CN101384581B - Benzoyl-piperidine derivatives as 5HT2/D3 modulators - Google Patents
Benzoyl-piperidine derivatives as 5HT2/D3 modulators Download PDFInfo
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Abstract
The present invention relates to compounds of the general formula (I) as dual modulators of the 5-HT2a and D3 receptors useful against CNS disorders, wherein A, R<1> , R<2> , n, p, q and r are as defined in the specification.
Description
Particularly, the present invention relates to following general formula compound:
Wherein:
A is optional by 1 to 55 to 6 yuan of heteroaryls or aryl that are selected from down the substituting group replacement of group: cyano group, halo, C
1-6-alkyl, C
1-6-haloalkyl, C
1-6-alkyl sulphonyl or C
1-6-alkoxyl group;
N is 1,2,3 or 4;
P is 1,2,3 or 4;
Q is 0 or 1;
R is 0,1,2 or 3;
R
1The C that is replaced by aryl
2-6-alkynyl or C
2-6-alkenyl,
Or it is optional by 1 to 5 C that is selected from down the substituting group replacement of group
1-6-alkyl:
Halo,
Hydroxyl,
C
1-6-alkyl,
C
1-6-haloalkyl,
-CO (O)-C
1-6-alkyl,
C
3-10-cycloalkyl,
The optional C that is replaced by 1,2 or 3 halo or replaced by aryl
1-6-alkoxyl group,
Optional by halo or C
1-6The aryl that-alkoxyl group replaces,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl replaces and
Phenoxy group,
Or C
1-6-alkoxyl group,
Or it is optional by one or more R
aThe C that replaces
3-10-cycloalkyl,
Or it is optional by one or more R
a4 to 10 yuan of Heterocyclylalkyls that replace,
Or it is optional by one or more R
aThe aryl that replaces,
Or it is optional by one or more R
a5 to 10 yuan of heteroaryls that replace,
Or-NR
bR
c, R wherein
bBe H or C
1-6-alkyl, and R wherein
cBe H, C
1-6-alkyl or optional by one or more R
aSubstituted aryl,
R wherein
aBe selected from:
Halo,
Cyano group,
Oxo,
Hydroxyl,
The halogeno-benzene alkylsulfonyl,
Optional by 1,2 or 3 C that is selected from down the substituting group replacement of group
1-6-alkyl:
5 to 10 yuan of Heterocyclylalkyls and
Optional by halo or by C
1-6The aryl that-alkoxyl group replaces,
C
1-6-haloalkyl,
C
1-6-halogenated alkoxy,
Optional by aryl or 5 to 10 yuan of C that heteroaryl replaces
1-6-alkoxyl group, this aryl or heteroaryl are optional by C
1-6-alkyl replaces,
Aryloxy,
-NH (CO)-C
1-6-alkyl,
-O (CO)-C
1-6-alkyl,
C
1-6-alkyl sulphonyl,
Aryl,
Optional by hydroxyl, C
1-64 to 10 yuan of Heterocyclylalkyls that-alkyl or oxo replace,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl or oxo replace and
Two (C
1-6) alkylamino;
R
2Be H, OH, C
1-6-alkyl or halo;
With and pharmacologically acceptable salts.
Be surprisingly found out that formula of the present invention (I) compound is thrombotonin 5-HT
2aAnd dopamine D
3The dual modulators of acceptor.
The compounds of this invention is to dopamine D
3And thrombotonin (serotonin; 5-HT) 5-HT
2aAcceptor has high affinity, it is believed that effectively to treat mental disorder and other disease, as depressed and anxiety, pharmacological dependence, dementia and memory defects.Mental disorder comprises multiple disease, and it comprises schizophrenia, dissociation of sensibility sexual dysfunction, two-phase sexual dysfunction, mania, psychotic depression, and other psychosis, comprises paranoia and vain hope.
Especially, the schizoid symptom that is characterized as complexity comprises positive symptom (i.e. vain hope and illusion) and negative symptoms (being fluency and the generation limited ability of anhedonia, thinking and speech).In addition, existing known, cognitive impairment is schizoid the 3rd main diagnostic classification, and it is damaged with other to it is characterized by the working memory forfeiture.Other symptom comprise offensiveness, depression and anxiety (Stahl, S.M. (2000) " the essence spirit pathology. neuroscience basis and practical application ", Cambridge University Press, second edition, Cambridge, Britain).Different classes of and the Clinical symptoms of this obstacle is defined in the diagnosis outline, as DSM-IV (diagnosis of mental disorder and statistics handbook, the 4th edition) or ICD-10 (International Classification of disease, the 10th edition).Be used for the treatment of schizophrenia, two-phase mania and other psychotic medicine at present and comprise typical antipsychotic drug (D
2/ D
3Preferably) or nearest atypical antipsychotic agents, the latter demonstrates and the multiple pharmacology of multiple acceptor interaction (D for example
1, D
2, D
3, D
4, 5-HT
1A, 5-HT
2A, 5-HT
2C, H
1, M
1, M
2, M
4Deng; Roth, people such as B.L. (2004) Magicshotguns versus magic bullets:selectively non-selective drugs for mooddisorders and schizophrenia.Nat.Rev.Drug Discov.3,353-359).Although these antipsychotic drugs successful relatively in the schizoid positive symptom for the treatment of (some patients show the treatment resistance), but validity is lower in treatment negative symptoms, cognitive impairment and relevant depression and anxiety, all these cause patients ' life quality to reduce and socioeconomic problem (Lieberman, J.A. wait the people, " clinical study (CATIE) of antipsychotics treatment effect. the validity of (2005) antipsychotics in the chronic schizophrenia patient " .N.Engl.J.Med.353,1209-1223).In addition, patient's conformability is subjected to the harm (Lieberman of general side effect such as weight increase, extrapyramidal symptom (EPS) and cardiovascular effect, J.A. wait the people, " clinical study (CATIE) of antipsychotics treatment effect. the validity of (2005) antipsychotics in the chronic schizophrenia patient " .N.Engl.J.Med.353,1209-1223).In current invention, described D
3And 5-HT
2AAcceptor has high-affinity and the compound of highly selective more, and is proposed to be used in treatment psychosis and other disease, has less related side effects.
Dopamine HCL is a kind of main catecholamine neurotransmitter, and it is involved in regulates multiple function, and these functions comprise mood, cognition, motor function and positive reinforcement (Purves, D. wait the people, (2004) Neuroscience.Sinauer, the third edition, Sunderland, Massachusetts).The biological activity of Dopamine HCL in human body, has been differentiated 5 kinds of different Dopamine Receptors D by acceptor (GPCRs) mediation of G albumen coupling
1-D
5, D wherein
2-sample acceptor (D
2, D
3And D
4) be coupled to the G-Protein G
α I(Missale, people such as C., (1998) " Dopamine Receptors: from the structure to the function ", Physiol.Rev.78,189-225).D
3Dopamine Receptors is expressed the highest (Gurevich in volt nuclear, E.V., Joyce, J.N. (1999) " express the distribution of neurone in people's forebrain of dopamine D 3 receptor: compare with the neurone of expressing the D2 acceptor ", Neuropsychopharmacology 20,60-80), point out it to regulate the midbrain edge channel, this path is by forming to the neural projection (neuronal projection) of volt nuclear from ventral tegmental area, hippocampus and amygdala, and it projects forehead and cingulate cortex and various thalamic nuclei.It is important that limbic circuit is considered to emotional behavior, thus D
3Receptor antagonist is proposed to be used in regulates psychotic symptoms such as illusion, vain hope and the disturbance of thought (Joyce, J.N. and Millan, M.J., (2005) " as the dopamine D 3 receptor antagonist of therapeutical agent ", Drug Discovery Today, July 1, Vol.10, No.13,917-25), these antagonists are to D simultaneously
2The striatum extrapyramidal system of regulating does not have effect (inducing relevant with EPS).In addition, the schizophreniac who has reported medication first shows D
3The expression of receptor level changes (Gurevich, E.V. wait people (1997) " middle limbic brain dopamine D 3 receptor and the use of antipsychotics in the schizophreniac. after death research ", Arch.Gen.Psychiatry54,225-232) discharge (Laruelle with Dopamine HCL, M. (2000) Imaging dopaminedysregulation in schizophrenia:implication for treatment (Dopamine HCL in schizophrenia imbalance: for the meaning for the treatment of). be set forth in Workshop Schizophr.:Pathol.Bases and Mech.Antipsychotic Action, Chicago), this shows that the homeostatic disorder of Dopamine HCL brought into play vital role in schizoid nosetiology.
