CN105348204A - 1-heterocyclyl-2-(heteroarylthio) benzene derivative and use method and application - Google Patents
1-heterocyclyl-2-(heteroarylthio) benzene derivative and use method and application Download PDFInfo
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- CN105348204A CN105348204A CN201510794623.5A CN201510794623A CN105348204A CN 105348204 A CN105348204 A CN 105348204A CN 201510794623 A CN201510794623 A CN 201510794623A CN 105348204 A CN105348204 A CN 105348204A
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- 0 *c(cc1)cc(Br)c1N Chemical compound *c(cc1)cc(Br)c1N 0.000 description 3
- OJHNKJNQHMVUPW-UHFFFAOYSA-N C(C1)NCCN1c(cccc1)c1Sc1ncccn1 Chemical compound C(C1)NCCN1c(cccc1)c1Sc1ncccn1 OJHNKJNQHMVUPW-UHFFFAOYSA-N 0.000 description 1
- JJSLRRLECVQBLQ-MOENNCHZSA-N CC(CC1)C(C)[C@H](C)CN1C(OC(C)(C)C)=O Chemical compound CC(CC1)C(C)[C@H](C)CN1C(OC(C)(C)C)=O JJSLRRLECVQBLQ-MOENNCHZSA-N 0.000 description 1
- VBWSIVDCBSAQJA-UHFFFAOYSA-N Cc1cc(C)nc(Sc(cc(cc2)C#N)c2N2CCNCC2)n1 Chemical compound Cc1cc(C)nc(Sc(cc(cc2)C#N)c2N2CCNCC2)n1 VBWSIVDCBSAQJA-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
-
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- 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
- C07D239/38—One sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention discloses a 1-heterocyclyl-2-(heteroarylthio) benzene derivative and a use method and application, and in particular, relates to a novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative and a pharmaceutical composition containing the novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative, and the novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative and the pharmaceutical composition can be used to inhibit 5-hydroxytryptamine reuptake. The present invention also relates to a preparation method of the novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative and the pharmaceutical composition, and application of the novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative and the pharmaceutical composition in the treatment of central nervous system functional disorders, particularly affective disorders.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to be used for the treatment of central nervous system dysfunction, particularly the compound of affective disorder and composition, and using method and purposes.Especially, of the present invention is can as 1-heterocyclic radical-2-(Heteroarylthio) benzene derivative of serotonin reuptake inhibitor.
Background technology
Serotonin (5-HT, serotonin), a kind of neurotransmitter of transmission of signal in brain and neural system, in central nervous system (CNS) dysfunction, especially, in anxiety, depression, invasion and impulsion mood, play important role.Serotonin Transporter (5-HTtransporter, 5-HTT/serotonintransporter, SERT) be a kind of transmembrane transporter 5-HT being had to high affinity, it reuptakes serotonin and enters presynaptic neuron from nerve synapse gap, directly affects the concentration of synaptic cleft serotonin.
In history, the pharmacological agent of affective disorder starts from the 1950's, comprise tricyclic antidepressant (TCAs) and oxidase inhibitor (MAOIs), these drug mains will lean on the blocking effect of neurotransmitter (Dopamine HCL, norepinephrine and serotonin) to play curative effect.But, the non-selective and less desirable side effect of target is limited to their use.To the eighties in 20th century, the appearance of selective serotonin reuptake inhibitor (selectiveserotoninreuptakeinhibitors, SSRIs), changes this situation.Compared with TCAs, this kind of curative effect of medication is suitable, but side effect is little, even if excessive use, the toxicity also less (SarkoJ.Andidepressant produced, oldandnew.Areviewoftheiradverseeffectsandtoxicityinoverd ose.EmergMedClinNorthAm, 2000; 18 (4): 637-54).Selective serotonin reuptake inhibitor mainly produces restraining effect to 5-HT transporter, can effectively central nervous system presynaptic membrane be suppressed to absorb 5-HT from synaptic cleft by being combined with 5-HT transporter, increase in gap and for the actual 5-HT utilized, thus the object for the treatment of can be reached.
In all indications relevant to serotonin dysfunction, dysthymia disorders is most important, because according to World Health Organization, dysthymia disorders has become the fourth-largest burden disease of the mankind.Expect the year two thousand twenty, the Disability adjusted life years of dysthymia disorders can leap to the second of all diseases.(BrometE,AndradeLH,HwangI,etal.,Cross-nationalepidemiologyofDSM-IVmajordepressiveepisode.BMCMed.2011,9:90)。
But; clinical study about dysthymia disorders shows that the phenomenon do not responded known SSRIs is very outstanding; another therapeutic action being SSRIs through commonly overlooked factor in anti depressant therapy there will be delay usually, and symptom also can worsen within former weeks for the treatment of sometimes.In addition, sexual dysfunction is common side effect for SSRIs.So, need exploitation can improve the compound of Cure of depression and other serotonin relative diseases.
The invention provides the new compound that a class has serotonin reuptake transporter inhibit activities, possess good potential applicability in clinical practice.Compared with existing similar compound, compound of the present invention has better drug effect, and medicine is for character and/or toxicological profile.
Summary of the invention
Below only summarize aspects more of the present invention, be not limited thereto.These aspects and other parts have more complete explanation later.All reference in this specification sheets are incorporated in this by entirety.When the disclosure of the specification and citing document variant time, be as the criterion with the disclosure of the specification.
The present invention relates to 1-heterocyclic radical-2-(Heteroarylthio) the benzene derivative derivative of a class novelty, itself and 5-HT transporter (SERT) have stronger binding affinity, 5-HT re-uptake can be suppressed, thus may be used for preparation treatment central nervous system (CNS) handicapped medicine, especially for the medicine of preparation treatment affective disorder, described affective disorder includes, but are not limited to, dysthymia disorders, anxiety disorder, social phobia, obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
The compounds of this invention stable in properties, security is good, have pharmacodynamics and pharmacokinetic advantage, such as good brain/blood plasma ratio (brainplasmaratio), good bioavailability or good metabolic stability etc., therefore possesses good potential applicability in clinical practice.
The present invention also provides the method for this compounds of preparation and the pharmaceutical composition containing this compounds.
On the one hand, the present invention relates to a kind of compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug
Wherein,
x, Y, R
1, R
2, R
3, R
4, R
5, R
6, R
7and R
8there is implication as described in the present invention.
In one embodiment, X is CR
xor N; And R
xthere is implication as described in the present invention.
In one embodiment,
for singly-bound or double bond.
In one embodiment, Y is N, CH or C.
In one embodiment, when
during for singly-bound, Y is N or CH.
In one embodiment, when
during for double bond, Y is C.
In one embodiment, R
1for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) NHCH
3,-C (=O) N (CH
3)
2,-C (=O)-(C
1-C
6alkyl) ,-C (=O)-(C
1-C
6alkoxyl group), C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group, C
1-C
6halogenated alkoxy, C
1-C
6alkylthio, C
1-C
6the C that alkylamino or hydroxyl replace
1-C
6alkyl.
In one embodiment, R
2for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) NHCH
3,-C (=O) N (CH
3)
2,-C (=O)-(C
1-C
6alkyl) ,-C (=O)-(C
1-C
6alkoxyl group), C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group, C
1-C
6halogenated alkoxy, C
1-C
6alkylthio, C
1-C
6the C that alkylamino or hydroxyl replace
1-C
6alkyl.
In one embodiment, R
3for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) NHCH
3,-C (=O) N (CH
3)
2,-C (=O)-(C
1-C
6alkyl) ,-C (=O)-(C
1-C
6alkoxyl group), C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group, C
1-C
6halogenated alkoxy, C
1-C
6alkylthio, C
1-C
6the C that alkylamino or hydroxyl replace
1-C
6alkyl.
In one embodiment, R
xfor H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) NHCH
3,-C (=O) N (CH
3)
2,-C (=O)-(C
1-C
6alkyl) ,-C (=O)-(C
1-C
6alkoxyl group), C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group, C
1-C
6halogenated alkoxy, C
1-C
6alkylthio, C
1-C
6the C that alkylamino or hydroxyl replace
1-C
6alkyl.
In one embodiment, R
5for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2,-C (=O) NHCH
3,-C (=O) N (CH
3)
2,-C (=O)-(C
1-C
6alkyl) ,-C (=O)-(C
1-C
6alkoxyl group), C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group or C
1-C
6halogenated alkoxy.
In one embodiment, R
4, R
6and R
7be H, D, F, Cl, Br, I ,-CN ,-NO independently of one another
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2,-C (=O) NHCH
3,-C (=O) N (CH
3)
2,-C (=O)-(C
1-C
6alkyl) ,-C (=O)-(C
1-C
6alkoxyl group), C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group or C
1-C
6halogenated alkoxy.
In one embodiment, R
8for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group, C
1-C
6the C that halogenated alkoxy or hydroxyl replace
1-C
6alkyl.
In one embodiment, R
1for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O)-(C
1-C
4alkyl) ,-C (=O)-(C
1-C
4alkoxyl group), C
1-C
4alkyl, C
2-C
4thiazolinyl, C
2-C
4alkynyl, C
1-C
4haloalkyl, C
1-C
4alkoxyl group, C
1-C
4halogenated alkoxy, C
1-C
4alkylthio, C
1-C
4the C that alkylamino or hydroxyl replace
1-C
4alkyl.
In one embodiment, R
2for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O)-(C
1-C
4alkyl) ,-C (=O)-(C
1-C
4alkoxyl group), C
1-C
4alkyl, C
2-C
4thiazolinyl, C
2-C
4alkynyl, C
1-C
4haloalkyl, C
1-C
4alkoxyl group, C
1-C
4halogenated alkoxy, C
1-C
4alkylthio, C
1-C
4the C that alkylamino or hydroxyl replace
1-C
4alkyl.
In one embodiment, R
3for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O)-(C
1-C
4alkyl) ,-C (=O)-(C
1-C
4alkoxyl group), C
1-C
4alkyl, C
2-C
4thiazolinyl, C
2-C
4alkynyl, C
1-C
4haloalkyl, C
1-C
4alkoxyl group, C
1-C
4halogenated alkoxy, C
1-C
4alkylthio, C
1-C
4the C that alkylamino or hydroxyl replace
1-C
4alkyl.
In one embodiment, R
xfor H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O)-(C
1-C
4alkyl) ,-C (=O)-(C
1-C
4alkoxyl group), C
1-C
4alkyl, C
2-C
4thiazolinyl, C
2-C
4alkynyl, C
1-C
4haloalkyl, C
1-C
4alkoxyl group, C
1-C
4halogenated alkoxy, C
1-C
4alkylthio, C
1-C
4the C that alkylamino or hydroxyl replace
1-C
4alkyl.
In one embodiment, R
5for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2, C
1-C
4alkyl, C
2-C
4thiazolinyl, C
2-C
4alkynyl, C
1-C
4haloalkyl, C
1-C
4alkoxyl group or C
1-C
4halogenated alkoxy.
In one embodiment, R
4, R
6and R
7be H, D, F, Cl, Br, I ,-CN ,-NO independently of one another
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2, C
1-C
4alkyl, C
2-C
4thiazolinyl, C
2-C
4alkynyl, C
1-C
4haloalkyl, C
1-C
4alkoxyl group or C
1-C
4halogenated alkoxy.
In one embodiment, R
1for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) CH
3,-C (=O) OCH
3, methyl, ethyl, n-propyl, sec.-propyl ,-CF
3,-CH
2cF
3, methoxyl group, oxyethyl group, n-propyl oxygen base or sec.-propyl oxygen base.
In one embodiment, R
2for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) CH
3,-C (=O) OCH
3, methyl, ethyl, n-propyl, sec.-propyl ,-CF
3,-CH
2cF
3, methoxyl group, oxyethyl group, n-propyl oxygen base or sec.-propyl oxygen base.
In one embodiment, R
3for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) CH
3,-C (=O) OCH
3, methyl, ethyl, n-propyl, sec.-propyl ,-CF
3,-CH
2cF
3, methoxyl group, oxyethyl group, n-propyl oxygen base or sec.-propyl oxygen base.
In one embodiment, R
xfor H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) CH
3,-C (=O) OCH
3, methyl, ethyl, n-propyl, sec.-propyl ,-CF
3,-CH
2cF
3, methoxyl group, oxyethyl group, n-propyl oxygen base or sec.-propyl oxygen base.
In one embodiment, R
5for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2, methyl, ethyl, n-propyl, sec.-propyl ,-CF
3or-CH
2cF
3.
In one embodiment, R
4, R
6and R
7be H, D, F, Cl, Br, I ,-CN ,-NO independently of one another
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2, methyl, ethyl, n-propyl, sec.-propyl ,-CF
3or-CH
2cF
3.
