8.7Hz,1H),8.05(dd,J＝7.3,1.2Hz,1H),7.66(dd,J＝8.6,7.7Hz,1H),7.42(dd,J＝8.5,7.4Hz,1H),7.24(d,J＝7.5Hz,1H),6.89(d,J＝1.4Hz,1H),6.86–6.77(m,2H),6.77–6.70(m,2H),6.68–6.61(m,2H),3.87(s,3H),3.87(s,3H),3.46(s,2H),3.13–3.03(m,4H),2.91(s,6H),2.57–2.46(m,4H)；MS(ESI)m/z[M+H]+：562.13。In a 50 mL round bottom flask, compound 43A (200 mg, 0.609 mmol), chloroform (6 mL), Compound 43B (657 mg, 2.44 mmol), pyridine (0.5 mL) was reacted in an oil bath at 65 ° C for 4 h, and the solvent was evaporated to dryness under vacuo. The residue was added with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjjj Product 43 (80 mg, yield 23.4%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (d, J = 8.5 Hz, 1H), 8.47 (d, J = 8.7 Hz, 1H), 8.05 (dd, J = 7.3, 1.2 Hz, 1H), 7.66 (dd, J = 8.6, 7.7 Hz, 1H), 7.42 (dd, J = 8.5, 7.4 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H) , 6.86–6.77 (m, 2H), 6.77–6.70 (m, 2H), 6.68–6.61 (m, 2H), 3.87 (s, 3H), 3.87 (s, 3H), 3.46 (s, 2H), 3.13 -3.03 (m, 4H), 2.91 (s, 6H), 2.57 - 2.46 (m, 4H); MS (ESI) m/z [M+H]+: 562.
实施例44Example 44
Figure PCTCN2015100201-appb-000103
Figure PCTCN2015100201-appb-000103
50mL圆底烧瓶中加入化合物44A(200mg，0.609mmol)，氯仿(6mL)，化合物44B(518mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，减压蒸干溶剂，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇100:1)分离纯化得到无色膏状产物44(225mg，产率73.2％)。1H NMR(400MHz,CDCl3)δ7.82–7.73(m,1H),7.05–6.92(m,4H),6.90(d,J＝1.6Hz,1H),6.87–6.75(m,4H),3.88(s,3H),3.87(s,3H),3.48(s,2H),3.18–3.10(m,4H),2.60–2.51(m,4H)；MS(ESI)m/z[M+H]+：505.03。In a 50 mL round bottom flask, compound 44A (200 mg, 0.609 mmol), chloroform (6 mL), Compound 44B (518 mg, 2.44 mmol), pyridine (0.5 mL), and reacted in an oil bath at 65 ° C for 4 h. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjj Product 44 (225 mg, yield 73.2%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 - 7.73 (m, 1H), 7.05 - 6.92 (m, 4H), 6.90 (d, J = 1.6 Hz, 1H), 6.87 - 6.75 (m, 4H), 3.88(s,3H), 3.87(s,3H), 3.48(s,2H), 3.18–3.10(m,4H), 2.60–2.51(m,4H);MS(ESI)m/z[M+H ] + :505.03.
实施例45Example 45
Figure PCTCN2015100201-appb-000104
Figure PCTCN2015100201-appb-000104
50mL圆底烧瓶中加入化合物45A(200mg，0.609mmol)，用N,N-二甲基甲酰胺(3mL)溶解，冰浴中搅拌5min，加入氢化钠(22mg，0.913mmol)，冰浴中搅拌10min，升至室温搅拌30min，加入化合物45B(139μL，1.22mmol)，室温下搅拌过夜。加水，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(二氯甲烷：甲醇70:1)分离纯化得到白色固体产物45(157mg，产率58.4％)。1H NMR(400MHz,CDCl3)δ7.02–6.95(m,2H),6.94–6.80(m,5H),3.89(s,3H),3.88(s,3H),3.77–3.70(m,4H),3.70–3.52(m,4H),3.50(s,2H),3.21–3.11(m,4H),2.64–2.54(m,4H)；MS(ESI)m/z[M+H]+：442.13。Compound 45A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask, dissolved with N,N-dimethylformamide (3 mL), stirred for 5 min in ice bath, sodium hydride (22 mg, 0.913 mmol). After 10 min, the mixture was stirred at room temperature for 30 min, and then compound 45B ( 139 μL, 1.22 mmol). The mixture was combined with EtOAc. EtOAc. %). 1 H NMR (400MHz, CDCl 3 ) δ7.02-6.95 (m, 2H), 6.94-6.80 (m, 5H), 3.89 (s, 3H), 3.88 (s, 3H), 3.77-3.70 (m, 4H ), 3.70–3.52 (m, 4H), 3.50 (s, 2H), 3.21–3.11 (m, 4H), 2.64–2.54 (m, 4H); MS (ESI) m/z [M+H] + : 442.13.
实施例46Example 46
Figure PCTCN2015100201-appb-000105
Figure PCTCN2015100201-appb-000105
将46B(2g，11.7mmol)和46A(3g，35.1mmol)溶于20ml乙腈中，让后加入碳酸钾(3.23g，23.4mmol)，升温至100度回流反应3h。减压除去溶剂乙腈，加入30ml水用乙酸乙酯萃取两次，除去上两个苄基的杂质，然后用二氯甲烷萃取两次，合并二氯甲烷，用硫酸钠干燥后得到浅黄色产物46C(1.5g,产率75％)46B (2g, 11.7mmol) and 46A (3g, 35.1mmol) were dissolved in 20 ml of acetonitrile, then potassium carbonate (3.23 g, 23.4 mmol) was added, and the mixture was heated to 100 ° reflux for 3 h. The solvent acetonitrile was removed under reduced pressure, and then extracted with ethyl acetate (30 mL), EtOAc (EtOAc) (1.5g, yield 75%)
将46C(126.6mg，0.718mmol)和46D(200mg，0.653mmol)溶于1,2-二氯乙烷中，冰浴条件下缓慢加入三乙酰氧基硼氢化钠(208mg，0.980mmol)，升至室温反应5h后，经硅藻土过滤，减压除去溶剂后硅胶柱层析(二氯甲烷：甲醇＝20:1)，得到透明胶状固体46(105mg，34.5％)。1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.3Hz,2H),7.36–7.23(m,7H),7.06(d,J＝8.1Hz,1H),6.86(d,J＝1.7Hz,1H),6.83(dd,J＝8.2,1.8Hz,1H),3.58(s,3H),3.54(s,2H),3.46(s,2H),2.47(brs,8H),2.46(s,3H)；MS(ESI)m/z[M+H]+：467.18。46C (126.6 mg, 0.718 mmol) and 46D (200 mg, 0.653 mmol) were dissolved in 1,2-dichloroethane, and sodium triacetoxyborohydride (208 mg, 0.980 mmol) was slowly added in an ice bath. After reacting for 5 h at room temperature, EtOAc (EtOAc m.) 1 H NMR (400MHz, CDCl 3 ) δ7.77 (d, J = 8.3Hz, 2H), 7.36-7.23 (m, 7H), 7.06 (d, J = 8.1Hz, 1H), 6.86 (d, J = 1.7 Hz, 1H), 6.83 (dd, J = 8.2, 1.8 Hz, 1H), 3.58 (s, 3H), 3.54 (s, 2H), 3.46 (s, 2H), 2.47 (brs, 8H), 2.46 ( </RTI></RTI>< RTI ID=0.0></RTI></RTI><RTIgt;
实施例47Example 47
Figure PCTCN2015100201-appb-000106
Figure PCTCN2015100201-appb-000106
50mL圆底烧瓶中加入化合物47A(200mg，0.609mmol)，氯仿(6mL)，化合物47B(649mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经制备薄层层析(二氯甲烷：甲醇50:1)分离纯化得到类白色固体47(38mg，产率11.2％)。1H NMR(400MHz,CDCl3)δ7.07–6.99(m,2H),6.95–6.88(s,1H),6.88–6.77(m,4H),3.89(s,3H),3.88(s,3H),3.50(s,2H),3.26–3.11(m,4H),2.65–2.50(m,4H)；MS(ESI)m/z[M+H]+：559.00。Compound 47A (200 mg, 0.609 mmol), chloroform (6 mL), compound 47B (649 mg, 2.44 mmol), pyridine (0.5 mL), was reacted in a 65 ° C oil bath for 4 h, the reaction solution was dried, residue Adding a saturated aqueous solution of sodium hydrogencarbonate, extracting with ethyl acetate, EtOAc, EtOAc (EtOAc) An off-white solid 47 (38 mg, yield 11.2%) was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ 7.07–6.99 (m, 2H), 6.95–6.88 (s, 1H), 6.88–6.77 (m, 4H), 3.89 (s, 3H), 3.88 (s, 3H) ), 3.50 (s, 2H), 3.26 - 3.11 (m, 4H), 2.65 - 2.50 (m, 4H); MS (ESI) m/z [M+H] + : 559.
实施例48Example 48
Figure PCTCN2015100201-appb-000107
Figure PCTCN2015100201-appb-000107
在25ml圆底烧瓶中加入化合物48A(500mg，2.81mmol)，化合物48B(444mg，2.55mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧 基硼氢化钠(649mg，3.06mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(30:1)为洗脱剂，得白色固体产物48(347mg,产率：40.5％)。1H NMR(400MHz,CDCl3)δ7.85(d,J＝7.8Hz,1H),7.69(d,J＝7.8Hz,1H),7.55(t,J＝7.6Hz,1H),7.38(t,J＝7.6Hz,1H),6.89(d,J＝8.9Hz,2H),6.72(d,J＝8.8Hz,2H),3.79(s,2H),3.20–3.07(m,4H),2.82–2.67(m,4H)；MS(ESI)m/z[M+H]+：337.88。To a 25 ml round bottom flask was added compound 48A (500 mg, 2. <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The white solid product 48 (347 mg, yield: 40.5%). 1H NMR (400MHz, CDCl3) δ 7.85 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.38 (t, J) = 7.6 Hz, 1H), 6.89 (d, J = 8.9 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 3.79 (s, 2H), 3.20 - 3.07 (m, 4H), 2.82 - 2.67 (m, 4H); MS ( ESI) m / z [m + H] +: 337.88.
实施例49Example 49
Figure PCTCN2015100201-appb-000108
Figure PCTCN2015100201-appb-000108
在25ml圆底烧瓶中加入化合物49A(300mg,0.90mmol),化合物49B(124mg,0.82mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(209mg,0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得黄色固体产物49(164mg,产率：42.8％)。1H NMR(400MHz,CDCl3)δ8.20(d,J＝8.7Hz,2H),7.71(d,J＝8.3Hz,2H),7.56(d,J＝8.6Hz,2H),7.31(d,J＝8.1Hz,2H),6.91–6.83(m,2H),6.82–6.74(m,2H),3.66(s,2H),3.24–3.11(m,4H),2.66–2.56(m,4H),2.46(s,3H)；MS(ESI)m/z[M+H]+：468.02。Compound 49A (300 mg, 0.90 mmol), Compound 49B (124 mg, 0.82 mmol), ethyl acetate (2 ml), EtOAc. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. A yellow solid product 49 (164 mg, yield: 42.8%). 1 H NMR (400MHz, CDCl 3 ) δ8.20 (d, J = 8.7Hz, 2H), 7.71 (d, J = 8.3Hz, 2H), 7.56 (d, J = 8.6Hz, 2H), 7.31 (d , J=8.1Hz, 2H), 6.91–6.83 (m, 2H), 6.82–6.74 (m, 2H), 3.66 (s, 2H), 3.24–3.11 (m, 4H), 2.66–2.56 (m, 4H) ), 2.46 (s, 3H); MS (ESI) m/z [M+H] + : 468.
实施例50Example 50
Figure PCTCN2015100201-appb-000109
Figure PCTCN2015100201-appb-000109
在25ml圆底烧瓶中加入化合物50A(300mg,0.90mmol),化合物50B(135mg,0.82mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(209mg,0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(6:1)为洗脱剂，得白色固体产物50(174mg,产率：44.3％)。1H NMR(400MHz,CDCl3)δ8.02(d,J＝8.1Hz,2H),7.70(d,J＝8.2Hz,2H),7.44(d,J＝8.1Hz,2H),7.30(d,J＝8.4Hz,2H),6.90–6.81(m,2H),6.77(d,J＝9.1Hz,2H),3.93(s,3H),3.61(s,2H),3.21–3.11(m,4H),2.64–2.55(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：481.13。Compound 50A (300 mg, 0.90 mmol), compound 50B (135 mg, 0.82 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (209 mg, 0.98 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. To a white solid product 50 (174 mg, yield: 44.3%). 1 H NMR (400MHz, CDCl 3 ) δ8.02 (d, J = 8.1Hz, 2H), 7.70 (d, J = 8.2Hz, 2H), 7.44 (d, J = 8.1Hz, 2H), 7.30 (d , J = 8.4 Hz, 2H), 6.90 - 6.81 (m, 2H), 6.77 (d, J = 9.1 Hz, 2H), 3.93 (s, 3H), 3.61 (s, 2H), 3.21 - 3.11 (m, 4H), 2.64 - 2.55 (m, 4H), 2.45 (s, 3H); MS (ESI) m/z [M+H] + : 481.
实施例51Example 51
Figure PCTCN2015100201-appb-000110
Figure PCTCN2015100201-appb-000110
在25ml圆底烧瓶中加入化合物51A(300mg,0.90mmol),化合物51B(87mg,0.82mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(209mg,0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(10:1)为洗脱剂，得白色固体产物51(167mg,产率：48.1％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.36(s,2H),7.35(d,J＝2.2Hz,2H),7.32(dd,J＝7.3,3.5Hz,3H),6.88–6.83(m,2H),6.79–6.75(m,2H),3.59(s,2H),3.19–3.15(m,4H),2.63–2.59(m,4H),2.46(s,3H)；MS(ESI)m/z[M+H]+：423.57。Compound 51A (300 mg, 0.90 mmol), Compound 51B (87 mg, 0.82 mmol), ethyl acetate (2 ml), EtOAc (EtOAc) After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc) To a white solid product 51 (167 mg, yield: 48.1%). 1 H NMR (400MHz, CDCl 3 ) δ7.71 (d, J = 8.3Hz, 2H), 7.36 (s, 2H), 7.35 (d, J = 2.2Hz, 2H), 7.32 (dd, J = 7.3, 3.5Hz, 3H), 6.88–6.83 (m, 2H), 6.79–6.75 (m, 2H), 3.59 (s, 2H), 3.19–3.15 (m, 4H), 2.63–2.59 (m, 4H), 2.46 (s, 3H); MS ( ESI) m / z [m + H] +: 423.57.
实施例52Example 52
Figure PCTCN2015100201-appb-000111
Figure PCTCN2015100201-appb-000111
在25ml圆底烧瓶中加入化合物52A(300mg,0.90mmol),化合物52B(122mg,0.82mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(209mg,0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(2:1)为洗脱剂，得白色固体产物52(170mg,产率：44.5％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.31(d,J＝8.0Hz,2H),7.22(d,J＝8.6Hz,2H),6.90–6.82(m,2H),6.81–6.75(m,2H),6.73(d,J＝8.7Hz,2H),3.49(s,2H),3.19–3.11(m,4H),2.97(s,6H),2.64–2.54(m,4H),2.46(s,3H).MS(ESI)m/z[M+H]+：466.21。Compound 52A (300 mg, 0.90 mmol), compound 52B (122 mg, 0.82 mmol), ethyl acetate (2 ml), EtOAc. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. To a white solid product 52 (170 mg, yield: 44.5%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.90 - 6.82 (m, 2H), 6.81 - 6.75 (m, 2H), 6.73 (d, J = 8.7 Hz, 2H), 3.49 (s, 2H), 3.19 - 3.11 (m, 4H), 2.97 (s, 6H), 2.64 - 2.54 (m, 4H), 2.46 (s, 3H). MS (ESI) m/z [M+H] + : 466.21.
实施例53Example 53
Figure PCTCN2015100201-appb-000112
Figure PCTCN2015100201-appb-000112
100mL圆底烧瓶中加入化合物53A(1g，6.23mmol)，再依次加入DMF(25mL)，DMSO(5mL)搅拌溶解，再加入碳酸钾(1.72g，12.5mmol)，碘甲烷(426μL，6.85mmol)，在25℃油浴中搅拌16h。反应液加水，用乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到得到白色固体53B(700mg，产率64.4％)。Compound 53A (1 g, 6.23 mmol) was added to a 100 mL round bottom flask, followed by DMF (25 mL), DMSO (5 mL), and then dissolved, and then potassium carbonate (1.72 g, 12.5 mmol), iodomethane (426 μL, 6.85 mmol) Stir in a 25 ° C oil bath for 16 h. The reaction mixture was combined with EtOAc EtOAc EtOAc.
100mL圆底烧瓶中依次加入化合物53B(700mg，4.01mmol)，53C(1.12g，6.02mmol)，碳酸氢钠(674mg，8.02mmol)，分子筛(20颗)，乙醇(30mL)，在100℃油浴中回流10h。反应液抽滤，乙醇洗涤，滤液旋干，得到的残渣经柱层析(二氯甲烷：甲醇100:1)得到白色固体53D(697mg，产率53.6％)。Compound 53B (700 mg, 4.01 mmol), 53 C (1.12 g, 6.02 mmol), sodium hydrogencarbonate (674 mg, 8.02 mmol), molecular sieves (20), ethanol (30 mL), and oil at 100 ° C were added to a 100 mL round bottom flask. Reflux in the bath for 10 h. The reaction solution was suction filtered, washed with EtOAc EtOAcjjjjjjj
100mL圆底烧瓶中加入化合物53D(348mg，1.07mmol)，用二氯甲烷(8mL)溶解，加入TFA(2mL)，室温下搅拌过夜，反应液旋干，并加入二氯甲烷再次旋干，得到的无色油状物53E，直接用于下一步反应。The compound 53D (348 mg, 1.07 mmol) was added to a 100 mL round bottom flask, which was dissolved in dichloromethane (8 mL), EtOAc (2 mL). The colorless oil, 53E, was used directly in the next reaction.
50mL圆底烧瓶中加入化合物53E，再依次加入二氯甲烷(12mL)，三乙胺(447μL，3.21mmol)，化合物53F(264mg，1.07mmol)，室温搅拌2h，加入三乙酰氧基硼氢化钠(340mg，1.61mmol)，在25℃油浴中搅拌过夜。反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到白色固体53(316mg，产率65.0％)。1H NMR(400MHz,CDCl3)δ8.21(dd,J＝7.9,1.1Hz,1H),7.88–7.81(m,2H),7.70–7.65(m,1H),7.64–7.54(m,2H),7.54–7.45(m,3H),5.12(s,1H),3.85(s,2H),3.32(s,3H),3.31(s,3H),2.82–2.62(m,4H),2.50–2.30(m,4H)；MS(ESI)m/z[M+Na]+：477.00。Compound 53E was added to a 50 mL round bottom flask, followed by dichloromethane (12 mL), triethylamine (447 μL, 3.21 mmol), compound 53F (264 mg, 1.07 mmol), stirred at room temperature for 2 h, and sodium triacetoxyborohydride was added. (340 mg, 1.61 mmol), stirred in a 25 ° C oil bath overnight. The reaction mixture was evaporated to dryness. EtOAc m. 1) Purification by isolation gave a white solid (yield: 316 mg, yield: 65.0%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (dd, J = 7.9, 1.1 Hz, 1H), 7.88 - 7.81 (m, 2H), 7.70 - 7.65 (m, 1H), 7.64 - 7.54 (m, 2H) ), 7.54–7.45 (m, 3H), 5.12 (s, 1H), 3.85 (s, 2H), 3.32 (s, 3H), 3.31 (s, 3H), 2.82–2.62 (m, 4H), 2.50– 2.30 (m, 4H); MS (ESI) m / z [m + Na] +: 477.00.
实施例54Example 54
Figure PCTCN2015100201-appb-000113
Figure PCTCN2015100201-appb-000113
在25ml圆底烧瓶中加入化合物54C(400mg，1.22mmol)，二氯甲烷(2ml)，三乙胺(246mg，2.44mmol)，搅拌下加入化合物54D(222mg，1.34mmol)。室温下搅拌过夜，TLC检测原料反应完全。将反应体系浓缩后用水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(30:1)为洗脱剂，得白色固体产物54(266mg,，产率：47.5％)。1H NMR(400MHz,DMSO)δ8.01(d,J＝1.0Hz,1H),7.89(d,J＝0.9Hz,1H),6.92–6.88(m,2H),6.88–6.79(m,5H),3.73(d,J＝1.7Hz,6H),3.09(s,4H),2.54–2.49(m,2H),2.46(d,J＝4.2Hz,4H)；MS(ESI)m/z[M+H]+：459.04。 Compound 54C (400 mg, 1.22 mmol), methylene chloride (2 ml), triethylamine (246 mg, 2.44 mmol) was added to a 25 ml round bottom flask, and compound 54D (222 mg, 1.34 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was concentrated, diluted with water, EtOAc EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Product 54 (266 mg, yield: 47.5%). 1H NMR (400MHz, DMSO) δ 8.01 (d, J = 1.0 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 6.92 - 6.88 (m, 2H), 6.88 - 6.79 (m, 5H) , 3.73 (d, J = 1.7 Hz, 6H), 3.09 (s, 4H), 2.54 - 2.49 (m, 2H), 2.46 (d, J = 4.2 Hz, 4H); MS (ESI) m/z [M +H] + : 459.04.
实施例55Example 55
Figure PCTCN2015100201-appb-000114
Figure PCTCN2015100201-appb-000114
向25ml圆底烧瓶中加入55A(166mg,0.5mmol)和甲醇(10ml)，搅拌溶解后加入55B(82mg,0.5mmol)，于70℃搅拌过夜，TLC检测反应完全，浓缩后经硅胶柱层析得到化合物55(331mg,92％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.31(d,J＝8.1Hz,2H),6.89–6.73(m,4H),3.80–3.72(m,4H),3.22–3.10(m,4H),2.66–2.54(m,4H),2.49–2.36(m,11H),1.90(s,2H),1.78–1.69(m,2H)。Add 55A (166 mg, 0.5 mmol) and methanol (10 ml) to a 25 ml round bottom flask, stir and dissolve, then add 55B (82 mg, 0.5 mmol), and stir at 70 ° C overnight, complete the reaction by TLC, and then pass through silica gel column chromatography Compound 55 (331 mg, 92%) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ7.71 (d, J = 8.3Hz, 2H), 7.31 (d, J = 8.1Hz, 2H), 6.89-6.73 (m, 4H), 3.80-3.72 (m, 4H), 3.22–3.10 (m, 4H), 2.66–2.54 (m, 4H), 2.49–2.36 (m, 11H), 1.90 (s, 2H), 1.78–1.69 (m, 2H).
实施例56Example 56
Figure PCTCN2015100201-appb-000115
Figure PCTCN2015100201-appb-000115
50ml圆底烧瓶中加入56A(583mg，3.0mmol)，二氯甲烷(10ml)溶解，再加入加入草酰氯(426μl，5.0mmol)以及N,N-二甲基甲酰胺(1滴)，室温下反应过夜。蒸干溶剂和过量的草酰氯，得到粗品56B。Add 50A (583mg, 3.0mmol) to a 50ml round bottom flask, dissolve in dichloromethane (10ml), add oxalyl chloride (426μl, 5.0mmol) and N,N-dimethylformamide (1 drop) at room temperature The reaction was overnight. The solvent and excess oxalyl chloride were evaporated to give a crude material.
50ml圆底烧瓶中加入56C(665mg，2.0mmol)，二氯甲烷(10ml)溶解，再加入三乙胺(421μl，3.0mmol)。将粗品56B用二氯甲烷(5ml)溶解，缓慢滴加，室温反应过夜，TLC检测原料反应完全。浓缩后经硅胶柱层析(二氯甲烷：甲醇＝100:1)分离得化合物56D(500mg，产率49.2％)。1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.3Hz,2H),7.32(d,J＝8.1Hz,2H),7.12(d,J＝8.6Hz,2H),6.92–6.82(m,4H),6.82–6.75(m,2H),3.81(s,3H),3.77–3.75(m,2H),3.55–3.53(m,2H),3.12–3.09(m,4H),2.65(t,J＝7.4Hz,2H),2.47(s,3H),2.38–2.34(m,2H),2.02–1.94(m,2H)；MS(ESI)m/z[M+Na]+：531.04。A 50 ml round bottom flask was charged with 56 C (665 mg, 2.0 mmol), dichloromethane (10 ml), and then triethylamine (421 μl, 3.0 mmol). The crude product 56B was dissolved in dichloromethane (5 ml), slowly added dropwise, and allowed to react at room temperature overnight. After concentration, it was isolated by silica gel column chromatography (dichloromethanol:methanol=100:1) to afford compound 56D (500 mg, yield 49.2%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.92 - 6.82 (m, 4H), 6.82–6.75 (m, 2H), 3.81 (s, 3H), 3.77–3.75 (m, 2H), 3.55–3.53 (m, 2H), 3.12–3.09 (m, 4H), 2.65 (t, J = 7.4 Hz, 2H), 2.47 (s, 3H), 2.38 - 2.34 (m, 2H), 2.02 - 1.94 (m, 2H); MS (ESI) m/z [M+Na] + : 531.04.
在50ml圆底烧瓶中加入化合物56D(500mg，0.983mmol)，四氢呋喃(10ml)溶解，于0℃下缓慢加入LiAlH4(149mg，3.93mmol)，60℃下反应1h。冷却到室温后，用甲醇淬灭反应，最后加入少量的饱和NaHCO3(1ml)，淬灭完全后，加硅藻土过滤，甲醇洗涤滤饼，浓缩后经硅胶柱层析(二氯甲烷：甲醇＝100:1)分离得产物56(280mg，产率42.8％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.31(d,J＝8.1Hz,2H),7.11(d,J＝8.5Hz,2H),6.87–6.83(m,4H),6.79–6.77(m,2H),3.81(s,3H),3.17–3.15(m,4H),2.62–2.56(m,6H),2.46(s,3H),2.43–2.39(m,2H),1.64–1.52(m,4H)；MS(ESI)m/z[M+H]+：495.13。Compound 56D (500 mg, 0.983 mmol), tetrahydrofuran (10 ml) was dissolved in a 50 ml round bottom flask, and LiAlH 4 (149 mg, 3.93 mmol) was slowly added at 0 ° C, and reacted at 60 ° C for 1 h. After cooling to room temperature, the reaction was quenched with methanol, and finally a small amount of saturated NaHCO 3 (1ml), after the complete quenching, plus filtered through Celite, the filter cake was washed with methanol, concentrated in vacuo purified by silica gel column chromatography (methylene chloride: Methanol = 100:1) product 56 (280 mg, yield 42.8%) was isolated. 1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.87 - 6.83 (m, 4H), 6.79–6.77 (m, 2H), 3.81 (s, 3H), 3.17–3.15 (m, 4H), 2.62–2.56 (m, 6H), 2.46 (s, 3H), 2.43–2.39 (m, 2H), 1.64 - 1.52 (m, 4H); MS (ESI) m/z [M+H] + : 495.
实施例57Example 57
Figure PCTCN2015100201-appb-000116
Figure PCTCN2015100201-appb-000116
50ml圆底烧瓶中加入57A(225mg，1.5mmol)，二氯甲烷(10ml)溶解，再加入草酰氯(213μl，2.5mmol)以及N,N-二甲基甲酰胺(1滴)，室温下反应过夜。蒸干溶剂和过量的草酰氯，得到粗品57B。57A (225mg, 1.5mmol) was added to a 50ml round bottom flask, dissolved in dichloromethane (10ml), then oxalyl chloride (213μl, 2.5mmol) and N,N-dimethylformamide (1 drop) were added and reacted at room temperature. overnight. The solvent and an excess of oxalyl chloride were evaporated to give a crude material.
在50ml圆底烧瓶中加入57C(332mg，1.0mmol)，二氯甲烷(10ml)溶解，然后加入三乙胺(209μl，1.5mmol)。将粗品57B用二氯甲烷(5ml)溶解，缓慢滴加，室温反应过夜。TLC检测原料反应完全。浓缩后经硅胶柱层析(二氯甲烷：甲醇＝100:1)分离得化 合物57D(350mg，产率75.3％)。Into a 50 ml round bottom flask was added 57 C (332 mg, 1.0 mmol), methylene chloride (10 ml), and then triethylamine (209 μl, 1.5 mmol). The crude product 57B was dissolved in dichloromethane (5 ml), slowly added dropwise and allowed to react at room temperature overnight. The TLC detects the reaction of the starting material completely. After concentration, it was separated by silica gel column chromatography (dichloromethane:methanol=100:1). Compound 57D (350 mg, yield 75.3%).
在50ml圆底烧瓶中加入57D(350mg，0.753mmol)，四氢呋喃(10ml)溶解，于0℃下缓慢加入LiAlH4(114mg，3.01mmol)，60℃下反应1h。冷却到室温后，用甲醇淬灭反应，最后加入少量的饱和NaHCO3(1ml)，淬灭完全后，加硅藻土过滤，甲醇洗涤滤饼，浓缩后经硅胶柱层析(二氯甲烷：甲醇＝100:1)分离得产物57(200mg，产率59.0％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.32–7.29(m,4H),7.23-7.19(m,3H),6.88–6.84(m,2H),6.80–6.76(m,2H),3.18–3.16(m,4H),2.70–2.66(m,2H),2.60–2.58(m,4H),2.46(s,3H),2.46-2.42(m,2H),1.91-1.84(m,2H)；MS(ESI)m/z[M+H]+：451.20。57D (350 mg, 0.753 mmol) was added to a 50 ml round bottom flask, and tetrahydrofuran (10 ml) was dissolved. LiAlH 4 (114 mg, 3.01 mmol) was slowly added at 0 ° C, and reacted at 60 ° C for 1 h. After cooling to room temperature, the reaction was quenched with methanol, and finally a small amount of saturated NaHCO 3 (1ml), after the complete quenching, plus filtered through Celite, the filter cake was washed with methanol, concentrated in vacuo purified by silica gel column chromatography (methylene chloride: Methanol = 100:1) Isolated product 57 (200 mg, yield 59.0%). 1 H NMR (400MHz, CDCl 3 ) δ 7.71 (d, J = 8.3 Hz, 2H), 7.32 - 7.29 (m, 4H), 7.23-7.19 (m, 3H), 6.88 - 6.84 (m, 2H), 6.80–6.76 (m, 2H), 3.18–3.16 (m, 4H), 2.70–2.66 (m, 2H), 2.60–2.58 (m, 4H), 2.46 (s, 3H), 2.46-2.42 (m, 2H) ), 1.91-1.84 (m, 2H); MS (ESI) m/z [M+H] + : 451.20.
实施例58Example 58
Figure PCTCN2015100201-appb-000117
Figure PCTCN2015100201-appb-000117
在25ml圆底烧瓶中加入化合物58A(249mg,1.52mmol),化合物58B(300mg,1.38mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(351mg,1.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物58(202mg,产率：37.2％)。1H NMR(400MHz,CDCl3)δ8.25(dd,J＝9.9,6.3Hz,3H),7.90–7.82(m,2H),7.78(d,J＝7.7Hz,1H),7.60(t,J＝7.5Hz,1H),7.53(t,J＝7.3Hz,1H),7.47(q,J＝7.1Hz,3H),6.45(t,J＝4.7Hz,1H),3.80(s,2H),3.67–3.57(m,4H),2.32–2.24(m,4H)；MS(ESI)m/z[M]+：394.88。Compound 58A (249 mg, 1.52 mmol), compound 58B (300 mg, 1.38 mmol), ethyl acetate (2 ml), and ethyl triacetoxyborohydride (351 mg, 1.66 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 58 (202 mg, yield: 37.2%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.25 (dd, J = 9.9, 6.3 Hz, 3H), 7.90 - 7.82 (m, 2H), 7.78 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.3 Hz, 1H), 7.47 (q, J = 7.1 Hz, 3H), 6.45 (t, J = 4.7 Hz, 1H), 3.80 (s, 2H) , 3.67 - 3.57 (m, 4H), 2.32 - 2.24 (m, 4H); MS (ESI) m/z [M] + : 394.88.
实施例59Example 59
Figure PCTCN2015100201-appb-000118
Figure PCTCN2015100201-appb-000118
在25ml圆底烧瓶中加入化合物59A(180mg,1.10mmol),化合物59B(300mg,098mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(254mg,1.20mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得无色油状产物59(157mg,产率：35.3％)。1H NMR(400MHz,CDCl3)δ8.28(d,J＝4.7Hz,2H),7.74(d,J＝8.3Hz,2H),7.33–7.25(m,2H),7.07(d,J＝8.1Hz,1H),6.89(d,J＝1.6Hz,1H),6.84(dd,J＝8.2,1.7Hz,1H),6.47(t,J＝4.7Hz,1H),3.87–3.78(m,4H),3.56(s,3H),3.47(s,2H),2.49–2.45(m,4H),2.43(s,3H)；MS(ESI)m/z[M+H]+：455.08。Compound 59A (180 mg, 1.10 mmol), compound 59B (300 mg, 098 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (254 mg, 1.20 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The product (59 mg, yield: 35.3%) was obtained as colorless oil. 1 H NMR (400MHz, CDCl 3 ) δ8.28 (d, J = 4.7Hz, 2H), 7.74 (d, J = 8.3Hz, 2H), 7.33-7.25 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H), 6.84 (dd, J = 8.2, 1.7 Hz, 1H), 6.47 (t, J = 4.7 Hz, 1H), 3.87 - 3.78 (m, 4H), 3.56 (s, 3H), 3.47 (s, 2H), 2.49 - 2.45 (m, 4H), 2.43 (s, 3H); MS (ESI) m/z [M+H] + : 455.08.
实施例60Example 60
Figure PCTCN2015100201-appb-000119
Figure PCTCN2015100201-appb-000119
在25ml圆底烧瓶中加入化合物60A(284mg,1.52mmol),化合物60B(300mg,1.38mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(351mg,1.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(1:1)为洗脱剂，得无色油状产物60(219mg,产率：38.1％)。1H NMR(400MHz,CDCl3)δ8.25(dd,J＝7.9,1.2Hz,1H),7.87(dd,J＝7.2,1.5Hz,2H),7.74(d,J＝7.2Hz,1H),7.58(ddd,J＝8.2,6.1,4.2Hz,2H),7.54–7.43(m,5H),6.98(td,J＝7.6,0.8Hz,1H),6.92(d,J＝8.3Hz,1H),3.84(s,2H),3.09–2.93(m,4H),2.52–2.35(m,4H)；MS(ESI)m/z[M]+：417.94。 Compound 60A (284 mg, 1.52 mmol), Compound 60B (300 mg, 1.38 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (351 mg, 1.66 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The product was obtained as a colorless oily product (yield: 219 mg, yield: 38.1%). 1 H NMR (400MHz, CDCl 3 ) δ8.25 (dd, J = 7.9,1.2Hz, 1H), 7.87 (dd, J = 7.2,1.5Hz, 2H), 7.74 (d, J = 7.2Hz, 1H) , 7.58 (ddd, J = 8.2, 6.1, 4.2 Hz, 2H), 7.54 - 7.43 (m, 5H), 6.98 (td, J = 7.6, 0.8 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H) ), 3.84 (s, 2H), 3.09 - 2.93 (m, 4H), 2.52 - 2.35 (m, 4H); MS (ESI) m/z [M] + : 417.94.
实施例61Example 61
Figure PCTCN2015100201-appb-000120
Figure PCTCN2015100201-appb-000120
在25ml圆底烧瓶中加入化合物61A(206mg,1.10mmol),化合物61B(300mg,0.98mmol),乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(254mg,1.20mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(1:1)为洗脱剂，得白色固体产物61(206mg,产率：44.1％)。1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.3Hz,2H),7.58(dd,J＝7.9,1.6Hz,1H),7.50(dd,J＝12.5,4.9Hz,1H),7.33(d,J＝8.1Hz,2H),7.09(d,J＝8.5Hz,1H),7.03(dd,J＝7.8,4.9Hz,2H),6.89(d,J＝6.9Hz,2H),3.61(s,3H),3.54(s,2H),3.25(s,4H),2.67(s,4H),2.47(s,3H)；MS(ESI)m/z[M+H]+：478.04。Compound 61A (206 mg, 1.10 mmol), compound 61B (300 mg, 0.98 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (254 mg, 1.20 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The product was obtained as a white solid (yield: &lt;RTIgt; 1 H NMR (400MHz, CDCl 3 ) δ7.79 (d, J = 8.3Hz, 2H), 7.58 (dd, J = 7.9,1.6Hz, 1H), 7.50 (dd, J = 12.5,4.9Hz, 1H) , 7.33 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.5 Hz, 1H), 7.03 (dd, J = 7.8, 4.9 Hz, 2H), 6.89 (d, J = 6.9 Hz, 2H) , 3.61 (s, 3H), 3.54 (s, 2H), 3.25 (s, 4H), 2.67 (s, 4H), 2.47 (s, 3H); MS (ESI) m/z [M+H] + : 478.04.
实施例62Example 62
Figure PCTCN2015100201-appb-000121
Figure PCTCN2015100201-appb-000121
在25ml圆底烧瓶中加入化合物62A(249mg，1.52mmol)，化合物62B(300mg,1.38mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(351mg，1.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物62(228mg,产率：41.9％)。1H NMR(400MHz,CDCl3)δ8.33(dd,J＝15.8,4.7Hz,3H),8.01–7.96(m,2H),7.93(d,J＝8.4Hz,2H),7.53(dt,J＝6.9,3.1Hz,4H),6.50(t,J＝4.7Hz,1H),3.85–3.81(m,4H),3.59(s,2H),2.53–2.47(m,4H)；MS(ESI)m/z[M+H]+：395.07。Compound 62A (249 mg, 1.52 mmol), Compound 62B (300 mg, 1.38 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (351 mg, 1.66 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a white solid (yield: 228mg, yield: 41.9%). 1 H NMR (400MHz, CDCl 3 ) δ8.33 (dd, J = 15.8,4.7Hz, 3H), 8.01-7.96 (m, 2H), 7.93 (d, J = 8.4Hz, 2H), 7.53 (dt, J = 6.9, 3.1 Hz, 4H), 6.50 (t, J = 4.7 Hz, 1H), 3.85 - 3.81 (m, 4H), 3.59 (s, 2H), 2.53 - 2.47 (m, 4H); MS (ESI) ) m/z [M+H] + : 395.07.