The neurotransmitter thrombotonin is involved in some psychosis illnesss, comprises schizophrenia (Kandel, people such as E.R., (eds.; 2000) Principles of Neural Science, the third edition, Appleton﹠amp; Lange, Norwalk, CT).The multinomial thrombotonin that studies show that is involved in mental disorder, and it comprises with psychotropic sphacelic acid (LSD; A kind of combination of serotonin agonist) treatment people, it can induce schizophrenia-sample symptom such as illusion (Leikin, people such as J.B., (1989) " by Clinical symptoms and the control of poisoning due to the phantastica thing ", Med.Toxicol.Adverse Drug Exp.4,324-350).In addition, having detected in the schizophreniac distributes in the serotonin receptor brain changes and serotonergic tonus (tone) change (Harrison, P.J. (1999) " influencing atypical antipsychotic agents in the schizophrenia infers the neurochemistry of acceptor target and changes: focus on Dopamine HCL (D1; D3; D4) and the 5-HT2A acceptor ", Br.J.Psychiatry Suppl.38,12-22).In Mammals, thrombotonin by 14 5-HTGPCR of gang bring into play its biologic activity (Barnes, N.M., Sharp, T. (1999) " maincenter 5-HT acceptor and function summary " thereof, Neuropharmacology 38,1083-1152).5-HT
2AThe advantage of acceptor is expressed in the prefrontal cortex of human brain, and in basal ganglion and hippocampus, express (Pompeiano with lower level, M. wait the people, (1994) " distribution of thrombotonin 5-HT2 receptor family mRNAs: the comparison of 5-HT2A and 5-HT2C acceptor ", Brain Res.Mol.Brain Res.23,163-178; Pazos, A., Probst, A., Palacios, J.M. (1987) " serotonin receptor in the human brain: the radioautograph of IV serum plain-2 acceptor ", Neuroscience 21,123-139), and main and G-Protein G
α qCoupling (Roth, people such as B.L., (1998) " serotonine-2-family receptors (serotonine 2A, serotonine 2B, serotonine 2C): structure and function ", Pharmacol.Ther.79,231-257).5-HT
2APolymorphism is studied (Spurlock to schizoid gene linkage, G. wait the people, (1998) " among the 5HT2A T102C polymorphism and schizoid based on family relation research and promotor in new pantomorphic evaluation ", Mol.Psychiatry 3,42-49) and to the responsiveness of antipsychotics (Arranz, people such as M.J., (2000) " pharmacogenetics prediction of leoponex response ", Lancet 355,1615-1616) further show 5-HT
2AAcceptor all has effect in psychotic treatment and pathology.In addition, dopaminergic nerve transmission demonstration is in 5-HT
2A(Porras under the afferent adjusting of acceptor, G. wait the people, " 5-HT2A and 5-HT2C/2B receptor subtype are regulated in rat volt nuclear and the striatum and discharged by the Dopamine HCL of inducing in amphetamine and the morphine body ", Neuropsychopharmacology 26,311-324-2002).All 5-HT
2AThe receptor antagonist suggestion is suitable for treating the obstacle relevant with the dopaminergic system dysfunction.In addition, 5-HT
2AReceptor antagonist has been considered to be of value to the treatment psychosis and (has summarized the Angelis in de, L. (2002) " the 5-HT2A antagonist in the mental disorder ", Curr.Opin.Investig.Drugs 3,106-112), and be one of definition feature of so-called atypical antipsychotics really, it is characterized by with respect to D
2Acceptor is to 5-HT
2AHave relatively higher avidity (Meltzer, people such as H.Y., (1989) " based on the classification to typical case and atypical antipsychotic of dopamine D-1, D-2 and thrombotonin 2pKi value ", J.Pharmacol.Exp.Ther.251,238-246).
As indicated above, The compounds of this invention is to dopamine D
3With thrombotonin 5-HT
2AAcceptor has high affinity, and be expected to effectively treat mental disorder, comprise schizophrenia, dissociation of sensibility sexual dysfunction, two-phase sexual dysfunction, mania, psychotic depression and other psychosis, comprise paranoia and vain hope (people such as Reavill-C, (2000) " pharmacotoxicological effect of new high-affinity selectivity people dopamine D 3 receptor antagonist SB-277011-A ", JPET 294:1154-1165; Harrison, P.J. (1999) " influencing atypical antipsychotic agents in the schizophrenia infers the neurochemistry of acceptor target and changes: focus on Dopamine HCL (D1, D3, D4) and the 5-HT2A acceptor ", Br.J.Psychiatry Suppl.38,12-22; De Angelis, L. (2002) " the 5-HT2A antagonist in the mental disorder ", Curr.Opin.Investig.Drugs 3,106-112; Joyce, J.N. and Millan, M.J., (2005) " as dopamine D 3 receptor antagonist of therapeutical agent ", Drug Discovery Today, July 1, Vol.10, No.13, P.917-25); Drug dependence and abuse and give up (Vorel, people such as S.R., (2002) " the dopamine D 3 receptor antagonism suppresses Cocaine in the rat and seeks the brain award that strengthens with Cocaine ", J.Neurosci., 22,9595-9603; Campos, people such as A.C., (2003) " brain stimulation award that Nicotine strengthens in the dopamine D 3 receptor antagonist SB277011A antagonism rat ", Soc.Neurosci.Abstr., 322.8; People such as Ashby, (2003) " acute administration selective d 3 receptor antagonist SB-277011-A acquistion and expression that responds for the condition positional preference of heroine capable of blocking in male rat ", Synapse, 48,154-156); Anxiety and depression (people such as Reavill-C, (2000) " pharmacotoxicological effect of new high-affinity selectivity people dopamine D 3 receptor antagonist SB-277011-A ", JPET294:1154-1165; Drescher, people such as K., (2002) " effect in the body of selective dopamine D 3 receptor antagonist A-437203 ", Am.Soc.Neurosci.894.6).
Formula (I) compound can with acid for example the conventional acceptable acid of pharmacy form acid salt, for example hydrochloride, hydrobromate, phosphoric acid salt, acetate, fumarate, maleate, salicylate, vitriol, pyruvate salt, Citrate trianion, lactic acid salt, mandelate, tartrate and mesylate.Hydrochloride preferably.The solvate of formula I compound and hydrate and their salt constitute a part of the present invention.
Formula (I) compound can have one or more unsymmetrical carbons, and can with the mixture of optical purity enantiomer, enantiomer for example the mixture of mixture, diastereo-isomerism racemic modification or the diastereo-isomerism racemic modification of racemic modification, optically pure diastereomer, diastereomer exist.The optical activity form can be for example by the fractionation of racemic modification, obtain by asymmetric synthesis or asymmetric chromatography (chromatography with chiral sorbent or eluent).The present invention includes all these forms.
Be appreciated that general formula of the present invention (I) compound can obtain derivative by derivatize in functional group, it can transform in vivo and be returned to parent compound.Acceptable and the unsettled derivative of metabolism of physiology can produce the parent compound of general formula (I) in vivo, also is included within the scope of the present invention.
" aryl " expression aromatic carbocyclic group is made up of a monocycle or one or more fused rings, and at least one ring is aroma properties in this fused rings.Preferred aryl groups is phenyl or naphthyl, and passes through hereinafter special those that describe of embodiment.
" aryloxy " expression aryl as hereinbefore defined, and this aryl connects by Sauerstoffatom.The example of aryloxy is phenoxy group.
" C
1-6-alkyl " expression straight or branched carbochain group, it contains 1 to 6 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, n-hexyl and by special those that describe of embodiment hereinafter.
" two (C
1-6-alkyl) amino " represent by two C as hereinbefore defined
1-6The nitrogen-atoms that-alkyl replaces.Two (C
1-6-alkyl) An Ji example is dimethylamino, diethylamino, dipropyl amino, methylethyl is amino and pass through hereinafter special those groups of describing of embodiment.
" C
1-6-haloalkyl " expression as mentioned the definition C
1-6-alkyl, it is replaced by one or more halogen atoms.C
1-6The example of-haloalkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group or the n-hexyl that is replaced by one or more Cl, F, Br or I atom and passes through hereinafter special those groups of describing of embodiment.Preferred C
1-C
7-haloalkyl is two fluoro-or three fluoro-methyl or ethyls.
" C
1-6-alkyl sulphonyl " expression alkylsulfonyl (SO
2), the C that it is defined as mentioned
1-6-alkyl replaces.
" halogeno-benzene alkylsulfonyl " expression has the group of following formula:
" C
1-6-alkoxyl group " group of expression, wherein said alkyl defines as mentioned, and this alkyl connects by Sauerstoffatom.
