CN102140104B - 1-(3-(S)-amino propyl)-piperidine-4-aminoacid amide compound and pharmaceutical composition thereof as well as preparation methods and applications of compound and pharmaceutical composition - Google Patents
1-(3-(S)-amino propyl)-piperidine-4-aminoacid amide compound and pharmaceutical composition thereof as well as preparation methods and applications of compound and pharmaceutical composition Download PDFInfo
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- 0 CCCCCNC(*)CC Chemical compound CCCCCNC(*)CC 0.000 description 8
- KUEILLOWCPFSET-UHFFFAOYSA-N CC1(CCN(CCC(c2cc(F)ccc2)NC(C2CCCCC2)=O)CC1)NC(c1ccc(C)cc1)=O Chemical compound CC1(CCN(CCC(c2cc(F)ccc2)NC(C2CCCCC2)=O)CC1)NC(c1ccc(C)cc1)=O KUEILLOWCPFSET-UHFFFAOYSA-N 0.000 description 1
- CVGAOTIFIJUIDK-HKBQPEDESA-N CC1(CCN(CC[C@@H](c2cc(F)ccc2)NC(C2CCCCC2)=O)CC1)NC(Cc1c(cccc2)c2ccc1)=O Chemical compound CC1(CCN(CC[C@@H](c2cc(F)ccc2)NC(C2CCCCC2)=O)CC1)NC(Cc1c(cccc2)c2ccc1)=O CVGAOTIFIJUIDK-HKBQPEDESA-N 0.000 description 1
- SJDQCCQEVRHRNN-SANMLTNESA-N CC1(CCN(CC[C@@H](c2cc(F)ccc2)NC(C2CCCCC2)=O)CC1)NC(c1ccccc1Cl)=O Chemical compound CC1(CCN(CC[C@@H](c2cc(F)ccc2)NC(C2CCCCC2)=O)CC1)NC(c1ccccc1Cl)=O SJDQCCQEVRHRNN-SANMLTNESA-N 0.000 description 1
- PYCKDAZBIHRFGB-SANMLTNESA-N CC1(CCN(CC[C@@H](c2cccc(F)c2)NC(C2CCCCC2)=O)CC1)NC(c(cc1OC)cc(OC)c1OC)=O Chemical compound CC1(CCN(CC[C@@H](c2cccc(F)c2)NC(C2CCCCC2)=O)CC1)NC(c(cc1OC)cc(OC)c1OC)=O PYCKDAZBIHRFGB-SANMLTNESA-N 0.000 description 1
- HHBNOMRKGKKZIR-UHFFFAOYSA-N CC1(CCNCC1)NC(Cc1cccc2c1cccc2)=O Chemical compound CC1(CCNCC1)NC(Cc1cccc2c1cccc2)=O HHBNOMRKGKKZIR-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
The invention belongs to the field of pharmaceutical chemistry and discloses 1-(3-(S)-amino propyl)-piperidine-4-aminoacid amide compounds as shown in a formula (I) and pharmaceutical compositions thereof as well as preparation methods and applications of the compounds and the pharmaceutical compositions. The compounds or pharmaceutically acceptable salts can be used as antagonists of a C Chemokine receptor (CCR5) and can be used for preparing medicaments for treating a disease mediated by the CCR5, especially for preparing medicaments for treating human immunodeficiency virus (HIV) infection, asthma, rheumatic arthritis, autoimmune diseases and chronic obstructive pulmonary disease (COPD).
Description
Technical field
The invention belongs to pharmaceutical chemistry field, more specifically, relate to 1-(3-(S)-aminopropyl)-piperidine-4-aminoamide compounds, its pharmaceutical composition and its production and use, this compounds can be used as CCR5 antagonist.
Background technology
Chemokine is the cytokine of a class guiding lymphocyte directional migration, exosmoses, tissue infiltration, tumour occur, have important effect in fetal development at inflammatory reaction, white corpuscle.Chemokine belongs to secretor type signaling molecule extended familys, and molecular weight about 8 is to 14kDa.Nearly 45 members of this family at present, their common trait is: contain four halfcystines (Cys) that position is conservative.Between two Cys according to it near N end, whether contain other amino acid, this family is divided into four classes: CC, CXC, C-X
3-C and C.Wherein, CC class (claim not only beta-chemokine) and CXC class (but also claiming α-chemokine) are most important two classes.
In body, the function of chemokine is by chemokine receptor mediated.The standard of Chemokine Receptors name at present is for example, according to the feature of the chemokine of its specific combination (,, if its aglucon is CC class chemokine subfamily, it is just named as CCR).The acceptor of chemokine belongs to the g protein coupled receptor family (GPCR) of 7 cross-films, and this receptoroid N holds in extracellular, and C holds in cell, contains seven very conservative cross-film regions that are made up of α spiral.They at energy coupling in the time that agonist is combined to G albumen, thereby extracellular signal is delivered in cell.Under the effect of agonist, Chemokine Receptors can cause a series of intracellular signal and change the behavior of cell, as suppressed adenylate cyclase (AC), mobilize calcium release, activate a series of protein kinase, guiding cell directional migration (chemotactic) and affect the release etc. of cytokine.
The Chemokine Receptors of finding at present has 19, and they are CCR1-11, CXCR1-6, XCR1 and CX
3cR1.Chemokine Receptors is considered to the important mediation person (Gerard etc., Nat Immunol, 2,108-15 (2001)) of inflammatory reaction and autoimmune disorder.Therefore, the conditioning agent (comprising agonist and antagonist) of Chemokine Receptors can be used in various diseases, as inflammation or anaphylactic disease, anaphylaxis, autoimmune disorder, inflammatory bowel disease, scleroderma, oxyphie myositis and tumour generation and transfer etc.
As one member's of Chemokine Receptors family CCR5, its endogenous agonist has RANTES, MIP-1 α, MIP-1 β, and dendritic cell, T lymphocyte, monocyte, scavenger cell and the participation that it is expressed in derived from peripheral blood maintains immunocyte and the inflammatory cell of long-term inflammatory reaction.Therefore, regulate the function of CCR5 may regulate T cell to the raising of inflammatory reaction injury region, thereby provide a new target spot for treatment inflammatory reaction and autoimmune disorder.For example, CCR5 disappearance makes mouse avoid the serious inflammation of DSS induction and the damage (Andres etc., JImmuno1., 164,6303-12 (2000)) of mucous membrane; On mouse, the small molecular antagonists TAK-779 of CCR5 has suppressed collagen-induced sacroiliitis (Yang etc., Eur J Immuno1., 32,2124-32 (2002)).So, the antagonist of CCR5 can be used for the treatment of following disease: asthma and local disorders are (as locality dermatitis, local anaphylaxis), rheumatic arthritis, arteriosclerosis, psoriasis, meat shape knurl disease and other fibrotic disease, autoimmune disorder (as multiple sclerosis, inflammatory enteritis).In addition, due to CD
8+t cell relevant with chronic obstructive pulmonary disease (COPD) (Cosio etc., Chest, 121,160S-165S, (2002)), therefore, the antagonist of CCR5 also may be used for the treatment of COPD.
Except the effect in inflammation and immune response, Chemokine Receptors may be also the important acceptor of some parasite and poisoning intrusion cell.For example, Duffy acceptor is that plasmodium enters erythrocytic acceptor, and the crowd who lacks Duffy acceptor is not easy to suffer from malaria.What is more important, has several Chemokine Receptors to participate in the invasion of HIV, is called as the co-receptor of HIV.
Research shows, the CD4 molecule on Th cell is essential for the intrusion of HIV, but only CD4 is not enough to mediate the fusion of HIV and cell.Further research is found, the molecule that is called as HIV intrusion co-receptor is in addition CCR5, CXCR4, CCR2b, CCR3, CCR8 and orphan receptor V28, STRL-33, GPR1, GPR15 and the APJ (Domes etc. in Chemokine Receptors, Virology, 235,179-90, (1997)).In vivo, CCR5 and CXCR4 are the main co-receptors that HIV enters, and CCR3 also may participate in entering of a part of HIV.CCR5 is the co-receptor of scavenger cell tropism (M-tropism) HIV-1 and CXCR4 is the co-receptor of the HIV-1 of T cytotropism (T-tropism).Therefore, CCR5 plays an important role to the propagation of HIV, regulates the substance of CCR5 affect the propagation of M tropism HIV-1 in crowd and disease is controlled in early days.In experiment, find that in vitro thereby chemokine RANTES, MIP-1 α and the MIP-1 β that can be combined with CCR5 can enter cell inhibition HIV infection by suppressing M tropism's HIV-1.Some can be combined with CCR5 and the micromolecular compound of antagonizing CCR 5 function also suppresses HIV intrusion cell in vitro very effectively.
In sum, this area has the compound of the CCR5 antagonist of potential drug purposes in the urgent need to exploitation conduct.
Summary of the invention
The inventor, designs and has synthesized the compound shown in general formula (I) through extensive and deep research the compound with CCR5 antagonistic activity.Test result shows, these compounds are potent CCR5 antagonists, and has anti-HIV-1 virus activity in cell, can be used as the inhibitor of HIV cell entry, and can develop into anti-AIDS drug, completed on this basis the present invention.
Therefore, an object of the present invention is to provide a class as 1-(3-(S)-aminopropyl)-piperidine-4-aminoamide compounds or its pharmacy acceptable salt shown in the general formula (I) of CCR5 antagonist.
Another object of the present invention is to provide the preparation method of above-claimed cpd.
Another object of the present invention is to provide a kind of pharmaceutical composition that comprises compound shown in one or more general formulas (I) for the treatment of significant quantity or its pharmacy acceptable salt.
An also object of the present invention is to provide this compounds or its pharmacy acceptable salt as CCR5 antagonist, the application in the medicine of the disease being mediated by CCR5 in preparation treatment.
In a first aspect of the present invention, the 1-shown in a kind of general formula (I) (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds or its pharmacy acceptable salt are provided,
Wherein,
R
1for hydrogen or following groups unsubstituted or that replaced by 1-3 substituting group: C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
6-C
12aryl or C
4-C
10aromaticity heterocyclic radical, described heterocycle comprises that 1-3 is selected from the heteroatoms in N, O and S; Described substituting group is selected from following atom or group: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
12aryl, C
6-C
10aryloxy, C
4-C
10aromaticity heterocyclic radical, C
3-C
8cycloalkyl, C
3-C
8cycloalkyl oxy, halogen, amino, sulfydryl, hydroxyl, CF
3, CN, NO
2and carboxyl;
X is C (O), OC (O), NR
8c (O) or SO
2;
R
2for hydrogen or following groups unsubstituted or that replaced by 1-3 substituting group: C
1-C
6alkyl, C
6-C
12aryl, C
2-C
6thiazolinyl, C
2-C
6alkynyl or C
3-C
8cycloalkyl; Described substituting group is selected from: halogen, hydroxyl, amino, nitro, itrile group, C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
12aryl and C
6-C
12aryloxy;
R
3for following groups unsubstituted or that replaced by 1-3 substituting group: phenyl, benzyl, naphthyl or C
4-C
10aromaticity heterocyclic radical; Described heterocycle comprises that 1-3 is selected from the heteroatoms in N, O and S; Described substituting group is selected from following atom or group: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, halogen, sulfydryl, hydroxyl, CF
3, CN, NO
2, amino and carboxyl; Wherein C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl or C
1-C
6alkoxyl group is optionally by halogen, hydroxyl, amino, C
3-C
8cycloalkyl, cyano group or sulfydryl replace;
G does not exist or is-CH
2cH
2-;
L is N or CH;
M does not exist or is N, CH or phenyl ring;
R
4do not exist or be hydrogen or unsubstituted or by the following groups of 1-3 substituting group replacement: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
10aryl, C
1-C
6alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl or carboxylate methyl ester base; Described substituting group is selected from: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
10aryl, halogen, amino, one or two C
1-C
6amino, C that alkyl replaces
1-C
4acyl group, nitro, itrile group, sulfydryl and hydroxyl;
R
5for hydrogen, C
1-C
6alkyl, C
3-C
8cycloalkyl, phenyl, benzyl, naphthyl, C
5-C
10aromaticity heterocyclic radical or C
4-C
7saturated heterocyclyl; Or R
5be connected M, Y, R
6and R
7form together 3-sec.-propyl-5-methyl-4-hydrogen-1,2,4-triazole-4-yl or 2-methyl-3-hydrogen-imidazoles [4,5-also] pyridin-3-yl; Described heterocycle comprises that 1-3 is selected from the heteroatoms in N, O and S;
Y is C (O), C (O) O, C (O) NH, NR
9or SO
2;
R
6do not exist or for unsubstituted or by the following groups of 1-3 substituting group replacement: C
1-C
6alkylidene group, C
2-C
6alkenylene or C
2-C
6alkynylene, described substituting group is selected from following atom or group: C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, amino, nitro, itrile group, sulfydryl and hydroxyl;
R
7do not exist or for unsubstituted or by the following groups of 1-3 substituting group replacement: C
1-C
6alkyl, C
3-C
8cycloalkyl, adamantyl, phenyl, benzyl, naphthyl, C
4-C
10aromaticity heterocyclic radical or C
4-C
7saturated heterocyclyl, described heterocycle comprises that 1-3 is selected from the heteroatoms in N, O and S, described substituting group is selected from following atom or group: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
10aryl, halogen, sulfydryl, hydroxyl, CF
3, CN, NO
2, amino, one or two C
1-C
6amino, C that alkyl replaces
1-C
4acyl group, carboxyl and carboxylate methyl ester base.
R
8for hydrogen, C
1-C
6alkyl or C
3-C
8cycloalkyl;
R
9for hydrogen, C
1-C
6alkyl, C
3-C
8cycloalkyl or C
1-C
4acyl group;
Described halogen is fluorine, chlorine, bromine or iodine.
In the preferred embodiment of the invention, compound of the present invention is the compound shown in following general formula (II):
Wherein,
R
1for pyridin-3-yl, cyclohexyl, cyclobutyl, cyclopropyl, C
1-C
4alkyl, 2-chloroethyl, benzyl, phenyl, phenoxymethyl, to fluorophenyl, difluoro cyclohexyl, indyl or C
1-C
4alkyl phenyl;
X is C (O), OC (O), NR
8c (O) or SO
2;
R
2for hydrogen or following groups unsubstituted or that replaced by 1-3 substituting group: C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl or C
3-C
8cycloalkyl, described substituting group is selected from: C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, amino, nitro, itrile group and hydroxyl;
G does not exist or is-CH
2cH
2-;
L is N or CH;
M does not exist or is N, CH or phenyl ring;
R
4do not exist or be hydrogen or unsubstituted or by the following groups of 1-3 substituting group replacement: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
10aryl, C
1-C
6alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl or carboxylate methyl ester base; Described substituting group is selected from: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
10aryl, halogen, amino, one or two C
1-C
6amino, C that alkyl replaces
1-C
4acyl group, nitro, itrile group, sulfydryl and hydroxyl;
R
5for hydrogen, C
1-C
6alkyl, C
3-C
8cycloalkyl, phenyl, benzyl, naphthyl, C
5-C
10aromaticity heterocyclic radical or C
4-C
7saturated heterocyclyl; Or R
5be connected M, Y, R
6and R
7form together 3-sec.-propyl-5-methyl-4-hydrogen-1,2,4-triazole-4-yl or 2-methyl-3-hydrogen-imidazoles [4,5-also] pyridin-3-yl; Described heterocycle comprises that 1-3 is selected from the heteroatoms in N, O and S;
Y is C (O), C (O) O, C (O) NH, NR
9or SO
2;
R
6do not exist or for unsubstituted or by the following groups of 1-3 substituting group replacement: C
1-C
6alkylidene group, C
2-C
6alkenylene or C
2-C
6alkynylene, described substituting group is selected from following atom or group: C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, amino, nitro, itrile group, sulfydryl and hydroxyl;
R
7do not exist or for unsubstituted or by the following groups of 1-3 substituting group replacement: C
1-C
6alkyl, C
3-C
8cycloalkyl, adamantyl, phenyl, benzyl, naphthyl, C
4-C
10aromaticity heterocyclic radical or C
4-C
7saturated heterocyclyl, described heterocycle comprises that 1-3 is selected from the heteroatoms in N, O and S, described substituting group is selected from following atom or group: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
10aryl, halogen, sulfydryl, hydroxyl, CF
3, CN, NO
2, amino, one or two C
1-C
6amino, C that alkyl replaces
1-C
4acyl group, carboxyl and carboxylate methyl ester base;
R
8for hydrogen, C
1-C
6alkyl or C
3-C
8cycloalkyl;
R
9for hydrogen, C
1-C
6alkyl, C
3-C
8cycloalkyl or C
1-C
4acyl group;
R
10and R
11be hydrogen, C independently of one another
1-C
6alkyl, C
1-C
6alkoxyl group, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
6alkane sulfydryl, halogen, sulfydryl, hydroxyl, CF
3, CN, NO
2, amino or carboxyl; Wherein C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
6alkoxyl group or C
1-C
6alkane sulfydryl is optionally by halogen, hydroxyl, amino, C
3-C
8cycloalkyl, cyano group or sulfydryl replace;
Described halogen is fluorine, chlorine, bromine or iodine.
For the compound shown in general formula (II), more preferably:
R
1for pyridin-3-yl, cyclohexyl, difluoro cyclohexyl, cyclobutyl, C
1-C
4alkyl, 2-chloroethyl, benzyl, phenyl, phenoxymethyl, to fluorophenyl or C
1-C
4alkyl phenyl, and be preferably cyclohexyl;
X is C (O), OC (O), NR
8c (O) or SO
2, and be preferably C (O);
R
2for hydrogen or following groups unsubstituted or that replaced by 1-3 substituting group: C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl or C
3-C
8cycloalkyl, described substituting group is selected from: C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, amino, nitro, itrile group and hydroxyl; And be preferably hydrogen;
G does not exist or is-CH
2cH
2-;
L is N or CH;
M does not exist or is N, CH or phenyl ring;
R
4for hydrogen or following groups unsubstituted or that replaced by 1-3 substituting group: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
10aryl, C
1-C
6alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, halogen, sulfydryl, hydroxyl, CF
3, CN, NO
2, amino, carboxyl or carboxylate methyl ester base; Described substituting group is selected from: C
1-C
6alkyl, C
1-C
6alkoxyl group, C
6-C
10aryl, halogen, amino, nitro, itrile group, sulfydryl and hydroxyl; And be preferably CH
3;
R
5for hydrogen, or R
5be connected M, Y, R
6and R
7form together 3-sec.-propyl-5-methyl-4-hydrogen-1,2,4-triazole-4-yl or 2-methyl-3-hydrogen-imidazoles [4,5-also] pyridin-3-yl;
Y is C (O), C (O) O, C (O) NH, NR
9or SO
2, and be preferably C (O);
R
6do not exist or for C
1-C
4the C that alkylidene group or hydroxyl replace
1-C
4alkylidene group;
R
7for following groups unsubstituted or that replaced by 1-3 substituting group: phenyl, naphthyl, adamantyl, morpholinyl, piperazinyl, piperidyl, pyrryl, thienyl, imidazolyl, triazolyl, tetrazyl, furyl, pyranyl, indyl, quinolyl, benzopyranyl, benzothienyl, benzofuryl, benzimidazolyl-or benzotriazole base, described substituting group is selected from following atom or group: C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, hydroxyl, CF
3, NO
2, amino, one or two C
1-C
6amino, C that alkyl replaces
1-C
4acyl group, carboxyl and carboxylate methyl ester base;
R
8for hydrogen or C
1-C
4alkyl,
R
9for hydrogen, C
1-C
4alkyl or C
1-C
4acyl group;
R
10for hydrogen, halogen, trifluoromethyl or C
1-C
4alkyl;
R
11for hydrogen or halogen.
In the present invention, particularly preferred particular compound is compound prepared by the embodiment of the present invention.Be specially:
The pharmacy acceptable salt of the 1-shown in general formula of the present invention (I) (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds, according to the pharmaceutically method preparation of conventional salify, can be the salt that compound of the present invention and hydrochloric acid, tartrate, Citric Acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid, sulfuric acid or methylsulfonic acid form.
In a second aspect of the present invention, the preparation method that 1-shown in general formula of the present invention (I) (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds or its pharmacy acceptable salt are provided, this preparation method comprises following method one and method two:
Method one:
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, X and Y definition described above;
P and P ' are tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzyl, 9-fluorenylmethyloxycarbonyl, CH independently
3cO-and CH
3one of them amino protecting group of OCO-;
Step is a): under organic bases or mineral alkali exist, and R
3there is Horner-Wadsworth-Emmons with diethyl phospho ethyl acetate and react in CHO, obtains α, β-unsaturated compound 1.Described organic bases or mineral alkali include but not limited to sodium hydride, potassium hydride KH, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, n-Butyl Lithium, tert-butyl lithium, the silica-based Lithamide of hexamethyl two, the silica-based sodium amide of hexamethyl two, lithium diisopropylamine or diethylamino lithium; Reaction solvent for use is DMF, methyl-sulphoxide, hexamethylphosphoramide, acetone, acetonitrile, methylene dichloride, ethylene dichloride, ether, ethyl acetate, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether or toluene; Temperature of reaction is-78～25 DEG C, and the reaction times is 0.5～12 hour.