实施例63Example 63
Figure PCTCN2015100201-appb-000122
Figure PCTCN2015100201-appb-000122
在25ml圆底烧瓶中加入化合物63A(162mg，0.99mmol)，化合物63B(200mg，0.92mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(234mg，1.10mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(3:1)为洗脱剂，得白色固体产物化合物63(163mg,产率：45.1％)。1H NMR(400MHz,CDCl3)δ8.26(dd,J＝7.9,1.1Hz,1H),8.18(dd,J＝4.9,1.2Hz,1H),7.95–7.85(m,2H),7.81(d,J＝7.6Hz,1H),7.62(td,J＝7.6,1.2Hz,1H),7.59–7.41(m,5H),6.68–6.54(m,2H),3.83(s,2H),3.48–3.29(m,4H),2.45–2.29(m,4H)；MS(ESI)m/z[M+H]+：394.27Compound 63A (162 mg, 0.99 mmol), compound 63B (200 mg, 0.92 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (234 mg, 1.10 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The compound was obtained as a white solid (yield: 163 mg, yield: 45.1%). 1 H NMR (400MHz, CDCl 3 ) δ8.26 (dd, J = 7.9,1.1Hz, 1H), 8.18 (dd, J = 4.9,1.2Hz, 1H), 7.95-7.85 (m, 2H), 7.81 ( d, J = 7.6 Hz, 1H), 7.62 (td, J = 7.6, 1.2 Hz, 1H), 7.59 - 7.41 (m, 5H), 6.68 - 6.54 (m, 2H), 3.83 (s, 2H), 3.48 – 3.29 (m, 4H), 2.45–2.29 (m, 4H); MS (ESI) m/z [M+H] + : 394.27
实施例64Example 64
Figure PCTCN2015100201-appb-000123
Figure PCTCN2015100201-appb-000123
在25ml圆底烧瓶中加入化合物64A(176mg，1.08mmol)，化合物64B(300mg,0.98mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(250mg，1.18mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取， 合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(1:1)为洗脱剂，得无色油状产物化合物64(189mg,产率：42.6％)。1H NMR(400MHz,CDCl3)δ8.19(dd,J＝4.9,1.4Hz,1H),7.77(d,J＝8.3Hz,2H),7.48(ddd,J＝8.8,7.2,2.0Hz,1H),7.30(d,J＝8.1Hz,2H),7.09(d,J＝8.1Hz,1H),6.91(d,J＝1.5Hz,1H),6.86(dd,J＝8.2,1.7Hz,1H),6.69–6.59(m,2H),3.58(s,3H),3.57–3.53(m,4H),3.50(s,2H),2.57–2.51(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：454.28。Compound 64A (176 mg, 1.08 mmol), compound 64B (300 mg, 0.98 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (250 mg, 1.18 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The compound was obtained as a colorless oily compound 64 (189 mg, yield: 42.6%). 1 H NMR (400MHz, CDCl 3 ) δ8.19 (dd, J = 4.9,1.4Hz, 1H), 7.77 (d, J = 8.3Hz, 2H), 7.48 (ddd, J = 8.8,7.2,2.0Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 6.86 (dd, J = 8.2, 1.7 Hz, 1H), 6.69–6.59 (m, 2H), 3.58 (s, 3H), 3.57–3.53 (m, 4H), 3.50 (s, 2H), 2.57–2.51 (m, 4H), 2.45 (s, 3H) ;MS (ESI) m/z [M+H] + : 454.28.
实施例65Example 65
Figure PCTCN2015100201-appb-000124
Figure PCTCN2015100201-appb-000124
在25ml圆底烧瓶中加入化合物65A(200mg,0.64mmol)，化合物65B(126mg,0.58mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(148mg,0.69mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(4:1)为洗脱剂，得白色固体产物化合物65(144mg，产率：45.6％)。1H NMR(400MHz,CDCl3)δ8.27(dd,J＝7.9,1.2Hz,1H),7.94–7.87(m,2H),7.78(d,J＝7.3Hz,1H),7.65–7.56(m,2H),7.55–7.47(m,3H),7.39(dd,J＝8.7,2.6Hz,1H),7.25(d,J＝2.6Hz,1H),7.19(d,J＝8.6Hz,1H),7.16–7.06(m,3H),7.04–6.97(m,1H),3.87(s,2H),3.45-3.25(m,4H),2.45-2.25(m,4H)；MS(ESI)m/z[M+H]+：544.23。Compound 65A (200 mg, 0.64 mmol), compound 65B (126 mg, 0.58 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (148 mg, 0.69 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc) The compound was obtained as a white solid (yield: 144 mg, yield: 45.6%). 1 H NMR (400MHz, CDCl 3 ) δ8.27 (dd, J = 7.9,1.2Hz, 1H), 7.94-7.87 (m, 2H), 7.78 (d, J = 7.3Hz, 1H), 7.65-7.56 ( m, 2H), 7.55 - 7.47 (m, 3H), 7.39 (dd, J = 8.7, 2.6 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H) ), 7.16–7.06 (m, 3H), 7.04–6.97 (m, 1H), 3.87 (s, 2H), 3.45-3.25 (m, 4H), 2.45-2.25 (m, 4H); MS (ESI) m /z[M+H] + :544.23.
实施例66Example 66
Figure PCTCN2015100201-appb-000125
Figure PCTCN2015100201-appb-000125
在25ml圆底烧瓶中加入化合物66A(200mg，0.64mmol)，化合物66B(96.3mg，0.58mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(148mg，0.69mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(3:1)为洗脱剂，得白色固体产物化合物66(106mg,，产率：39.6％)。1H NMR(400MHz,CDCl3)δ7.38(dd,J＝8.6,2.6Hz,1H),7.33(d,J＝2.6Hz,1H),7.22–7.14(m,2H),7.13–7.06(m,2H),6.99(td,J＝7.6,1.7Hz,1H),6.95(d,J＝1.6Hz,1H),6.88(dd,J＝8.2,1.7Hz,1H),6.84(d,J＝8.1Hz,1H),3.91(s,3H),3.89(s,3H),3.65-3.45(m,4H),3.53(s,2H),2.65-2.45(s,4H)；MS(ESI)m/z[M+H]+：464.30。Compound 66A (200 mg, 0.64 mmol), compound 66B (96.3 mg, 0.58 mmol), ethyl acetate (2 ml), and ethyl triacetoxyborohydride (148 mg, 0.69 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The compound was obtained as a white solid (yield: Compound: 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (dd, J = 8.6, 2.6 Hz, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.22 - 7.14 (m, 2H), 7.13 - 7.06 ( m, 2H), 6.99 (td, J = 7.6, 1.7 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.88 (dd, J = 8.2, 1.7 Hz, 1H), 6.84 (d, J) = 8.1 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.65-3.45 (m, 4H), 3.53 (s, 2H), 2.65-2.45 (s, 4H); MS (ESI) m/z [M+H] + : 464.30.
实施例67Example 67
Figure PCTCN2015100201-appb-000126
Figure PCTCN2015100201-appb-000126
在25ml圆底烧瓶中加入化合物67A(200mg，0.64mmol)，化合物67B(177mg，0.58mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(148mg，0.69mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(3:1)为洗脱剂，得白色固体产物67(146mg,产率：41.7％)。1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.3Hz,2H),7.40(dd,J＝8.6,2.6Hz,1H),7.32(d,J＝9.0Hz,3H),7.20(d,J＝8.6Hz,1H),7.16(dd,J＝7.7,1.5Hz,1H),7.14–7.06(m,3H),7.00(td,J＝7.6,1.7Hz,1H),6.92(d,J＝1.4Hz,1H),6.87(d,J＝8.2Hz,1H),3.59(s,3H),3.58-3.51(m,4H),3.53(s,2H),2.65-2.51(m,4H),2.46(s,3H)；MS(ESI)m/z[M+H]+：604.25。 Compound 67A (200 mg, 0.64 mmol), compound 67B (177 mg, 0.58 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (148 mg, 0.69 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The product was obtained as a white solid (yield: 146 mg, yield: 41.7%). 1 H NMR (400MHz, CDCl 3 ) δ7.78 (d, J = 8.3Hz, 2H), 7.40 (dd, J = 8.6,2.6Hz, 1H), 7.32 (d, J = 9.0Hz, 3H), 7.20 (d, J = 8.6 Hz, 1H), 7.16 (dd, J = 7.7, 1.5 Hz, 1H), 7.14 - 7.06 (m, 3H), 7.00 (td, J = 7.6, 1.7 Hz, 1H), 6.92 ( d, J = 1.4 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 3.59 (s, 3H), 3.58-3.51 (m, 4H), 3.53 (s, 2H), 2.65-2.51 (m , 4H), 2.46 (s, 3H); MS (ESI) m/z [M+H] + : 604.25.
实施例68Example 68
Figure PCTCN2015100201-appb-000127
Figure PCTCN2015100201-appb-000127
100mL圆底烧瓶中依次加入68A(参考实施例16的方法制备得到)(104mg，0.280mmol)，钯碳(10mg)，乙醇(20mL)，在氢气氛围下室温，常压搅拌过夜。反应液抽滤，甲醇洗涤，合并滤液，旋干，得到浅棕色膏状物68B。直接用于下一步反应。Into a 100 mL round bottom flask, 68A (prepared by the method of Example 16) (104 mg, 0.280 mmol), palladium carbon (10 mg), and ethanol (20 mL) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction solution was suction filtered, washed with methanol, and the filtrate was evaporated and evaporated. Used directly in the next step.
50mL圆底烧瓶中加入68B，溶于二氯甲烷(10mL)，加入三乙胺(46μL，0.329mmol)，68C(50mg，0.264mmol)，室温下搅拌过夜，反应液旋干，残渣加饱和碳酸氢钠水溶液和乙酸乙酯萃取，有机相用无水硫酸钠干燥，旋干，得到的残渣经制备TLC(二氯甲烷：甲醇50:1)分离纯化得到无色膏状物化合物68(41mg，产率28.0％)。1H NMR(400MHz,CDCl3)δ7.52–7.47(m,2H),7.26–7.20(m,2H),6.93–6.84(m,4H),6.84–6.76(m,3H),4.05(d,J＝13.0Hz,1H),3.90(s,3H),3.88(s,3H),3.53(q,J＝7.1Hz,2H),3.46–3.39(m,1H),3.39–3.31(m,1H),3.13(d,J＝13.1Hz,1H),2.92–2.78(m,2H),2.72(dd,J＝11.4,9.3Hz,1H),2.64–2.54(m,1H),2.41(s,3H),2.25(td,J＝11.0,3.1Hz,1H),1.23(d,J＝6.1Hz,3H),1.05(t,J＝7.1Hz,3H)；MS(ESI)m/z[M+H]+：524.27。Add 68B to a 50 mL round bottom flask, dissolve in dichloromethane (10 mL), add triethylamine (46 μL, 0.329 mmol), 68 C (50 mg, 0.264 mmol), stir at room temperature overnight, and then spin to dryness. The aqueous solution of sodium hydrogencarbonate and ethyl acetate were extracted, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Yield 28.0%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 - 7.47 (m, 2H), 7.26 - 7.20 (m, 2H), 6.93 - 6.84 (m, 4H), 6.84 - 6.76 (m, 3H), 4.05 (d) , J = 13.0 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.53 (q, J = 7.1 Hz, 2H), 3.46 - 3.39 (m, 1H), 3.39 - 3.31 (m, 1H), 3.13 (d, J = 13.1 Hz, 1H), 2.92 - 2.78 (m, 2H), 2.72 (dd, J = 11.4, 9.3 Hz, 1H), 2.64 - 2.54 (m, 1H), 2.41 (s) , 3H), 2.25 (td, J = 11.0, 3.1 Hz, 1H), 1.23 (d, J = 6.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); MS (ESI) m/z [ M+H] + : 524.27.
实施例69Example 69
Figure PCTCN2015100201-appb-000128
Figure PCTCN2015100201-appb-000128
100mL圆底烧瓶中依次加入69A(参考实施例16的方法制备得到)(102mg，0.275mmol)，钯碳(25mg)，乙醇(20mL)，在氢气氛围下室温，常压搅拌过夜。反应液抽滤，甲醇洗涤，合并滤液，旋干，得到浅棕色膏状物69B。直接用于下一步反应。Into a 100 mL round bottom flask, 69A (prepared by the method of Example 16) (102 mg, 0.275 mmol), palladium carbon (25 mg), ethanol (20 mL) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere at room temperature overnight. The reaction solution was suction filtered, washed with methanol, and the filtrate was evaporated and evaporated. Used directly in the next step.
50mL圆底烧瓶中加入69B，溶于二氯甲烷(10mL)，加入三乙胺(66μL，0.470mmol)，69C(72mg，0.376mmol)，室温下搅拌过夜，反应液旋干，残渣加饱和碳酸氢钠水溶液和乙酸乙酯萃取，有机相用无水硫酸钠干燥，旋干，得到的残渣经制备TLC(二氯甲烷：甲醇50:1)分离纯化得到无色膏状物化合物69(53mg，产率36.8％)。1H NMR(400MHz,CDCl3)δ7.56–7.50(m,2H),7.26–7.22(m,2H),7.10–6.70(m,5H),6.59–6.52(m,2H),3.91(s,3H),3.88(s,3H),3.80–3.57(m,2H),3.57–3.43(m,4H),2.98–2.52(m,4H),2.42(s,3H),2.19–1.86(m,2H),1.78–1.46(m,2H),1.06(t,J＝7.1Hz,3H)；MS(ESI)m/z[M+H]+：524.19。Add 50B to a 50 mL round bottom flask, dissolve in dichloromethane (10 mL), add triethylamine (66 μL, 0.470 mmol), 69 C (72 mg, 0.376 mmol), stir at room temperature overnight, the reaction solution is dried, and the residue is saturated with carbonic acid. The aqueous solution of sodium hydrogencarbonate and ethyl acetate were extracted, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness, and the obtained residue was purified by preparative TLC (dichloromethane:methanol 50:1) Yield 36.8%). 1 H NMR (400MHz, CDCl 3 ) δ 7.56–7.50 (m, 2H), 7.26–7.22 (m, 2H), 7.10–6.70 (m, 5H), 6.59–6.52 (m, 2H), 3.91 (s) , 3H), 3.88 (s, 3H), 3.80–3.57 (m, 2H), 3.57–3.43 (m, 4H), 2.98–2.52 (m, 4H), 2.42 (s, 3H), 2.19–1.86 (m) , 2H), 1.78 - 1.46 (m, 2H), 1.06 (t,J = 7.1 Hz, 3H); MS (ESI) m/z [M+H] + : 524.19.
实施例70Example 70
Figure PCTCN2015100201-appb-000129
Figure PCTCN2015100201-appb-000129
50mL圆底烧瓶中加入化合物70A(200mg，0.609mmol)，用二氯甲烷(10mL)溶解，置于冰浴中，搅拌5min，加入吡啶(0.5mL)，继续在冰浴中搅拌10min，升至室温搅拌30min，加入化合物醋酐(2mL)，室温下搅拌过夜。反应液中加入水和乙酸乙酯，萃取分层，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(石油醚：乙酸乙酯5:1)分离纯化得到白色固体化合物70(103mg，产率45.8％)。1H NMR(400MHz,CDCl3)δ7.00–6.94(m,2H),6.94–6.80(m,5H),3.90(s,3H),3.88(s,3H),3.50(s,2H),3.22–3.11(m,4H),2.66–2.54(m,4H),2.27(s,3H)；MS(ESI)m/z[M+Na]+：393.14。The compound 70A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask, which was dissolved in dichloromethane (10 mL), and the mixture was stirred and stirred for 5 min, pyridine (0.5 mL) was added and the mixture was stirred for 10 min. After stirring at room temperature for 30 min, compound acetic anhydride (2 mL) was added and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the layers were separated, and the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography ( petroleum ether: ethyl acetate 5:1). Compound 70 (103 mg, yield 45.8%) was obtained as white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.00 - 6.94 (m, 2H), 6.94 - 6.80 (m, 5H), 3.90 (s, 3H), 3.88 (s, 3H), 3.50 (s, 2H), 3.22 - 3.11 (m, 4H), 2.66 - 2.54 (m, 4H), 2.27 (s, 3H); MS (ESI) m/z [M+Na] + : 393.14.
实施例71Example 71
Figure PCTCN2015100201-appb-000130
Figure PCTCN2015100201-appb-000130
50mL圆底烧瓶中加入化合物71A(200mg，0.609mmol)，用DMF(4mL)溶解，置于冰浴中，搅拌5min，加入氢化钠(22mg，0.913mmol)，继续在冰浴中搅拌10min，升至室温搅拌30min，加入化合物71B(142μL，1.22mmol)，室温下搅拌过夜。反应液中加入水和乙酸乙酯，萃取分层，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇100:1)分离纯化得到白色固体化合物71(82mg，产率31.1％)。1H NMR(400MHz,CDCl3)δ8.22–8.15(m,2H),7.66–7.59(m,1H),7.54–7.46(m,2H),7.13–7.07(m,2H),7.00–6.91(m,3H),6.87(dd,J＝8.2,1.6Hz,1H),6.83(d,J＝8.1Hz,1H),3.90(s,3H),3.88(s,3H),3.52(s,2H),3.26–3.15(m,4H),2.68–2.56(m,4H)；MS(ESI)m/z[M+H]+：433.10。Compound 71A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask, dissolved in DMF (4 mL), and then stirred in ice-cooled for 5 min, sodium hydride (22 mg, 0.913 mmol) was added, and the mixture was stirred in an ice bath for 10 min. After stirring for 30 min at room temperature, compound 71B (142 uL, 1.22 mmol) Water and ethyl acetate were added to the reaction mixture, and the layers were separated, and the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography (dichloromethane: methanol 100:1). White solid compound 71 (82 mg, yield 31.1%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 - 8.15 (m, 2H), 7.66 - 7.59 (m, 1H), 7.54 - 7.46 (m, 2H), 7.13 - 7.07 (m, 2H), 7.00 - 6.91 (m, 3H), 6.87 (dd, J = 8.2, 1.6 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.52 (s, 2H), 3.26 - 3.15 (m, 4H), 2.68 - 2.56 (m, 4H); MS (ESI) m/z [M+H] + : 433.10.
实施例72Example 72
Figure PCTCN2015100201-appb-000131
Figure PCTCN2015100201-appb-000131
50mL圆底烧瓶中加入化合物72A(200mg，0.609mmol)，氯仿(6mL)，化合物72B(446mg，2.44mmol)，吡啶(0.5mL)，在65℃油浴中反应4h，反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇100:1)分离纯化得到白色固体化合物72(67mg，产率23.2％)。1H NMR(400MHz,CDCl3)δ7.69(dd,J＝5.0,1.3Hz,1H),7.56(dd,J＝3.8,1.3Hz,1H),7.08(dd,J＝5.0,3.8Hz,1H),6.94–6.75(m,7H),3.89(s,3H),3.88(s,3H),3.49(s,2H),3.21–3.10(m,4H),2.61–2.52(m,4H)；MS(ESI)m/z[M+H]+：475.15。Compound 72A (200 mg, 0.609 mmol), chloroform (6 mL), compound 72B (446 mg, 2.44 mmol), pyridine (0.5 mL) was reacted in a 50 ° C oil bath for 4 h, the reaction solution was dried, residue Adding saturated aqueous sodium hydrogencarbonate solution, extracting with ethyl acetate, EtOAc, EtOAc (EtOAc) Solid compound 72 (67 mg, yield 23.2%). 1 H NMR (400MHz, CDCl 3 ) δ7.69 (dd, J = 5.0,1.3Hz, 1H), 7.56 (dd, J = 3.8,1.3Hz, 1H), 7.08 (dd, J = 5.0,3.8Hz, 1H), 6.94–6.75 (m, 7H), 3.89 (s, 3H), 3.88 (s, 3H), 3.49 (s, 2H), 3.21–3.10 (m, 4H), 2.61–2.52 (m, 4H) MS (ESI) m/z [M+H] + : 495.
实施例73Example 73
Figure PCTCN2015100201-appb-000132
Figure PCTCN2015100201-appb-000132
50mL圆底烧瓶中加入化合物73A(200mg，0.609mmol)，用DMF(4mL)溶解，置于冰浴中，搅拌5min，加入氢化钠(22mg，0.913mmol)，继续在冰浴中搅拌10min，升至室温搅拌30min，加入化合物73B(108μL，0.913mmol)，室温下搅拌过夜。反应液中加入水和乙酸乙酯，萃取分层，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇100:1)分离纯化得到白色固体化合物73(89mg，产率34.9％)。1H NMR(400MHz,CDCl3)δ7.45–7.28(m,5H),6.94–6.84(m,6H),6.82(d,J＝8.1Hz,1H),5.01(s,2H),3.90(s,3H),3.88(s,3H),3.51(s,2H),3.15–3.03(m,4H),2.65–2.54(m,4H)；MS(ESI)m/z[M+H]+：419.20。Compound 73A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask, dissolved in DMF (4 mL), and stirred in ice-cooled for 5 min, sodium hydride (22 mg, 0.913 mmol) was added, and the mixture was stirred in an ice bath for 10 min. After stirring to room temperature for 30 min, compound 73B (108 [mu]L, 0.913 mmol) was added and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the layers were separated, and the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography (dichloromethane: methanol 100:1). White solid compound 73 (89 mg, yield 34.9%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 - 7.28 (m, 5H), 6.94 - 6.84 (m, 6H), 6.82 (d, J = 8.1 Hz, 1H), 5.01 (s, 2H), 3.90 ( s,3H),3.88(s,3H),3.51(s,2H),3.15–3.03(m,4H),2.65–2.54(m,4H);MS(ESI)m/z[M+H] + :419.20.
实施例74Example 74
Figure PCTCN2015100201-appb-000133
Figure PCTCN2015100201-appb-000133
将74A(2g，24.1mmol)和74B(400mg,2.41mmol)溶于10ml甲醇中，室温搅拌12h后，缓慢加入硼氢化钠(109.4,2.892mmol)，反应15min后，经硅藻土过滤后减压除去溶剂后，加入水用乙酸乙酯萃取两次除去杂质，然后用二氯甲烷萃取2次合并二氯甲烷，加入硫酸钠干燥后，减压除去溶剂得到74C(188.5mg，产率33％)。74A (2g, 24.1mmol) and 74B (400mg, 2.41mmol) were dissolved in 10ml of methanol, stirred at room temperature for 12h, then sodium borohydride (109.4, 2.892mmol) was added slowly, after 15min reaction, filtered by diatomite After the solvent was removed by pressure, the mixture was extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) ).
将74C(188.5mg，0.798mmol)和74D(222mg,0.725mg)溶于5ml1,2-二氯乙烷中，冰浴条件下缓慢加入三乙酰氧基硼氢化钠(230mg，1.09mmol)，室温反应5h后，经硅藻土过滤，硅胶柱层析(二氯甲烷：甲醇＝20:1)，得到产物74(113mg，产率30.2％)。1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.3Hz,2H),7.31(d,J＝8.1Hz,2H),7.06(d,J＝8.1Hz,1H),6.90(d,J＝1.2Hz,1H),6.88–6.79(m,4H),3.90(s,3H),3.88(s,3H),3.58(s,3H),3.47(s,2H),3.46(s,2H),2.46(m,11H)；MS(ESI)m/z[M+H]+：527.05。74C (188.5 mg, 0.798 mmol) and 74D (222 mg, 0.725 mg) were dissolved in 5 ml of 1,2-dichloroethane, and sodium triacetoxyborohydride (230 mg, 1.09 mmol) was slowly added at room temperature under ice bath. After reacting for 5 hours, the mixture was filtered over EtOAc EtOAcjjjjjjjj 1 H NMR (400MHz, CDCl 3 ) δ7.77 (d, J = 8.3Hz, 2H), 7.31 (d, J = 8.1Hz, 2H), 7.06 (d, J = 8.1Hz, 1H), 6.90 (d , J = 1.2 Hz, 1H), 6.88 - 6.79 (m, 4H), 3.90 (s, 3H), 3.88 (s, 3H), 3.58 (s, 3H), 3.47 (s, 2H), 3.46 (s, 2H), 2.46 (m, 11H ); MS (ESI) m / z [m + H] +: 527.05.
实施例75Example 75
Figure PCTCN2015100201-appb-000134
Figure PCTCN2015100201-appb-000134
50mL圆底烧瓶中加入75A(90mg，0.731mmol)，二氯亚砜(1mL)，在80℃的油浴中回流反应2h，旋干，得到75B，再依次加入75C(200mg，0.609mmol)，THF(20mL)，DMAP(10mg)，TEA(102μL，0.731mmol)，室温下搅拌过夜，反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇100:1)分离纯化得到白色固体化合物75(28mg，产率10.6％)。1H NMR(400MHz,CDCl3)δ9.40–9.36(m,1H),8.84(dd,J＝4.9,1.7Hz,1H),8.44(dt,J＝8.0,1.9Hz,1H),7.46(ddd,J＝8.0,4.9,0.7Hz,1H),7.16–7.07(m,2H),6.99–6.92(m,3H),6.87(dd,J＝8.1,1.7Hz,1H),6.83(d,J＝8.1Hz,1H),3.91(s,3H),3.88(s,3H),3.53(s,2H),3.29–3.14(m,4H),2.69–2.55(s,4H)；MS(ESI)m/z[M+H]+：434.21。75A (90mg, 0.731mmol), thionyl chloride (1mL) was added to a 50mL round bottom flask, refluxed in an oil bath of 80 ° C for 2h, spin dry to give 75B, then add 75C (200mg, 0.609mmol), THF (20 mL), DMAP (10 mg), EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) The residue was purified by column chromatography (dichloromethane: methanol: 100:1) to afford white solid compound 75 (28 mg, yield: 10.6%). 1 H NMR (400MHz, CDCl 3 ) δ9.40-9.36 (m, 1H), 8.84 (dd, J = 4.9,1.7Hz, 1H), 8.44 (dt, J = 8.0,1.9Hz, 1H), 7.46 ( Ddd, J=8.0, 4.9, 0.7 Hz, 1H), 7.16–7.07 (m, 2H), 6.99–6.92 (m, 3H), 6.87 (dd, J=8.1, 1.7 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.53 (s, 2H), 3.29–3.14 (m, 4H), 2.69–2.55 (s, 4H); MS (ESI) m/z [M+H] + : 434.21.
实施例76Example 76
Figure PCTCN2015100201-appb-000135
Figure PCTCN2015100201-appb-000135
50mL圆底烧瓶中加入76A(127mg，0.731mmol)，二氯亚砜(1mL)，二氯甲烷(2mL)，1滴DMF，在35℃的油浴中反应4h，旋干，得到76B，再依次加入76C(200mg，0.609mmol)，二氯甲烷(12mL)，TEA(127μL，0.913mmol)，室温下搅拌30min，反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经制备薄层层析(二氯甲烷：甲醇50:1)分离纯化得到无色膏状物化合物76(57mg，产率19.4％)。1H NMR(400MHz,CDCl3)δ9.41(s,1H),8.74(s,1H),8.13–8.07(m,1H),8.05–7.99(m,1H),7.86–7.76(m,2H),7.24–7.16(m,2H),7.04–6.91(m,3H),6.87(dd,J＝8.2,1.6Hz,1H),6.83(d,J＝8.1Hz,1H),3.90(s,3H),3.88(s,3H),3.52(s,2H),3.27–3.15(m,4H),2.67–2.55(m,4H)；MS(ESI)m/z[M+H]+：484.26。A 50 mL round bottom flask was charged with 76A (127 mg, 0.731 mmol), chlorosulfoxide (1 mL), dichloromethane (2 mL), 1 drop of DMF, reacted in an oil bath of 35 ° C for 4 h, and dried to give 76B. 76C (200 mg, 0.609 mmol), methylene chloride (12 mL), EtOAc (EtOAc, EtOAc (EtOAc) The organic phase was washed with water and dried over anhydrous sodium sulfate, and the residue obtained was purified by preparative thin layer chromatography (dichloromethane:methanol 50:1) to afford compound 76 (yield: %). 1 H NMR (400 MHz, CDCl 3 ) δ 9.41 (s, 1H), 8.74 (s, 1H), 8.13 - 8.07 (m, 1H), 8.05 - 7.79 (m, 1H), 7.86 - 7.76 (m, 2H) ), 7.24–7.16 (m, 2H), 7.04–6.91 (m, 3H), 6.87 (dd, J=8.2, 1.6 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.52 (s, 2H), 3.27 - 3.15 (m, 4H), 2.67 - 2.55 (m, 4H); MS (ESI) m/z [M+H] + :484.26 .
实施例77Example 77
Figure PCTCN2015100201-appb-000136
Figure PCTCN2015100201-appb-000136
参照实施例76的实验方案和相关文献制备得到化合物77，MS(ESI)m/z[M+H]+：511.25。Compound 77 was obtained according to the experimental scheme of Example 76 and related literature. MS (ESI) m/z [M+H] + : 511.25.
实施例78Example 78
Figure PCTCN2015100201-appb-000137
Figure PCTCN2015100201-appb-000137
在25ml圆底烧瓶中加入化合物78A(300mg,1.17mmol),乙酸乙酯(5ml)，三乙胺(161mg,1.59mmol)，搅拌溶解为澄清溶液，加入化合物78B(231mg,1.06mmol),搅拌下加入三乙酰氧基硼氢化钠(270mg,1.27mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(4:1)为洗脱剂，得无色油状产物78(208mg,产率：43.6％)。1H NMR(400MHz,CDCl3)δ8.23(dd,J＝7.9,1.0Hz,1H),7.92–7.89(m,2H),7.82(d,J＝7.6Hz,1H),7.66–7.57(m,3H),7.54–7.45(m,3H),7.24(dd,J＝8.5,2.0Hz,1H),7.06(td,J＝8.8,2.1Hz,1H),3.83(s,2H),3.04–2.92(m,1H),2.82(d,J＝11.6Hz,2H),2.04(td,J＝11.4,2.6Hz,2H),1.98–1.84(m,4H)；MS(ESI)m/z[M+H]+：451.91。 Compound 75A (300 mg, 1.17 mmol), ethyl acetate (5 ml), triethylamine (161 mg, 1.59 mmol) was dissolved in a 25 ml round bottom flask, dissolved in a clear solution, and compound 78B (231 mg, 1.06 mmol) was added and stirred. Sodium triacetoxyborohydride (270 mg, 1.27 mmol) was added. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc) The product was obtained as a colorless oily product 78 ( 208 mg, yield: 43.6%). 1 H NMR (400MHz, CDCl3) δ8.23 (dd, J = 7.9,1.0Hz, 1H), 7.92-7.89 (m, 2H), 7.82 (d, J = 7.6Hz, 1H), 7.66-7.57 (m , 3H), 7.54–7.45 (m, 3H), 7.24 (dd, J=8.5, 2.0 Hz, 1H), 7.06 (td, J=8.8, 2.1 Hz, 1H), 3.83 (s, 2H), 3.04– 2.92 (m, 1H), 2.82 (d, J = 11.6 Hz, 2H), 2.04 (td, J = 11.4, 2.6 Hz, 2H), 1.98 - 1.84 (m, 4H); MS (ESI) m/z [ M+H] + : 451.91.
实施例79Example 79
Figure PCTCN2015100201-appb-000138
Figure PCTCN2015100201-appb-000138
在25ml圆底烧瓶中加入化合物79A(300mg,0.89mmol)，化合物79B(108mg,0.82mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(208mg,0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(30:1)为洗脱剂，得白色固体产物79(174mg,产率：47.5％)。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.4Hz,3H),7.60(dd,J＝8.9,7.9Hz,2H),7.46(t,J＝7.7Hz,1H),7.32(d,J＝8.1Hz,2H),6.90–6.82(m,2H),6.82–6.74(m,2H),3.59(s,2H),3.23–3.11(m,4H),2.65–2.54(m,4H),2.46(s,3H)；MS(ESI)m/z[M+Na]+：470.02。Compound 79A (300 mg, 0.89 mmol), compound 79B (108 mg, 0.82 mmol), ethyl acetate (2 ml), EtOAc. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The white solid product 79 (174 mg, yield: 47.5%). 1 H NMR (400MHz, CDCl3) δ7.71 (d, J = 8.4Hz, 3H), 7.60 (dd, J = 8.9,7.9Hz, 2H), 7.46 (t, J = 7.7Hz, 1H), 7.32 ( d, J=8.1 Hz, 2H), 6.90–6.82 (m, 2H), 6.82–6.74 (m, 2H), 3.59 (s, 2H), 3.23–3.11 (m, 4H), 2.65–2.54 (m, 4H), 2.46 (s, 3H ); MS (ESI) m / z [m + Na] +: 470.02.
实施例80Example 80
Figure PCTCN2015100201-appb-000139
Figure PCTCN2015100201-appb-000139
在25ml圆底烧瓶中加入化合物80A(300mg，1.17mmol)，乙酸乙酯(5ml)，三乙胺(161mg,1.59mmol)，搅拌溶解为澄清溶液，加入化合物80B(324mg，1.06mmol),搅拌下加入三乙酰氧基硼氢化钠(270mg,1.27mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(2:1)为洗脱剂，得无色油状产物80(222mg,产率：41.2％)。1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.3Hz,2H),7.69(dd,J＝8.7,5.1Hz,1H),7.29(d,J＝8.0Hz,2H),7.22(dd,J＝8.5,2.0Hz,1H),7.06(ddd,J＝15.8,7.6,3.2Hz,2H),6.91(d,J＝1.6Hz,1H),6.85(dd,J＝8.2,1.7Hz,1H),3.57(s,3H),3.50(s,2H),3.13–3.02(m,1H),2.98(d,J＝11.3Hz,2H),2.44(s,3H),2.23–2.13(m,2H),2.06(dd,J＝9.1,3.3Hz,4H)；MS(ESI)m/z[M]+：510.88。Compound 80A (300 mg, 1.17 mmol), ethyl acetate (5 ml), triethylamine (161 mg, 1.59 mmol) was dissolved in a 25 ml round bottom flask, dissolved in a clear solution, and compound 80B (324 mg, 1.06 mmol) was added and stirred. Sodium triacetoxyborohydride (270 mg, 1.27 mmol) was added. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a colorless oil (yield: 222 mg, yield: 41.2%). 1 H NMR (400MHz, CDCl3) δ7.75 (d, J = 8.3Hz, 2H), 7.69 (dd, J = 8.7,5.1Hz, 1H), 7.29 (d, J = 8.0Hz, 2H), 7.22 ( Dd, J = 8.5, 2.0 Hz, 1H), 7.06 (ddd, J = 15.8, 7.6, 3.2 Hz, 2H), 6.91 (d, J = 1.6 Hz, 1H), 6.85 (dd, J = 8.2, 1.7 Hz , 1H), 3.57 (s, 3H), 3.50 (s, 2H), 3.13 - 3.02 (m, 1H), 2.98 (d, J = 11.3 Hz, 2H), 2.44 (s, 3H), 2.23 - 2.13 ( m, 2H), 2.06 (dd, J = 9.1, 3.3 Hz, 4H); MS (ESI) m/z [M] + : 510.88.
实施例81Example 81
Figure PCTCN2015100201-appb-000140
Figure PCTCN2015100201-appb-000140
在25ml圆底烧瓶中加入化合81A(300mg,0.89mmol)，化合物81B(143mg,0.82mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(208mg，0.98mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(2:1)为洗脱剂，得白色固体产物81(183mg，产率：45.5％)。1H NMR(400MHz,CDCl3)δ7.83(d,J＝7.8Hz,1H),7.71(d,J＝8.3Hz,2H),7.66(d,J＝7.8Hz,1H),7.55(t,J＝7.6Hz,1H),7.38(d,J＝7.6Hz,1H),7.32(d,J＝8.1Hz,2H),6.90–6.83(m,2H),6.82–6.75(m,2H),3.73(s,2H),3.21–3.14(m,4H),2.67–2.61(m,4H),2.46(s,3H)；MS(ESI)m/z[M+H]+：490.96。To a 25 ml round bottom flask was added compound 81A (300 mg, 0.89 mmol), Compound 81B (143 mg, 0.82 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (208 mg, 0.98 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a white solid (yield: 183 mg, yield: 45.5%). 1 H NMR (400MHz, CDCl3) δ7.83 (d, J = 7.8Hz, 1H), 7.71 (d, J = 8.3Hz, 2H), 7.66 (d, J = 7.8Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 6.90 - 6.83 (m, 2H), 6.82 - 6.75 (m, 2H), 3.73 (s, 2H), 3.21 - 3.14 (m, 4H), 2.67 - 2.61 (m, 4H), 2.46 (s, 3H); MS (ESI) m/z [M+H] + : 490.96.
实施例82Example 82
Figure PCTCN2015100201-appb-000141
Figure PCTCN2015100201-appb-000141
在25ml圆底烧瓶中加入化合物82A(200mg,0.91mmol)，化合物82B(254mg,0.83mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(212mg，1.00mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物化合物82(209mg,产率：49.5％)。1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.2Hz,1H),7.81(d,J＝8.1Hz,1H),7.77(d,J＝8.3Hz,2H),7.50–7.44(m,1H),7.40–7.33(m,1H),7.32–7.28(m,2H),7.10(d,J＝8.1Hz,1H),6.94(d,J＝1.6Hz,1H),6.87(dd,J＝8.2,1.8Hz,1H),3.59(s,3H),3.57(d,J＝5.1Hz,4H),3.55(s,2H),2.70–2.64(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：510.00。Compound 82A (200 mg, 0.91 mmol), Compound 82B (254 mg, 0.83 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (212 mg, 1.00 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The title compound 82 (209 mg, yield: 49.5%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.50 - 7.44 (m,1H), 7.40–7.33 (m,1H), 7.32–7.28 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 6.87 ( Dd, J = 8.2, 1.8 Hz, 1H), 3.59 (s, 3H), 3.57 (d, J = 5.1 Hz, 4H), 3.55 (s, 2H), 2.70 - 2.64 (m, 4H), 2.45 (s , MS (ESI) m/z [M+H] + : 510.00.