Each R of the present invention
1, R
2, R
3, R
x, R
4, R
5, R
6, R
7and R
8independent optionally by one or more R
wreplaced; With
Each R
wbe D, F, Cl, Br, I ,-NO independently
2,-CN ,-N
3,-NH
2,-OH ,-SH, oxo (=O), C
1-C
4alkyl, C
2-C
4thiazolinyl, C
2-C
4alkynyl, C
1-C
4haloalkyl, C
1-C
4alkoxyl group, C
1-C
4halogenated alkoxy, C
1-C
4alkylamino, C
1-C
4alkylthio, NH
2-(C
1-C
4alkylidene group)-, HO-(C
1-C
4alkylidene group)-, HS-(C
1-C
4alkylidene group)-, (C
1-C
4alkoxyl group)-(C
1-C
4alkylidene group)-, (C
1-C
4alkylamino)-(C
1-C
4alkylidene group)-, (C
1-C
4alkylthio)-(C
1-C
4alkylidene group)-, C
3-C
6cycloalkyl, (C
3-C
6cycloalkyl)-(C
1-C
4alkylidene group)-, the heterocyclic radical of 3-7 annular atoms composition, (heterocyclic radical that 3-7 annular atoms forms)-(C
1-C
4alkylidene group)-, phenyl, phenyl-(C
1-C
4alkylidene group)-, the heteroaryl of 5-6 annular atoms composition or (heteroaryl that 5-6 annular atoms forms)-(C
1-C
4alkylidene group)-.
In one embodiment, compound of the present invention, its be have one of following structure compound or there is the steric isomer of compound of one of following structure, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises compound disclosed by the invention.
In one embodiment, the pharmaceutical composition that the present invention relates to, comprises pharmaceutically acceptable vehicle, carrier, adjuvant or their arbitrary combination further.
In one embodiment, the pharmaceutical composition that the present invention relates to, comprise the medicine for the treatment of central nervous system dysfunction further, the medicine of described treatment central nervous system dysfunction is antidepressant drug, anxiolytic medicament, salts medicine as mood stabilizers, atypical antipsychotics thing, antiepileptic drug, antiparkinsonism drug, medicine, central nervous stimulant, nicotinic antagonists or their arbitrary combination as selective serotonin reuptake inhibitor.
In another embodiment, the present invention treats the medicine of central nervous system dysfunction is amitriptyline (amitriptyline), Desipramine (desipramine), mirtazapine (mirtazapine), Bupropion (bupropion), Reboxetine (reboxetine), fluoxetine (fluoxetine), trazodone (trazodone), Sertraline (sertraline), duloxetine (duloxetine), fluvoxamine (fluvoxamine), Midalcipran (milnacipran), left-handed Midalcipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), vilazodone (vilazodone), Venlafaxine (venlafaxine), dapoxetine (dapoxetine), nefazodone (nefazodone), femoxetine (femoxetine), chlorimipramine (clomipramine), citalopram (citalopram), S-escitalopram (escitalopram), paroxetine (paroxetine), Quilonum Retard (lithiumcarbonate), buspirone (buspirone), olanzapine (olanzapine), Quetiapine (quetiapine), risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), Perospirone (perospirone), leoponex (clozapine), modafinil (modafinil), mecamylamine (mecamylamine), Cabergoline (cabergoline), diamantane (adamantane), imipramine (imipramine), pramipexole (pramipexole), thyroxine (thyroxine), Dextromethorphane Hbr (dextromethorphan), Quinidine (quinidine), TREXUPONT (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), pipamperone (pipamperone), dimension is for smooth (vestipitant), zeisin (chlordiazepoxide), trilafon (perphenazine) or their arbitrary combination.
On the other hand, the present invention relates to compound disclosed by the invention or composition is preparing the purposes in medicine, described medicine is used for prevention, treats or alleviate central nervous system dysfunction.Such as, in one embodiment, described medicine is used for prevention, treats or alleviate mammalian central nervous system dysfunction, and in another embodiment, described medicine is for preventing, treating or alleviate the central nervous system dysfunction of people.
In one embodiment, described central nervous system dysfunction refers to dysthymia disorders, anxiety disorder, social phobia, obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, schizophrenia, somnopathy, bipolar disorders, obsessional idea and behavior disorder, dyskinesia, sexual dysfunction, musculoskeletal pain obstacle, cognitive disorder, dysmnesia, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom and premenstrualtension syndrome.
On the other hand, the present invention relates to compound disclosed by the invention or composition is preparing the purposes in medicine, described medicine is used for prevention, treats or alleviate affective disorder.
In one embodiment, described affective disorder includes, but are not limited to, dysthymia disorders, anxiety disorder, social phobia, obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
On the other hand, the present invention relates to compound disclosed by the invention or composition is preparing the purposes in medicine, described medicine is for suppressing serotonin reuptake transporter.
On the other hand, the present invention relates to the preparation of compound shown in formula (I), the method for abstraction and purification.
Biological results shows, the compounds of this invention has strong avidity to people source 5-HT transporter (SERT), and therefore compound provided by the invention can be used as good selective serotonin reuptake inhibitor.
In addition, some compounds of the present invention have the combined action of serotonin reuptake transporter inhibition and norepinephrine reuptake inhibition, other compounds of the present invention have the combined action of serotonin reuptake transporter inhibition and dopamine reuptake inhibition, and the other compound of the present invention has the triple reuptake inhibition of serotonin, norepinephrine and Dopamine HCL.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.These aspects and otherwise content will do more specifically complete description below.
Circumstantial letter of the present invention
definition and general terms
Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with of the present invention and material can be used in putting into practice the present invention.The present invention is never limited to method of the present invention and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.
Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.
Except as otherwise noted or in context, have obvious conflict, article used in the present invention " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used in the present invention refer to the article of one or more than one (i.e. at least one) object.
Term " steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer, etc.
Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (lowenergybarrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropictautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.
Term " optionally " or " optionally " refer to the event that describes subsequently or situation can but not necessarily occur, and this description comprises situation that wherein said event or situation occur and wherein its absent variable situation.
Term " optionally by .... replaced ", can " not replace or quilt ... .. replaced " to exchange with term and use, namely described structure be unsubstituted or be replaced by one or more substituting group of the present invention, substituting group of the present invention includes, but are not limited to D, F, Cl, N
3,-CN ,-OH ,-SH ,-NH
2, alkyl, alkoxyl group, alkylthio, alkylamino, cycloalkyl, heterocyclic radical, aryl, heteroaryl etc.
At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C
1-C
6alkyl " refer in particular to independent disclosed methyl, ethyl, C
3alkyl, C
4alkyl, C
5alkyl and C
6alkyl.
Term " halogen " and " halo " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1-20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.In one embodiment, alkyl group contains 1-6 carbon atom; In another embodiment, alkyl group contains 1-4 carbon atom; Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH
3), ethyl (Et ,-CH
2cH
3), n-propyl (n-Pr ,-CH
2cH
2cH
3), sec.-propyl (i-Pr ,-CH (CH
3)
2), normal-butyl (n-Bu ,-CH
2cH
2cH
2cH
3), isobutyl-(i-Bu ,-CH
2cH (CH
3)
2), sec-butyl (s-Bu ,-CH (CH
3) CH
2cH
3), the tertiary butyl (t-Bu ,-C (CH
3)
3), etc.
Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely has a carbon-to-carbon sp
2double bond, wherein, described alkenyl group can optionally replace by one or more substituting group described in the invention, it comprises " cis " and the location of " trans ", or the location of " E " and " Z ".
Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely have a carbon-to-carbon sp triple bond, wherein, described alkynyl group can optionally replace by one or more substituting group described in the invention.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom.The substituting group that described alkoxy base can optionally be described by one or more the present invention replace.
The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH
3), oxyethyl group (EtO ,-OCH
2cH
3), 1-propoxy-(n-PrO, n-propoxy-,-OCH
2cH
2cH
3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH
3)
2), 1-butoxy (n-BuO, n-butoxy ,-OCH
2cH
2cH
2cH
3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH
2cH (CH
3)
2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH
3) CH
2cH
3), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH
3)
3), etc.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represent alkyl, thiazolinyl or alkoxy base replace by one or more halogen atom, wherein alkyl, thiazolinyl and alkoxy base have implication as described in the present invention, such example comprises, but be not limited to, trifluoromethyl, trifluoromethoxy etc.In one embodiment, C
1-C
6haloalkyl comprises the C that fluorine replaces
1-C
6alkyl; In another embodiment, C
1-C
4haloalkyl comprises the C that fluorine replaces
1-C
4alkyl; In yet another embodiment, C
1-C
4haloalkyl comprises the C that fluorine replaces
1-C
2alkyl.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug
1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Bergeetal., describepharmaceuticallyacceptablesaltsindetailinJ.Pharm aceuticalSciences, described in 1977,66:1-19..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N
+(C
1-4alkyl)
4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C
1-C
8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, thanomin or its mixture.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
1-heterocyclic radical-2-(Heteroarylthio) the benzene derivative derivative that the present invention relates to, its pharmacy acceptable salt, pharmaceutical preparation and composition thereof, selective serotonin reuptake inhibitor can be used as, to mankind's central nervous system dysfunction, particularly the treatment of affective disorder has potential purposes, described affective disorder includes, but are not limited to, dysthymia disorders, anxiety disorder, social phobia, obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
Unless otherwise mentioned, all suitable isotropic substance changes of compound of the present invention, steric isomer, tautomer, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug are included in the scope of the invention.
Shown in formula (I), compound can exist in a salt form.In one embodiment, described salt refers to pharmacy acceptable salt.
On the other hand, the present invention relates to the intermediate of compound shown in preparation formula (I).
The pharmaceutical composition of the compounds of this invention, preparation and administration
The invention provides a kind of pharmaceutical composition, comprise compound shown in formula (I) or its independent steric isomer, the racemize of isomer or non-racemic mixture or its pharmacy acceptable salt or solvate.In an embodiment of the invention, described pharmaceutical composition comprises the pharmaceutically acceptable carrier of at least one, assistant agent or vehicle further, and optionally, other treat and/or prevent composition.
Suitable carrier, assistant agent and vehicle agent be for those skilled in the art know and be described in detail in such as AnselH.C.etal., Ansel ' sPharmaceuticalDosageFormsandDrugDeliverySystems (2004) Lippincott, Williams & Wilkins, Philadelphia; GennaroA.R.etal., Remington:TheScienceandPracticeofPharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; And in RoweR.C., HandbookofPharmaceuticalExcipients (2005) PharmaceuticalPress, Chicago.
Also it should be understood that some compound of the present invention can exist in a free form to be used for the treatment of, if or suitably can exist with the form of its pharmaceutically acceptable derivates.Some nonrestrictive embodiments of pharmaceutically acceptable derivative comprise pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or to directly or indirectly providing any other adducts or the derivative of compound of the present invention or its meta-bolites or residue during patient's administration in need.
Suitable pharmaceutically acceptable vehicle can be different according to selected concrete formulation.In addition, pharmaceutically acceptable vehicle can be selected according to their specific functions in the composition.Suitable pharmaceutically acceptable vehicle comprises the vehicle with Types Below: thinner, weighting agent, tackiness agent, disintegrating agent, lubricant, glidant, granulating agent, Drug coating, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, correctives, odor mask, tinting material, anti-hard caking agent, wetting Agent for Printing Inks, sequestrant, fluidizer, tackifier, antioxidant, sanitas, stablizer, tensio-active agent and buffer reagent.Technician can recognize, some pharmaceutically acceptable vehicle can provide more than a kind of function, and provides alternative function, and this depends in preparation have in how many these vehicle and preparation to there are which other vehicle.
Pharmaceutical composition disclosed by the invention uses techniques and methods well known by persons skilled in the art to prepare.The description of some common methods of this area can see Remington'sPharmaceuticalSciences (MackPublishingCompany).
Therefore, on the other hand, the present invention relates to the technique of pharmaceutical compositions, described pharmaceutical composition comprises the present invention and to come into the open compound and pharmaceutically acceptable vehicle, carrier, assistant agent, solvent or their combination, and this technique comprises the various composition of mixing.Comprise the present invention to come into the open the pharmaceutical composition of compound, can mix under such as envrionment temperature and normal atmosphere and prepare.
Compound disclosed by the invention is usually formulated into and is adapted to pass through the formulation of required approach to patient's administration.Such as, formulation comprises those formulations being suitable for following route of administration: (1) oral administration, such as tablet, capsule, caplet agent, pill, containing tablet, pulvis, syrup, elixir, suspensoid, solution, emulsion, sachet agent and cachet; (2) parenteral admin, such as sterile solution agent, suspensoid and redissolution powder; (3) transdermal administration, such as percutaneous plaster agent; (4) rectal administration, such as suppository; (5) suck, such as aerosol, solution and dry powder doses; (6) topical, such as ointment, salve, lotion, solution, paste, sprays, foaming agent and gelifying agent.