Step is b): α, and β-unsaturated compound 1 exists lower generation Micheal addition reaction to obtain compound 2 with (R)-N-benzyl-1-phenylethylamine at organic bases (as n-Butyl Lithium, tert-butyl lithium, the silica-based Lithamide of hexamethyl two, the silica-based sodium amide of hexamethyl two, lithium diisopropylamine, diethylamino lithium, sodium hydride, sodium methylate, sodium ethylate or sodium tert-butoxide); Reaction solvent for use is tetrahydrofuran (THF), normal hexane, ether, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether or toluene; Temperature of reaction is-78～25 DEG C, and the reaction times is 0.5～12 hour.
Step is c): compound 2 hydrogenations remove after benzyl (Bn) and styroyl and R
1or R
2the aldehydes or ketones generation reduction amination or and the R that replace
1or R
2the acid generation linked reaction or and the R that replace
1or R
2the halohydrocarbon generation nucleophilic substitution reaction replacing, obtains N-trisubstituted amine compound 3.
Or
Step c '): compound 2 hydrogenations remove after benzyl and styroyl, and free amino connects upper protecting group P ' by linked reaction or nucleophilic substitution reaction, then with R
2the aldehydes or ketones generation reduction amination or and the R that replace
2the acid generation linked reaction or and the R that replace
2the halohydrocarbon generation nucleophilic substitution reaction replacing, obtains the N-trisubstituted amine compound 3 ' with amino protecting group P '.Described reduction amination reagent used comprises sodium triacetoxy borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE or sodium cyanoborohydride; Described linked reaction reagent used comprises 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), I-hydroxybenzotriazole (HOBt), dicyclohexylcarbodiimide (DCC), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or O-(7-azo benzotriazole-1-oxygen)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU); The alkali that described nucleophilic substitution reaction uses comprises sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, hydrated barta, sodium methylate, sodium ethylate, diethylamine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine or piperidines; The catalyzer that described hydrogenation uses comprises palladium carbon, hydroxide target or Raney's nickel; Reaction solvent for use comprises N, dinethylformamide, methyl-sulphoxide, hexamethylphosphoramide, acetone, acetonitrile, methylene dichloride, ethylene dichloride, ether, ethyl acetate, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or toluene; Temperature of reaction is-40～80 DEG C, and the reaction times is 0.5～24 hour.
Steps d): compound 3 or compound 3 ' prepare beta-amino aldehyde cpd 4 or compound 4 ' through oxidizing reaction after being reduced to alcohol by reductive agent again.Described reductive agent comprises sodium borohydride, POTASSIUM BOROHYDRIDE, zinc borohydride, lithium borohydride, lithium aluminum hydride, three tert.-butoxy lithium aluminum hydrides or di-isopropyl aluminum hydride; Reaction solvent for use comprises acetone, acetonitrile, ether, ethyl acetate, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or toluene; Temperature of reaction is-40～50 DEG C, and the reaction times is 0.5～12 hour.
Step is e): 4-piperidine carboxylic acid carries out, after esterification, amino protection is obtained to compound 5.
Step is f): compound 5 is introduced R in the α position of ester group under the effect of alkali or by nucleophilic substitution reaction
4obtain compound 6.Described alkali comprises sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, hydrated barta, sodium methylate, sodium ethylate, diethylamine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine or piperidines; Reaction solvent for use comprises N, dinethylformamide, methyl-sulphoxide, hexamethylphosphoramide, acetone, acetonitrile, methylene dichloride, ethylene dichloride, ether, ethyl acetate, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or toluene; Temperature of reaction is 0～80 DEG C, and the reaction times is 0.5～24 hour.
Step g): compound 6 obtains carboxylic acid cpd 7 by saponification reaction ester hydrolysis under the effect of alkali.Described alkali comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or hydrated barta; Reaction solvent for use comprises acetone, acetonitrile, ether, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or toluene; Temperature of reaction is-15～40 DEG C, and the reaction times is 0.5～8 hour.
Step is h): carboxylic acid cpd 7 is prepared into acid amides triazo-compound by mixed anhydride method or chloride method or active ester method, and this compound is reset the isocyanic ester obtaining and is hydrolyzed and obtains aminocompound 8 under the effect of alkali by Ku Ertisi.The reagent that reaction is used comprises isobutyl chlorocarbonate, chloroformic acid benzyl ester, sodiumazide or potassium azide; Described alkali comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or hydrated barta; Reaction solvent for use comprises N, dinethylformamide, methyl-sulphoxide, hexamethylphosphoramide, acetone, acetonitrile, methylene dichloride, ethylene dichloride, ether, ethyl acetate, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or toluene; Temperature of reaction is-15～110 DEG C, and the reaction times is 0.5～24 hour.
Step I): aminocompound 8 with contain R
5compound and contain-R
6-R
7compound react respectively, generate compound 9.
Step is j): after compound 9 deprotection base P, with beta-amino aldehyde cpd 4, reduction amination occurs and obtain end product 1-(3-(S)-aminopropyl)-piperidine-4-aminoamide compounds; Described reduction amination reagent used comprises sodium triacetoxy borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE or sodium cyanoborohydride; Reaction solvent for use comprises N, dinethylformamide, methyl-sulphoxide, hexamethylphosphoramide, acetone, acetonitrile, methylene dichloride, ethylene dichloride, ether, ethyl acetate, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or toluene; Temperature of reaction is 0～40 DEG C, and the reaction times is 0.5～24 hour.
Step j '): after compound 9 deprotection base P, there is reduction amination with beta-amino aldehyde cpd 4 ', then deaminize protecting group P ', and then and R
1the aldehydes or ketones generation reduction amination or and the R that replace
1the acid generation linked reaction or and the R that replace
1the halohydrocarbon generation nucleophilic substitution reaction replacing, obtains final product 1-(3-(S)-aminopropyl)-piperidine-4-aminoamide compounds.Described reduction amination reagent used comprises sodium triacetoxy borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE or sodium cyanoborohydride; Described linked reaction reagent used comprises 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), I-hydroxybenzotriazole (HOBt), dicyclohexylcarbodiimide (DCC), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or O-(7-azo benzotriazole-1-oxygen)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU); The alkali that described nucleophilic substitution reaction uses comprises sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, hydrated barta, sodium methylate, sodium ethylate, diethylamine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine or piperidines; The catalyzer that described hydrogenation uses comprises palladium carbon, hydroxide target or Raney's nickel; Reaction solvent for use comprises N, dinethylformamide, methyl-sulphoxide, hexamethylphosphoramide, acetone, acetonitrile, methylene dichloride, ethylene dichloride, ether, ethyl acetate, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or toluene; Temperature of reaction is-15～80 DEG C, and the reaction times is 0.5～24 hour.
Method two:
Wherein, R
1, R
2, R
3, R
5, R
6, R
7, X and Y definition described above;
Step is a): the piperidone that has protecting group P on N-atom with contain R
5amine by reduction amination coupling, then with contain-R
6-R
7carbonyl compound generation condensation reaction obtain compound 10a; Described reduction amination reagent used comprises sodium triacetoxy borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE or sodium cyanoborohydride; Reaction solvent for use comprises N, dinethylformamide, methyl-sulphoxide, hexamethylphosphoramide, acetone, acetonitrile, methylene dichloride, ethylene dichloride, ether, ethyl acetate, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or toluene; Temperature of reaction is 0～40 DEG C, and the reaction times is 0.5～24 hour.
Step is b): compound 10a sloughs protecting group P and obtains compound 10b,
Step is c): then compound 10b with beta-amino aldehyde cpd 4, reduction amination occurs and obtain end product 1-(3-(S)-aminopropyl)-piperidine-4-aminoamide compounds.Described reduction amination reagent used comprises sodium triacetoxy borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE or sodium cyanoborohydride; Reaction solvent for use comprises N, dinethylformamide, methyl-sulphoxide, hexamethylphosphoramide, acetone, acetonitrile, methylene dichloride, ethylene dichloride, ether, ethyl acetate, tetrahydrofuran (THF), normal hexane, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or toluene; Temperature of reaction is 0～40 DEG C, and the reaction times is 0.5～24 hour.
In a third aspect of the present invention, a kind of pharmaceutical composition that suppresses CCR5 activity that has is provided, it comprises the 1-shown in one or more general formulas (I) for the treatment of significant quantity (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds or its pharmacy acceptable salt, and can further comprise pharmaceutically acceptable carrier, can also comprise proteinase inhibitor and/or reverse transcriptase inhibitors.
In a fourth aspect of the present invention, the purposes of (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds of the 1-shown in a kind of general formula of the present invention (I) or its pharmacy acceptable salt is provided, it is as the antagonist of CCR5, in the application of preparing in the medicine for the treatment of the disease being mediated by CCR5.More specifically, for the preparation of the medicine for the treatment of HIV infection, asthma, rheumatoid arthritis, autoimmune disorder and chronic obstructive pulmonary disease (COPD).
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that these embodiment only do not limit the scope of the invention for the present invention is described.
Preparation Example
Embodiment 1
Compound I-1a:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) benzamide
Step 1:(E)-3-(3-fluorophenyl) ethyl propenoate (1a)
Under nitrogen protection; by sodium hydride (0.48g; 12mmol) add and be dissolved with diethyl phospho ethyl acetate (2.69g; in dry tetrahydrofuran (20mL) 12mmol); 0 DEG C is stirred 0.5 hour; dry tetrahydrofuran (10mL) solution that is dissolved with 3-fluorobenzaldehyde (1.24g, 10mmol) is slowly added dropwise to above-mentioned reaction system, and 0 DEG C is stirred 3 hours.Be warming up to room temperature, use successively saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate drying, concentrates to obtain yellow oily liquid, i.e. compound 1a (1.94g, yield 100%).
1HNMR(CDCl
3，300MHz)δ：1.34(t，3H，J＝7.2Hz)，4.27(q，2H，J＝7.2Hz)，6.42(d，1H，J＝15.9Hz)，7.04-7.10(m，1H)，7.19-7.39(m，3H)，7.63(d，1H，J＝15.9Hz).
Step 2:(S)-3-(benzyl ((R)-1-styroyl) amino)-3-(3-fluorophenyl) ethyl propionate (2a)
By (R)-N-benzyl-1-phenylethylamine (2.467g, 11.7mmol) be dissolved in dry tetrahydrofuran (20mL) solution, be cooled to-78 DEG C, to the n-BuLi (n-Butyl Lithium) (8mL, 12.7mmol) that drips 1.6M in system.Be warming up to room temperature, dry tetrahydrofuran (20mL) solution that is dissolved with compound 1a (2.062g, 10.6mmol) is added dropwise to above-mentioned reaction system, be cooled to-78 DEG C of reactions 2 hours.To react cancellation, organic phase saturated common salt water washing, anhydrous sodium sulfate drying with saturated ammonium chloride, concentrated, silica gel column chromatography (petrol ether/ethyl acetate=30: 1), obtain yellow oily liquid, be compound 2a (2.753g, yield 64%).[α]
D 23＝+2.3°(c＝1.0，CHCl
3)；
1HNMR(CDCl
3，300MHz)δ：1.08(t，3H，J＝7.1Hz)，1.27(d，3H，J＝6.9Hz)，2.50-2.66(m，2H)，3.70(qAB，2H，J＝14.6Hz)，3.93-4.01(m，3H)，4.46(dd，1H，J＝5.4Hz，9.5Hz)，6.92-6.99(m，1H)，7.14-7.43(m，13H).
Step 3:(S)-3-(cyclohexanecarbonyl amine)-3-(3-fluorophenyl) ethyl propionate (3a)
Compound 2a (2.753g, 6.8mmol) is dissolved in ethanol (40mL), adds Pd (OH)
2(280mg), normal pressure hydrogenation 12 hours, reacting liquid filtering is removed Pd (OH)
2ethanol is removed in decompression, in said mixture, add methylene dichloride (20mL), add successively heptanaphthenic acid (1.04g, 8.2mmol), EDCI (1-ethyl-3-(3-dimethyl propylamine) carbodiimide hydrochloride) (1.95g, 10.2mmol), HOBt (I-hydroxybenzotriazole) (1.38g, 10.2mmol) and nitrogen methylmorpholine (1.8mL, 13.6mmol), stirring at room temperature 12 hours.Decompression is removed methylene dichloride resistates and is separated (ethyl acetate/petroleum ether=5/1, v/v) through silica gel column chromatography, and obtaining product is white solid, i.e. compound 3a (1.44g, yield 66%).
1HNMR(CDCl
3，300MHz)δ：1.19(t，3H，J＝7.2Hz)，1.23-1.37(m，3H)，1.40-1.52(m，2H)，1.66-1.71(m，1H)，1.78-1.84(m，2H)，1.89-1.94(m，2H)，2.12-2.22(m，1H)，2.77-2.92(m，2H)，4.09(q，2H，J＝7.2Hz)，5.39-5.45(m，1H)，6.75-6.78(m，1H)，6.92-7.01(m，2H)，7.05-7.08(m，1H)，7.26-7.33(m，1H).
Step 4:(S)-N-(1-(3-fluorophenyl)-3-oxopropyl) cyclohexanecarbonyl amine (4a)
Under ice bath, by lithium aluminium hydride (105mg, dry tetrahydrofuran (6mL) solution 2.75mmol) is slowly added dropwise in dry tetrahydrofuran (20mL) solution that is dissolved with compound 3a (840mg, 2.62mmol).Be warming up to room temperature, stir 2 hours.Water will react cancellation, and 15% aqueous sodium hydroxide washes is washed, and filter.Organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, obtain yellow oily liquid.-78 DEG C time, methyl-sulphoxide (0.25ml, 3.51mmol) is added in dry methylene chloride (5mL) solution that is dissolved with oxalyl chloride (0.23ml, 2.63mmol), stir 1 hour.Dry methylene chloride (5mL) solution that is dissolved with above-mentioned product is slowly added dropwise to above-mentioned reaction system, stirs and add triethylamine (0.98ml, 7.03mmol) after 3 hours.Be warming up to room temperature, use successively saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, obtain white solid, i.e. compound 4a (370mg, yield 51%).
The step 5:1-carbonic acid tert-butyl ester-piperidines-4-methyl carbonate (5a)
-10 DEG C time, thionyl chloride (4.0mL) is slowly dropped in anhydrous methanol (30.0mL),-10 DEG C time, stir 1 hour, 4-piperidine carboxylic acid (6.45g, 50.0mL) is added in system, reflux 2 hours, stirred overnight at room temperature, concentrated, ether washing 3 times for resistates, dry, obtain white solid.Above-mentioned solid is dissolved in to Isosorbide-5-Nitrae-dioxane/water (70.0mL/24.0mL), 0 DEG C time, adds triethylamine (13.76mL, 96.8mmol), stir 15 minutes, add (Boc) in batches
2o (dimethyl dicarbonate butyl ester) (11.3g, 51.77mmol), room temperature reaction 6 hours.System is concentrated, remove Isosorbide-5-Nitrae-dioxane, resistates is extracted with ethyl acetate, and merges organic phase, and saturated sodium bicarbonate solution is washed, saturated common salt washing, anhydrous sodium sulfate drying, concentrated, obtain colorless oil product 5a (11.98g, yield 100.0%).
1HNMR(CDCl
3，300MHz)δ：1.47(s，9H)，1.58-1.68(m，2H)，1.86-1.91(m，2H).2.46(tt，1H，J＝11.2Hz，4.0Hz)，2.84(ddd，2H，J＝13.6Hz，11.6Hz，3.2Hz)，3.70(s，3H)，4.03(dt，2H，J＝13.6Hz，3.6Hz).
The step 6:1-carbonic acid tert-butyl ester-4-methyl-piperidines-4-methyl carbonate (6a)
Under nitrogen protection; diisopropylamine (11.06mL; 78.88mmol) be dissolved in dry tetrahydrofuran (40.0mL); cryosel is bathed and is chilled to-15 DEG C; by the n-BuLi (46.0mL of 1.6M; 73.6mmol) slowly drop in system ,-15 DEG C are stirred 1 hour, make LDA (diisopropyl ethyl amine).
Under nitrogen protection, compound 5a (12.59g, 49.0mmol) is dissolved in to dry tetrahydrofuran (75.0mL); be cooled to-50 DEG C; the LDA of above-mentioned preparation is slowly dropped in system, and-50 DEG C～-40 DEG C are stirred 1 hour, are cooled to-78 DEG C.By methyl iodide (6.10mL, dry tetrahydrofuran (50.0mL) solution 98.0mmol) slowly drops in system,-78 DEG C are stirred 1 hour, be warming up to room temperature, TLC follows the tracks of to react to raw material and all disappears, and will react cancellation with the hydrochloric acid soln of 1N, concentrates, remove tetrahydrofuran (THF), resistates extracted with diethyl ether, merges organic phase, saturated common salt washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography (petrol ether/ethyl acetate=10: 1), obtain colorless oil, be compound 6a (11.42g, yield 86.0%).
Step 7:1-tert-butoxycarbonyl-4-methyl piperidine-4-formic acid (7a)
Compound 6a (5.77g, 22.4mmol) is dissolved in methyl alcohol (20.0mL), under room temperature condition, the LiOH solution (28.0mL) of 2N is dropped in system, stirring at room temperature 1 hour, concentrated, remove methyl alcohol, resistates extracted with diethyl ether, water is adjusted pH to 1-2 with 1N hydrochloric acid, and dichloromethane extraction merges organic phase, saturated common salt washing, anhydrous sodium sulfate drying, concentrates to obtain white solid 7a (4.79g, yield 88.0%).
1HNMR(CDCl
3，300MHz)δ：1.27(s，3H)，1.35-1.42(m，2H)，1.49(s，9H)，2.07(m，2H)，2.98-3.08(m，2H)，3.76-3.84(m，2H).EI-MS(M/Z)：243(M
+).IR(KBr)：3427，2976，1653，1443，1282，1173，1088，874，764cm
-1.
Step 8:4-amino-4-methyl piperidine-1-carbonic acid tert-butyl ester (8a)
Compound 7a (1.215g, 5.0mmol) be dissolved in dry tetrahydrofuran (25.0mL), be cooled to-15 DEG C, in system, drip N-methylmorpholine (0.58mL, 5.25mmol), stir 15 minutes, drip isobutyl chlorocarbonate (0.69mL, 5.25mmol),-15 DEG C are stirred 1 hour, 0 DEG C drips sodiumazide (0.488g, water (4.0mL) solution 7.5mmol), stir 1.5 hours, reactant is poured in frozen water, extracted with diethyl ether, merge organic phase, saturated sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying, concentrated under room temperature condition, obtain oily trinitride.Crude product trinitride is dissolved in dry toluene (25.0mL), and 90 DEG C are stirred 1 hour, concentrated, remove toluene, obtain oily isocyanic ester.Isocyanic ester is dissolved in the tetrahydrofuran (THF)/water (10.0mL/10.0mL) of ice, the potassium hydroxide solution of the 10N of ice is dropped in system, 0 DEG C is stirred 0.5 hour, system evaporate to dryness, methyl alcohol and washed with dichloromethane for resistates, concentrated, silica gel column chromatography (methylene chloride/methanol=30: 1), obtain white solid 8a (1.899g, yield 89.0%).
1hNMR (CDCl
3, 300MHz) and δ: 1.23 (s, 3H), 1.44 (s, 9H), 1.41-1.54 (m, 4H), 2.25 (s, 2H), 3.42 (m, 4H) .EI-MS (M/Z): 214 (M
+) .HR-EI-MS calculated value: C
11h
22n
2o
4: 214.1681, measured value: 214.1686.
Step 9: compound 9a:4-benzamide-4-methyl piperidine-1-carbonic acid tert-butyl ester
By compound 8a (214mg, 1mmo1), add methylene dichloride (5mL), add successively phenylformic acid (146mg, 1.2mmol), EDCI (1-ethyl-3-(3-dimethyl propylamine) carbodiimide hydrochloride) (287mg, 1.5mmol), HOBt (I-hydroxybenzotriazole) (203mg, 1.5mmol) with nitrogen methylmorpholine (0.22mL, 2mmol), stirring at room temperature 12 hours.Decompression is removed methylene dichloride resistates and is separated (ethyl acetate/petroleum ether=2/1, v/v) through silica gel column chromatography, and obtaining product is white solid, i.e. compound 9a (195mg, yield 61%).
1HNMR(CDCl
3，300MHz)δ：1.47(s，9H)，1.55(s，3H)，1.64-1.74(m，2H)，2.18-2.23(m，2H)，3.17-3.26(m，2H)，3.75(dt，2H，J＝4.8Hz，13.5Hz)，5.83(br，1H)，7.42-7.54(m，3H)，7.73-7.75(m，2H).