" C
1-6-halogenated alkoxy " expression as mentioned the definition C
1-6-alkoxyl group, it is replaced by one or more halogen atoms.C
1-6The example of-halogenated alkoxy includes but not limited to by the methoxy or ethoxy of one or more Cl, F, Br or the replacement of I atom, and passes through hereinafter special those groups of describing of embodiment.Preferred C
1-C
7-halogenated alkoxy is two fluoro-or three fluoro-methoxy or ethoxies.
" halo " or " halogen " expression chlorine, iodine, fluorine and bromine.
" C
3-10-cycloalkyl " the saturated part of expression unit price; formed by one, two or three carbocyclic ring; have 3 to 10 carbon atoms as ring members; include but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and many tap bolts group; as two ring [2.2.2] octyls, two ring [2.2.1] heptane bases, two ring [3.2.1] octyl or adamantyls, and pass through hereinafter special those groups of describing of embodiment.
The monocyclic, bicyclic or tricyclic base of 5 to 10 annular atomses of " 5 to 10 yuan of heteroaryls " expression, it has at least one aromatic ring, and further contains one, two or three ring hetero atom that is selected from N, O or S, and all the other annular atomses are C.Heteroaryl can be chosen wantonly by one, two, three or four substituting group and replace, wherein each substituting group be independently hydroxyl, cyano group, alkyl, alkoxyl group, sulfane base, halo, haloalkyl, hydroxyalkyl, alkoxy carbonyl, amino, ethanoyl ,-NHCOOC (CH
3)
3Or the benzyl of halogen atom replacement, perhaps the non-aromatic part for cyclic rings also can be replaced by oxo, unless specialize in addition.The example of heteroaryl moieties includes but not limited to the optional imidazolyl that replaces, the optional thienyl that replaces, the optional De oxazolyl that replaces, the optional De isoxazolyl that replaces, the optional thiazolyl that replaces, the optional pyrazinyl that replaces, the optional pyrryl that replaces, the optional pyridyl that replaces, the optional pyrimidyl that replaces, the optional pyridazinyl that replaces, the optional indyl that replaces, the optional pseudoindoyl that replaces, 2 of optional replacement, the 3-indolinyl, the optional indazolyl that replaces, the optional naphthyridinyl that replaces, the optional isoquinolyl that replaces, optional carbazole-9-the base that replaces, the optional furyl that replaces, the optional benzofuryl that replaces, the optional quinolyl that replaces, the optional benzo [1 that replaces, 3] dioxolyl, the optional benzo [1 that replaces, 2,3] thiadiazolyl group, optional benzo [b] thienyl that replaces, the optional 9H-thioxanthene base that replaces, the optional thieno-[2 that replaces, 3-c] pyridyl, the optional 3H-imidazo [4 that replaces, 5, b] pyridyl, the optional phthalazinyl that replaces, 2 of optional replacement, 3-dihydrobenzo [1,4] dioxine bases etc., perhaps those of the special example of this paper.Preferred 5 to 10 yuan of heteroaryls are 5 or 6 yuan of heteroaryls.
The saturated part of " 5 to 10 Heterocyclylalkyl " expression unit price is made up of one, two or three ring, comprises 1,2 or 3 heteroatoms (being selected from nitrogen, oxygen or sulphur).Heterocyclylalkyl can be chosen wantonly by one, two, three or four substituting group and replace, wherein each substituting group is hydroxyl, alkyl, alkoxyl group, sulfane base, halo, haloalkyl, hydroxyalkyl, alkoxy carbonyl, amino, alkylamino, dialkyl amido, aminocarboxyl or carbonylamino independently, unless specialize in addition.The example of heterocyclic moiety includes but not limited to piperidyl, piperazinyl, high piperazinyl, azepine
Base, pyrrolidyl, pyrazolidyl, imidazolinyl, imidazolidyl oxazolidinyl isoxazole alkyl, morpholinyl, thiazolidyl, the isothiazole alkyl, quinuclidinyl, quinolyl, isoquinolyl, benzimidazolyl-, chromanyl, thiadiazoles alkyl (thiadiazolylidinyl), the benzothiazole alkyl, benzopyrrole alkyl (benzoazolylidinyl), the dihydrofuran base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl, the parathiazan base, dioxo parathiazan base, parathiazan base sulfoxide, parathiazan base sulfone, the dihydroquinoline base, the dihydro-isoquinoline base, tetrahydric quinoline group, tetrahydro isoquinolyl, 1-oxo-parathiazan, 1,1-dioxo-parathiazan, 1, the 4-Diazesuberane, 1,4-oxa-azepan and by special those groups described of embodiment hereinafter.Preferred 5 to 10 yuan of Heterocyclylalkyls are 5 or 6 yuan of Heterocyclylalkyls.
" one or more " represent 1,2,3,4,5,6,7,8,9 or 10 in this article, preferred 1,2,3,4 or 5, and more preferably 1,2 or 3.
" oxo " expression group=O.
" pharmacy is acceptable " represents that it can be used for pharmaceutical compositions, its normally safety, nontoxicity, be not worthless at biology and other side, comprise for animals and the human medicine acceptable those.
" pharmacologically acceptable salts " of compound expression is that as defined herein pharmacy is acceptable and have those of required parent compound pharmacological activity.This class salt comprises the acid salt that forms with mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.; The perhaps acid salt that forms with organic acid such as acetic acid, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, Citric Acid, ethyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, L-glutamic acid, oxyacetic acid, hydroxynaphthoic acid (hydroxynaphtoic acid), 2-ethylenehydrinsulfonic acid, lactic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, methylsulfonic acid, muconic acid, 2-naphthene sulfonic acid, propionic acid, Whitfield's ointment, succsinic acid, tartrate, tosic acid, trimethylacetic acid etc.
Formula (I) compound also comprises formula (Ia) compound:
Wherein A, R
1And R
2As mentioned formula (I) is defined.
Preferred formula (Ia) compound is such compound, wherein:
A is aryl (for example phenyl) or 5 to 6 yuan of heteroaryls (for example thienyl), chooses wantonly and is selected from halo (for example F or Cl) or C by 1 to 5
1-6The substituting group of-alkoxyl group (for example OMe) replaces;
R
1The C that is replaced by aryl
2-6-alkynyl (for example ethynyl phenyl), or optional by 1 to 5 C that is selected from down the substituting group replacement of group
1-6-alkyl:
Halo,
Hydroxyl,
-CO (O)-C
1-6-alkyl,
C
3-10-cycloalkyl,
The optional C that is replaced by aryl
1-6-alkoxyl group,
Optional by halo or C
1-6The aryl that-alkoxyl group replaces,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl replaces and
Phenoxy group,
Or C
1-6-alkoxyl group,
Or it is optional by one or more R
aThe C that replaces
3-10-cycloalkyl, and R
aBe selected from 1,2,3 C
1-6-alkyl, hydroxyl, C
1-6-alkoxyl group, oxo, C
1-6-haloalkyl and halo,
Or it is optional by one or more R
a4 to 10 yuan of Heterocyclylalkyls that replace, and R
aBe selected from 1,2,3 phenyl, phenoxy group and C
1-6-alkyl,
Or it is optional by one or more R
aThe aryl that replaces, and R
aBe selected from:
Cyano group,
The optional C that is replaced by 5 to 6 yuan of Heterocyclylalkyls
1-6-alkyl,
Halo,
C
1-6-haloalkyl,
C
1-6-halogenated alkoxy,
The optional C that is replaced by 5 to 6 yuan of heteroaryls
1-6-alkoxyl group, this heteroaryl is optional by C
1-6-alkyl replaces,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl replaces,
Optional by hydroxyl, by oxo or by C
1-64 to 10 yuan of Heterocyclylalkyls that-alkyl replaces,
-NH (CO)-C
1-6-alkyl,
The halogeno-benzene alkylsulfonyl,
Phenyl and
Two (C
1-6) alkylamino;
Or it is optional by one or more R
a5 to 10 yuan of heteroaryls that replace, and R
aBe selected from:
Halo,
The optional C that is replaced by aryl
1-6-alkyl, this aryl is replaced by halo,
C
1-6-alkoxyl group,
Oxo,
C
1-6-halogenated alkoxy,
C
1-6-alkyl sulphonyl,
Optional by C
1-65 to 6 yuan of Heterocyclylalkyls that-alkyl replaces and
Aryl,
Or-NR
bR
c, R wherein
bBe H or C
1-6-alkyl, and R wherein
cBe H, C
1-6-alkyl or optional by one or more R
aThe aryl that replaces, and R
aBe selected from: halo, C
1-6-alkyl and C
1-6-alkoxyl group;
R
2Be H, OH, C
1-6-alkyl or halo;
With and pharmacologically acceptable salts.