In one embodiment, compound disclosed by the invention can be mixed with oral dosage form.In another embodiment, compound disclosed by the invention can be mixed with inhalant dosage form.In another embodiment, compound disclosed by the invention can be mixed with nose administration formulation.In yet another embodiment, compound disclosed by the invention can be mixed with transdermal administration.Also in one embodiment, compound disclosed by the invention can be mixed with Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablet, molded tablet, can chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or enteric coated tablet, sugar-coat or film coated tablet provide.
Pharmaceutical composition provided by the invention can provide with soft capsule or hard capsule, and it can be prepared by gelatin, methylcellulose gum, starch or alginate calcium.
Pharmaceutical composition provided by the invention by injection, infusion or can implant administered parenterally, for local or Formulations for systemic administration.The administered parenterally used as the present invention comprises in intravenously, intra-arterial, intraperitoneal, sheath, in ventricle, in urethra, in breastbone, in encephalic, intramuscular, synovial membrane and subcutaneous administration.
The purposes of the compounds of this invention and composition
Compound provided by the invention and pharmaceutical composition can be used for for the preparation of prevention, treat or alleviate Mammals, comprise the medicine of the central nervous system dysfunction of the mankind, also may be used for the medicine for the preparation of suppressing serotonin reuptake transporter.
Specifically, in composition of the present invention, the amount of compound detectably optionally can suppress the re-uptake of serotonin effectively, compound of the present invention can as treatment mankind central nervous system (CNS) dysfunction, the particularly medicine of affective disorder, described affective disorder includes, but are not limited to, dysthymia disorders, anxiety disorder, social phobia, obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
Compound of the present invention can be applied to, but is never limited to, and uses the significant quantity of compound of the present invention or composition to prevent, treat or alleviate central nervous system dysfunction disease to patient's administration.The described central nervous system dysfunction in response to serotonin regulation and control, include, but are not limited to further, dysthymia disorders, anxiety disorder, social phobia, obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, schizophrenia, somnopathy, bipolar disorders, obsessional idea and behavior disorder, dyskinesia, sexual dysfunction, musculoskeletal pain obstacle, cognitive disorder, dysmnesia, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom and premenstrualtension syndrome etc.
Compound of the present invention and pharmaceutical composition, except useful to human treatment, also can be applicable to the Mammals in veterinary treatment pet, the animal of introduced variety and the animal on farm.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.
General synthesis step
For describing the present invention, below list embodiment.But need be appreciated that and the invention is not restricted to these embodiments, only be to provide and put into practice method of the present invention.
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as AldrichChemicalCompany, ArcoChemicalCompanyandAlfaChemicalCompany, all not through being further purified, unless other aspects show during use.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemical reagent factory in morning, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao's purchase obtains.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.
1hNMR spectrum uses Bruker400MHz or 600MHz nuclear magnetic resonance spectrometer record.
1hNMR spectrum is with CDC1
3, DMSO-d
6, CD
3oD or acetone-d
6for solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, double doublet), dt (doubletoftriplets, two triplet).Coupling constant, represents with hertz (Hz).
The condition determination of Algorithm (MS) data is: (pillar model: ZorbaxSB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min to Agilent6120 level Four bar HPLC-M.Moving phase: 5%-95% is (containing the CH of 0.1% formic acid
3cN) (containing the H of 0.1% formic acid
2o) ratio in, adopts electron spray ionisation (ESI), under 210nm/254nm, detects with UV.
Pure compound uses Agilent1260pre-HPLC or Caleseppump250pre-HPLC (pillar model: NOVASEP50/80mmDAC), detects at 210nm/254nm UV.
The use of brief word below runs through the present invention:
BOC, Boc tert-butoxycarbonyl
CH
2cl
2, DCM methylene dichloride
CDC1
3deuterochloroform
DMFN, dinethylformamide
DMSO dimethyl sulfoxide (DMSO)
EDTA ethylenediamine tetraacetic acid (EDTA)
Et
3n, TEA triethylamine
EtOAc, EA ethyl acetate
MeOH methyl alcohol
G gram
H hour
HCl hydrogenchloride
NH
3ammonia
KCl Repone K
MgSO
4magnesium sulfate
K
2cO
3salt of wormwood
MeCN, CH
3cN acetonitrile
ML, ml milliliter
PE sherwood oil (60-90 DEG C)
RT, rt, r.t. room temperature
Rt retention time
TFA trifluoroacetic acid
Tris-HCl tri-(methylol) aminomethane-hydrochloric acid
BSA bovine serum albumin
(Boc)
2o tert-Butyl dicarbonate
Pd
2(dba)
3three (dibenzalacetone) two palladium
Pd (PPh
3)
2cl
2bi triphenyl phosphorus palladium chloride
Two (the 2-diphenylphosphine phenyl) ether of DPEphos
Pd (dppf) Cl
2[two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride
Following synthetic schemes describes preparation the present invention and to come into the open the step of compound, unless otherwise indicated, and wherein each R
1, R
2, R
3, R
5with X, there is definition of the present invention.
Synthetic schemes 1
Formula (
6) shown in compound can be prepared by synthetic schemes 1: compound (
1) with two (2-chloroethyl) semicarbazide hydrochloride generate under the effect of alkali compound (
2), compound (
2) with tertbutyloxycarbonyl protection after obtain compound (
3); Then compound (
3) and compound (
4) coupling obtain compound (
5); Final compound (
5) in the ethyl acetate solution or trifluoroacetic acid of hydrogenchloride, slough Boc protecting group after, Re-boostering test obtain target compound (
6).
Synthetic schemes 2
Formula (
10) shown in compound can be prepared by synthetic schemes 2: compound (
1) by iodo after diazotization obtain compound (
7), compound (
7) carry out with 4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formates under the effect of alkali Suzuki linked reaction obtain compound (
8); Compound (
8) and compound (
4) under the effect of alkali palladium chtalyst coupling obtain compound (
9); Compound (
9) in the dichloromethane solution of trifluoroacetic acid or the ethyl acetate solution of hydrogenchloride, slough Boc protecting group after, Re-boostering test obtain target compound (
10).
Synthetic schemes 3
Formula (
10) shown in compound can also be prepared by synthetic schemes 3: first, compound (
11) and compound (
12) carry out under the effect of alkali substitution reaction obtain compound (
13); Then compound (
13) carry out with 4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formates under the effect of alkali Suzuki linked reaction obtain compound (
9); Final compound (
9) in the dichloromethane solution of trifluoroacetic acid or the ethyl acetate solution of hydrogenchloride, slough Boc protecting group after, Re-boostering test obtain target compound (
10).
Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
Embodiment
embodiment 14,6-dimethoxy-2-((5-methyl-2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 1-(the bromo-4-aminomethyl phenyl of 2-) piperazine
By bromo-for 2-4-monomethylaniline (2.00g, 10.75mmol), two (2-chloroethyl) amine hydrochlorate (2.23g, 12.90mmol) with salt of wormwood (4.46g, 32.25mmol) join in propyl carbinol (30mL) successively, then reaction solution reacts 50 hours under being placed in room temperature.After reaction terminates, reaction solution is poured in water (100mL), and extract with methylene dichloride (25mL × 3), the organic phase anhydrous sodium sulfate drying merged, filter, and concentrating under reduced pressure, it is dark oil liquid (1.40g, 50.9%) that gained residue obtains title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:255.1(M+1).
step 2) synthesis of 4-(the bromo-4-aminomethyl phenyl of 2-) piperazine-1-t-butyl formate
1-(the bromo-4-aminomethyl phenyl of 2-) piperazine (1.40g, 5.49mmol) and triethylamine (1.52mL, 10.97mmol) are joined in methylene dichloride (30mL), more slowly adds (Boc)
2o (1.80g, 8.23mmol), reacts 2 hours under then reaction solution being placed in room temperature.After reaction terminates, add water in reaction solution (50mL), separatory, organic phase anhydrous sodium sulfate drying, filter, and concentrating under reduced pressure, it is yellow solid (1.30g, 66.7%) that gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=20/1) purifying.
MS(ESI,pos.ion)m/z:355.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.39(d,J＝0.8Hz,1H),7.05(dd,J＝8.4,0.8Hz,1H),6.90(d,J＝7.8Hz,1H),3.58(brs,4H),2.92(brs,4H),2.26(s,3H),1.48(s,9H).
step 3) synthesis of 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-aminomethyl phenyl) piperazine-1-t-butyl formate
By 4-(the bromo-4-aminomethyl phenyl of 2-) piperazine-1-t-butyl formate (0.40g, 1.13mmol), 4,6-dimethoxypyridin-2-mercaptan (0.29g, 1.69mmol), Pd
2(dba)
3(52mg; 57 μm of ol), two (2-diphenylphosphine) phenylate (61mg, 113 μm of ol) and sodium tert-butoxide (0.22g, 2.25mmol) add in toluene (20mL); reaction solution is warming up to backflow under nitrogen protection gradually, reacts 30 hours.After reaction terminates, reaction solution is cooled to room temperature, and slowly pour in water (20mL), then methylene dichloride (15mL × 3) is used to extract, the organic phase anhydrous sodium sulfate drying merged, filters, and concentrating under reduced pressure, it is yellow oily liquid (460mg, 91.4%) that gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=15/1) purifying.
MS(ESI,pos.ion)m/z:447.2(M+1)；
1HNMR(400MHz,CDCl
3)δ(ppm):7.49(d,J＝1.6Hz,1H),7.13(dd,J＝8.0,1.6Hz,1H),6.97(d,J＝7.6Hz,1H),5.71(s,1H),3.73(s,6H),3.42(t,J＝4.4Hz,4H),2.90(brs,4H),2.30(s,3H),1.45(s,9H).
step 4) synthesis of 4,6-dimethoxy-2-((5-methyl-2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
By 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-aminomethyl phenyl) piperazine-1-t-butyl formate (440mg, 0.99mmol) join in methylene dichloride (10mL), then add trifluoroacetic acid (2mL), react 1 hour under reaction solution being placed in room temperature.After reaction terminates, reaction solution methylene dichloride (10mL) dilution, then regulates pH to 9 ~ 10 with saturated sodium carbonate solution.Separatory, organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure, it is yellow solid (320mg, 93.8%) that gained residue obtains title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:347.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.48(d,J＝1.2Hz,1H),7.13(dd,J＝7.8,1.2Hz,1H),6.98(d,J＝7.8Hz,1H),5.70(s,1H),3.73(s,6H),2.96-2.95(m,4H),2.91-2.89(m,4H),2.28(s,3H).
embodiment 24,6-dimethyl-2-((5-methyl-2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-aminomethyl phenyl) piperazine-1-t-butyl formate
By 4-(the bromo-4-aminomethyl phenyl of 2-) piperazine-1-t-butyl formate (0.30g, 0.84mmol), 4,6-dimethyl pyrimidine-2-mercaptan (0.14g, 1.01mmol), Pd
2(dba)
3(39mg; 42 μm of ol), two (2-diphenylphosphine) phenylate (45mg; 84 μm of ol) and sodium tert-butoxide (0.16g; 1.69mmol) join in dimethyl sulfoxide (DMSO) (20mL), reaction solution is warming up to 125 DEG C of reactions 30 hours under nitrogen protection gradually.After reaction terminates, reaction solution is cooled to room temperature, and slowly pour in water (20mL), then methylene dichloride (15mL × 3) is used to extract, the organic phase anhydrous sodium sulfate drying merged, filters, and concentrating under reduced pressure, it is yellow oily liquid (180mg, 51.4%) that gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:415.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.47(s,1H),7.13(d,J＝7.8Hz,1H),6.98(d,J＝7.8Hz,1H),6.69(s,1H),3.27(brs,4H),2.85(brs,4H),2.32(s,6H),2.29(s,3H),1.44(s,9H).
step 2) synthesis of 4,6-dimethyl-2-((5-methyl-2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-aminomethyl phenyl) piperazine-1-t-butyl formate (180mg, 0.43mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (105mg, 76.7%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:315.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.47(s,1H),7.13(dd,J＝7.2,0.6Hz,1H),7.00(d,J＝8.4Hz,1H),6.69(s,1H),2.91(brs,4H),2.76-7.75(m,4H),2.33(s,6H),2.29(s,3H).
embodiment 32-((5-methyl-2-(piperazine-1-base) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
step 1) synthesis of 4-(4-methyl-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 2 step 1, by 4-(the bromo-4-aminomethyl phenyl of 2-) piperazine-1-t-butyl formate (0.30g, 0.84mmol), 4-(trifluoromethyl) pyrimidine-2-mercaptan (0.23g, 1.27mmol), Pd
2(dba)
3(39mg, 42 μm of ol), two (2-diphenylphosphine) phenylate (45mg, 84 μm of ol) and sodium tert-butoxide (0.16g, 1.69mmol) in dimethyl sulfoxide (DMSO) (20mL), reaction prepares thick product, it is yellow oily liquid (175mg, 45.6%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:455.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.70(d,J＝4.8Hz,1H),7.46(s,1H),7.27(d,J＝4.8Hz,1H),7.23(d,J＝7.8Hz,1H),7.04(d,J＝7.8Hz,1H),3.25(brs,4H),2.89-2.87(m,4H),2.34(s,3H),1.46(s,9H).