Step 10: Compound I-1a:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) benzamide
In methylene dichloride (5mL) solution that is dissolved with compound 9a (191mg, 0.6mmol), add trifluoroacetic acid (0.18mL, 2.4mmol), stirred overnight at room temperature.Reaction system is spin-dried for, and adds saturated sodium carbonate solution regulator solution pH to alkalescence.Dichloromethane extraction 3 times, merges organic phase, saturated common salt washing, and anhydrous sodium sulfate drying, concentrates to obtain white solid.Above-mentioned product is added and is dissolved with compound 4a (177mg, 0.64mmol), in ethylene dichloride (5mL) solution of sodium triacetoxy borohydride (270mg, 1.27mmol) and acetic acid (74 μ L, 1.27mmol).Under room temperature, stir reaction system saturated sodium bicarbonate successively, saturated common salt water washing 22 hours, anhydrous sodium sulfate drying, concentrated rear silica gel column chromatography (methylene chloride/methanol=20: 1), obtain white solid, be Compound I-1a (132mg, yield 48%).Mp：89-91℃；[α]
D 22＝-17.7°(c＝0.35，CHCl
3)；
1HNMR(CDCl
3，300MHz)δ：1.24-1.29(m，3H)，1.41-1.51(m，2H)，1.54(m，3H)，1.76-1.83(m，6H)，1.91-1.95(m，2H)，2.10-2.19(m，2H)，2.26-2.41(m，6H)，2.61-2.65(m，1H)，2.78-2.82(m，1H)，5.07-5.09(m，1H)，5.89(s，1H)，6.93(d，2H，J＝9.0Hz)，7.01(d，1H，J＝7.5Hz)，7.24-7.31(m，1H)，7.43-7.51(m，3H)，7.73(d，2H，J＝7.5Hz)，8.19(d，1H，J＝6.3Hz).EI-MS(M/Z)：479(M
+).
Embodiment 2
Compound I-1b:(S) the chloro-N-of-2-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) benzamide
Step 1:4-(2-chlorobenzamide)-4-methyl piperidine-1-carbonic acid tert-butyl ester (9b)
Adopt the method identical with step 9 in embodiment 1, except adopting 2-chloro-benzoic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (188mg, yield 53%);
1hNMR (CDCl
3, 300MHz) and δ: 1.49 (s, 9H), 1.57 (s, 3H), 1.61-1.71 (m, 2H), 2.20-2.25 (m, 2H), 3.18-3.27 (m, 2H), 3.81 (dt, 2H, J=4.8Hz, 14.1Hz), 5.86 (br, 1H), 7.32-7.44 (m, 3H), 7.64-7.67 (m, 1H).
Step 2: Compound I-1b:(S) the chloro-N-of-2-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) benzamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9b to replace the compound 9a of embodiment 1 step 10.
White solid (173mg, yield 75%), Mp:85-87 DEG C, [α]
d 22=-18.9 ° of (c=0.65, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.41-1.51 (m, 3H), 1.58 (s, 3H), 1.69-1.73 (m, 2H), 1.81-1.85 (m, 5H), 1.92-1.96 (m, 3H), 2.09-2.20 (m, 2H), 2.30-2.41 (m, 6H), 2.64-2.69 (m, 1H), 2.81-2.85 (m, 1H), 5.07-5.13 (m, 1H), 5.85 (s, 1H), 6.94 (d, 1H, J=9.3Hz), 7.03 (d, 1H, J=6.9Hz), 7.30-7.43 (m, 4H), 7.62-7.65 (m, 1H), 8.16 (d, 1H, J=6.0Hz) .EI-MS (M/Z): 513 (M
+).
Embodiment 3
Compound I-1c:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-methyl benzamide
Step 1:4-methyl-4-(4-methylbenzene acid amides) piperidines-1-carbonic acid tert-butyl ester (9c)
Adopt the method identical with step 9 in embodiment 1, except adopting 4-tolyl acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (242mg, yield 73%);
1hNMR (CDCl
3, 300MHz) and δ: 1.47 (s, 9H), 1.53 (s, 3H), 1.63-1.72 (m, 2H), 2.17-2.23 (m, 2H), 2.41 (s, 3H), 3.16-3.25 (m, 2H), 3.72-3.77 (m, 2H), 5.79 (br, 1H), 7.24 (d, 2H, J=8.1Hz), 7.63 (d, 2H, J=8.1Hz).
Step 2: Compound I-1c:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-methyl benzamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9c to replace the compound 9a of embodiment 1 step 10.
White solid (165mg, yield 46%), Mp:91-93 DEG C, [α]
d 22=-14.8 ° of (c=0.65, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.25-1.33 (m, 4H), 1.42-1.50 (m, 2H), 1.54 (s, 3H), 1.77-1.84 (m, 6H), 1.91-1.95 (m, 2H), 2.11-2.15 (m, 2H), 2.20-2.35 (m, 5H), 2.40 (s, 3H), 2.62-2.66 (m, 1H), 2.79-2.82 (m, 1H), 5.07-5.09 (m, 1H), 5.83 (s, 1H), 6.93 (d, 2H, J=8.7Hz), 7.01 (d, 1H, J=6.9Hz), 7.22-7.28 (m, 3H), 7.63 (d, 2H, J=7.5Hz), 8.19 (d, 1H, J=6.3Hz) .EI-MS (M/Z): 493 (M
+).
Embodiment 4
Compound I-1d:(S) the chloro-N-of-4-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-benzamide
Step 1:4-(4-chlorobenzamide)-4-methyl piperidine-1-carbonic acid tert-butyl ester (9d)
Adopt the method identical with step 9 in embodiment 1, except adopting 4-chloro-benzoic acid to replace the phenylformic acid of embodiment 1 step 9.
Colourless oil liquid (315mg, yield 89%);
1hNMR (CDCl
3, 300MHz) and δ: 1.46 (s, 9H), 1.52 (s, 3H), 1.63-1.72 (m, 2H), 2.13-2.19 (m, 2H), 3.16-3.25 (m, 2H), 3.68-3.73 (m, 2H), 5.75 (br, 1H), 7.40 (d, 2H, J=8.7Hz), 7.66 (d, 2H, J=8.7Hz).
Step 2: Compound I-1d:(S) the chloro-N-of-4-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-benzamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9d to replace the compound 9a of embodiment 1 step 10.
White solid (132mg, yield 45%), Mp:90-92 DEG C, [α]
d 22=-15.4 ° of (c=1.1, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.39-1.47 (m, 3H), 1.54 (s, 3H), 1.67-1.71 (m, 3H), 1.80-1.94 (m, 8H), 2.10-2.19 (m, 2H), 2.30-2.40 (m, 5H), 2.65-2.68 (m, 1H), 2.80-2.84 (m, 1H), 5.04-5.11 (m, 1H), 5.76 (br, 1H), 6.93 (d, 2H, J=9.0Hz), 7.01 (d, 1H, J=7.5Hz), 7.29-7.32 (m, 1H), 7.41 (d, 2H, J=8.4Hz), 7.66 (d, 2H, J=8.4Hz), 7.99 (br, 1H) .EI-MS (M/Z): 513 (M
+).
Embodiment 5
Compound I-1e:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-2-nitrobenzamide
Step 1:4-methyl-4-(2-oil of mirbane acid amides) piperidines-1-carbonic acid tert-butyl ester (9e)
Adopt the method identical with step 9 in embodiment 1, except adopting the phenylformic acid of 2-nitrobenzoyl acid substitution embodiment 1 step 9.
White foam shape solid (228mg, yield 63%);
1hNMR (CDCl
3, 300MHz) and δ: 1.48 (s, 9H), 1.59 (s, 3H), 1.63-1.73 (m, 2H), 2.15-2.19 (m, 2H), 3.21-3.30 (m, 2H), 3.70-3.78 (m, 2H), 5.50 (br, 1H), 7.50-7.53 (m, 1H), 7.58-7.61 (m, 1H), 7.66-7.72 (m, 1H), 8.08 (d, 1H, J=9.0Hz).
Step 2: Compound I-1e:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-2-nitrobenzamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9e to replace the compound 9a of embodiment 1 step 10.
White solid (46mg, yield 46%), Mp:113-115 DEG C, [α]
d 22=-19 ° of (c=0.1, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.45-1.50 (m, 3H), 1.60 (s, 3H), 1.66-1.68 (m, 4H), 1.81-1.84 (m, 3H), 1.90-1.94 (m, 3H), 2.12-2.17 (m, 2H), 2.37-2.41 (m, 6H), 2.69-2.73 (m, 1H), 2.84-2.87 (m, 1H), 5.04-5.10 (m, 1H), 5.50 (br, 1H), 6.95 (d, 2H, J=9.3Hz), 7.04 (d, 1H, J=8.1Hz), 7.30-7.33 (m, 2H), 7.51 (d, 1H, J=6.6Hz), 7.57-7.72 (m, 2H), 8.08 (d, 1H, J=8.1Hz) .EI-MS (M/Z): 525 (M+1)
+, 524 (M
+).
Embodiment 6
Compound I-1f:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-fluorobenzamide
Step 1:4-(4-fluorobenzene acid amides)-4-methyl piperidine-1-carbonic acid tert-butyl ester (9f)
Adopt the method identical with step 9 in embodiment 1, except adopting 4-fluorobenzoic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (148mg, yield 44%);
1hNMR (CDCl
3, 300MHz) and δ: 1.47 (s, 9H), 1.54 (s, 3H), 1.65-1.74 (m, 2H), 2.16-2.20 (m, 2H), 3.18-3.27 (m, 2H), 3.71-3.75 (m, 2H), 5.75 (br, 1H), 7.12 (t, 2H, J=8.4Hz), 7.74 (dd, 2H, J=5.4Hz, 8.6Hz).
Step 2: Compound I-1f:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-fluorobenzamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9f to replace the compound 9a of embodiment 1 step 10.
White solid (89mg, yield 53%), Mp:84-86 DEG C, [α]
d 22=-20 ° of (c=1.1, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.45-1.50 (m, 3H), 1.55 (s, 3H), 1.68-1.72 (m, 2H), 1.80-1.84 (m, 4H), 1.90-1.94 (m, 4H), 2.13-2.16 (m, 2H), 2.33-2.42 (m, 6H), 2.69-2.72 (m, 1H), 2.84-2.87 (m, 1H), 5.05-5.11 (m, 1H), 5.75 (s, 1H), 6.94 (d, 2H, J=9.6Hz), 7.03 (d, 1H, J=7.5Hz), 7.12 (t, 2H, J=8.1Hz), 7.30-7.33 (m, 1H), 7.72-7.76 (m, 2H), 7.99 (br, 1H) .EI-MS (M/Z): 497 (M
+).
Embodiment 7
Compound I-1g:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-2-iodobenzene methane amide
Step 1:4-(2-iodobenzene acid amides)-4-methyl piperidine-1-carbonic acid tert-butyl ester (9g)
Adopt the method identical with step 9 in embodiment 1, except adopting 2-iodo-benzoic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (165mg, yield 37%);
1hNMR (CDCl
3, 300MHz) and δ: 1.48 (s, 9H), 1.59 (s, 3H), 1.63-1.73 (m, 2H), 2.18-2.23 (m, 2H), 3.25-3.34 (m, 2H), 3.71-3.79 (m, 2H), 5.43 (br, 1H), 7.08-7.14 (m, 1H), 7.40 (d, 2H, J=3.9Hz), 7.87 (d, 1H, J=8.7Hz).
Step 2: Compound I-1g:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-2-iodobenzene methane amide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9g to replace the compound 9a of embodiment 1 step 10.
White solid (100mg, yield 59%), Mp:87-89 DEG C, [α]
d 22=-17.7 ° of (c=0.6, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.44-1.51 (m, 4H), 1.60 (s, 3H), 1.66-1.72 (m, 3H), 1.81-1.85 (m, 3H), 1.90-1.94 (m, 4H), 2.13-2.22 (m, 2H), 2.39-2.55 (m, 5H), 2.74-2.77 (m, 1H), 2.87-2.90 (m, 1H), 5.05-5.11 (m, 1H), 5.43 (br, 1H), 6.95 (d, 2H, J=9.0Hz), 7.05 (d, 1H, J=g.4Hz), 7.09-7.15 (m, 1H), 7.28-7.29 (m, 1H), 7.38-7.41 (m, 2H), 7.87 (d, 1H, J=8.7Hz) .EI-MS (M/Z): 605 (M
+).
Embodiment 8
Compound I-1h:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-iodobenzene methane amide
Step 1:4-(4-iodobenzene acid amides)-4-methyl piperidine-1-carbonic acid tert-butyl ester (9h)
Adopt the method identical with step 9 in embodiment 1, except adopting 4-iodo-benzoic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (352mg, yield 79%);
1hNMR (CDCl
3, 300MHz) and δ: 1.45 (s, 9H), 1.51 (s, 3H), 1.64-1.67 (m, 2H), 2.14-2.17 (m, 2H), 3.15-3.23 (m, 2H), 3.68-3.72 (m, 2H), 5.78 (br, 1H), 7.43 (d, 1H, J=8.4Hz), 7.77 (d, 1H, J=8.4Hz).
Step 2: Compound I-1h:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-iodobenzene methane amide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9h to replace the compound 9a of embodiment 1 step 10.
White solid (148mg, yield 60%), Mp:82-84 DEG C, [α]
d 22=-12.1 ° of (c=0.75, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.44-1.51 (m, 2H), 1.55 (s, 3H), 1.69-1.72 (m, 3H), 1.81-1.91 (m, 8H), 2.08-2.17 (m, 2H), 2.33-2.42 (m, 6H), 2.69-2.72 (m, 1H), 2.82-2.86 (m, 1H), 5.04-5.10 (m, 1H), 5.78 (s, 1H), 6.94 (d, 2H, J=9.0Hz), 7.03 (d, 1H, J=8.1Hz), 7.30-7.33 (m, 1H), 7.46 (d, 2H, J=8.4Hz), 7.80 (d, 2H, J=8.4Hz), 7.96 (br, 1H) .EI-MS (M/Z): 605 (M
+).
Embodiment 9
Compound I-1i:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-3-dimethylamino benzamide
Step 1:4-(3-dimethylamino benzamide)-4-methyl piperidine-1-carbonic acid tert-butyl ester (9i)
Adopt the method identical with step 9 in embodiment 1, except adopting 3-dimethylaminobenzoic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (248mg, yield 69%)
Step 2: Compound I-1i:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-3-dimethylamino benzamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9i to replace the compound 9a of embodiment 1 step 10.
White solid (85mg, yield 43%), Mp:89-91 DEG C, [α]
d 22=-21.8 ° of (c=0.4, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.23-1.31 (m, 3H), 1.44-1.48 (m, 2H), 1.53 (s, 3H), 1.70-1.83 (m, 6H), 1.90-1.94 (m, 2H), 2.07-2.14 (m, 2H), 2.30-2.40 (m, 6H), 2.60-2.64 (m, 1H), 2.78-2.80 (m, 1H), 2.98 (s, 6H), 5.06-5.08 (m, 1H), 5.86 (s, 1H), 6.83 (d, 1H, J=7.8Hz), 6.90-6.93 (m, 3H), 7.00 (d, 1H, J=6.6Hz), 7.18-7.27 (m, 3H), 8.20 (br, 1H) .EI-MS (M/Z, %): 522 (M
+).
Embodiment 10
Compound I-1j:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-3,4,5-trimethoxy-benzamide
Step 1:4-methyl-4-(3,4,5-trimethoxy benzamide) piperidines-1-carbonic acid tert-butyl ester (9j)
Adopt the method identical with step 9 in embodiment 1, except adopting 3,4,5-trimethoxybenzoic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (296mg, yield 73%);
1hNMR (CDCl
3, 300MHz) and δ: 1.48 (s, 9H), 1.55 (s, 3H), 1.69-1.76 (m, 2H), 2.17-2.21 (m, 2H), 3.19-3.28 (m, 2H), 3.69-3.77 (m, 2H), 3.89 (s, 3H), 3.93 (s, 6H), 5.73 (br, 1H), 6.95 (s, 2H).
Step 2: Compound I-1j:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-3,4,5-trimethoxy-benzamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9j to replace the compound 9a of embodiment 1 step 10.
White solid (212mg, yield 64%), Mp:77-79 DEG C, [α]
d 22=-14.8 ° of (c=1, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.24-1.48 (m, 5H), 1.53 (s, 3H), 1.66-1.69 (m, 1H), 1.78-1.90 (m, 7H), 2.06-2.22 (m, 2H), 2.36-2.52 (m, 6H), 2.75-2.78 (m, 1H), 2.85-2.89 (m, 1H), 3.87 (s, 3H), 3.89 (s, 6H), 4.94-5.00 (m, 1H), 5.99 (br, 1H), 6.91-7.02 (m, 5H), 7.23-7.30 (m, 1H), 7.86 (d, 1H, J=7.2Hz) .EI-MS (M/Z): 569 (M
+).
Embodiment 11
Compound I-1k:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-methoxy benzamide
Step 1:4-(4-anisole acid amides) 4-methyl piperidine-1-carbonic acid tert-butyl ester (9k)
Adopt the method identical with step 9 in embodiment 1, except adopting 4-methoxybenzoic acid to replace the phenylformic acid of embodiment 1 step 9.
Colourless oil liquid (200mg, yield 57%);
1hNMR (CDCl
3, 300MHz) and δ: 1.47 (s, 9H), 1.53 (s, 3H), 1.62-1.72 (m, 2H), 2.18-2.22 (m, 2H), 3.16-3.25 (m, 2H), 3.71-3.76 (m, 2H), 3.86 (s, 3H), 5.75 (br, 1H), 6.92 (d, 2H, J=9.0Hz), 7.70 (d, 2H, J=9.0Hz).
Step 2: Compound I-1k:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-methoxy benzamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9k to replace the compound 9a of embodiment 1 step 10.
White solid (140mg, yield 69%), Mp:67-69 DEG C, [α]
d 21=-15.1 ° of (c=0.95, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.17-1.30 (m, 3H), 1.41-1.48 (m, 2H), 1.52 (s, 3H), 1.66-1.69 (m, 1H), 1.77-1.90 (m, 7H), 2.07-2.22 (m, 2H), 2.36-2.46 (m, 3H), 2.50-2.54 (m, 3H), 2.76-2.80 (m, 1H), 2.86-2.90 (m, 1H), 3.84 (s, 3H), 4.95-5.01 (m, 1H), 5.91 (br, 1H), 6.89-6.94 (m, 3H), 7.01 (d, 1H, J=7.5Hz), 7.23-7.30 (m, 1H), 7.69 (d, 2H, J=g.7Hz), 7.95 (d, 1H, J=7.5Hz).
13cNMR (CD
3oD, 100MHz) δ: 179.4,171.0,164.8 (d,
1j
cF=243.6Hz), 164.3,146.6 (d,
3j
cF=6.4Hz), 132.0 (d,
3j
cF=8.2Hz), 130.8,129.2,124.0,115.7 (d,
2j
cF=21.4Hz), 115.1,114.9 (d,
2j
cF=22.4Hz), 56.4,56.1,52.5,52.4,51.1,50.9,46.7,35.2,32.6,31.2,31.1,27.3,27.2,27.1.EI-MS (M/Z): 509 (M
+).
Embodiment 12
Compound I-1l:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) niacinamide
Step 1:4-methyl-4-(niacinamide) piperidines-1-carbonic acid tert-butyl ester (9l)
Adopt the method identical with step 9 in embodiment 1, except adopting nicotinic acid to replace the phenylformic acid of embodiment 1 step 9.
Colourless oil liquid (202mg, yield 63%);
1hNMR (CDCl
3, 300MHz) and δ: 1.48 (s, 9H), 1.56 (s, 3H), 1.67-1.76 (m, 2H), 2.21-2.26 (m, 2H), 3.21-3.31 (m, 2H), 3.71-3.75 (m, 2H), 6.15 (br, 1H), 7.49 (dd, 1H, J=5.1Hz, 7.8Hz), 8.21 (d, 1H, J=7.8Hz), 8.74 (d, 1H, J=5.1Hz), 9.11 (s, 1H).
Step 2: Compound I-1l:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) niacinamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9l to replace the compound 9a of embodiment 1 step 10.
White solid (33mg, yield 14%); Mp:58-60 DEG C; [α]
d 22=-34.4 ° of (c=0.45, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.39-1.44 (m, 3H), 1.63 (s, 3H), 1.68-1.78 (m, 6H), 1.88-1.96 (m, 2H), 2.07-2.12 (m, 2H), 2.26-2.31 (m, 8H), 3.12-3.19 (m, 2H), 5.18-5.21 (m, 2H), 6.77-6.81 (m, 1H), 7.09-7.13 (m, 3H), (8.26 d, 1H, J=7.5Hz), 8.41 (br, 2H), 8.70-8.72 (m, 1H), 9.28 (br, 1H).