In specific embodiment, formula (Ia) compound is those compounds, wherein R
1Be optional by one or more R
a5 to 10 yuan of heteroaryls, for example following compounds replacing:
2-methyl-2H-indazole-3-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
6-chloro-2-methyl-quinoline-3-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-chloro-1-(3,4-, two chloro-benzyls)-6-oxo-1,6-dihydro-Nicotinicum Acidum trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-6-methyl-niacinamide;
[1,8] naphthyridines-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-fluoro-1H-indole-2-carboxylic acid (trans-4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-trifluoromethoxy-1H-indole-2-carboxylic acid (trans-4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-methoxyl group-1H-indole-2-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Thiophene-2-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
3H-imidazo [4,5-b] pyridine-6-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-methylsulfonyl-thiophene-2-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
6-fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-niacinamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-6-morpholine-4-base-niacinamide;
3-methyl-chroman-3-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
2-morpholine-4-base-pyrimidine-5-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
6-morpholine-4-base-pyridazine-3-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-morpholine-4-base-pyrazine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Benzo [1,3] dioxole-5-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
3-methyl-isoxazoles-5-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Trans N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-2-methoxyl group-Isonicotinamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-6-morpholine-4-base-niacinamide;
2,3-dihydro-benzo [1,4] dioxine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-(4-methyl-piperazine-1-yl)-pyridine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-morpholine-4-base-pyridine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-phenyl-pyridine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Quinoline-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Quinoline-4-formic acid is trans-(4-{2-[4-(4-methoxyl group-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Quinoline-4-formic acid is trans-4-[2-(4-benzoyl-4-hydroxy-piperdine-1-yl)-ethyl]-cyclohexyl }-acid amides;
Quinoline-4-formic acid is trans-4-[2-(4-benzoyl-4-fluoro-piperidine-1-yl)-ethyl]-cyclohexyl }-acid amides;
Quinoline-4-formic acid is trans-(4-{2-[4-(3,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
2,3-dihydro-indoles-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
6-trifluoromethyl-2,3-dihydro-indoles-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1,3-dihydro-isoindole-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
3,4-dihydro-1H-isoquinoline 99.9-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Quinoline-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-methylsulfonyl-thiophene-2-carboxylic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Chroman-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
(R)-chroman-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
(S)-chroman-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-6-morpholine-4-base-niacinamide;
2,3-dihydro-indoles-1-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Quinoline-4-formic acid trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-methylsulfonyl-thiophene-2-carboxylic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Chroman-3-formic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-methylsulfonyl-thiophene-2-carboxylic acid (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Quinoline-4-formic acid (4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Chroman-3-formic acid (trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Chroman-3-formic acid (trans-4-{2-[4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides; With
Benzo [1,3] dioxole-5-formic acid (trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides.
In specific embodiment, formula (Ia) compound is those compounds, wherein R
1Be-NR
bR
c, R wherein
bBe H or C
1-6-alkyl, and R wherein
cBe H, C
1-6-alkyl or optional by one or more R
aThe aryl that replaces, for example following compound:
Trans 1-(2,4-, two chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea;
Trans 1-(4-chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea;
Trans 1-(4-oxyethyl group-phenyl)-3-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea;
Trans 1-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-p-methylphenyl-urea;
Trans 1-(4-chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-1-methyl-urea;
Trans-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-1,1-dimethyl-urea;
Trans 1-(4-chloro-phenyl)-3-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea;
Trans 1-(4-chloro-phenyl)-3-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea; With
Trans 1-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-(4-oxyethyl group-phenyl)-urea.
In specific embodiment, formula (Ia) compound is those compounds, wherein R
1Be optional by one or more R
aThe aryl that replaces, for example following compound:
4-chloro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
4-(3,5-dimethyl ,-isoxazole-4-base methoxyl groups)-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-trifluoromethyl-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-morpholine-4-base-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-pyrroles-1-base-benzamide;
4-oxyethyl group-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
4-acetylamino-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;
4-cyano group-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-pyrazol-1-yl-benzamide;
2,4-, two chloro-N-are trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
4-(4-chloro-benzenesulfonyl)-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-trifluoromethoxy-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-(1,1,2,2-tetrafluoro-oxyethyl group)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyridin-3-yl-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyridin-4-yl-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyridine-2-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-(4-methyl-piperazine-1-yl)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-phthalazines-1-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-4-pyridine-2-base-benzamide;
Xenyl-4-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
2-fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide;
4-(3,3-dimethyl-2-oxo-azetidine-1-yl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-ylmethyl-benzamide;
4-tert.-butoxy-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
4-dimethylamino-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
4-(1,1-dioxo-6-parathiazan-4-yl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
3-fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-(3-hydroxyl-tetramethyleneimine-1-yl)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-(4-hydroxy-piperdine-1-yl)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-parathiazan-4-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-piperidines-1-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-2-morpholine-4-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl-cyclohexyl)-3-(5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-oxyethyl group-benzamide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-3-(5-methyl-[1,2,4] oxadiazole-3-yl)-benzamide;
4-chloro-N-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
Xenyl-4-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
N-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-morpholine-4-base-benzamide;
4-cyano group-N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyrroles-1-base-benzamide;
N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide;
4-chloro-N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
N-trans (4-{2-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide; With
N-(trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-morpholine-4-base-benzamide.
In specific embodiment, formula (Ia) compound is those compounds, wherein R
1Be optional by one or more R
aThe C that replaces
3-10-cycloalkyl, for example following compound:
Cyclopropane-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Diamantane-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
2-cyclopropyl-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
2-methyl-cyclopropane-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-methoxyl group-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-hydroxyl-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
(1S, 4R)-two the ring [2.2.1] heptane-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
(1R, 4R)-7,7-dimethyl-2-oxo-two ring [2.2.1] heptane-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-trifluoromethyl-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1-methyl-cyclohexyl alkane formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-methyl-cyclohexyl alkane formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
6-hydroxyl-two ring [2.2.2] octane-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1-trifluoromethyl-cyclopropane-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
3-chloro-cyclobutane formate trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1-hydroxyl-cyclopropane-carboxylic acid (trans-4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Cyclobutane formate trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-hydroxyl-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
2,2-, two fluoro-cyclopropane-carboxylic acids trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Cyclopropane-carboxylic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Cyclobutane formate (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
4-trifluoromethyl-naphthenic acid trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Cyclopropane-carboxylic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
2,2-, two fluoro-cyclopropane-carboxylic acids (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides; With
Cyclopropane-carboxylic acid trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides.
In specific embodiment, formula (Ia) compound is those compounds, wherein R
1Be optional by one or more R
a5 to 10 yuan of Heterocyclylalkyls, for example following compounds replacing:
Tetrahydrochysene-pyrans-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Morpholine-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
3-phenoxy group-tetramethyleneimine-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1,1-dioxo-parathiazan-4-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid is trans-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid is trans-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
(S)-tetrahydrochysene-furans-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
(R)-tetrahydrochysene-furans-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
4-phenyl-Piperazine-1-formic acid trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Morpholine-4-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetramethyleneimine-1-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Tetrahydrochysene-pyrans-4-formic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Tetrahydrochysene-pyrans-4-formic acid (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides; With
Tetrahydrochysene-pyrans-4-formic acid (trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides.