step 2) synthesis of 2-((5-methyl-2-(piperazine-1-base) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-methyl-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (170mg, 0.37mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (100mg, 75.7%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:355.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.72(d,J＝4.8Hz,1H),7.46(s,1H),7.29(d,J＝4.8Hz,1H),7.25(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),3.10-3.09(m,4H),2.90(brs,4H),2.34(s,3H).
embodiment 42-((5-methyl-2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(4-methyl-2-(pyrimidine-2-base sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 2 step 1, by 4-(the bromo-4-aminomethyl phenyl of 2-) piperazine-1-t-butyl formate (0.50g, 1.41mmol), pyrimidine-2-mercaptan (0.17g, 1.55mmol), Pd
2(dba)
3(64mg, 70 μm of ol), two (2-diphenylphosphine) phenylate (76mg, 141 μm of ol) and sodium tert-butoxide (0.27g, 1.81mmol) in dimethyl sulfoxide (DMSO) (20mL), reaction prepares thick product, it is yellow oily liquid (230mg, 42.3%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:387.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.47(d,J＝4.8Hz,2H),7.44(s,1H),7.18(dd,J＝7.8,0.6Hz,1H),7.01(d,J＝7.8Hz,1H),6.96(t,J＝4.8Hz,1H),3.26(brs,4H),2.87(t,J＝4.8Hz,4H),2.32(s,3H),1.44(s,9H).
step 2) synthesis of 2-((5-methyl-2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-methyl-2-(pyrimidine-2-base sulfenyl) phenyl) piperazine-1-t-butyl formate (150mg, 0.39mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (100mg, 90.1%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:287.3(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.47(d,J＝4.8Hz,2H),7.43(s,1H),7.19(dd,J＝8.4,1.2Hz,1H),7.03(d,J＝7.8Hz,1H),6.95(t,J＝4.8Hz,1H),2.92(brs,4H),2.74-2.73(m,4H),2.31(s,3H).
embodiment 51-(4-methyl-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine
step 1) synthesis of 4-(4-methyl-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 2 step 1, by 4-(the bromo-4-aminomethyl phenyl of 2-) piperazine-1-t-butyl formate (0.40g, 1.13mmol), 5-(trifluoromethyl) pyridine-2-mercaptan (0.30g, 1.69mmol), Pd
2(dba)
3(52mg, 57 μm of ol), two (2-diphenylphosphine) phenylate (61mg, 113 μm of ol) and sodium tert-butoxide (0.22g, 2.25mmol) in dimethyl sulfoxide (DMSO) (20mL), reaction prepares thick product, it is yellow oily liquid (350mg, 68.5%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:454.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.63(s,1H),7.60(dd,J＝8.4,1.8Hz,1H),7.40(d,J＝1.2Hz,1H),7.22(dd,J＝7.8,1.2Hz,1H),7.02(d,J＝8.4Hz,1H),6.91(d,J＝8.4Hz,1H),3.28(brs,4H),2.91(brs,4H),2.31(s,3H),1.44(s,9H).
step 2) synthesis of 1-(4-methyl-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-methyl-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (300mg, 0.66mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (220mg, 94.0%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:354.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.63(s,1H),7.61(dd,J＝8.4,1.2Hz,1H),7.40(s,1H),7.24(d,J＝7.8Hz,1H),7.05(d,J＝8.4Hz,1H),6.94(d,J＝8.4Hz,1H),3.08(brs,4H),2.89(brs,4H),2.32(s,3H).
embodiment 62-((2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 1-(2-bromophenyl) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 1, by o-bromoaniline (2.00g, 11.63mmol), two (2-chloroethyl) amine hydrochlorate (2.49g, 13.95mmol) with salt of wormwood (4.82g, 34.88mmol) in propyl carbinol (30mL), reaction prepares thick product, it is dark oil liquid (1.52g, 54.3%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:241.2(M+1).
step 2) synthesis of 4-(2-bromophenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 2, by 1-(2-bromophenyl) piperazine (1.50g, 6.22mmol), triethylamine (1.72mL, 12.44mmol) and (Boc)
2o (2.04g, 9.33mmol) in methylene dichloride (30mL), reaction prepares thick product, it is yellow solid (1.91g, 90.1%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=20/1) purifying.
MS(ESI,pos.ion)m/z:341.1(M+1).
step 3) synthesis of 4-(2-(pyrimidine-2-base sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(2-bromophenyl) piperazine-1-t-butyl formate (0.40g, 1.17mmol), pyrimidine-2-mercaptan (0.20g, 1.76mmol), Pd
2(dba)
3(54mg, 59 μm of ol), two (2-diphenylphosphine) phenylate (63mg, 117 μm of ol) and sodium tert-butoxide (0.23g, 2.44mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (230mg, 52.7%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:373.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.47(d,J＝4.8Hz,2H),7.63(dd,J＝7.8,1.2Hz,1H),7.39(td,J＝7.8,1.2Hz,1H),7.14(d,J＝7.8Hz,1H),7.12(d,J＝7.2Hz,1H),6.96(t,J＝4.8Hz,1H),3.31(brs,4H),2.93(t,J＝4.8Hz,4H),1.44(s,9H).
step 4) synthesis of 2-((2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(2-(pyrimidine-2-base sulfenyl) phenyl) piperazine-1-t-butyl formate (220mg, 0.59mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (125mg, 77.6%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:273.2(M+1)；
1HNMR(400MHz,CDCl
3)δ(ppm):8.43(d,J＝4.8Hz,2H),7.58(d,J＝7.6Hz,1H),7.39(t,J＝8.0Hz,1H),7.16-7.10(m,2H),7.01(t,J＝4.8Hz,1H),3.14-3.13(m,4H),2.99(brs,4H).
embodiment 74,6-dimethoxy-2-((2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(2-bromophenyl) piperazine-1-t-butyl formate (0.40g, 1.17mmol), 4,6-dimethoxypyridin-2-mercaptan (0.30g, 1.76mmol), Pd
2(dba)
3(54mg, 59 μm of ol), two (2-diphenylphosphine) phenylate (63mg, 117 μm of ol) and sodium tert-butoxide (0.23g, 2.44mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (200mg, 39.4%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:433.2(M+1)；
1HNMR(400MHz,CDCl
3)δ(ppm):7.64(dd,J＝7.6,1.6Hz,1H),7.33(td,J＝7.6,1.6Hz,1H),7.09-7.04(m,2H),5.70(s,1H),3.72(s,6H),3.43(t,J＝4.8Hz,4H),2.94(t,J＝4.8Hz,4H),1.46(s,9H).
step 2) synthesis of 4,6-dimethoxy-2-((2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (190mg, 0.44mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (105mg, 68.5%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:333.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.61(dd,J＝7.8,1.2Hz,1H),7.31(td,J＝7.8,1.2Hz,1H),7.05(d,J＝7.8Hz,1H),7.04-7.01(m,1H),5.68(s,1H),3.70(s,6H),2.95(brs,4H),2.86(t,J＝4.8Hz,4H).
embodiment 84,6-dimethyl-2-((2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(2-bromophenyl) piperazine-1-t-butyl formate (0.40g, 1.17mmol), 4,6-dimethyl pyrimidine-2-mercaptan (0.25g, 1.76mmol), Pd
2(dba)
3(54mg, 59 μm of ol), two (2-diphenylphosphine) phenylate (63mg, 117 μm of ol) and sodium tert-butoxide (0.23g, 2.44mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (200mg, 42.6%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:401.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.65(dd,J＝7.8,1.2Hz,1H),7.33(td,J＝7.8,1.2Hz,1H),7.10-7.06(m,2H),6.70(s,1H),3.32(t,J＝4.8Hz,4H),2.91(t,J＝4.8Hz,4H),2.33(s,6H),1.45(s,9H).
step 2) synthesis of 4,6-dimethyl-2-((2-(piperazine-1-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (190mg, 0.47mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (120mg, 83.9%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:301.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.64(dd,J＝7.8,1.2Hz,1H),7.37(t,J＝7.8Hz,1H),7.12-7.10(m,2H),6.74(s,1H),3.18(brs,4H),3.01(brs,4H),2.35(s,6H).
embodiment 92-((2-(piperazine-1-base) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
step 1) synthesis of 4-(2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(2-bromophenyl) piperazine-1-t-butyl formate (0.40g, 1.17mmol), 4-(trifluoromethyl) pyrimidine-2-mercaptan (0.32g, 1.76mmol), Pd
2(dba)
3(54mg, 59 μm of ol), two (2-diphenylphosphine) phenylate (63mg, 117 μm of ol) and sodium tert-butoxide (0.23g, 2.44mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (240mg, 46.5%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:441.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.69(d,J＝4.8Hz,1H),7.62(dd,J＝7.8,1.2Hz,1H),7.43(td,J＝7.8,1.2Hz,1H),7.27(d,J＝1.8Hz,1H),7.15(t,J＝7.2Hz,2H),3.28(brs,4H),2.93(brs,4H),1.45(s,9H).
step 2) synthesis of 2-((2-(piperazine-1-base) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (230mg, 0.52mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (150mg, 84.3%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:341.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.43(d,J＝4.8Hz,1H),7.64(dd,J＝7.8,1.2Hz,1H),7.45(td,J＝7.8,1.2Hz,1H),7.37(d,J＝1.8Hz,1H),7.12(t,J＝7.2Hz,2H),3.11(t,J＝4.8Hz,4H),2.90(t,J＝4.8Hz,4H).
embodiment 102-((2-(piperazine-1-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 1-(the bromo-4-of 2-(trifluoromethyl) phenyl) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 1, by the bromo-4-of 2-(trifluoromethyl) aniline (2.00g, 8.33mmol), two (2-chloroethyl) amine hydrochlorate (1.78g, 10.00mmol) with salt of wormwood (3.45g, 25.00mmol) in propyl carbinol (30mL), reaction prepares thick product, it is dark oil liquid (1.47g, 57.0%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:309.1(M+1).
step 2) synthesis of 4-(the bromo-4-of 2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 2, by 1-(the bromo-4-of 2-(trifluoromethyl) phenyl) piperazine (1.45g, 4.69mmol), triethylamine (0.95mL, 9.38mmol) and (Boc)
2o (1.54g, 7.04mmol) in methylene dichloride (30mL), reaction prepares thick product, it is yellow solid (1.63g, 84.9%) that thick product obtains title compound after column chromatography (petrol ether/ethyl acetate (v/v)=20/1) purifying.
MS(ESI,pos.ion)m/z:409.1(M+1).
step 3) synthesis of 4-(2-(pyrimidine-2-base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.50g, 1.22mmol), pyrimidine-2-mercaptan (0.21g, 1.83mmol), Pd
2(dba)
3(56mg, 61 μm of ol), two (2-diphenylphosphine) phenylate (66mg, 122 μm of ol) and sodium tert-butoxide (0.23g, 2.44mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (290mg, 53.9%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:441.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.48(d,J＝5.4Hz,2H),7.88(d,J＝1.2Hz,1H),7.60(dd,J＝8.4,1.2Hz,1H),7.13(d,J＝8.4Hz,1H),7.01(t,J＝4.8Hz,1H),3.33(t,J＝4.8Hz,4H),2.99(t,J＝4.8Hz,4H),1.44(s,9H).
step 4) synthesis of 2-((2-(piperazine-1-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(2-(pyrimidine-2-base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (280mg, 0.64mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (180mg, 83.3%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:341.2(M+1)；
1HNMR(600MHz,DMSO-d
6)δ(ppm):8.72-8.66(m,2H),7.60-7.58(m,2H),7.33-7.18(m,2H),3.24(brs,4H),2.84(brs,4H).
embodiment 114,6-dimethoxy-2-((2-(piperazine-1-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.50g, 1.22mmol), 4,6-dimethoxypyridin-2-mercaptan (0.32g, 1.83mmol), Pd
2(dba)
3(56mg, 61 μm of ol), two (2-diphenylphosphine) phenylate (66mg, 122 μm of ol) and sodium tert-butoxide (0.23g, 2.44mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (300mg, 49.1%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:501.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.02(s,1H),7.55(dd,J＝8.4,1.2Hz,1H),7.09(d,J＝8.4Hz,1H),5.75(s,1H),3.74(s,6H),3.50(t,J＝4.8Hz,4H),3.01(brs,4H),1.46(s,9H).
