CN109836378A - A kind of sphingomyelins synthase inhibitor, preparation method and its application - Google Patents

Abstract

The present invention provides logical formula (I) compound represented, its pharmaceutically acceptable salt or stereoisomers, and wherein X, Y, M, Z, R and Ar are defined as in the description respectively.The present invention also provides compound, its pharmaceutically acceptable salt or stereoisomers shown in the logical formula (I) above-mentioned comprising at least one therapeutically effective amount, and the purposes of the drug of compound above-mentioned, its pharmaceutically acceptable salt or stereoisomer or pharmaceutical composition above-mentioned in preparation for preventing and/or treating the disease caused by being increased extremely by sphingomyelin levels.Logical formula (I) compound represented, its pharmaceutically acceptable salt or stereoisomer provided by the invention, the inhibition sphingomyelins synthase of energy selectivity, inside and outside drug action is significant, highly-safe.

Description

A kind of sphingomyelins synthase inhibitor, preparation method and its application

Technical field

The present invention relates to field of pharmaceutical chemistry technology, more particularly to a kind of sphingomyelins synthase inhibitor, preparation method And its application.

Background technique

Atherosclerosis is the most common disease in disease of cardiovascular system, and main pathological characters are endarterium Under lipidosis, and with the proliferation of smooth muscle cell, migration, the formation of fibrous plaque, and then cause vessel walls is managed Chamber is narrow and thrombosis, and gradually development forms atherosclerotic plaques, and atherosclerosis is often accompanied by hypertension, high gallbladder Sterol mass formed by blood stasis or diabetes etc., it is very big to people's health harm, it is one of the elderly's major causes of death.

The generation formation of atherosclerosis is the pathologic process for sending out miscellaneous, and the age smokes, drinks, hypertension, high blood Sugar, hyperlipidemia etc. are all the risk factors that atherosclerosis occurs, develops, as people are to Pathogenesis of Atherosclerosis Understand in depth, the therapeutic agent of atherosclerosis is also continuously developed listing, such as antiplatelet drug, expand blood vessel medicine, haemolysis Bolt medicine, lipid-lowering medicine, antioxidant, inhibitors of cyclooxygenases etc., however clinically these medical treatment Atherosclerosis of prolonged application Change, still can bring the adverse reaction of some drugs.

Sphingomyelins is the major lipids ingredient in cell membrane and plasma protein, there is extensive and important biological function, Epidemiological survey shows have a large amount of sphingomyelins to accumulate in atherosclerotic plaques, and the clinical test of large sample shows sheath Phospholipid level and lipid risk score are positively correlated, in human familial's hyperlipidemia patient's sphingomyelin level also compared with normal person Height, in the animal model of atherosclerosis, the sphingomyelin levels in blood plasma are also obviously increased, and the sphingomyelin levels in blood plasma increase Add and sphingomyelins aggregation is one of risk factor of atherosclerosis.It is numerous in recent years that researches show that sphingomyelins is athero- in artery Very important effect is played in the generation of hardening, on the one hand sphingomyelins can delay rouge egg by the esterlysis of inhibition triglycerides The lipid metabolic pathways such as the removing of white remnant induce atherosclerosis, and another aspect sphingomyelins can be by adjusting NF- κ B The activation of (nuclear factor-kappa B, nuclear factor-kappa B) adjusts the associated inflammation of atherosclerosis Reaction, to influence the process of atherosclerosis.

Sphingomyelins synthase (Sphingomyelin synthase, SMS) is the key enzyme for synthesizing sphingomyelins final step, The height of direct regulation and control sphingomyelin levels；Numerous researchs disclose, dynamic by inhibiting SMS activity reduction sphingomyelin levels to be likely to become The new way of pulse atherosclerosis treatment.In recent years, some research institutions and pharmacy corporation had started to carry out SMS inhibitor both at home and abroad The development of drug, but currently, do not there is also the drug of SMS inhibitor to enter clinical research, exploitation SMS micromolecular inhibitor both at home and abroad Energy helps to search out the therapeutic agent of safer and more effective antiatherosclerosis.

Summary of the invention

The purpose of the present invention is to provide a kind of sphingomyelins synthase inhibitor, preparation method and its applications.Concrete scheme It is as follows:

Present invention firstly provides logical formula (I) compound represented, its pharmaceutically acceptable salt or stereoisomers.

Wherein, X, Y and Z are separately selected from carbon atom or nitrogen-atoms, and X, Y and

Z is not simultaneously selected from nitrogen-atoms；

M is selected from-NH- or-O-；

Ar is selected from aryl being substituted or being unsubstituted, be substituted or the heteroaryl that is unsubstituted；Preferably, described The aryl being substituted or the heteroaryl being substituted it is optional replaced following one or more substituent groups:

Halogen ,-C_1-10Alkyl ,-C_1-10The C that alkoxy, halogen replace_1-10The C that alkyl and halogen replace_1-10Alkoxy；

R is selected from hydrogen, deuterium, halogen, nitro, cyano ,-C_1-6Alkyl ,-C_1-6Alkoxy, the C being substituted_1-6Alkyl is substituted C_1-6Alkoxy；Preferably, the C being substituted_1-6Alkyl, the C being substituted_1-6Alkoxy is optional to be taken by following one or more Replaced Dai Ji:

Hydrogen, deuterium, halogen, nitro, cyano ,-C_1-6Alkyl and-C_1-6Alkoxy.

Some embodiments of the present invention are related to compound, its pharmaceutically acceptable salt or stereoisomer above-mentioned, Wherein, when Y and Z is carbon atom, X is nitrogen-atoms or carbon atom；When X and Y is carbon atom, Z is nitrogen-atoms；

Ar is selected from phenyl, pyridyl group, the phenyl being substituted or the pyridyl group being substituted, wherein the phenyl being substituted Or the pyridyl group that is substituted it is optional replaced following one or more substituent groups:

Halogen ,-C_1-8Alkyl ,-C_1-8The C that alkoxy, halogen replace_1-8The C that alkyl, halogen replace_1-8Alkoxy；

R is hydrogen.

Some embodiments of the present invention are related to compound, its pharmaceutically acceptable salt or stereoisomer above-mentioned, Wherein, Ar isR₁Selected from-F ,-Cl ,-Br ,-C_1-8Alkyl ,-C_1-8The C that alkoxy, halogen replace_1-8Alkyl, halogen Substituted C_1-8Alkoxy；R₂Selected from-H ,-F ,-Cl ,-Br ,-C_1-3Alkyl.

Some embodiments of the present invention are related to compound, its pharmaceutically acceptable salt or stereoisomer above-mentioned, Wherein, R₁For-F ,-Cl ,-CH₃、-CH₂CH₃、-OCH₃、-OCH₂CH₃、-O-(CH₂)_n-CH₃、-O-(CH₂)_n-Cl；N is the whole of 2-6 Number.

Some embodiments of the present invention are related to compound, its pharmaceutically acceptable salt or stereoisomer above-mentioned, Wherein, X and Y is carbon atom, and Z is nitrogen-atoms；R₂For-H.

Some embodiments of the present invention are related to compound, its pharmaceutically acceptable salt or stereoisomer above-mentioned, Wherein, Y and Z is carbon atom, and X is nitrogen-atoms or carbon atom.

Some embodiments of the present invention are related to compound, its pharmaceutically acceptable salt or stereoisomer above-mentioned, Wherein, Ar is selected from

In certain embodiments of the present invention, leading to formula (I) compound represented can specifically:

N- [2- (the chloro- 5- fluorine benzyloxy of 2-) phenyl] niacin formamide；

N- [2- (2,6- dichloro-benzyloxy) phenyl] niacin formamide；

N- [2- (2- methyl -5- fluorine benzyloxy) phenyl] niacin formamide；

N- [2- (2- methoxybenzyl oxygroup) phenyl] niacin formamide；

N- { 2- [(2- ethyl) benzyloxy] phenyl } niacin formamide；

N- { 2- [(2,6- dimethyl) benzyloxy)] phenyl } niacin formamide；

N- { 2- [(2- ethyoxyl) benzyloxy] phenyl } niacin formamide；

N- { 2- [(2- methoxyl group -5- chlorine) benzyloxy] phenyl } niacin formamide；

N- { 2- [(2,5- dichloro) benzyloxy] phenyl } niacin formamide；

N- { 2- [(2- methyl-5-chloro) benzyloxy] phenyl } niacin formamide；

N- { 2- [2- (4- neoprene oxygroup) benzyloxy] phenyl } niacin formamide；

N- { 2- [2- (5- chlorine amoxy) benzyloxy] phenyl } niacin formamide；

N- { 2- [2- (6- chlorine hexyloxy) benzyloxy] phenyl } niacin formamide；

N- [2- (2- hexyloxy benzyloxy) phenyl] niacin formamide；

N- [2- (2- oxygroup in heptan benzyloxy) phenyl] niacin formamide；

N- { 2- [(2- hexyloxy) -5- benzyl chloride oxygroup] phenyl } niacin formamide；

N- { 2- [(2- oxygroup in heptan) -5- benzyl chloride oxygroup] phenyl } niacin formamide；

N- { 2- [2- (4- neoprene oxygroup) benzyloxy] phenyl } isonicotinic acid formamide；

N- { 2- [2- (5- chlorine amoxy) benzyloxy] phenyl } isonicotinic acid formamide；

N- { 2- [(the chloro- oxy-benzyl in 2- heptan of 5-) amino] phenyl } niacinamide；

N- { 2- [(the chloro- 2- of 5- (6- chlorine hexyloxy) benzyl) amino] phenyl } niacinamide；

N- { 2- [(the chloro- 5- luorobenzyl of 2-) amino] phenyl } niacinamide；

N- { 2- [(2,6-dichloro benzyl) amino] phenyl } niacinamide；

N- { 2- [(the fluoro- 2- methylbenzyl of 5-) amino] phenyl } niacinamide；

N- { 2- [(2- (4- neoprene oxygroup) benzyl) amino] phenyl } Pyrazinamide；

N- { 2- [(2- (5- chlorine amoxy) benzyl) amino] phenyl } Pyrazinamide；

N- { 2- [(2- hexyloxy benzyl) amino] phenyl } Pyrazinamide；

N- { 2- [(the chloro- oxy-benzyl in 2- heptan of 5-) amino] phenyl } benzamide；

N- { 2- [(6- chlorine hexyloxy benzyl) amino] phenyl } niacinamide；

N- { 2- [2- (6- chlorine hexyloxy) benzyloxy] phenyl } isonicotinic acid formamide；

N- { 2- [2- (oxygroup in heptan) benzyloxy] phenyl } isonicotinic acid formamide.

The present invention also provides the preparation methods of logical formula (I) compound represented above-mentioned comprising following steps:

Compound 1 and compound 2 are condensed to yield compound 3；

Compound 3 goes benzyl protection that compound 4 is made by catalytic hydrogenation；

Compound 4 withFinal product should be made and lead to formula (I) compound represented；

Wherein, M is-O-；R₃Selected from-OH ,-F ,-Cl or-Br.

In certain embodiments of the present invention,It is specifically as follows the bromobenzyl being substituted；More specifically, institute The bromobenzyl being substituted stated it is optional replaced following one or more substituent groups: halogen ,-C_1-8Alkyl ,-C_1-8Alkoxy, The C that halogen replaces_1-8The C that alkyl, halogen replace_1-8Alkoxy.

The present invention also provides the preparation methods of logical formula (I) compound represented above-mentioned comprising following steps:

Compound 6 and compound 2 are condensed to yield compound 7；

Compound 7 restores nitro under catalytic hydrogenation conditions, obtains compound 8；

Compound 8 and Ar-CHO reduction amination obtain logical formula (I) compound represented；Wherein, M is-NH-；R₃Selected from- OH ,-F ,-Cl or-Br.

In certain embodiments of the present invention, Ar-CHO is specifically as follows the benzaldehyde being substituted；More specifically, institute The benzaldehyde being substituted stated it is optional replaced following one or more substituent groups: halogen ,-C_1-8Alkyl ,-C_1-8Alcoxyl The C that base, halogen replace_1-8The C that alkyl, halogen replace_1-8Alkoxy.

X, Y, Z, R and Ar involved in the preparation method of aforesaid compound provided by the invention are as previously described.

The present invention also provides a kind of pharmaceutical compositions, and it includes the aforementioned formula of at least one therapeutically effective amount (I) institutes Show compound, its pharmaceutically acceptable salt or stereoisomer and chooses any one kind of them or a variety of pharmaceutically acceptable carriers And/or diluent.