In specific embodiment, formula (Ia) compound is those compounds, wherein R
1Be optional by 1 to 5 C that is selected from down the substituting group replacement of group
1-6-alkyl:
Halo,
Hydroxyl,
C
1-6-alkyl,
-CO (O)-C
1-6-alkyl,
C
3-10-cycloalkyl,
The optional C that is replaced by 1,2 or 3 halo or replaced by aryl
1-6-alkoxyl group,
Optional by halo or C
1-6The aryl that-alkoxyl group replaces,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl replaces and
Phenoxy group,
Following compound for example:
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide;
2-(4-chloro-phenyl)-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-isobutyramide;
3-oxyethyl group-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-propionic acid amide;
3,3,3-, three fluoro-N-are trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-propionic acid amide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-propionic acid amide;
2,2,2-, three fluoro-N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-butyramide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-butyramide;
N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-phenoxy group-propionic acid amide;
N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-hydroxyl-2,2-dimethyl-propionic acid amide;
The 2-benzo [d] isoxazole-3-base-N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-2-(3-methyl-isoxazole-5-bases)-ethanamide;
2-(3,5-dimethoxy-phenyl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
2-benzo [1,3] dioxole-5-base-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
Acetic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-the cyclohexyl carboxyamide base)-methyl ester;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide;
Trans N-(4-{2-[4-(4-fluoro-benzoyl)-4-methyl-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide;
N-is trans-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-propionic acid amide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-2-(3-methyl-isoxazole-5-base)-ethanamide;
N-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-2-hydroxyl-ethanamide;
(R)-N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-2-methoxyl group-propionic acid amide;
2-benzyloxy-N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-butyramide;
2-cyclopropyl-N-(4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-2-(3-methyl-isoxazole-5-base)-ethanamide;
2-benzyloxy-N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-butyramide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-2-cyclopropyl-ethanamide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-propionic acid amide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2,5-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(4-fluoro-2-methyl-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-{ is trans-4-[2-(4-benzoyl-piperidine-1-yl)-ethyl]-cyclohexyl }-ethanamide;
N-(trans-4-{2-[4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-(trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-(trans-4-{2-[4-(5-fluoro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide.
In specific embodiment, formula (Ia) compound is those compounds, wherein R
1Be C
1-6-alkoxyl group, for example following compound:
Trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-Urethylane; With
4-oxyethyl group-N-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide.
In specific embodiment, formula (Ia) compound is those compounds, wherein R
1The C that is replaced by aryl
2-6-alkynyl or C
2-6-alkenyl, for example following compound 3-phenyl-propynoic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides.
Formula (I) compound also comprises formula (Ib) compound:
Wherein A, R
1And R
2As mentioned formula (I) is defined, for example following compound:
N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide;
2-(4-chloro-phenyl)-N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-isobutyramide; With
1-(4-chloro-phenyl)-3-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-urea.
Formula (I) compound also comprises formula (Ic) compound:
Wherein A, R
1And R
2As mentioned formula (I) is defined, for example following compound:
N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide;
2-(4-chloro-phenyl)-N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-isobutyramide;
4-chloro-N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-benzamide; With
1-(4-chloro-phenyl)-3-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-urea.
Formula (I) compound also comprises formula (Id) compound:
Wherein A, R
1And R
2As mentioned formula (I) is defined, for example following compound:
4-oxyethyl group-N-4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-benzamide;
N-{4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide;
Tetrahydrochysene-furans-3-formic acid 4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-acid amides;
1-(4-chloro-phenyl)-3-{4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-urea; With
1-(4-oxyethyl group-phenyl)-3-{4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-urea.
Of the present invention to advance be to contain formula (I), (Ia), (Ib), (Ic) and (Id) pharmaceutical composition of compound on the one hand, is used for the treatment of schizophrenia, cognitive disorder and drug habit.
It is the method for preparation formula defined above (Ia) compound on the one hand that the present invention advances, and this method comprises makes formula II compound:
Wherein A and R
2As hereinbefore defined,
A) or with the acid of formula III:
HOOCR
1 (III)
At coupling reagent such as O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) exist down, The suitable solvent such as dimethyl formamide (react acquisition formula (Ia) compound in the DMF) Huo diox, in the presence of alkali (for example triethylamine or diisopropylethylamine):
Wherein:
R
1The C that is replaced by aryl
2-6-alkynyl or C
2-6-alkenyl,
Or it is optional by 1 to 5 C that is selected from down the substituting group replacement of group
1-6-alkyl:
Halo,
Hydroxyl,
C
1-6-alkyl,
-CO (O)-C
1-6-alkyl,
C
3-10-cycloalkyl,
The optional C that is replaced by 1,2 or 3 halo or replaced by aryl
1-6-alkoxyl group,
Optional by halo or C
1-6The aryl that-alkoxyl group replaces,
Optional by G
1-65 to 10 yuan of heteroaryls that-alkyl replaces and
Phenoxy group,
Or C
1-6-alkoxyl group,
Or it is optional by one or more R
aThe C that replaces
3-10-cycloalkyl,
Or it is optional by one or more R
a5 to 10 yuan of Heterocyclylalkyls that replace,
Or it is optional by one or more R
aThe aryl that replaces,
Or it is optional by one or more R
a5 to 10 yuan of heteroaryls that replace,
B) or with isocyanic ester or reactive intermediate such as carboxylamine p-nitrophenyl ester in The suitable solvent such as dimethyl formamide (DMF) or acetonitrile, in the presence of alkali (for example triethylamine or diisopropylethylamine), react acquisition formula (Ia) compound:
Wherein
R
1Be-NR
bR
c, R wherein
bBe H or C
1-6-alkyl, and R wherein
cBe H, C
1-6-alkyl or
Optional by one or more R
aThe aryl that replaces;
Or 5 to 10 yuan of Heterocyclylalkyls, the nitrogen-atoms that it contains and R
1(Ia) carbonyl that connects
Be connected, optional by one or more R
aReplace,
Or 5 to 10 yuan of heteroaryls, the nitrogen-atoms that it contains and R
1(Ia) carbonyl phase that connects
Connect, optional by one or more R
aReplace,
And if desired,
The compound that obtains is changed into the acceptable acid salt of pharmacy.
The preparation of formula of the present invention (I) compound can be carried out with continuous and convergent synthetic route.Synthetic being shown in hereinafter in the schema of the present invention.Carry out this reaction and the needed technology of purifying products therefrom is well known by persons skilled in the art.The substituting group and the indicator that are used for following method description have the above implication of giving of this paper, unless opposite indication is arranged.
In more detail, formula (I) compound can by followingly give method, by method that embodiment gives or prepare by similar approach.The suitable reaction condition of each reactions steps is that art technology is known.Initial substance both can be obtained commercially, perhaps can be by being similar to hereinafter the method for giving, preparing by the described method of institute's citing document among specification sheets or the embodiment or by methods known in the art.
In following schema, A, R
1And R
2Definition as mentioned.
Schema 1
The heteroaryl of formula (Ia) or benzoyl-piperidine-1-base is trans-ethyl-cyclohexyl-amides or anti-form-1, and 4-cyclohexyl ethyl derivative can be described in schema 1, from 4-nitrophenyl acetic acid, use Raney nickel to carry out hydrogenation as catalyzer prepares.With ni-mhization preferably obtain required trans-isomer (according to Journal of Medicinal Chemistry, 1998,41,760-771).Method known according to those skilled in the art and described document description prepare this ethyl ester (for example by with ethanol in acid as processing in the presence of the HCl) and with this HCl salt crystallization detachable suitable/trans mixture, and cause the separation of pure trans amino ester muriate B.In the presence of alkali such as triethylamine and catalyzer such as dimethyl aminopyridine, react as a contracting two carbonic acid tertiary butyl ester with protecting group; with diisobutylaluminium hydride (DIBAL-H) in The suitable solvent such as toluene-78 ℃ of reduction; obtain aldehyde C, it can not purifiedly namely be used for next step.In solvent such as methylene dichloride or 1,2-ethylene dichloride and reductive agent such as sodium triacetoxy borohydride exist down, with the phenyl that replaces or heteroaryl piperidine-4-base-ketone D with aldehyde C reductive amination, obtain intermediate E, this D is commercially available acquisition both, perhaps the method by document description, the method for describing by this patent or obtain by methods known in the art.Remove Boc protectiveness group under acidic conditions such as trifluoroacetic acid or the hydrochloric acid, in The suitable solvent such as THF, EtOAc or methylene dichloride, obtaining trans-aminocyclohexyl ethyl intermediate F (being generally TFA or hydrochloride).The coupling of amine intermediate F and carboxylic acid cpd (both commercially available acquisition or obtain by the method for document description or by methods known in the art) extensively is described in the document (Comprehensive OrganicTransformations:A Guide to Functional Group Preparations for example, second edition, Richard C.Larock.John Wiley ﹠amp; Sons, New York, NY.1999), and can be by using coupling reagent such as N, N '-N,N'-carbonyldiimidazole (CDI) or O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU), (in the DMF) Huo diox, in the presence of alkali (for example triethylamine or diisopropylethylamine), finish, obtain formula (Ia) compound at suitable solvent such as dimethyl formamide.In other cases, also can be in the presence of alkali (for example triethylamine or diisopropylethylamine), in solvent such as methylene dichloride, use acyl chlorides.