step 2) synthesis of 4,6-dimethoxy-2-((2-(piperazine-1-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (290mg, 0.58mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (200mg, 86.2%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:401.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.98(s,1H),7.54(d,J＝7.8Hz,1H),7.11(d,J＝8.4Hz,1H),5.73(s,1H),3.71(s,6H),3.12(brs,4H),3.05-3.04(m,4H).
embodiment 124,6-dimethyl-2-((2-(piperazine-1-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.50g, 1.22mmol), 4,6-dimethyl pyrimidine-2-mercaptan (0.26g, 1.83mmol), Pd
2(dba)
3(56mg, 61 μm of ol), two (2-diphenylphosphine) phenylate (66mg, 122 μm of ol) and sodium tert-butoxide (0.23g, 2.44mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (290mg, 50.7%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:469.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.00(d,J＝1.2Hz,1H),7.54(dd,J＝8.4,1.8Hz,1H),7.10(d,J＝8.4Hz,1H),6.75(s,1H),3.40(t,J＝4.8Hz,4H),2.98(t,J＝4.8Hz,4H),2.35(s,6H),1.45(s,9H).
step 2) synthesis of 4,6-dimethyl-2-((2-(piperazine-1-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (280mg, 0.60mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (200mg, 90.9%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:369.2(M+1)；
1HNMR(400MHz,CDCl
3/MeOD)δ(ppm):7.93(s,1H),7.53(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),6.77(s,1H),3.08-3.07(m,4H),2.94-2.93(m,4H),2.30(s,6H).
embodiment 132-((2-(piperazine-1-base)-5-(trifluoromethyl) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
step 1) synthesis of 4-(4-(trifluoromethyl)-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.50g, 1.22mmol), 4-(trifluoromethyl) pyrimidine-2-mercaptan (0.33g, 1.83mmol), Pd
2(dba)
3(56mg, 61 μm of ol), two (2-diphenylphosphine) phenylate (66mg, 122 μm of ol) and sodium tert-butoxide (0.23g, 2.44mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (310mg, 49.9%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:509.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.72(d,J＝4.8Hz,1H),7.90(d,J＝1.2Hz,1H),7.64(dd,J＝7.8,1.2Hz,1H),7.31(d,J＝4.8Hz,1H),7.15(d,J＝8.4Hz,1H),3.31(t,J＝4.8Hz,4H),2.99(t,J＝4.8Hz,4H),1.44(s,9H).
step 2) synthesis of 2-((2-(piperazine-1-base)-5-(trifluoromethyl) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-(trifluoromethyl)-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (300mg, 0.59mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (190mg, 78.8%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:409.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.72(d,J＝4.8Hz,1H),7.89(s,1H),7.64(d,J＝8.4Hz,1H),7.30(d,J＝5.4Hz,1H),7.17(d,J＝8.4Hz,1H),3.09(brs,4H),2.83(t,J＝4.8Hz,4H).
embodiment 141-(2-(pyridine-2-base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine
step 1) synthesis of 4-(2-(pyridine-2-base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.50g, 1.22mmol), pyridine-2-mercaptan (0.16g, 1.47mmol), Pd
2(dba)
3(56mg, 61 μm of ol), two (2-diphenylphosphine) phenylate (66mg, 122 μm of ol) and sodium tert-butoxide (0.23g, 2.44mmol) in toluene (20mL), reaction prepares thick product, it is light yellow solid (165mg, 30.7%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:440.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.46(d,J＝3.6Hz,1H),7.71(s,1H),7.55(d,J＝8.4Hz,1H),7.51(td,J＝7.2,1.2Hz,1H),7.11(d,J＝8.4Hz,1H),7.08(dd,J＝7.2,5.4Hz,1H),7.02(d,J＝7.8Hz,1H),3.35(t,J＝4.8Hz,4H),3.02(t,J＝4.8Hz,4H),1.45(s,9H).
step 2) synthesis of 1-(2-(pyridine-2-base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(2-(pyridine-2-base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (160mg, 0.26mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (97mg, 78.5%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:340.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.44(dd,J＝4.8,0.8Hz,1H),7.69(s,1H),7.54(d,J＝8.4Hz,1H),7.49(td,J＝7.8,1.8Hz,1H),7.11(d,J＝8.4Hz,1H),7.06(dd,J＝7.2,5.4Hz,1H),6.99(d,J＝8.4Hz,1H),3.07(t,J＝4.8Hz,4H),2.81(t,J＝4.8Hz,4H).
embodiment 151-(4-(trifluoromethyl)-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine
step 1) synthesis of 4-(4-(trifluoromethyl)-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.40g, 0.98mmol), 5-(trifluoromethyl) pyridine-2-mercaptan (0.19g, 1.08mmol), Pd
2(dba)
3(45mg, 49 μm of ol), two (2-diphenylphosphine) phenylate (53mg, 98 μm of ol) and sodium tert-butoxide (0.19g, 1.95mmol) in toluene (20mL), reaction prepares thick product, it is light yellow solid (200mg, 40.3%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:508.0(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.65(s,1H),7.82(s,1H),7.68(dd,J＝8.4,1.2Hz,1H),7.65(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,1H),7.00(d,J＝8.4Hz,1H),3.34(t,J＝4.8Hz,4H),3.03(t,J＝4.8Hz,4H),1.45(s,9H).
step 2) synthesis of 1-(4-(trifluoromethyl)-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-(trifluoromethyl)-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (150mg, 0.30mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (100mg, 83.3%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:408.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.65(s,1H),7.82(s,1H),7.68-7.64(m,2H),7.17(d,J＝8.4Hz,1H),6.97(d,J＝8.4Hz,1H),3.08(t,J＝4.8Hz,4H),2.78(t,J＝4.8Hz,4H).
embodiment 164-(piperazine-1-base)-3-(pyrimidine-2-base sulfenyl) cyanobenzene
step 1) synthesis of the bromo-4-of 3-(piperazine-1-base) cyanobenzene
This step title compound prepares with reference to the method described by embodiment 1 step 1, by 4-amino-3-bromobenzylcyanide (2.00g, 10.15mmol), two (2-chloroethyl) amine hydrochlorate (2.17g, 12.18mmol) with salt of wormwood (4.21g, 30.45mmol) in propyl carbinol (30mL), reaction prepares thick product, it is dark oil liquid (1.55g, 57.4%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:266.1(M+1).
step 2) synthesis of 4-(the bromo-4-cyano-phenyl of 2-) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 2, by the bromo-4-of 3-(piperazine-1-base) cyanobenzene (1.55g, 5.82mmol), triethylamine (1.18mL, 1.61mmol) and (Boc)
2o (1.91g, 8.74mmol) in methylene dichloride (30mL), reaction prepares thick product, it is yellow solid (1.76g, 82.6%) that thick product obtains title compound after column chromatography (petrol ether/ethyl acetate (v/v)=20/1) purifying.
MS(ESI,pos.ion)m/z:366.0(M+1).
step 3) synthesis of 4-(4-cyano group-2-(pyrimidine-2-base sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-cyano-phenyl of 2-) piperazine-1-t-butyl formate (0.40g, 1.09mmol), pyrimidine-2-mercaptan (0.18g, 1.64mmol), Pd
2(dba)
3(50mg, 55 μm of ol), two (2-diphenylphosphine) phenylate (59mg, 109 μm of ol) and sodium tert-butoxide (0.21g, 2.18mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (220mg, 50.9%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.MS(ESI,pos.ion)m/z:398.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.49(d,J＝4.8Hz,2H),7.91(d,J＝1.8Hz,1H),7.62(dd,J＝8.4,1.8Hz,1H),7.08(d,J＝8.4Hz,1H),7.04(t,J＝4.8Hz,1H),3.37(t,J＝4.8Hz,4H),3.04(t,J＝4.8Hz,4H),1.44(s,9H).
step 4) synthesis of 4-(piperazine-1-base)-3-(pyrimidine-2-base sulfenyl) cyanobenzene
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-cyano group-2-(pyrimidine-2-base sulfenyl) phenyl) piperazine-1-t-butyl formate (210mg, 0.53mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (135mg, 86.0%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:298.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.67(d,J＝1.2Hz,1H),7.58-7.56(m,2H),7.14-7.12(m,1H),7.09(t,J＝8.4Hz,2H),3.13(t,J＝4.8Hz,4H),2.88-2.87(m,4H).
embodiment 173-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-(piperazine-1-base) cyanobenzene
step 1) synthesis of 4-(4-cyano group-2-((4,6-dimethoxypyridin-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-cyano-phenyl of 2-) piperazine-1-t-butyl formate (0.40g, 1.09mmol), 4,6-dimethoxypyridin-2-mercaptan (0.28g, 1.64mmol), Pd
2(dba)
3(50mg, 55 μm of ol), two (2-diphenylphosphine) phenylate (59mg, 109 μm of ol) and sodium tert-butoxide (0.21g, 2.18mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (250mg, 50.0%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:458.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.99(d,J＝1.8Hz,1H),7.58(dd,J＝8.4,1.8Hz,1H),7.04(d,J＝8.4Hz,1H),5.75(s,1H),3.74(s,6H),3.47(t,J＝4.8Hz,4H),3.05(t,J＝4.8Hz,4H),1.45(s,9H).
step 2) synthesis of 3-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-(piperazine-1-base) cyanobenzene
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-cyano group-2-((4,6-dimethoxypyridin-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (240mg, 0.52mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (120mg, 64.2%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:358.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.03(d,J＝1.8Hz,1H),7.65(dd,J＝8.4,1.8Hz,1H),7.11(d,J＝8.4Hz,1H),5.79(s,1H),3.77(s,6H),3.27(t,J＝4.8Hz,4H),3.17(t,J＝4.8Hz,4H).
embodiment 183-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-(piperazine-1-base) cyanobenzene
step 1) synthesis of 4-(4-cyano group-2-((4,6-dimethyl pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-cyano-phenyl of 2-) piperazine-1-t-butyl formate (0.40g, 1.09mmol), 4,6-dimethyl pyrimidine-2-mercaptan (0.23g, 1.64mmol), Pd
2(dba)
3(50mg, 55 μm of ol), two (2-diphenylphosphine) phenylate (59mg, 109 μm of ol) and sodium tert-butoxide (0.21g, 2.18mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (210mg, 45.3%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:426.4(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.95(d,J＝1.8Hz,1H),7.58(dd,J＝8.4,1.8Hz,1H),7.05(d,J＝8.4Hz,1H),6.76(s,1H),3.40(t,J＝4.8Hz,4H),3.03(t,J＝4.8Hz,4H),2.35(s,6H),1.44(s,9H).
step 2) synthesis of 3-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-(piperazine-1-base) cyanobenzene
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-cyano group-2-((4,6-dimethyl pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (200mg, 0.47mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (120mg, 78.4%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:326.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.93(d,J＝1.2Hz,1H),7.56(dd,J＝8.4,1.8Hz,1H),7.05(d,J＝8.4Hz,1H),6.75(s,1H),3.06(brs,4H),2.85(t,J＝4.8Hz,4H),2.35(s,6H).
embodiment 194-(piperazine-1-base)-3-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) cyanobenzene
step 1) synthesis of 4-(4-cyano group-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 3, by 4-(the bromo-4-cyano-phenyl of 2-) piperazine-1-t-butyl formate (0.40g, 1.09mmol), 4-(trifluoromethyl) pyrimidine-2-mercaptan (0.30g, 1.64mmol), Pd
2(dba)
3(50mg, 55 μm of ol), two (2-diphenylphosphine) phenylate (59mg, 109 μm of ol) and sodium tert-butoxide (0.21g, 2.18mmol) in toluene (20mL), reaction prepares thick product, it is yellow oily liquid (210mg, 41.3%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:466.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.72(d,J＝4.8Hz,1H),7.89(d,J＝1.8Hz,1H),7.67(dd,J＝8.4,2.4Hz,1H),7.33(d,J＝4.8Hz,1H),7.10(d,J＝8.4Hz,1H),3.31(t,J＝4.8Hz,4H),3.03(t,J＝4.8Hz,4H),1.44(s,9H).
step 2) synthesis of 4-(piperazine-1-base)-3-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) cyanobenzene
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-cyano group-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (200mg, 0.43mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (110mg, 70.1%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:366.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.74(d,J＝4.8Hz,1H),7.91(s,1H),7.67(d,J＝8.4Hz,1H),7.33(d,J＝4.8Hz,1H),7.20(d,J＝8.4Hz,1H),3.09(brs,4H),2.83(t,J＝4.8Hz,4H).