Pharmaceutical composition of the invention can further include one or more medicine or physiologically acceptable carriers and/or Diluent, these carriers will be prepared suitably in order to be administered.For example, medicine or physiologically acceptable carrier can be salt water, Hot pressurized water, ringer's solution, buffered saline, glucose, maltodextrin, glycerol, ethyl alcohol and its mixture.Medicine group of the invention It can also include medicine or physiologically acceptable additive, such as diluent, lubricant, adhesive, glidant, disintegration at object Agent, sweetener, corrigent, wetting agent, dispersing agent, surfactant, solvent, coating agent, foaming agent or aromatic.

The example for the diluent that can be used include but is not limited to lactose, sucrose, starch, kaolin, salt, mannitol and Dicalcium Phosphate；The example of lubricant includes but is not limited to the stearate, lycopodium and stearic acid of talcum, starch, magnesium or calcium；It is viscous The example of mixture include but is not limited to microcrystalline cellulose, bassora gum, glucose solution, mucialga of arabic gummy, gelatin solution, sucrose and Gelatinized corn starch；The example of glidant includes but is not limited to colloidal silicon dioxide；The example of disintegrating agent includes but is not limited to be crosslinked carboxylic first Base sodium cellulosate, primojel, alginic acid, cornstarch, potato starch, bentonite, methylcellulose, agar and carboxylic first Base cellulose；The example of sweetener includes but is not limited to sucrose, lactose, mannitol and artificial sweetener, such as ring sodium sulfonate And saccharin and any number of spray drying corrigent；The example of corrigent includes but is not limited to rectify from the natural of plant extract Taste agent, such as fruit and the preferable compound of taste, such as, but not limited to peppermint and gaultherolin；The example packet of wetting agent Include but be not limited to propylene glycol monostearate, anhydro sorbitol monooleate, one laurate of diethylene glycol (DEG) and polyoxyethylene laural Base ether.

The pharmaceutically acceptable carrier being optionally added in pharmaceutical composition of the invention may also is that water, alcohol, bee Honey, mannitol, sorbierite, dextrin, lactose, caramel, gelatin, calcium sulfate, magnesium stearate, talcum powder, kaolin, glycerol, tween, Agar, calcium carbonate, calcium bicarbonate, surfactant, cyclodextrin and its derivative, phospholipid, phosphoric acid salt, starch and its spread out Biology, silicon derivative, cellulose family and its derivative, pyrrolidinone compounds, polyethylene glycols, crylic acid resin, phthalate, One or more of acrylic copolymer, benzenetricarboxylic acid esters.

Pharmaceutical composition provided by the present invention can be prepared as any form, such as particle, powder, tablet, coating tablet The sustained release preparation of agent, capsule, pill, syrup, drops, solution, suspension and emulsion or active constituent, wherein capsule Example includes hard or soft gelatin capsule agent, and granule and pulvis can be in the form of right and wrong effervesces or effervesce.

Pharmaceutical composition of the invention can be administered by all means according to conventional method, including oral, intravenous, In intra-arterial, intraperitoneal, thoracic cavity, transdermal, nasal cavity, sucking, rectum, eye and subcutaneous import.

The present invention also provides aforesaid compound, its pharmaceutically acceptable salt or stereoisomer or medicines above-mentioned Compositions are in preparation for preventing, treating the application in the drug for increasing caused disease extremely by sphingomyelin levels, institute Stating disease includes but is not limited at least one of atherosclerosis, fatty liver and obesity.

The present invention also provides a kind of for preventing and/or treating atherosclerosis, fatty liver or the method for obesity, institute The method of stating includes the aforesaid compound to object in need application therapeutically effective amount, its pharmaceutically acceptable salt or three-dimensional different Structure body or pharmaceutical composition above-mentioned.

Aforesaid compound, its pharmaceutically acceptable salt or the general dosage range of stereoisomer provided by the present invention Be about daily 0.001mg/kg to 1000mg/kg, preferably from about 0.01mg/kg to 100mg/kg, even more preferably about 0.1 to 20mg/kg, the dosage range of pharmaceutical composition are to be calculated with the amount of its above compound contained.

Term " halogen " refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

Term " alkyl " include saturation aliphatic group, including straight chained alkyl (such as methyl, ethyl, propyl, butyl, Amyl, hexyl, heptyl, octyl, nonyl, decyl etc.), branched alkyl (isopropyl, tert-butyl, isobutyl group etc.), group of naphthene base The alkyl that (cyclopropyl, cyclopenta, cyclohexyl, suberyl and cyclooctyl), alkyl-substituted naphthenic base and naphthenic base replace.

In certain embodiments, have on the skeleton of the alkyl of linear chain or branched chain 6 or less carbon atom (for example, Straight chain is C_1-6, branch C_3-6), and more preferable 4 or less carbon atom.Again it is preferred to naphthenic base on its ring structure With 3-8 carbon atom, there are 5 or 6 carbon more preferably on its ring structure.

Term " C_1-8Alkyl " includes the alkyl comprising 1 to 8 carbon atom.

Term " alkyl being substituted " refers to that the hydrogen in hydrocarbon skeleton on one or more carbon is substituted the alkyl base of base replacement Group.The substituent group may include: alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyl epoxide, aryl carbonyl epoxide, alkoxy carbonyl Base oxygroup, aryloxycarbonyl epoxide, hydroxycarbonyl group, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino Carbonyl, dialkyl amino carbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate ester, cyano, amino (including alkyl amino, two Alkyl amino, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (including alkyl-carbonyl-amino, aryl carbonyl Base amino, carbamoyl and urea groups), amidino groups, imino group, sulfydryl, alkylthio group, arylthio, hydroxy carbonyl, sulfuric ester, Alkyl sulphinyl, sulfonic group, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocycle, alkyl virtue Base or aromatic group or heteroaromatic group.

Term " aryl " includes 6 yuan -8 yuan of mono-cyclic aromatic group, such as phenyl, cyclo-octene base；" aryl " further includes 8 Polycyclic (two rings, tricyclic) aryl, such as naphthalene, phenanthrene etc. of -14 yuan of member.

Term " heteroaryl " its refer at least one ring carbon atom by selected from O, S, N hetero atom substitute armaticity ring Shape group may include 1-4 hetero atom；Heteroaryl can be 5-14 member heteroaryl with the miscellaneous side's base of monocycle or polyheteroaromatic Base, 5-12 unit's heteroaryl, 5-10 unit's heteroaryl, 5-8 unit's heteroaryl, 5-6 unit's heteroaryl, for example, pyrroles, furans, thiophene, thiazole, Isothiazole, imidazoles, triazole, tetrazolium, pyrazoles, azoles, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine, benzothiazole, benzodiazole, benzo Thiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinolin, naphthyridines, indoles, benzofuran, purine, benzene And furans, deazapurine or indolizine.These heteroaryls are also referred to as " aryl-heterocyclic ", " heterocycle ", " heteroaryl " or " heteroaromatic base Group ".

Typical heteroaryl includes 2- or 3- thienyl；2- or 3- furyl；2- or 3- pyrrole radicals；2-, 4- or 5- imidazoles Base；3-, 4- or 5- pyrazolyl；2-, 4- or 5- thiazolyl；3-, 4- or 5- isothiazolyl；2-, 4- or 5- oxazolyl；3-, 4- or 5- Isoxazolyl；3- or 5-1,2,4- triazolyls；4- or 5-1,2,3- triazolyls；Tetrazole radical；2-, 3- or 4- pyridyl group；3- or 4- rattle away Piperazine base；3-, 4- or 5- pyrazinyl；2- pyrazinyl；2-, 4- or 5- pyrimidine radicals.

Term " heteroaryl " further includes that the ring of wherein heteroaromatic rings and one or more aryl, cyclic aliphatic or heterocycle is condensed Group, wherein its linking group or tie point are located on heteroaromatic rings.The example include but is not limited to 1-, 2-, 3-, 5-, 6-, 7- or 8- indolizine base；1-, 3-, 4-, 5-, 6- or 7- isoindolyl；2-, 3-, 4-, 5-, 6- or 7- indyl；2-,3-,4-, 5-, 6- or 7- indazolyl；2-, 4-, 5-, 6-, 7- or 8- purine radicals；1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- quinazinyl；2-, 3-, 4-, 5-, 6-, 7- or 8- quinolyl；1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinolyl；1-, 4-, 5-, 6-, 7- or 8- phthalazines Base；2-, 3-, 4-, 5- or 6- naphthyridines base；2-, 3-, 5-, 6-, 7- or 8- quinazolyl；3-, 4-, 5-, 6-, 7- or 8- cinnoline base； 2-, 4-, 6- or 7- pteridyl；1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazyl；1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- Carbazyl；1-, 3-, 4-, 5-, 6-, 7-, 8- or 9- carboline base；1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10- phenanthridinyl；1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9- acridinyl；1-, 2-, 4-, 5-, 6-, 7-, 8- or 9- piperidinyl；2-,3-,4-,5-,6-, 8-, 9- or 10- phenanthroline；1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- phenazinyl；1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or Lysivane base；1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10- phenazinyl；2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- benzisoquinoline base；2-, 3-, 4- or thieno [2,3-b] furyl；2-,3-,5-,6-,7-,8-, 9-, 10- or 11-7H- pyrazine simultaneously [2,3-c] carbazyl；2-, 3-, 5-, 6- or 7-2H- furans simultaneously [3,2-b]-pyranose；2-, 3-, 4-, 5-, 7- or 8-5H- pyrido [2,3-d]-o- piperazine base；1-, 3- or 5-1H- pyrazolo [4,3-d]-oxazolyl；2-, 4- or 5-4H- imidazo [4,5-d] thiazolyl；3-, 5- or 8- pyrazine simultaneously [2,3-d] pyridazinyl；2-, 3-, 5- or 6- imidazo [2,1- B] thiazolyl；1-, 3-, 6-, 7-, 8- or 9- furans simultaneously [3,4-c] cinnoline base；1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H- pyrido [2,3-c] carbazyl；2-, 3-, 6- or 7- imidazo [1,2-b] [1,2,4] triazine radical；7- benzo [b] thiophene Pheno base；2-, 4-, 5-, 6- or 7- benzoxazolyl group；2-, 4-, 5-, 6- or 7- benzimidazolyl；2-, 3-, 4-, 5-, 6- or 7- benzo Thiazolyl；1-, 2-, 4-, 5-, 6-, 7-, 8- or 9- benzo oxa- base；2-, 4-, 5-, 6-, 7- or 8- benzimidazole dihydrochloride base；1-,2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1H- pyrrolo- [1,2-b] [2] benzo-aza base.Typically condensed heteroaryl includes 2-, 3-, 4-, 5-, 6-, 7- or 8- quinolyl；1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinolyl；2-, 3-, 4-, 5-, 6- or 7- Indyl；2-, 3-, 4-, 5-, 6- or 7- benzo [b] thienyl；2-, 4-, 5-, 6- or 7- benzoxazolyl group；2-, 4-, 5-, 6- or 7- benzimidazolyl；2-, 4-, 5-, 6- or 7- benzothiazolyl.

The aromatic ring of " aryl " or " heteroaryl " can be replaced on one or more ring positions by substituent group described above, Such as halogen, hydroxyl, alkoxy, alkyl carbonyl epoxide, aryl carbonyl epoxide, alkoxy-carbonyl oxy, aryloxycarbonyl oxygen Base, hydroxycarbonyl group, alkyl-carbonyl, alkyl amino-carbonyl, aryl-alkyl amino carbonyl, alkenyl amino carbonyl, alkyl-carbonyl, aryl Carbonyl, aromatic yl alkyl carbonyl, alkenyl carbonyl, alkoxy carbonyl, amino carbonyl, alkylthiocarbonyl, phosphate, phosphonate ester, cyano, Amino (including alkyl amino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (including Alkyl-carbonyl-amino, aryl-amino-carbonyl, carbamoyl and urea groups), amidino groups, imino group, sulfydryl, alkylthio group, arylthio, hydroxyl Base thiocarbonyl, sulfuric ester, alkyl sulphinyl, sulfonate group, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, Azido, heterocycle, alkylaryl or aromatic group or heteroaromatic group, wherein aryl group can also be with non-aromatic rouge Ring or heterocyclic fused or bridging, to form polycyclic (such as naphthane).