13cNMR (CD
3oD, 100MHz) δ: 179.6,169.6,164.9 (d,
1j
cF=162.5Hz), 153.0,149.9,146.3 (d,
3j
cF=4.3Hz), 138.0,133.3,132.1 (d,
3j
cF=5.4Hz), 125.5,123.9,115.9 (d,
2j
cF=14.2Hz), 114.9 (d,
2j
cF=15.0Hz), 52.6,51.6,51.3,46.7,35.2,33.0,31.8,31.3,30.9,27.3,27.2,27.1,26.8.EI-MS (M/Z): 480 (M
+).
Embodiment 13
Compound I-1m:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-trifluoromethyl benzamide
Step 1:4-methyl-4-(4-trifluoromethyl benzamide) piperidines-1-carbonic acid tert-butyl ester (9m)
Adopt the method identical with step 9 in embodiment 1, except adopting 4-trifluoromethylbenzoic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (235mg, yield 61%);
1hNMR (CDCl
3, 300MHz) and δ: 1.46 (s, 9H), 1.54 (s, 3H), 1.66-1.75 (m, 2H), 2.15-2.20 (m, 2H), 3.18-3.27 (m, 2H), 3.67-3.75 (m, 2H), 5.81 (br, 1H), 7.70 (d, 2H, J=8.1Hz), 7.83 (d, 2H, J=8.1Hz).
Step 2: Compound I-1m:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-4-trifluoromethyl benzamide
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9m to replace the compound 9a of embodiment 1 step 10.
White solid (84mg, yield 44%); Mp:93-95 DEG C; [α]
d 21=-19.0 ° of (c=1.05, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.42-1.49 (m, 3H), 1.55 (s, 3H), 1.68-1.71 (m, 1H), 1.80-1.93 (m, 8H), 2.12-2.26 (m, 2H), 2.36-2.44 (m, 7H), 2.70-2.72 (m, 1H), 2.83-2.86 (m, 1H), 5.03-6.08 (m, 1H), 5.99 (br, 1H), 6.92-7.03 (m, 3H), 7.70 (d, 2H, J=7.5Hz), 7.84 (d, 2H, J=7.5Hz), 7.92-7.95 (m, 1H).
13cNMR (CD
3oD, 100MHz) δ: 179.3,170.0,164.9 (d,
1j
cF=162.5Hz), 146.8 (d,
3j
cF=4.3Hz), 141.0,134.3 (d,
2j
cF=21.5Hz), 132.0 (d,
3j
cF=5.1Hz), 129.8,126.9 (d,
4j
cF=2.5Hz), 126.7,124.9,124.0,115.6 (d,
2j
cF=14.2Hz), 114.9 (d,
2j
cF=14.6Hz), 53.1,52.7,51.1,50.9,46.8,35.5,33.0,31.2,31.1,27.3,27.2,27.1.EI-MS (M/Z): 547 (M
+).
Embodiment 14
Compound I-1n:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) cyclohexanecarbonyl amine
Step 1:4-(cyclohexanecarbonyl amine) 4-methyl piperidine-1-carbonic acid tert-butyl ester (9n)
Adopt the method identical with step 9 in embodiment 1, except adopting heptanaphthenic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (367mg, yield 57%);
1hNMR (CDCl
3, 300MHz) and δ: 1.21-1.32 (m, 3H), 1.38 (s, 3H), 1.45 (s, 9H), 1.49-1.58 (m, 3H), 1.69-1.86 (m, 6H), 1.98-2.07 (m, 3H), 3.03-3.12 (m, 2H), 3.65-3.73 (m, 2H), 5.11 (br, 1H).
Step 2: Compound I-1n:(S)-N-(1-(3-cyclohexanecarbonyl amine)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) cyclohexanecarbonyl amine
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9n to replace the compound 9a of embodiment 1 step 10.
Faint yellow solid (70mg, yield 20%); Mp:83-85 DEG C; [α]
d 21=-25.2 ° of (c=0.75, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.42 (s, 3H), 1.68-1.72 (m, 5H), 1.78-1.89 (m, 17H), 2.12-2.27 (m, 7H), 2.35-2.43 (m, 3H), 2.61-2.65 (m, 1H), 2.76-2.81 (m, 1H), 5.09 (br, 2H), 6.92-6.95 (m, 2H), 7.02-7.04 (m, 1H), 8.09-8.11 (m, 1H).
13cNMR (CD
3oD, 100MHz) δ: 180.0,179.3,164.9 (d,
1j
cF=162.5Hz), 146.8 (d,
3j
cF=4.4Hz), 132.0 (d,
3j
cF=5.5Hz), 124.0,115.6 (d,
2j
cF=14.2Hz), 114.9 (d,
2j
cF=14.9Hz), 56.3,52.7,51.7,51.0,50.8,47.3,46.8,35.5,33.0,31.3,31.2,31.1,27.4,27.3,27.2.EI-MS (M/Z): 485 (M
+).
Embodiment 15
Compound I-1o:(S)-N-(1-(3-fluorophenyl)-3-(4-methyl-4-(2-phenyl-acetamides) piperidin-1-yl) propyl group) cyclohexanecarbonyl amine
Step 1:4-methyl-4-(2-phenyl-acetamides) piperidines-1-carbonic acid tert-butyl ester (9o)
Adopt the method identical with step 9 in embodiment 1, except adopting toluylic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (231mg, yield 70%);
1hNMR (CDCl
3, 300MHz) and δ: 1.38 (s, 3H), 1.45 (s, 9H), 1.60-1.65 (m, 2H), 1.91-1.96 (m, 2H), 2.78-2.86 (m, 2H), 3.56 (s, 2H), 3.62-3.67 (m, 2H), 5.03 (br, 1H), 7.25-7.27 (m, 2H), 7.31-7.41 (m, 3H).
Step 2: Compound I-1o:(S)-N-(1-(3-fluorophenyl)-3-(4-methyl-4-(2-phenyl-acetamides) piperidin-1-yl) propyl group) cyclohexanecarbonyl amine
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9o to replace the compound 9a of embodiment 1 step 10.
White solid (180mg, yield 70%), Mp:74-76 DEG C, [α]
d 22=-24.2 ° of (c=0.65, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.21-1.27 (m, 3H), 1.38 (s, 3H), 1.41-1.47 (m, 2H), 1.52-1.62 (m, 2H), 1.67-1.69 (m, 3H), 1.77-1.81 (m, 3H), 1.86-1.90 (m, 2H), 1.98-2.02 (m, 2H), 2.09-2.29 (m, 4H), 2.45-2.48 (m, 1H), 2.62-2.66 (m, 1H), 3.52 (s, 2H), 5.01-5.06 (m, 1H), 5.30 (s, 1H), 6.87-6.99 (m, 3H), 7.23-7.37 (m, 6H), 8.07 (d, 1H, J=6.3Hz) .EI-MS (M/Z): 493 (M
+).
Embodiment 16
Compound I-1p:(S)-N-(1-(3-fluorophenyl)-3-(4-methyl-4-(2-(3,4,5-trimethoxyphenyl) ethanamide) piperidin-1-yl) propyl group) cyclohexanecarbonyl amine
Step 1:4-methyl-4-(2-(3,4,5-trimethoxyphenyl) ethanamide) piperidines-1-carbonic acid tert-butyl ester (9p)
Adopt the method identical with step 9 in embodiment 1, except adopting 3,4,5-trimethoxy toluylic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (193mg, yield 46%);
1hNMR (CDCl
3, 300MHz) and δ: 1.39 (s, 3H), 1.45 (s, 9H), 1.49-1.55 (m, 2H), 1.96-2.00 (m, 2H), 2.85-2.95 (m, 2H), 3.48 (s, 2H), 3.64-3.68 (m, 2H), 3.86 (s, 9H), 5.15 (br, 1H), 6.47 (s, 2H).
Step 2: Compound I-1p:(S)-N-(1-(3-fluorophenyl)-3-(4-methyl-4-(2-(3,4,5-trimethoxyphenyl) ethanamide) piperidin-1-yl) propyl group) cyclohexanecarbonyl amine
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9p to replace the compound 9a of embodiment 1 step 10.
White solid (47mg, yield 35%), Mp:68-70 DEG C, [α]
d 22=-6.3 ° of (c=0.3, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.30-1.37 (m, 3H), 1.42 (s, 3H), 1.46-1.56 (m, 4H), 1.65-1.71 (m, 4H), 1.78-1.91 (m, 6H), 2.12-2.23 (m, 4H), 2.59-2.66 (m, 1H), 2.77-2.82 (m, 1H), 3.48 (s, 2H), 3.86 (d, 9H, J=5.4Hz), 5.01 (br, 1H), 5.32 (s, 1H), 6.48 (s, 2H), 6.95 (d, 2H, J=6.9Hz), 7.04 (d, 1H, J=6.9Hz), 7.31-7.35 (m, 1H).
13cNMR (CD
30D, 100MHz) δ: 179.3,174.6,163.7 (d,
1j
cF=243.6Hz), 154.9,147.0,138.4,134.0,132.0 (d,
3j
cF=6.4Hz), 124.0,115.6 (d,
2j
cF=20.9Hz), 114.9 (d,
2j
cF=22.3Hz), 107.9,61.6,57.2,56.3,52.7,52.1,50.8,50.7,46.8,45.4,35.3,32.8,31.2,31.1,27.4,27.3,27.2.EI-MS (M/Z): 583 (M
+).
Embodiment 17
Compound I-1q:(S)-N-(3-(4-(2-(4-chloro-phenyl-) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) cyclohexanecarbonyl amine
Step 1:4-(2-(4-chloro-phenyl-) ethanamide)-4 methyl-piperidines-1-carbonic acid tert-butyl ester (9q)
Adopt the method identical with step 9 in embodiment 1, except adopting 4-chlorobenzene acetic acid to replace the phenylformic acid of embodiment 1 step 9.
Colourless oil liquid (262mg, yield 71%);
1hNMR (CDCl
3, 300MHz) and δ: 1.37 (s, 3H), 1.44 (s, 9H), 1.48-1.54 (m, 2H), 1.91-1.96 (m, 2H) 2.85-2.95 (m, 2H), 3.49 (s, 2H), 3.60-3.65 (m, 2H), 5.03 (br, 1H), (7.19 d, 2H, J=8.7Hz), 7.34 (d, 2H, J=8.7Hz).
Step 2: Compound I-1q:(S)-N-(3-(4-(2-(4-chloro-phenyl-) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) cyclohexanecarbonyl amine
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9q to replace the compound 9a of embodiment 1 step 10.
White solid (182mg, yield 66%), Mp:66-68 DEG C, [α]
d 21=-18.8 ° of (c=0.8, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.21-1.29 (m, 2H), 1.38 (s, 3H), 1.43-1.47 (m, 2H), 1.68-1.71 (m, 3H), 1.77-1.81 (m, 3H), 1.85-1.90 (m, 3H), 2.11-2.19 (m, 6H), 2.40-2.42 (m, 2H), 2.61-2.65 (m, 1H), 2.72-2.77 (m, 1H), 3.47 (s, 2H), 4.96-5.02 (m, 1H), 5.41 (br, 1H), 6.92 (d, 2H, J=9.0Hz), 7.00 (d, 1H, J=8.4Hz), 7.18-7.34 (m, 4H), 7.92 (d, 1H, J=6.9Hz).
13cNMR (CD
3oD, 100MHz) δ: 179.4,174.2,164.7 (d,
1j
cF=243.7Hz), 146.5 (d,
3j
cF=6.gHz), 136.6,134.2,132.2,132.1 (d,
3j
cF=8.2Hz), 130.0,124.0,115.8 (d,
2j
cF=21.4Hz), 114.9 (d,
2j
cF=21.8Hz), 52.4,51.9,50.8,50.6,50.4,46.7,44.3,34.9,32.4,31.2,31.1,27.3,27.2.EI-MS (M/Z): 527 (M
+).
Embodiment 18
Compound I-1r:(S)-N-(3-(4-(2-(4-fluorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) cyclohexanecarbonyl amine
Step 1:4-(2-(4-fluorophenyl) ethanamide)-4 methyl-piperidines-1-carbonic acid tert-butyl ester (9r)
Adopt the method identical with step 9 in embodiment 1, except adopting 4-fluorophenylacetic acid to replace the phenylformic acid of embodiment 1 step 9.
Colourless oil liquid (219mg, yield 63%);
1hNMR (CDCl
3, 300MHz) and δ: 1.38 (s, 3H), 1.45 (s, 9H), 1.48-1.55 (m, 2H), 1.93-1.97 (m, 2H), 2.84-2.93 (m, 2H), 3.51 (s, 2H), 3.61-3.68 (m, 2H), 5.03 (br, 1H), 7.07 (t, 2H, J=8.7Hz), 7.22-7.26 (m, 2H).
Step 2: Compound I-1r:(S)-N-(3-(4-(2-(4-fluorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) cyclohexanecarbonyl amine
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9r to replace the compound 9a of embodiment 1 step 10.
White solid (121mg, yield 64%), Mp:65-67 DEG C, [α]
d 21=-22.6 ° of (c=1.05, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.21-1.29 (m, 3H), 1.38 (s, 3H), 1.43-1.47 (m, 1H), 1.66-1.88 (m, 8H), 1.91-1.98 (m, 1H), 2.07-2.24 (m, 6H), 2.46 (t, 2H, J=6.3Hz), 2.65-2.71 (m, 1H), 2.74-2.80 (m, 1H), 3.47 (s, 2H), 4.95-5.01 (m, 1H), 5.45 (br, 1H), 6.93 (d, 2H, J=9.0Hz), 7.00-7.06 (m, 3H), 7.22 (dd, 2H, J=5.4Hz, 8.7Hz), 7.88 (d, 1H, J=7.2Hz).
13cNMR (CD
3oD, 100MHz) δ: 179.3,174.4,164.9 (d,
1j
cF=162.5Hz), 163.8 (d,
1j
cF=161.5Hz), 146.9 (d,
3j
cF=4.4Hz), 133.9 (d,
4j
cF=1.9Hz), 132.3 (d,
3j
cF=5.1Hz), 132.0 (d,
3j
cF=5.5Hz), 124.0 (d,
4j
cF=1.4Hz), 116.6 (d,
2j
cF=14.2Hz), 115.6 (d,
2j
cF=14.2Hz), 114.9 (d,
2j
cF=14.9Hz), 56.4,52.8,52.2,50.9,50.7,46.8,44.2,35.5,33.0,31.2,27.4,27.3,27.2.EI-MS (M/Z): 511 (M
+).
Embodiment 19
Compound I-1s:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) cyclohexanecarbonyl amine
Step 1:4-(2-(3,4-dichlorophenyl) ethanamide)-4 methyl-piperidines-1-carbonic acid tert-butyl ester (9s)
Adopt the method identical with step 9 in embodiment 1, except adopting 3,4-fenac to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (268mg, yield 67%);
1hNMR (CDCl
3, 300MHz) and δ: 1.38 (s, 3H), 1.45 (s, 9H), 1.49-1.58 (m, 2H), 1.95-1.99 (m, 2H), 2.97-3.06 (m, 2H), 3.46 (s, 2H), 3.57-3.65 (m, 2H), 5.18 (br, 1H), 7.11 (dd, 1H, J=2.1Hz, 8.1Hz), 7.37 (d, 1H, J=2.1Hz), 7.42 (d, 1H, J=8.1Hz).
Step 2: Compound I-1s:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) cyclohexanecarbonyl amine
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9s to replace the compound 9a of embodiment 1 step 10.
White solid (90mg, yield 31%), Mp:86-88 DEG C, [α]
d 21=-22.5 ° of (c=0.75, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.23-1.29 (m, 3H), 1.40 (s, 3H), 1.44-1.48 (m, 1H), 1.65-1.72 (m, 3H), 1.79-1.82 (m, 3H), 1.89-1.93 (m, 2H), 2.08-2.17 (m, 7H), 2.28-2.37 (m, 2H), 2.51-2.54 (m, 1H), 2.68-2.71 (m, 1H), 3.45 (s, 2H), 5.03-5.07 (m, 1H), 5.31 (br, 1H), 6.89-6.93 (m, 2H), 7.00 (d, 1H, J=7.8Hz), 7.12 (d, 1H, J=8.4Hz), 7.38-7.43 (m, 2H), 8.06-8.08 (m, 1H).
13cNMR (CD
3oD, 100MHz) δ: 179.3,173.4,164.9 (d,
1j
cF=162.5Hz), 146.8 (d,
3j
cF=4.4Hz), 138.6,133.6,132.7,132.2,132.0 (d,
3j
cF=4.0Hz), 130.6,124.0,115.6 (d,
2j
cF=14.2Hz), 114.9 (d,
2j
cF=14.5Hz), 56.4,52.7,52.3,50.9,50.8,46.8,43.9,35.4,33.0,31.2,31.1,27.4,27.3,27.2.EI-MS (M/Z): 561 (M
+).
Embodiment 20
Compound I-1t:(S)-N-(1-(3-fluorophenyl)-3-(4-methyl-4-(2-(naphthyl-1-yl) ethanamide) piperidin-1-yl) propyl group) cyclohexanecarbonyl amine
Step 1:4-methyl-4-(2-(naphthyl-1-yl) ethanamide) piperidines-1-carbonic acid tert-butyl ester (9t)
Adopt the method identical with step 9 in embodiment 1, except adopting 1-naphthylacetic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (225mg, yield 59%);
1hNMR (CDCl
3, 300MHz) and δ: 1.29 (s, 3H), 1.32-1.38 (m, 2H), 1.40 (s, 9H), 1.76-1.80 (m, 2H), 2.40-2.49 (m, 2H), 3.43-3.50 (m, 2H), 3.99 (s, 2H), 4.93 (br, 1H), 7.39-7.58 (m, 4H), 7.82-7.99 (m, 3H).
Step 2: Compound I-1t:(S)-N-(1-(3-fluorophenyl)-3-(4-methyl-4-(2-(naphthyl-1-yl) ethanamide) piperidin-1-yl) propyl group) cyclohexanecarbonyl amine
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9t to replace the compound 9a of embodiment 1 step 10.
White solid (103mg, yield 35%); Mp:83-85 DEG C; [α]
d 21=-26.5 ° of (c=0.8, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.21-1.26 (m, 3H), 1.34 (s, 3H), 1.40-1.44 (m, 4H), 1.65-1.69 (m, 3H), 1.79-2.00 (m, 11H), 2.28-2.31 (m, 1H), 2.46-2.49 (m, 1H), 3.99 (s, 2H), 4.88 (br, 1H), 4.97-4.99 (m, 1H), 6.84-6.96 (m, 3H), 7.42-7.53 (m, 4H), 7.82-7.90 (m, 2H), 7.00-8.02 (m, 2H) .EI-MS (M/Z): 543 (M
+).
Embodiment 21
Compound I-1u:(S)-N-(1-(3-fluorophenyl)-3-(4-methyl-4-(2-adamantyl acetamides) piperidin-1-yl) propyl group) cyclohexanecarbonyl amine
Step 1:4-methyl-4-(2-diamantane ethanamide) piperidines-1-carbonic acid tert-butyl ester (9u)
Adopt the method identical with step 9 in embodiment 1, except adopting adamantane acetic acid to replace the phenylformic acid of embodiment 1 step 9.
Colourless oil liquid (395mg, yield 51%);
1hNMR (CDCl
3, 300MHz) and δ: 1.26-1.28 (m, 2H), 1.41 (s, 3H), 1.46 (s, 9H), 1.50-1.57 (m, 2H), 1.61-1.64 (m, 7H), 1.69-1.73 (m, 4H), 1.88 (s, 2H), 1.97-1.98 (m, 4H), 3.10-3.19 (m, 2H), 3.63-3.68 (m, 2H), 4.99 (br, 1H).
Step 2 Compound I-1u:(S)-N-(1-(3-fluorophenyl)-3-(4-methyl-4-(2-adamantyl acetamides) piperidin-1-yl) propyl group) cyclohexanecarbonyl amine
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9u to replace the compound 9a of embodiment 1 step 10.
White solid (100mg, yield 23%); Mp:108-110 DEG C; [α]
d 21=-23.2 ° of (c=0.25, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.23-1.31 (m, 4H), 1.42 (s, 3H), 1.62-1.82 (m, 23H), 1.87 (s, 2H), 2.10-2.26 (m, 7H), 2.34-2.40 (m, 4H), 2.59-2.62 (m, 1H), 2.74-2.76 (m, 1H), 5.01 (br, 1H), 5.05-5.07 (m, 1H), 6.90-6.93 (m, 2H), 7.01 (d, 1H, J=7.2Hz), 8.04-8.07 (m, 1H).
13cNMR (CD
3oD, 100MHz) δ: 179.3,174.8,164.9 (d,
1j
cF=162.5Hz), 146.8,132.0 (d,
3j
cF=5.4Hz), 123.9,115.7,114.8 (d,
2j
cF=14.6Hz), 56.4,53.0,52.7,52.3,50.9,50.7,46.8,44.3,38.4,35.6,34.5,31.2,31.1,30.6,27.3,27.2.EI-MS (M/Z): 552 (M+1)
+.