embodiment 204-(piperazine-1-base)-3-(pyridine-2-base sulfenyl) cyanobenzene
step 1) synthesis of 4-(4-cyano group-2-(pyridine-2-base sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 2 step 1, by 4-(the bromo-4-cyano-phenyl of 2-) piperazine-1-t-butyl formate (0.50g, 1.37mmol), pyridine-2-mercaptan (0.18g, 1.64mmol), Pd
2(dba)
3(63mg, 67 μm of ol), two (2-diphenylphosphine) phenylate (74mg, 137 μm of ol) and sodium tert-butoxide (0.26g, 2.73mmol) in DMSO (20mL), reaction prepares thick product, it is light yellow solid (250mg, 46.2%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.MS(ESI,pos.ion)m/z:397.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.48(d,J＝3.6Hz,1H),7.66(d,J＝1.8Hz,1H),7.56(d,J＝8.4Hz,2H),7.14-7.11(m,2H),7.05(d,J＝8.4Hz,1H),3.40(t,J＝4.8Hz,4H),3.06(t,J＝4.8Hz,4H),1.45(s,9H).
step 2) synthesis of 4-(piperazine-1-base)-3-(pyridine-2-base sulfenyl) cyanobenzene
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-cyano group-2-(pyridine-2-base sulfenyl) phenyl) piperazine-1-t-butyl formate (200mg, 0.50mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (120mg, 80.0%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:297.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.47(d,J＝4.2Hz,1H),7.65(d,J＝1.8Hz,1H),7.58-7.50(m,2H),7.11(dd,J＝7.2,5.4Hz,1H),7.07(t,J＝8.4Hz,2H),3.10(t,J＝4.8Hz,4H),2.85(t,J＝4.8Hz,4H).
embodiment 214-(piperazine-1-base)-3-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) cyanobenzene
step 1) synthesis of 4-(4-cyano group-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 2 step 1, by 4-(the bromo-4-cyano-phenyl of 2-) piperazine-1-t-butyl formate (0.50g, 1.37mmol), 5-(trifluoromethyl) pyridine-2-mercaptan (294mg, 1.64mmol), Pd
2(dba)
3(63mg, 67 μm of ol), two (2-diphenylphosphine) phenylate (74mg, 137 μm of ol) and sodium tert-butoxide (0.26g, 2.73mmol) in DMSO (20mL), reaction prepares thick product, it is light yellow solid (250mg, 39.4%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:465.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.65(s,1H),7.82(d,J＝1.8Hz,1H),7.72(dd,J＝8.4,1.8Hz,1H),7.66(dd,J＝8.4,1.8Hz,1H),7.11(d,J＝8.4Hz,1H),7.08(d,J＝8.4Hz,1H),3.34(t,J＝4.8Hz,4H),3.07(t,J＝4.8Hz,4H),1.45(s,9H).
step 2) synthesis of 4-(piperazine-1-base)-3-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) cyanobenzene
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 4-(4-cyano group-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl) piperazine-1-t-butyl formate (200mg, 0.43mmol) in methylene dichloride (10mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (125mg, 79.6%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:365.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.65(s,1H),7.81(d,J＝1.8Hz,1H),7.70(dd,J＝8.4,1.8Hz,1H),7.65(dd,J＝8.4,1.8Hz,1H),7.11(d,J＝8.4Hz,1H),7.04(d,J＝8.4Hz,1H),3.11(t,J＝4.8Hz,4H),2.79(t,J＝4.8Hz,4H).
embodiment 222-((2-(1,2,3,6-tetrahydropyridine-4-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
step 1) synthesis of the iodo-4-of the bromo-1-of 2-(trifluoromethyl) benzene
By bromo-for 2-4-(trifluoromethyl) aniline (3.00g, 12.50mmol) join in the mixed solvent of acetonitrile (30mL) and water (10mL) with concentrated hydrochloric acid (15mL), after being cooled to-10 DEG C, slowly drip water (5mL) solution of Sodium Nitrite (0.95g, 13.75mmol) more wherein.Gained reaction mixture was placed in-10 DEG C of reactions after 30 minutes, added water (5mL) solution of potassiumiodide (2.49g, 15.00mmol) wherein, continued stirring reaction 2 hours, was then incubated to room temperature reaction and spent the night.After reaction terminates, saturated sodium bicarbonate solution (30mL) is added in reaction solution, and extract with methylene dichloride (50mL × 3), the organic phase of merging uses saturated sodium thiosulfate solution (30mL) and saturated aqueous common salt (30mL) washing successively.The organic phase anhydrous sodium sulfate drying separated, filters, and concentrating under reduced pressure, it is yellow oily liquid (3.95g, 90.0%) that gained residue obtains title compound through silica gel column chromatography (sherwood oil) purifying.
MS(ESI,pos.ion)m/z:350.8(M+1).
step 2) synthesis of 4-(the bromo-4-of 2-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate
Under nitrogen protection; by bromo-for 2-1-iodo-4-(trifluoromethyl) benzene (0.50g; 1.42mmol), 4-(4; 4,5,5-tetramethyl--1; 3; 2-dioxy boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formates (0.48g, 1.57mmol), Pd (PPh
3)
2cl
2(25mg, 36 μm of ol) and sodium carbonate (0.23g, 2.14mmol) join in the mixed solvent of acetonitrile (10mL) and water (3mL).Reaction solution was warming up to 90 DEG C of stirring reactions after 12 hours, was cooled to room temperature and added water (20mL), then used ethyl acetate (20mL × 3) to extract.The organic phase anhydrous sodium sulfate drying merged, filter, and concentrating under reduced pressure, it is yellow oily liquid (470mg, 81.0%) that gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=20/1) purifying.
MS(ESI,pos.ion)m/z:350.0(M+1-56)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.82(s,1H),7.53(d,J＝7.8Hz,1H),7.29(d,J＝7.8Hz,1H),5.67(brs,1H),4.07(brs,2H),3.66(brs,2H),2.43(brs,2H),1.51(s,9H).
step 3) synthesis of 4-(2-(pyrimidine-2-base sulfenyl)-4-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate
Under nitrogen protection; by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl)-5; 6-dihydropyridine-1 (2H)-t-butyl formate (0.40g, 0.98mmol), pyrimidine-2-mercaptan (0.14g, 1.28mmol), Pd
2(dba)
3(46mg, 50 μm of ol), DPEphos (54mg, 100 μm of ol) and sodium tert-butoxide (0.14g, 1.48mmol) join in dimethyl sulfoxide (DMSO) (15mL), and reaction solution is warming up to 110 DEG C of stirring reactions 48 hours gradually.After reaction terminates, reaction solution be cooled to room temperature and add water (20mL), then using methylene dichloride (20mL × 3) to extract.The organic phase anhydrous sodium sulfate drying merged, filter, and concentrating under reduced pressure, it is yellow oily liquid (190mg, 44.1%) that gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=8/1) purifying.
MS(ESI,pos.ion)m/z:382.1(M+1-56)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.44(d,J＝4.8Hz,2H),7.89(s,1H),7.61(d,J＝7.8Hz,1H),7.36(d,J＝7.8Hz,1H),6.97(t,J＝4.8Hz,1H),5.59(brs,1H),3.90-3.89(m,2H),3.50(t,J＝5.4Hz,2H),2.38(brs,2H),1.45(s,9H).
step 4) synthesis of 2-((2-(1,2,3,6-tetrahydropyridine-4-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
By 4-(2-(pyrimidine-2-base sulfenyl)-4-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (190mg, 0.43mmol) be dissolved in methylene dichloride (6mL), then add trifluoroacetic acid (2mL).Reaction solution is placed in after stirred at ambient temperature reacts 1 hour, with methylene dichloride (10mL) dilution, and regulates pH to 9 ~ 10 with saturated sodium carbonate solution.Separatory, organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure, it is yellow oily liquid (120mg, 81.6%) that gained residue obtains title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:338.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.44(d,J＝4.8Hz,2H),7.90(s,1H),7.64(d,J＝7.8Hz,1H),7.38(d,J＝7.8Hz,1H),6.99(t,J＝4.8Hz,1H),5.60(brs,1H),3.56(brs,2H),3.19(t,J＝5.4Hz,2H),2.53(brs,2H).
embodiment 234,6-dimethyl-2-((2-(1,2,3,6-tetrahydropyridine-4-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates
Under nitrogen protection; by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.40g, 0.98mmol), 4; 6-dimethyl pyrimidine-2-mercaptan (0.21g, 1.48mmol), Pd
2(dba)
3(46mg, 50 μm of ol), DPEphos (54mg, 100 μm of ol) and sodium tert-butoxide (0.19g, 1.97mmol) join in toluene (15mL).Reaction solution was warming up to 100 DEG C of reactions after 15 hours, was cooled to room temperature and added water (20mL), then using methylene dichloride (20mL × 3) to extract.The organic phase anhydrous sodium sulfate drying merged, filter, and concentrating under reduced pressure, it is yellow oily liquid (150mg, 32.8%) that gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=8/1) purifying.
MS(ESI,pos.ion)m/z:466.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.98(s,1H),7.55(d,J＝8.0Hz,1H),7.30(d,J＝8.0Hz,1H),6.70(s,1H),5.62(brs,1H),3.92-3.91(m,2H),3.50(t,J＝5.4Hz,2H),2.39(brs,2H),2.31(s,6H),1.45(s,9H).
step 2) synthesis of 4,6-dimethyl-2-((2-(1,2,3,6-tetrahydropyridine-4-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (140mg, 0.30mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (70mg, 64.2%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:366.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.98(s,1H),7.54(d,J＝7.8Hz,1H),7.31(d,J＝7.8Hz,1H),6.70(s,1H),5.64(brs,1H),3.40(brs,2H),3.01(t,J＝5.4Hz2H),2.36(brs,2H),2.30(s,6H).
embodiment 244,6-dimethoxy-2-((2-(1,2,3,6-tetrahydropyridine-4-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates
This step title compound prepares with reference to the method described by embodiment 23 step 1, by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.40g, 0.98mmol), 4,6-dimethoxypyridin-2-mercaptan (0.20g, 1.18mmol), Pd
2(dba)
3(46mg, 50 μm of ol), DPEphos (54mg, 100 μm of ol) and sodium tert-butoxide (0.14g, 1.48mmol) in toluene (12mL), reaction prepares thick product, it is yellow oily liquid (160mg, 32.6%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:498.2(M+1).
step 2) synthesis of 4,6-dimethoxy-2-((2-(1,2,3,6-tetrahydropyridine-4-base)-5-(trifluoromethyl) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (160mg, 0.32mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (105mg, 82.0%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:398.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.00(s,1H),7.61(d,J＝7.8Hz,1H),7.36(d,J＝7.8Hz,1H),5.73(s,1H),5.60(brs,1H),3.70(s,6H),3.67(brs,2H),3.29(brs,2H),2.55(brs,2H).
embodiment 252-((2-(1,2,3,6-tetrahydropyridine-4-base)-5-(trifluoromethyl) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
step 1) synthesis of 4-(4-(trifluoromethyl)-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates
This step title compound prepares with reference to the method described by embodiment 23 step 1, by 4-(the bromo-4-of 2-(trifluoromethyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.40g, 0.98mmol), 4-(trifluoromethyl) pyrimidine-2-mercaptan (0.27g, 1.47mmol), Pd
2(dba)
3(46mg, 50 μm of ol), DPEphos (54mg, 100 μm of ol) and sodium tert-butoxide (0.19g, 1.96mmol) in toluene (12mL), reaction prepares thick product, it is yellow solid (180mg, 36.1%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:450.1(M+1-56)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.69(d,J＝4.8Hz,1H),7.91(s,1H),7.66(d,J＝7.2Hz,1H),7.39(d,J＝8.4Hz,1H),7.29(d,J＝5.4Hz,1H),5.61(brs,1H),3.92-3.91(m,2H),3.52(t,J＝5.4Hz,2H),2.39(brs,2H),1.46(s,9H).
step 2) synthesis of 2-((2-(1,2,3,6-tetrahydropyridine-4-base)-5-(trifluoromethyl) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(4-(trifluoromethyl)-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (160mg, 0.32mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (120mg, 93.8%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:406.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.68(d,J＝4.8Hz,1H),7.91(s,1H),7.68(d,J＝7.2Hz,1H),7.41(d,J＝7.8Hz,1H),7.29(d,J＝4.8Hz,1H),5.64(brs,1H),3.56(brs,2H),3.19(brs,2H),2.53(brs,2H).
embodiment 262-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of the iodo-4-toluene of the bromo-1-of 2-
This step title compound prepares with reference to the method described by embodiment 22 step 1, by the bromo-4-monomethylaniline of 2-(3.00g, 16.12mmol), concentrated hydrochloric acid (15mL), Sodium Nitrite (1.22g, 17.74mmol) with potassiumiodide (3.21g, 19.35mmol) in the mixed solvent of acetonitrile (30mL) and water (10mL), reaction prepares thick product, it is red oil (3.82g, 79.7%) that thick product obtains title compound after silica gel column chromatography (sherwood oil) purifying.