Term " alkoxy " includes the substituted and unsubstituted alkyl being covalently attached with oxygen atom.The reality of alkoxy Example includes methoxyl group, ethyoxyl, isopropyl oxygroup, propoxyl group, butoxy and amoxy.The example of substituted alkoxy includes Halogenated alkoxy.Alkoxy can be replaced by following group: alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyl epoxide, aryl carbonyl oxygen Base, alkoxy-carbonyl oxy, aryloxycarbonyl epoxide, hydroxycarbonyl group, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl Base, alkyl amino-carbonyl, dialkyl amino carbonyl, alkylthiocarbonyl, phosphate-based, cyano, amino (including alkyl amino, two Alkyl amino, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (including alkyl-carbonyl-amino, aryl carbonyl Base amino, carbamoyl and urea groups), amidino groups, imino group, sulfydryl, alkylthio group, arylthio, hydroxy carbonyl, alkyl Asia sulphur Acyl group, sulfonic group, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocycle, alkylaryl or aromatics Group.

The officinal salt of compound of the present invention can by organic solvent such as acetonitrile, tetrahydrofuran with it is corresponding Organic acid or inorganic acid reaction, to be converted into corresponding salt, typical organic acid has oxalic acid, tartaric acid, maleic acid, amber Acid, citric acid, typical inorganic acid have nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid.

Term " stereoisomer " includes formula (I) compound represented enantiomter that may be present, diastereo-isomerism Body, racemization isomers, cis-trans-isomer, tautomer, geometric isomer, epimer and its mixture, are included in In the scope of the invention.

Logical formula (I) compound represented, its pharmaceutically acceptable salt or stereoisomer provided by the invention, can select Property inhibition sphingomyelins synthase, inside and outside drug action is significant, highly-safe, can be used for preventing and/or treating by sphingomyelins Horizontal abnormality increases caused disease.

Specific embodiment

Technical solution of the present invention is described below in conjunction with specific embodiment, described embodiment is only this Invention a part of the embodiment, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art exist Every other embodiment obtained under the premise of creative work is not made, shall fall within the protection scope of the present invention.

Embodiment 1:N- [2- (the chloro- 5- fluorine benzyloxy of 2-) phenyl] niacin formamide

The synthesis of first step N- [(2- benzyloxy) phenyl] niacin formamide

Niacin (3.52g, 17.66mmol), methylene chloride (100ml), thionyl chloride are added into dry eggplant type flask (13.5g, 113.72mmol) is stirred at room temperature 5 minutes, adds 2 drop pyridines, is heated to reflux 3 hours, evaporating solvent under reduced pressure and surplus Remaining thionyl chloride, obtains niacin formyl chloride (3g), which can be directly used in the next step without further purification.

2- benzyloxy-aniline (3.52g, 17.66mmol) is dissolved in dry methylene chloride (100ml), triethylamine is added (2.68g, 26.49mmol) is simultaneously stirred evenly.Under the conditions of ice-water bath, slowly thereto be added dropwise niacin formyl chloride (3g, 21.19mmol) dichloromethane solution.Drop finishes, and reacts at room temperature 5 hours.After reaction system is washed with water twice, saturated sodium-chloride is washed Twice, anhydrous magnesium sulfate is dry, and concentration rear pillar chromatographs to obtain N- [(2- benzyloxy) phenyl] niacin formamide 4.23g, yield 78.6%.

The synthesis of second step N- [(2- hydroxyl) phenyl] niacin formamide

10% is added into methanol (80ml) solution of N- [(2- benzyloxy) phenyl] niacin formamide (3g, 9.86mmol) Pd/C (0.4g) is then reacted at room temperature 8 hours under 8MPa Hydrogen Vapor Pressure.It filters and removes Pd/C, filtrate is concentrated to get product N- [(2- hydroxyl) phenyl] niacin formamide (1.87g), yield 88.6%.

Third step N- [2- (the chloro- 5- fluorine benzyloxy of 2-) phenyl] niacin formamide

N- [(2- hydroxyl) phenyl] niacin formamide (0.1g, 0.47mmol) is dissolved in DMF (10ml), potassium carbonate is added (0.13g, 0.93mmol) adds the chloro- 5- fluorobenzyl bromide (0.1g, 0.47mmol) of 2-, and room temperature reaction is overnight.Add water, acetic acid second Ester extracts, and saturated common salt washing, anhydrous magnesium sulfate is dry, and concentration rear pillar chromatography (PE/EA0-50%) obtains N-2- [(the chloro- 5- fluorine of 2- Benzyloxy) phenyl] niacin formamide (0.13g), yield 78%.¹H NMR(400MHz,Chloroform-d)δ9.03-8.99 (m, 1H) .8.70 (dd, J=4.9,1.7Hz, 1H), 8.63 (s, 1H), 8.56 (dd, J=8.0,1.7Hz, 1H), 8.22 (dt, J =8.0,2.0Hz, 1H), 7.48-7.41 (m, 3H), 7.35-7.31 (m, 1H), 7.31-7.29 (m, 1H), 7.27-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.91 (s, 1H), 5.26 (s, 2H) MS:m/z (ESI) 357 [M+1]⁺。

Embodiment 2:N- [2- (2,6- dichloro-benzyloxy) phenyl] niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2,6- dichloro bromine Benzyl reacts to obtain target compound 76mg, yield 78%, and appearance is faint yellow solid.

¹H NMR (400MHz, Chloroform-d) δ 9.01-8.97 (m, 1H), 8.74 (dd, J=4.9,1.7Hz, 1H), 8.61 (s, 1H), 8.53 (dd, J=8.0,1.7Hz, 1H), 8.19 (dt, J=8.0,2.0Hz, 1H), 7.45-7.38 (m, 3H), 7.32-7.28 (m, 1H), 7.28-7.25 (m, 1H), 7.25-7.20 (m, 1H), 7.16 (td, J=7.7,1.7Hz, 1H), 7.10 (td, J=7.7,1.6Hz, 1H), 5.42 (s, 2H) .MS m/z (ESI): 373.0 [M+H]⁺。

Embodiment 3:N- [2- (2- methyl -5- fluorine benzyloxy) phenyl] niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- methyl -5- fluorine Bromobenzyl reacts to obtain target compound 130mg, yield 68%, and appearance is white solid.¹H NMR(400MHz,Chloroform-d) δ 9.04-8.98 (m, 1H), 8.70 (dd, J=4.9,1.7Hz, 1H), 8.63 (s, 1H), 8.56 (dd, J=8.0,1.7Hz, 1H), 8.22 (dt, J=8.0,2.0Hz, 1H), 7.48-7.41 (m, 3H), 7.35-7.31 (m, 1H), 7.31-7.29 (m, 1H), 7.27-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.91 (s, 1H), 5.26 (s, 2H), 2.36 (s, 3H) .MS: m/z(ESI)337[M+1]⁺。

Embodiment 4:N- [2- (2- methoxybenzyl oxygroup) phenyl] niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- methoxy bromide Benzyl reacts to obtain target compound 95mg, yield 55%, and appearance is the white solid of class.¹H NMR(400MHz,Chloroform-d)δ 9.03-8.97 (m, 1H), 8.65 (dd, J=4.9,1.7Hz, 1H), 8.60 (s, 1H), 8.54 (dd, J=8.0,1.7Hz, 1H), 8.26 (dt, J=8.0,2.0Hz, 1H), 7.44-7.37 (m, 3H), 7.33-7.30 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 6.91 (d, 1H), 5.26 (s, 2H), 3.90(s,3H).MS:m/z(ESI)335[M+1]⁺。

Embodiment 5:N- { 2- [(2- ethyl) benzyloxy] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- ethyl bromobenzyl Reaction obtains target compound 77mg, yield 56%, and appearance is white solid.¹H NMR(400MHz,Chloroform-d)δ 9.03-8.97 (m, 1H), 8.65 (dd, J=4.9,1.7Hz, 1H), 8.60 (s, 1H), 8.54 (dd, J=8.0,1.7Hz, 1H), 8.26 (dt, J=8.0,2.0Hz, 1H), 7.44-7.37 (m, 3H), 7.33-7.30 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 6.91 (d, 1H), 5.26 (s, 2H), 2.71(m,2H),1.18(m,3H).MS:m/z(ESI)333[M+1]⁺

Embodiment 6:N- { 2- [(2,6- dimethyl) benzyloxy)] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2,6- dimethyl Bromobenzyl reacts to obtain target compound 108mg, yield 70%, and appearance is faint yellow solid.¹HNMR(400MHz, Chloroform-d) δ 9.03-8.97 (m, 1H), 8.65 (dd, J=4.9,1.7Hz, 1H), 8.60 (s, 1H), 8.54 (dd, J= 8.0,1.7Hz, 1H), 8.26 (dt, J=8.0,2.0Hz, 1H), 7.44-7.37 (m, 3H), 7.33-7.30 (m, 1H), 7.29- 7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 5.26 (s, 2H), 2.29(m,3H),2.26(s,3H).MS:m/z(ESI)333[M+1]⁺。

Embodiment 7:N- { 2- [(2- ethyoxyl) benzyloxy] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- ethoxy bromide Benzyl reacts to obtain target compound 50mg, yield 72%, and appearance is faint yellow solid.¹HNMR(400MHz,Chloroform-d) δ 9.05-8.99 (m, 1H), 8.66 (dd, J=4.9,1.7Hz, 1H), 8.61 (s, 1H), 8.55 (dd, J=8.0,1.7Hz, 1H), 8.27 (dt, J=8.0,2.0Hz, 1H), 7.44-7.37 (m, 3H), 7.33-7.30 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 6.91 (d, 1H), 5.26 (s, 2H), 4.10(m,2H),1.10(m,3H).MS:m/z(ESI)349[M+1]⁺。

Embodiment 8:N- { 2- [(2- methoxyl group -5- chlorine) benzyloxy] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- methoxyl group -5- Chlorine bromobenzyl reacts to obtain target compound 43mg, yield 83%, and appearance is yellow solid.

¹H NMR(400MHz,DMSO-d₆) δ 9.28 (s, 1H), 8.86 (d, J=4.6Hz, 1H), 8.48 (d, J=8.2Hz, 1H), 7.63 (s, 1H), 7.20 (d, J=8.8Hz, 1H), 7.12 (s, 1H), 7.05 (d, J=8.0Hz, 1H), 6.97 (d, J= 8.7Hz, 2H), 6.57 (t, J=7.7Hz, 1H), 6.42 (d, J=8.2Hz, 1H), 6.12 (s, 1H), 3.80 (d, J=1.8Hz, 3H).MS m/z(ESI):369.0[M+H]⁺。

Embodiment 9:N- { 2- [(2,5- dichloro) benzyloxy] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2,5- dichloro bromine Benzyl reacts to obtain target compound 40mg, yield 53%, and appearance is gray solid.¹H NMR(400MHz,Chloroform-d)δ 9.09-9.01 (m, 1H), 8.69 (dd, J=4.8,1.8Hz, 1H), 8.64 (s, 1H), 8.55 (dd, J=8.0,1.7Hz, 1H), 8.27 (dt, J=8.0,2.0Hz, 1H), 7.44-7.37 (m, 3H), 7.33-7.30 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (s, 1H), 5.26 (s, 2H) .MS:m/z (ESI) 373 [M+1]⁺。

Embodiment 10:N- { 2- [(2- methyl-5-chloro) benzyloxy] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- methyl-5-chloro Bromobenzyl reacts to obtain target compound 48mg, yield 79%, and appearance is yellow solid.