实施例83Example 83
Figure PCTCN2015100201-appb-000142
Figure PCTCN2015100201-appb-000142
在25ml圆底烧瓶中加入化合物83A(200mg，0.91mmol),化合物83B(254mg,0.83mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(212mg，1.00mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物化合物83(181mg,产率：42.8％)。1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.2Hz,1H),7.83(d,J＝8.1Hz,1H),7.78(d,J＝8.3Hz,2H),7.48(t,J＝7.4Hz,1H),7.37(t,J＝7.5Hz,1H),7.32(d,J＝8.2Hz,2H),7.23–7.19(m,1H),7.18(d,J＝1.8Hz,1H),6.83(d,J＝8.3Hz,1H),3.59(s,3H),3.58–3.53(m,4H),3.52(s,2H),2.68–2.61(m,4H),2.45(s,3H)；MS(ESI)m/z[M]+：509.83。Compound 83A (200 mg, 0.91 mmol), compound 83B (254 mg, 0.83 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (212 mg, 1.00 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a white solid (yield: 181 mg, yield: 42.8%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.48 (t , J = 7.4 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.23 - 7.19 (m, 1H), 7.18 (d, J = 1.8 Hz) , 1H), 6.83 (d, J = 8.3 Hz, 1H), 3.59 (s, 3H), 3.58 - 3.53 (m, 4H), 3.52 (s, 2H), 2.68 - 2.61 (m, 4H), 2.45 ( s, 3H); MS (ESI) m/z [M] + : 509.
实施例84Example 84
Figure PCTCN2015100201-appb-000143
Figure PCTCN2015100201-appb-000143
在25ml圆底烧瓶中加入化合物84A(200mg,0.91mmol)，化合物84B(181mg,0.83mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(212mg，1.00mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(4:1)为洗脱剂，得白色固体产物化合物84(170mg，产率：45.6％)。1H NMR(400MHz,CDCl3)δ8.26(dd,J＝7.9,1.2Hz,1H),7.91(dd,J＝5.3,3.3Hz,2H),7.86(d,J＝8.2Hz,1H),7.81(dd,J＝7.7,3.6Hz,2H),7.63(td,J＝7.6,1.3Hz,1H),7.58(ddd,J＝6.3,3.7,1.3Hz,1H),7.55–7.49(m,3H),7.49–7.45(m,1H),7.39–7.33(m,1H),3.89(s,2H),3.43–3.32(m,4H),2.54–2.47(m,4H)；MS(ESI)m/z[M]+：449.97。To a 25 ml round bottom flask was added compound 84A (200 mg, 0.91 mmol), Compound 84B (181 mg, 0.83 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (212 mg, 1.00 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc) The compound was obtained as a white solid (yield:ield: 45.6%). 1 H NMR (400MHz, CDCl 3 ) δ8.26 (dd, J = 7.9,1.2Hz, 1H), 7.91 (dd, J = 5.3,3.3Hz, 2H), 7.86 (d, J = 8.2Hz, 1H) , 7.81 (dd, J = 7.7, 3.6 Hz, 2H), 7.63 (td, J = 7.6, 1.3 Hz, 1H), 7.58 (ddd, J = 6.3, 3.7, 1.3 Hz, 1H), 7.55 - 7.49 (m , 3H), 7.49–7.45 (m, 1H), 7.39–7.33 (m, 1H), 3.89 (s, 2H), 3.43–3.32 (m, 4H), 2.54–2.47 (m, 4H); MS (ESI) ) m/z [M] + : 449.97.
实施例85Example 85
Figure PCTCN2015100201-appb-000144
Figure PCTCN2015100201-appb-000144
在25ml圆底烧瓶中加入化合物85A(483mg，1.45mmol)，化合物85B(200mg,1.2mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(382mg,1.8mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(4:1)为洗脱剂，得白色固体产物85(275mg,产率：47.3％)。1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.3Hz,2H),7.32(d,J＝8.1Hz,2H),7.12(t,J＝8.2Hz,1H),6.93(s,1H),6.89–6.83(m,2H),6.77(dd,J＝8.4,2.2Hz,1H),6.54(t,J＝2.2Hz,1H),6.38(dd,J＝8.0,2.0Hz,1H),3.91(d,J＝5.4Hz,6H),3.51(s,2H),3.17–3.07(m,4H),2.61–2.51(m,4H),2.46(s,3H)；MS(ESI)m/z[M+H]+：483.03。 To a 25 ml round bottom flask was added compound 85A (483 mg, 1.45 mmol), Compound 85B (200 mg, 1.2 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (382 mg, 1.8 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc) The product was obtained as a white solid (yield: 275 mg, yield: 47.3%). 1H NMR (400MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.12 (t, J = 8.2 Hz, 1H), 6.93 (s, 1H) ), 6.89 - 6.83 (m, 2H), 6.77 (dd, J = 8.4, 2.2 Hz, 1H), 6.54 (t, J = 2.2 Hz, 1H), 6.38 (dd, J = 8.0, 2.0 Hz, 1H) , 3.91 (d, J = 5.4 Hz, 6H), 3.51 (s, 2H), 3.17 - 3.07 (m, 4H), 2.61 - 2.51 (m, 4H), 2.46 (s, 3H); MS (ESI) m /z[M+H] + : 483.03.
实施例86Example 86
Figure PCTCN2015100201-appb-000145
Figure PCTCN2015100201-appb-000145
在25ml圆底烧瓶中加入化合物86A(375mg，1.12mmol)，化合物86B(100mg,0.94mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(297mg,1.41mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(30:1)为洗脱剂，得白色固体产物86(179mg,产率：45.2％)。1H NMR(400MHz,CDCl3)δ8.56(d,J＝1.6Hz,1H),8.51(dd,J＝4.8,1.4Hz,1H),7.68(dd,J＝9.6,5.0Hz,3H),7.33–7.22(m,3H),7.09(t,J＝8.2Hz,1H),6.73(dd,J＝8.4,2.1Hz,1H),6.48(t,J＝2.2Hz,1H),6.36(dd,J＝8.0,1.8Hz,1H),3.54(s,2H),3.11–3.04(m,4H),2.57–2.50(m,4H),2.41(s,3H)；MS(ESI)m/z[M+H]+：424.02。Compound 86A (375 mg, 1.12 mmol), compound 86B (100 mg, 0.94 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (297 mg, 1.41 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The white solid product 86 (179 mg, yield: 45.2%). 1H NMR (400MHz, CDCl3) δ 8.56 (d, J = 1.6 Hz, 1H), 8.51 (dd, J = 4.8, 1.4 Hz, 1H), 7.68 (dd, J = 9.6, 5.0 Hz, 3H), 7.33 –7.22 (m, 3H), 7.09 (t, J = 8.2 Hz, 1H), 6.73 (dd, J = 8.4, 2.1 Hz, 1H), 6.48 (t, J = 2.2 Hz, 1H), 6.36 (dd, J=8.0, 1.8 Hz, 1H), 3.54 (s, 2H), 3.11–3.04 (m, 4H), 2.57–2.50 (m, 4H), 2.41 (s, 3H); MS (ESI) m/z [ M+H] + : 424.02.
实施例87Example 87
Figure PCTCN2015100201-appb-000146
Figure PCTCN2015100201-appb-000146
50mL圆底烧瓶中加入化合物87A(784mg，2.39mmol)，氯仿(6mL)，化合物87B(2.28g，9.55mmol)，吡啶(0.5mL)，在65℃油浴中反应6h，反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到无色膏状物87C(170mg，产率12.0％)。Compound 87A (784 mg, 2.39 mmol), chloroform (6 mL), compound 87B (2.28 g, 9.55 mmol), pyridine (0.5 mL) was reacted in a 50 mL round bottom flask, and reacted in an oil bath at 65 ° C for 6 h, and the reaction solution was dried. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue, and ethyl acetate was evaporated, and the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, and the residue obtained was purified by column chromatography (dichloromethane: methanol 200:1). Colorless paste 87C (170 mg, yield 12.0%).
25mL圆底烧瓶中加入化合物87C(100mg，0.168mmol)，化合物87D(21mg，0.168mmol)，Pd(dppf)Cl2二氯甲烷络合物(14mg，0.017mmol)，醋酸钾(49mg，0.504mmol)，THF/EtOH/水(2mL/2mL/2mL)混合溶剂，氮气保护下在80℃油浴中反应过夜，反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇100:1)分离纯化得到类白色固体87(41mg，产率44.7％)。1H NMR(400MHz,CDCl3)δ8.88(d,J＝1.9Hz,1H),8.68(dd,J＝4.8,1.5Hz,1H),7.97–7.86(m,3H),7.75–7.68(m,2H),7.43(dd,J＝7.7,4.9Hz,1H),6.94–6.73(m,7H),3.88(s,3H),3.87(s,3H),3.49(s,2H),3.21–3.09(m,4H),2.61–2.50(m,4H)；MS(ESI)m/z[M+H]+：545.94。Into a 25 mL round bottom flask was added compound 87C (100 mg, 0.168 mmol), compound 87D (21 mg, 0.168 mmol), Pd (dppf) Cl 2 dichloromethane complex (14 mg, 0.017 mmol), potassium acetate (49 mg, 0.504 mmol) THF, EtOH / water (2mL / 2mL / 2mL) mixed solvent, under nitrogen protection in 80 ° C oil bath overnight, the reaction solution was spun dry, the residue was added saturated aqueous sodium bicarbonate, ethyl acetate extraction, combined organic The residue was washed with water and dried over anhydrous sodium sulfate. 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (d, J = 1.9 Hz, 1H), 8.68 (dd, J = 4.8, 1.5 Hz, 1H), 7.97 - 7.86 (m, 3H), 7.75 - 7.68 ( m, 2H), 7.43 (dd, J = 7.7, 4.9 Hz, 1H), 6.94 - 6.73 (m, 7H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.21. -3.09 (m, 4H), 2.61 - 2.50 (m, 4H); MS (ESI) m/z [M+H] + : 545.94.
实施例88Example 88
Figure PCTCN2015100201-appb-000147
Figure PCTCN2015100201-appb-000147
50mL圆底烧瓶中加入88A(436mg，2.69mmol)，溶于DMSO(6mL)，再依次加入TBAI(8mg，0.02mmol)，碳酸钾(464mg，3.36mmol)，88B(452mg，2.24mmol)，在120℃油浴中搅拌反应6h，反应液加水，乙酸乙酯萃取，水洗涤，无水硫酸钠干燥，旋干，得到的残渣经柱层析(二氯甲烷：甲醇100:1)纯化得到浅黄色油状物88C(339mg，产率53.4％)。88A (436mg, 2.69mmol) was added to a 50mL round bottom flask, dissolved in DMSO (6mL), then TBAI (8mg, 0.02mmol), potassium carbonate (464mg, 3.36mmol), 88B (452mg, 2.24mmol), The reaction was stirred for 6 h in a 120 ° C oil bath, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjj Yellow oil 88C (339 mg, yield 53.4%).
50mL圆底烧瓶中加入化合物88C(200mg，0.706mmol)，溶于二氯甲烷(12mL)，再加入化合物88D(117mg，0.706mmol)， 室温搅拌2h，加入三乙酰氧基硼氢化钠(195mg，0.918mmol)，室温下搅拌过夜。反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(石油醚：乙酸乙酯4:1)分离纯化得到黄色固体88E(167mg，产率38.5％)。Compound 88C (200 mg, 0.706 mmol) was added to a 50 mL round bottom flask, dissolved in dichloromethane (12 mL), and then compound 88D (117 mg, 0.706 mmol). After stirring at room temperature for 2 h, sodium triacetoxyborohydride (195 mg, 0.918 mmol) was added and stirred at room temperature overnight. The reaction mixture was evaporated to dryness. EtOAc EtOAc m. :1) Isolation and purification gave a yellow solid 88E (167 mg, yield 38.5%).
100mL圆底烧瓶中依次加入88E(167mg，0.385mmol)，钯碳(40mg)，乙醇(20mL)，四氢呋喃(5mL)，在氢气氛围下室温，常压搅拌过夜。反应液抽滤，甲醇洗涤，合并滤液，旋干，得到无色膏状物88F。直接用于下一步反应。88E (167 mg, 0.385 mmol), palladium on carbon (40 mg), ethanol (20 mL), and tetrahydrofuran (5 mL) were added to a 100 mL round bottom flask, and stirred under a hydrogen atmosphere at room temperature overnight. The reaction solution was suction filtered, washed with methanol, and the filtrate was evaporated and evaporated. Used directly in the next step.
50mL圆底烧瓶中加入化合物88F，溶于二氯甲烷(15mL)，再加入对甲苯磺酰氯(74mg，0.387mmol)，三乙胺(67μL，0.483mmol)，室温下搅拌过夜。反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇150:1)分离纯化得到白色固体化合物88(131mg，产率72.9％)。1H NMR(400MHz,CDCl3)δ7.58–7.47(m,4H),7.41–7.34(m,2H),7.33–7.28(m,1H),7.22–7.14(m,2H),6.93–6.85(m,2H),6.84–6.69(m,5H),6.39–6.24(m,1H),3.87(s,3H),3.86(s,3H),3.77(d,J＝13.3Hz,1H),3.57–3.40(m,3H),3.05–2.95(m,1H),2.93–2.82(m,2H),2.82–2.72(m,1H),2.37(s,3H),2.35–2.26(m,1H)；MS(ESI)m/z[M+H]+：558.18。Compound 88F was added to a 50 mL round bottom flask, dissolved in dichloromethane (15 mL), and then toluenesulfonyl chloride (74 mg, 0.387 mmol), triethylamine (67 μL, 0.483 mmol). The reaction mixture was evaporated to dryness. EtOAc m. 1) Isolation and purification gave Compound 88 (131 mg, yield: 72.9%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 - 7.47 (m, 4H), 7.41 - 7.34 (m, 2H), 7.33 - 7.28 (m, 1H), 7.22 - 7.14 (m, 2H), 6.93 - 6.85 (m, 2H), 6.84–6.69 (m, 5H), 6.39–6.24 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.77 (d, J = 13.3 Hz, 1H), 3.57–3.40 (m, 3H), 3.05–2.95 (m, 1H), 2.93–2.82 (m, 2H), 2.82–2.72 (m, 1H), 2.37 (s, 3H), 2.35–2.26 (m, 1H) MS (ESI) m/z [M+H] + : 558.
实施例89Example 89
Figure PCTCN2015100201-appb-000148
Figure PCTCN2015100201-appb-000148
在50ml圆底烧瓶中加入化合物89A(1000mg，10.51mmol)，二氯甲烷(2ml)，三乙胺(1592mg,15.77mmol)，搅拌下加入化合物89B(2406mg，12.62mmol)。室温下搅拌过夜，TLC检测原料反应完全。将反应体系浓缩后用水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得白色固体产物89C。Compound 89A (1000 mg, 10.51 mmol), dichloromethane (2 ml), triethylamine (1592 mg, 15.77 mmol) was added to a 50 ml round bottom flask. Compound 89B (2406 mg, 12.62 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction system is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is evaporated. Solid product 89C.
在25ml圆底烧瓶中加入化合物89C(400mg，1.61mmol)，化合物89D(291mg,1.77mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(409mg,1.93mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物化合物89(311mg,产率：48.6％)。1H NMR(400MHz,CDCl3)δ8.30(d,J＝4.7Hz,2H),7.85(d,J＝8.4Hz,2H),7.35(dd,J＝3.3,1.8Hz,1H),7.26(d,J＝8.1Hz,2H),6.48(t,J＝4.7Hz,1H),6.23(t,J＝3.3Hz,1H),6.19–6.15(m,1H),3.65(s,2H),3.60–3.52(m,4H),2.43–2.39(m,4H),2.37(s,3H)；MS(ESI)m/z[M+H]+：398.40。Compound 89C (400 mg, 1.61 mmol), compound 89D (291 mg, 1.77 mmol), ethyl acetate (2 ml), EtOAc (EtOAc) After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The title compound 89 (311 mg, yield: 48.6%) was obtained as white solid. 1 H NMR (400MHz, CDCl 3 ) δ8.30 (d, J = 4.7Hz, 2H), 7.85 (d, J = 8.4Hz, 2H), 7.35 (dd, J = 3.3,1.8Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 6.48 (t, J = 4.7 Hz, 1H), 6.23 (t, J = 3.3 Hz, 1H), 6.19 - 6.15 (m, 1H), 3.65 (s, 2H) , 3.60 - 3.52 (m, 4H), 2.43 - 2.39 (m, 4H), 2.37 (s, 3H); MS (ESI) m/z [M+H] + : 398.40.
实施例90Example 90
Figure PCTCN2015100201-appb-000149
Figure PCTCN2015100201-appb-000149
在100ml圆底烧瓶中加入化合物90A(3358mg,18.15mmol)，化合物90B(2000mg,18.15mmol)，Pd2(dba)3(833mg,0.91mmol)，Xantphos(1050mg,1.82mmol)，DIPEA(4691mg,36.3mmol)，二氧六环(30ml)，上氮气保护。105℃搅拌反应过夜后，将反应体系降至室温，过滤，滤液浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(50:1)为洗脱剂，得无色油状物90C。Compound 90A (3358 mg, 18.15 mmol), compound 90B (2000 mg, 18.15 mmol), Pd 2 (dba) 3 (833 mg, 0.91 mmol), Xantphos (1050 mg, 1.82 mmol), DIPEA (4691 mg, 36.3 mmol), dioxane (30 ml), protected with nitrogen. After the reaction was stirred at 105 ° C overnight, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to silica gel column chromatography eluting
在50ml圆底烧瓶中加入化合物90C(1824mg,8.52mmol)，二氯甲烷(20ml)，搅拌溶解后于冰浴中降温至0℃，再将化合物90D(4412mg,25.57mmol)分批加入反应体系后，0℃继续反应2小时，TLC检测原料反应完全。将反应体系依次用饱和碳酸氢钠水溶液，饱和氯化钠水溶液洗，无水硫酸钠干燥。浓缩后经硅胶柱层析，以二氯甲烷：甲醇(50:1)为洗脱剂，得白色固体产物90E。The compound 90C (1824 mg, 8.52 mmol), dichloromethane (20 ml) was added to a 50 ml round bottom flask, stirred and dissolved, and then cooled to 0 ° C in an ice bath, and then compound 90D (4412 mg, 25.57 mmol) was added to the reaction system in portions. Thereafter, the reaction was continued at 0 ° C for 2 hours, and the reaction of the starting material was completely confirmed by TLC. The reaction system was washed successively with a saturated aqueous After concentrating, the title compound was obtained from EtOAcjjjjjj
在25ml圆底烧瓶中加入化合物90E(250mg,1.02mmol)，化合物90F(184mg，1.12mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(259mg,1.23mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得无色油状产物90(185mg,产率：46.1％)。1H NMR(400MHz,CDCl3)δ8.31(d,J＝4.7Hz,2H),8.02–7.94(m,3H),7.85(d,J＝7.9Hz,1H),7.58(dd,J＝10.5,4.4Hz,2H),7.51(ddd,J＝17.2,11.7,7.0Hz,3H),6.50(t,J＝4.7Hz,1H),3.89–3.78(m,4H),3.59(s,2H),2.56–2.42(m,4H)；MS(ESI)m/z[M+H]+：395.16。To a 25 ml round bottom flask was added compound 90E (250 mg, 1.02 mmol), Compound 90F (184 mg, 1.12 mmol), ethyl acetate (2ml), After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The product (90 mg, yield: 46.1%) was obtained as colorless oil. 1 H NMR (400MHz, CDCl 3 ) δ8.31 (d, J = 4.7Hz, 2H), 8.02-7.94 (m, 3H), 7.85 (d, J = 7.9Hz, 1H), 7.58 (dd, J = 10.5, 4.4 Hz, 2H), 7.51 (ddd, J = 17.2, 11.7, 7.0 Hz, 3H), 6.50 (t, J = 4.7 Hz, 1H), 3.89 - 3.78 (m, 4H), 3.59 (s, 2H) ), 2.56 - 2.42 (m, 4H); MS (ESI) m/z [M+H] + : 395.16.
实施例91Example 91
Figure PCTCN2015100201-appb-000150
Figure PCTCN2015100201-appb-000150
在100ml圆底烧瓶中加入化合物91A(2000mg，10.34mmol)，化合物91B(2118mg，11.37mmol)，碳酸钾(2140mg，15.51mmol)，DMF(5ml),70℃搅拌反应过夜后，将反应体系降至室温，加入100ml乙酸乙酯稀释后，依次水洗3次，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩有机层得白色固体产物91C。The compound 91A (2000 mg, 10.34 mmol), the compound 91B (2118 mg, 11.37 mmol), potassium carbonate (2140 mg, 15.51 mmol), DMF (5 ml) was added to a 100 ml round bottom flask, and the reaction was cooled after stirring at 70 ° C overnight. The mixture was diluted with EtOAc (3 mL).
在50ml圆底烧瓶中加入化合物91C(1764mg,5.17mmol)，化合物91D(1446mg,5.69mmol)，醋酸钾(1522mg，15.51mmol),醋酸钯(38mg，0.17mmol)，DMF(5ml)，上氮气保护，70℃搅拌反应16小时，将反应体系降至室温，加入100ml乙酸乙酯稀释后，依次水洗3次，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩有机层得淡黄色固体产物91D，直接投入下一步反应。Compound 91C (1764 mg, 5.17 mmol), compound 91D (1446 mg, 5.69 mmol), potassium acetate (1522 mg, 15.51 mmol), palladium acetate (38 mg, 0.17 mmol), DMF (5 ml) The reaction was stirred at 70 ° C for 16 hours, and the reaction system was cooled to room temperature. After diluted with 100 ml of ethyl acetate, the mixture was washed three times with water, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. 91D, directly into the next reaction.
在50ml圆底烧瓶中加入上一步反应的产物化合物E，加入THF:H2O(1：1)溶液15ml，搅拌分散为悬浊液，加入过硼酸钠(1987mg，12.9mmol),在室温下搅拌过夜，旋干反应体系，加入50ml乙酸乙酯稀释后，依次水洗，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩有机层得白色固体产物91F。Add the product E of the previous reaction to a 50 ml round bottom flask, add 15 ml of a THF:H 2 O (1:1) solution, stir to disperse into a suspension, and add sodium perborate (1987 mg, 12.9 mmol) at room temperature. After stirring overnight, the reaction mixture was dried with EtOAc EtOAc EtOAc.
在25ml圆底烧瓶中加入化合物91F(400mg，1.05mmol),二氯甲烷(2ml)，三乙胺(159mg，1.58mmol)，搅拌下加入化合物91G(230mg，1.2mmol)。室温下搅拌过夜，TLC检测原料反应完全。将反应体系浓缩后用水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得白色固体产物91H。Compound 91F (400 mg, 1.05 mmol), dichloromethane (2 ml), triethylamine (159 mg, 1.58 mmol) was added to a 25 ml round bottom flask and compound 91G (230 mg, 1.2 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction system is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is evaporated. Solid product 91H.
在50ml圆底烧瓶中加入化合物91H(400mg，0.92mmol),二氯甲烷(5ml)，三氟乙酸(1ml)。室温下搅拌3小时，TLC检测原料反应完全。将反应体系浓缩后用水稀释，1mol/L的氢氧化钠水溶液调pH值为9-10，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后得白色固体产物91I。Compound 91H (400 mg, 0.92 mmol), dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added to a 50 ml round bottom flask. After stirring at room temperature for 3 hours, the reaction of the starting material by TLC was completed. The reaction system was concentrated, diluted with water, and aq.
在25ml圆底烧瓶中加入化合物91I(150mg，0.45mmol)，化合物91J(45mg，0.41mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(104mg，0.49mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物91(84mg，产率：48.3％)。1H NMR(400MHz,CDCl3)δ8.61(d,J＝1.3Hz,1H),8.56(dd,J＝4.8,1.2Hz,1H),7.91(s,2H),7.74(t,J＝8.4Hz,3H),7.40–7.30(m,3H),3.83–3.75(m,4H),3.57(s,2H),2.52–2.47(m,4H),2.47(s,3H)；MS(ESI)m/z[M+H]+：426.19。To a 25 ml round bottom flask was added compound 91 I (150 mg, 0.45 mmol), Compound 91J (45 mg, 0.41 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (104 mg, 0.49 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 91 (84 mg, yield: 48.3%). 1 H NMR (400MHz, CDCl3) δ8.61 (d, J = 1.3Hz, 1H), 8.56 (dd, J = 4.8,1.2Hz, 1H), 7.91 (s, 2H), 7.74 (t, J = 8.4 Hz, 3H), 7.40–7.30 (m, 3H), 3.83–3.75 (m, 4H), 3.57 (s, 2H), 2.52–2.47 (m, 4H), 2.47 (s, 3H); MS (ESI) m/z [M+H] + : 426.19.
实施例92Example 92
Figure PCTCN2015100201-appb-000151
Figure PCTCN2015100201-appb-000151
在25ml圆底烧瓶中加入化合物92I(150mg，0.45mmol),化合物92J(68mg，0.41mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(104mg，0.49mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得白色固体产物92(99mg，产率：50.1％)。1H NMR(400MHz,CDCl3)δ7.91(s,2H),7.74(d,J＝8.3Hz,2H),7.36(d,J＝8.2Hz,2H),6.92(d,J＝1.3Hz,1H),6.87–6.82(m,2H),3.90(s,3H),3.89(s,3H),3.82–3.74(m,4H),3.49(s,2H),2.48(d,J＝7.8Hz,7H)；MS(ESI)m/z[M+H]+：485.03。 Compound 92I (150 mg, 0.45 mmol), Compound 92J (68 mg, 0.41 mmol), ethyl acetate (2 ml), EtOAc. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a white solid (yield: EtOAc (yield: 50.1%). 1H NMR (400MHz, CDCl3) δ 7.91 (s, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 1.3 Hz, 1H) ), 6.87–6.82 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.82–3.74 (m, 4H), 3.49 (s, 2H), 2.48 (d, J = 7.8 Hz, 7H); MS (ESI) m/z [M+H] + : 485.
实施例93Example 93
Figure PCTCN2015100201-appb-000152
Figure PCTCN2015100201-appb-000152
在25ml圆底烧瓶中加入化合物93A(300mg，1.84mmol),化合物93B(511mg，1.67mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(425mg，2mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(5:1)为洗脱剂，得白色固体产物93(345mg，产率：45.6％)。1H NMR(400MHz,CDCl3)δ8.28(d,J＝6.5Hz,2H),7.79(d,J＝8.3Hz,2H),7.32(d,J＝8.2Hz,2H),7.08(d,J＝8.1Hz,1H),6.90(d,J＝1.6Hz,1H),6.86(dd,J＝8.2,1.6Hz,1H),6.67(dd,J＝5.2,1.4Hz,2H),3.60(s,3H),3.50(s,2H),3.39–3.30(m,4H),2.59–2.51(m,4H),2.46(s,3H)；MS(ESI)m/z[M+Na]+：476.08。Compound 93A (300 mg, 1.84 mmol), compound 93B (511 mg, 1.67 mmol), ethyl acetate (2 ml) was added to a 25 ml round bottom flask, and sodium triacetoxyborohydride (425 mg, 2 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc m. The product was obtained as a white solid (yield: 345 mg, yield: 45.6%). 1H NMR (400MHz, CDCl3) δ 8.28 (d, J = 6.5 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.08 (d, J) = 8.1 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.86 (dd, J = 8.2, 1.6 Hz, 1H), 6.67 (dd, J = 5.2, 1.4 Hz, 2H), 3.60 (s) , 3H), 3.50 (s, 2H), 3.39 - 3.30 (m, 4H), 2.59 - 2.51 (m, 4H), 2.46 (s, 3H); MS (ESI) m/z [M+Na] + : 476.08.
实施例94Example 94
Figure PCTCN2015100201-appb-000153
Figure PCTCN2015100201-appb-000153
在25ml圆底烧瓶中加入化合物94A(250mg，1.52mmol)，化合物94B(425mg，1.39mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(353mg,1.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得白色固体产物94(269mg，产率：42.6％)。1H NMR(400MHz,CDCl3)δ8.13(d,J＝1.3Hz,1H),8.05(dd,J＝2.5,1.5Hz,1H),7.84(d,J＝2.6Hz,1H),7.76(d,J＝8.3Hz,2H),7.30(d,J＝8.2Hz,2H),7.07(d,J＝8.1Hz,1H),6.89(d,J＝1.5Hz,1H),6.85(dd,J＝8.2,1.6Hz,1H),3.59(d,J＝4.9Hz,4H),3.57(s,3H),3.49(s,2H),2.56–2.50(m,4H),2.44(s,3H)；MS(ESI)m/z[M+Na]+：477.27。Compound 94A (250 mg, 1.52 mmol), compound 94B (425 mg, 1.39 mmol), ethyl acetate (2 ml). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The white solid product 94 (269 mg, yield: 42.6%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 1.3 Hz, 1H), 8.05 (dd, J = 2.5, 1.5 Hz, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 6.85 (dd , J = 8.2, 1.6 Hz, 1H), 3.59 (d, J = 4.9 Hz, 4H), 3.57 (s, 3H), 3.49 (s, 2H), 2.56 - 2.50 (m, 4H), 2.44 (s, 3H); MS (ESI) m/z [M+Na] + : 477.27.
实施例95Example 95
Figure PCTCN2015100201-appb-000154
Figure PCTCN2015100201-appb-000154
在25ml圆底烧瓶中加入化合物95A(250mg，1.52mmol)，化合物95B(303mg，1.39mmol)，乙酸乙酯(2ml)，搅拌下加入三乙酰氧基硼氢化钠(353mg，1.66mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得无色油状产物95(236mg,产率：43.1％)。1H NMR(400MHz,CDCl3)δ8.29–8.24(m,1H),8.08(d,J＝1.1Hz,1H),8.07–8.03(m,1H),7.92–7.87(m,2H),7.85(d,J＝2.5Hz,1H),7.79(d,J＝7.6Hz,1H),7.64(dd,J＝10.7,4.3Hz,1H),7.57(t,J＝7.4Hz,1H),7.54–7.47(m,3H),3.84(s,2H),3.47–3.36(m,4H),2.43–2.32(m,4H)；MS(ESI)m/z[M+H]+：395.13。To a 25 ml round bottom flask was added compound 95A (250 mg, 1.52 mmol), Compound 95B (303 mg, 1.39 mmol), ethyl acetate (2 ml), and sodium triacetoxyborohydride (353 mg, 1.66 mmol). After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The product 95 (236 mg, yield: 43.1%) was obtained as colorless oil. 1 H NMR (400MHz, CDCl 3 ) δ8.29-8.24 (m, 1H), 8.08 (d, J = 1.1Hz, 1H), 8.07-8.03 (m, 1H), 7.92-7.87 (m, 2H), 7.85 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.64 (dd, J = 10.7, 4.3 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.54 - 7.47 (m, 3H), 3.84 (s, 2H), 3.47 - 3.36 (m, 4H), 2.43 - 2.32 (m, 4H); MS (ESI) m/z [M+H] + : 395.
实施例96Example 96
Figure PCTCN2015100201-appb-000155
Figure PCTCN2015100201-appb-000155
50mL圆底烧瓶中加入化合物96A(784mg，2.39mmol)，氯仿(6mL)，化合物96B(2.28g，9.55mmol)，吡啶(0.5mL)，在65℃油浴中反应6h，反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到无色膏状物96C(170mg，产率12.0％)。Compound 96A (784 mg, 2.39 mmol), chloroform (6 mL), compound 96B (2.28 g, 9.55 mmol), pyridine (0.5 mL) was reacted in a 50 mL round bottom flask, and reacted in an oil bath at 65 ° C for 6 h. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue, and ethyl acetate was evaporated, and the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, and the residue obtained was purified by column chromatography (dichloromethane: methanol 200:1). Colorless paste 96C (170 mg, yield 12.0%).
25mL圆底烧瓶中加入化合物96C(70mg，0.118mmol)，化合物96D(15mg，0.118mmol)，Pd(dppf)Cl2二氯甲烷络合物(10mg，0.012mmol)，醋酸钾(35mg，0.354mmol)，THF/EtOH/水(2mL/2mL/2mL)混合溶剂，氮气保护下在80℃油浴中反应过夜，反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇100:1)分离纯化得到类白色固体96(59mg，产率91.5％)。1H NMR(400MHz,CDCl3)δ9.29(s,1H),8.99(s,2H),7.99–7.94(m,2H),7.76–7.69(m,2H),6.94–6.73(m,7H),3.88(s,3H),3.87(s,3H),3.48(s,2H),3.20–3.10(m,4H),2.61–2.50(m,4H)；MS(ESI)m/z[M+H]+：546.90。Into a 25 mL round bottom flask was added compound 96C (70 mg, 0.118 mmol), compound 96D (15 mg, 0.118 mmol), Pd(dppf)Cl 2 dichloromethane complex (10 mg, 0.012 mmol), potassium acetate (35 mg, 0.354 mmol) THF, EtOH / water (2mL / 2mL / 2mL) mixed solvent, under nitrogen protection in 80 ° C oil bath overnight, the reaction solution was spun dry, the residue was added saturated aqueous sodium bicarbonate, ethyl acetate extraction, combined organic The mixture was washed with water and dried over anhydrous sodium sulfate, and the residue obtained was purified by column chromatography (dichloromethane: methanol: 100:1) to afford white-white solid 96 (59 mg, yield 91.5%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.29 (s, 1H), 8.99 (s, 2H), 7.79 - 7.94 (m, 2H), 7.76 - 7.69 (m, 2H), 6.94 - 6.73 (m, 7H) ), 3.88 (s, 3H), 3.87 (s, 3H), 3.48 (s, 2H), 3.20 - 3.10 (m, 4H), 2.61 - 2.50 (m, 4H); MS (ESI) m / z [M +H] + : 546.90.
实施例97Example 97
Figure PCTCN2015100201-appb-000156
Figure PCTCN2015100201-appb-000156
50mL圆底烧瓶中加入化合物97A(250mg，0.761mmol)，用DMF(4mL)溶解，置于冰浴中，搅拌5min，加入氢化钠(27mg，1.14mmol)，继续在冰浴中搅拌10min，升至室温搅拌30min，加入化合物97B(214mg，1.52mmol)，室温下搅拌过夜。反应液中加入水和乙酸乙酯，萃取分层，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到白色固体97(107mg，产率32.5％)。1H NMR(400MHz,CDCl3)δ7.21–7.14(m,2H),6.94–6.79(m,5H),3.90(s,3H),3.88(s,3H),3.50(s,2H),3.23–3.14(m,4H),2.63–2.51(m,5H),1.28–1.21(m,2H),1.12–1.05(m,2H)；MS(ESI)m/z[M+H]+：433.03。Compound 97A (250 mg, 0.761 mmol) was added to a 50 mL round bottom flask, which was dissolved in DMF (4 mL), and then stirred and stirred for 5 min, and sodium hydride (27 mg, 1.14 mmol) was added and the mixture was stirred in an ice bath for 10 min. After stirring to room temperature for 30 min, compound 97B (214 mg, 1.52 mmol. Water and ethyl acetate were added to the reaction mixture, and the layers were separated, and the organic layer was combined, washed with water, dried over anhydrous sodium sulfate, and the residue obtained was purified by column chromatography (dichloromethane: methanol 200:1). White solid 97 (107 mg, yield 32.5%). 1 H NMR (400MHz, CDCl 3 ) δ7.21-7.14 (m, 2H), 6.94-6.79 (m, 5H), 3.90 (s, 3H), 3.88 (s, 3H), 3.50 (s, 2H), 3.23–3.14(m,4H), 2.63–2.51(m,5H), 1.28–1.21(m,2H),1.12–1.05(m,2H);MS(ESI)m/z[M+H] + : 433.03.
实施例98Example 98