Schema 2
In other embodiments, intermediate F also can (work as R with isocyanic ester
cDuring=H), perhaps reactive intermediate (R
c≠ H) as suitable discuss acyl chlorides, or by means known in the art preparations to the nitro amino manthanoate, or use triphosgene, in the presence of suitable solvent such as acetonitrile or methylene dichloride and alkali (as triethylamine or diisopropylethylamine), react, acquisition formula (Ia) compound is described in above schema 2.
Schema 3
In some cases, phenyl or heteroaryl piperidine-4-base-ketone D can be in the reductive amination step with more complicated aldehyde I according to schema 3 couplings.We use quinoline-4-formic acid [4-(2-oxo-ethyl)-cyclohexyl]-acid amides in some cases.The preparation of quinoline-4-formic acid [4-(2-oxo-ethyl)-cyclohexyl]-acid amides I is described in schema 2, from 4-nitro-phenylacetic acid A, it is as use Raney nickel hydrogenation as described in the schema 1, and as at the trans-amino-ethyl ester muriate B of preparation described in the schema 1.In the case; being different from blocking group assigns reagent to react as a contracting two carbonic acid tertiary butyl ester; this amine or amine hydrochlorate can with quinoline-4-carbonyl chlorine in the presence of alkali such as triethylamine, in solvent such as methylene dichloride, react, obtain trans-4-[(quinoline-4-carbonyl)-amino]-cyclohexyl-ethyl acetate.Under acidity or alkaline condition such as lithium hydroxide, at solvent mixture such as THF: in the water, the hydrolysis of this ester functional group obtains corresponding sour G.To prepare sour intermediate in order reducing and to be that known in the document (people such as T.Fukuyama for example, Synthesis 2000,8,1121-1123).In the case; this acid and the sulfur alcohol sodium reaction for preparing solvent such as glycol dimethyl ether from sulfur alcohol and alkali such as butyllithium in advance; obtain trans-4-[(quinoline-4-carbonyl)-amino]-cyclohexyl-thioacetic acid S-ethyl ester (H); its available palladium on carbon and triethyl-silicane reduce in solvent such as acetone/methylene dichloride (1: 1) mixture; obtain required trans-quinoline-4-formic acid [4-(2-oxo-ethyl)-cyclohexyl]-acid amides (I); it can be used in the reductive amination; use reductive agent such as sodium triacetoxy borohydride; in solvent such as methylene dichloride, directly obtain trans-quinoline-4-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides (Ia).
Schema 4
R wherein
1Be NR
bR
cPerhaps be different from NR
bR
cGeneral formula (Ic) compound also can be according to schema 4 preparation.In the case; the intermediate N that is used in the reductive amination of phenyl or heteroaryl piperidine-4-base-ketone begins preparation from 2-formyl radical-1-cyclopropane-carboxylic acid ethyl ester (88-90% trans-isomer(ide)); this 2-formyl radical-1-cyclopropane-carboxylic acid ethyl ester can be (known in the document in reductibility BOC amination; for example Tetrahedron Letters 42 (2001), 5093-5094) in, by forming α-amidoalkyl sulfone K, using t-butyl carbamate and anhydrous p-toluene sulfonic acid in solvent such as first alcohol and water, to react.With this α-amidoalkyl sulfone K crystallization in solvent such as normal heptane, only obtain trans-isomer(ide).By forming imines as intermediate, α-amidoalkyl sulfone intermediate K and the reaction of sodium borohydride in solvent such as tetrahydrofuran (THF) produce trans-2-(tert-butoxycarbonyl amino-methyl)-cyclopropane-carboxylic acid ethyl ester L.This ethyl ester M in suitable solvent such as toluene ,-78 ℃ of reduction, obtains aldehyde M with reductive agent such as diisobutylaluminium hydride (DIBAL-H), and it is not purified can be used for next step.The phenyl of this aldehyde and replacement or heteroaryl piperidine-4-base-ketone D as the reductive amination under 1,2-methylene dichloride and reductive agent such as the sodium triacetoxy borohydride existence, obtains intermediate N at solvent.Removing this Boc protectiveness group under acidic conditions such as the trifluoroacetic acid, in suitable solvent such as THF; obtain intermediate (being generally salt); it is as using coupling reagent such as O-benzotriazole-1-base-N in the schema 1; N; N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU), suitable solvent such as dimethyl formamide (in the DMF) Huo diox, in the presence of alkali (for example triethylamine or diisopropylethylamine), can with the carboxylic acid coupling; obtain formula (Ic) compound, wherein R
1Not NR
bR
cAt R
1Be NR
bR
cSituation under, above-mentioned intermediate can with isocyanate reaction, obtain corresponding formula (Ic) compound.
Schema 5
R wherein
1Be NR
bR
cAnd R wherein
1Not NR
bR
cGeneral formula (Ib) compound, they also can be according to schema 5, by alkylation step, use the enough good leavings groups be installed on the coupling partner to prepare.This coupling partner T (methylsulfonic acid trans-(tert-butoxycarbonyl amino-methyl) cyclobutyl methyl esters) can from can discuss trans-tetramethylene dioctyl phthalate dimethyl ester O obtain, use reductive agent such as sodium borohydride, in solvent such as methyl alcohol, O be reduced to trans-2-hydroxymethyl-cyclobutane formate methyl esters P.According to the method for method known to those skilled in the art and document description (for example use oxalyl chloride, dimethyl sulfoxide (DMSO) and triethylamine under the Swern condition, in solvent such as methylene dichloride) this alcohol functional group of oxidation, obtain intermediate Q, succeeded by the same steps as of in schema 4, having described, namely by forming the reductibility BOC amination of α-amidoalkyl sulfone intermediate.With reductive agent such as sodium borohydride ethyl ester S is reduced into pure T, with this alcohol change into good leavings group (for example by with methylsulfonyl chloride at alkali such as N, the N-diisopropylethylamine exists down, in solvent such as methylene dichloride reaction and change into methanesulfonates T), this leavings group in alkylation step with the phenyl that replaces or heteroaryl piperidine-4-base-ketone D at alkali (N for example, the N-diisopropylethylamine) exists down, under refluxad reacts, obtain the intermediate of structure N.Latter two steps (remove the Boc blocking group and form acid amides or urea) and description identical in schema 1,2 and 4.
Schema 6
R wherein
2The phenyl of expression OH or heteroaryl piperidine-4-base-ketone D intermediate can be according to schemas 6 and according to the method preparation that also partly is described in the document (for example patent DE 25365103).In the presence of alkali such as the triethylamine, with or without catalyzer such as sodium iodide, solvent for example in the acetonitrile, use for example 80 ℃ temperature, use bromotoluene to import benzyl, obtain intermediate W.Under refluxing, use bromine, can be implemented in (1-benzyl-piperidin-4-yl)-the ketone α position of (4-fluoro-phenyl)-ketone imports bromine.Handle this α bromoketone X with sodium methylate, obtain 6-benzyl-2-(4-fluoro-phenyl)-2-methoxyl group-1-oxa--6-azepine-spiral shell [2.5] octane (Y), can with its in solvent such as ether, hydrolysis under the chlorination acid treatment, obtain (1-benzyl-4-hydroxy-piperdine-4-yl)-(4-fluoro-phenyl)-ketone (Z).Under hydrogenation conditions, use palladium make catalyzer, in solvent such as ethyl acetate and methyl alcohol, can carry out removing of this benzyl, obtain required (1-benzyl-4-hydroxy-piperdine-4-yl)-(4-fluoro-phenyl)-ketone (intermediate D).In last step of hydrogenation, also can observe the reduction of ketone, can form the diatomic alcohol compounds as by product.
Schema 7
R wherein
2The phenyl of expression fluorine atom or heteroaryl piperidine-4-base-ketone D intermediate can be according to schema 7 preparations.This phenyl or heteroaryl piperidine-4-base-ketone can at first be protected with suitable blocking group such as tert-butoxycarbonyl; after importing fluorine atom, this group can be removed under condition well known by persons skilled in the art (for example handling in The suitable solvent such as methylene dichloride as trifluoroacetic acid with acid).The introducing of fluorine can followingly be carried out: with alkali in The suitable solvent, under anhydrous condition (for example trimethyl carbinol/potassium tert.-butoxide in DMF), in the presence of fluorizating agent such as N-fluorine BBI, handle to the temperature of room temperature at 0 ℃, with the corresponding carbon deprotonation on this ketone α position, after three steps, obtain aryl-(4-fluoro-piperidine-4-yl)-ketone or heteroaryl-(4-fluoro-piperidine-4-yl)-ketone D.