Embodiment 22
Compound I-2a:(S)-N-(1-(3-benzamide-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-2,6-dichloro-benzamide
Step 1:(S)-3-(tertbutyloxycarbonyl amine)-3-(3-fluorophenyl) ethyl propionate (11)
In ethanol (10mL) solution that is dissolved with compound 2a (674mg, 1.66mmol), add (Boc)
2o (726mg, 3.33mmol) and 20% palladium hydroxide/carbon (74mg), normal pressure hydrogenation 24 hours under room temperature.Remove by filter catalyzer, silica gel column chromatography (petrol ether/ethyl acetate=7: 1), obtain white solid, i.e. compound 11 (354mg, yield 65%) after filtrate is concentrated.
1HNMR(CDCl
3，300MHz)δ：1.17(t，3H，J＝7.1Hz)，1.42(s，9H)，2.79-2.80(m，2H)，4.07(q，2H，J＝7.1Hz)，5.09(br，1H)，5.58(br，1H)，6.91-7.08(m，3H)，7.25-7.31(m，1H).
Step 2:(S)-1-(3-fluorophenyl)-3-oxopropyl t-butyl carbamate (12)
Adopt the method identical with step 4 in embodiment 1, except adopting compound 11 to replace the compound 3a of embodiment 1 step 4.
White solid (133mg, yield 50%);
1hNMR (CDCl
3, 300MHz) and δ: 1.41 (s, 9H), 2.90-2.96 (m, 2H), 5.17 (br, 1H), 5.26 (br, 1H), 6.92-7.08 (m, 3H), 7.26-7.33 (m, 1H), 9.72 (s, 1H).
Step 3:4-(2,6-dichloro-benzamide)-4-methyl piperidine-1-carbonic acid tert-butyl ester (9v)
Adopt the method identical with step 9 in embodiment 1, except adopting 2,6-dichlorobenzoic acid to replace the phenylformic acid of embodiment 1 step 9.
White foam shape solid (1.268g, yield 53%);
1hNMR (CDCl
3, 300MHz) and δ: 1.47 (s, 9H), 1.56 (s, 3H), 1.64-1.67 (m, 2H), 2.19-2.24 (m, 2H), 3.17-3.26 (m, 2H), 3.75-3.82 (m, 2H), 5.40 (br, 1H), (7.26-7.33 m, 3H).
Step 4:(S)-3-(4-(2,6-dichloro-benzamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) the propyl carbamic acid tert-butyl ester (13)
Adopt the method identical with step 10 in embodiment 1, except adopting compound 9v to replace the compound 9a of embodiment 1 step 10, compound 12 replaces the compound 4a of embodiment 1 step 10.
White foam shape solid (440mg, yield 51%);
1hNMR (CDCl
3, 300MHz) and δ: 1.42 (s, 9H), 1.65 (s, 3H), 1.71-1.85 (m, 4H) 2.25-2.40 (m, 6H), 2.57-2.60 (m, 1H), 2.71-2.74 (m, 1H), 4.77 (br, 1H), 5.41 (br, 1H), 6.88-7.05 (m, 3H), 7.19-7.31 (m, 4H).
Step 5: Compound I-2a:(S)-N-(1-(3-benzamide-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl)-2,6-dichloro-benzamide
Trifluoroacetic acid (0.22mL, 2.8mmo1) is added in methylene dichloride (3mL) solution that is dissolved with compound 13 (0.1g, 0.19mmol) to stirred overnight at room temperature.Add diisopropyl ethyl amine to pH be 8, phenylformic acid (28mg will be added in above-mentioned reaction system, 0.23mmol), EDCI (54mg, 0.28mmol), HOBt (38mg, 0.28mmol) and diisopropyl ethyl amine (13 μ L, 0.75mmol), stirred overnight at room temperature.Use successively dilute hydrochloric acid, saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated rear silica gel column chromatography (methylene chloride/methanol=30: 1), obtain white solid, i.e. Compound I-2a (61mg, two step yields 59%).Mp：180-182℃；
1HNMR(CDCl
3，300MHz)δ：1.57(s，3H)，1.60-1.74(m，2H)，1.83-1.96(m，2H)，2.21-2.30(m，2H)，2.36-2.81(m，6H)，5.27-5.33(m，1H)，5.43(br，1H)，6.91-6.98(m，1H)，7.02-7.06(m，1H)，7.12-7.15(m，1H)，7.23-7.35(m，4H)，7.45-7.54(m，3H)，7.92-7.94(m，2H)，9.35(br，1H).EI-MS(M/Z)：541(M
+).
Embodiment 23
Compound I-2b:(S)-N-(3-(4-(2,6-dichloro-benzamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) niacinamide
Adopt the method identical with embodiment 22, except adopting nicotinic acid to replace the phenylformic acid in embodiment 22.
White solid (37mg, yield 62%); Mp:134-136 DEG C; [α]
d 21=-7.4 ° of (c=0.35, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.56 (s, 3H), 1.82-1.95 (m, 2H), 2.19-2.64 (m, 8H), 2.71-2.82 (m, 2H), 5.25-5.31 (m, 1H), 5.76 (br, 1H), 6.93-7.04 (m, 2H), (7.10-7.13 d, 1H, J=7.2Hz), 7.20-7.36 (m, 5H), 7.41-7.45 (m, 1H), 8.20-8.23 (d, 1H, J=8.1Hz), 8.72-8.73 (d, 1H, J=4.5Hz), 9.11 (br, 1H) .EI-MS (M/Z): 542 (M
+).
Embodiment 24
Compound I-2c:(S)-2, the chloro-N-of 6-bis-(1-(3-(hexamethylene carbonylamino)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) benzamide
Adopt the method identical with embodiment 22, except adopting heptanaphthenic acid to replace the phenylformic acid in embodiment 22.
White solid (70mg, yield 67%); Mp:128-130 DEG C; [α]
d 20=-20 ° of (c=0.117, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.32-1.49 (m, 4H), 1.57 (s, 3H), 1.80-1.93 (m, 8H), 2.06-2.19 (m, 2H), 2.29-2.51 (m, 7H), 2.66-2.70 (m, 1H), 2.81-2.85 (m, 1H), 5.03 (dd, 1H, J=6.5Hz, 11.6Hz), 5.59 (br, 1H), 6.89-7.03 (m, 3H), 7.22-7.33 (m, 4H), 8.10 (br, 1H) .EI-MS (M/Z): 547 (M
+).
Embodiment 25
Compound I-2d:(S)-2, the chloro-N-of 6-bis-(1-(3-(3-chlorine the third amino)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-4-yl) benzamide
Adopt the method identical with embodiment 22, except adopting 3-chloropropionic acid to replace the phenylformic acid in embodiment 22.
White solid (19mg, yield 19%); Mp:98-100 DEG C;
1hNMR (CDCl
3, 300MHz) and δ: 1.59 (s, 3H), 1.61-1.78 (m, 2H), 1.83-2.03 (m, 3H), 2.14-2.23 (m, 2H), 2.34-2.62 (m, 3H), 2.65-2.75 (m, 4H), 2.92-3.01 (m, 2H), 5.09-5.15 (m, 1H), 5.65 (br, 1H), 6.93-7.13 (m, 3H), 7.30-7.36 (m, 4H), 8.43-8.45 (m, 1H) .EI-MS (M/Z): 527 (M
+).
Embodiment 26
Compound I-3a:(S)-N-(1-(3-aniline-3-phenyl propyl)-4-methyl piperidine-4-yl)-2,6-dichloro-benzamide
Step 1: ethyl cinnamate (15)
Adopt the method identical with embodiment 1 step 1, except adopting phenyl aldehyde to replace the 3-fluorobenzaldehyde of embodiment 1 step 1.
Yellow oily liquid (1.62g, yield 92%);
1hNMR (CDCl
3, 300MHz) and δ: 1.34 (t, 3H, J=7.0Hz), 4.27 (q, 2H, J=7.0Hz), 6.44 (d, 1H, J=16.2Hz), 7.38-7.40 (m, 3H), 7.52-7.55 (m, 2H), 7.69 (d, 1H, J=16.2Hz).
Step 2:(S)-3-(benzyl ((R)-1-styroyl) amino)-3-phenylpropionic acid ethyl ester (16)
Adopt the method identical with embodiment 1 step 2, except adopting compound 15 to replace the compound 1a of embodiment 1 step 2.
Yellow oily liquid (14.86g, yield 83%);
1hNMR (CDCl
3, 300MHz) and δ: 1.03 (t, 3H, J=7.0Hz), 1.23 (d, 3H, J=6.9Hz), 2.51-2.69 (m, 2H), 3.70 (qAB, 2H, J=14.7Hz), 3.92 (dt, 2H, J=7.0Hz, 1.7Hz), 4.00 (q, 1H, J=6.9Hz), 4.44 (dd, 1H, J=5.6Hz, 9.3Hz), 7.15-7.43 (m, 15H).
Step 3:(S)-3-(tertbutyloxycarbonyl amine)-3-phenylpropionic acid ethyl ester (17)
Adopt the method identical with embodiment 22 steps 1, except adopting compound 16 to replace the compound 2a of embodiment 22 steps 1.
White solid (270mg, yield 55%);
1hNMR (CDCl
3, 300MHz) and δ: 1.16 (t, 3H, J=7.0Hz), 1.42 (s, 9H), 2.75-2.90 (m, 2H), 4.07 (q, 2H, J=7.0Hz), 5.10 (br, 1H), 5.49 (br, 1H), (7.22-7.36 m, 5H).
Step 4:(S)-3-oxo-1-phenyl propyl t-butyl carbamate (18)
Adopt the method identical with embodiment 22 steps 2, except adopting compound 17 to replace the compound 11 of embodiment 22 steps 2.
White solid (360mg, yield 60%);
1hNMR (CDCl
3, 300MHz) and δ: 1.42 (s, 9H), 2.87-3.03 (m, 2H), 5.09 (br, 1H), 5.20 (br, 1H), 7.27-7.35 (m, 5H), 9.75 (t, 1H, J=2.8Hz).
Step 5:(S)-3-(4-(2,6-dichloro-benzamide)-4-methyl piperidine-1-yl)-1-phenyl propyl t-butyl carbamate (19)
Adopt the method identical with embodiment 22 steps 4, except adopting compound 18 to replace the compound 12 of embodiment 22 steps 4.
White solid (650mg, yield 88%);
1hNMR (CDCl
3, 300MHz) and δ: 1.42 (s, 9H), 1.56 (s, 3H), 1.78-1.82 (m, 4H), 2.21-2.40 (m, 6H), 2.57-2.62 (m, 1H), 2.71-2.75 (m, 1H), 4.78 (br, 1H), 5.38 (br, 1H), 6.67 (br, 1H), 7.20-7.35 (m, 8H).
Step 6 Compound I-3a:(S)-N-(1-(3-aniline-3-phenyl propyl)-4-methyl piperidine-4-yl)-2,6-dichloro-benzamide
Adopt the method identical with embodiment 22 steps 5, except adopting compound 19 to replace the compound 13 of embodiment 22 steps 5.
White solid (20mg, yield 20%); Mp:208-210 DEG C;
1hNMR (CDCl
3, 300MHz) and δ: 1.52 (s, 3H), 1.55-1.84 (m, 3H), 1.95-2.03 (m, 1H), 2.17-2.40 (m, 3H), 2.48-2.64 (m, 4H), 2.71-2.78 (m, 1H), 5.21-5.27 (m, 1H), 5.84 (br, 1H), 7.20-7.28 (m, 4H), 7.32-7.33 (m, 4H), 7.41-7.54 (m, 3H), 7.83-7.86 (d, 2H, J=8.7Hz), 8.90 (br, 1H) .EI-MS (M/Z): 523 (M
+).
Embodiment 27
Compound I-3b:(S)-N-(3-(4-(2,6-dichloro-benzamide)-4-methyl piperidine-1-yl)-1-phenyl propyl) niacinamide
Adopt the method identical with embodiment 23 steps 5, except adopting compound 19 to replace the compound 13 of embodiment 23 steps 5.
White solid (20mg, yield 35%); Mp:176-178 DEG C; [α]
d 22=-9 ° of (c=0.2, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.54 (s, 3H), 1.65-1.96 (m, 4H), 2.25-2.43 (m, 4H), 2.63-2.80 (m, 4H), 5.18-5.25 (m, 1H), 5.91 (br, 1H), 7.21-7.37 (m, 10H), 8.27-8.29 (m, 2H), 8.64-8.65 (m, 1H), 9.12 (br, 1H) .EI-MS (M/Z): 524 (M
+).
Embodiment 28
Compound I-3c:(S)-2, the chloro-N-of 6-bis-(1-(3-(3-chlorine the third amino)-3-phenyl propyl)-4-methyl piperidine-4-yl) benzamide
Adopt the method identical with embodiment 25 steps 5, except adopting compound 19 to replace the compound 13 of embodiment 25 steps 5.
White solid (15mg, yield 20%); Mp:114-116 DEG C; [α]
d 22=-8.3 ° of (c=0.35, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.58 (s, 3H), 1.82-2.03 (m, 6H), 2.33-2.69 (m, 8H), 2.91-3.02 (m, 2H), 4.68-4.78 (m, 1H), 4.92-4.99 (m, 1H), 7.17-7.24 (m, 5H), 7.34 (t, 1H, J=8.0Hz), 7.49-7.82 (m, 2H), 8.70 (br, 1H).
Embodiment 29
Compound I-4:(S)-N-(3-(4-(N-ethyl-2-phenyl-acetamides) piperidin-1-yl)-1-(3-fluorophenyl) propyl group) cyclohexanecarbonyl amine
Step 1:1-benzyl-N-ethylpiperidine-4-amine (21)
Be dissolved with 1-benzyl-4-piperidone (1.89g at one, in tetrahydrofuran (THF) (20mL) solution 10mmol), add ethylamine hydrochloride (897mg, methyl alcohol (4mL) solution 11mmol), stirring at room temperature half an hour, add sodium triacetoxy borohydride (2.54g, 12mmol), room temperature reaction 22 hours, is spin-dried for reaction solvent.Add methylene dichloride dilution, use successively 5% sodium bicarbonate, water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated rear silica gel column chromatography (petrol ether/ethyl acetate=1: 1), obtain colourless oil liquid, i.e. compound 21 (1.615g, yield 74%).
1HNMR(300MHz，CDCl
3)δ：1.11(t，3H，J＝7.2Hz)，1.33-1.46(m，2H)，1.84-1.88(m，2H)，1.97-2.05(m，2H)，2.43-2.52(m，1H)，2.67(q，2H，J＝7.2Hz)，2.83-2.87(m，2H)，3.50(s，2H)，7.24-7.32(m，5H).
Step 2:N-(1-benzyl piepridine-4-yl)-N-ethyl-2-phenyl-acetamides (22)
Be dissolved with compound 21 (2.384g at one, in methylene dichloride (30mL) solution 10.9mmol), add successively toluylic acid (1.785g, 13.1mmol), EDCI (3.133g, 16.4mmol), HOBt (2.214g, 16.4mmol) and triethylamine (3mL, 21.9mmol), stirring at room temperature 12 hours, use successively 5% sodium bicarbonate, water, saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography (petrol ether/ethyl acetate=1: 1) after concentrated, obtain colourless oil liquid, be compound 22 (2.925g, yield 80%).
Step 3:N-ethyl-2-phenyl-N-piperidin-4-yl ethanamide (23)
Be dissolved with compound 22 (2.925g at one, methyl alcohol (30mL) solution 8.7mmol) adds 10% palladium carbon (585mg) and ammonium formiate (3.839g successively, 60.9mmol), reflux 6 hours, be spin-dried for solvent, add methylene dichloride dilution, use successively 5% sodium bicarbonate, water, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography (methylene chloride/methanol=10: 1) after concentrated, obtain colourless oil liquid, i.e. compound 23 (1.641g, yield 77%).
Step 4:(S)-3-(4-(N-ethyl-2-phenyl-acetamides) piperidin-1-yl)-1-(3-fluorophenyl) the propyl carbamic acid tert-butyl ester (24)
Adopt the method identical with embodiment 1 step 10, except adopting compound 23 to replace the compound 9a of embodiment 1 step 10.
White foam shape solid (32mg, yield 32%).
1HNMR(300MHz，CDCl
3)δ：1.18-1.26(m，5H)，1.41(s，9H)，1.74-1.78(m，5H)，2.00-2.10(m，2H)，2.25-2.37(m，2H)，2.82-3.05(m，2H)，3.30(q，2H，J＝6.9Hz)，3.71(s，2H)，4.77(br，1H)，6.92-7.03(m，3H)，7.24-7.31(m，6H).
Step 5:(S)-N-(3-(4-(N-ethyl-2-phenyl-acetamides) piperidin-1-yl)-1-(3-fluorophenyl) propyl group) cyclohexanecarbonyl amine (I-4)
Be dissolved with compound 24 (32mg at one, in methylene dichloride (3mL) solution 0.06mmol), add trifluoroacetic acid (74uL, 1mmol), stirring at room temperature 6 hours, add diisopropyl ethyl amine to pH be 8, add successively heptanaphthenic acid (10mg, 0.08mmol), EDCI (19mg, 0.1mmol), HOBt (14mg, 0.1mmol) and triethylamine (18uL, 0.13mmol), stirring at room temperature 12 hours, use successively 5% sodium bicarbonate, water, saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography (petrol ether/ethyl acetate=1: 1) after concentrated, obtain faint yellow gluey solid, be Compound I-4 (12mg, yield 34%).
1HNMR(300MHz，CDCl
3)δ：1.17-1.26(m，6H)，1.36-1.47(m，4H)，1.71-1.88(m，9H)，2.04-2.32(m，6H)，2.86-3.09(m，2H)，3.30(q，2H，J＝7.2Hz)，3.72(s，2H)，5.03-5.10(m，1H)，6.88-7.02(m，3H)，7.23-7.35(m，6H).
Embodiment 30
Compound I-5:N-((1S)-3-(3-(3-sec.-propyl-5-methyl-4-hydrogen-1,2,4-triazole-4-yl)-8-azabicyclo [3.2.1] octane-8-yl)-1-(4-(trifluoromethyl) phenyl) propyl group)-2-phenoxy acetamide
Step 1:(E)-3-(4-trifluoromethyl) phenyl) ethyl propionate (25)
Adopt the method identical with embodiment 1 step 1, except adopting p-trifluoromethyl benzaldehyde to replace the 3-fluorobenzaldehyde of embodiment 1 step 1.
Colourless oil liquid (2.74g, yield 84%);
1hNMR (CDCl
3, 300MHz) and δ: 1.35 (t, 3H, J=7.2Hz), 4.27 (q, 2H, J=7.2Hz), 6.50 (d, 1H, J=16.2Hz), 7.63 (s, 4H), 7.68 (d, 1H, J=15.6Hz).
Step 2:(S)-3-(benzyl ((R)-1-styroyl) amino)-3-(4-(trifluoromethyl) phenyl) ethyl propionate (26)
Adopt the method identical with embodiment 1 step 2, except middle employing compound 25 replaces the compound 1a of embodiment 1 step 2.
Colourless oil liquid (3.337g, yield 70%);
1hNMR (CDCl
3, 300MHz) and δ: 1.11 (t, 3H, J=6.9Hz), 1.35 (d, 3H, J=6.9Hz), 2.63-2.67 (m, 2H), 3.75 (q, 2H, J=5.7Hz), 3.96-4.06 (m, 3H), 4.56-4.60 (m, 1H), 7.23-7.48 (m, 10H), 7.58-7.67 (m, 4H).
Step 3:(S)-3-(tertbutyloxycarbonyl amine)-3-(4-(trifluoromethyl) phenyl) ethyl propionate (27)
Adopt the method identical with embodiment 22 steps 1, except adopting compound 26 to replace the compound 2a of embodiment 22 steps 1.
White solid (2.303g, yield 87%); Mp:75-78 DEG C; [α]
d 21=-14.6 ° of (c=0.64, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.17 (t, 3H, J=6.9Hz), 1.42 (s, 9H), 2.82-2.84 (m, 2H), 4.06 (q, 2H, J=6.9Hz), 5.67 (brs, 1H), 7.41 (d, 2H, J=8.1Hz), 7.59 (d, 2H, J=8.1Hz) .EI-MS (M/Z): 361 (M
+).
Step 4:(S)-3-oxo-1-(4-(trifluoromethyl) phenyl) propyl carbamic acid tert-butyl ester (28)
Adopt the method identical with embodiment 22 steps 2, except adopting compound 27 to replace the compound 11 of embodiment 22 steps 2.
White solid (434mg, yield 60%).