Figure PCTCN2015100201-appb-000157
Figure PCTCN2015100201-appb-000157
100mL圆底烧瓶中加入化合物98A(1g，6.23mmol)，再依次加入DMF(25mL)，DMSO(5mL)搅拌溶解，再加入碳酸钾(1.72g，12.5mmol)，碘甲烷(426μL，6.85mmol)，在25℃油浴中搅拌16h。反应液加水，用乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到得到白色固体98B(700mg，产率64.4％)。Compound 98A (1 g, 6.23 mmol) was added to a 100 mL round bottom flask, followed by DMF (25 mL), DMSO (5 mL), and then dissolved, and then potassium carbonate (1.72 g, 12.5 mmol), iodomethane (426 μL, 6.85 mmol) Stir in a 25 ° C oil bath for 16 h. The reaction mixture was combined with EtOAc EtOAc.
100mL圆底烧瓶中依次加入化合物98B(700mg，4.01mmol)，98C(1.12g，6.02mmol)，碳酸氢钠(674mg，8.02mmol)，分子筛(20颗)，乙醇(30mL)，在100℃油浴中回流10h。反应液抽滤，乙醇洗涤，滤液旋干，得到的残渣经柱层析(二氯甲烷：甲 醇100:1)得到白色固体98D(697mg，产率53.6％)。Compound 98B (700 mg, 4.01 mmol), 98C (1.12 g, 6.02 mmol), sodium hydrogencarbonate (674 mg, 8.02 mmol), molecular sieves (20), ethanol (30 mL), and oil at 100 ° C, in a 100 mL round bottom flask Reflux in the bath for 10 h. The reaction solution was suction filtered, washed with ethanol, and the filtrate was evaporated to dryness. Alcohol 100: 1) gave 98D (697 mg, yield 53.6%) as a white solid.
100mL圆底烧瓶中加入化合物98D(348mg，1.07mmol)，用二氯甲烷(8mL)溶解，加入TFA(2mL)，室温下搅拌过夜，反应液旋干，并加入二氯甲烷再次旋干，得到的无色油状物98E，直接用于下一步反应。The compound 98D (348 mg, 1.07 mmol) was added to a 100 mL round bottom flask, which was dissolved in dichloromethane (8 mL), EtOAc (2 mL). The colorless oil 98E was used directly in the next reaction.
50mL圆底烧瓶中加入化合物98E，再依次加入二氯甲烷(12mL)，三乙胺(447μL，3.21mmol)，化合物98F(328mg，1.07mmol)，室温搅拌2h，加入三乙酰氧基硼氢化钠(340mg，1.61mmol)，在25℃油浴中搅拌过夜。反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到白色固体98(347mg，产率63.0％)。1H NMR(400MHz,CDCl3)δ7.80–7.74(m,2H),7.34–7.27(m,2H),7.06(d,J＝8.1Hz,1H),6.86(d,J＝1.4Hz,1H),6.82(dd,J＝8.2,1.6Hz,1H),5.24(s,1H),3.59(s,3H),3.50(s,2H),3.37(s,3H),3.31(s,3H),3.00–2.89(m,4H),2.65–2.48(m,4H),2.45(s,3H)；MS(ESI)m/z[M+H]+：515.01。Compound 98E was added to a 50 mL round bottom flask, followed by dichloromethane (12 mL), triethylamine (447 μL, 3.21 mmol), compound 98F (328 mg, 1.07 mmol), stirred at room temperature for 2 h, and sodium triacetoxyborohydride was added. (340 mg, 1.61 mmol), stirred in a 25 ° C oil bath overnight. The reaction mixture was evaporated to dryness. EtOAc m. 1) Isolation and purification gave 98 (yield: 63.0%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 - 7.74 (m, 2H), 7.34 - 7.27 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 6.82 (dd, J=8.2, 1.6 Hz, 1H), 5.24 (s, 1H), 3.59 (s, 3H), 3.50 (s, 2H), 3.37 (s, 3H), 3.31 (s, 3H) ), 3.00 - 2.89 (m, 4H), 2.65 - 2.48 (m, 4H), 2.45 (s, 3H); MS (ESI) m/z [M+H] + : 515.01.
实施例99Example 99
Figure PCTCN2015100201-appb-000158
Figure PCTCN2015100201-appb-000158
在50ml圆底烧瓶中加入化合物99A(500mg,2.40mmol)，化合物99B(736mg,2.40mmol)，乙酸乙酯(5ml)，搅拌下加入三乙酰氧基硼氢化钠(763mg,3.60mmol)。室温下搅拌过夜，TLC检测原料反应完全。用饱和碳酸氢钠水溶液淬灭反应，再用乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(3:1)为洗脱剂，得淡黄色固体产物99(539mg,产率：45.1％)。1H NMR(400MHz,CDCl3)δ9.04(d,J＝2.7Hz,1H),8.20(dd,J＝9.5,2.8Hz,1H),7.79(d,J＝8.3Hz,2H),7.33(d,J＝8.1Hz,2H),7.09(d,J＝8.1Hz,1H),6.90(s,1H),6.88–6.83(m,1H),6.58(d,J＝9.5Hz,1H),3.83–3.75(m,4H),3.61(s,3H),3.51(s,2H),2.57–2.51(m,4H),2.47(s,3H)；MS(ESI)m/z[M]+：498.97。Compound 99A (500 mg, 2.40 mmol), compound 99B (736 mg, 2.40 mmol), ethyl acetate (5 ml), EtOAc. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The product was obtained as a pale yellow solid (yield: 539 mg, yield: 45.1%). 1H NMR (400MHz, CDCl3) δ 9.04 (d, J = 2.7 Hz, 1H), 8.20 (dd, J = 9.5, 2.8 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.33 (d) , J = 8.1 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.88 - 6.83 (m, 1H), 6.58 (d, J = 9.5 Hz, 1H), 3.83 – 3.75 (m, 4H), 3.61 (s, 3H), 3.51 (s, 2H), 2.57–2.51 (m, 4H), 2.47 (s, 3H); MS (ESI) m/z [M] + : 498.97.
实施例100Example 100
Figure PCTCN2015100201-appb-000159
Figure PCTCN2015100201-appb-000159
50mL圆底烧瓶中加入化合物100A(250mg，0.761mmol)，用DMF(4mL)溶解，置于冰浴中，搅拌5min，加入氢化钠(27mg，1.14mmol)，继续在冰浴中搅拌10min，升至室温搅拌30min，加入化合物100B(382mg，1.52mmol)，室温下搅拌过夜。反应液中加入水和乙酸乙酯，萃取分层，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到类白色固体100(79mg，产率19.1％)。1H NMR(400MHz,CDCl3)δ7.21–7.15(m,2H),7.00–6.80(m,5H),3.90(s,3H),3.88(s,3H),3.77(d,J＝15.0Hz,1H),3.53(s,2H),3.27–3.17(m,4H),3.14(d,J＝15.0Hz,1H),2.70–2.50(m,5H),2.46–2.36(m,1H),2.16–2.02(m,2H),1.96(d,J＝18.5Hz,1H),1.70(ddd,J＝13.9,9.3,4.6Hz,1H),1.45(ddd,J＝13.2,9.4,3.9Hz,1H),1.16(s,3H),0.90(s,3H)；MS(ESI)m/z[M+H]+：543.01。Compound 100A (250 mg, 0.761 mmol) was added to a 50 mL round bottom flask, dissolved in DMF (4 mL), and then stirred in ice-cooled for 5 min, sodium hydride (27 mg, 1.14 mmol) was added, and the mixture was stirred in an ice bath for 10 min. After stirring to room temperature for 30 min, compound 100B (382 mg, 1.52 mmol. Water and ethyl acetate were added to the reaction mixture, and the layers were separated, and the organic layer was combined, washed with water, dried over anhydrous sodium sulfate, and the residue obtained was purified by column chromatography (dichloromethane: methanol 200:1). An off-white solid 100 (79 mg, yield 19.1%). 1 H NMR (400MHz, CDCl 3 ) δ7.21-7.15 (m, 2H), 7.00-6.80 (m, 5H), 3.90 (s, 3H), 3.88 (s, 3H), 3.77 (d, J = 15.0 Hz, 1H), 3.53 (s, 2H), 3.27–3.17 (m, 4H), 3.14 (d, J = 15.0 Hz, 1H), 2.70–2.50 (m, 5H), 2.46–2.36 (m, 1H) , 2.16–2.02 (m, 2H), 1.96 (d, J = 18.5 Hz, 1H), 1.70 (ddd, J = 13.9, 9.3, 4.6 Hz, 1H), 1.45 (ddd, J = 13.2, 9.4, 3.9 Hz , 1H), 1.16 (s, 3H), 0.90 (s, 3H); MS (ESI) m/z [M+H] + : 543.01.
实施例101Example 101
Figure PCTCN2015100201-appb-000160
Figure PCTCN2015100201-appb-000160
在25ml圆底烧瓶中加入化合物101C(280mg,0.85mmol),二氯甲烷(2ml),三乙胺(173mg,1.71mmol)，搅拌下加入化合物101D(152mg,0.85mmol)。室温下搅拌过夜，TLC检测原料反应完全。将反应体系浓缩后用水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(20:1)为洗脱剂，得无色油状产物101(249mg,产率：62.5％)。1H NMR(400MHz,CDCl3)δ9.00(d,J＝2.3Hz,1H),8.89(dd,J＝4.9,1.6Hz,1H),8.14–8.10(m,1H),7.51–7.47(m,1H),6.91–6.77(m,7H),3.91(d,J＝5.4Hz,6H),3.52(s,2H),3.20–3.15(m,4H),2.65–2.52(m,4H)；MS(ESI)m/z[M+H]+：470.56。Compound 101C (280 mg, 0.85 mmol), dichloromethane (2 ml), triethylamine (173 mg, 1.71 mmol) was added to a 25 ml round bottom flask and compound 101D (152 mg, 0.85 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction system is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is evaporated. Oily product 101 (249 mg, yield: 62.5%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (d, J = 2.3 Hz, 1H), 8.89 (dd, J = 4.9, 1.6 Hz, 1H), 8.14 - 8.10 (m, 1H), 7.51 - 7.47 ( m,1H), 6.91–6.77 (m,7H), 3.91 (d, J=5.4 Hz, 6H), 3.52 (s, 2H), 3.20–3.15 (m, 4H), 2.65–2.52 (m, 4H) ;MS (ESI) m/z [M+H] + : 470.56.
实施例102Example 102
Figure PCTCN2015100201-appb-000161
Figure PCTCN2015100201-appb-000161
在25ml圆底烧瓶中加入化合物102C(200mg,0.74mmol),二氯甲烷(2ml),三乙胺(132mg,0.74mmol)，搅拌下加入化合物102D(149mg,1.48mmol)。室温下搅拌过夜，TLC检测原料反应完全。将反应体系浓缩后用水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(30:1)为洗脱剂，得白色固体产物102(193mg,产率：63.6％)。1H NMR(400MHz,CDCl3)δ8.98(d,J＝2.1Hz,1H),8.87(dd,J＝4.9,1.6Hz,1H),8.57(d,J＝1.7Hz,1H),8.52(dd,J＝4.8,1.5Hz,1H),8.15–8.04(m,1H),7.69(d,J＝7.8Hz,1H),7.48(dd,J＝8.0,4.9Hz,1H),7.33–7.23(m,1H),6.90–6.81(m,2H),6.81–6.72(m,2H),3.56(s,2H),3.20–3.09(m,4H),2.65–2.52(m,4H)；MS(ESI)m/z[M+H]+：410.28。Compound 102C (200 mg, 0.74 mmol), methylene chloride (2 ml), triethylamine (132 mg, 0.74 mmol) was added to a 25 ml round bottom flask, and Compound 102D (149 mg, 1.48 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction mixture was concentrated, diluted with water, EtOAc EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Product 102 (193 mg, yield: 63.6%). 1 H NMR (400MHz, CDCl 3 ) δ8.98 (d, J = 2.1Hz, 1H), 8.87 (dd, J = 4.9,1.6Hz, 1H), 8.57 (d, J = 1.7Hz, 1H), 8.52 (dd, J = 4.8, 1.5 Hz, 1H), 8.15 - 8.04 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.48 (dd, J = 8.0, 4.9 Hz, 1H), 7.33 - 7.23 (m, 1H), 6.90–6.81 (m, 2H), 6.81–6.72 (m, 2H), 3.56 (s, 2H), 3.20–3.09 (m, 4H), 2.65–2.52 (m, 4H); MS (ESI) m / z [ m + H] +: 410.28.
实施例103Example 103
Figure PCTCN2015100201-appb-000162
Figure PCTCN2015100201-appb-000162
在25ml圆底烧瓶中加入化合物103C(180mg,0.55mmol)，二氯甲烷(2ml)，三乙胺(111mg，1.10mmol)，搅拌下加入化合物103D(100mg，0.55mmol)。室温下搅拌过夜，TLC检测原料反应完全。将反应体系浓缩后用水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以石油醚：乙酸乙酯(3:1)为洗脱剂，得无色油状产物103(171mg,产率：65.7％)。1H NMR(400MHz,CDCl3)δ7.15(d,J＝9.1Hz,2H),6.97–6.81(m,5H),3.91(s,3H),3.90(s,3H),3.52(s,2H),3.24–3.12(m,5H),2.64–2.56(m,4H),2.33(d,J＝13.2Hz,2H),2.00–1.91(m,2H),1.79–1.66(m,3H),1.39–1.27(m,3H)；MS(ESI)m/z[M+H]+：475.22。Compound 103C (180 mg, 0.55 mmol), methylene chloride (2 ml), triethylamine (111 mg, 1.10 mmol) was added to a 25 ml round bottom flask and compound 103D (100 mg, 0.55 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction system is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is combined, dried over anhydrous sodium sulfate, and then evaporated to silica gel column eluted with petroleum ether: ethyl acetate (3:1) as eluent. Color oil product 103 (171 mg, yield: 65.7%). 1 H NMR (400MHz, CDCl 3 ) δ7.15 (d, J = 9.1Hz, 2H), 6.97-6.81 (m, 5H), 3.91 (s, 3H), 3.90 (s, 3H), 3.52 (s, 2H), 3.24–3.12 (m, 5H), 2.64–2.56 (m, 4H), 2.33 (d, J = 13.2 Hz, 2H), 2.00–1.91 (m, 2H), 1.79–1.66 (m, 3H) , 1.39-1.27 (m, 3H); MS (ESI) m / z [m + H] +: 475.22.
实施例104Example 104
Figure PCTCN2015100201-appb-000163
Figure PCTCN2015100201-appb-000163
在25ml圆底烧瓶中加入化合物104C(169mg,0.51mmol),二氯甲烷(2ml),三乙胺(104mg,1.03mmol)，搅拌下加入化合物104D(100mg,0.51mmol)。室温下搅拌过夜，TLC检测原料反应完全。将反应体系浓缩后用水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩后经硅胶柱层析，以二氯甲烷：甲醇(30:1)为洗脱剂，得无色油状产物104(151mg,产率：60.8％)。1H NMR(400MHz,CDCl3)δ7.34(s,1H),7.09–7.00(m,2H),6.93(s,1H),6.89–6.78(m,4H),3.91(d,J＝5.6Hz,6H),3.61(s,3H),3.51(s,2H),3.22–3.11(m,4H),2.69–2.53(m,4H),2.46(s,3H)；MS(ESI)m/z[M+H]+：487.03。Compound 104C (169 mg, 0.51 mmol), methylene chloride (2 ml), triethylamine (104 mg, 1.03 mmol) was added to a 25 ml round bottom flask and compound 104D (100 mg, 0.51 mmol) was added with stirring. After stirring at room temperature overnight, the reaction of the starting material was completely confirmed by TLC. The reaction system is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is evaporated. Oily product 104 (151 mg, yield: 60.8%). 1H NMR (400MHz, CDCl3) δ 7.34 (s, 1H), 7.09 - 7.00 (m, 2H), 6.93 (s, 1H), 6.89 - 6.78 (m, 4H), 3.91 (d, J = 5.6 Hz, 6H), 3.61 (s, 3H), 3.51 (s, 2H), 3.22 - 3.11 (m, 4H), 2.69 - 2.53 (m, 4H), 2.46 (s, 3H); MS (ESI) m/z [ M+H] + : 487.03.
实施例105Example 105
Figure PCTCN2015100201-appb-000164
Figure PCTCN2015100201-appb-000164
参照实施例103的制备方案制备得到化合物105。MS(ESI)m/z[M+H]+：461.61。Compound 105 was prepared by following the preparation scheme of Example 103. MS (ESI) m / z [ M + H] +: 461.61.
实施例106Example 106
Figure PCTCN2015100201-appb-000165
Figure PCTCN2015100201-appb-000165
50mL圆底烧瓶中加入化合物106A(500mg，2.67mmol)，再依次加入二氯甲烷(12mL)，化合物106B(818mg，2.67mmol)，室温搅拌2h，加入三乙酰氧基硼氢化钠(849mg，4.00mmol)，在25℃油浴中搅拌过夜。反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到无色膏状物106C(502mg，产率39.4％)。Compound 106A (500 mg, 2.67 mmol) was added to a 50 mL round bottom flask, and then dichloromethane (12 mL) was added. Compound 106B (818 mg, 2.67 mmol) was stirred at room temperature for 2 h, and sodium triacetoxyborohydride (849 mg, 4.00) was added. Methyl), stirred overnight in a 25 ° C oil bath. The reaction mixture was evaporated to dryness. EtOAc m. 1) Isolation and purification gave a colorless cream (yield: 502 mg, yield: 39.4%).
50mL圆底烧瓶中加入化合物106C(205mg，0.429mmol)，再依次加入叠氮基三甲基硅(564μL，4.29mmol)，TBAF(1M THF溶液)(515μL，0.515mmol)，在100℃油浴中搅拌12h。反应体系中加入水，搅拌，析出类白色固体，抽滤，水洗，收集滤饼，溶于二氯甲烷-甲醇混合溶剂，抽滤，得到的滤液旋干，残渣中加入乙醇，抽滤，乙醇洗涤，收集滤饼，干燥后得到白色固体化合物106(128mg，产率57.3％)。1H NMR(400MHz,DMSO-d6)δ7.90–7.82(m,2H),7.73–7.65(m,2H),7.50–7.41(m,2H),7.14–7.06(m,2H),7.04(d,J＝8.2Hz,1H),7.00(d,J＝1.3Hz,1H),6.91(dd,J＝8.2,1.4Hz,1H),3.52(s,1H),3.49(s,2H),3.32–3.26(m,4H),3.16(s,3H),2.55–2.50(m,4H),2.41(s,3H)；MS(ESI)m/z[M+Na]+：542.90。Compound 106C (205 mg, 0.429 mmol) was added to a 50 mL round bottom flask, followed by azidotrimethylsilyl (564 μL, 4.29 mmol), TBAF (1M in THF) (515 μL, 0.515 mmol), oil bath at 100 ° C Stir for 12h. Water is added to the reaction system, stirred, and a white solid is precipitated, suction filtered, washed with water, and the filter cake is collected, dissolved in a dichloromethane-methanol mixture solvent, and filtered, and the obtained filtrate is dried, and ethanol is added to the residue. After washing, the cake was collected and dried to give Compound Compound Compound Compound Compound Compound Compound Compound Compound 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.90 - 7.82 (m, 2H), 7.73 - 7.65 (m, 2H), 7.50 - 7.41 (m, 2H), 7.14 - 7.06 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 1.3 Hz, 1H), 6.91 (dd, J = 8.2, 1.4 Hz, 1H), 3.52 (s, 1H), 3.49 (s, 2H) , 3.32 - 3.26 (m, 4H), 3.16 (s, 3H), 2.55 - 2.50 (m, 4H), 2.41 (s, 3H); MS (ESI) m/z [M+Na] + : 542.90.
实施例107Example 107
Figure PCTCN2015100201-appb-000166
Figure PCTCN2015100201-appb-000166
100mL圆底烧瓶中加入化合物107A(2g，9.04mmol)，溶于二氯甲烷(50mL)，再加入化合物107B(1.5g，9.04mmol)，室温搅拌2h，加入三乙酰氧基硼氢化钠(2.87g，13.6mmol)，室温下搅拌过夜。反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到黄色固体107C(1.73g，产率51.5％)。Compound 107A (2 g, 9.04 mmol) was added to a 100 mL round bottom flask, dissolved in dichloromethane (50 mL), and then compound 107B (1.5 g, 9.04 mmol) was stirred at room temperature for 2 h, and sodium triacetoxyborohydride (2.87) was added. g, 13.6 mmol), stirred at room temperature overnight. The reaction mixture was evaporated to dryness. EtOAc m. 1) Isolation and purification afforded a yellow solid (yield:::::::::::::::
100mL圆底烧瓶中依次加入107C(1.73g，4.66mmol)，钯碳(525mg)，乙醇(20mL)，四氢呋喃(5mL)，在氢气氛围下室温，常压搅拌反应6h。反应液抽滤，乙醇洗涤，合并滤液，旋干，得到浅棕色膏状物107D。直接用于下一步反应。107 C (1.73 g, 4.66 mmol), palladium on carbon (525 mg), ethanol (20 mL), and tetrahydrofuran (5 mL) were added to a 100 mL round bottom flask, and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 h. The reaction solution was suction filtered, washed with ethanol, and the filtrate was combined and evaporated to give a pale brown cream. Used directly in the next step.
100mL圆底烧瓶中依次加入107D，异丙醇(20mL)，水(2mL)，搅拌溶解，再依次加入乙醛(40％水溶液)(471μL，4.66mmol)，钯碳(496mg)，甲酸铵(2.94g，46.6mmol)，室温搅拌反应过夜。反应液抽滤，乙醇洗涤，合并滤液，旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到浅棕色膏状物107E。直接用于下一步反应。In a 100 mL round bottom flask, 107 D, isopropanol (20 mL), water (2 mL) were added successively, stirred and dissolved, and then acetaldehyde (40% aqueous solution) (471 μL, 4.66 mmol), palladium carbon (496 mg), ammonium formate ( 2.94 g, 46.6 mmol), stirred at room temperature overnight. The reaction mixture was suction filtered, washed with EtOAc, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 107E. Used directly in the next step.
50mL圆底烧瓶中加入化合物107E，溶于二氯甲烷(20mL)，再加入化合物107F(499μL，3.75mmol)，三乙胺(523μL，3.75mmol)， 室温下搅拌2h。反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到白色固体化合物107(579mg，产率23.6％)。1H NMR(400MHz,CDCl3)δ7.47–7.39(m,2H),7.36–7.31(m,1H),7.29–7.22(m,1H),6.93–6.76(m,7H),4.06(d,J＝13.0Hz,1H),3.90(s,3H),3.88(s,3H),3.56(q,J＝7.1Hz,2H),3.47–3.32(m,2H),3.12(d,J＝13.0Hz,1H),2.93–2.78(m,2H),2.73(dd,J＝11.5,9.3Hz,1H),2.64–2.54(m,1H),2.24(td,J＝11.1,3.0Hz,1H),1.23(d,J＝6.1Hz,3H),1.07(t,J＝7.1Hz,3H)；MS(ESI)m/z[M+Na]+：550.13。Compound 107E was added to a 50 mL round-bottomed flask, dissolved in dichloromethane (20 mL), EtOAc (EtOAc, EtOAc (EtOAc) The reaction mixture was evaporated to dryness. EtOAc m. 1) Isolation and purification gave Compound 107 (yield: 579 mg, yield: 23.6%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 - 7.39 (m, 2H), 7.36 - 7.31 (m, 1H), 7.29 - 7.22 (m, 1H), 6.93 - 6.76 (m, 7H), 4.06 (d) , J = 13.0 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.56 (q, J = 7.1 Hz, 2H), 3.47 - 3.32 (m, 2H), 3.12 (d, J = 13.0 Hz, 1H), 2.93–2.78 (m, 2H), 2.73 (dd, J=11.5, 9.3 Hz, 1H), 2.64–2.54 (m, 1H), 2.24 (td, J=11.1, 3.0 Hz, 1H) ), 1.23 (d, J = 6.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); MS (ESI) m/z [M+Na] + : 550.13.
实施例108Example 108
Figure PCTCN2015100201-appb-000167
Figure PCTCN2015100201-appb-000167
100mL圆底烧瓶中加入化合物108A(1.67g，7.55mmol)，溶于二氯甲烷(50mL)，再加入化合物108B(1.25g，7.55mmol)，室温搅拌2h，加入三乙酰氧基硼氢化钠(2.40g，11.3mmol)，室温下搅拌过夜。反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到黄色固体108C(1.60g，产率57.1％)。Compound 108A (1.67 g, 7.55 mmol) was added to a 100 mL round bottom flask, dissolved in dichloromethane (50 mL), and then compound 108B (1.25 g, 7.55 mmol) was stirred at room temperature for 2 h, and sodium triacetoxyborohydride was added. 2.40 g, 11.3 mmol), stirred at room temperature overnight. The reaction mixture was evaporated to dryness. EtOAc m. 1) Isolation and purification gave a yellow solid 108C (1.60 g, yield 57.1%).
100mL圆底烧瓶中依次加入108C(1.60g，4.31mmol)，钯碳(450mg)，乙醇(20mL)，四氢呋喃(5mL)，在氢气氛围下室温，常压搅拌反应6h。反应液抽滤，乙醇洗涤，合并滤液，旋干，得到浅棕色膏状物108D。直接用于下一步反应。108 C (1.60 g, 4.31 mmol), palladium carbon (450 mg), ethanol (20 mL), tetrahydrofuran (5 mL) were added to a 100 mL round bottom flask, and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 h. The reaction solution was suction filtered, washed with ethanol, and the filtrate was combined and evaporated to give a pale brown cream. Used directly in the next step.
100mL圆底烧瓶中依次加入108D，异丙醇(20mL)，水(2mL)，搅拌溶解，再依次加入乙醛(40％水溶液)(435μL，4.31mmol)，钯碳(459mg)，甲酸铵(2.72g，43.1mmol)，室温搅拌反应过夜。反应液抽滤，乙醇洗涤，合并滤液，旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到浅棕色膏状物108E。直接用于下一步反应。In a 100 mL round bottom flask, 108 D, isopropanol (20 mL), water (2 mL) were added successively, stirred and dissolved, and then acetaldehyde (40% aqueous solution) (435 μL, 4.31 mmol), palladium carbon (459 mg), ammonium formate ( 2.72 g, 43.1 mmol), stirred at room temperature overnight. The reaction mixture was suction filtered, washed with EtOAc, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 108E. Used directly in the next step.
50mL圆底烧瓶中加入化合物108E，溶于二氯甲烷(20mL)，再加入化合物108F(479μL，3.60mmol)，三乙胺(502μL，3.60mmol)，室温下搅拌2h。反应液旋干，残渣中加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，合并有机相，水洗涤，无水硫酸钠干燥，旋干后得到的残渣经柱层析(二氯甲烷：甲醇200:1)分离纯化得到白色固体化合物108(437mg，产率19.2％)。1H NMR(400MHz,CDCl3)δ7.47–7.38(m,2H),7.36–7.31(m,1H),7.29–7.22(m,1H),6.93–6.76(m,7H),4.06(d,J＝13.0Hz,1H),3.56(q,J＝7.1Hz,2H),3.47–3.32(m,2H),3.12(d,J＝13.0Hz,1H),2.92–2.78(m,2H),2.73(dd,J＝11.5,9.3Hz,1H),2.65–2.53(m,1H),2.24(td,J＝11.2,3.1Hz,1H),1.23(d,J＝6.1Hz,3H),1.07(t,J＝7.1Hz,3H)；MS(ESI)m/z[M+H]+：528.17。Compound 108E was added to a 50 mL round-bottom flask, dissolved in dichloromethane (20 mL), EtOAc (EtOAc, EtOAc (EtOAc) The reaction mixture was evaporated to dryness. EtOAc m. 1) Isolation and purification gave Compound 108 (yield: </RTI><RTIgt; 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 - 7.38 (m, 2H), 7.36 - 7.31 (m, 1H), 7.29 - 7.22 (m, 1H), 6.93 - 6.76 (m, 7H), 4.06 (d) , J = 13.0 Hz, 1H), 3.56 (q, J = 7.1 Hz, 2H), 3.47 - 3.32 (m, 2H), 3.12 (d, J = 13.0 Hz, 1H), 2.92 - 2.78 (m, 2H) , 2.73 (dd, J = 11.5, 9.3 Hz, 1H), 2.65 - 2.53 (m, 1H), 2.24 (td, J = 11.2, 3.1 Hz, 1H), 1.23 (d, J = 6.1 Hz, 3H), 1.07 (t, J = 7.1Hz, 3H); MS (ESI) m / z [m + H] +: 528.17.
实施例109Example 109
Figure PCTCN2015100201-appb-000168
Figure PCTCN2015100201-appb-000168
参照以上的实施例实施方案和相关文献制备得到化合物109，MS(ESI)m/z[M+H]+：497.60。Preparation of Compound 109, MS (ESI) m/z [M+H] + : 497.60.
实施例110Example 110
Figure PCTCN2015100201-appb-000169
Figure PCTCN2015100201-appb-000169
参照以上的实施例实施方案和相关文献制备得到化合物110，MS(ESI)m/z[M+H]+：497.23。 Preparation of compound 110, MS (ESI) m/z [M+H] + : 497.23.
实施例111Example 111
Figure PCTCN2015100201-appb-000170
Figure PCTCN2015100201-appb-000170
参照以上的实施例实施方案和相关文献制备得到化合物111，MS(ESI)m/z[M+H]+：511.21。Preparation of Compound 111, MS (ESI) m/z [M+H] + : 511.21.
实施例112Example 112
Figure PCTCN2015100201-appb-000171
Figure PCTCN2015100201-appb-000171
参照以上的实施例实施方案和相关文献制备得到化合物112，MS(ESI)m/z[M+H]+：511.42。Preparation of Compound 112, MS (ESI) m/z [M+H] + : 51.42.
实施例113Example 113
Figure PCTCN2015100201-appb-000172
Figure PCTCN2015100201-appb-000172
参照以上的实施例实施方案和相关文献制备得到化合物113，MS(ESI)m/z[M+H]+：511.43。Preparation of Compound 113, MS (ESI) m/z [M+H] + : 51.43.
实施例114Example 114
Figure PCTCN2015100201-appb-000173
Figure PCTCN2015100201-appb-000173
参照以上的实施例实施方案和相关文献制备得到化合物114，MS(ESI)m/z[M+H]+：509.72。Preparation of Compound 114, MS (ESI) m/z [M+H] + : 509.72.
实施例115Example 115
Figure PCTCN2015100201-appb-000174
Figure PCTCN2015100201-appb-000174
参照以上的实施例实施方案和相关文献制备得到化合物115，MS(ESI)m/z[M+H]+：509.23。Preparation of Compound 115, MS (ESI) m/z [M+H] + : 509.23.
实施例116Example 116
Figure PCTCN2015100201-appb-000175
Figure PCTCN2015100201-appb-000175
参照以上的实施例实施方案和相关文献制备得到化合物116，MS(ESI)m/z[M+H]+：509.33。 Preparation of Compound 116, MS (ESI) m/z [M+H] + : 509.33.
实施例117Example 117
Figure PCTCN2015100201-appb-000176
Figure PCTCN2015100201-appb-000176
参照以上的实施例实施方案和相关文献制备得到化合物117，MS(ESI)m/z[M+H]+：497.26。Preparation of Compound 117, MS (ESI) m/z [M+H] + : 497.26.
实施例118Example 118
Figure PCTCN2015100201-appb-000177
Figure PCTCN2015100201-appb-000177
参照以上的实施例实施方案和相关文献制备得到化合物118，MS(ESI)m/z[M+H]+：495.60。Preparation of Compound 118, MS (ESI) m/z [M+H] + : 495.60.
实施例119Example 119
Figure PCTCN2015100201-appb-000178
Figure PCTCN2015100201-appb-000178
参照以上的实施例实施方案和相关文献制备得到化合物119，MS(ESI)m/z[M+H]+：510.64。Preparation of Compound 119, MS (ESI) m/z [M+H] + : 510.64.
实施例120Example 120
Figure PCTCN2015100201-appb-000179
Figure PCTCN2015100201-appb-000179
参照以上的实施例实施方案和相关文献制备得到化合物120，MS(ESI)m/z[M+H]+：510.34。Compound 120 was prepared by reference to the above Examples and related literature to obtain MS (ESI) m/z [M+H] + : 510.34.
实施例121Example 121
Figure PCTCN2015100201-appb-000180
Figure PCTCN2015100201-appb-000180
参照以上的实施例实施方案和相关文献制备得到化合物121，MS(ESI)m/z[M+H]+：510.46。Preparation of Compound 121, MS (ESI) m/z [M+H] + : 510.46.
实施例122Example 122
Figure PCTCN2015100201-appb-000181
Figure PCTCN2015100201-appb-000181
参照以上的实施例实施方案和相关文献制备得到化合物122，MS(ESI)m/z[M+H]+：508.21。 Preparation of Compound 122, MS (ESI) m/z [M+H] + : 508.21.
实施例123Example 123
Figure PCTCN2015100201-appb-000182
Figure PCTCN2015100201-appb-000182
参照以上的实施例实施方案和相关文献制备得到化合物123，MS(ESI)m/z[M+H]+：514.46。Preparation of Compound 123, MS (ESI) m/z [M+H] + : 514.46.
实施例124Example 124
Figure PCTCN2015100201-appb-000183
Figure PCTCN2015100201-appb-000183
参照以上的实施例实施方案和相关文献制备得到化合物124，MS(ESI)m/z[M+H]+：508.22。Preparation of Compound 124, MS (ESI) m/z [M+H] + : 508.22.
实施例125Example 125
Figure PCTCN2015100201-appb-000184
Figure PCTCN2015100201-appb-000184
参照以上的实施例实施方案和相关文献制备得到化合物125，MS(ESI)m/z[M+H]+：501.60。Preparation of compound 125, MS (ESI) m/z [M+H] + : 501.60.
实施例126Example 126
Figure PCTCN2015100201-appb-000185
Figure PCTCN2015100201-appb-000185
参照以上的实施例实施方案和相关文献制备得到化合物126，1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.16(s,1H),7.63–7.55(m,1H),7.55–7.41(m,4H),7.09(dd,J＝8.2,1.7Hz,1H),7.02–6.93(m,3H),6.91–6.83(m,2H),4.27(s,2H),3.78(s,3H),3.76(s,3H),3.73–3.63(m,2H),3.35–3.24(m,2H),3.23–2.98(m,4H)；MS(ESI)m/z[M+H]+：486.62。The compound 126, 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 10.16 (s, 1H), 7.63 - 7.55 (m, 1H) was prepared by reference to the above examples and related literature. , 7.55–7.41 (m, 4H), 7.09 (dd, J=8.2, 1.7 Hz, 1H), 7.02–6.93 (m, 3H), 6.91–6.83 (m, 2H), 4.27 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.73–3.63 (m, 2H), 3.35–3.24 (m, 2H), 3.23–2.98 (m, 4H); MS (ESI) m/z [M+ H] + : 486.62.
实施例127Example 127
Figure PCTCN2015100201-appb-000186
Figure PCTCN2015100201-appb-000186
参照以上的实施例实施方案和相关文献制备得到化合物127，MS(ESI)m/z[M+H]+：483.23。Preparation of Compound 127, MS (ESI) m/z [M+H] + : 483.23.
实施例128Example 128
Figure PCTCN2015100201-appb-000187
Figure PCTCN2015100201-appb-000187
参照以上的实施例实施方案和相关文献制备得到化合物128，MS(ESI)m/z[M+H]+：487.62。 Preparation of Compound 128, MS (ESI) m/z [M+H] + : 487.62.
实施例129Example 129
Figure PCTCN2015100201-appb-000188
Figure PCTCN2015100201-appb-000188
参照以上的实施例实施方案和相关文献制备得到化合物129，MS(ESI)m/z[M+H]+：486.23。Preparation of Compound 129, MS (ESI) m/z [M+H] + : 486.23.
实施例130Example 130
Figure PCTCN2015100201-appb-000189
Figure PCTCN2015100201-appb-000189
参照以上的实施例实施方案和相关文献制备得到化合物130，MS(ESI)m/z[M+H]+：482.61。Preparation of Compound 130, MS (ESI) m/z [M+H] + : 482.61.
实施例131Example 131
Figure PCTCN2015100201-appb-000190
Figure PCTCN2015100201-appb-000190
参照以上的实施例实施方案和相关文献制备得到化合物131，MS(ESI)m/z[M+H]+：482.32。Preparation of Compound 131, MS (ESI) m/z [M+H] + : 482.32.
实施例132Example 132
Figure PCTCN2015100201-appb-000191
Figure PCTCN2015100201-appb-000191
参照以上的实施例实施方案和相关文献制备得到化合物132，MS(ESI)m/z[M+H]+：486.31。Preparation of compound 132, MS (ESI) m/z [M+H] + : 486.31.
实施例133Example 133
Figure PCTCN2015100201-appb-000192
Figure PCTCN2015100201-appb-000192
参照以上的实施例实施方案和相关文献制备得到化合物133，MS(ESI)m/z[M+H]+：483.60。Preparation of Compound 133, MS (ESI) m/z [M+H] + : 483.6.
实施例134Example 134
Figure PCTCN2015100201-appb-000193
Figure PCTCN2015100201-appb-000193
参照以上的实施例实施方案和相关文献制备得到化合物134，MS(ESI)m/z[M+H]+：482.63。 Preparation of compound 134, MS (ESI) m/z [M+H] + : 482.63.
实施例135Example 135
Figure PCTCN2015100201-appb-000194
Figure PCTCN2015100201-appb-000194
参照以上的实施例实施方案和相关文献制备得到化合物135，MS(ESI)m/z[M+H]+：486.72。Preparation of Compound 135, MS (ESI) m/z [M+H] + : 486.72.
实施例136Example 136
Figure PCTCN2015100201-appb-000195
Figure PCTCN2015100201-appb-000195
参照以上的实施例实施方案和相关文献制备得到化合物136，MS(ESI)m/z[M+H]+：493.21。Preparation of Compound 136, MS (ESI) m/z [M+H] + : 493.21.
实施例137Example 137
Figure PCTCN2015100201-appb-000196