Schema 8
R wherein
2Expression methyl or other C
1-6The phenyl of-alkyl or heteroaryl piperidine-4-base-ketone D intermediate can be according to schema 8, the preparation of usefulness carbon-to-carbon linked reaction; wherein the Pd complex catalysis is for the acylation reaction of the carboxylic acid anhydride of boric acid and original position acquisition, and the PIVALIC ACID CRUDE (25) acid anhydride that this acylation reaction is used with corresponding N-Boc-4-methyl-the 4-piperidine carboxylic acid reacts also uses corresponding phenyl for boric acid.This tert-butoxycarbonyl blocking group can be removed under condition well known by persons skilled in the art (for example handling in The suitable solvent such as methylene dichloride as trifluoroacetic acid with acid), after three steps, obtains aryl-(4-methyl-piperidin-4-yl)-ketone D.
Schema 9
R wherein
1Be NR
bR
cGeneral formula (Id) compound and R wherein
1Not NR
bR
cFormula (Id) compound can be according to schema 9 usefulness Compound D phenyl or heteroaryl piperidine-4-base-ketone preparation, use alkali (for example N, N-diisopropylethylamine), in The suitable solvent such as acetonitrile, under refluxad with this phenyl or heteroaryl piperidine-4-base-ketone with 4-(Boc-amino) butyl bromide alkylation.Use acidic conditions (for example trifluoroacetic acid, in solvent such as methylene dichloride) and remove amine protecting group group (in our situation, being the Boc group) as has been described afterwards; use coupling agent such as O-benzotriazole-1-base-N; N; N '; N '-tetramethyl-urea a tetrafluoro borate (TBTU), in The suitable solvent such as dimethyl formamide (DMF), in the presence of alkali (for example triethylamine or diisopropylethylamine); this amine intermediate and carboxylic acid coupling can be obtained formula (Id) compound, wherein R
1Not NR
bR
c, perhaps in other cases with the isocyanic ester coupling, obtain corresponding formula (Id) compound, wherein R
1Be NR
bR
c
Flow process Figure 10
The acetic acid amide derivatives of structure AH can begin to prepare easily from compd B according to flow process Figure 10.Reaction sequence comprises: in first step, at alkali such as Et
3Under N exists, at solvent such as CH
2Cl
2In handle compd B with AcCl, obtain formula AE compound.With reagent such as LiAlH
4At solvent such as CH
2Cl
2In, 0 ℃ of reduction, obtain formula AF compound.In the known multiple oxidizing condition of document, (Synthesis 1981 for A.Mancuso, D.Swern, 165-185) obtain intermediate A G in the Swern oxidation of pure AF.The piperidines of aldehyde AG and suitably replacement is at reductive agent such as Na (AcO)
3As 1, react in the 2-ethylene dichloride under BH exists, at solvent, obtain formula AH compound.
Flow process Figure 11
Wherein A be formula Ia compound that replace or unsubstituted thienyl can as described in the schema 1, use piperidin-4-yl-thiophene-2-base-ketone of formula AL to prepare as intermediate D.The preparation of formula AL intermediate is described in flow process Figure 11.The thiophene of formula AI can be used alkali such as n-BuLi deprotonation in solvent such as THF, with 4-formyl radical-piperidines-1-t-butyl formate reaction, obtains the alcohol of formula AJ.With reagent such as TPAP/NMO or MnO
2At solvent such as CH
2Cl
2In the alcohol of oxidation-type AJ, obtain the ketone of formula AK.Handle formula AK compound with acid as HCl, obtain formula AL compound.
Flow process Figure 12
Wherein the R compound (flow process Figure 11) that equals the structure AL of 5-fluorine can prepare according to flow process Figure 12.This method is to use subsequently alkali example n-BuLi, in solvent such as THF with the dual deprotonation of thiophene; after deprotonation first time step, react with fluorizating agent such as N-fluorine BBI (N-fluorodibenzenesulfonimide); after deprotonation second time step, with 4-formyl radical-piperidines-1-t-butyl formate reaction, obtain the alcohol of formula AM.
Described compound is in conjunction with 5-HT
2A, D
3And D
2The ability of acceptor uses the combination of radioligand and the clone acceptor of selective expression in the HEK-293EBNA cell to measure.
People D
2, people D
3With people 5-HT
2AThe membrane prepare of acceptor
With the people D that encodes respectively
2Or D
3Dopamine Receptors or people 5-HT
2AThe expression plasmid transient transfection HEK-293EBNA cell of serotonin receptor.48h harvested cell after the transfection, with cold PBS washing 3 times, be stored in-80 ℃ stand-by.Pellet is suspended in the cold 50mM Tris-HCl buffered soln (pH 7.4) that contains 10mM EDTA, with Polytron (Kinematica AG, Basel, Switzerland) with 12.000rpm homogenate 20-30 second.4 ℃ with the centrifugal 30min of 48.000X g after, pellet is suspended in the cold 10mM Tris-HCl buffered soln (pH 7.4) that contains 0.1mM EDTA again homogenate as mentioned above, centrifugal.This pellet further is suspended in again in the ice-cold 10mM Tris-HCl buffered soln (pH 7.4) that contains 0.1mM EDTA of smaller size smaller, with Polytron with 12.000rpm homogenate 20-30 second.With Bio-Rad (Bradford) analysis of protein method (Biorad Laboratories GmbH, M ü nchen, Germany), according to the indication of manufacturers, use gamma globulin as standard, measure the protein content of this homogenate.Divide equal portions to be kept at-80 ℃ this homogenate, melt at once before the use.
Radioligand is in conjunction with test conditions
The membrane product sample aliquot is melted in room temperature, be suspended in again and analyze buffered soln (D
2, D
3: 50mM Tris-HCl, 120mM NaCl, 5mM MgCl
2, 1mM EDTA, 5mM KCl, 1.5mM CaCl
2, pH=7.4; 5-HT
2A: 50mM Tris-HCl, 10mM MgCl
2, 1mMEGTA, pH=7.4),, be adjusted to ultimate density and be respectively about 7.5 μ g albumen/hole (D with 12.000rpm homogenate 20-30 second with Polytron
2, D
3) and 15 μ g albumen/hole (5-HT
2A).
Use radioligand in conjunction with the binding affinity (Ki) of measuring compound.In the cumulative volume of 200 μ l, (final concentration is about: for D with the radioligand of film and fixed concentration
2Be 0.7nM[
3H]-spiperone, for D
3Be 0.5nM[
3H]-spiperone, for 5-HT
2ABe 1.1nM[
3H]-Sufrexal) and 10 μ M-0.1nM between the test compound of 10 concentration at incubated at room 1h.Hatch when finishing, use in conjunction with GF/C filter (Packard BioScience, Z ü rich, Switzerland; Preincubate 1h in 0.1% polymine (PEI)/analysis buffered soln) and Filtermate 196 collectors (Packard BioScience) reaction mixture is filled in the unifilter 96-hole white culture plate, wash 3 times with cold analysis buffered soln.Reaction mixture with same composition is measured non-specific binding in the presence of the unlabelled spiperone of 10 μ M.Every hole adds 45 μ l Microscint 40 (PerkinElmer, Schwerzenbach, Switzerland), with plate sealing, vibration 20min is through the Topcount of quench correction microplate scintillometer (Canberra Packard SA, Z ü rich, Switzerland) go up and count 3min.
Data computation
With the CPM value average (y1) of the competing compound of each duplicate concentration, calculate the combination of % specificity according to equation (((y1-non-specific binding)/(total binding-non-specific binding)) x100) then.In conjunction with drawing with XLfit, this XLfit is a kind of curve fitting procedure with the % specificity, and it uses Levenburg Marquardt algorithm with iterative manner data to be drawn.Used unit point competition analysis equation is y=A+ ((B-A)/(1+ ((x/C)
D))), wherein y is the combination of % specificity, and A is minimum y value, and B is maximum y value, and C is IC
50, x is the log of competing compound concentration
10, D is slope of a curve (Hill coefficient).Determine IC from these curves
50(inhibition concentration when 50% specificity of radioligand is replaced in conjunction with quilt) and Hill coefficient.Use Cheng-Prusoff equation Ki=(IC
50([L]/Kd) calculates affinity costant (Ki) to/1+, and wherein [L] is the concentration of radioligand, and Kd is the dissociation constant of radioligand on described acceptor, and it is measured by saturation isotherm.
The compounds of this invention is thrombotonin 5-HT
2aAnd dopamine D
3The selectivity dual modulators of acceptor, as shown in hereinafter activity was shown, this table had provided the thrombotonin 5-HT of some embodiment of The compounds of this invention
2a, dopamine D
3And dopamine D
2The Ki value in nM of acceptor.