¹H NMR(400MHz,DMSO-d₆) δ 9.27 (dd, J=2.3,0.9Hz, 1H), 8.85 (dd, J=4.9,1.7Hz, 1H), 8.47 (dt, J=8.0,2.0Hz, 1H), 7.62 (ddd, J=8.0,4.9,0.9Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 7.13 (dd, J=6.7,4.7Hz, 2H), 7.05 (dd, J=7.9,1.5Hz, 1H), 6.98 (td, J=7.8,1.5Hz, 1H), 6.58 (td, J=7.6,1.5Hz, 1H), 6.43 (dd, J=8.2,1.4Hz, 1H), 6.20 (t, J=6.0Hz, 1H), 4.23 (d, J=6.0Hz, 2H), 2.25 (s, 3H) .MS m/z (ESI): 353.1 [M+H]⁺。

Embodiment 11:N- { 2- [2- (4- neoprene oxygroup) benzyloxy] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- (4- neoprene oxygen Base) bromobenzyl reacts to obtain target compound 120mg, yield 75%, appearance white solid.¹H NMR(400MHz, Chloroform-d) δ 9.04-8.99 (m, 1H), 8.64 (dd, J=4.9,1.7Hz, 1H), 8.60 (s, 1H), 8.53 (dd, J= 8.0,1.7Hz, 1H), 8.25 (dt, J=8.0,2.0Hz, 1H), 7.44-7.37 (m, 3H), 7.33-7.30 (m, 1H), 7.29- 7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 6.91 (d, 1H), 5.06(s,2H),4.10(m,2H),3.60(m,2H),1.78(m,2H),1.75(m,2H).MS:m/z(ESI)411[M+1]⁺。

Embodiment 12:N- { 2- [2- (5- chlorine amoxy) benzyloxy] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- (penta oxygen of 5- chlorine Base) bromobenzyl reacts to obtain target compound 25mg, yield 43%, appearance white solid.¹HNMR(400MHz,Chloroform- D) δ 9.04-8.99 (m, 1H), 8.64 (dd, J=4.9,1.7Hz, 1H), 8.60 (s, 1H), 8.53 (dd, J=8.0,1.7Hz, 1H), 8.25 (dt, J=8.0,2.0Hz, 1H), 7.44-7.37 (m, 3H), 7.33-7.30 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 6.91 (d, 1H), 5.06 (s, 2H), 4.10(m,2H),3.60(m,2H),1.78(m,2H),1.75(m,2H),1.29(m,2H).MS:m/z(ESI)425[M+1]⁺。

Embodiment 13:N- { 2- [2- (6- chlorine hexyloxy) benzyloxy] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and (2- (and 6- chlorine oneself Oxygroup) bromobenzyl reacts to obtain target compound 44mg, yield 35%, appearance light yellow solid.

¹H NMR (400MHz, DMSO-d6) δ 9.70 (s, 1H), 9.05 (dd, J=2.3,0.8Hz, 1H), 8.76 (dd, J =4.8,1.7Hz, 1H), 8.24 (dt, J=8.0,1.9Hz, 1H), 7.77 (dd, J=7.9,1.6Hz, 1H), 7.55 (ddd, J =7.9,4.8,0.9Hz, 1H), 7.46 (dd, J=7.5,1.7Hz, 1H), 7.28 (ddd, J=8.2,7.4,1.8Hz, 1H), 7.22-7.12 (m, 2H), 7.05-6.96 (m, 2H), 6.90 (td, J=7.5,1.0Hz, 1H), 5.17 (s, 2H), 3.97 (s, 2H), 3.59 (t, J=6.6Hz, 2H), 1.67 (s, 4H), 1.38 (s, 4H) .MS m/z (ESI): 439.2 [M+H]⁺。

Embodiment 14:N- [2- (2- hexyloxy benzyloxy) phenyl] niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- hexyloxy bromine Benzyl reacts to obtain target compound 42mg, yield 88%, appearance white solid.¹H NMR(400MHz,Chloroform-d)δ 9.04-8.99 (m, 1H), 8.64 (dd, J=4.9,1.7Hz, 1H), 8.60 (s, 1H), 8.53 (dd, J=8.0,1.7Hz, 1H), 8.25 (dt, J=8.0,2.0Hz, 1H), 7.44-7.37 (m, 3H), 7.33-7.30 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 6.91 (d, 1H), 4.96 (s, 2H), 4.60(m,2H),1.78(m,2H),1.47(m,2H),1.37(m,4H),0.89(m,2H).MS:m/z(ESI)405[M+1]⁺。

Embodiment 15:N- [2- (2- oxygroup in heptan benzyloxy) phenyl] niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- oxygroup in heptan bromine Benzyl reacts to obtain target compound 82mg, yield 46%, appearance off-white powder.

¹H NMR (400MHz, Chloroform-d) δ 9.01 (d, J=2.3Hz, 1H), 8.75 (dd, J=4.9,1.8Hz, 2H), 8.55-8.47 (m, 1H), 8.19-8.11 (m, 1H), 7.41 (ddd, J=8.0,4.8,0.9Hz, 1H), 7.38-7.29 (m, 2H), 7.14-7.01 (m, 3H), 7.00-6.90 (m, 2H), 5.23 (s, 2H), 3.95 (t, J=6.5Hz, 2H), 1.68 (dd, J=8.2,6.3Hz, 2H), 1.41-1.13 (m, 8H), 0.85 (t, J=6.8Hz, 3H) .MS m/z (ESI): 419.2 [M+ H]⁺。

Embodiment 16:N- { 2- [(2- hexyloxy) -5- benzyl chloride oxygroup] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- hexyloxy -5- Chlorine bromobenzyl reacts to obtain target compound 18mg, yield 38%, appearance white solid.¹H NMR(400MHz,Chloroform- D) δ 9.04-8.99 (m, 1H), 8.64 (dd, J=4.9,1.7Hz, 1H), 8.60 (s, 1H), 8.53 (dd, J=8.0,1.7Hz, 1H), 8.25 (dt, J=8.0,2.0Hz, 1H), 7.44-7.37 (m, 3H), 7.33-7.30 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 5.03 (s, 2H), 4.64 (m, 2H), 1.79(m,2H),1.49(m,2H),1.38(m,4H),0.91(m,2H).MS:m/z(ESI)439[M+1]⁺。

Embodiment 17:N- { 2- [(2- oxygroup in heptan) -5- benzyl chloride oxygroup] phenyl } niacin formamide

Synthetic method similar to Example 1, intermediate N [(2- hydroxyl) phenyl] niacin formamide and 2- oxygroup in heptan -5- Chlorine bromobenzyl reacts to obtain target compound 59mg, yield 45%, appearance white solid.

¹H NMR(400MHz,DMSO-d₆) δ 9.97 (s, 1H), 8.47-8.33 (m, 2H), 7.64 (d, J=7.9Hz, 1H), 7.42 (s, 1H), 7.19 (d, J=8.4Hz, 2H), 6.91 (dt, J=18.9,8.4Hz, 3H), 6.67 (d, J=8.2Hz, 1H), 6.55 (t, J=7.7Hz, 1H), 5.13 (d, J=15.4Hz, 1H), 4.66 (d, J=15.3Hz, 1H), 1.55 (s, 2H), 1.23 (d, J=13.0Hz, 8H), 0.89-0.74 (m, 3H) .MS m/z (ESI): 453.1 [M+H]⁺。

Embodiment 18:N- { 2- [2- (4- neoprene oxygroup) benzyloxy] phenyl } isonicotinic acid formamide

The synthesis of first step N- [(2- benzyloxy) phenyl] isonicotinic acid formamide

Isonicotinic acid (1.76g, 8.83mmol), methylene chloride (30ml), thionyl chloride are added into dry eggplant type flask (6.75g, 56.86mmol) is stirred at room temperature 5 minutes, adds 2 drop pyridines, is heated to reflux 3 hours, evaporating solvent under reduced pressure and surplus Remaining thionyl chloride obtains acyl chlorides (1.3g).The crude product can be directly used in the next step without further purification.

2- benzyloxy-aniline (1g, 5mmol) is dissolved in dry methylene chloride (30ml), addition triethylamine (0.76g, 7.53mmol) and stir evenly.Under the conditions of ice-water bath, isonicotinic acid formyl chloride (0.9g, 6.52mmol) slowly is added dropwise thereto Dichloromethane solution.Drop finishes, and reacts at room temperature 5 hours.After reaction system is washed with water twice, saturated sodium-chloride is washed twice, anhydrous Magnesium sulfate is dry, and concentration rear pillar chromatographs to obtain N- [(2- benzyloxy) phenyl] isonicotinic acid formamide 1.15g, yield 75%.

The synthesis of second step N- [(2- hydroxyl) phenyl] isonicotinic acid formamide

It is added into methanol (30ml) solution of N- [(2- benzyloxy) phenyl] isonicotinic acid formamide (1g, 3.29mmol) 10%Pd/C (0.1g) is then reacted at room temperature 8 hours under 8MPa Hydrogen Vapor Pressure.It filters and removes Pd/C, filtrate is concentrated to get production Product N- [(2- hydroxyl) phenyl] isonicotinic acid formamide (0.57g), yield 81%.

The synthesis of third step N- { 2- [2- (4- neoprene oxygroup) benzyloxy] phenyl } isonicotinic acid formamide

N- [(2- hydroxyl) phenyl] isonicotinic acid formamide (0.1g, 0.47mmol) is dissolved in DMF (10ml), carbonic acid is added Potassium (0.13g, 0.93mmol) adds 2- (4- neoprene oxygroup) benzyl bromine (0.15g, 0.56mmol), and room temperature reaction is overnight.Add Water, ethyl acetate extract, and saturated common salt washing, anhydrous magnesium sulfate is dry, and concentration rear pillar chromatography (PE/EA 0-50%) obtains N- { 2- [2- (4- neoprene oxygroup) benzyloxy] phenyl } isonicotinic acid formamide (0.67g), yield 35%.MS:m/z(ESI)411[M+1]⁺。

Embodiment 19:N- { 2- [2- (5- chlorine amoxy) benzyloxy] phenyl } isonicotinic acid formamide

Synthetic method similar to Example 18, intermediate N [(2- hydroxyl) phenyl] isonicotinic acid formamide and 2- (5- chlorine Amoxy) bromobenzyl reacts to obtain target compound 59mg, yield 45%, appearance white solid.MS:m/z(ESI)425[M+1]⁺。

Embodiment 20:N- { 2- [(the chloro- oxy-benzyl in 2- heptan of 5-) amino] phenyl } niacinamide

The synthesis of first step N- (2- nitrobenzophenone) niacin formamide

By compound ortho-nitraniline (15.0g, 0.1mol), triethylamine (33.3g, 0.3mol) is dissolved in methylene chloride In (150mL), it is cooled to 0 DEG C, compound niacin formyl chloride (18.4g, 0.1mol) is slowly added dropwise to reaction system.It is added dropwise Afterwards, it reacts 2 hours for 0 DEG C.TLC shows end of reaction, and 500mL water is added, and liquid separation, organic phase washed once with hydrochloric acid (1N), with satisfying It is primary with salt washing, it is dry with anhydrous sodium sulfate, it is spin-dried for, the compound N-(2- nitrobenzophenone) being beaten with methyl tertiary butyl ether(MTBE) Niacin crude formamide (6.0g, 25.0mmol), yield 22.7% are directly used in and react in next step.

The synthesis of second step N- (2- aminophenyl) niacin formamide

By Raney's nickel (1.2g), methanol is added in compound N-(2- nitrobenzophenone) niacin formamide (6.0g, 25.0mmol) In (60mL), under 50Psi Hydrogen Vapor Pressure, react at room temperature 10 hours.TLC shows end of reaction, and reaction system is filtered, filtrate rotation It is dry to obtain compound N-(2- aminophenyl) niacin formamide (4.0g, 19.0mmol), yield 76.0%.

¹H NMR (400MHz, DMSO-d6, ppm): 9.83 (brs, 1H), 9.14 (s, 1H), 8.74 (d, J=4.8Hz, 1H), 8.33 (d, J=7.6Hz, 1H), 7.44 (dd, J=8Hz J=5.2Hz, 2H), 7.18 (d, J=7.6Hz, 1H), 7.0- 6.96 (m, 1H), 6.79 (dd, J=8Hz J=1.2Hz, 1H), 6.61 (t, J=7.2Hz, 1H), 4.98 (brs, 2H).

The synthesis of third step N- { 2- [(the chloro- oxy-benzyl in 2- heptan of 5-) amino] phenyl } niacinamide

Methanol (5mL) is added into reaction flask, compound N-(2- aminophenyl) niacin formamide (0.50g, 2.3mmol) It is stirred at room temperature 0.5 hour with 2- oxygroup in heptan -5- chlorobenzaldehyde (1.2g, 4.6mmol), is then added into solution NaBH₃The drop acetic acid of CN (0.7g, 11.5mmol) and 3.Above-mentioned solution is stirred overnight at 50 DEG C.Reaction solution is directly spin-dried for scraper plate. The filtering of scraper plate silica gel is impregnated with methylene chloride and methanol 10:1 to be spin-dried for obtaining compound N-{ 2- [(the chloro- oxy-benzyl in 2- heptan of 5-) ammonia Base] phenyl } niacinamide (50.0mg, 0.1mmol), yield 4.8%.