Figure PCTCN2015100201-appb-000196
参照以上的实施例实施方案和相关文献制备得到化合物137，MS(ESI)m/z[M+H]+：517.24。Preparation of compound 137, MS (ESI) m/z [M+H] + : 517.24.
实施例138Example 138
Figure PCTCN2015100201-appb-000197
Figure PCTCN2015100201-appb-000197
参照以上的实施例实施方案和相关文献制备得到化合物138，MS(ESI)m/z[M+H]+：477.26。Preparation of Compound 138, MS (ESI) m/z [M+H] + : 477.26.
实施例139Example 139
Figure PCTCN2015100201-appb-000198
Figure PCTCN2015100201-appb-000198
参照以上的实施例实施方案和相关文献制备得到化合物139，1H NMR(400MHz,CDCl3)δ7.81–7.76(m,2H),7.74–7.68(m,2H),7.46(dd,J＝3.6,0.9Hz,1H),7.42(dd,J＝5.1,0.8Hz,1H),7.14(dd,J＝5.0,3.7Hz,1H),6.96–6.73(m,7H),3.89(s,3H),3.87(s,3H),3.50(s,2H),3.21–3.10(m,4H),2.64–2.50(m,4H).MS(ESI)m/z[M+H]+：550.90。Compound 139 was prepared by reference to the above examples and related literature. 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 - 7.76 (m, 2H), 7.74 - 7.68 (m, 2H), 7.46 (dd, J = 3.6, 0.9 Hz, 1H), 7.42 (dd, J = 5.1, 0.8 Hz, 1H), 7.14 (dd, J = 5.0, 3.7 Hz, 1H), 6.96 - 6.73 (m, 7H), 3.89 (s, 3H) ), 3.87 (s, 3H), 3.50 (s, 2H), 3.21 - 3.10 (m, 4H), 2.64 - 2.50 (m, 4H). MS (ESI) m/z [M+H] + : 550.90.
实施例140Example 140
Figure PCTCN2015100201-appb-000199
Figure PCTCN2015100201-appb-000199
参照以上的实施例实施方案和相关文献制备得到化合物140，1H NMR(400MHz,CDCl3)δ8.76–8.70(m,2H),7.96–7.90(m,2H), 7.79–7.72(m,2H),7.55–7.49(m,2H),6.94–6.74(m,7H),3.88(s,3H),3.87(s,3H),3.49(s,2H),3.21–3.07(m,4H),2.62–2.49(m,4H).MS(ESI)m/z[M+H]+：546.01；MS(ESI)m/z[M+H]+：546.23。The compound 140 was prepared by reference to the above examples and related literature. 1 H NMR (400 MHz, CDCl 3 ) δ 8.76 - 8.70 (m, 2H), 7.96 - 7.90 (m, 2H), 7.79 - 7.72 (m, 2H), 7.55–7.49 (m, 2H), 6.94–6.74 (m, 7H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.21–3.07 (m, 4H) , 2.62-2.49 (m, 4H) .MS (ESI) m / z [m + H] +: 546.01; MS (ESI) m / z [m + H] +: 546.23.
实施例141Example 141
Figure PCTCN2015100201-appb-000200
Figure PCTCN2015100201-appb-000200
参照以上的实施例实施方案和相关文献制备得到化合物141，1H NMR(400MHz,CDCl3)δ7.82–7.73(m,4H),7.56–7.54(m,1H),6.90(d,J＝1.1Hz,1H),6.88–6.79(m,5H),6.79–6.72(m,2H),6.54(dd,J＝3.4,1.8Hz,1H),3.89(s,3H),3.87(s,3H),3.48(s,2H),3.18–3.09(m,4H),2.60–2.51(m,4H).MS(ESI)m/z[M+H]+：534.96。The compound 141, 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 - 7.73 (m, 4H), 7.56 - 7.54 (m, 1H), 6.90 (d, J =) was prepared by reference to the above examples and related literature. 1.1 Hz, 1H), 6.88–6.79 (m, 5H), 6.79–6.72 (m, 2H), 6.54 (dd, J=3.4, 1.8 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H) ), 3.48 (s, 2H), 3.18 - 3.09 (m, 4H), 2.60 - 2.51 (m, 4H). MS (ESI) m/z [M+H] + : 534.96.
实施例142Example 142
Figure PCTCN2015100201-appb-000201
Figure PCTCN2015100201-appb-000201
参照以上的实施例实施方案和相关文献制备得到化合物142，1H NMR(400MHz,CDCl3)δ7.91–7.84(m,2H),7.72–7.65(m,2H),7.49–7.37(m,2H),7.30–7.23(m,1H),7.23–7.16(m,1H),6.94–6.74(m,7H),3.89(s,3H),3.87(s,3H),3.49(s,2H),3.21–3.10(m,4H),2.62–2.49(m,4H).MS(ESI)m/z[M+H]+：563.01。The compound 142, 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 - 7.84 (m, 2H), 7.72 - 7.65 (m, 2H), 7.49 - 7.37 (m, 2H), 7.30–7.23 (m, 1H), 7.23–7.16 (m, 1H), 6.94–6.74 (m, 7H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H) , 3.21 - 3.10 (m, 4H), 2.62 - 2.49 (m, 4H). MS (ESI) m/z [M+H] + : 563.
实施例143Example 143
Figure PCTCN2015100201-appb-000202
Figure PCTCN2015100201-appb-000202
参照以上的实施例实施方案和相关文献制备得到化合物143，1H NMR(400MHz,CDCl3)δ7.89–7.83(m,2H),7.74–7.67(m,2H),7.40(t,J＝8.0Hz,1H),7.22–7.17(m,1H),7.15–7.11(m,1H),7.00–6.95(m,1H),6.93–6.73(m,7H),3.89(s,3H),3.88(s,3H),3.87(s,3H),3.49(s,2H),3.19–3.09(m,4H),2.61–2.49(m,4H).MS(ESI)m/z[M+H]+：575.05。The compound 143, 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 - 7.83 (m, 2H), 7.74 - 7.67 (m, 2H), 7.40 (t, J =) was prepared by reference to the above examples and related literature. 8.0 Hz, 1H), 7.22–7.17 (m, 1H), 7.15–7.11 (m, 1H), 7.00–6.95 (m, 1H), 6.93–6.73 (m, 7H), 3.89 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.19 - 3.09 (m, 4H), 2.61 - 2.49 (m, 4H). MS (ESI) m/z [M+H] + :575.05.
实施例144Example 144
Figure PCTCN2015100201-appb-000203
Figure PCTCN2015100201-appb-000203
参照以上的实施例实施方案和相关文献制备得到化合物144，1H NMR(400MHz,CDCl3)δ7.89–7.83(m,2H),7.74–7.69(m,2H),7.65(d,J＝4.0Hz,1H),7.41(d,J＝4.0Hz,1H),6.93–6.72(m,7H),3.89(s,3H),3.87(s,3H),3.49(s,2H),3.18–3.11(m,4H),2.61–2.51(m,4H).MS(ESI)m/z[M+H]+：575.85。The compound 144, 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 - 7.83 (m, 2H), 7.74 - 7.69 (m, 2H), 7.65 (d, J =) was prepared by reference to the above examples and related literature. 4.0 Hz, 1H), 7.41 (d, J = 4.0 Hz, 1H), 6.93 - 6.72 (m, 7H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.18 - 3.11 (m, 4H), 2.61 - 2.51 (m, 4H). MS (ESI) m/z [M+H] + : 575.85.
实施例145Example 145
Figure PCTCN2015100201-appb-000204
Figure PCTCN2015100201-appb-000204
参照以上的实施例实施方案和相关文献制备得到化合物145，MS(ESI)m/z[M+H]+：500.37。Preparation of Compound 145, MS (ESI) m/z [M+H] + : 500.37.
实施例146Example 146
Figure PCTCN2015100201-appb-000205
Figure PCTCN2015100201-appb-000205
参照以上的实施例实施方案和相关文献制备得到化合物146，1H NMR(400MHz,CDCl3)δ7.47–7.38(m,2H),7.36–7.31(m,1H),7.28–7.22(m,1H),6.92(d,J＝1.6Hz,1H),6.90–6.77(m,6H),3.89(s,3H),3.88(s,3H),3.56(q,J＝7.1Hz,2H),3.50(s,2H),3.25–3.16(m,4H),2.64–2.52(m,4H),1.07(t,J＝7.1Hz,3H).MS(ESI)m/z[M+H]+：514.08。The compound 146, 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 - 7.38 (m, 2H), 7.36 - 7.31 (m, 1H), 7.28 - 7.22 (m, 1H), 6.92 (d, J = 1.6 Hz, 1H), 6.90 - 6.77 (m, 6H), 3.89 (s, 3H), 3.88 (s, 3H), 3.56 (q, J = 7.1 Hz, 2H), 3.50(s,2H), 3.25–3.16(m,4H), 2.64–2.52(m,4H),1.07(t,J=7.1Hz,3H).MS(ESI)m/z[M+H] + :514.08.
实施例147Example 147
Figure PCTCN2015100201-appb-000206
Figure PCTCN2015100201-appb-000206
参照以上的实施例实施方案和相关文献制备得到化合物147，MS(ESI)m/z[M+H]+：529.11。Preparation of Compound 147, MS (ESI) m/z [M+H] + : 529.11.
实施例148Example 148
Figure PCTCN2015100201-appb-000207
Figure PCTCN2015100201-appb-000207
参照实施例16制备得到化合物16E，将化合物16E300mg(0.916mmol)溶解于15mL二氯甲烷中，然后加入三乙胺140μL(1.01mmol)，室温下搅拌，再分批加入化合物148B 223mg(1.01mmol)，加毕，室温下反应过夜。反应液有固体析出，抽滤，得到的滤饼经硅胶柱层析(二氯甲烷：甲醇10:1)纯化得到白色固体，该固体用25mL二氯甲烷分散，室温搅拌1h，抽滤，二氯甲烷洗涤，收集滤饼，干燥后得到白色固体化合物148(28mg，产率6.0％)。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.09–8.02(m,2H),7.82–7.74(m,2H),6.97–6.75(m,7H),3.73(s,6H),3.47(s,2H),3.09–3.02(m,4H),2.52–2.45(m,4H).MS(ESI)m/z[M+H]+,512.2。The compound 16E was obtained according to the preparation of Example 16 and the compound 16E was dissolved in 15 mL of dichloromethane, then 140 μL (1.01 mmol) of triethylamine was added thereto, and stirred at room temperature, and then compound 148B 223 mg (1.01 mmol) was added portionwise. After the addition, the reaction was carried out overnight at room temperature. The reaction mixture was solid and precipitated. The obtained cake was purified by silica gel column chromatography (dichloromethane: methanol: 10:1) to give a white solid. After washing with methyl chloride, the cake was collected and dried to give Compound 148 (yield: 1 H NMR (400MHz, DMSO- d 6) δ9.96 (s, 1H), 8.09-8.02 (m, 2H), 7.82-7.74 (m, 2H), 6.97-6.75 (m, 7H), 3.73 (s , 6H), 3.47 (s, 2H), 3.09 - 3.02 (m, 4H), 2.52 - 2.45 (m, 4H). MS (ESI) m/z [M+H] + , 512.2.
实施例149Example 149
Figure PCTCN2015100201-appb-000208
Figure PCTCN2015100201-appb-000208
参照实施例16制备得到化合物16E，将化合物16E 300mg(0.916mmol)溶解于15mL二氯甲烷中，然后加入三乙胺140μL(1.01mmol)，室温下搅拌，再分批加入化合物149B 223mg(1.01mmol)，加毕，室温下反应过夜。反应液有固体析出，抽滤，得到的滤饼经硅胶柱层析(二氯甲烷：甲醇10:1)纯化得到白色固体，该固体用25mL二氯甲烷分散，室温搅拌1h，抽滤，二氯甲烷洗涤，收集滤饼，该固体用30mL甲醇回流溶解，放置析出固体，抽滤，甲醇洗涤，收集滤饼，干燥后得到白色固体化合物149(48mg，产率10.2％)。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.28–8.23(m,1H),8.15–8.09(m,1H),7.90–7.82(m,1H),7.66(t,J＝7.8Hz,1H),6.98–6.74(m,7H),3.73(s,6H),3.47(s,2H),3.09–3.00(m,4H),2.52–2.43(m,4H).MS(ESI)m/z[M+H]+,512.1。Compound 16E was prepared according to Example 16 and Compound 16E 300 mg (0.916 mmol) was dissolved in 15 mL of dichloromethane, then, then, triethylamine, 140 μL (1.01 mmol), and stirred at room temperature, and then added 149B 223 mg (1.01 mmol) ), after the addition, the reaction was carried out overnight at room temperature. The reaction mixture was solid and precipitated. The obtained cake was purified by silica gel column chromatography (dichloromethane: methanol: 10:1) to give a white solid. The methyl chloride was washed, and the cake was collected. The solid was dissolved in 30 mL of methanol, and the solid was precipitated, filtered, and washed with methanol. The filter cake was collected to afford white solid compound 149 (48 mg, yield 10.2%). 1 H NMR (400MHz, DMSO- d 6) δ9.94 (s, 1H), 8.28-8.23 (m, 1H), 8.15-8.09 (m, 1H), 7.90-7.82 (m, 1H), 7.66 (t , J = 7.8 Hz, 1H), 6.98 - 6.74 (m, 7H), 3.73 (s, 6H), 3.47 (s, 2H), 3.09 - 3.00 (m, 4H), 2.52 - 2.43 (m, 4H). MS (ESI) m / z [ m + H] +, 512.1.
实施例150Example 150
Figure PCTCN2015100201-appb-000209
Figure PCTCN2015100201-appb-000209
参照以上的实施例实施方案和相关文献制备得到化合物150，MS(ESI)m/z[M+H]+：540.22。 Compound 150 was obtained by reference to the above example and related literature to obtain MS (ESI) m/z [M+H] + : 540.22.
实施例151Example 151
Figure PCTCN2015100201-appb-000210
Figure PCTCN2015100201-appb-000210
将5-甲酰基水杨酸151A(1.66g,10.0mM)溶于N,N-二甲基甲酰胺(30mL)中，加入碳酸钾(4.14g,30mM)和碘甲烷(2.18mL,35mM)，室温过夜。TLC监测反应完全，加入水和乙酸乙酯萃取，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩干燥得到产品151B。5-formylsalicylic acid 151A (1.66 g, 10.0 mM) was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (4.14 g, 30 mM) and methyl iodide (2.18 mL, 35 mM) , overnight at room temperature. The reaction was completed by TLC. EtOAc was evaporated.
将以上产品151B溶于二氯甲烷(150mL)中，加入1-(4-硝基苯基)哌嗪(1.9g,9.2mM)，滴入醋酸(500μL)，搅拌半小时后，分批加入三乙酰氧基硼氢化钠(3.18g,15mM)，室温搅拌过夜。TLC监测反应完全，加入饱和碳酸氢钠水溶液，二氯甲烷萃取，合并有机层，分别用5％柠檬酸水溶液、水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩干燥得到油状产品151C。静置2h后析出固体，用石油醚/乙酸乙酯(2/1)打浆，过滤，干燥得产品151C。The above product 151B was dissolved in dichloromethane (150 mL), 1-(4-nitrophenyl)piperazine (1.9 g, 9.2 mM) was added, and acetic acid (500 μL) was added dropwise thereto, and after stirring for half an hour, it was added in portions. Sodium triacetoxyborohydride (3.18 g, 15 mM) was stirred at room temperature overnight. The reaction was completed by TLC, EtOAc (EtOAc m. After standing for 2 h, a solid precipitated, which was beaten with petroleum ether/ethyl acetate (2/1), filtered and dried to give product 151 C.
将以上产品151C溶于甲醇(100mL)中，于0℃条件下缓慢滴加一水氢氧化锂(2.1g,50mM)的水(25mL)溶液，升温至45℃，搅拌过夜。TLC监测反应完全，浓缩，加入水和乙醚萃取，用浓盐酸将水相pH调至2，析出固体，过滤，用水和乙酸乙酯洗涤，干燥得到产品151D。The above product 151C was dissolved in methanol (100 mL), and a solution of lithium hydroxide (2.1 g, 50 mM) in water (25 mL) was slowly added dropwise at 0 ° C, warmed to 45 ° C and stirred overnight. The reaction was monitored by TLC, EtOAc (EtOAc)EtOAc.
往产品151D中加入甲醇(30mL)、四氢呋喃(30mL)和10％钯/碳(150mg)，在氢气条件下反应。经TLC监测反应完全，硅藻土过滤，浓缩滤液得产品151E。To the product 151D, methanol (30 mL), tetrahydrofuran (30 mL) and 10% palladium/carbon (150 mg) were added and reacted under hydrogen. The reaction was completely monitored by TLC, filtered over Celite, and filtrated to give product 151E.
将化合物151E 300mg(0.879mmol)分散于15mL水中，然后加入碳酸钾242mg(1.76mmol)，室温下搅拌，再分批加入对甲苯磺酰氯151F 184mg(0.967mmol)，加毕，室温下反应过夜。反应液用2M HCl调节pH至3，有固体析出，抽滤，水洗涤，抽干，用混合溶剂(二氯甲烷：甲醇5:1)洗涤，收集有机溶剂洗涤液，旋干，经硅胶柱层析(二氯甲烷：甲醇10:1)纯化得到白色固体，该固体用15mL二氯甲烷分散，室温搅拌1h，抽滤，二氯甲烷洗涤，收集滤饼，该固体用水分散，滴加饱和碳酸钠溶解，再滴加稀盐酸调节pH至6，析出固体，抽滤，水洗涤，收集滤饼，干燥后得到白色固体化合物151(69mg，产率15.8％)。1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.61–7.53(m,3H),7.47–7.39(m,1H),7.36–7.28(m,2H),7.11–7.05(m,1H),6.93–6.85(m,2H),6.82–6.73(m,2H),3.80(s,3H),3.47(s,2H),3.10–2.95(m,4H),2.52–2.40(m,4H),2.33(s,3H).MS(ESI)m/z[M+H]+,496.2。 Compound 151E 300 mg (0.879 mmol) was dispersed in 15 mL of water, then 242 mg (1.76 mmol) of potassium carbonate was added thereto, and stirred at room temperature, and then 184 mg (0.967 mmol) of p-toluenesulfonyl chloride 151F was added in portions, and the mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH 3 with 2M HCl, and a solid was precipitated, suction filtered, washed with water, dried, washed with a mixed solvent (dichloromethane:methanol 5:1), and the organic solvent was collected and evaporated to dryness. Chromatography (dichloromethane:methanol: 10:1) was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted The sodium carbonate was dissolved, and dilute hydrochloric acid was added dropwise to adjust the pH to 6 to precipitate a solid, which was filtered, washed with water, and then filtered to afford a white solid compound 151 (69 mg, yield 15.8%). 1 H NMR (400MHz, DMSO- d 6) δ9.75 (s, 1H), 7.61-7.53 (m, 3H), 7.47-7.39 (m, 1H), 7.36-7.28 (m, 2H), 7.11-7.05 (m,1H), 6.93–6.85 (m, 2H), 6.82–6.73 (m, 2H), 3.80 (s, 3H), 3.47 (s, 2H), 3.10–2.95 (m, 4H), 2.52–2.40 (m, 4H), 2.33 ( s, 3H) .MS (ESI) m / z [m + H] +, 496.2.
实施例152Example 152
Figure PCTCN2015100201-appb-000211
Figure PCTCN2015100201-appb-000211
参照以上的实施例实施方案和相关文献制备得到化合物152，MS(ESI)m/z[M+H]+：496.25。Preparation of Compound 152, MS (ESI) m/z [M+H] + : 496.25.
实施例153Example 153
Figure PCTCN2015100201-appb-000212
Figure PCTCN2015100201-appb-000212
参照以上的实施例实施方案和相关文献制备得到化合物153，MS(ESI)m/z[M+H]+：526.26。Preparation of compound 153, MS (ESI) m/z [M+H] + : 526.26.
实施例154Example 154
Figure PCTCN2015100201-appb-000213
Figure PCTCN2015100201-appb-000213
参照以上的实施例实施方案和相关文献制备得到化合物154，MS(ESI)m/z[M+H]+：558.12。Preparation of Compound 154, MS (ESI) m/z [M+H] + : 558.12.
实施例155Example 155
Figure PCTCN2015100201-appb-000214
Figure PCTCN2015100201-appb-000214
按照实施例151制备得到151E。将化合物151E 300mg(0.879mmol)分散于15mL水中，然后加入碳酸钾242mg(1.76mmol)，室温下搅拌，再分批加入丹酰氯155B 283mg(1.05mmol)，加毕，室温下反应过夜。反应液用2M HCl调节pH至3，有固体析出，抽滤，水洗涤，抽干，用混合溶剂(二氯甲烷：甲醇5:1)洗涤，收集有机溶剂洗涤液，旋干，经硅胶柱层析(二氯甲烷：甲醇10:1)纯化得到白色固体，该固体用15mL二氯甲烷分散，室温搅拌1h，抽滤，二氯甲烷洗涤，收集滤饼，干燥后得到白色固体化合物155(10mg，产率2.0％)。1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.46–8.34(m,2H),8.12–8.05(m,1H),7.67–7.52(m,3H),7.44–7.37(m,1H),7.29–7.23(m,1H),7.10–7.03(m,1H),6.86–6.78(m,2H),6.75–6.66(m,2H),3.79(s,3H),3.42(s,2H),3.01–2.91(m,4H),2.81(s,6H),2.45–2.35(m,4H).MS(ESI)m/z[M+H]+,575.1。151E was obtained as in Example 151. Compound 151E 300 mg (0.879 mmol) was dispersed in 15 mL of water, then 242 mg (1.76 mmol) of potassium carbonate was added, and stirred at room temperature, then danyl chloride 155B 283 mg (1.05 mmol) was added portionwise, and the reaction was carried out overnight at room temperature. The reaction solution was adjusted to pH 3 with 2M HCl, and a solid was precipitated, suction filtered, washed with water, dried, washed with a mixed solvent (dichloromethane:methanol 5:1), and the organic solvent was collected and evaporated to dryness. Chromatography (dichloromethane:methanol: 10:1)mield eluted eluted eluted eluted eluted eluted eluted 10 mg, yield 2.0%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.46 - 8.34 (m, 2H), 8.12 - 8.05 (m, 1H), 7.67 - 7.52 (m, 3H), 7.44 - 7.37 (m, 1H), 7.29–7.23 (m, 1H), 7.10–7.03 (m, 1H), 6.86–6.78 (m, 2H), 6.75–6.66 (m, 2H), 3.79 (s, 3H), 3.42 (s, 2H), 3.01 - 2.91 (m, 4H), 2.81 (s, 6H), 2.45 - 2.35 (m, 4H). MS (ESI) m/z [M+H] + , 575.1.
实施例156Example 156
Figure PCTCN2015100201-appb-000215
Figure PCTCN2015100201-appb-000215
按照实施例151制备得到151E。将化合物151E 300mg(0.879mmol)分散于15mL水中，然后加入碳酸钾242mg(1.76mmol)，室温下搅拌，再分批加入2-萘磺酰氯156B 239mg(1.05mmol)，加毕，室温下反应过夜。反应液用2M HCl调节pH至3，有固体析出，抽滤，水洗涤，抽干，用混合溶剂(二氯甲烷：甲醇5:1)洗涤，收集有机溶剂洗涤液，旋干，经硅胶柱层析(二氯甲烷：甲醇10:1)纯化得到白色固体，该固体用15mL二氯甲烷分散，室温搅拌1h，抽滤，二氯甲烷洗涤，收集滤饼，干燥后得到白色固体化合物156(113mg，产率24.2％)。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.32(s,1H),8.13–8.05(m,2H),8.01(d,J＝8.0Hz,1H),7.82–7.37(m,5H),7.17–7.05(m,1H),6.97–6.88(m,2H),6.81–6.71(m,2H),3.81(s,3H),3.36(s,2H),3.10–2.95(m,4H),2.52–2.37(m,4H).MS(ESI)m/z[M+H]+,532.2。151E was obtained as in Example 151. Compound 151E 300 mg (0.879 mmol) was dispersed in 15 mL of water, then 242 mg (1.76 mmol) of potassium carbonate was added, and stirred at room temperature, then 2-naphthalenesulfonyl chloride 156B 239 mg (1.05 mmol) was added portionwise, and the reaction was carried out overnight at room temperature. . The reaction solution was adjusted to pH 3 with 2M HCl, and a solid was precipitated, suction filtered, washed with water, dried, washed with a mixed solvent (dichloromethane:methanol 5:1), and the organic solvent was collected and evaporated to dryness. Chromatography (dichloromethane:methanol 10:1)mield eluted eluted eluted eluted eluted eluted eluted 113 mg, yield 24.2%). 1 H NMR (400MHz, DMSO- d 6) δ9.97 (s, 1H), 8.32 (s, 1H), 8.13-8.05 (m, 2H), 8.01 (d, J = 8.0Hz, 1H), 7.82- 7.37 (m, 5H), 7.17 - 7.05 (m, 1H), 6.97 - 6.88 (m, 2H), 6.81 - 6.71 (m, 2H), 3.81 (s, 3H), 3.36 (s, 2H), 3.10– 2.95 (m, 4H), 2.52-2.37 (m, 4H) .MS (ESI) m / z [m + H] +, 532.2.
实施例157Example 157
Figure PCTCN2015100201-appb-000216
Figure PCTCN2015100201-appb-000216
将1-(4-硝基苯基)哌嗪157A(1.036g,5mM)溶于甲醇(10mL)中，于0℃条件下慢滴入二碳酸二叔丁酯(1.24mL,5.4mM)的甲醇(5mL)溶液。经TLC监测反应完全，浓缩去除溶剂，用石油醚/乙酸乙酯(20/1)打浆，过滤，干燥得产品157B。1-(4-Nitrophenyl)piperazine 157A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC, the solvent was evaporated, and then purified with petroleum ether/ethyl acetate (20/1), filtered and dried to give product 157B.
将以上产品157B溶于甲醇(15mL)中，加入10％钯/碳(150mg)，在氢气条件下反应过夜。经TLC监测反应完全，硅藻土过滤，浓缩滤液得产品157C。The above product 157B was dissolved in methanol (15 mL), and then 10% palladium/carbon (150 mg) was added and reacted under hydrogen overnight. The reaction was completely monitored by TLC, filtered over Celite, and filtered to yield product 157C.
取以上产品157C(720mg,2.59mM)溶于二氯甲烷(15mL)中，加入三乙胺(542μL,3.89mM)和4-联苯磺酰氯(655mg,2.59mM)，反应2.5h，经TLC监测反应完全，加入5％柠檬酸水溶液，用二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(石油醚/乙酸乙酯＝2/1)得到产品157F。The above product 157C (720 mg, 2.59 mM) was dissolved in dichloromethane (15 mL), triethylamine (542 μL, 3.89 mM) and 4-diphenylsulfonyl chloride (655 mg, 2.59 mM) were added and reacted for 2.5 h. The reaction was completed, 5% aqueous citric acid was added, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated.
将以上产品157F溶于甲醇(8mL)中，滴入4M HCl/甲醇(8mL)，反应半小时，经TLC监测反应完全，浓缩得到产品157G。The above product 157F was dissolved in methanol (8 mL), and 4M HCl/methanol (8 mL) was added dropwise, and the reaction was allowed to stand for half an hour, and the reaction was completely monitored by TLC to give product 157G.
将产品157G(150mg,0.35mM)溶于二氯甲烷(8mL)中，加入三乙胺(146μL,1.05mM)和2-溴-4′-甲氧基苯乙酮(80mg,0.35mM)，搅拌过夜。TLC监测反应完全，浓缩，柱层析(二氯甲烷/甲醇＝50/1)得到化合物157(71mg，产率37.5％)。1H NMR(400MHz,CDCl3)δ8.07–8.00(m,2H),7.77(d,J＝8.5Hz,2H),7.65(d,J＝8.5Hz,2H),7.63–7.57(m,2H),7.49(t,J＝7.3Hz,2H),7.43(d,1H),7.00(d,J＝8.9Hz,2H),6.96(d,J＝8.9Hz,2H),6.81(d,J＝8.9Hz,2H),6.42(s,1H),3.90(s,3H),3.85(s,2H),3.30–3.18(m,4H),2.89–2.70(m,4H)。Product 157G (150 mg, 0.35 mM) was dissolved in dichloromethane (8 mL), triethylamine (146 uL, 1.05 mM) and 2-bromo-4'-methoxyacetophenone (80 mg, 0.35 mM). Stir overnight. The reaction was monitored by TLC, EtOAc (EtOAc:MeOH) 1 H NMR (400 MHz, CDCl 3 ) δ 8.07 - 8.00 (m, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.63 - 7.57 (m, 2H), 7.49 (t, J = 7.3 Hz, 2H), 7.43 (d, 1H), 7.00 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 6.42 (s, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 3.30 - 3.18 (m, 4H), 2.89 - 2.70 (m, 4H).
实施例158Example 158
Figure PCTCN2015100201-appb-000217
Figure PCTCN2015100201-appb-000217
将1-(4-硝基苯基)哌嗪158A(1.036g,5mM)溶于甲醇(10mL)中，于0℃条件下慢滴入二碳酸二叔丁酯(1.24mL,5.4mM)的甲醇(5mL)溶液。经TLC监测反应完全，浓缩去除溶剂，用石油醚/乙酸乙酯(20/1)打浆，过滤，干燥得产品158B。1-(4-Nitrophenyl)piperazine 158A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC, the solvent was evaporated, and then purified with petroleum ether/ethyl acetate (20/1), filtered and dried to give product 158B.
将以上产品158B溶于甲醇(15mL)中，加入10％钯/碳(150mg)，在氢气条件下反应过夜。经TLC监测反应完全，硅藻土过滤，浓缩滤液得产品158C。The above product 158B was dissolved in methanol (15 mL), and 10% palladium/carbon (150 mg) was added and reacted under hydrogen overnight. The reaction was completely monitored by TLC, filtered over Celite, and filtrated to give product 158.
取以上产品158C(832mg,3mM)溶于二氯甲烷(20mL)中，加入三乙胺(557μL,4mM)和丹酰氯(809mg,3mM)，反应过夜。经TLC监测反应完全，加入5％柠檬酸水溶液，用二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(石油醚/乙酸乙酯＝3/1)得到产品158D。The above product 158C (832 mg, 3 mM) was dissolved in dichloromethane (20 mL), and triethylamine (557 μL, 4 mM) and dansyl chloride (809 mg, 3 mM) were added and allowed to react overnight. The reaction was completely monitored by TLC, 5% aqueous citric acid was added, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. .
将以上产品158D溶于甲醇(10mL)中，滴入4M HCl/甲醇(10mL)，反应半小时，经TLC监测反应完全，浓缩得到产品158E。The above product 158D was dissolved in methanol (10 mL), and 4M HCl/methanol (10 mL) was added dropwise, and the reaction was allowed to stand for half an hour.
将产品158E(134mg,0.30mM)溶于二氯甲烷(5mL)中，加入三乙胺(125μL,0.9mM)和2-溴-4′-甲氧基苯乙酮(69mg,0.30mM)，搅拌过夜。TLC监测反应完全，浓缩，柱层析(二氯甲烷/甲醇＝40/1)得到化合物158(64mg，产率38.2％)。1H NMR(400MHz,CDCl3)δ8.50(d,J＝8.5Hz,1H),8.35(d,J＝8.6Hz,1H),8.07(dd,J＝7.3,1.1Hz,1H),8.05–7.99(m,2H),7.65–7.56(m,1H),7.41(dd,J＝8.5,7.4Hz,1H),7.21(d,J＝7.4Hz,1H),6.95(d,J＝8.9Hz,2H),6.77(d,J＝9.0Hz,2H),6.66(d,J＝9.0Hz,2H),6.53(s,1H),3.89(s,3H),3.82(s,2H),3.26–3.07(m,4H),2.91(s,6H),2.77–2.68(m,4H)。 Product 158E (134 mg, 0.30 mM) was dissolved in dichloromethane (5 mL), triethylamine (125 [mu]L, 0.9 mM) and 2-bromo-4'-methoxyacetophenone (69 mg, 0.30 mM). Stir overnight. The reaction was monitored by TLC, EtOAc (EtOAc:MeOH: 1 H NMR (400MHz, CDCl 3 ) δ8.50 (d, J = 8.5Hz, 1H), 8.35 (d, J = 8.6Hz, 1H), 8.07 (dd, J = 7.3,1.1Hz, 1H), 8.05 –7.99(m,2H), 7.65–7.56(m,1H), 7.41 (dd, J=8.5, 7.4 Hz, 1H), 7.21 (d, J=7.4 Hz, 1H), 6.95 (d, J=8.9) Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 6.53 (s, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 3.26–3.07 (m, 4H), 2.91 (s, 6H), 2.77–2.68 (m, 4H).
实施例159Example 159
Figure PCTCN2015100201-appb-000218
Figure PCTCN2015100201-appb-000218
参照以上的实施例实施方案和相关文献制备得到化合物159，MS(ESI)m/z[M+H]+：580.31。Preparation of Compound 159, MS (ESI) m/z [M+H]+: 580.31.
实施例160Example 160
Figure PCTCN2015100201-appb-000219
Figure PCTCN2015100201-appb-000219
将160F(10mmol,1.41g)、160G(15mmol,1.5g)以及三乙胺(15mmol,2.08ml)加入50ml圆底烧瓶中，用DMSO(15ml)溶解，100℃下反应10h。待冷却到室温，加水100ml,有固体析出，然后再加入50ml乙酸乙酯继续搅拌10min，抽滤，用水洗涤3次，得化合物160H，黄色固体1.67g，产率75.6％。1H NMR(400MHz,DMSO)δ8.30(s,1H),8.08(d,J＝9.4Hz,2H),6.97(d,J＝9.5Hz,2H),3.98(s,2H),3.66-3.63(m,2H),3.37-3.33(m,2H)160F (10 mmol, 1.41 g), 160 g (15 mmol, 1.5 g) and triethylamine (15 mmol, 2.08 ml) were added to a 50 ml round bottom flask, dissolved in DMSO (15 ml), and reacted at 100 ° C for 10 h. After cooling to room temperature, 100 ml of water was added, and a solid was precipitated. Then, 50 ml of ethyl acetate was further added and the mixture was stirred for 10 min, filtered, and washed three times with water to give compound 160H, a yellow solid, 1.67 g, yield 75.6%. 1 H NMR (400MHz, DMSO) δ8.30 (s, 1H), 8.08 (d, J = 9.4Hz, 2H), 6.97 (d, J = 9.5Hz, 2H), 3.98 (s, 2H), 3.66- 3.63 (m, 2H), 3.37-3.33 (m, 2H)
将3,4-二甲氧基苯甲醛160A(499mg,3.0mM)溶于甲醇(10mL)中，分批加入硼氢化钠(170mg,4.5mM)，室温搅拌15分钟，TLC监测反应完全，加入饱和氯化铵水溶液淬灭，浓缩除去甲醇，加入二氯甲烷萃取，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩干燥得到产品160B。3,4-Dimethoxybenzaldehyde 160A (499 mg, 3.0 mM) was dissolved in methanol (10 mL), sodium borohydride (170 mg, 4.5 mM) was added in portions and stirred at room temperature for 15 min. The mixture was diluted with a saturated aqueous solution of ammonium chloride, and the mixture was evaporated, evaporated, evaporated, evaporated.
将以上产品160B溶于乙醚(10mL)中，于0℃条件下缓慢滴加三溴化鳞(282μL,3mM)的乙醚(2mL)溶液，室温搅拌过夜。TLC监测反应完全，加入饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，合并有机层，分别用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(石油醚/乙酸乙酯＝5/1)得到产品160C(578mg,收率83.3％)。The above product 160B was dissolved in diethyl ether (10 mL), and a solution of tribromofluoride (282 μL, 3 mM) in diethyl ether (2 mL) was slowly added dropwise at 0 ° C overnight. The reaction was completed by TLC. EtOAc (EtOAc)EtOAc. 5/1) Product 160C (578 mg, yield 83.3%) was obtained.
将4-(4-硝基苯基)哌嗪-2-酮(221mg,1.0mM)溶于四氢呋喃(25mL)中，加入叔丁醇钾(112mg,1.0mM)，升至50℃搅拌15分钟，加入上述所得产品160C的四氢呋喃(5mL)溶液，于50℃继续搅拌3h，加入水和二氯甲烷萃取，合并有机层，分别用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，加入少量二氯甲烷溶解，在搅拌下缓慢滴入石油醚/乙酸乙酯(1/1)，析出固体，除尽未反应的4-(4-硝基苯基)哌嗪2-酮，滤液浓缩，重复此操作可析出产品160D，过滤，洗涤，干燥得到产品160D(105mg,收率28.3％)。4-(4-Nitrophenyl)piperazin-2-one (221 mg, 1.0 mM) was dissolved in tetrahydrofuran (25 mL), potassium t-butoxide (112 mg, 1.0 mM) was added, and the mixture was stirred at 50 ° C for 15 min. The solution of the above-mentioned product 160C in tetrahydrofuran (5 mL) was added, and the mixture was stirred at 50 ° C for 3 h, and then extracted with water and dichloromethane. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate The methylene chloride was dissolved, and petroleum ether/ethyl acetate (1/1) was slowly added dropwise with stirring to precipitate a solid, and the unreacted 4-(4-nitrophenyl)piperazine 2-one was removed, and the filtrate was concentrated. This operation was repeated to precipitate product 160D, which was filtered, washed, and dried to give product 160D (105 mg, yield: 28.3%).
往产品160D中加入甲醇(30mL)和10％钯/碳(20mg)，在氢气条件下反应。经TLC监测反应完全，硅藻土过滤，浓缩滤液得产品160E。Methanol (30 mL) and 10% palladium on carbon (20 mg) were added to product 160D and reacted under hydrogen. The reaction was completely monitored by TLC, filtered over Celite, and filtered to yield product 160E.