Step 5:3-oxo-8-azabicyclo [3,2,1] octane-8-urethanum (30)
Under ice bath slowly by Vinyl chloroformate (43.41g, 400mmol) be added drop-wise to and be dissolved with tropinone 29 (27.84g, 200mmol), in chloroform (300mL) the suspendible system of Anhydrous potassium carbonate (110g, 800mmol), slowly heating, now gas is emitted, temperature rising reflux 3-5 hour, filters washed with dichloromethane filter cake.In filtrate, add saturated aqueous common salt, methylene dichloride (100mL) extracting twice, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, the 40-60 DEG C of concentrated brown oil that obtains of underpressure distillation, silica gel column chromatography (methylene chloride/methanol=20: 1), obtain colourless oil liquid, i.e. compound 30 (34.7g, yield 88%).
1HNMR(300MHz，CDCl
3)δ：1.26(t，3H，J＝6.9Hz)，1.63-1.67(m，2H)，2.05-2.07(m，2H)，2.27-2.34(m，2H)，2.62(brs，2H)，4.16(q，2H，J＝6.9Hz)，4.51(brs，2H).
Step 6:3-amino-8-azabicyclo [3,2,1] octane-8-urethanum (31)
Under ice bath, by compound 30 (1.97g, 10mmo1) be dissolved in methyl alcohol (50mL), add ammonium formiate (6.4g, 100mmo1), under vigorous stirring, add distilled water (6mL), after ammonium formiate dissolves completely, carefully repeatedly under ice is abundant, add slowly 10%Pd/C (1g) in batches, adding rear reaction system at room temperature stirs 10 hours, add saturated sodium bicarbonate, filter, filtrate extracts 3 times with methylene dichloride (50mL), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, the concentrated brown oil that obtains of underpressure distillation, silica gel column chromatography (methylene chloride/methanol=20: 1), obtain colourless oil liquid, be compound 31 (1.583g, yield 80%).
1HNMR(300MHz，CDCl
3)δ：1.25(t，3H，J＝7.2Hz)，1.42-1.44(m，2H)，1.91-1.96(m，2H)，2.10-2.17(m，4H)，3.30-3.34(m，1H)，4.09-4.16(m，4H)，4.22(brs，2H).
Step 7:3-isobutyl amino-8-azabicyclo [3,2,1] octane-8-urethanum (32)
By isopropylformic acid (0.35g, 4mmol) be dissolved in dry tetrahydrofuran (THF) (10mL), under room temperature, add DCC (dicyclohexylcarbodiimide) (0.83g, 4mmol), stir half an hour, add in tetrahydrofuran (THF) (10mL) solution that is dissolved with compound 31 (0.396g, 2mmol), room temperature reaction filtered after 10 hours, concentrated.Methylene dichloride dilution, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, underpressure distillation concentrates to obtain colourless oil liquid, i.e. compound 32 (0.515g, yield 90%).
1HNMR(300MHz，CDCl
3)δ：1.14(d，6H，J＝6.6Hz)，1.25(t，3H，J＝7.2Hz)，1.64-1.69(m，2H)，1.80-1.83(m，2H)，2.05-2.10(m，2H)，2.18(brs，2H)，2.27-2.34(m，1H)，4.13(q，2H，J＝7.2Hz)，4.28(brs，2H)，5.28(s，1H)，5.87(brs，1H).EI-MS(M/Z)：268(M
+).
Step 8:3-(3-sec.-propyl-5-methyl-4-hydrogen-1,2,4-triazole-4-yl)-8-azabicyclo [3,2,1] octane-8-urethanum (33)
Under nitrogen protection, by phosphorus pentachloride (0.542g, 2.6mmol) divide to join for three times and contain compound 32 (0.536g, 2mmol), N, accelerine (12mg, in methylene dichloride (15mL) 0.1mmol), under ice bath, react after 2 hours, add acethydrazide (0.444g, 6mmol) with 2-methyl-2-butanols (10mL), room temperature reaction is concentrated after 12 hours, add toluene (20mL) and tosic acid (17mg, 0.1mmol), back flow reaction 6 hours, toluene is removed in decompression, regulation system pH to 12, methylene dichloride (50mL) extraction 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography (methylene chloride/methanol=20: 1), obtain colourless oil liquid, be compound 33 (447mg, yield 73%).
Step 9:3-(3-sec.-propyl-5-methyl-4-hydrogen-1,2,4-triazole-4-yl)-8-azabicyclo [3,2,1] octane-8-carboxylamine uncle] ester (34)
To in the compound of above-mentioned preparation 33, add 6N hydrochloric acid (10mL), stirring and refluxing reaction 12 hours, cooling rear with 1N sodium hydroxide solution adjusting pH to 12, add (Boc)
2o (318mg, 1.46mmol), stirring at room temperature reaction 24 hours, methylene dichloride (10mL) extraction 3 times, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography (methylene chloride/methanol=20: 1), obtain colourless oil liquid, be compound 34 (317mg, yield 65%).Mp：183-185℃；
1HNMR(CDCl
3，300MHz)δ：1.37(d，6H，J＝6.9Hz)，1.50(s，9H)，1.69-1.77(m，4H)，2.16-2.19(m，2H)，2.50(s，3H)，2.47-2.57(m，2H)，2.89-2.95(m，1H)，3.96-4.03(m，1H)，4.36-4.44(d，2H).
13CNMR(CDCl
3，100MHz)δ：13.1，21.3，25.6，28.2，31.5，32.1，34.8，35.6，45.3，49.7，50.4，150.7，154.5，159.4.EI-MS(M/Z)：334(M
+).
Step 10:(1S)-3-(3-(3-sec.-propyl-5-methyl-4-hydrogen-1,2,4-triazole-4-yl)-8-azabicyclo [3,2,1] octane-8-yl)-1-(4-(trifluoromethyl) phenyl) the propyl carbamic acid tert-butyl ester (35)
Adopt the method identical with embodiment 1 step 10, except adopting compound 34 to replace the compound 9a of embodiment 1 step 10, compound 28 replaces the compound 4a of embodiment 1 step 10.
Colourless oil liquid (38mg, yield 70%).
Step 11: Compound I-5:N-((1S)-3-(3-(3-sec.-propyl-5-methyl-4-hydrogen-1,2,4-triazole-4-yl)-8-azabicyclo [3,2,1] octane-8-yl)-1-(4-(trifluoromethyl) phenyl) propyl group)-2-phenoxy acetamide
Adopt the method identical with embodiment 22 steps 5, except adopting compound 35 to replace the compound 13 of embodiment 22 steps 5, phenoxy acetic acid replaces the phenylformic acid of embodiment 22 steps 5.
Colloidal solid (35mg, yield 88%), Mp:78-81 DEG C, [α]
d 22=-2.1 ° of (c=0.45, CHCl
3),
1hNMR (CDCl
3, 300MHz) δ: 1.36 (d, 6H, J=6.9Hz), 1.54-1.58 (m, 4H), 1.83-1.88 (m, 2H), 2.03-2.06 (m, 2H), 2.11-2.16 (m, 2H), 2.38-2.42 (m, 2H), 2.46 (s, 3H), 2.96-3.05 (m, 1H), 3.26-3.28 (m, 2H), 3.59 (s, 2H), 4.48-4.54 (m, 1H), 5.19-5.26 (m, 1H), 6.11-6.14 (d, 1H), 7.25-7.39 (m, 7H), 7.56-7.59 (d, 2H) .EI-MS (M/Z): 568 (M-1
+).
Embodiment 31
The fluoro-N-of Compound I-6:4-((1S)-3-(3-(2-methyl-3H-imidazoles [4,5-also] pyridin-3-yl)-8-azabicyclo [3,2,1] octane-8-yl)-1-(naphthalene-1-yl) propyl group) benzamide
Step 1:(E)-3-(naphthalene-1-yl) ethyl propionate (36)
Adopt the method identical with embodiment 1 step 1, except adopting β-naphthaldehyde to replace the 3-fluorobenzaldehyde of embodiment 1 step 1.
Colourless oil liquid (1.85g, yield 82%);
1hNMR (CDCl
3, 300MHz) and δ: 1.38 (t, 3H, J=7.2Hz), 4.31 (q, 2H, J=7.2Hz), 6.53 (d, 1H, J=16.2Hz), 7.48-7.56 (m, 3H), 7.74-7.77 (d, 1H), 7.86-7.90 (m, 2H), 8.19-8.20 (d, 4H), 8.50-8.55 (d, 1H, J=15.9Hz).
Step 2:(S)-3-(benzyl ((R)-1-styroyl) amino)-3-(naphthalene-1-yl) ethyl propionate (37)
Adopt the method identical with embodiment 1 step 2, except adopting compound 36 to replace the compound 1a of embodiment 1 step 2.
Colourless oil liquid (3.189g, yield 89%); [α]
d 20=+45.8 ° of (c=1.02, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 0.80 (t, 3H, J=7.2Hz), 1.22 (d, 3H, J=6.9Hz), 2.74-2.92 (m, 2H), 3.73 (q, 2H, J=7.2Hz), 3.77-3.92 (m, 2H), 3.96-4.03 (m, 1H), 5.11-5.56 (m, 1H), 7.14-7.29 (m, 8H), 7.41-7.49 (m, 5H), 7.79-7.83 (m, 3H), 8.29 (brs, 1H).
Step 3:(S)-3-(tertbutyloxycarbonyl amine)-3-(naphthalene-1-yl) ethyl propionate (38)
Adopt the method identical with embodiment 22 steps 1, except adopting compound 37 to replace the compound 2a of embodiment 22 steps 1.
White solid (2.078g, yield 83%); Mp:88-90 DEG C; [α]
d 20=-13.6 ° of (c=0.99, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.12 (t, 3H, J=6.9Hz), 1.43 (s, 9H), 2.98-3.00 (m, 2H), 4.02-4.09 (q, 2H, J=6.9Hz), 5.55 (brs, 1H), 5.96 (brs, 1H), 7.41-7.59 (m, 4H), 7.77-7.98 (m, 2H), 8.14 (d, 1H, J=8.1Hz) .EI-MS (M/Z): 343 (M
+).
Step 4:(S)-1-(naphthalene-1-yl)-3-oxopropyl t-butyl carbamate (39)
Adopt the method identical with embodiment 22 steps 2, except adopting compound 38 to replace the compound 11 of embodiment 22 steps 2.
White solid (1087mg, yield 60%)
Step 5:3-(3-nitropyridine-2-amino)-8-azabicyclo [3,2,1] octane-8-urethanum (40)
By compound 32 (843mg, 6mmol), the chloro-3-nitropyridine of 2-(955mg, 6mmol) and salt of wormwood (3.32g, 24mmol) be dissolved in dry acetonitrile, under reflux conditions, react 8 hours, be cooled to room temperature, removal of solvent under reduced pressure, methylene dichloride (10mL) extraction 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography (methylene chloride/methanol=20: 1), obtain faint yellow solid, i.e. compound 40 (1.59g, yield 83%).Mp：140-144℃；
1HNMR(CDCl
3，300MHz)δ：1.23(t，3H，J＝6.9Hz)，1.76-1.80(m，2H)，1.91-2.05(m，4H)，2.24(brs，2H)，4.07-4.13(m，3H)，4.28(brs，2H)，6.04(d，1H)，6.33-6.36(d，1H)，8.07-8.11(d，1H)，8.92(brs，1H).
Step 6:3-(3-aminopyridine-2-amino)-8-azabicyclo [3,2,1] octane-8-urethanum (41)
Under room temperature, by compound 40 (3.3g, 12.5mmo1) be dissolved in methyl alcohol (50mL), add 10%Pd/C (350mg), normal pressure hydrogenation reaction 10 hours, filters, silica gel column chromatography (methylene chloride/methanol=5: 1) after concentrated, obtain brown solid, i.e. compound 41 (3.41g, yield 94%).Mp：93-96℃；
1HNMR(CDCl
3，300MHz)δ：1.23(t，3H，J＝6.9Hz)，1.72-1.78(m，2H)，1.99(s，4H)，2.20(brs，2H)，3.03(brs，2H)，3.75(brs，1H)，4.11(q，1H，J＝6.9Hz)，4.26(brs，2H)，6.21(d，1H)，6.94(dd，1H，J＝3.0Hz)，7.64(d，1H).
Step 7:3-(2-methyl-3-hydrogen-imidazoles [4,5-also] pyridin-3-yl)-8-azabicyclo [3,2,1] octane-8-urethanum (42)
By compound 41 (2.91g, 12.5mmol) be dissolved in acetic anhydride (10mL) and reflux 24 hours, acetic anhydride is removed in decompression, resistates ice-water bath add saturated sodium carbonate to pH be 10, methylene dichloride (10mL) extraction 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography (methylene chloride/methanol=5: 1), obtain light brown solid, i.e. compound 42 (2.73g, yield 85%).Mp：91-93℃；
1HNMR(CDCl
3，300MHz)δ：1.28(t，3H，J＝6.9Hz)，2.04-2.08(m，4H)，2.42(brs，2H)，2.41-2.55(m，2H)，2.52(s，3H)，4.16-4.32(m，3H)，4.47(brs，2H)，7.07-7.12(q，1H)，7.86(dd，1H，J＝1.5Hz)，8.22(dd，1H，J＝1.5Hz).
Step 8:3-(8-azabicyclo [3,2,1] octane-3-yl)-2-methyl-3-hydrogen-imidazoles [4,5-also] pyridine (43)
Adopt the method identical with embodiment 30 steps 9, except adopting compound 42 to replace the compound 34 of embodiment 30 steps 9.
Light brown solid (1.24g, yield 64%); Mp:170-174 DEG C;
1hNMR (CDCl
3, 300MHz) and δ: 1.80-1.84 (m, 2H), 1.99-2.01 (m, 2H), 2.26-2.43 (m, 4H), 2.60 (s, 3H), 3.68-3.72 (m, 2H), 4.64-4.68 (m, 1H), 7.07-7.11 (q, 1H), 7.83-7.86 (dd, 1H), 8.22-8.24 (dd, 1H, J=4.5Hz).
13cNMR (CDCl
3, 400MHz) and δ: 15.2,33.7,34.5,46.4,52.0,117.4,125.8,135.1,142.3,148.5,153.1.EI-MS (M/Z): 242 (M
+).
Step 9:(1S)-3-(3-(2-methyl-3-hydrogen-imidazoles [4,5-is also] pyridin-3-yl)-8-azabicyclo [3,2,1] octane-8-yl)-1-(naphthalene-1-yl) the propyl carbamic acid tert-butyl ester (44)
Adopt the method identical with embodiment 1 step 10, except adopting compound 43 to replace the compound 9a of embodiment 1 step 10, compound 39 replaces the compound 4a of embodiment 1 step 10.
Light yellow oily liquid (38mg, yield 87%);
1hNMR (CDCl
3, 300MHz) and δ: 1.43 (s, 9H), 1.89-1.93 (m, 4H), 2.11-2.12 (m, 4H), 2.49-2.57 (m, 4H), 2.70 (s, 3H), 3.39-3.46 (m, 2H), 4.86-4.94 (m, 1H), 5.81 (brs, 1H), 6.08 (brs, 1H), 7.10-7.14 (m, 1H), 7.46-7.53 (m, 4H), 7.76-7.92 (dd, 1H), 7.86-7.89 (dd, 1H), (8.25-8.26 dd, 1H).
The fluoro-N-of step 10:4-((1S)-3-(3-(2-methyl-3-hydrogen-imidazoles [4,5-is also] pyridin-3-yl)-8-azabicyclo [3,2,1] octane-8-yl)-1-(naphthalene-1-yl) propyl group) benzamide (I-6)
Adopt the method identical with embodiment 22 steps 5, except adopting compound 44 to replace the compound 13 of embodiment 22 steps 5, to the phenylformic acid of fluorophenyl acid substitution embodiment 22 steps 5.
Light yellow oily liquid (19mg, yield 57%),
1hNMR (CDCl
3, 300MHz) δ: 1.28-1.37 (m, 4H), 1.68-1.74 (m, 2H), 1.83-1.87 (m, 2H), 2.35-2.46 (m, 2H), 2.63 (s, 3H), 2.82-2.85 (m, 2H), 3.37-3.42 (m, 2H), 4.08-4.13 (m, 1H), 5.21 (brs, 1H), 7.26-7.29 (m, 1H), 7.51-7.54 (m, 1H), 7.75-7.80 (m, 5H), 7.90-7.93 (m, 1H), 8.16-8.19 (m, 1H), 8.24-8.31 (m, 4H), 8.32-8.34 (m, 1H) .EI-MS (M/Z): 547 (M
+).
Embodiment 32
Compound I-7a:(S)-4-benzyl-1-(3-(ring fourth methane amide)-3-(4-(fluoroform man) phenyl) propyl group) piperidines-4-methyl-formiate
Step 1:4-methyl-formiate-4-benzyl piepridine-1-t-butyl carbamate (45)
Adopt the method identical with embodiment 1 step 6, except adopting cylite to replace the methyl iodide of embodiment 1 step 6.
Colourless oil liquid (3.03g, yield 87%);
1hNMR (CDCl
3, 300MHz) and δ: 1.40-1.46 (m, 2H), 1.44 (s, 9H), 2.05-2.10 (d, 2H), 2.81 (brs, 4H), 3.63 (s, 3H), 3.88-3.96 (s, 2H), 7.01-7.03 (m, 2H), (7.21-7.28 m, 3H).
Step 2:(S)-4-benzyl-1-(3-(tertiary fourth oxygen methane amide)-3-(4-(trifluoromethyl) phenyl) propyl group) piperidines-4-methyl-formiate (46)
Adopt the method identical with embodiment 30 steps 10, except adopting compound 45 to replace the compound 34 of embodiment 30 steps 10.
Colourless oil liquid (183mg, yield 86%); [α]
d 22=-14.2 ° of (c=0.34, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.44 (s, 9H), 1.60-1.80 (m, 4H), 2.16-2.31 (m, 8H), 2.84 (s, 2H), 3.61 (s, 3H), 4.77-4.84 (brs, 1H), 7.02 (d, 2H), 7.21-7.29 (m, 3H), 7.37 (d, 2H), 7.56 (d, 2H).
Step 3:(S)-4-benzyl-1-(3-(ring fourth methane amide)-3-(4-(trifluoromethyl) phenyl) propyl group) piperidines 4-methyl-formiate (I-7a)
Adopt the method identical with embodiment 22 steps 5, except adopting compound 49 to replace the compound 13 of embodiment 22 steps 5, ring butyric acid replaces the phenylformic acid of embodiment 22 steps 5.
Faint yellow gluey solid (155mg, yield 85%); [α]
d 20=-26.4 ° of (c=0.36, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.64-2.15 (m, 11H), 2.43-2.51 (m, 2H), 2.85 (s, 2H), 2.98-3.17 (m, 6H), 3.65 (s, 3H), 4.97-5.03 (m, 1H), 7.04 (d, 2H), 7.24-7.34 (m, 5H), 7.55 (d, 2H), 7.92-7.95 (brs, 1H) .EI-MS (M/Z): 516 (M
+).
Embodiment 33
Compound I-7b:(S)-N-(3-(4-benzyl-4-(methylol) piperidin-1-yl)-1-(4-(fluoroform man) phenyl) propyl group) ring fourth methane amide
Under ice bath by LiAlH
4(5mg, 0.13mmol) join in dry tetrahydrofuran (THF) (1mL) and stir 15 minutes, mixture is cooled to-15 DEG C, by Compound I-7a (52mg, tetrahydrofuran (THF) (1mL) 0.1mmol) is slowly added drop-wise to above-mentioned reaction also in liquid, adding rear continuation stirs 1 hour, add saturated ammonium chloride (1mL) cancellation reaction, add anhydrous sodium sulphate, filter concentrated rear silica gel column chromatography (methylene chloride/methanol=20: 1), obtain white solid, be Compound I-7b (41mg, yield 84%).
Mp：71-73℃；[α]
D 22＝-29°(c＝0.16，CHCl
3)；
1HNMR(CDCl
3，300MHz)δ：1.60-1.74(m，12H)，1.88-2.00(m，6H)，2.73(s，2H)，2.99-3.04(m，1H)，3.45(s，3H)，5.05-5.11(m，1H)，7.17(d，2H)，7.24-7.35(m，5H)，7.57(d，2H)，8.12-8.14(m，1H).EI-MS(M/Z)：488(M
+).
Embodiment 34
Compound I-8:(S)-4-benzyl-1-(3-(ring fourth methane amide)-3-(naphthalene-1-yl) propyl group) piperidines-4-methyl-formiate
Step 1:(S)-4-benzyl-1-(3-(tertiary fourth oxygen methane amide)-3-(naphthalene-1-yl) propyl group) piperidines-4-methyl-formiate (47)
Adopt the method identical with embodiment 1 step 10, except adopting compound 39 to replace the compound 4a of embodiment 1 step 10, compound 45 replaces the compound 9a of embodiment 1 step 10.
Colorless oil solid (15mg, yield 75%); [α]
d 20=-6 ° of (c=0.05, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.45 (s, 9H), 1.68-1.72 (m, 2H), 2.17-2.25 (m, 4H), 2.67-2.82 (m, 2H), 2.85 (s, 2H), 3.61 (s, 1H), 4.76-4.81 (m, 1H), 7.02-7.05 (m, 2H), 7.21-7.33 (m, 4H), 7.43-7.52 (m, 3H), 7.74-7.77 (m, 1H), 7.84-7.86 (m, 1H), (8.06-8.12 m, 1H).