¹H NMR (400MHz, DMSO-d6, ppm): 9.92 (s, 1H), 9.20 (s, 1H), 8.76 (d, J=3.6Hz, 1H), 8.38 (d, J=7.6Hz, 1H), 7.59 (dd, J=7.6Hz J=4.8Hz, 1H), 7.30 (d, J=2Hz, 1H), 7.22 (dd, J =8.8Hz J=2.8Hz, 1H), 7.15 (d, J=7.2Hz, 1H), 7.02-6.99 (m, 2H), 6.62 (d, J=7.6Hz, 1H), 6.40 (d, J=8Hz, 1H), 5.83 (brs, 1H), 4.28 (s, 2H), 4.04 (t, J=6Hz, 2H), 1.76-1.69 (m, 2H), 1.45-1.37(m,2H),1.33-1.14(m,6H),0.87-0.80(m,3H)。MS:m/z(ESI)452[M+1]⁺

Embodiment 21:N- { 2- [(the chloro- 2- of 5- (6- chlorine hexyloxy) benzyl) amino] phenyl } niacinamide

Synthetic method similar to Example 20, intermediate N (2- aminophenyl) niacin formamide and 2- (the own oxygen of 6- chlorine Base) -5- chlorobenzaldehyde reacts to obtain target compound 59mg, yield 45%, appearance white solid.

¹H NMR (400MHz, DMSO-d6, ppm): 9.91 (s, 1H), 9.19 (s, 1H), 8.76 (d, J=3.6Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 7.59 (dd, J=7.6Hz J=4.8Hz, 1H), 7.29 (d, J=7.2Hz, 1H), 7.19- 7.12 (m, 2H), 7.02-6.95 (m, 2H), 6.86 (t, J=7.2Hz, 1H), 6.59 (t, J=7.2Hz, 1H), 6.48 (d, J= 8Hz, 1H), 5.72 (brs, 1H), 4.30 (s, 2H), 4.03 (t, J=6Hz, 2H), 3.63 (t, J=6.4Hz, 2H), 1.75- 1.68(m,4H),1.50-1.36(m,4H)。MS:m/z(ESI)472[M+1]⁺。

Embodiment 22:N- { 2- [(the chloro- 5- luorobenzyl of 2-) amino] phenyl } niacinamide

Synthetic method similar to Example 20, intermediate N (2- aminophenyl) niacin formamide and the chloro- 5- fluorobenzene of 2- Formaldehyde reacts to obtain target compound 33mg, yield 20%, appearance off-white solid.¹H NMR(400MHz,DMSO-d6, Ppm): 9.91 (s, 1H), 9.19 (s, 1H), 8.76 (d, J=3.6Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 7.59 (dd, J =7.6Hz J=4.8Hz, 1H), 7.35 (s, 1H), 7.19-7.12 (m, 2H), 7.02-6.95 (m, 2H), 6.86 (t, J= 7.2Hz, 1H), 6.59 (t, J=7.2Hz, 1H), 6.48 (d, J=8Hz, 1H), 4.30 (s, 2H).MS:m/z(ESI)356[M+ 1]⁺。

Embodiment 23:N- { 2- [(2,6-dichloro benzyl) amino] phenyl } niacinamide

Synthetic method similar to Example 20, intermediate N (2- aminophenyl) niacin formamide and 2,5- dichloro-benzenes first Aldehyde reaction obtains target compound 54mg, yield 26%, appearance light yellow solid.¹H NMR(400MHz,DMSO-d6,ppm): 9.87 (s, 1H), 9.19 (s, 1H), 8.75 (d, J=3.6Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 7.59 (dd, J= 7.6Hz J=4.8Hz, 1H), 7.29 (d, J=7.2Hz, 1H), 7.19-7.12 (m, 2H), 7.02-6.95 (m, 2H), 6.86 (t, J=7.2Hz, 1H), 6.59 (t, J=7.2Hz, 1H), 6.48 (d, J=8Hz, 1H), 4.30 (s, 2H).MS:m/z(ESI) 372[M+1]⁺。

Embodiment 24:N- { 2- [(the fluoro- 2- methylbenzyl of 5-) amino] phenyl } niacinamide

Synthetic method similar to Example 20, intermediate N (2- aminophenyl) niacin formamide and 2- methyl -5- fluorine Benzaldehyde reacts to obtain target compound 45mg, yield 22%, appearance light yellow solid.¹H NMR(400MHz,DMSO-d6, Ppm): 9.87 (s, 1H), 9.19 (s, 1H), 8.75 (d, J=3.6Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 7.59 (dd, J =7.6Hz J=4.8Hz, 1H), 7.29 (d, J=7.2Hz, 1H), 7.19-7.12 (m, 2H), 7.02-6.95 (m, 2H), 6.86 (s, 1H), 6.59 (t, J=7.2Hz, 1H), 6.48 (d, J=8Hz, 1H), 4.30 (s, 2H), 2.29 (s, 3H).MS:m/z (ESI)336[M+1]⁺。

Embodiment 25:N- { 2- [(2- (4- neoprene oxygroup) benzyl) amino] phenyl } Pyrazinamide

Synthetic method similar to Example 20, intermediate N (2- aminophenyl) isonicotinic acid formamide and 4- (neoprene oxygen Base) benzaldehyde reacts to obtain target compound 27mg, yield 18%, appearance light yellow solid.¹H NMR(400MHz, Chloroform-d) δ 9.06-9.00 (m, 1H), 8.65 (dd, J=4.9,1.7Hz, 1H), 8.62 (s, 1H), 8.55 (dd, J= 7.9,1.7Hz, 1H), 8.27 (dt, J=7.9,2.0Hz, 1H), 7.45-7.38 (m, 3H), 7.33-7.30 (m, 1H), 7.29- 7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 6.91 (d, 1H), 4.45(s,2H),4.08(m,2H),3.63(m,2H),1.77(m,2H),1.74(m,2H).MS:m/z(ESI)410[M+1]⁺。

Embodiment 26:N- { 2- [(2- (5- chlorine amoxy) benzyl) amino] phenyl } Pyrazinamide

Synthetic method similar to Example 20, intermediate N (2- aminophenyl) isonicotinic acid formamide and 2- (5- chlorine penta Oxygroup) benzaldehyde reacts to obtain target compound 57mg, yield 30%, appearance light yellow solid.¹H NMR(400MHz, Chloroform-d) δ 9.05-9.00 (m, 1H), 8.64 (dd, J=4.9,1.7Hz, 1H), 8.60 (s, 1H), 8.53 (dd, J= 7.9,1.7Hz, 1H), 8.25 (dt, J=7.9,2.0Hz, 1H), 7.43-7.36 (m, 3H), 7.33-7.31 (m, 1H), 7.29- 7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 6.91 (d, 1H), 4.45(s,2H),4.08(m,2H),3.63(m,2H),1.77(m,2H),1.74(m,2H),1.39(m,2H).MS:m/z(ESI) 424[M+1]⁺。

Embodiment 27:N- { 2- [(2- hexyloxy benzyl) amino] phenyl } Pyrazinamide

Synthetic method similar to Example 20, intermediate N (2- aminophenyl) isonicotinic acid formamide and 2- (hexyloxy) Benzaldehyde reacts to obtain target compound 31mg, yield 38%, appearance yellow solid.¹H NMR(400MHz,Chloroform- D) δ 9.08-9.03 (m, 1H), 8.67 (dd, J=4.9,1.7Hz, 1H), 8.63 (s, 1H), 8.56 (dd, J=7.9,1.7Hz, 1H), 8.28 (dt, J=7.9,2.0Hz, 1H), 7.43-7.36 (m, 3H), 7.33-7.31 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 6.99 (m, 1H), 6.91 (d, 1H), 4.40 (s, 2H), 4.06(m,2H),1.75(m,2H),1.46(m,2H),1.39(m,4H),0.88(t,3H).MS:m/z(ESI)404[M+1]⁺。

Embodiment 28:N- { 2- [(the chloro- oxy-benzyl in 2- heptan of 5-) amino] phenyl } benzamide

The synthesis of first step N- (2- nitrobenzophenone) benzamide

By compound ortho-nitraniline (5.9g, 0.043mol), triethylamine (6.5g, 0.064mol) is dissolved in methylene chloride In (50mL), it is cooled to 0 DEG C, the methylene chloride of compound chlorobenzoyl chloride (6g, 0.043mol) is slowly added dropwise to reaction system (15ml) solution.After being added dropwise, 0 DEG C is reacted 2 hours.TLC shows end of reaction, and 500mL water, liquid separation is added, and organic phase is used Hydrochloric acid (1N) is washed once, is washed once with saturated common salt, dry with anhydrous sodium sulfate, is spin-dried for, column chromatographs to obtain N- (2- nitrobenzene Base) benzamide (5.3g), yield 51.2%.

The synthesis of second step N- (2- aminophenyl) benzamide

By Raney's nickel (1.2g), methanol is added in compound N-(2- nitrobenzophenone) benzamide (5.0g, 20.6mmol) In (60mL), under 50Psi Hydrogen Vapor Pressure, react at room temperature 10 hours.TLC shows end of reaction, and reaction system is filtered, filtrate rotation It is dry to obtain compound N-(2- aminophenyl) benzamide (3.8g, 17.9mmol), yield 86.74%.

The synthesis of third step N- { 2- [(the chloro- oxy-benzyl in 2- heptan of 5-) amino] phenyl } benzamide

Methanol (5mL) is added into reaction flask, compound N-(2- aminophenyl) benzamide (0.50g, 2.36mmol) It is stirred at room temperature 0.5 hour with 2- oxygroup in heptan -5- chlorobenzaldehyde (1.2g, 4.7mmol), is then added into solution NaBH₃The drop acetic acid of CN (0.74g, 11.5mmol) and 3.Above-mentioned solution is stirred overnight at 50 DEG C.Reaction solution is directly spin-dried for scraper plate.

The filtering of scraper plate silica gel is impregnated with methylene chloride and methanol 10:1 to be spin-dried for obtaining compound N-{ 2- [(the chloro- oxygen in 2- heptan of 5- Base benzyl) amino] phenyl } benzamide (100mg), yield 4.7%.¹H NMR(400MHz,Chloroform-d)δ 9.08-9.03 (m, 1H), 8.67 (dd, J=4.9,1.7Hz, 1H), 8.63 (s, 1H), 8.56 (dd, J=7.9,1.7Hz, 1H), 8.28 (dt, J=7.9,2.0Hz, 1H), 7.43-7.36 (m, 3H), 7.33-7.31 (m, 2H), 7.29-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.19 (td, J=7.6,1.6Hz, 1H), 7.01 (s, 1H), 4.40 (s, 2H), 4.09 (m, 2H), 1.78(m,2H),1.48(m,2H),1.26(m,6H),,0.90(t,3H).MS:m/z(ESI)451[M+1]⁺

Embodiment 29:N- { 2- [(6- chlorine hexyloxy benzyl) amino] phenyl } niacinamide

Synthetic method similar to Example 20, intermediate N (2- aminophenyl) niacin formamide and 2- (the own oxygen of 6- chlorine Base) benzaldehyde reacts to obtain target compound 33mg, yield 58%, appearance white solid.¹H NMR(400MHz,DMSO-d₆)δ 9.92 (s, 1H), 9.19 (d, J=2.2Hz, 1H), 8.76 (dd, J=4.8,1.6Hz, 1H), 8.36 (dt, J=8.2,1.9Hz, 1H), 7.56 (dd, J=8.0,4.9Hz, 1H), 7.29 (dd, J=7.6,1.7Hz, 1H), 7.22-7.09 (m, 2H), 7.07- 6.92 (m, 2H), 6.90-6.78 (m, 1H), 6.58 (td, J=7.5,1.3Hz, 1H), 6.47 (dd, J=8.2,1.3Hz, 1H), 5.72 (t, J=6.3Hz, 1H), 4.31 (d, J=6.1Hz, 2H), 4.01 (t, J=6.3Hz, 2H), 3.62 (t, J=6.6Hz, 2H), 1.72 (p, J=6.9Hz, 4H), 1.45 (td, J=9.7,8.4,5.2Hz, 4H) .MS m/z (ESI): 438.2 [M+H]⁺。

Embodiment 30:N- { 2- [2- (6- chlorine hexyloxy) benzyloxy] phenyl } isonicotinic acid formamide

Synthetic method similar to Example 18, intermediate N [(2- hydroxyl) phenyl] isonicotinic acid formamide and 2- (6- chlorine Hexyloxy) bromobenzyl reacts to obtain target compound 30mg, yield 29%, appearance white solid.