将以上产品160E溶于二氯甲烷(15mL)中，加入三乙胺(58μL,0.42mM)和4-联苯磺酰氯(71mg,0.28mM)，反应2.5h，经TLC监测反应完全，加入5％柠檬酸水溶液，用二氯甲烷萃取，分别用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇＝60/1)得到产品160(36mg,收率23.1％)。1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.3Hz,2H),7.64(d,J＝8.3Hz,2H),7.59(d,J＝7.2Hz,2H),7.48(t,J＝7.3Hz,2H),7.45–7.38(m,1H),7.04(d,J＝8.8Hz,2H),6.91–6.79(m,4H),6.74(d,J＝8.8Hz,2H),4.61(s,2H),3.95–3.89(m,2H),3.88(s,3H),3.86(s,3H),3.44–3.31(m,4H)。The above product 160E was dissolved in dichloromethane (15 mL), triethylamine (58 μL, 0.42 mM) and 4-diphenylsulfonyl chloride (71 mg, 0.28 mM) were added and reacted for 2.5 h, and the reaction was completely monitored by TLC. The aqueous solution of citric acid was extracted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate %). 1 H NMR (400MHz, CDCl 3 ) δ7.78 (d, J = 8.3Hz, 2H), 7.64 (d, J = 8.3Hz, 2H), 7.59 (d, J = 7.2Hz, 2H), 7.48 (t , J = 7.3 Hz, 2H), 7.45 - 7.38 (m, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.91 - 6.79 (m, 4H), 6.74 (d, J = 8.8 Hz, 2H) , 4.61 (s, 2H), 3.95 - 3.89 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.44 - 3.31 (m, 4H).
实施例161Example 161
Figure PCTCN2015100201-appb-000220
Figure PCTCN2015100201-appb-000220
参照以上的实施例160实施方案和相关文献制备得到化合物161，1H NMR(400MHz,MeOD)δ7.87(s,1H),7.81–7.70(m,5H),7.65(d,J＝7.3Hz,2H),7.48(t,J＝7.4Hz,2H),7.40(dd,J＝13.2,5.8Hz,3H),7.35–7.30(m,2H),7.03(d,J＝9.0Hz,2H),6.85(d,J＝8.9Hz,2H),4.66(s,2H),3.92–3.85(m,2H),3.41(d,J＝5.2Hz,2H),2.04(m,2H)，MS(ESI)m/z[M+H]+：498.23。The compound 161 was obtained by referring to the above Example 160 and related literature. 1 H NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.81 - 7.70 (m, 5H), 7.65 (d, J = 7.3 Hz) , 2H), 7.48 (t, J = 7.4 Hz, 2H), 7.40 (dd, J = 13.2, 5.8 Hz, 3H), 7.35 - 7.30 (m, 2H), 7.03 (d, J = 9.0 Hz, 2H) , 6.85 (d, J = 8.9 Hz, 2H), 4.66 (s, 2H), 3.92 - 3.85 (m, 2H), 3.41 (d, J = 5.2 Hz, 2H), 2.04 (m, 2H), MS ( ESI) m/z [M+H] + : 498.21.
实施例162Example 162
Figure PCTCN2015100201-appb-000221
Figure PCTCN2015100201-appb-000221
参照以上的实施例实施方案和相关文献制备得到化合物162，MS(ESI)m/z[M+H]+：562.34。Preparation of Compound 162, MS (ESI) m/z [M+H] + : 562.34.
实施例163Example 163
Figure PCTCN2015100201-appb-000222
Figure PCTCN2015100201-appb-000222
参照以上的实施例实施方案和相关文献制备得到化合物163，MS(ESI)m/z[M+H]+：554.34。Preparation of Compound 163, MS (ESI) m/z [M+H] + : 554.34.
实施例164Example 164
Figure PCTCN2015100201-appb-000223
Figure PCTCN2015100201-appb-000223
参照以上的实施例实施方案和相关文献制备得到化合物164，MS(ESI)m/z[M+H]+：572.16。Preparation of Compound 164, MS (ESI) m/z [M+H] + : 572.16.
实施例165Example 165
Figure PCTCN2015100201-appb-000224
Figure PCTCN2015100201-appb-000224
参照以上的实施例实施方案和相关文献制备得到化合物165，MS(ESI)m/z[M+H]+：504.23。Preparation of Compound 165, MS (ESI) m/z [M+H] + :504.23.
实施例166Example 166
Figure PCTCN2015100201-appb-000225
Figure PCTCN2015100201-appb-000225
参照以上的实施例实施方案和相关文献制备得到化合物166，1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.27(s,1H),7.98–7.93(m,2H),7.92–7.87(m,2H),7.44(d,J＝1.9Hz,1H),7.09(dd,J＝8.2,1.9Hz,1H),7.02–6.93(m,3H),6.90–6.83(m,2H),4.27(s,2H), 3.79(s,3H),3.77(s,3H),3.73–3.64(m,2H),3.33–3.24(m,2H),3.21–3.11(m,2H),3.11–2.96(m,2H)；MS(ESI)m/z[M+H]+：536.20。The compound 166, 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.47 (s, 1H), 10.27 (s, 1H), 7.98 - 7.93 (m, 2H) was prepared by reference to the above examples and related literature. , 7.92–7.87 (m, 2H), 7.44 (d, J = 1.9 Hz, 1H), 7.09 (dd, J = 8.2, 1.9 Hz, 1H), 7.02–6.93 (m, 3H), 6.90–6.83 (m) , 2H), 4.27 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.73 - 3.64 (m, 2H), 3.33 - 3.24 (m, 2H), 3.21 - 3.11 (m, 2H) ), 3.11 - 2.96 (m, 2H); MS (ESI) m/z [M+H] + : 536.20.
实施例167Example 167
Figure PCTCN2015100201-appb-000226
Figure PCTCN2015100201-appb-000226
参照以上的实施例实施方案和相关文献制备得到化合物167，1H NMR(400MHz,CDCl3)δ7.58–7.50(m,2H),7.03–6.96(m,2H),6.93(d,J＝1.4Hz,1H),6.90–6.74(m,6H),6.34(s,1H),3.91(s,3H),3.90(s,3H),3.78(s,3H),3.51(s,2H),3.37–3.27(m,4H),2.63–2.51(m,4H).MS(ESI)m/z[M+H]+：498.14。The compound 167, 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 - 7.50 (m, 2H), 7.03 - 6.96 (m, 2H), 6.93 (d, J =) was prepared by reference to the above examples and related literature. 1.4Hz, 1H), 6.90–6.74 (m, 6H), 6.34 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.78 (s, 3H), 3.51 (s, 2H), 3.37 - 3.27 (m, 4H), 2.63 - 2.51 (m, 4H). MS (ESI) m/z [M+H] + : 498.
实施例168Example 168
Figure PCTCN2015100201-appb-000227
Figure PCTCN2015100201-appb-000227
参照以上的实施例实施方案和相关文献制备得到化合物168，1HNMR(400MHz,CDCl3)δ7.86–7.83(m,1H),7.82–7.76(m,2H),7.62–7.56(m,2H),7.55–7.51(m,1H),6.93–6.71(m,8H),3.89(s,3H),3.87(s,3H),3.49(s,2H),3.21–3.08(m,4H),2.64–2.48(m,4H).MS(ESI)m/z[M+H]+：535.00。The compound 168, 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 - 7.83 (m, 1H), 7.82 - 7.76 (m, 2H), 7.62 - 7.56 (m, 2H) were prepared with reference to the above examples and related literature. ), 7.55–7.51 (m, 1H), 6.93–6.71 (m, 8H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.21–3.08 (m, 4H), 2.64-2.48 (m, 4H) .MS ( ESI) m / z [m + H] +: 535.00.
实施例169Example 169
Figure PCTCN2015100201-appb-000228
Figure PCTCN2015100201-appb-000228
参照以上的实施例实施方案和相关文献制备得到化合物169，1H NMR(400MHz,CDCl3)δ7.85–7.78(m,2H),7.74–7.67(m,2H),7.62(dd,J＝2.9,1.4Hz,1H),7.48–7.40(m,2H),6.94–6.70(m,7H),3.89(s,3H),3.87(s,3H),3.49(s,2H),3.20–3.08(m,4H),2.63–2.49(m,4H).MS(ESI)m/z[M+H]+：550.95。Compound 169 was prepared by reference to the above examples and related literature. 1 H NMR (400 MHz, CDCl 3 ) δ 7.85 - 7.78 (m, 2H), 7.74 - 7.67 (m, 2H), 7.62 (dd, J = 2.9, 1.4 Hz, 1H), 7.48–7.40 (m, 2H), 6.94–6.70 (m, 7H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.20–3.08 (m, 4H), 2.63 - 2.49 (m, 4H). MS (ESI) m/z [M+H] + : 550.95.
实施例170Example 170
Figure PCTCN2015100201-appb-000229
Figure PCTCN2015100201-appb-000229
参照以上的实施例实施方案和相关文献制备得到化合物170，1H NMR(400MHz,CDCl3)δ8.77(s,2H),7.94–7.89(m,2H),7.69–7.63(m,2H),6.93–6.74(m,7H),4.09(s,3H),3.88(s,3H),3.87(s,3H),3.48(s,2H),3.20–3.10(m,4H),2.61–2.49(m,4H).MS(ESI)m/z[M+H]+：577.05。The compound 170 was prepared with reference to the above examples and related literature. 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 2H), 7.94 - 7.89 (m, 2H), 7.69 - 7.63 (m, 2H) , 6.93–6.74 (m, 7H), 4.09 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.48 (s, 2H), 3.20–3.10 (m, 4H), 2.61–2.49 (m, 4H) .MS (ESI ) m / z [m + H] +: 577.05.
实施例171Example 171
Figure PCTCN2015100201-appb-000230
Figure PCTCN2015100201-appb-000230
参照以上的实施例实施方案和相关文献制备得到化合物171，1H NMR(400MHz,CDCl3)δ8.01–7.95(m,2H),6.90(d,J＝1.4Hz,1H),6.88–6.79(m,4H),6.60(s,1H),3.88(s,6H),3.49(s,2H),3.38–3.27(m,4H),2.61–2.52(m,4H),2.34(s,6H).MS(ESI)m/z[M+H]+：497.91。 The compound 171, 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 - 7.95 (m, 2H), 6.90 (d, J = 1.4 Hz, 1H), 6.88 - 6.79 was prepared by reference to the above examples and related literature. (m, 4H), 6.60 (s, 1H), 3.88 (s, 6H), 3.49 (s, 2H), 3.38 - 3.27 (m, 4H), 2.61 - 2.52 (m, 4H), 2.34 (s, 6H) MS (ESI) m/z [M+H] + : 495.91.
参比化合物Reference compound
参照文献WO2010075469制备得到下列化合物，以下化合物的波谱学数据与文献一致：The following compounds were prepared by reference to WO2010075469, and the spectroscopy data of the following compounds are consistent with the literature:
Figure PCTCN2015100201-appb-000231
Figure PCTCN2015100201-appb-000231
参照文献WO2014150395制备得到下列化合物，以下化合物的波谱学数据与文献一致：The following compounds were prepared by reference to WO2014150395, and the spectroscopy data of the following compounds are consistent with the literature:
Figure PCTCN2015100201-appb-000232
Figure PCTCN2015100201-appb-000232
本发明部分化合物生物测试结果Biological test results of some compounds of the present invention
一、荧光定量PCR实验检测药物对肝细胞PCSK9基因表达水平的影响1. Quantitative PCR assay to detect the effect of drugs on the expression of PCSK9 gene in hepatocytes
本实验目的是反映化合物对PCSK9基因表达的抑制作用，化合物对PCSK9基因表达的抑制作用越强烈，表明化合物潜在的降脂功效越强。The purpose of this experiment is to reflect the inhibitory effect of the compound on the expression of PCSK9 gene. The stronger the inhibition of PCSK9 gene expression by the compound, the stronger the potential lipid-lowering effect of the compound.
检测药物对HepG2细胞PCSK9mRNA的作用：To test the effect of drugs on PCSK9 mRNA in HepG2 cells:
将HepG2细胞(ATCC)，按每孔7×105细胞/孔的密度接种至6孔板，37℃，5％CO2培养过夜。次日，换液并加入待测药物和阳性药处理24小时。用Trizol试剂(Invitrogen)提取总RNA，RNase-Free DNase(Promega)处理。每份样品取1ug RNA，用M-MLV逆转录酶(Promega)反转录成cDNA作为实时荧光定量PCR的模板。使用经过验证的PCSK9定量PCR引物、β-Actin定量PCR引物作为PCSK9及内参基因β-Actin的引物。用模板、引物、Power SYBR Green PCR Master Mix(Invitrogen)配制各样品的定量PCR反应体系，在定量PCR仪CFX96Real-Time PCR Detection System(Bio-Rad)上按PCR仪器说明书要求进行实时荧光定量PCR反应，获得表达量数据。采用ΔΔCT法处理表达量数据，以β-Actin为内参，空白对照的PCSK9表达量设定为1，求得其余样品中PCSK9相对于对照的相对表达量(相对于对照的倍数)，以此评估药物对肝细胞PCSK9基因表达水平的影响。HepG2 cells (ATCC) were seeded at a density of 7 x 10 5 cells/well per well into 6-well plates and incubated overnight at 37 ° C, 5% CO 2 . The next day, change the solution and add the drug to be tested and the positive drug for 24 hours. Total RNA was extracted with Trizol reagent (Invitrogen) and treated with RNase-Free DNase (Promega). One ug of RNA was taken from each sample and reverse transcribed into cDNA using M-MLV reverse transcriptase (Promega) as a template for real-time PCR. A validated PCSK9 quantitative PCR primer, β-Actin quantitative PCR primer was used as a primer for PCSK9 and the internal reference gene β-Actin. The quantitative PCR reaction system of each sample was prepared by using template, primer, Power SYBR Green PCR Master Mix (Invitrogen), and real-time PCR was performed on the quantitative PCR instrument CFX96 Real-Time PCR Detection System (Bio-Rad) according to the requirements of the PCR instrument. , obtain expression data. The expression level data were processed by ΔΔCT method, and β-Actin was used as the internal reference. The expression level of PCSK9 in the blank control was set to 1, and the relative expression level of PCSK9 relative to the control in the remaining samples (multiples relative to the control) was obtained. The effect of drugs on the expression level of PCSK9 gene in hepatocytes.
实验表明：本发明化合物，例如：1，5，9，10，11，12，13，14，16，17，21，22，25，27，28，29，32，33，34，38，39，41，42，43，44，46，47，50，51，52，54，55，56，57，58等，能够对PCSK9mRNA表达起到强烈的抑制作用。Experiments have shown that the compounds of the invention, for example: 1,5,9,10,11,12,13,14,16,17,21,22,25,27,28,29,32,33,34,38,39 41, 42, 43, 44, 46, 47, 50, 51, 52, 54, 55, 56, 57, 58 and the like can strongly inhibit the expression of PCSK9 mRNA.
二、LDL摄取率测试实验：Second, the LDL uptake rate test experiment:
本实验的目的是在细胞水平上反映化合物对降低LDL的作用。LDL水平过高能致动脉粥样硬化。本实验从细胞水平直接检测肝细胞摄取LDL的能力，可直接反映化合物的降脂效果。The purpose of this experiment was to reflect the effect of compounds on lowering LDL at the cellular level. Excessive LDL levels can cause atherosclerosis. This experiment directly detects the ability of hepatocytes to take up LDL at the cellular level, which directly reflects the lipid-lowering effect of the compound.
LDL摄取率细胞模型：LDL uptake rate cell model:
肝细胞表面表达LDL受体，具有摄取LDL的能力。在培养基中添加荧光物质Dil标记的LDL(Dil-LDL)，在荧光显微镜下可观察到HepG2肝癌细胞将Dil-LDL摄取到细胞内。药物可使肝细胞表面LDL受体的量增多从而增强肝细胞对LDL的摄取能力，因此可用在显微镜下观察到的荧光强度评价样品对肝细胞摄取LDL能力的影响。The surface of hepatocytes expresses LDL receptors and has the ability to take up LDL. The fluorescent substance Dil-labeled LDL (Dil-LDL) was added to the medium, and HepG2 liver cancer cells were observed to take Dil-LDL into the cells under a fluorescence microscope. The drug can increase the amount of LDL receptors on the surface of hepatocytes to enhance the ability of hepatocytes to take up LDL. Therefore, the fluorescence intensity observed under a microscope can be used to evaluate the effect of the sample on the ability of hepatocytes to take up LDL.
常规培养HepG2细胞(ATCC)，按每孔2.5×104个细胞的密度接种至96孔板，37℃，5％CO2培养过夜。次日，弃上清，加入样 品和阳性药处理20小时。弃上清，每孔加入含2μg/ml荧光性的Dil-LDL(Invitrogen)的新鲜培养基，在37℃，5％CO2条件下继续孵育4小时。弃上清，用PBS洗涤细胞2次，换新鲜培养基，在荧光显微镜(Leica DM IL LED Microsystems)下观察每孔细胞的荧光强度。以不加样品及Dil-LDL处理的正常细胞作为阴性对照。用在显微镜下观察到的荧光强度评价样品对肝细胞摄取LDL能力的影响，并加以分级，便于比较。分级方法如下：HepG2 cells (ATCC) were routinely cultured, seeded into 96-well plates at a density of 2.5 x 104 cells per well, and cultured overnight at 37 ° C, 5% CO 2 . The next day, the supernatant was discarded, and the sample and the positive drug were added for treatment for 20 hours. The supernatant was discarded, and fresh medium containing 2 μg/ml of fluorescent Dil-LDL (Invitrogen) was added to each well, and incubation was continued for 4 hours at 37 ° C under 5% CO 2 . The supernatant was discarded, and the cells were washed twice with PBS, replaced with fresh medium, and the fluorescence intensity of each well was observed under a fluorescence microscope (Leica DM IL LED Microsystems). Normal cells treated with no sample and Dil-LDL were used as negative controls. The effect of the sample on the ability of hepatocytes to take up LDL was evaluated by fluorescence intensity observed under a microscope and graded for comparison. The classification method is as follows:
－表示较正常细胞对照而言，无增加的荧光强度；- indicates no increased fluorescence intensity compared to normal cell controls;
+表示较正常细胞对照而言，略微增加的荧光强度；+ indicates a slightly increased fluorescence intensity compared to normal cell controls;
++表示较正常细胞对照而言，中等增加的荧光强度；++ indicates a moderately increased fluorescence intensity compared to normal cell controls;
+++表示较正常细胞对照而言，强烈增加的荧光强度；+++ indicates a strongly increased fluorescence intensity compared to normal cell controls;
++++表示较正常细胞对照而言，非常强烈增加的荧光强度。++++ indicates a very strongly increased fluorescence intensity compared to normal cell controls.
实验结果表明：本发明化合物能够显著地增强肝细胞对LDL的摄取能力。与文献WO2010075469和文献WO2014150395中具有代表性的化合物C1，C2，C3，C4，C5(结构式见上文)相比，使用较低的浓度本发明化合物处理的肝细胞表现出显著摄取LDL的能力，而参比化合物在低浓度处理过的肝细胞，对LDL几乎没有摄取能力。说明本发明化合物增加肝细胞摄取LDL的活性显著强于参比化合物C1，C2，C3，C4，C5。The experimental results show that the compound of the present invention can significantly enhance the uptake ability of hepatocytes to LDL. Compared with the representative compounds C1, C2, C3, C4, C5 (see above for the structural formula) in the documents WO2010075469 and WO2014150395, hepatocytes treated with the lower concentration of the compound of the present invention exhibit a remarkable ability to take LDL. The reference compound was treated with low concentrations of hepatocytes and had little uptake of LDL. It is indicated that the compounds of the present invention increase the uptake of LDL by hepatocytes significantly more strongly than the reference compounds C1, C2, C3, C4, C5.
Figure PCTCN2015100201-appb-000233
Figure PCTCN2015100201-appb-000233
Figure PCTCN2015100201-appb-000234
Figure PCTCN2015100201-appb-000234
三、化合物对ERK和AMPK信号途径的双重活化测试实验结果：Third, the compound activation test results of ERK and AMPK signaling pathway:
用本发明化合物对HepG2细胞处理，并检测ERK和AMPK的活化。HepG2 cells were treated with the compounds of the invention and the activation of ERK and AMPK was detected.
结果显示：较之未经处理的对照细胞而言，在经化合物处理的细胞中经磷酸化和活化的ERK和AMPK显著增加。其中包括化合物5，8，9，14，16，21，22，25，27，28，29，31，32，33，34，38，39，41，42，43，44，46，50，51，52，54，55，56，57，59等。The results showed a significant increase in phosphorylated and activated ERK and AMPK in compound treated cells compared to untreated control cells. These include compounds 5,8,9,14,16,21,22,25,27,28,29,31,32,33,34,38,39,41,42,43,44,46,50,51 , 52, 54, 55, 56, 57, 59, etc.
并且，采用高脂饲养诱导的胰岛素抵抗肥胖小鼠模型，本发明化合物具有降糖和降低体重的效果，具有明显改善糖耐量和胰岛素抵抗，增强胰岛素敏感性的特征。Furthermore, the insulin-resistant obese mouse model induced by high-fat feeding has the effects of reducing blood sugar and reducing body weight, and has the characteristics of significantly improving glucose tolerance, insulin resistance, and insulin sensitivity.
另一方面，已有研究文献表明：AMPK的活化能够抑制mTOR和Akt的下游激酶，提示AMPK/Akt/mTOR可能是肿瘤治疗理想的靶点。已有研究文献中细胞实验和动物实验均提示，mTOR信号通路抑制后可以抑制肿瘤细胞的生长，本发明化合物活化的ERK和AMPK，可以进一步影响mTOR和Akt的下游激酶，提示本发明化合物可以进一步开发成为抗肿瘤药物。On the other hand, studies have shown that activation of AMPK can inhibit the downstream kinases of mTOR and Akt, suggesting that AMPK/Akt/mTOR may be an ideal target for tumor therapy. Both cell and animal experiments in the literature have suggested that inhibition of mTOR signaling pathway can inhibit the growth of tumor cells. The activated ERK and AMPK of the compounds of the present invention can further affect the downstream kinases of mTOR and Akt, suggesting that the compounds of the present invention can be further Developed as an anti-tumor drug.
四、SD大鼠模型体内降脂实验：IV. In vivo lipid-lowering experiment in SD rat model:
模型建立：定制高脂饲料饲养SD大鼠，正常组用普通大小鼠生长饲料饲养，4周后采集动物血清，检测指标变化。高脂饲料诱导的大鼠和正常组大鼠相比，血清中LDL-C、TC等含量有明显升高并具有统计学差异，证明高血脂模型建立成功。Model establishment: SD rats were fed with high-fat diet, and the normal group was fed with normal large mouse growth feed. After 4 weeks, animal serum was collected and the index was changed. Compared with the normal group, the levels of LDL-C and TC in serum induced by high-fat diet were significantly increased and statistically significant, which proved that the hyperlipidemia model was successfully established.
急性毒性试验：采用单剂量连续给药7天，受试化合物在500mg/kg的剂量下，未表现出明显副作用。Acute toxicity test: continuous administration of a single dose for 7 days, the test compound showed no significant side effects at a dose of 500 mg/kg.
试验组别和剂量设计：正常对照组，高脂模型对照组，辛伐他汀组(8mg/kg)，化合物31组(20mg/kg)，化合物38组(20mg/kg)，化合物160组(20mg/kg)，化合物166组(20mg/kg)。Test group and dose design: normal control group, high fat model control group, simvastatin group (8 mg/kg), compound 31 group (20 mg/kg), compound 38 group (20 mg/kg), compound 160 group (20 mg) /kg), Compound 166 group (20 mg/kg).
动物数量：每组10只。Number of animals: 10 per group.
给药途径：口服灌胃。Route of administration: oral gavage.
给药频率：每天一次。Dosing frequency: once a day.
给药时间：4周。Dosing time: 4 weeks.
血清指标测定：给药4周后，采取动物血液，进行测定。Measurement of serum index: After 4 weeks of administration, animal blood was taken and assayed.
测定结果归纳总结如图2，图3，图4，图5。The results of the measurements are summarized in Figure 2, Figure 3, Figure 4, and Figure 5.
图2，图3，图4，图5的结果显示：本发明化合物31，化合物38，化合物160，化合物166均能显著降低模型动物的LDL-C和TC。图4和图5表明，高脂模型组和辛伐他汀组动物的谷丙转氨酶和谷草转氨酶水平有显著的升高，表明肝功能异常，但是，本发明化合物，在表现出显著体内降脂活性的同时，并没有增加谷丙转氨酶和谷草转氨酶水平，化合物31，化合物38，化合物160，化合物166组动物的谷丙转氨酶和谷草转氨酶水平与正常饮食组动物一致。说明本发明化合物在降脂的同时，提示并没有对肝脏造成损伤，但是辛伐他汀在降脂的同时，实验动物谷丙转氨酶和谷草转氨酶水平升高，说明服用辛伐他汀的模型动物肝功能受到了损伤，也揭示了他汀类药物明显的肝脏毒性。The results of Figure 2, Figure 3, Figure 4, and Figure 5 show that Compound 31, Compound 38, Compound 160, and Compound 166 of the present invention can significantly reduce LDL-C and TC in model animals. Figures 4 and 5 show that the levels of alanine aminotransferase and aspartate aminotransferase in the high-fat model group and the simvastatin group are significantly elevated, indicating abnormal liver function, but the compound of the present invention exhibits significant lipid-lowering activity in vivo. At the same time, the levels of alanine aminotransferase and aspartate aminotransferase were not increased. The levels of alanine aminotransferase and aspartate aminotransferase in compound 31, compound 38, compound 160 and compound 166 were consistent with those in the normal diet group. It is indicated that the compound of the present invention does not cause damage to the liver at the same time as lipid-lowering, but the level of alanine aminotransferase and aspartate aminotransferase in the experimental animal is increased while the lipid-lowering simvastatin indicates the liver function of the model animal taking simvastatin. The damage was also revealed by the apparent hepatotoxicity of statins.
五、SD大鼠模型非酒精性脂肪肝炎实验：V. SD rat model non-alcoholic steatohepatitis experiment:
研究动物说明：本实验采用的研究动物为上述“SD大鼠模型体内降脂实验”使用动物，动物血清指标研究完成后，将动物处死并解剖，取动物肝脏组织，部分福尔马林固定，部分-80℃冷冻保存，固定超过48hr后进行病理切片染色(H&E染色、油红-O染色)检查。重点关注肝脏结构完整性、炎性细胞浸润与脂肪肝严重程度，并进行评分(评分标准：0级：正常；1级：<20％；2级：20-40％；3级：40-60％；4级：60-80％；5级：>80％)。结果见下表。Study animals: The experimental animals used in this experiment used the animals in the above-mentioned "SD rat model lipid-lowering experiment". After the animal serum index study was completed, the animals were sacrificed and dissected, and the liver tissue of the animals was taken, and some formalin was fixed. Partially stored at -80 ° C for cryopreservation, after more than 48 hrs, pathological section staining (H&E staining, oil red-O staining) was performed. Focus on liver structural integrity, inflammatory cell infiltration and fatty liver severity, and score (score: 0; normal; level 1: <20%; level 2: 20-40%; level 3: 40-60 %; Level 4: 60-80%; Level 5: >80%). See the table below for the results.
试验动物组别Test animal group 空包变性Empty packet denaturation 炎症Inflammation 脂肪fat 被膜下充血Capsular congestion
正常动物 Normal animal 00 00 00 00
高脂对照组High fat control group 44 33 44 33
辛伐他汀组 Simvastatin group 44 33 44 22
化合物31组 Compound 31 group 22 00 11 11
化合物38组 Compound 38 group 11 11 11 11
化合物160组 Compound 160 group 11 11 00 00
化合物166组 Compound 166 11 00 00 11
结果显示，高脂模型组与正常组相比，肝脏中脂肪细胞的体积明显增大，出现大泡性脂肪变性，脂肪的聚积严重破坏了肝脏的组织结构，造成肝脏空泡变性，并伴有大量炎性细胞浸润，以上现象表明，非酒精性脂肪肝炎造模成功。动物灌胃服用本发明部分化合物后，从空泡变性评分来看，化合物31，化合物38，化合物160，化合物166均对肝脏结构有一定的保护作用，由于脂肪细胞造成的 肝脏损伤得到了一定修复，减小了空泡变性程度；化合物31，化合物38，化合物160，化合物166还能显著降低炎性细胞浸润，减少肝脏炎症程度，能减少脂肪的聚集和脂肪细胞体积增大，肝脏脂肪程度减轻。但是，辛伐他汀组动物肝脏解剖，其肝脏结构完整性、炎性细胞浸润与脂肪肝严重程度与高脂模型组一致，脂肪肝症状并没有缓解。本发明化化合物31，化合物38，化合物160，化合物166均对肝脏组织有一定的保护作用，本发明化合物具有治疗脂肪肝的药用价值。The results showed that compared with the normal group, the volume of fat cells in the liver was significantly increased in the high-fat model group, and macrofoamy steatosis occurred. The accumulation of fat severely damaged the liver tissue structure, causing liver vacuolar degeneration, accompanied by A large number of inflammatory cell infiltration, the above phenomenon shows that non-alcoholic fatty hepatitis model was successful. After taking some of the compounds of the present invention by intragastric administration, compound 31, compound 38, compound 160 and compound 166 all have a certain protective effect on liver structure from the vacuolar degeneration score, which is caused by fat cells. Liver damage has been repaired to reduce the degree of vacuolar degeneration; Compound 31, Compound 38, Compound 160, Compound 166 can also significantly reduce inflammatory cell infiltration, reduce liver inflammation, reduce fat accumulation and increase fat cell volume. Large, liver fat is reduced. However, liver anatomy of the simvastatin group, liver structural integrity, inflammatory cell infiltration and fatty liver severity were consistent with the high-fat model group, and fatty liver symptoms were not alleviated. The compound 31, the compound 38, the compound 160 and the compound 166 of the invention all have a certain protective effect on liver tissues, and the compound of the invention has the medicinal value for treating fatty liver.
以上两项实验“SD大鼠模型体内降脂实验”和“SD大鼠模型非酒精性脂肪肝炎实验”，揭示了本发明化合物具有如下特点：The above two experiments, "Intravenous lipid-lowering test in SD rat model" and "SD rat model non-alcoholic steatohepatitis experiment", revealed that the compound of the present invention has the following characteristics:
(1)、本发明化合物表现出降脂活性，不会影响肝脏正常功能。在安全剂量范围内，本发明化合物体现出体内降脂的活性，并没有引起大鼠转氨酶水平的升高，提示并没有对肝脏造成损伤。但是，辛伐他汀降脂药物，表现出降脂活性的同时，进一步使得动物转氨酶水平的升高，说明正常的肝脏功能受到了损伤，表现出明显的肝脏毒性。本发明化合物降脂但不影响肝脏功能的特点，在临床应用上，提示本发明化合物比他汀类药物具有较为显著的安全性优势。(1) The compound of the present invention exhibits a lipid-lowering activity and does not affect the normal function of the liver. Within the safe dose range, the compounds of the present invention exhibited lipid-lowering activity in vivo and did not cause an increase in the level of transaminase in the rat, suggesting that no damage was caused to the liver. However, simvastatin lipid-lowering drugs, while exhibiting lipid-lowering activity, further increased the level of animal transaminase, indicating that normal liver function was damaged and showed significant liver toxicity. The compound of the present invention has the characteristics of lowering lipid but not affecting liver function, and clinical application indicates that the compound of the present invention has a more significant safety advantage than the statin.
(2)、本发明化合物对高脂模型动物脂肪肝症状具有潜在的治疗作用，而他汀类等降脂药并没有以上疗效。从“SD大鼠模型非酒精性脂肪肝炎实验”中可以看出，本发明化合物减少肝脏炎症程度，能减少脂肪的聚集和脂肪细胞体积增大，肝脏脂肪程度减轻，脂肪细胞造成的肝脏损伤得到了一定修复，减小了空泡变性程度。然而，辛伐他汀组动物肝脏解剖，其肝脏结构完整性、炎性细胞浸润与脂肪肝严重程度与高脂模型组一致，脂肪肝症状并没有缓解。(2) The compound of the present invention has a potential therapeutic effect on fatty liver symptoms in a high-fat model animal, and the lipid-lowering drugs such as statins do not have the above effects. It can be seen from the "SD rat model non-alcoholic steatohepatitis experiment" that the compound of the present invention reduces the degree of liver inflammation, can reduce fat accumulation and increase the volume of fat cells, reduce the degree of liver fat, and obtain liver damage caused by fat cells. It has been repaired to reduce the degree of vacuolar denaturation. However, in the liver anatomy of the simvastatin group, liver structural integrity, inflammatory cell infiltration, and fatty liver severity were consistent with the high-fat model group, and fatty liver symptoms were not alleviated.
综合以上体内和体外药效学实验，可以看出，本发明化合物降脂作用机制，不同于现有上市降脂药物(例如：他汀类，贝特类等等)，其优异降脂活性以及其良好的安全性特点，以及在脂肪肝治疗中的潜在治疗价值，有望成为广大心血管疾病患者获得良好治疗收益的新一代降脂药物。 Based on the above in vivo and in vitro pharmacodynamic experiments, it can be seen that the lipid-lowering mechanism of the compound of the present invention is different from the existing listed lipid-lowering drugs (for example, statins, fibrates, etc.), and its excellent lipid-lowering activity and its Good safety characteristics and potential therapeutic value in the treatment of fatty liver are expected to become a new generation of lipid-lowering drugs for patients with cardiovascular diseases to obtain good therapeutic benefits.