Step 2:(S)-4-benzyl-1-(3-(ring fourth methane amide)-3-(naphthalene-1-yl) propyl group) piperidines-4-methyl-formiate (I-8)
Adopt the method identical with embodiment 22 steps 5, except adopting compound 47 to replace the compound 13 of embodiment 22 steps 5, ring butyric acid replaces the phenylformic acid of embodiment 22 steps 5.
Colourless colloidal solid (15mg, yield 99%); [α]
d 20=-18 ° of (c=0.07, CHCl
3);
1hNMR (CDCl
3, 300MHz) and δ: 1.82-1.99 (m, 2H), 2.10-2.36 (m, 11H), 2.57-2.60 (m, 2H), 2.86 (s, 2H), 2.99-3.17 (m, 4H), 3.64 (s, 3H), 5.81-5.83 (m, 1H), 7.02-7.05 (d, 2H), 7.24-7.28 (m, 3H), 7.42-7.51 (m, 4H), 7.52-7.83 (m, 1H), 7.84-7.86 (d, 1H), 8.04-8.06 (d, 1H) .EI-MS (M/Z): 498 (M
+).
Embodiment 35
Compound I-9a:(S)-N-(3-(4-(4-(benzyl (sec.-propyl) amino) phenyl) piperazine-1-yl)-1-(4-(trifluoromethyl) phenyl) propyl group) cyclohexanecarbonyl amine
Step 1:4-(4-aminophenyl) piperazine-1-t-butyl carbamate (48)
Adopt the method identical with embodiment 1 step 7-8, except adopting compound 4-(4-methoxycarbonyl phenyl) piperazine-1-t-butyl carbamate to replace the compound 6a of embodiment 1 step 7.
Colourless oil liquid (1.8g, yield 50%)
Step 2:4-(4-(isopropylamino) phenyl) piperazine-1-t-butyl carbamate (49)
Under nitrogen protection; by compound 48 (1.748g; 6.16mmol) be dissolved in acetone (30mL); add successively sodium triacetoxy borohydride (3.90g; 18.5mmol); Glacial acetic acid (1.19g, 18.5mmol), continues reaction 7 hours under room temperature; after finishing, reaction add water and sodium hydrogen carbonate solution to pH to 10; methylene dichloride (30mL) extraction 3 times, merges organic phase, saturated common salt water washing; anhydrous sodium sulfate drying; obtain light brown solid, i.e. compound 49 (1.897g, yield 97%).Mp：67-68℃；
1HNMR(CDCl
3，300MHz)δ：1.19(d，6H，J＝6.0Hz)，1.48(s，9H)，2.96(s，4H)，3.54-3.58(m，5H)，6.58(brs，2H)，6.84(brs，2H).
Step 3:4-(4-(benzyl (sec.-propyl) amino) phenyl) piperazine-1-t-butyl carbamate (50)
Under ice bath, bromobenzyl (0.96g, 5.62mmol) is carefully slowly joined to compound 49 (1.494g, 4.68mmol), in the dry acetonitrile (30mL) of salt of wormwood (2.58g, 18.72mmol), stirring reaction 5 hours, concentrated except desolventizing, methylene dichloride (10mL) extraction 3 times, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, obtain brown oily liquids, i.e. compound 50 (1.773g, yield 93%).
1HNMR(CDCl
3，300MHz)δ：1.18(d，6H，J＝6.6Hz)，1.47(s，9H)，2.94(s，4H)，3.52-3.55(m，4H)，4.09-4.15(m，1H)，4.34(s，2H)，6.67-6.69(m，2H)，6.80-6.83(m，2H)，7.29-7.37(m，5H).
Step 4:(S)-3-(4-(4-(benzyl (sec.-propyl) amino) phenyl) piperazine-1-yl)-1-(4-(trifluoromethyl) phenyl) the propyl carbamic acid tert-butyl ester (51)
Adopt the method identical with embodiment 30 steps 10, except adopting compound 50 to replace the compound 34 of embodiment 30 steps 10.
Colourless oil liquid (173mg, yield 50%)
Step 5:(S)-N-(3-(4-(4-(benzyl (sec.-propyl) amino) phenyl) piperazine-1-yl)-1-(4-(trifluoromethyl) phenyl) propyl group) cyclohexanecarbonyl amine (I-9a)
Adopt the method identical with embodiment 29 steps 5, except adopting compound 51 to replace the compound 24 of embodiment 29 steps 5.
Light brown colloidal solid (123mg, yield 79%);
1hNMR (CDCl
3, 300MHz) and δ: 1.18 (d, 6H, J=6.9Hz), 1.39-2.22 (m, 14H), 2.46 (s, 2H), 2.66-2.73 (m, 4H), 3.12 (s, 4H), 4.10-4.19 (m, 1H), 4.35 (s, 2H), 5.08-5.14 (m, 1H), 6.68 (d, 2H), 6.82 (d, 2H), 7.15-7.31 (m, 5H), 7.31 (d, 2H), 7.35 (d, 2H), 8.18 (brs, 1H).
Embodiment 36
Compound I-9b:(S)-N-(3-(4-(4-(N-sec.-propyl ethanamide) phenyl) piperazine-1-yl)-1-(4-(trifluoromethyl) phenyl) propyl group) cyclohexanecarbonyl amine
Under room temperature, to be dissolved with Compound I-9a (147mg, in ethanol solution (20mL) 0.24mmol), add 10%Pd/C (50mg), normal pressure hydrogenation reaction 10 hours, filter, removal of solvent under reduced pressure, methylene dichloride (10mL) dilution, in system, add acetic anhydride (102mg, 1.1mmol), react 3 hours, under ice bath, saturated sodium bicarbonate adjusting pH is 8, saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography (methylene chloride/methanol=20: 1) after concentrated, obtain light brown solid, be Compound I-9b (59mg, yield 94%).Mp：73-75℃；
1HNMR(CDCl
3，300MHz)δ：1.02(d，6H，J＝6.9Hz)，1.39-1.51(m，2H)，1.61-1.73(m，8H)，1.74(s，3H)，1.87-1.91(m，2H)，2.01-2.18(m，2H)，2.32-2.43(m，2H)，2.58-2.69(m，2H)，3.18-3.28(m，3H)，4.96-5.04(m，1H)，6.89(d，2H)，6.98(d，2H)，7.35(d，2H)，7.57(d，2H)，7.75(d，1H).EI-MS(M/Z)：572(M
+).
Embodiment 37
Compound I-10a:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) encircles propyl formamide
Step 1:(S)-3-(ring propyl formamide)-3-(3-fluorophenyl) ethyl propionate (3b)
Adopt the method identical with embodiment 1 step 3, except adopting compound cyclopropanecarboxylic acid to replace the heptanaphthenic acid of embodiment 1 step 3.
White solid (270mg, yield 54%);
1hNMR (CDCl
3, 300MHz) and δ: 1.18 (t, 3H, J=7.2Hz), 1.23-1.37 (m, 3H), 1.66-1.71 (m, 1H), 1.78-1.84 (m, 2H), 2.77-2.92 (m, 2H), (4.09 q, 2H, J=7.2Hz), 5.39-5.45 (m, 1H), 6.74-6.78 (m, 1H), 6.92-7.02 (m, 2H), 7.04-7.08 (m, 1H), (7.26-7.32 m, 1H).
Step 2:(S)-N-(1-(3-fluorophenyl)-3-oxopropyl) ring propyl formamide (4b)
Adopt the method identical with step 4 in embodiment 1, except adopting compound 3b to replace the compound 3a of embodiment 1 step 4.
White solid (133mg, yield 50%);
Step 3:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) ring propyl formamide (I-10a)
Adopt the method identical with embodiment 1 step 10, except adopting compound 4b to replace the 4a of embodiment 1 step 10, adopt compound 9s to replace the 9a of embodiment 1 step 10.
White solid (33mg, yield 67%),
1hNMR (CDCl
3, 300MHz) δ: 1.23-1.25 (m, 3H), 1.41 (s, 3H), 1.44-1.48 (m, 1H), 1.89-1.93 (m, 2H), 2.09-2.17 (m, 7H), 2.28-2.35 (m, 2H), 2.51-2.54 (m, 1H), 2.65-2.71 (m, 1H), 3.44 (s, 2H), 5.03-5.06 (m, 1H), 5.30 (br, 1H), 6.89-6.92 (m, 2H), 7.01 (d, 1H, J=7.8Hz), 7.11 (d, 1H, J=8.4Hz), 7.39-7.43 (m, 2H), 8.05-8.08 (m, 1H).
Embodiment 38
Compound I-10b:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group)-4,4-difluoro cyclohexanecarbonyl amine
Step 1:(S)-3-(4,4-difluoro cyclohexanecarbonyl amine)-3-(3-fluorophenyl) ethyl propionate (3c)
Adopt the method identical with embodiment 1 step 3, except adopting compound 4,4-difluoro heptanaphthenic acid replaces the heptanaphthenic acid of embodiment 1 step 3.
White solid (185mg, yield 64%);
1hNMR (CDCl
3, 300MHz) and δ: 1.20 (t, 3H, J=7.2Hz), 1.23-1.35 (m, 3H), 1.68-1.71 (m, 1H), 1.78-1.83 (m, 2H), 1.87-1.94 (m, 2H), 2.13-2.22 (m, 1H), 2.77-2.91 (m, 2H), 4.07 (q, 2H, J=7.2Hz), 5.38-5.45 (m, 1H), 6.75-6.77 (m, 1H), 6.93-7.01 (m, 2H), 7.04-7.08 (m, 1H), (7.26-7.32 m, 1H).
Step 2:(S)-N-(1-(3-fluorophenyl)-3-oxopropyl) ring propyl formamide (4c)
Adopt the method identical with step 4 in embodiment 1, except adopting compound 3c to replace the compound 3a of embodiment 1 step 4.
White solid (78mg, yield 50%);
Step 3:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group)-4,4-difluoro cyclohexanecarbonyl amine (I-10b)
Adopt the method identical with embodiment 1 step 10, except adopting compound 4c to replace the 4a of embodiment 1 step 10, adopt compound 9s to replace the 9a of embodiment 1 step 10.
White solid (21mg, yield 71%),
1hNMR (CDCl
3, 300MHz) δ: 1.21-1.27 (m, 3H), 1.51 (m, 3H), 1.76-1.82 (m, 6H), 1.92-1.95 (m, 2H), 2.10-2.17 (m, 2H), 2.23-2.41 (m, 6H), 2.62-2.65 (m, 1H), 2.78-2.83 (m, 1H), 5.06-5.09 (m, 1H), 5.87 (s, 1H), 6.94 (d, 2H, J=9.0Hz), 7.00 (d, 1H, J=7.5Hz), 7.25-7.31 (m, 1H), 7.44-7.51 (m, 3H), 7.75 (d, 2H, J=7.5Hz), 8.18 (d, 1H, J=6.3Hz).
Embodiment 39
Compound I-10c:(S)-2-ring propoxy--N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) ethanamide
Step 1:(S)-3-(2-ring propoxy-methane amide)-3-(3-fluorophenyl) ethyl propionate (3d)
Adopt the method identical with embodiment 1 step 3, except adopting compound 2-to encircle the heptanaphthenic acid that the third fluoroacetic acid replaces embodiment 1 step 3.
White solid (181mg, yield 49%);
1hNMR (CDCl
3, 300MHz) and δ: 1.17 (t, 3H, J=7.2Hz), 1.23-1.36 (m, 3H), 1.66-1.72 (m, 1H), 1.79-1.84 (m, 2H), 2.78-2.92 (m, 2H), (4.08 q, 2H, J=7.2Hz), 4.56 (s, 2H), 5.37-5.44 (m, 1H), 6.73-6.78 (m, 1H), 6.92-7.01 (m, 2H), 7.03-7.08 (m, 1H), (7.26-7.33 m, 1H).
Step 2:(S)-N-(1-(3-fluorophenyl)-3-oxopropyl) ring propyl formamide (4d)
Adopt the method identical with step 4 in embodiment 1, except adopting compound 3d to replace the compound 3a of embodiment 1 step 4.
White solid (68mg, yield 39%);
Step 3:(S)-2-ring propoxy--N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group) ethanamide (I-10c)
Adopt the method identical with embodiment 1 step 10, except adopting compound 4d to replace the 4a of embodiment 1 step 10, adopt compound 9s to replace the 9a of embodiment 1 step 10.
White solid (23mg, yield 58%),
1hNMR (CDCl
3, 300MHz) δ: 1.21-1.25 (m, 3H), 1.42 (s, 3H), 1.44-1.49 (m, 1H), 1.87-1.93 (m, 2H), 2.09-2.19 (m, 7H), 2.27-2.35 (m, 2H), 2.52-2.54 (m, 1H), 2.65-2.72 (m, 1H), 3.45 (s, 2H), 4.56 (s, 2H), 5.03-5.07 (m, 1H), 5.31 (br, 1H), 6.88-6.92 (m, 2H), 7.02 (d, 1H, J=7.8Hz), 7.12 (d, 1H, J=8.4Hz), 7.38-7.43 (m, 2H), 8.04-8.08 (m, 1H).
Embodiment 40
Compound I-10d:(S)-N-(1-(3-(2-(1 hydrogen-indol-3-yl) kharophen)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-1-yl)-2-(3,4-dichlorophenyl) ethanamide)
Step 1:(S)-3-(2-(1 hydrogen-indol-3-yl-) ethanamide)-3-(3-fluorophenyl) ethyl propionate (3e)
Adopt the method identical with embodiment 1 step 3, except adopting compound 3-(1 hydrogen-indoles) acetic acid to replace the heptanaphthenic acid of embodiment 1 step 3.
White solid (132mg, yield 39%);
1hNMR (CDCl
3, 300MHz) and δ: 1.17 (t, 3H, J=7.2Hz), 2.77-2.92 (m, 2H), 3.63 (s, 2H), 4.08 (q, 2H, J=7.2Hz), 5.39-5.45 (m, 1H), 6.75-6.78 (m, 1H), 6.92-7.01 (m, 2H), 7.05-7.08 (m, 1H), 7.26-7.33 (m, 1H), 7.43-7.47 (m, 4H), 7.51-7.54 (m, 1H).
Step 2:(S)-N-(1-(3-fluorophenyl)-3-oxopropyl)-2-(1 hydrogen-indol-3-yl-) ethanamide (4e)
Adopt the method identical with step 4 in embodiment 1, except adopting compound 3e to replace the compound 3a of embodiment 1 step 4.
White solid (47mg, yield 32%);
Step 3:(S)-N-(1-(3-(2-(1 hydrogen-indol-3-yl) kharophen)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-1-yl)-2-(3,4-dichlorophenyl) ethanamide) (I-10d)
Adopt the method identical with embodiment 1 step 10, except adopting compound 4e to replace the 4a of embodiment 1 step 10, adopt compound 9s to replace the 9a of embodiment 1 step 10.
White solid (22mg, yield 38%),
1hNMR (CDCl
3, 300MHz) δ: 1.23-1.26 (m, 3H), 1.42 (s, 3H), 1.43-1.48 (m, 1H), 1.88-1.93 (m, 2H), 2.09-2.16 (m, 3H), 2.29-2.35 (m, 2H), 2.51-2.55 (m, 1H), 3.45 (s, 2H), 3.64 (s, 2H), 5.02-5.06 (m, 1H), 5.31 (br, 1H), 6.88-6.92 (m, 2H), 7.02 (d, 1H, J=7.gHz), 7.10 (d, 1H, J=8.4Hz), 7.37-7.43 (m, 7H), 8.05-8.09 (m, 1H).
Embodiment 41
Compound I-10e:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group)-1 hydrogen-indoles-5-base-methane amide
Step 1:(S)-3-(3-fluorophenyl)-3-(1 hydrogen-indoles-5-base-) methane amide) ethyl propionate (3f)
Adopt the method identical with embodiment 1 step 3, except adopting compound 5-(1 hydrogen-indoles) formic acid to replace the heptanaphthenic acid of embodiment 1 step 3.
White solid (137mg, yield 36%);
1hNMR (CDCl
3, 300MHz) and δ: 1.19 (t, 3H, J=7.2Hz), 2.77-2.91 (m, 2H), 4.07 (q, 2H, J=7.2Hz), 5.37-5.45 (m, 1H), 6.75-6.79 (m, 1H), 6.94-7.01 (m, 2H), 7.05-7.09 (m, 1H), 7.25-7.33 (m, 1H), 7.43-7.48 (m, 4H), 7.50-7.54 (m, 1H).
Step 2:(S)-N-(1-(3-fluorophenyl)-3-oxopropyl)-1 hydrogen-indoles-5-methane amide (4f)
Adopt the method identical with step 4 in embodiment 1, except adopting compound 3f to replace the compound 3a of embodiment 1 step 4.
White solid (43mg, yield 32%);
Step 3:(S) and-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)]-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group)-1 hydrogen-indoles-5-base-methane amide (I-10e)
Adopt the method identical with embodiment 1 step 10, except adopting compound 4f to replace the 4a of embodiment 1 step 10, adopt compound 9s to replace the 9a of embodiment 1 step 10.
White solid (21mg, yield 37%);
1hNMR (CDCl
3, 300MHz) and δ: 1.22-1.26 (m, 3H), 1.41 (s, 3H), 1.43-1.47 (m, 1H), 1.89-1.93 (m, 2H), 2.09-2.17 (m, 3H), 2.28-2.35 (m, 2H), 2.51-2.54 (m, 1H), 3.46 (s, 2H), 5.01-5.06 (m, 1H), 5.32 (br, 1H), 6.88-6.93 (m, 2H), 7.01 (d, 1H, J=7.8Hz), 7.11 (d, 1H, J=8.4Hz), 7.36-7.43 (m, 7H), 8.05-8.08 (m, 1H).
Embodiment 42
Compound I-10f:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group)-1 hydrogen-indol-3-yl-methane amide
Step 1:(S)-3-(3-fluorophenyl)-3-(1 hydrogen-indol-3-yl-) methane amide) ethyl propionate (3g)
Adopt the method identical with embodiment 1 step 3, except adopting compound 3-(1 hydrogen-indoles) formic acid to replace the heptanaphthenic acid of embodiment 1 step 3.
White solid (147mg, yield 38%);
1hNMR (CDCl
3, 300MHz) and δ: 1.18 (t, 3H, J=7.2Hz), 2.77-2.90 (m, 2H), 4.06 (q, 2H, J=7.2Hz), 5.36-5.45 (m, 1H), 6.75-6.78 (m, 1H), 6.95-7.01 (m, 2H), 7.05-7.08 (m, 1H), 7.26-7.33 (m, 1H), 7.43-7.47 (m, 4H), 7.51-7.54 (m, 1H).
Step 2:(S)-N-(1-(3-fluorophenyl)-3-oxopropyl)-1 hydrogen-indoles-3-methane amide (4g)
Adopt the method identical with step 4 in embodiment 1, except adopting compound 3g to replace the compound 3a of embodiment 1 step 4.
White solid (41mg, yield 32%);
Step 3:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(3-fluorophenyl) propyl group)-1 hydrogen-indol-3-yl-methane amide (I-10f)
Adopt the method identical with embodiment 1 step 10, except adopting compound 4g to replace the 4a of embodiment 1 step 10, adopt compound 9s to replace the 9a of embodiment 1 step 10.
White solid (20mg, yield 35%);
1hNMR (CDCl
3, 300MHz) and δ: 1.21-1.26 (m, 3H), 1.42 (s, 3H), 1.43-1.48 (m, 1H), 1.88-1.93 (m, 2H), 2.09-2.16 (m, 3H), 2.29-2.35 (m, 2H), 2.51-2.55 (m, 1H), 3.47 (s, 2H), 5.01-5.05 (m, 1H), 5.33 (br, 1H), 6.88-6.94 (m, 2H), 7.02 (d, 1H, J=7.8Hz), 7.10 (d, 1H, J=8.4Hz), 7.35-7.43 (m, 7H), 8.05-8.09 (m, 1H).
Embodiment 43
Compound I-10g:(S)-N-(1-(3-(cyclohexylamino)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-1-yl)-2-(3,4-dichlorophenyl) ethanamide
Step 1:(S)-3-(cyclohexyl methane amide)-3-(3-fluorophenyl) ethyl propionate (3h)
Adopt the method identical with embodiment 1 step 3, except adopting compound cyclohexyl SULPHURYL CHLORIDE to replace the heptanaphthenic acid of embodiment 1 step 3.
White solid (132mg, yield 78%);
1hNMR (CDCl
3, 300MHz) and δ: 1.17 (t, 3H, J=7.2Hz), 1.24-1.37 (m, 3H), 1.40-1.51 (m, 2H), 1.65-1.71 (m, 1H), 1.78-1.83 (m, 2H), 1.88-1.94 (m, 2H), 2.12-2.21 (m, 1H), 2.78-2.92 (m, 2H), 4.08 (q, 2H, J=7.2Hz), 5.38-5.45 (m, 1H), 6.75-6.79 (m, 1H), 6.93-7.01 (m, 2H), 7.05-7.09 (m, 1H), 7.25-7.33 (m, 1H).