¹H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.80–8.74(m,2H),7.83–7.71(m,3H), 7.45 (dd, J=7.5,1.7Hz, 1H), 7.32-7.11 (m, 3H), 7.05-6.96 (m, 2H), 6.90 (td, J=7.5, 1.0Hz, 1H), 5.16 (s, 2H), 3.97 (t, J=6.3Hz, 2H), 3.59 (t, J=6.6Hz, 2H), 1.66 (dt, J=11.0, 5.9Hz, 4H), 1.38 (p, J=3.6Hz, 4H) .MS m/z (ESI): 439.1 [M+H]⁺。

Embodiment 31:N- { 2- [2- (oxygroup in heptan) benzyloxy] phenyl } isonicotinic acid formamide

Synthetic method similar to Example 18, intermediate N [(2- hydroxyl) phenyl] isonicotinic acid formamide and 2- oxygroup in heptan Bromobenzyl reacts to obtain target compound 55mg, yield 40%, appearance white solid.

¹H NMR (400MHz, DMSO-d6) δ 9.76 (s, 1H), 8.82-8.72 (m, 2H), 7.77 (dd, J=17.0, 6.5Hz, 3H), 7.44 (d, J=7.5Hz, 1H), 7.27 (t, J=7.8Hz, 1H), 7.22-7.10 (m, 2H), 7.00 (dd, J= 10.4,7.9Hz, 2H), 6.90 (t, J=7.5Hz, 1H), 5.15 (s, 2H), 3.96 (t, J=6.4Hz, 2H), 1.71-1.57 (m, 2H), 1.28 (d, J=52.1Hz, 8H), 0.83 (t, J=6.5Hz, 3H) .MS m/z (ESI): 419.2 [M+H]⁺。

Biological experiment example:

In following each experimental examples, the target compound of embodiment 1-31 preparation is referred to as embodiment compound 1-31.

Experimental example one, the compounds of this invention are to liver homogenate sphingomyelins synthase (SMS) active inhibiting effect

1. experiment purpose

Half-suppressed rate of this measuring compound provided by the invention to sphingomyelins synthase (SMS) activity suppression effect (IC50)。

2. experimental method

It measures the present invention in conjunction with inhibitor activity test method using ultra performance liquid chromatography tandem mass spectrometry and provides Compound enzyme reaction system after optimization under half inhibiting rate.

2.1 chromatographic conditions use C18 chromatographic column (Waters) with aqueous (A) -0.1% formic acid, contain acetonitrile (B) -0.1% first Acid is mobile phase, gradient elution, flow velocity 0.50mL/min.

2.2 Mass Spectrometry Conditions use electrospray ionisation source (ESI) positive ion mode, more reaction detection mode (MRM) C6- nerves Amide and C6- sphingomyelins ion pair are respectively 398.4/380.4, and 704.7/184, the detection ion pair of internal standard Diclofenac is 296/215。

2.3 the preparation of standard curve

A certain amount of C6-SM (C6- sphingomyelins, Sigma, cat#77238) and C6-Ceramide (C6- nerve are weighed respectively Amide, Santa Cruze, cat#sc-3527) it is dissolved in ethyl alcohol and obtains the stock solution of 1mg/mL, it is pressed with 70% acetonitrile solution The working solution of 60,20,6,2,0.6,0.2,0.06,0.02 and 0.006 μ g/ml is obtained according to gradient dilution, takes the working solution of 10 μ L Into the SMS enzyme reaction solution of 190 μ L, 800 μ L are added with the ratio of 1:4 and contain the 50% of internal standard (diclofenac, 100ng/ml) Acetonitrile methanol, is centrifuged 15 minutes, takes 200 μ L of centrifuged supernatant by 13000 turns per minute of room temperature, ultimate density 3000,1000, 300,100,30,10,3,1 and 0.3ng/ml.

The configuration of 2.4 compounds

Embodiment compound 1 to 31 and D609 are weighed, is dissolved in the mother liquor for being configured to 10mM in dimethyl sulfoxide, gradually Gradient dilution, test concentrations 1000uM, 333uM, 111uM, 33uM, 11uM, 3uM, 1uM, 0.3uM, 0.1uM and 0.03uM, Each concentration multiple holes.

2.5 enzyme reaction

SMS enzyme reaction solution include 50nM Tris-HCL (Invitrogen, 10010023), 25nM KCL (Sigma, And 0.5nM EDTA (Sigma, EDS-100G) 746436).

Fresh male ICR mouse (Shanghai western Poole-Bi Kai experimental animal Co., Ltd, 20g) appropriate liver is taken, is added Appropriate phosphate buffer (Invitrogen, 10010023) is configured to the tissue fluid of 300mg/mL, after ice bath homogenate, per minute It 13000 turns, is centrifuged 15 minutes, obtains liver homogenate liquid supernatant, take kit standard product (Sigma, 1002254738) with phosphate Buffer is diluted to 1000 μ g/mL, 800 μ g/mL, 600 μ g/mL, 400 μ g/mL, 200 μ g/mL, 100 μ g/mL, 50 μ g/mL, and 25 μ g/mL obtains examination criteria curve, and A liquid B liquid mixes to obtain protein quantification working solution with the volume ratio of 1:50, according to standard curve concentration 20 μ L are sequentially added from low to high to corresponding vacancy, are sequentially added 200 μ L enzyme reaction working solutions, are gently shaken up；It is anti-in 37 DEG C After answering 30min, 562nm detects light absorption value, and albumen stoste is finally quantitative to 400mg/mL.

It takes 76 μ L of SMS enzyme reaction solution that corresponding hole location is added, is separately added into 2 μ L C6-Ceramide and C6-SM, adds 10 The liver homogenate liquid of 40 μ g/ml of μ L and 10 μ L D609 solution or compound solution, gently shake up, and 37 DEG C of reaction 30min are added 400 μ L of terminate liquid terminates enzyme reaction, obtains supernatant after 13000 turns of room temperatures centrifugation 15min per minute, LC/MS analyzes sample.

3. experimental result

Compound provided by the invention has preferable sphingomyelins synthase activity depression effect, for sphingomyelins synthase 50% inhibition concentration (IC50) < 50 μM, effect are better than D609 (see the table below 1), and D609 is a sphingomyelins synthase reported in the literature Inhibitor (Aimin Meng；Chiara Luberto；Et al.Experimental Cell Research, 2004,292, 385-392.)。

Table 1 embodiment compound 1-31 and positive control D609 is to sphingomyelins synthase activity depression effect

Experimental example two, the compounds of this invention are to the effect of cell sphingomyelins synthase (SMS) activity suppression

1. experiment purpose

This experiment detects invention compound to the active influence of U937 cell SMS.

1.1 cell culture

Source of people U937 cell (ATCC) is normally cultivated, and complete medium includes that the RPMI 1640 containing L-Glutamine is cultivated Base (corning, 21517002), 10%FBS (Ausbina, 0986180), 100U/mlP/S (Gibco, 1902422).Experiment When, the solvent (DMSO) of cell and various concentration, D609 and untested compound carry out cracking processing after being incubated for 2h altogether.

The configuration of 1.2 compounds

Compound uses dmso solution, 3 times of gradient dilutions, the compound concentration in experiment is respectively 810 μM, 270μM、90μM、30μM、10μM、3μM。

1.3 reaction process

After cell is rinsed 2 times using phosphate buffer, homogenized is carried out using the lysate of ice bath.Lysate includes 25mM sucrose (Sigma, 57-50-1), 5mM HEPES (Sigma, 7365-45-9), 1mM phenylmethylsulfonyl fluoride (Sigma, 52332), the chymotrypsin protein inhibitor of 20 μ g/mL, leupeptin, antiprotease and pepstatin (Sigma, 11206893001), 4 DEG C, 1000 × g is centrifuged 10min, and obtained supernatant is cell protein solution.Supernatant is taken to pass through Bio-Rad kit (Sigma, 1002254738) carries out protein quantification measurement.Protein concentration is 1mg/mL when reaction.

SMS enzyme reaction solution include 50nM Tris-HCL (Invitrogen, 10010023), 25nM KCL (Sigma, 746436), 0.5nM EDTA (Gibco, 1947027).

Above-mentioned 76 μ L of SMS enzyme reaction solution is taken, 2 μ LC6-Cermide (Santa, sc-3572) are added, above-mentioned cell egg is added White 10 μ L of solution, the 10 μ L of compound solution of various concentration, shakes up.400 μ L of terminate liquid termination is added instead after reacting at room temperature 30min It answers, supernatant is obtained after 13000 turns of centrifugations 15min per minute, LC/MS analyzes the content of sample measurement SMS.

1.4LC/MS reaction condition

1.4.1LC/MS condition

Chromatographic column is C18 chromatographic column (Waters), and mobile phase A is the aqueous formic acid containing 0.1%, and B is containing 0.1% formic acid Acetonitrile solution, flow velocity 0.5mL/min, autosampler temperature are 4 DEG C.

Eluent gradient condition is as follows:

Time (minute)	A (%)	B (%)
			Starting	50	50
2.00	2	98
			2.20	2	98
2.41	50	50
			3.00	50	50

Mass Spectrometry Conditions:

Ionization mode	Electric spray ion source
		Scan pattern	Cation
Scanning mode	Multiple-reaction monitoring
		Gas curtain gas (psi)	35
Spraying gas (psi)	60
		Auxiliary heating gas (psi)	60
Ionizing voltage (V)	5500
		Temperature (DEG C)	550.0

Ion pair information is as follows:

1.4.2 standard curve making

Suitable C6-SM and C6-Ceramide is weighed respectively be dissolved in ethyl alcohol obtain the stock solution of 1mg/mL；Use 70% second Nitrile water gradient dilution obtains the working solution of 60,20,6,2,0.6,0.2,0.06,0.02 and 0.006 μ g/mL.Take the 10 above-mentioned works of μ L Make liquid into the enzyme reaction working solution of 190 μ L, 800 μ L, 50% acetonitrile methanol containging interior traget is added with the ratio of 1:4, per minute It 13000 turns, is centrifuged 15 minutes, takes supernatant 200 μ L to 96 orifice plates, 4000 turns per minute are centrifuged 15 minutes, and ultimate density is 3000,1000,300,100,30,10,3,1 and 0.3ng/mL.

2. experimental result

Reduce to untested compound dose-dependant SMS activity.The EC of untested compound₅₀Value is better than D609 less than 50 μM.

2 compound of table is to SMS inhibitory activity EC₅₀Value

Compound	EC50(uM)
		Embodiment compound 1	9
Embodiment compound 4	21
		Embodiment compound 5	18
Embodiment compound 7	16
		Embodiment compound 16	35
Embodiment compound 17	40
		Embodiment compound 18	32
Embodiment compound 20	20
		Embodiment compound 24	45
Embodiment compound 29	15
		D609	90

The influence of experimental example three, the compounds of this invention to lipid-metabolism

1. experiment purpose and method

The influence that this experiment detection invention compound is metabolized HepG2 cytolipin.

A) cell culture

HepG2 cell is purchased from Shanghai Cell Bank of Chinese Academy of Sciences (the Shanghai Chinese wins biotechnology).Cell culture is low in DMEM In sugar culture-medium (Gibco, 21885108), (Ausbina, 0986180) containing 10% fetal calf serum, 1% penicillin/streptomycin (Gibco, 1902422).37 DEG C are placed in, 5% CO₂It is cultivated in incubator.With 1 × 10 when experiment⁶Density is inoculated in 6 orifice plates. Adherent 24 hours to cell, the DMEM culture without FBS is replaced, the chemical combination of 0.5mM free fatty acid (FFA) and various concentration is added Object or PBS are detected after effect 24 hours by TG kit.

Testing material therefor includes: oil red (Sigma, 1320-06-5), TG kit (Nanjing is built up, A110-1).

B) compound configures

A certain amount of compound is weighed, it is respectively 0.5mg/mL, 1mg/mL, 2mg/ that dmso solution, which is configured to concentration, ML, 5mg/mL, 10mg/mL, for testing.

2. experimental result

The visible a large amount of lipidosis of cell of phosphate buffer processing, and lipid can be substantially reduced after compound processing Deposition, it is seen that the compound of the present invention can reduce to dose-dependant HepG2 intracellular TG (triglyceride) content.

EC of 3 compound of table to TG level₅₀Value

Compound	EC50(uM)
		Embodiment compound 1	0.08
Embodiment compound 4	0.06
		Embodiment compound 5	0.15
Embodiment compound 7	0.09
		Embodiment compound 17	0.19
Embodiment compound 20	0.21
		Embodiment compound 29	0.16
D609	0.83

Experimental example four, the compounds of this invention knock out the drug efficacy study of mouse (ApoE-/-) to apolipoprotein E gene

1. experiment purpose and method

The drop SM effect for knocking out mouse (ApoE-/-) after the compounds of this invention administration to apolipoprotein E gene is investigated in this experiment, Lipid-lowering effect, and inhibit the effect of atherosclerosis.