Claims (17)

  1. 式V的化合物Compound of formula V
    Figure PCTCN2015100201-appb-100001
    Figure PCTCN2015100201-appb-100001
    其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类；其中：a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof; wherein:
    Y选自环烷基、杂环基、芳基、杂芳基，其中，Y is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
    所述的环烷基、杂环基、芳基、杂芳基各自独立地被一个或多个选自氢，卤，-OH，-NR′R″，-NO2，-Si(R′)3，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，-S(O)mR′，-S(O)nNR′R″，-OS(O)nR′，-OS(O)nNR′R″，
    Figure PCTCN2015100201-appb-100002
    Figure PCTCN2015100201-appb-100003
    -OS(O)nNH(C＝O)NR′R″，-S(O)nNH(C＝O)NR′R″，-NR′S(O)nR″，-NR′S(O)nNR′R″，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基的取代基所取代；    The cycloalkyl, heterocyclic, aryl, heteroaryl groups are each independently selected from one or more selected from the group consisting of hydrogen, halogen, -OH, -NR'R", -NO 2 , -Si(R') 3 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", -S(O) m R', -S(O) n NR'R", -OS(O) n R', -OS(O) n NR'R",
    Figure PCTCN2015100201-appb-100002
    Figure PCTCN2015100201-appb-100003
    -OS(O) n NH(C=O)NR'R", -S(O) n NH(C=O)NR'R", -NR'S(O) n R", -NR'S( O) n NR'R", substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, Substituted by a heteroarylalkyl, heterocyclyl or heterocyclic substituent;
    R1，R2，R3，R4，R5，R6，R7，R8独立地是氢，卤，经取代的或未经取代的硅基，氨基，硝基，氧代基，硫基，砜基，氰基，羰基，磺酰氧基，磷酰氧基，烷基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
    M为氮原子，或者碳原子；M is a nitrogen atom, or a carbon atom;
    W为氮原子，或者碳原子；W is a nitrogen atom, or a carbon atom;
    Z为-O-，-S-，-NH-，-CR5R6-，-C(O)O-，-C(O)NR5-，-SO2O-，-SO2NR5-，-P(O)R5R6或者Z不为任何原子(即是，与Z相连的化学基团通过化学键直接连接)；Z is -O-, -S-, -NH-, -CR 5 R 6 -, -C(O)O-, -C(O)NR 5 -, -SO 2 O-, -SO 2 NR 5 - , -P(O)R 5 R 6 or Z is not an atom (ie, the chemical group attached to Z is directly linked by a chemical bond);
    环X为3～10元环，所述的3～10元环X选自环烷基，杂环基、芳基、杂芳基，其中，Ring X is a 3- to 10-membered ring, and the 3- to 10-membered ring X is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
    所述的环烷基、杂环基、芳基、杂芳基各自独立地被一个或多个选自氢，卤，-OH，-NR′R″，-NO2，-Si(R′)3，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，-S(O)mR′，-S(O)nNR′R″，-OS(O)nR′，-OS(O)nNR′R″，
    Figure PCTCN2015100201-appb-100004
    Figure PCTCN2015100201-appb-100005
    -OS(O)nNR′(C＝O)NR′R″，-S(O)nNR′(C＝O)NR′R″，-NR′S(O)nR″，-NR′S(O)nNR′R″，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基的取代基所取代；    The cycloalkyl, heterocyclic, aryl, heteroaryl groups are each independently selected from one or more selected from the group consisting of hydrogen, halogen, -OH, -NR'R", -NO 2 , -Si(R') 3 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", -S(O) m R', -S(O) n NR'R", -OS(O) n R', -OS(O) n NR'R",
    Figure PCTCN2015100201-appb-100004
    Figure PCTCN2015100201-appb-100005
    -OS(O) n NR'(C=O)NR'R", -S(O) n NR'(C=O)NR'R", -NR'S(O) n R", -NR' S(O) n NR'R", substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl Substituted with a substituent of a heteroarylalkyl group, a heterocyclic group or a heterocyclic group;
    R′和R″独立的是氢或者经取代的或未经取代的烷基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基，R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaryl Alkyl, heterocyclic or heterocyclylalkyl,
    在-NR′R″，-C(O)NR′R″，-OC(O)NR′R″，-OS(O)nNR′R″，-OS(O)nNH(C＝O)NR′R″中，其中NR′R″可以为4至20元含氮杂环基； In -NR'R", -C(O)NR'R", -OC(O)NR'R", -OS(O) n NR'R", -OS(O) n NH(C=O) In NR'R", wherein NR'R" may be a 4 to 20 membered nitrogen-containing heterocyclic group;
    m＝0，1，2；m=0,1,2;
    n＝1，2，3；n=1, 2, 3;
    p＝1，2，3；p=1, 2, 3;
    q＝0，1，2，3，4，5，6；q=0,1,2,3,4,5,6;
    s＝0，1，2；s=0,1,2;
    t＝0，1，2。t=0, 1, 2.
  2. 根据权利要求1的通式化合物化合物(V)，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中包括通式化合物化合物(VI)，The compound (V) of the formula of the formula according to claim 1, a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, and a compound of the formula (VI),
    Figure PCTCN2015100201-appb-100006
    Figure PCTCN2015100201-appb-100006
    其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中：a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein:
    R9，R10，R11，R12，R13，R14，R15，R16独立地是氢，卤，经取代的或未经取代的硅基，氨基，硝基，氧代基，硫基，砜基，氰基，羰基，磺酰氧基，磷酰氧基，烷基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
    R5，R6，R7，R8，Z，M，q，t，环X和环Y同权利要求1。R 5 , R 6 , R 7 , R 8 , Z, M, q, t, ring X and ring Y are the same as claim 1.
  3. 根据权利要求1的通式化合物化合物(V)，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中包括通式化合物化合物(VII)，The compound (V) of the formula according to claim 1, a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, and a compound of the formula (VII),
    Figure PCTCN2015100201-appb-100007
    Figure PCTCN2015100201-appb-100007
    其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中：a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein:
    R9，R10，R11，R12，R13，R14，R15，R16独立地是氢，卤，经取代的或未经取代的硅基，氨基，硝基，氧基，硫基，砜基，氰基，羰基，磺酰氧基，磷酰氧基，烷基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxy, sulphur , sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
    R17，R18，R19，R20，R21独立地是氢，卤，-OH，-NR′R″，-NO2，-Si(R′)3，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″， -OC(O)OR′，-OC(O)NR′R″，-S(O)mR′，-S(O)nNR′R″，-OS(O)nR′，-OS(O)nNR′R″，
    Figure PCTCN2015100201-appb-100008
    Figure PCTCN2015100201-appb-100009
    -OS(O)nNH(C＝O)NR′R″，-S(O)nNH(C＝O)NR′R″，-NR′S(O)nR″，-NR′S(O)nNR′R″，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；    R 17 , R 18 , R 19 , R 20 , R 21 are independently hydrogen, halo, -OH, -NR'R", -NO 2 , -Si(R') 3 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", -S(O) m R', -S(O) n NR'R", -OS(O) n R', -OS(O) n NR'R",
    Figure PCTCN2015100201-appb-100008
    Figure PCTCN2015100201-appb-100009
    -OS(O) n NH(C=O)NR'R", -S(O) n NH(C=O)NR'R", -NR'S(O) n R", -NR'S( O) n NR'R", substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
    R5，R6，R7，R8，R′，R″，Z，环X，M，m，n，q，t同权利要求1。R 5 , R 6 , R 7 , R 8 , R', R", Z, ring X, M, m, n, q, t are the same as claim 1.
  4. 根据权利要求3的通式化合物化合物(VII)，其中，R9，R10，R11，R12，R13，R14，R15，R16独立地是-H，卤，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；The compound of the formula (VII) according to Claim 3, wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently -H, halogen, substituted or Unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic or heterocyclic Alkyl group
    R17，R18，R19，R20，R21独立地是-H，卤，-OH，-NO2，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，取代的或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基，还选自包括：R 17 , R 18 , R 19 , R 20 , R 21 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R' , -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", substituted or unsubstituted amino, alkyl, alkane Oxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, also selected from :
    Figure PCTCN2015100201-appb-100010
    Figure PCTCN2015100201-appb-100010
    R27选自苯基，C1-6烷基，环(C3-8)烷基，噻吩基，呋喃基，咪唑基，吡啶基，嘧啶基，哒嗪基，喹啉基，异喹啉基，苯乙炔基，苯甲基，苯乙烯基，萘基，取代氨基，吗啉基，哌啶基，N-甲基哌嗪基，四氢吡咯基，六氢吡啶基，樟脑烷基，对甲苯基，R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
    其中，C1-6烷基任选被0至13个取代基取代，Wherein C 1-6 alkyl is optionally substituted by 0 to 13 substituents,
    噻吩基，呋喃基和咪唑基任选被0至3个取代基取代，The thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
    吡啶基任选被0至4个取代基取代，The pyridyl group is optionally substituted with from 0 to 4 substituents.
    嘧啶基和哒嗪基任选被0至3个取代基取代，The pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
    苯基任选被0至5个取代基取代，The phenyl group is optionally substituted with from 0 to 5 substituents.
    喹啉基和异喹啉基萘基选任选被0至6个取代基取代，The quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
    萘基选任选被0至7个取代基取代，The naphthyl group is optionally substituted with from 0 to 7 substituents.
    以上的取代基选自：羟基，卤素，氰基，硝基，硅基，-COOH，羧酸酯基，取代或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；The above substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring An alkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
    R28选自氢，取代或者未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基。R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
  5. 根据权利要求1的通式化合物化合物(V)，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中包括通式化合物化合物(VIII)， The compound (V) of the formula according to claim 1, a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, which comprises the compound (VIII) of the formula compound,
    Figure PCTCN2015100201-appb-100011
    Figure PCTCN2015100201-appb-100011
    其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中：a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein:
    R22，R23，R24，R25，R26独立地是氢，卤，-OH，-NR′R″，-NO2，-Si(R′)3，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，-S(O)mR′，-S(O)nNR′R″，-OS(O)nR′，-OS(O)nNR′R″，
    Figure PCTCN2015100201-appb-100012
    Figure PCTCN2015100201-appb-100013
    -OS(O)nNH(C＝O)NR′R″，-S(O)nNH(C＝O)NR′R″，-NR′S(O)nR″，-NR′S(O)nNR′R″，经取代的或未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基；    R 22 , R 23 , R 24 , R 25 , R 26 are independently hydrogen, halo, -OH, -NR'R", -NO 2 , -Si(R') 3 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", -S(O) m R', -S(O) n NR'R", -OS(O) n R', -OS(O) n NR'R",
    Figure PCTCN2015100201-appb-100012
    Figure PCTCN2015100201-appb-100013
    -OS(O) n NH(C=O)NR'R", -S(O) n NH(C=O)NR'R", -NR'S(O) n R", -NR'S( O) n NR'R", substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group or a heterocyclic group;
    环Y，R1，R2，R3，R4，R5，R6，R7，R8，R′，R″，M，W，Z，m，n，p，q，s，t同权利要求1。Ring Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R′, R′′, M, W, Z, m, n, p, q, s, t Same as claim 1.
  6. 根据权利要求5的通式化合物化合物(VIII)，其中，R22，R23，R24，R25，R26独立地是-H，卤，-OH，-NO2，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，取代的或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基，还选自包括：The compound of the formula (VIII) according to claim 5, wherein R 22 , R 23 , R 24 , R 25 and R 26 are independently -H, halo, -OH, -NO 2 , -CN, -(CH) 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R ", substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl , a heterocyclic or heterocyclylalkyl group, further selected from the group consisting of:
    Figure PCTCN2015100201-appb-100014
    Figure PCTCN2015100201-appb-100014
    R27选自苯基，C1-6烷基，环(C3-8)烷基，噻吩基，呋喃基，咪唑基，吡啶基，嘧啶基，哒嗪基，喹啉基，异喹啉基，苯乙炔基，苯甲基，苯乙烯基，萘基，取代氨基，吗啉基，哌啶基，N-甲基哌嗪基，四氢吡咯基，六氢吡啶基，樟脑烷基，对甲苯基，R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
    其中，C1-6烷基任选被0至13个取代基取代，Wherein C 1-6 alkyl is optionally substituted by 0 to 13 substituents,
    噻吩基，呋喃基和咪唑基任选被0至3个取代基取代，The thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
    吡啶基任选被0至4个取代基取代，The pyridyl group is optionally substituted with from 0 to 4 substituents.
    嘧啶基和哒嗪基任选被0至3个取代基取代，The pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
    苯基任选被0至5个取代基取代，The phenyl group is optionally substituted with from 0 to 5 substituents.
    喹啉基和异喹啉基萘基选任选被0至6个取代基取代，The quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
    萘基选任选被0至7个取代基取代，The naphthyl group is optionally substituted with from 0 to 7 substituents.
    以上的取代基选自：羟基，卤素，氰基，硝基，硅基，-COOH，羧酸酯基，取代或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；The above substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring An alkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
    R28选自氢，取代或者未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环 基或杂环基。R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
  7. 根据权利要求1的通式化合物化合物(V)，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中包括通式化合物化合物(IX)，The compound (V) of the formula of the formula according to claim 1, a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, and a compound of the formula (IX),
    Figure PCTCN2015100201-appb-100015
    Figure PCTCN2015100201-appb-100015
    其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类，其中：a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein:
    R9，R10，R11，R12，R13，R14，R15，R16，R17，R18，R19，R20，R21同权利要求3；R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 are the same as claim 3;
    R22，R23，R24，R25，R26同权利要求5；R 22 , R 23 , R 24 , R 25 , R 26 are the same as claim 5;
    R5，R6，R7，R8，M，q，t同权利要求1。R 5 , R 6 , R 7 , R 8 , M, q, t are the same as claim 1.
  8. 根据权利要求7的通式化合物化合物(IX)，其中，R17，R18，R19，R20，R21，R22，R23，R24，R25，R26独立地是-H，卤，-OH，-NO2，-CN，-(CH2)0-6COOR′，-C(O)R′，-OC(O)R′，-C(O)NR′R″，-OC(O)OR′，-OC(O)NR′R″，取代的或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基，还选自包括：The compound of the formula (IX) according to claim 7, wherein R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 and R 26 are independently -H, Halogen, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R",- OC(O)OR', -OC(O)NR'R", substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl a base, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group, further selected from the group consisting of:
    Figure PCTCN2015100201-appb-100016
    Figure PCTCN2015100201-appb-100016
    R27选自苯基，C1-6烷基，环(C3-8)烷基，噻吩基，呋喃基，咪唑基，吡啶基，嘧啶基，哒嗪基，喹啉基，异喹啉基，苯乙炔基，苯甲基，苯乙烯基，萘基，取代氨基，吗啉基，哌啶基，N-甲基哌嗪基，四氢吡咯基，六氢吡啶基，樟脑烷基，对甲苯基，R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
    其中，C1-6烷基任选被0至13个取代基取代，Wherein C 1-6 alkyl is optionally substituted by 0 to 13 substituents,
    噻吩基，呋喃基和咪唑基任选被0至3个取代基取代，The thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
    吡啶基任选被0至4个取代基取代，The pyridyl group is optionally substituted with from 0 to 4 substituents.
    嘧啶基和哒嗪基任选被0至3个取代基取代，The pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
    苯基任选被0至5个取代基取代，The phenyl group is optionally substituted with from 0 to 5 substituents.
    喹啉基和异喹啉基萘基选任选被0至6个取代基取代，The quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
    萘基选任选被0至7个取代基取代，The naphthyl group is optionally substituted with from 0 to 7 substituents.
    以上的取代基选自：羟基，卤素，氰基，硝基，硅基，-COOH，羧酸酯基，取代或未经取代的氨基，烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环基或杂环基烷基；The above substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring An alkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
    R28选自氢，取代或者未经取代的烷基，烷氧基，烯基，炔基，环烷基，环烷基烷基，芳基，芳烷基，杂芳基，杂芳基烷基，杂环 基或杂环基。R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
  9. 根据权利要求1～8的化合物，该化合物选自以下化合物，但不局限于以下化合物范围：The compound according to claims 1 to 8, which is selected from the following compounds, but is not limited to the following compound ranges:
    Figure PCTCN2015100201-appb-100017
    Figure PCTCN2015100201-appb-100017
    Figure PCTCN2015100201-appb-100018
    Figure PCTCN2015100201-appb-100018
    Figure PCTCN2015100201-appb-100019
    Figure PCTCN2015100201-appb-100019
    Figure PCTCN2015100201-appb-100020
    Figure PCTCN2015100201-appb-100020
    Figure PCTCN2015100201-appb-100021
    Figure PCTCN2015100201-appb-100021
    Figure PCTCN2015100201-appb-100022
    Figure PCTCN2015100201-appb-100023
    或其药用可接受的盐。
    Figure PCTCN2015100201-appb-100022
    Figure PCTCN2015100201-appb-100023
    Or a pharmaceutically acceptable salt thereof.
  10. 一种制备权利要求1所述通式(V)所示的化合物，其立体异构体，其互变异构体，其溶剂化物及其药用可接受的盐类的方法，其中一种制备方法包括以下步骤：A process for preparing a compound represented by the formula (V) according to claim 1, a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein one preparation The method includes the following steps:
    Figure PCTCN2015100201-appb-100024
    Figure PCTCN2015100201-appb-100024
    X1和X2为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。X1和X2在一定的反应温度条件下，在一定的碱性试剂存在的条件下，通过偶联得到化合物V；X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
    另一种制备方法包括以下步骤：Another preparation method includes the following steps:
    Figure PCTCN2015100201-appb-100025
    Figure PCTCN2015100201-appb-100025
    X1和X3为该方案的起始物料，可以通过市售产品获得，或者根据文献报道的方法制备获得。将X1和X3在一定的反应条件下，通过还原氨化的反应制备得到V。 X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
  11. 一种药物组合物，其包含权利要求1至9中任意一项的化合物和药学上可以接受的载体。A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.
  12. 一种药物组合物，所述组合物包括给予需要治疗的患者有效治疗量的权利要求1至9中任意一项的化合物。A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 administered to a patient in need of treatment in a therapeutically effective amount.
  13. 权利要求1至9中任意一项化合物在制备用于降低患者血浆和/或肝的脂类水平的药物中的用途。Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for lowering lipid levels in a patient's plasma and/or liver.
  14. 权利要求1至9中任意一项化合物在制备用于治疗高脂血症，高胆固醇血症，高甘油三酯血症，肝脂肪变性和代谢综合征构成的疾病或病况的药物中的用途。Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of a disease or condition consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis and metabolic syndrome.
  15. 权利要求1至9中任意一项化合物在制备用于增加LDLR表达和/或降低PCSK9表达的药物中的用途。Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for increasing LDLR expression and/or reducing PCSK9 expression.
  16. 权利要求1至9中任意一项化合物在制备用于减少LDL-胆固醇和/或血浆甘油三酯的药物中的用途。Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for reducing LDL-cholesterol and/or plasma triglycerides.
  17. 根据权利要求1至9任意一项所述的化合物在制备用于治疗II型糖尿病，高血糖症，肥胖症，胰岛素抵抗症或抗肿瘤药物中的用途。 Use of a compound according to any one of claims 1 to 9 for the preparation of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity, insulin resistance or anti-tumor drugs.
PCT/CN2015/100201 2015-01-01 2015-12-31 Substituted nitrogen-containing heterocyclic derivatives and applications thereof WO2016107603A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510001596.1 2015-01-01
CN201510001596 2015-01-01