MS(ESI,pos.ion)m/z:296.9(M+1)；
1HNMR(400MHz,CDCl
3)δ(ppm):7.70(d,J＝8.0Hz,1H),7.46(d,J＝1.2Hz,1H),6.81(dd,J＝8.0,1.2Hz,1H),2.28(s,3H).
step 2) synthesis of 4-(the bromo-4-aminomethyl phenyl of 2-)-5,6-dihydropyridine-1 (2H)-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 22 step 2, by the iodo-4-toluene of the bromo-1-of 2-(2.00g, 6.74mmol), 4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formates (2.29g, 7.41mmol), Pd (PPh
3)
2cl
2(240mg, 0.34mmol) with sodium carbonate (1.07g, 10.10mmol) in the mixed solvent of acetonitrile (30mL) and water (9mL), reaction prepares thick product, it is yellow oily liquid (1.66g, 70.0%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=20/1) purifying.
MS(ESI,pos.ion)m/z:296.0(M+1-56)；
1HNMR(400MHz,CDCl
3)δ(ppm):7.39(s,1H),7.06-7.01(m,2H),5.61(brs,1H),4.03-4.02(m,2H),3.64(t,J＝5.4Hz,2H),2.42(brs,2H),2.32(s,3H),1.51(s,9H).
step 3) synthesis of 4-(4-methyl-2-(pyrimidine-2-base sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 22 step 3, by 4-(the bromo-4-aminomethyl phenyl of 2-)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.40g, 1.14mmol), pyrimidine-2-mercaptan (0.15g, 1.36mmol), Pd
2(dba)
3(52mg, 57 μm of ol), DPEphos (65mg, 0.12mmol) with sodium tert-butoxide (0.16g, 1.70mmol) in dimethyl sulfoxide (DMSO) (15mL), reaction prepares thick product, it is yellow oily liquid (190mg, 43.7%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:384.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.46(d,J＝4.8Hz,2H),7.46(s,1H),7.22(d,J＝7.7Hz,1H),7.17(d,J＝7.7Hz,1H),6.95(t,J＝4.8Hz,1H),5.55(brs,1H),3.88-3.87(m,2H),3.49(t,J＝5.4Hz,2H),2.40(brs,2H),2.37(s,3H),1.47(s,9H).
step 4) synthesis of 2-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(4-methyl-2-(pyrimidine-2-base sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (190mg, 0.50mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (130mg, 92.9%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:284.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.48(d,J＝4.8Hz,2H),7.47(s,1H),7.24(d,J＝7.8Hz,1H),7.19(d,J＝7.8Hz,1H),6.96(t,J＝4.8Hz,1H),5.59(brs,1H),3.39(brs,2H),3.03(t,J＝5.4Hz,2H),2.40(brs,2H),2.38(s,3H).
embodiment 274,6-dimethoxy-2-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates
This step title compound prepares with reference to the method described by embodiment 22 step 3, by 4-(the bromo-4-aminomethyl phenyl of 2-)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.30g, 0.85mmol), 4,6-dimethoxypyridin-2-mercaptan (0.18g, 1.02mmol), Pd
2(dba)
3(39mg, 43 μm of ol), DPEphos (46mg, 85 μm of ol) and sodium tert-butoxide (0.12g, 1.28mmol) in dimethyl sulfoxide (DMSO) (15mL), reaction prepares thick product, it is yellow oily liquid (170mg, 45.1%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:444.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.45(s,1H),7.14(d,J＝7.8Hz,1H),7.09(d,J＝7.7Hz,1H),5.67(s,1H),5.50(brs,1H),3.92(brs,2H),3.69(s,6H),3.53(t,J＝5.4Hz,2H),2.37(brs,2H),2.32(s,3H),1.46(s,9H).
step 2) synthesis of 4,6-dimethoxy-2-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(2-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (150mg, 0.34mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (110mg, 94.8%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:344.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.44(s,1H),7.12(d,J＝7.8Hz,1H),7.10(d,J＝7.8Hz,1H),5.65(s,1H),5.53(brs,1H),3.68(s,6H),3.41(brs,2H),3.02(t,J＝5.4Hz,2H),2.32(brs,2H),2.30(s,3H).
embodiment 284,6-dimethyl-2-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates
This step title compound prepares with reference to the method described by embodiment 22 step 3, by 4-(the bromo-4-aminomethyl phenyl of 2-)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.40g, 1.14mmol), 4,6-dimethyl pyrimidine-2-mercaptan (0.19g, 1.36mmol), Pd
2(dba)
3(52mg, 57 μm of ol), DPEphos (65mg, 0.12mmol) with sodium tert-butoxide (0.16g, 1.71mmol) in dimethyl sulfoxide (DMSO) (15mL), reaction prepares thick product, it is yellow oily liquid (200mg, 42.8%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:412.3(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.45(s,1H),7.14(d,J＝7.8Hz,1H),7.09(d,J＝7.8Hz,1H),6.65(s,1H),5.55(brs,1H),3.84-3.83(m,2H),3.43(t,J＝5.4Hz,2H),2.38(brs,2H),2.32(s,3H),2.29(s,6H),1.44(s,9H).
step 2) synthesis of 4,6-dimethyl-2-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl)-4-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (150mg, 0.36mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (100mg, 87.7%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:312.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.46(s,1H),7.15(d,J＝7.8Hz,1H),7.11(d,J＝7.8Hz,1H),6.66(s,1H),5.58(brs,1H),3.36-3.35(m,2H),2.98(t,J＝5.4Hz,2H),2.38(brs,2H),2.33(s,3H),2.31(s,6H).
embodiment 292-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
step 1) synthesis of 4-(4-methyl-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates
This step title compound prepares with reference to the method described by embodiment 22 step 3, by 4-(the bromo-4-aminomethyl phenyl of 2-)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.40g, 1.14mmol), 4-(trifluoromethyl) pyrimidine-2-mercaptan (0.24g, 1.37mmol), Pd
2(dba)
3(52mg, 57 μm of ol), DPEphos (65mg, 0.12mmol) with sodium tert-butoxide (0.16g, 1.64mmol) in dimethyl sulfoxide (DMSO) (15mL), reaction prepares thick product, it is yellow oily liquid (190mg, 37.1%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:352.1(M+1-Boc)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.65(d,J＝4.8Hz,1H),7.43(s,1H),7.23(d,J＝4.8Hz,1H),7.22(s,1H),7.16(d,J＝7.8Hz,1H),5.53(brs,1H),3.87-3.86(m,2H),3.48(t,J＝5.4Hz,2H),2.38(brs,2H),2.35(s,3H),1.45(s,9H).
step 2) synthesis of 2-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl)-4-(trifluoromethyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(4-methyl-2-((4-(trifluoromethyl) pyrimidine-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (190mg, 0.42mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (120mg, 81.1%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:352.0(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.66(d,J＝4.8Hz,1H),7.43(s,1H),7.24(s,1H),7.23(s,1H),7.18(d,J＝7.8Hz,1H),5.57(brs,1H),3.38(brs,2H),3.01(t,J＝5.4Hz,2H),2.36(brs,2H),2.35(s,3H).
embodiment 302-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl)-5-(trifluoromethyl) pyridine
step 1) synthesis of 4-(4-methyl-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates
This step title compound prepares with reference to the method described by embodiment 22 step 3, by 4-(the bromo-4-aminomethyl phenyl of 2-)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.40g, 1.14mmol), 5-(trifluoromethyl) pyridine-2-mercaptan (0.24g, 1.36mmol), Pd
2(dba)
3(52mg, 57 μm of ol), DPEphos (65mg, 0.12mmol) with sodium tert-butoxide (0.16g, 1.64mmol) in dimethyl sulfoxide (DMSO) (15mL), reaction prepares thick product, it is yellow oily liquid (130mg, 25.4%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:451.1(M+1).
step 2) synthesis of 2-((5-methyl-2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl)-5-(trifluoromethyl) pyridine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(4-methyl-2-((5-(trifluoromethyl) pyridine-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (130mg, 0.29mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (90mg, 89.1%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:351.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.60(s,1H),7.65(dd,J＝8.4,2.4Hz,1H),7.43(s,1H),7.28(d,J＝7.8Hz,1H),7.22(d,J＝7.8Hz,1H),6.92(d,J＝8.4Hz,1H),5.47(brs,1H),3.65(brs,2H),3.30(t,J＝5.4Hz,2H),2.65(brs,2H),2.38(s,3H).
embodiment 312-((2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 2-((2-bromophenyl) sulfenyl) pyrimidine
By 2-bromo thiophenol (1.00g, 5.29mmol), 2-chloropyrimide (667mg, 5.82mmol) with salt of wormwood (1.46g, 10.58mmol) join 1 successively, in 4-dioxane (20mL), reaction solution is warming up to 100 DEG C of stirring reactions 24 hours gradually.After reaction terminates, reaction solution is cooled to room temperature, filters, filtrate reduced in volume, it is white solid (1.25g, 88.7%) that gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=20/1) purifying.
MS(ESI,pos.ion)m/z:267.0(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.49(d,J＝3.6Hz,2H),7.75(dd,J＝7.2,1.2Hz,1H),7.73(dd,J＝7.8,0.6Hz,1H),7.38(td,J＝7.2,1.2Hz,1H),7.30(td,J＝7.8,1.2Hz,1H),6.98(t,J＝4.8Hz,1H).
step 2) synthesis of 4-(2-(pyrimidine-2-base sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate
Under nitrogen protection; by 2-((2-bromophenyl) sulfenyl) pyrimidine (1.00g; 3.74mmol), 4-(4; 4,5,5-tetramethyl--1; 3; 2-dioxy boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formates (1.27g, 4.12mmol), Pd (dppf) Cl
2(205mg, 0.37mmol) and potassium acetate (918mg, 9.36mmol) join in the mixed solvent of DMF (15mL) and water (3mL), and then reaction solution is warming up to 90 DEG C of stirring reactions 36 hours gradually.After reaction terminates, reaction solution be cooled to room temperature and add water (50mL), then using methylene dichloride (20mL × 3) to extract.The organic phase anhydrous sodium sulfate drying merged, filter, and concentrating under reduced pressure, it is light yellow liquid (571mg, 41.3%) that gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=15/1) purifying.
MS(ESI,pos.ion)m/z:370.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.46(d,J＝5.4Hz,2H),7.62(d,J＝7.8Hz,1H),7.40(td,J＝7.2,1.2Hz,1H),7.32(td,J＝7.2,1.2Hz,1H),7.25(dd,J＝7.2,0.6Hz,1H),6.95(t,J＝4.8Hz,1H),5.55(brs,1H),3.87(q,J＝3.0Hz,2H),3.50(t,J＝5.4Hz,2H),2.41-2.40(m,2H),1.45(s,9H).
step 3) synthesis of 2-((2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(2-(pyrimidine-2-base sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (200mg, 0.54mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (100mg, 68.5%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:270.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.44(d,J＝4.8Hz,2H),7.63(dd,J＝7.8,1.2Hz,1H),7.42(td,J＝7.8,1.2Hz,1H),7.36(td,J＝7.8,1.2Hz,1H),7.32(d,J＝7.8Hz,1H),6.96(t,J＝4.8Hz,1H),5.54(brs,1H),3.69-3.68(m,2H),3.31(t,J＝5.4Hz,2H),2.73(brs,2H).
embodiment 324,6-dimethyl-2-((2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
step 1) synthesis of 2-((2-bromophenyl) sulfenyl)-4,6-dimethyl pyrimidines
This step title compound prepares with reference to the method described by embodiment 31 step 1, by 2-bromo thiophenol (1.46g, 7.72mmol), 2-chloro-4,6-dimethyl pyrimidine (1.21g, 8.49mmol) with salt of wormwood (2.13g, 15.44mmol) 1, in 4-dioxane (20mL), reaction prepares thick product, it is light yellow liquid (1.94g, 85.1%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=30/1) purifying.
MS(ESI,pos.ion)m/z:295.0(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.74(dd,J＝7.8,1.2Hz,1H),7.68(dd,J＝7.8,1.2Hz,1H),7.33(td,J＝7.8,1.2Hz,1H),7.24(td,J＝7.8,1.2Hz,1H),6.70(brs,1H),2.32(s,6H).
step 2) synthesis of 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates
This step title compound prepares with reference to the method described by embodiment 31 step 2, by 2-((2-bromophenyl) sulfenyl)-4,6-dimethyl pyrimidine (1.00g, 3.39mmol), 4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formate (1.15g, 3.73mmol), Pd (dppf) Cl
2(188mg, 0.34mmol) with potassium acetate (831mg, 8.47mmol) in the mixed solvent of DMF (15mL) and water (2mL), reaction prepares thick product, thick product is light yellow solid (460mg, 34.1%) through obtaining title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=15/1) purifying.