1.1 animal

7-8 week old, male apolipoprotein E gene knock out mouse (ApoE-/-, Nanjing model animal center) according to original body mass Solvent group, embodiment compound group, positive drug Simvastatin group, every group of number of animals n=are randomly divided into blood lipid level initial value 8.Animal gives cholesterol feed and feeds (0.15% cholesterol, D12079B, test diet).

1.2 compound

Embodiment compound dosage is 15mg/kg, is dissolved in 0.5%CMCNa (Aladdin) solution and forms uniform mix Suspension.Simvastatin dosage is 40mg/kg, administered volume 10ml/kg, gastric infusion or solvent twice daily, until It is spaced 6 hours less.Continue 12 weeks, takes 1 detection four items of blood lipid tests of blood: total cholesterol (TC), triglycerides (TG), high density weekly Lipoproteins-C (HDL-C), low density lipoprotein-cholesterol (LDL-C).Terminal animal euthanasia, takes liver homogenate, presses It is horizontal according to the method measurement SM of embodiment 1.Observe aorta wall pathological change.

2. experimental result

Animal gives 15mg/kg embodiment compound, can reduce within 12 weeks total cholesterol value, low-density lipoprotein white value, drop Low SM value, while patch is formed and is reduced；Wherein, embodiment compound reduces SM extent value and is substantially better than Simvastatin group.As a result Show that compound tool provided by the invention is significantly reduced SM, lipid-loweringing and the drug effect for reducing atherosclerotic plaque formation.

Drug efficacy study of 4 compound of table to the lipid-loweringing of ApoE-/- mouse and inhibition SM

Experimental example five, the compounds of this invention are to the drug efficacy study of atherosclerotic rat

1. experiment purpose and method

This experiment investigates the compounds of this invention to the lipid-lowering effect of atherosclerotic rat.

A) experimental animal

7-8 week old, 50 male SD rats (the western Poole-Bi Kai Experimental Animal Center in Shanghai) are randomly divided into model group, real Apply a compound group (15mg/kg) and Simvastatin group (20mg/kg), every group of number of animals n=10.The feeding high in fat of the equal feeding of animal Material, in addition to model group, animal gave drug since the 4th week, was administered continuously 6 weeks.High lipid food (TD.88137, Shanghai sail pool Bioisystech Co., Ltd).

B) configuration of compound

Compound, which is dissolved in 0.5%CMCNa (Aladdin), forms uniform suspension, gastric infusion, and administered volume is 2ml/kg, daily administration 2 times.

1.3 experimentation

Before experiment starts, before administration in the 4th week, blood is taken at the end of experiment, separation serum measures four items of blood lipid tests: total cholesterol (TC), triglycerides (TG), highdensity lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), observation Aorta wall pathological change.

2. experimental result

Compared with model group, compound group animal triglycerides provided by the invention, total cholesterol, low-density lipoprotein- Cholesterol is substantially reduced, and artery plaque is reduced.For aortic tunica intima without obviously thickening, smooth muscle cell arrangement is more regular under light microscopic, But it can be seen that Mild edema.Compound provided by the invention has the function of adjusting blood lipid as the result is shown, to atherosclerosis Treatment has remarkable effect.

Pharmacodynamic results of 5 compound of table to three rouge rat model of high glycerine

Experimental example six, the compounds of this invention are to the pharmacodynamic study of atherosclerotic rabbit

1. experiment purpose and method

This experiment purpose is the effect in order to test lipid-loweringing of the compound provided by the invention to atherosclerosis rabbits.Ginseng Examine pertinent literature (Mountain Western Medicine S University's journal, in October, 2003,34 (5)).

High cholesterol diet (containing 0.5% cholesterol, 5% lard, 15% yolk powder and basal feed) is moored from Shanghai sail gives birth to The customization of object Technology Co., Ltd..New zealand rabbit (Shanghai Experimental Animal Center) is randomly divided into Normal group, and model group is implemented Example compound group (10mg/kg) and Simvastatin group (10mg/kg), every group of number of animals n=8.Normal group feeding is commonly raised Material, intraperitoneal injection of saline.Inject bovine serum albumin, the equal feeding high cholesterol diet of other group of animal.Rabbit was from the 13rd week Start to give drug, be administered continuously 26 weeks.

Before experiment starts, before administration in the 13rd week, blood is taken at the end of experiment, separation serum measures four items of blood lipid tests: total cholesterol (TC), triglycerides (TG), highdensity lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), inflammation Level of factor observes aorta wall pathological change.

2. experimental result

Compared with model group, 15mg/kg embodiment compound group animal triglycerides, low density lipoprotein-cholesterol are bright Aobvious to reduce, total cholesterol level significantly reduces.For aortic tunica intima without obviously thickening, smooth muscle cell arrangement is more regular under light microscopic. Embodiment compound has the function of adjusting blood lipid as the result is shown.There is good therapeutic effect to atherosclerosis.

Pharmacodynamic results of 6 compound of table to Atherosclerosis Model rabbit

Experimental example seven, the compounds of this invention are to Ether-a-go-go-related gene (hERG) electric current inhibitory effect

1. experiment purpose

Using the manual patch-clamp detection embodiment compound 1 of electro physiology, embodiment compound 4, embodiment compound 5, reality It applies a compound 7, embodiment compound 16, embodiment compound 17, embodiment compound 18, embodiment compound 20 and implements Effect of the example compound 29 to hERG potassium channel, the preliminary cardiac safety of research the compounds of this invention.

2. experimental program

The configuration of 2.1 compounds

Test compound is dissolved in DMSO, is configured to the mother liquor of 10,3.3,1.1,0.37mM.Next using extracellular Liquid carries out secondary dilution, and final test solution concentration is 30,10,3.3,1.1,0.37 μM.

2.2 reagents prepare

Extracellular fluid: 130mM NaCl, 4mM KCl, 1.8mM CaCl₂、1mM MgCl₂, 10mM glucose and 10mM HEPES(pH 7.4)。

Intracellular fluid: 130mM KCl, 1mM MgCl₂, 5mM EGTA, 5mM MgATP and 10MgATP HEPES (pH 7.2)

Cell culture medium composition: DMEM (Gibco, 11330032), 15% fetal calf serum (PAA, A15-101), 1% mould The manual Patch Clamp System experimental program of 2.3 electro physiology of element-streptomysin (Biowest, L0022-100)

The HEK293 cell of hERG potassium-channel will be overexpressed (from medical college, New York University Mohamed Doctor Boutjdir laboratory-Nantong Ke Ruisi) use the training of DMEM/15% fetal calf serum/1% Pen .- Strep composition Feeding base is incubated at 37 DEG C, 5%CO₂In incubator.When experiment, cell is transferred to the cell bath of insertion inverted microscope platform In, perfusion extracellular fluid, stablizing can start to test after cell precipitation for 5 minutes.Using HEKA EPC-10 patch clamp amplifier With PATCHMASTER acquisition system (HEKA instrument company, D-67466Lambrcht, Pfalz, Germany) record membrance current.It is all Experiment is completed under room temperature (22-24 DEG C).Instrument (Sutter Instrument is drawn using P-97 microelectrode in experiment Company, One Digital Drive, Novato, CA 94949) electrode (BF150-110-10) is straightened.Electrode internal diameter is 1- 1.5mm is 2-4M Ω full of the water resistance that enters after interior liquid.

Experiment is carried out using whole-cell recording technique pattern, according to the electrophysiological stimulation scheme record current value of lower section.It is first Membrane voltage is clamped down in -80mV, cell is given and continues 2s, the stimulation of+20mV voltage activates hERG potassium channel, then repolarization to - 50mV continues 5s, generates export-oriented tail current, and the every 15s of frequency of stimulation is primary.Current value is the peak value of tail current.It is used in experiment Whole-cell recording technique pattern recording channel electric current.Perfusion extracellular fluid (2ml about per minute) and continue to record first, waits electric current Stablize (current attenuation (Run-Down) is less than 5% in 5 minutes), tail current peak value is to compare current value at this time.Then perfusion Extracellular fluid containing drug to be measured simultaneously continues to record until drug stablizes shape to the suppression experimental result production arrival of hERG electric current State, tail current peak value is current value after dosing at this time.If after reaching after stable situation with extracellular fluid perfusion wash HERG current reverts can then continue perfusion and test other concentration or drug.Using the solution containing drug to be measured, by concentration by low Perfusion and record current value are carried out to high sequence.Use PATCHMASTER V2X60 (HEKA instrument company, D- 67466Lambrecht, Pfalz, Germany) carry out data acquisition, using Origin 8.5 (OriginLab company, Northampton, MA) software analyzed and counted.

3. result

The IC50 that the compounds of this invention inhibits the electric current of hERG is as shown in the table.By the following table 7 data it is found that of the present inventionization Conjunction object is weaker to the electric current inhibiting effect of hERG, and safety is good.

The IC50 value that 7 the compounds of this invention of table inhibits the electric current of hERG

Compound	IC50(uM)
		Embodiment compound 1	>30
Embodiment compound 4	>30
		Embodiment compound 5	>30
Embodiment compound 7	>30
		Embodiment compound 16	>30
Embodiment compound 17	>30
		Embodiment compound 18	>30
Embodiment compound 20	>30
		Embodiment compound 29	>30

The pharmacokinetics experiment of experimental example eight, the compounds of this invention

1. experiment purpose

With 200-250g, the male SD rat (the western Poole-Bi Kai Experimental Animal Center in Shanghai) of 8 week old is experimental animal, Embodiment compound 1 is given with oral using high performance liquid chromatography tandem mass spectrometry measurement vein, embodiment compound 4 is implemented Example compound 5, embodiment compound 7, embodiment compound 16, embodiment compound 17, embodiment compound 18, embodiment Close object 20, embodiment compound 24, after 29 compound of embodiment compound, the drug concentration in different time blood plasma.Research is originally Invention compound evaluates its Pharmacokinetic Characteristics in the intracorporal pharmacokinetics behavior of rat.

2. experimental program

Compound is used in 2.1 experiments

Embodiment compound 1, embodiment compound 4, embodiment compound 5, embodiment compound 7, embodiment compound 16, embodiment compound 17, embodiment compound 18, embodiment compound 20, embodiment compound 29.

The preparation of 2.2 compounds

A certain amount of compound is weighed, dimethyl sulfoxide/polyethylene glycol 400/water=10/10/80 is dissolved in, is configured to uniform Solution.

2.3 experimentation

Rat vein gives above-described embodiment compound, before administration with 0.083 after administration, 0.25,0.5,1.0,2.0, 4.0, it is taken a blood sample 0.2mL by eye socket within 6.0,8.0,12.0,24.0 hours, as in anticoagulant tube, 4 DEG C, 6000 turns of centrifugations 10 per minute Minute, separated plasma, -80 DEG C of preservations.

Take the blood plasma of 50 μ L above-mentioned different moments, be added 150 μ L orinases containing 200ng/mL (Aladdin, T129578 acetonitrile solution mixing, shaking) 5 minutes, 12000 turns per minute are centrifuged after ten minutes, 100 μ L supernatants of taking-up, then with After the mixing of 200 μ L deionized waters, sample introduction is analyzed for Liquid Chromatography-Tandem Mass Spectrometry.

2.4 liquid phase chromatogram conditions and analysis software

Liquid chromatographic system is LC-20AD UFLC highly effective liquid phase chromatographic system (Shimadzu, LC-20AD).Mass spectrometer system is AB Sciex API4000 three-level level four bars mass spectrum is equipped with electrospray ionisation source (ESI) (Applied Biosystems, Canada). Software for controlling LC-MS instrument and quantitative analysis is Analyst 1.6 (Applied Biosystems, Canada), medicine Dynamic parameter of learning is divided using WinNonlin (version 5.2, Pharsight, Mountain View, CA) non-compartment model Analysis.

Liquid chromatogram separation uses Synergi Fusion-RP C18 chromatographic column (50 × 2.0mm, 4 μm of internal diameter).Column temperature dimension It holds in room temperature.The composition and gradient and Mass Spectrometry Conditions of mobile phase see the table below respectively:

The liquid-phase condition of untested compound:

Untested compound and interior target Mass Spectrometry Conditions see the table below:

The preparation of 2.5 standard curves and quality-control sample

Untested compound is dissolved in the stock solution for being configured to that concentration is 1mg/mL in dimethyl sulfoxide, it is dilute with 50% acetonitrile It releases to obtain a series of standard working solution, concentration 10,3,1,0.3,0.1,0.03 and 0.01 μ g/mL and a series of mark Quasi- Quality Control solution (8,0.5 and 0.03 μ g/mL).5 μ L standard solution and 45 μ L blank plasma matrix are uniformly mixed, standard is obtained Each concentration point of curve standard solution (1000,500,200,100,10,5,2 and 1ng/mL) and quality control standard solution (800, 50 and 3ng/mL).