Publications (1)

Publication Number Publication Date
WO2016107603A1 true WO2016107603A1 (en) 2016-07-07

Family

ID=56284316

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/100201 WO2016107603A1 (en) 2015-01-01 2015-12-31 Substituted nitrogen-containing heterocyclic derivatives and applications thereof

Country Status (2)

Country Link
CN (1) CN105753814A (en)
WO (1) WO2016107603A1 (en)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
WO2018165718A1 (en) 2017-03-17 2018-09-20 Cardio Therapeutics Pty Ltd Heterocyclic inhibitors of pcsk9
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10568882B2 (en) 2015-08-21 2020-02-25 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
US10821106B2 (en) 2015-08-21 2020-11-03 Srx Cardio, Llc Composition and methods of use of novel phenylalanine small organic compounds to directly modulate PCSK9 protein activity
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11214625B2 (en) 2015-10-29 2022-01-04 Min Chen Application of PCSK9 inhibitors in the preparation of drugs for the treatment of inflammatory immune diseases
US11285153B2 (en) 2017-09-29 2022-03-29 Sunshine Lake Pharma Co., Ltd. Substituted pyrimidine piperazine compound and use thereof
US11530184B2 (en) 2020-06-30 2022-12-20 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
CN116283819A (en) * 2023-03-22 2023-06-23 中国科学院长春应用化学研究所 Preparation method and application of isothiazole-5 (2H) -imine compound
CN109776509B (en) * 2018-01-30 2023-07-07 成都麻沸散医药科技有限公司 N-substituted imidazole formate derivative and application thereof
US11780811B2 (en) 2020-06-30 2023-10-10 Imbria Pharmaceuticals, Inc. Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
US11883396B2 (en) 2021-05-03 2024-01-30 Imbria Pharmaceuticals, Inc. Methods of treating kidney conditions using modified forms of trimetazidine
US11891369B2 (en) 2016-02-23 2024-02-06 Srx Cardio, Llc Compounds for binding proprotein convertase subtilisin/kexin type 9
US11939329B2 (en) 2022-01-21 2024-03-26 Xinthera, Inc. PARP1 inhibitors and uses thereof
US11945782B2 (en) 2015-08-21 2024-04-02 Srx Cardio, Llc Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106866575A (en) * 2017-03-21 2017-06-20 苏州汉德创宏生化科技有限公司 The synthetic method of 2 (1 piperidyl) 5 bromo thiazoles

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997028128A1 (en) * 1996-02-02 1997-08-07 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
CN103562202A (en) * 2011-01-25 2014-02-05 密执安大学评议会 BCL-2/BCL-XL inhibitors and therapeutic methods using the same
US20140235646A1 (en) * 2007-02-02 2014-08-21 Motonari Uesugi Methods and Compositions for the Treatment of Body Weight Related Disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997028128A1 (en) * 1996-02-02 1997-08-07 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
US20140235646A1 (en) * 2007-02-02 2014-08-21 Motonari Uesugi Methods and Compositions for the Treatment of Body Weight Related Disorders
CN103562202A (en) * 2011-01-25 2014-02-05 密执安大学评议会 BCL-2/BCL-XL inhibitors and therapeutic methods using the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHOU, HAIBIN ET AL.: "Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 10, 26 March 2012 (2012-03-26), pages 4664 - 4682, XP002725242, DOI: doi:10.1021/jm300178u *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10821106B2 (en) 2015-08-21 2020-11-03 Srx Cardio, Llc Composition and methods of use of novel phenylalanine small organic compounds to directly modulate PCSK9 protein activity
US10568882B2 (en) 2015-08-21 2020-02-25 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
US11945782B2 (en) 2015-08-21 2024-04-02 Srx Cardio, Llc Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity
US11944619B2 (en) 2015-08-21 2024-04-02 Srx Cardio, Llc Phenylalanine small organic compounds to directly modulate PCSK9 protein activity
US10980801B2 (en) 2015-08-21 2021-04-20 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
US11925637B2 (en) 2015-08-21 2024-03-12 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
US11214625B2 (en) 2015-10-29 2022-01-04 Min Chen Application of PCSK9 inhibitors in the preparation of drugs for the treatment of inflammatory immune diseases
US11891369B2 (en) 2016-02-23 2024-02-06 Srx Cardio, Llc Compounds for binding proprotein convertase subtilisin/kexin type 9
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
EP3609882A4 (en) * 2017-03-17 2020-10-28 Cardio Therapeutics Pty Ltd Heterocyclic inhibitors of pcsk9
US11091466B2 (en) 2017-03-17 2021-08-17 Cardio Therapeutics Pty Ltd Heterocyclic inhibitors of PCSK9
US11897868B2 (en) 2017-03-17 2024-02-13 Cardio Therapeutics Pty Ltd Heterocyclic inhibitors of PCSK9
WO2018165718A1 (en) 2017-03-17 2018-09-20 Cardio Therapeutics Pty Ltd Heterocyclic inhibitors of pcsk9
US11376330B2 (en) 2017-06-20 2022-07-05 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10918728B2 (en) 2017-06-20 2021-02-16 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10953102B2 (en) 2017-06-20 2021-03-23 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11844840B2 (en) 2017-06-20 2023-12-19 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11285153B2 (en) 2017-09-29 2022-03-29 Sunshine Lake Pharma Co., Ltd. Substituted pyrimidine piperazine compound and use thereof
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
CN109776509B (en) * 2018-01-30 2023-07-07 成都麻沸散医药科技有限公司 N-substituted imidazole formate derivative and application thereof
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11780811B2 (en) 2020-06-30 2023-10-10 Imbria Pharmaceuticals, Inc. Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11530184B2 (en) 2020-06-30 2022-12-20 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11746090B2 (en) 2020-06-30 2023-09-05 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11883396B2 (en) 2021-05-03 2024-01-30 Imbria Pharmaceuticals, Inc. Methods of treating kidney conditions using modified forms of trimetazidine
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
US11939329B2 (en) 2022-01-21 2024-03-26 Xinthera, Inc. PARP1 inhibitors and uses thereof
US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
US12006322B2 (en) 2022-04-28 2024-06-11 Xin Thera, Inc. Substituted pyridines as PARP1 inhibitors
CN116283819A (en) * 2023-03-22 2023-06-23 中国科学院长春应用化学研究所 Preparation method and application of isothiazole-5 (2H) -imine compound

Also Published As

Publication number Publication date
CN105753814A (en) 2016-07-13

Similar Documents

Publication Publication Date Title
WO2016107603A1 (en) Substituted nitrogen-containing heterocyclic derivatives and applications thereof
WO2016107602A1 (en) Substituted nitrogen heterocyclic derivatives and use thereof
CN102485721B (en) 2，3-benzodiazine ketone compound replaced and uses thereof
JP2005521698A (en) New tricyclic compounds
US20060205739A1 (en) Aroylfuranes and aroylthiophenes
EA010656B1 (en) Tetrahydroquinolinones and their use as antagonists of metabotropic glutamate receptors
JPS62103065A (en) Pyridine derivative
EP1985297A1 (en) Carboxylic acid compound and use thereof
CN101268048A (en) Carbazole derivatives
CN108033952B (en) Phenylalanine derivative and the preparation method and application thereof containing triazole ring
CN110386927B (en) Histone Acetyltransferase (HAT) inhibitors and uses thereof
WO1996020190A1 (en) Piperazine 2,5 dione derivatives as modulators of multi-drug resistance
WO1995021830A1 (en) Pharmaceutical piperazin compounds
CN109651208B (en) N-aryl sulfonamide compound, pharmaceutical composition and application thereof
WO2024008129A1 (en) Compound as kat6 inhibitor
WO2020221006A1 (en) Bet inhibitor, and preparation method and use thereof
JP2012504588A (en) Pyrimide derivatives and their pharmaceutical use
KR102537615B1 (en) 1,3,4-Oxadiazol Derivative Compounds as Histone Deacetylase 6 Inhibitor, and the Pharmaceutical Composition Comprising the same
WO2016041515A1 (en) Tetrahydropalmatine derivatives and application thereof
CN101314584A (en) HGF/c-Met signalling channel restrainer, preparation method and application thereof
CA2787860C (en) Substituted 2-imidazolidones and analogs and their use against cancer
WO2016041514A1 (en) Tetrahydroberberine derivatives and application thereof
WO2023011416A1 (en) Multi-target inhibitor targeting hdac and nad synthesis and use of multi-target inhibitor
CN101243074A (en) Heterocyclic compounds
CA2844783A1 (en) Substituted 2-imidazolidinones and 2-imidazolones and their use in the treatment of cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15875279

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15875279

Country of ref document: EP

Kind code of ref document: A1