MS(ESI,pos.ion)m/z:398.0(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.64(d,J＝7.8Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝7.2Hz,1H),7.21(d,J＝7.8Hz,1H),6.66(s,1H),5.57(brs,1H),3.88-3.87(m,2H),3.47(t,J＝5.4Hz,2H),2.40(brs,2H),2.30(s,6H),1.46(s,9H).
step 3) synthesis of 4,6-dimethyl-2-((2-(1,2,3,6-tetrahydropyridine-4-base) phenyl) sulfenyl) pyrimidine
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(2-((4,6-dimethyl pyrimidine-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (200mg, 0.50mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow oily liquid (100mg, 66.7%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:298.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.64(d,J＝7.8Hz,1H),7.35(t,J＝7.2Hz,1H),7.27(d,J＝7.8Hz,1H),7.23(d,J＝7.2Hz,1H),6.67(s,1H),5.60(brs,1H),3.37(brs,2H),2.99(t,J＝5.4Hz,2H),2.37(brs,2H),2.31(s,6H).
embodiment 333-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-(1,2,3,6-tetrahydropyridine-4-base) cyanobenzene
step 1) synthesis of 4-(the bromo-4-cyano-phenyl of 2-)-5,6-dihydropyridine-1 (2H)-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 31 step 2, by 3-bromo-4-iodobenzene formonitrile HCN (2.19g, 7.11mmol), 4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formates (2.42g, 7.82mmol), Pd (dppf) Cl
2(360mg, 0.65mmol) and sodium carbonate (2.26g, 11.34mmol) are at DMF (20mL) and H
2in the mixed solvent of O (2mL), reaction prepares thick product, it is white solid (2.00g, 77.5%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=15/1) purifying.
MS(ESI,pos.ion)m/z:307.0(M+1-56)；
1HNMR(600MHz,CDCl
3)δ(ppm):7.83(d,J＝1.9Hz,1H),7.55(dd,J＝7.8,1.8Hz,1H),7.25(d,J＝7.8Hz,1H),5.67(brs,1H),4.04(brs,2H),3.62(t,J＝5.4Hz,2H),2.39(brs,2H),1.48(s,9H).
step 2) synthesis of 4-(4-cyano group-2-((4,6-dimethoxypyridin-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates
This step title compound prepares with reference to the method described by embodiment 23 step 1, by 4-(the bromo-4-cyano-phenyl of 2-)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.50g, 1.38mmol), 4,6-dimethoxypyridin-2-mercaptan (356mg, 2.06mmol), Pd
2(dba)
3(63mg, 69 μm of ol), DPEphos (75mg, 0.14mmol) with sodium tert-butoxide (400mg, 4.13mmol) in toluene (15mL), reaction prepares thick product, it is light yellow liquid (250mg, 39.9%) that thick product obtains title compound after silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:455.2(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.03(d,J＝1.8Hz,1H),7.61(dd,J＝7.8,1.8Hz,1H),7.32(d,J＝8.4Hz,1H),5.74(s,1H),5.60(brs,1H),3.99(brs,2H),3.74(s,6H),3.57(t,J＝5.4Hz,2H),2.39(brs,2H),1.48(s,9H).
step 3) synthesis of 3-((4,6-dimethoxypyridin-2-base) sulfenyl)-4-(1,2,3,6-tetrahydropyridine-4-base) cyanobenzene
This step title compound prepares with reference to the method described by embodiment 22 step 4, by 4-(4-cyano group-2-((4,6-dimethoxypyridin-2-base) sulfenyl) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (200mg, 0.55mmol) in methylene dichloride (6mL), reaction prepares thick product with trifluoroacetic acid (2mL), it is yellow solid (140mg, 71.8%) that thick product obtains title compound after silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purifying.
MS(ESI,pos.ion)m/z:355.1(M+1)；
1HNMR(600MHz,CDCl
3)δ(ppm):8.02(d,J＝1.2Hz,1H),7.60(dd,J＝8.4,1.2Hz,1H),7.33(d,J＝8.4Hz,1H),5.72(s,1H),5.62(brs,1H),3.71(s,6H),3.53-3.52(m,2H),3.13(t,J＝5.4Hz,2H),2.40(brs,2H).
Biological test
embodiment A: assessing compound is to the avidity of the humanization 5-HT transporter of expressing in Chinese hamster ovary celI
experimental technique
Under 22 DEG C of conditions, to cell membrane homogenate albumen (12 μ g), 2nM [
3h] in the mixed system that formed of imipramine and damping fluid (50mMTris-HCl (pH7.4), 120mMNaCl, 5mMKCl and 0.1%BSA), add or do not add test compounds, hatching 60 minutes altogether.
And in the mixed system of above-mentioned condition, add 10 μMs of imipramine, for recording non-specific binding value.
Sample after hatching 96 like cell collector (Unifilter, Packard) under vacuum by the glass fiber filter (GF/B of pre-dipped 0.3%PEI, Packard) fast filtering, and use ice-cold 50mMTris-HCl and 150mMNaCl repeatedly to rinse several times.Dry filter membrane, in scintillometer (Topcount, Packard), calculates residual radioactivity with scintillation solution (Microscint0, Packard).Experimental result is to represent relative to the suppression per-cent of control group radioligand specific binding.
Standard reference compound is imipramine, obtains competitive curve, thus calculate IC by the experiment test of series concentration
50.Result is see Table A, and Table A is the avidity experimental result of the compounds of this invention to humanization 5-HT transporter (SERT).
Table A the compounds of this invention is to the avidity measurement result in people source 5-HT transporter (SERT)
Experimental result shows, and the compounds of this invention has stronger avidity to people source 5-HT transporter (SERT).
pharmacokinetic Evaluation after the quiet note of Embodiment B rat or the quantitative the compounds of this invention of gavage
The present invention assesses the pharmacokinetic of the compounds of this invention in rat body, and animal information refers to table B.
Table B animal subject information table of the present invention
test method
By the compounds of this invention with the form of the salt brine solution of 5%DMSO+5%KolliphorHS15+2% (2%HCl)+88%Saline or 10%DMSO+10%KolliphorHS15+80% normal saline solution, administration is carried out to animal subject.For intravenous administration group, dosage is 1mg/kg or 2mg/kg, then time point is upon administration 0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 little venous blood samplings constantly (0.3mL), and 3,000 or 4, under 000rpm centrifugal 10 minutes, collect plasma solutions, and preserve at-20 DEG C or-70 DEG C.For gastric infusion group, dosage is 2.5mg/kg or 5mg/kg, then time point is upon administration 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 little venous blood samplings constantly (0.3mL), and 3,000 or 4, under 000rpm centrifugal 10 minutes, collect plasma solutions, and preserve at-20 DEG C or-70 DEG C.
Collect to above-mentioned each group the plasma solutions obtained and carry out LC/MS/MS analysis.Analytical results shows, the compounds of this invention measured by the mode of intravenous administration and gastric infusion in rat body has that to expose value large, and clearance rate is low, the high good pharmacokinetic property of bioavailability.Illustrate that the compounds of this invention druggability is better, there is better potential applicability in clinical practice.
Experimental result shows, the compounds of this invention has good pharmacokinetic property in rat body.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment, embodiment or example are contained at least one embodiment of the present invention, embodiment or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment, embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office, embodiment or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiments, embodiment or the example that describe in this specification sheets and different embodiment, embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.
Claims (10)
1. a compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug,
Wherein:
X is CR
xor N;
for singly-bound or double bond;
When
during for singly-bound, Y is N or CH;
When
during for double bond, Y is C;
R
1, R
2, R
3and R
xbe H, D, F, Cl, Br, I ,-CN ,-NO independently of one another
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) NHCH
3,-C (=O) N (CH
3)
2,-C (=O)-(C
1-C
6alkyl) ,-C (=O)-(C
1-C
6alkoxyl group), C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group, C
1-C
6halogenated alkoxy, C
1-C
6alkylthio, C
1-C
6the C that alkylamino or hydroxyl replace
1-C
6alkyl;
R
4, R
5, R
6and R
7be H, D, F, Cl, Br, I ,-CN ,-NO independently of one another
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2,-C (=O) NHCH
3,-C (=O) N (CH
3)
2,-C (=O)-(C
1-C
6alkyl) ,-C (=O)-(C
1-C
6alkoxyl group), C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group or C
1-C
6halogenated alkoxy; With
R
8for H, D, F, Cl, Br, I ,-CN ,-NO
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6alkoxyl group, C
1-C
6the C that halogenated alkoxy or hydroxyl replace
1-C
6alkyl.
2. compound according to claim 1, wherein R
1, R
2, R
3and R
xbe H, D, F, Cl, Br, I ,-CN ,-NO independently of one another
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O)-(C
1-C
4alkyl) ,-C (=O)-(C
1-C
4alkoxyl group), C
1-C
4alkyl, C
2-C
4thiazolinyl, C
2-C
4alkynyl, C
1-C
4haloalkyl, C
1-C
4alkoxyl group, C
1-C
4halogenated alkoxy, C
1-C
4alkylthio, C
1-C
4the C that alkylamino or hydroxyl replace
1-C
4alkyl.
3. compound according to claim 1, wherein R
4, R
5, R
6and R
7be H, D, F, Cl, Br, I ,-CN ,-NO independently of one another
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2, C
1-C
4alkyl, C
2-C
4thiazolinyl, C
2-C
4alkynyl, C
1-C
4haloalkyl, C
1-C
4alkoxyl group or C
1-C
4halogenated alkoxy.
4. compound according to claim 1 and 2, wherein R
1, R
2, R
3and R
xbe H, D, F, Cl, Br, I ,-CN ,-NO independently of one another
2,-NH
2,-OH ,-SH ,-COOH ,-CONH
2,-C (=O) CH
3,-C (=O) OCH
3, methyl, ethyl, n-propyl, sec.-propyl ,-CF
3,-CH
2cF
3, methoxyl group, oxyethyl group, n-propyl oxygen base or sec.-propyl oxygen base.
5. the compound according to claim 1 or 3, wherein R
4, R
5, R
6and R
7be H, D, F, Cl, Br, I ,-CN ,-NO independently of one another
2,-NH
2,-OH ,-COOH ,-C (=O) NH
2, methyl, ethyl, n-propyl, sec.-propyl ,-CF
3or-CH
2cF
3.
6. compound according to claim 1, its be have one of following structure compound or there is the steric isomer of compound of one of following structure, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
7. a pharmaceutical composition, comprises the compound described in claim 1-6 any one; With
Described pharmaceutical composition optionally comprises pharmaceutically acceptable vehicle, carrier, adjuvant or their arbitrary combination further.
8. pharmaceutical composition according to claim 7, it comprises the medicine for the treatment of central nervous system dysfunction further, and the medicine of described treatment central nervous system dysfunction is amitriptyline, Desipramine, mirtazapine, Bupropion, Reboxetine, fluoxetine, trazodone, Sertraline, duloxetine, fluvoxamine, Midalcipran, left-handed Midalcipran, desmethylvenlafaxine, vilazodone, Venlafaxine, dapoxetine, nefazodone, femoxetine, chlorimipramine, citalopram, S-escitalopram, paroxetine, Quilonum Retard, buspirone, olanzapine, Quetiapine, risperidone, Ziprasidone, Aripiprazole, Perospirone, leoponex, modafinil, mecamylamine, Cabergoline, diamantane, imipramine, pramipexole, thyroxine, Dextromethorphane Hbr, Quinidine, TREXUPONT, samidorphan, buprenorphine, melatonin, alprazolam, pipamperone, dimension is for smooth, zeisin, trilafon or their arbitrary combination.
9. the compound described in claim 1-6 any one or the pharmaceutical composition described in claim 7-8 any one are preparing the purposes in medicine, and described medicine is used for prevention, treats or alleviate central nervous system dysfunction.
10. purposes according to claim 9, described medicine is used for prevention, treats or alleviate affective disorder.
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| CN109912514A (en) * | 2017-12-13 | 2019-06-21 | 广东东阳光药业有限公司 | (2- heteroaryl aminocarbonyl phenyl) azepine ring derivatives and application thereof |
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| CN108409729A (en) * | 2017-02-09 | 2018-08-17 | 广东东阳光药业有限公司 | Phenyl octahydro -1H- pyridos [1,2-a] pyrazines derivatives and application thereof |
| CN109912514A (en) * | 2017-12-13 | 2019-06-21 | 广东东阳光药业有限公司 | (2- heteroaryl aminocarbonyl phenyl) azepine ring derivatives and application thereof |
| CN109912514B (en) * | 2017-12-13 | 2022-11-18 | 广东东阳光药业有限公司 | (2-heteroarylaminophenyl) nitrogen heterocyclic derivative and application thereof |
| CN108863986A (en) * | 2018-08-06 | 2018-11-23 | 广东东阳光药业有限公司 | The Phenylpiperazine derivatives and application thereof that difluoromethyl replaces |
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| CN105348204B (en) | 2018-09-14 |
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