Step 2:(S)-N-(1-(3-fluorophenyl)-3-oxopropyl) cyclohexyl methane amide (4h)
Adopt the method identical with step 4 in embodiment 1, except adopting compound 3h to replace the compound 3a of embodiment 1 step 4.
White solid (61mg, yield 52%);
Step 3:(S)-N-(1-(3-(cyclohexylamino)-3-(3-fluorophenyl) propyl group)-4-methyl piperidine-1-yl)-2-(3,4-dichlorophenyl) ethanamide (I-10g)
Adopt the method identical with embodiment 1 step 10, except adopting compound 4h to replace the 4a of embodiment 1 step 10, adopt compound 9s to replace the 9a of embodiment 1 step 10.
White solid (25mg, yield 43%),
1hNMR (CDCl
3, 300MHz) δ: 1.24-1.27 (m, 3H), 1.42-1.51 (m, 2H), 1.53 (m, 3H), 1.75-1.83 (m, 6H), 1.91-1.94 (m, 2H), 2.11-2.19 (m, 2H), 2.26-2.43 (m, 6H), 2.62-2.65 (m, 1H), 2.78-2.81 (m, 1H), 5.05-5.09 (m, 1H), 5.88 (s, 1H), 6.94 (d, 2H, J=9.0Hz), 7.02 (d, 1H, J=7.5Hz), 7.23-7.31 (m, 1H), 7.43-7.52 (m, 3H), 7.74 (d, 2H, J=7.5Hz), 8.18 (d, 1H, J=6.3Hz).
Embodiment 44
Compound I-11:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(naphthalene-1-yl) propyl group) cyclohexyl methane amide
Step 1:(S)-3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(naphthalene-1-yl) the propyl group carbonic acid tert-butyl ester (52)
Adopt the method identical with embodiment 1 step 10, except adopting compound 39 to replace the 4a of embodiment 1 step 10, adopt compound 9s to replace the 9a of embodiment 1 step 10.
White solid (62mg, yield 52%);
Step 2:(S)-N-(3-(4-(2-(3,4-dichlorophenyl) ethanamide)-4-methyl piperidine-1-yl)-1-(naphthalene-1-yl) propyl group) cyclohexyl methane amide (I-11)
Adopt the method identical with embodiment 24, except adopting compound 52 to replace 13 of embodiment 24.
White solid (32mg, yield 46%),
1hNMR (CDCl
3, 300MHz) δ: 1.24-1.28 (m, 3H), 1.41-1.51 (m, 2H), 1.52 (m, 3H), 1.76-1.82 (m, 6H), 1.91-1.93 (m, 2H), 2.12-2.19 (m, 2H), 2.27-2.42 (m, 6H), 2.61-2.65 (m, 1H), 2.77-2.82 (m, 1H), 5.04-5.09 (m, 1H), 5.89 (s, 1H), 6.95 (d, 2H, J=9.0Hz), 7.01 (d, 1H, J=7.5Hz), 7.24-7.31 (m, 4H), 7.42-7.51 (m, 3H), 7.73 (d, 2H, J=7.5Hz), 8.19 (d, 1H, J=6.3Hz).
The test example of biologic activity
CCR5 belongs to G-protein linked receptor (GPCR) family.Drug development technical development for GPCR is comparatively perfect, wherein receptors ligand combined techniques, GTP γ S combined techniques and Ca
2+the experimental techniques such as stream detection method are widely used in the drug screening that Chemokine Receptors is relevant.Compound in the present invention adopted filtering type [
35s] GTP γ S in conjunction with experiment, SPA-WGA method [
35s] GTP γ S suppresses activity in conjunction with the CCR5 that flows three kinds of methods of test experience test the compounds of this invention in experiment and calcium.
A.[
35s] GTP γ S is in conjunction with experiment
After CCR5 is combined with agonist, occurred conformation changes, thereby CCR5 and G albumen are interacted, and has activated G albumen.G albumen is by α, and tri-kinds of subunits of β and γ form, and this heterotrimer represents with G α β γ.The activation of CCR5 causes that GDP molecule is exchanged for GTP, and heterotrimer G α β γ albumen is dissociated into G α and G β γ albumen from acceptor.The ability of being combined with GTP due to α subunit depends on the effect of CCR5 and agonist, and the GTP amount of measuring the combination of α subunit just can reflect the activation capability of agonist to CCR5.,,, adopt simultaneously also for easy to detect in order to get rid of because GTP enzymic hydrolysis GTP causes the activation that can not accurately reflect CCR5 with the protein bound GTP amount of G in conjunction with in testing at GTP γ S
35the analog GTP γ S of the GTP of S mark substitutes GTP, and GTP γ S can be combined but can not be hydrolyzed with the α subunit being activated.Like this, in the time that CCR5 is not activated, α subunit is in conjunction with GDP; After CCR5 activates, α subunit is in conjunction with GTP γ S, and GTP γ S is irreversibly combined on α subunit.Therefore, mensuration α subunit combination [
35s] quantity of-GTP γ S just can reflect the degree that CCR5 is activated by agonist.In the time adding antagonist, the ability that makes agonist activate CCR5 is declined.
G free in the experiment of this class protein bound [
35s]-GTP γ S can use the method for film suction filtration to separate, and is referred to as filtering type GTP γ S experiment.
Or utilize SPA (Scintillation Proximity Assay) technology detect same G protein bound [
35s]-GTP γ S, be just called SPA-WGA method [
35s] GTP γ S is in conjunction with experiment.The principle of SPA technology is: the subatomic particle that the decay process of radioactive atom discharges, for example β ray (electronics) can excite microballoon luminous and detected by photometry instrument under enough near distance.In aqueous phase solution, the energy major part of this class ray is by solvent absorbing, and propagation distance is very limited.Therefore, if luminous microballoon is connected on cytolemma by wheat germ agglutinin (WGA), only have same G protein bound [
35s]-GTP γ S just has enough short distance and excites microballoon luminous, thus the activation of reflection acceptor.
CCR5 measures by following experiment the activation of G albumen.
Express lysis buffer for CHO (Chinese hamster ovary cell) permanent cell line (CHO-CCR5) (5mMTris-HCl, pH 7.5,5mM EDTA and the 5mM EGTA) cracking of CCR5, with the centrifugal 10min of 15,000 × g.Reaction buffer for cytolemma (5mM Tris-HCl, pH 7.5,5mM MgCl
2, 1mM EGTA, 100mM NaCl) resuspended after, with the legal albumen of Bioford of Bio-Rad.Then, carry out GTP γ S in conjunction with experiment in reaction buffer, wherein, reaction system is 100 μ L, containing 10 μ g membranins, and 40 μ M GDP, 0.5nM[
35s]-GTP γ S (1200Ci/mmol), add after compound to be measured, after vibration mixes, the test tube of reaction is hatched 1 hour in 30 DEG C.After reaction finishes, test tube is placed on ice, dilute with stopped reaction with PBS, and use GF/C filter membrane vacuum filtration at once.In conjunction with radioactive activity add after scintillation solution with liquid flashing counting determining, Here it is filtering type GTP γ S experimental technique.The preceding step of SPA-WGA measuring method is with GTP γ S experimental technique, just finish to add after PBS termination reaction in reaction, in reaction system, add SPA-WGA microballoon, then add compound to be measured, after system mixes, hatch 1 hour in 30 DEG C, then put part termination reaction on ice.Room temperature is centrifugal, 1000rpm, 15min.Use subsequently liquid flashing counting determining.
In conjunction with radioactive activity liquid flashing counting determining.Basis is measured without agonist in the situation that in conjunction with (basal), and non-specific binding (non-specific) is measured in the situation that having the non isotopic GTP γ of 10 μ M S to exist.[
35s]-GTP γ S is in conjunction with per-cent 100 × [c.pm.
sample-c.p.m.
non-specific binding]/[c.p.m.
basis combination-c.p.m.
non-specific binding] calculate.IC
50be suppress that the RANTES (a kind of cytokine that monocytes/macrophages is had to strong chemotaxis) of 10nM causes [
35s] compound concentration of-GTP γ S in conjunction with 50% time, obtain from the concentration curve of compound.
When concentration-inhibitions curve of research compound, taking the highest CPM value under agonist RANTES effect or RFU value as 100%, background CPM value or RFU value are 0%, then pass through the Sigmaplot of statistical software matching, and obtain the IC of antagonist
50value.When compound concentration is 1 μ M, when the CCR5 ability that its antagonism detects does not exceed 90%, for the convenient virtual concentration that needs of mapping, in this research, virtual point is: in the time that compound is 1mM, its antagonizing CCR 5 ability is 100%.
B. stream test experience in calcium
After being activated, G albumen can regulate experiment Ca in kytoplasm by several different mechanism
2+the variation of concentration, thereby the level that reflection GPCR is activated.The Fluo-4calcium dye (fluorescence-4 calcium ion dyestuff) of Invitrogen company is the conventional Ca of a class
2+the fluorescence dye detecting, and the detection of signal can complete with the FlexStation of molecular device or FLIPR conventionally.The present invention is by overexpression G in CHO-CCR5 stable cell lines
qthe mode of family protein-G16, has realized G
i/othe CCR5 acceptor of albumen coupling is to G
qthe activation of signal path.
Experiment starts to use serum-free medium culturing cell in first 4 hours, use 0.04%EDTA-PBS peptic cell, and buffer solution for cleaning once with HBSS (Hank ' s balanced salt solution).With the HBSS resuspension cell that contains 2.5mM Probenecid (benemid), preprepared Fluo-4AM (a kind of fluorescence dye) and Cremophor EL (polyoxyethylenated castor oil) mixed solution are joined in cell suspension, after mixing, in 37 DEG C of incubators, react 40min, then the centrifugal 3min of 800rpm, abandon supernatant, 5mL HBSS washes cell 2 times.Spread 96 orifice plates (100 μ L/ hole) with 11mL HBSS suspension cell, the centrifugal 3min of 96 orifice plate 1000rpm, room temperature lucifuge is incubated 10min, add the drug solution of 50 μ L, instrument FlexStation is set, adds agonist solution (25 μ L/ hole), determination data.
C. molecular level active testing result
[
35s] GTP γ S is in conjunction with flowing test experience and show in experiment and calcium, and a series of compounds of the present invention are antagonists of CCR5, and they suppress the RANTES activation CCR5 of 10nM and the combination of the GTP γ S that causes, its inhibition situation and IC
50be listed in the table below 1.
Table 1
| Embodiment sequence number | Compound number | IC 50(nM) |
| 1 | I-1a | Inhibiting rate 22.68% when inhibiting rate 25.79% 30nM concentration when 300nM concentration |
| 2 | I-1b | Inhibiting rate 5.94% when inhibiting rate 12.24% 30nM concentration when 300nM concentration |
| 3 | I-1c | Inhibiting rate 6.20% when inhibiting rate 26.76% 30nM concentration when 300nM concentration |
| Embodiment sequence number | Compound number | IC 50(nM) |
| 4 | I-1d | Inhibiting rate 3.98% when inhibiting rate 8.34% 30nM concentration when 300nM concentration |
| 5 | I-1e | Inhibiting rate 9.86% when inhibiting rate 4.07% 30nM concentration when 300nM concentration |
| 6 | I-1f | Inhibiting rate 8.61% when 300nM concentration |
| 7 | I-1g | Inhibiting rate 42.50% when inhibiting rate 87.21% 30nM concentration when 300nM concentration |
| 8 | I-1h | Inhibiting rate 21.67% when 300nM concentration |
| 9 | I-1i | Inhibiting rate 10.26% when inhibiting rate 15.57% 30nM concentration when 300nM concentration |
| 10 | I-1j | - |
| 11 | I-1k | Inhibiting rate 8.88% when inhibiting rate 32.61% 30nM concentration when 300nM concentration |
| 12 | I-1l | Inhibiting rate 35.04% when inhibiting rate 44.24% 30nM concentration when 300nM concentration |
| 13 | I-1m | Inhibiting rate 3.37% when inhibiting rate 6.86% 30nM concentration when 300nM concentration |
| 14 | I-1n | Inhibiting rate 6.01% when inhibiting rate 28.88% 30nM concentration when 300nM concentration |
| 15 | I-1o | Inhibiting rate 23.71% when inhibiting rate 31.15% 30nM concentration when 300nM concentration |
| 16 | I-1p | Inhibiting rate 21.88% when inhibiting rate 97.79% 30nM concentration when 300nM concentration |
| 17 | I-1q | Inhibiting rate 27.45% when inhibiting rate 90.96% 30nM concentration when 300nM concentration |
| 18 | I-1r | Inhibiting rate 30.83% when inhibiting rate 95.46% 30nM concentration when 300nM concentration |
| 19 | I-1s | Inhibiting rate 36.34% when inhibiting rate 97.04% 30nM concentration when 300nM concentration |
| 20 | I-1t | Inhibiting rate 25.02% when inhibiting rate 60.09% 30nM concentration when 300nM concentration |
| 21 | I-1u | Inhibiting rate 21.19% when inhibiting rate 46.11% 30nM concentration when 300nM concentration |
| 22 | I-2a | 1μM |
| 23 | I-2b | - |
| 24 | I-2c | 480nM |
| 25 | I-2d | - |
| 26 | I-3a | - |
| 27 | I-3b | - |
| 28 | I-3c | - |
| 29 | I-4 | Inhibiting rate 85.73% when inhibiting rate 97.25% 30nM concentration when 300nM concentration |
| 30 | I-5 | 253nM |
| Embodiment sequence number | Compound number | IC 50(nM) |
| 31 | I-6 | - |
| 32 | I-7a | - |
| 33 | I-7b | - |
| 34 | I-8 | - |
| 35 | I-9a | - |
| 36 | I-9b | - |
| 37 | I-10a | + |
| 38 | I-10b | + |
| 39 | I-10c | + |
| 40 | I-10d | + |
| 41 | I-10e | + |
| 42 | I-10f | + |
| 43 | I-10g | + |
| 44 | I-11 | + |
Note: when "-" is illustrated in 300nM concentration, this compound does not show CCR5 antagonistic activity; When "+" is illustrated in 300nM concentration, this compound shows certain CCR5 antagonistic activity.
The activity data of listing in table 1 fully shows, compound of the present invention is all the antagonist of chemokine receptor CCR 5, and wherein 2 compounds (being specially: I-1g and I-4) are to the active IC of the inhibition of CCR5 acceptor
50reach 30nM rank, the IC of 9 compounds (being specially: I-1l, I-1p, I-1q, I-1r, I-1s, I-1t, I-1u, I-2c and I-11)
50reach 300nM rank.
Therefore, the compounds of this invention is effective CCR5 antagonist, can be used as the medicine of the disease of CCR5 mediation, as the medicine for the treatment of HIV-1 poisoning intrusion, autoimmune disorder, asthma, rheumatoid arthritis, chronic obstructive pulmonary disease etc.
Claims (7)
1. the 1-shown in general formula (II) (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds or its pharmacy acceptable salt,
R
1for cyclohexyl;
X is C (O);
R
2for hydrogen;
G does not exist;
L is C;
M is N;
R
4for CH
3;
R
5for hydrogen;
Y is C (O);
R
6do not exist or for C
1-C
4alkylidene group;
R
7for following groups unsubstituted or that replaced by 1-3 substituting group: phenyl, naphthyl or adamantyl, described substituting group is selected from following atom or group: C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, CF
3, NO
2, amino and one or two C
1-C
6the amino that alkyl replaces;
R
10for hydrogen, halogen or trifluoromethyl;
R
11for hydrogen or halogen,
Described halogen is fluorine, chlorine, bromine or iodine.
2.1-(3-(S)-aminopropyl)-piperidine-4-aminoamide compounds or its pharmacy acceptable salt, is characterized in that, is specially following compound:
3. the preparation method of (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds of the 1-described in any one or its pharmacy acceptable salt in a claim 1～2, it is characterized in that, by comprising following method preparation:
Method one:
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, X and Y definition identical with claim 1;
P and P ' are tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzyl, 9-fluorenylmethyloxycarbonyl, CH independently
3cO-or CH
3oCO-;
Step is a): under organic bases or mineral alkali exist, and R
3there is Horner-Wadsworth-Emmons with diethyl phospho ethyl acetate and react in CHO, obtains α, β-unsaturated compound 1;
Step is b): α, and under organic bases exists, there is Micheal addition reaction with (R)-N-benzyl-1-phenylethylamine and obtain compound 2 in β-unsaturated compound 1;
Step is c): compound 2 hydrogenations remove after benzyl and styroyl and R
1or R
2the aldehydes or ketones generation reduction amination or and the R that replace
1and R
2the acid generation linked reaction or and the R that replace
1or R
2the halohydrocarbon generation nucleophilic substitution reaction replacing, obtains N-trisubstituted amine compound 3; Or
Step c '): compound 2 hydrogenations remove after benzyl and styroyl, and free amino connects upper protecting group P ' by linked reaction or nucleophilic substitution reaction, then with R
2the aldehydes or ketones generation reduction amination or and the R that replace
2the acid generation linked reaction or and the R that replace
2the halohydrocarbon generation nucleophilic substitution reaction replacing, obtains the N-trisubstituted amine compound 3 ' with P ';
Steps d): compound 3 or compound 3 ' prepare beta-amino aldehyde cpd 4 or compound 4 ' through oxidizing reaction after being reduced to alcohol by reductive agent again;
Step is e): 4-piperidine carboxylic acid carries out, after esterification, amino protection is obtained to compound 5;
Step is f): compound 5 is introduced R in the α position of ester group under the effect of alkali or by nucleophilic substitution reaction
4obtain compound 6;
Step g): compound 6 obtains carboxylic acid cpd 7 by saponification reaction ester hydrolysis under the effect of alkali;
Step is h): carboxylic acid cpd 7 is prepared into acid amides triazo-compound by mixed anhydride method or chloride method or active ester method, and this compound is reset the isocyanic ester obtaining and is hydrolyzed and obtains aminocompound 8 under the effect of alkali by Ku Ertisi;
Step I): aminocompound 8 with contain R
5compound and contain-R
6-R
7compound react respectively, generate compound 9;
Step is j): after compound 9 deprotection base P, with beta-amino aldehyde cpd 4, reduction amination occurs and obtain end product 1-(3-(S)-aminopropyl)-piperidine-4-aminoamide compounds; Or
Step j ') there is reduction amination with beta-amino aldehyde cpd 4 ' after compound 9 deprotection base P, then deaminize protecting group P ', and then and R
1the aldehydes or ketones generation reduction amination or and the R that replace
1the acid generation linked reaction or and the R that replace
1the halohydrocarbon generation nucleophilic substitution reaction replacing, obtains final product 1-(3-(S)-aminopropyl)-piperidine-4-aminoamide compounds;
Method two:
Wherein, R
1, R
2, R
3, R
5, R
6, R
7, X and Y definition identical with claim 1;
Step is a): the piperidone that has protecting group P on N-atom with contain R
5amine by reduction amination coupling, then with contain-R
6-R
7carbonyl compound generation condensation reaction obtain compound 10a;
Step is b): compound 10a sloughs protecting group P and obtains compound 10b,
Step is c): then compound 10b with beta-amino aldehyde cpd 4, reduction amination occurs and obtain end product 1-(3-(S)-aminopropyl)-piperidine-4-aminoamide compounds.
4. (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds of the 1-described in any one or its pharmacy acceptable salt purposes in preparation CCR5 antagonist in claim 1～2.
5. the purposes in the medicine of the disease that in claim 1～2, (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds of the 1-described in any one or its pharmacy acceptable salt are mediated by CCR5 in preparation treatment.
6. (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds of the 1-described in any one or its pharmacy acceptable salt purposes in the medicine of preparation treatment HIV infection, asthma, rheumatoid arthritis, autoimmune disorder or chronic obstructive pulmonary disease in claim 1～2.
7. one kind has the pharmaceutical composition that suppresses CCR5 activity, it comprises the 1-described in any one in one or more claims 1～2 for the treatment of significant quantity (3-(S)-aminopropyl)-piperidine-4-aminoamide compounds or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
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| CN1441781A (en) * | 2000-05-17 | 2003-09-10 | 阿斯特拉曾尼卡有限公司 | Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity |
| CN1437599A (en) * | 2000-05-26 | 2003-08-20 | 辉瑞大药厂 | Tryasolyl tropane derivatives for therapy |
| CN1642913A (en) * | 2002-03-25 | 2005-07-20 | 阿斯利康(瑞典)有限公司 | Piperidine or 8-aza-bicyclo[3.2.1]oct-3-yl derivatives useful as modulators of chemokine receptor activity (especially CCR5) |
| WO2004018425A1 (en) * | 2002-08-21 | 2004-03-04 | Astrazeneca Ab | N-4-piperidinyl compounds as ccr5 modulators |
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