Internal standard orinase solid powder is dissolved in the stock solution that 1mg/mL is configured in dimethyl sulfoxide.Stock solution 100% dilution in acetonitrile is used to obtain the solution of 200ng/mL as protein precipitant.

2.6 experimental result

The pharmacokinetic parameter of the compounds of this invention is as shown in table 8 below:

The pharmacokinetic parameter of 8 the compounds of this invention of table

Conclusion: in the compounds of this invention medicine generation, absorbs preferably, and Half-life in vivo is longer, has preferable characteristics of pharmacokinetics.

The acute toxicity testing of experimental example nine, the compounds of this invention

1. experiment purpose

With 20-22g, the male ICR mouse (the western Poole-Bi Kai Experimental Animal Center in Shanghai) of 8 week old is experimental animal, mouth Clothes give 10mg/kg, 30mg/kg, 90mg/kg, 270mg/kg, 810mg/kg, 2430mg/kg embodiment compound, administration 1 It is secondary, 14 days, including clinical observation, weight and pathological examination is observed continuously.

2. experimental program

Compound is used in 2.1 experiments

Embodiment compound 1, embodiment compound 4, embodiment compound 5, embodiment compound 7, embodiment compound 16, embodiment compound 17, embodiment compound 18, embodiment compound 20, embodiment compound 29.

The preparation of 2.2 compounds

A certain amount of embodiment compound is weighed, 0.5%CMCNa is dissolved in, is configured to uniform solution.

2.3 experimentation

Acute toxicity after giving embodiment compound using upper laxative remedy observation mouse, 10 mouse of each dosage group are female It is male fifty-fifty.Administered volume is 10mL/kg, is administered once.

2.4 experimental result

It is observed continuously after administration 14 days, all animals do not occur other Novel presentations.Each group administration animal is administered the 2nd day Weight is slightly decreased, but more not significant than difference with control group.It is carried out substantially after all animals euthanasia after 14 day observation period Dissection checks that body surface is shown no obvious abnormalities, and thoracic cavity, abdominal cavity, pelvic cavity, cranial cavity have no naked eyes lesions visible.

Median lethal dose > 2000mg/kg under this experiment condition, after the compounds of this invention oral administration.Safety compared with It is good.

Experimental example ten, the compounds of this invention long term toxicity test

1. experiment purpose

With 180-200g, the male SD rat (the western Poole-Bi Kai Experimental Animal Center in Shanghai) of 7-8 week old is that experiment is dynamic Object measures on SD rat possible toxic effect after long term administration compound provided by the invention.

2. experimental program

Compound is used in 2.1 experiments

Embodiment compound 1, embodiment compound 4, embodiment compound 5, embodiment compound 7, embodiment compound 16, embodiment compound 17, embodiment compound 18, embodiment compound 20, embodiment compound 29.

The preparation of 2.2 compounds

A certain amount of compound is weighed, 0.5%CMCNa is dissolved in, is configured to uniform solution.

2.3 experimentation

SD rat is given once daily the compound provided by the invention of various dose 30,90,270,540mg/kg, and one day one It is secondary, continue 15 days.Every group animal 10, half male and half female.The daily situation of observation animal daily, changes of weight, diet, appearance, Behavior etc..Terminal dissects animal, measures blood biochemistry index, and taking internal organ carries out histopathological examination.

2.4 experimental result

It is administered and is observed continuously 15 days, all animals do not occur other Novel presentations, after 15 day observation period all Gross anatomy inspection is carried out after animal euthanasia, body surface is shown no obvious abnormalities, and thoracic cavity, abdominal cavity, pelvic cavity, cranial cavity have no that naked eyes are visible Lesion.

It can be seen that the safety of the compounds of this invention is good, do not observe that the dosage (NOAEL) of adverse reaction is 540mg/kg.

A kind of sphingomyelins synthase inhibitor, preparation method and its application provided by the present invention have been carried out in detail above It introduces.Principle and implementation of the present invention are described for specific embodiment used herein, and above embodiments are said It is bright to be merely used to help understand method and its central idea of the invention.It should be pointed out that for those of ordinary skill in the art For, it without departing from the principle of the present invention, can be with several improvements and modifications are made to the present invention, these improve and repair Decorations also fall into the protection of the claims in the present invention.

Claims (12)

1. logical formula (I) compound represented, its pharmaceutically acceptable salt or stereoisomer:

Wherein, X, Y and Z are separately selected from carbon atom or nitrogen-atoms, and X, Y and Z are not nitrogen-atoms simultaneously；

M is selected from-NH- or-O-；

Ar is selected from aryl being substituted or being unsubstituted, be substituted or the heteroaryl that is unsubstituted；Preferably, the warp Substituted aryl or the heteroaryl being substituted it is optional replaced following one or more substituent groups:

Halogen ,-C_1-10Alkyl ,-C_1-10The C that alkoxy, halogen replace_1-10The C that alkyl and halogen replace_1-10Alkoxy；

R is selected from hydrogen, deuterium, halogen, nitro, cyano ,-C_1-6Alkyl ,-C_1-6Alkoxy, the C being substituted_1-6Alkyl is substituted C_1-6Alkoxy；Preferably, the C being substituted_1-6Alkyl or the C being substituted_1-6Alkoxy is optional to be replaced by following one or more Replaced base:

Hydrogen, deuterium, halogen, nitro, cyano ,-C_1-6Alkyl and-C_1-6Alkoxy.

2. compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, which is characterized in that work as Y With Z be carbon atom when, X be nitrogen-atoms or carbon atom；When X and Y is carbon atom, Z is nitrogen-atoms；

Ar is selected from phenyl, pyridyl group, the phenyl being substituted or the pyridyl group being substituted, wherein the phenyl being substituted or warp Substituted pyridyl group it is optional replaced following one or more substituent groups:

Halogen ,-C_1-8Alkyl ,-C_1-8The C that alkoxy, halogen replace_1-8The C that alkyl, halogen replace_1-8Alkoxy；

R is hydrogen.

3. compound according to claim 2, its pharmaceutically acceptable salt or stereoisomer, which is characterized in that Ar ForR₁Selected from-F ,-Cl ,-Br ,-C_1-8Alkyl ,-C_1-8The C that alkoxy, halogen replace_1-8Alkyl, halogen replace C_1-8Alkoxy；R₂Selected from-H ,-F ,-Cl ,-Br ,-C_1-3Alkyl.

4. compound according to claim 3, its pharmaceutically acceptable salt or stereoisomer, which is characterized in that R₁ For-F ,-Cl ,-CH₃、-CH₂CH₃、-OCH₃、-OCH₂CH₃、-O-(CH₂)_n-CH₃、-O-(CH₂)_n-Cl；N is the integer of 2-6.

5. compound according to claim 4, its pharmaceutically acceptable salt or stereoisomer, which is characterized in that X and Y is carbon atom, and Z is nitrogen-atoms；R₂For-H.

6. compound according to claim 4, its pharmaceutically acceptable salt or stereoisomer, which is characterized in that Y and Z is carbon atom, and X is nitrogen-atoms or carbon atom.

7. compound according to claim 1 to 6, its pharmaceutically acceptable salt or stereoisomer, special Sign is that Ar is selected from

8. compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, which is characterized in that institute State compound are as follows:

N- [2- (the chloro- 5- fluorine benzyloxy of 2-) phenyl] niacin formamide；

N- [2- (2,6- dichloro-benzyloxy) phenyl] niacin formamide；

N- [2- (2- methyl -5- fluorine benzyloxy) phenyl] niacin formamide；

N- [2- (2- methoxybenzyl oxygroup) phenyl] niacin formamide；

N- { 2- [(2- ethyl) benzyloxy] phenyl } niacin formamide；

N- { 2- [(2,6- dimethyl) benzyloxy)] phenyl } niacin formamide；

N- { 2- [(2- ethyoxyl) benzyloxy] phenyl } niacin formamide；

N- { 2- [(2- methoxyl group -5- chlorine) benzyloxy] phenyl } niacin formamide；

N- { 2- [(2,5- dichloro) benzyloxy] phenyl } niacin formamide；

N- { 2- [(2- methyl-5-chloro) benzyloxy] phenyl } niacin formamide；

N- { 2- [2- (4- neoprene oxygroup) benzyloxy] phenyl } niacin formamide；

N- { 2- [2- (5- chlorine amoxy) benzyloxy] phenyl } niacin formamide；

N- { 2- [2- (6- chlorine hexyloxy) benzyloxy] phenyl } niacin formamide；

N- [2- (2- hexyloxy benzyloxy) phenyl] niacin formamide；

N- [2- (2- oxygroup in heptan benzyloxy) phenyl] niacin formamide；

N- { 2- [(2- hexyloxy) -5- benzyl chloride oxygroup] phenyl } niacin formamide；

N- { 2- [(2- oxygroup in heptan) -5- benzyl chloride oxygroup] phenyl } niacin formamide；

N- { 2- [2- (4- neoprene oxygroup) benzyloxy] phenyl } isonicotinic acid formamide；

N- { 2- [2- (5- chlorine amoxy) benzyloxy] phenyl } isonicotinic acid formamide；

N- { 2- [(the chloro- oxy-benzyl in 2- heptan of 5-) amino] phenyl } niacinamide；

N- { 2- [(the chloro- 2- of 5- (6- chlorine hexyloxy) benzyl) amino] phenyl } niacinamide；

N- { 2- [(the chloro- 5- luorobenzyl of 2-) amino] phenyl } niacinamide；

N- { 2- [(2,6-dichloro benzyl) amino] phenyl } niacinamide；

N- { 2- [(the fluoro- 2- methylbenzyl of 5-) amino] phenyl } niacinamide；

N- { 2- [(2- (4- neoprene oxygroup) benzyl) amino] phenyl } Pyrazinamide；

N- { 2- [(2- (5- chlorine amoxy) benzyl) amino] phenyl } Pyrazinamide；

N- { 2- [(2- hexyloxy benzyl) amino] phenyl } Pyrazinamide；

N- { 2- [(the chloro- oxy-benzyl in 2- heptan of 5-) amino] phenyl } benzamide；

N- { 2- [(6- chlorine hexyloxy benzyl) amino] phenyl } niacinamide；

N- { 2- [2- (6- chlorine hexyloxy) benzyloxy] phenyl } isonicotinic acid formamide；

N- { 2- [2- (oxygroup in heptan) benzyloxy] phenyl } isonicotinic acid formamide.

9. a kind of preparation method of such as logical formula (I) compound represented of any of claims 1-8, feature exist In, comprising the following steps:

Compound 1 and compound 2 are condensed to yield compound 3；

Compound 3 goes benzyl protection that compound 4 is made by catalytic hydrogenation；

Compound 4 withFinal product should be made and lead to formula (I) compound represented；

Wherein, M is-O-；R₃Selected from-OH ,-F ,-Cl or-Br.

10. a kind of preparation method of such as logical formula (I) compound represented of any of claims 1-8, feature exist In, comprising the following steps:

Compound 6 and compound 2 are condensed to yield compound 7；

Compound 7 restores nitro under catalytic hydrogenation conditions, obtains compound 8；

Compound 8 and Ar-CHO reduction amination obtain logical formula (I) compound represented；

Wherein, M is-NH-；R₃Selected from-OH ,-F ,-Cl or-Br.

11. a kind of pharmaceutical composition, which is characterized in that any one of the claim 1-8 comprising at least one therapeutically effective amount Compound shown in the logical formula (I), its pharmaceutically acceptable salt or stereoisomer；Preferably, described pharmaceutical composition Also comprising choosing any one kind of them or a variety of medicine or physiologically acceptable carrier and/or diluent.

12. compound of any of claims 1-8, its pharmaceutically acceptable salt or stereoisomer, Huo Zhequan Benefit require 11 described in pharmaceutical composition in preparation increase caused disease extremely by sphingomyelin levels for preventing and/or treating The purposes of the drug of disease；Preferably, increasing caused disease extremely by sphingomyelin levels includes atherosclerosis, fatty liver And at least one of obesity.