Active table
| Embodiment | 9 | 20 | 22 | 23 |
| Ki(nM) D 3/5HT 2A/D 2 | 6/2/106 | 18/5/586 | 15/4/149 | 72/5/73 |
| Embodiment | 29 | 33 | 25 | 41 |
| Ki(nM) D 3/5HT 2A/D 2 | 32/8/450 | 110/65/1977 | 13/269/777 | 4/11/677 |
| Embodiment | 46 | 50 | 57 | 58 |
| Ki(nM) | 15/2/30 | 29/2/288 | 53/21/1334 | 19/80/3542 |
| D 3/5HT 2A/D 2 | ||||
| Embodiment | 61 | 64 | 70 | 72 |
| Ki(nM) D 3/5HT 2A/D 2 | 35/64/2895 | 4/26/3998 | 97/22/2714 | 39/26/2133 |
| Embodiment | 14 | 26 | 29 | 30A25 |
| Ki(nM) D 3/5HT 2A/D 2 | 144/12/96 | 17/14/684 | 37/8/450 | 26/5/1285 |
| Embodiment | 30A27 | 30A28 | 30A29 | 30A36 |
| Ki(nM) D 3/5HT 2A/D 2 | 8/8/1117 | 9/5/470 | 207/25/1008 | 26/5/1285 |
| Embodiment | 30A37 | 30A58 | 30A59 | 30A64 |
| Ki(nM) D 3/5HT 2A/D 2 | 29/11/2002 | 30/15/2070 | 19/5/888 | 19/13/625 |
| Embodiment | 34 | 39 | 40 | 42 |
| Ki(nM) D 3/5HT 2A/D 2 | 23/6/192 | 2/3/1844 | 8/9/502 | 146/11/352 |
| Embodiment | 42A7 | 63A14 | 65A11 | |
| Ki(nM) D 3/5HT 2A/D 2 | 86/26/176 | 44/83/8539 | 71/38/1447 |
Formula I compound and pharmacologically acceptable salts useful as drug thereof, for example form of pharmaceutical preparation.Pharmaceutical preparation can dosage forms for oral administration, for example the form of tablet, coating tablet, drageeing, hard and soft gelatin capsule, solution, emulsion or suspensoid.Yet, but use also per rectum, for example suppository form or carry out through parenteral, for example injection solution form.
Formula I compound and pharmacologically acceptable salts thereof can be processed with useful in preparing drug formulations with the inorganic or organic carrier of pharmacy inertia.Can use lactose, W-Gum or derivatives thereof, talcum powder, stearic acid or its salt etc., for example as this class carrier of tablet, coating tablet, drageeing and hard-gelatin capsules.The appropriate carrier of Gelseal for example is vegetables oil, wax, fat, semisolid and aqueous polyvalent alcohol etc.; Yet depending on the character of active substance does not need carrier usually under the situation of Gelseal.The appropriate carrier of preparation solution or syrup for example is water, polyvalent alcohol, sucrose, Nulomoline, glucose etc.Auxiliary agent can be used for the water-based injection solution of formula I compound water soluble salt as alcohol, polyvalent alcohol, glycerine, plant wet goods, but is not essential usually.The appropriate carrier of suppository for example is natural oil or winterized stearin, wax, fat, semisolid or aqueous polyvalent alcohol etc.
In addition, pharmaceutical preparation can contain salt, buffer reagent, odor mask or the oxidation inhibitor of sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweetener, tinting material, seasonings, change osmotic pressure.They also can contain the material that other has therapeutic value.
As preceding mentioning, the medicine that contains formula I compound or its pharmaceutically acceptable salt and treatment inert excipient also is purpose of the present invention, the method for preparing this type of medicine is purpose of the present invention equally, this method comprise with one or more formulas I compound or its pharmacologically acceptable salts and if necessary one or more other treat valuable material and make the galenic formulation together with one or more treatment inert supports.
Dosage can change in wide in range limit, should meet the individual demand of each particular case certainly.Usually, the effective dose that per os or parenteral are used is 0.01-20mg/kg/ days, and for the indication of all descriptions, preferred dose is 0.1-10mg/kg/ days.The Coming-of-Age Day dosage of body weight 70kg correspondingly is 0.7-1400mg/ days, preferred 7-700mg/ days.
Provide following examples with further elaboration the present invention:
Test method
Embodiment 1
4-chloro-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide
Intermediate B
Trans-(4-amino-cyclohexyl)-ethyl acetate
Step 1.
(50g 276mmol) adds in the solution of 22.08g 50% sodium hydroxide solution in the 450mL deionized water of stirring with (4-nitro-phenyl)-acetic acid.This clear yellow solution is transferred in the autoclave, and this autoclave is equipped with sponge nickel (sponge nickle) catalyzer of 30g (511mmol) water-wet.With autoclave sealing, purge with nitrogen, then with pressurized with hydrogen to 115bar.Reaction mixture stirred and be heated to 125 ℃ reach 48h.This moment is with this autoclave cooling, ventilation, other 30g (511mmol) sponge nickel catalyst of packing under nitrogen.This autoclave is used nitrogen purging again, be forced into 115bar then, under stirring this container is heated to 130 ℃ (observing the 130bar peak pressure).Continuous hydrogenation 5 days to 130 ℃.With the autoclave cooling, nitrogen purging is used in ventilation, and content is removed, and filters to remove catalyzer through flocculating aids then.After the desolventizing, obtain thick material 74g.The not purified next step that namely is directly used in of this intermediate.MS(m/e)：158.3(M+H
+)。
Step 2
With gained trans-(74g, solution 476mmol) is adjusted to pH5 with 25%HCl to (4-amino-cyclohexyl)-acetic acid.This mixture is evaporated to drying, dried overnight under vacuum.Resistates is suspended in the 146mL 6.5N HCl ethanolic soln, 0.6L ethanol is added in this mixture.After the backflow 4h, with this mixture cooling, filter, under vacuum, filtrate is concentrated into drying.Resistates is dissolved in the ethanol, handles with ether, but spend the night in refrigerator and cooled, obtain trans-(4-amino-cyclohexyl)-ethyl acetate hydrochloride (19.7g, 32%, through two steps), be white solid, with its filtration, dry under vacuum.MS(m/e)：186.1(M+H
+)。
Intermediate C
Step 1
Trans-(4-tert-butoxycarbonyl amino-cyclohexyl)-ethyl acetate
To trans-(4-amino-cyclohexyl)-ethyl acetate (1.28g, 7mmol) add in the solution in methylene dichloride (15mL) contracting two dimethyl dicarbonate butyl esters (2,26g, 10mmol), triethylamine (0.699mL, 7mmol) and 4-dimethylaminopyridine (0.042mL, 0.35mmol).This mixture is stirred 8h, show up to TLC to react completely.Add water, with solution dichloromethane extraction 3 times.With organic layer water and the salt water washing that merges, use dried over mgso, filter evaporation.With crude product by flash chromatography at the silica gel hexane: ethyl acetate (4: 2 to 3: 2) purifying, obtain 1.2g (60%) product, be white solid.MS(m/e)：284.4(M-H
+)。
Step 2
Trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate
(1.04g 4mmol) adds 1.2M DIBAL-H (5.1mL, 6mmol) solution in toluene in the solution in toluene (10mL) to trans-(4-tert-butoxycarbonyl amino-cyclohexyl)-ethyl acetate at-78 ℃.-78 ℃ of stirrings, the TLC demonstration reacts completely behind 0.5h with this mixture.Add water, with solution dichloromethane extraction 3 times.With organic layer water and the salt water washing that merges, use dried over mgso, filter evaporation.The not purified next step that namely is used for of crude product.MS(m/e)：242.3(M+H
+)。
Intermediate E
Trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-t-butyl carbamate
With 4-(4-fluoro benzoyl) piperidines (0.850g; 3.4mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate (0.926g; 4mmol) 1; mixture in the 2-ethylene dichloride (10mL) is at stirring at room 4h; add sodium triacetoxy borohydride (1.33g; 6mmol), with gained solution stirring 12 hours, show up to TLC to react completely.This mixture is filtered, is concentrated into drying, with column chromatography at silica gel CH
2Cl
2-CH
2Cl
2/ MeOH (1-9: 1) purifying.The product fraction is concentrated, obtain 1.4g (3.25mmol, 93.2% productive rate) faint yellow solid.MS(m/e)：433.4(M+H
+)。
Intermediate F
Trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (can be used as trifluoro
Acetate obtains)
With 1.4g (3.25mmol) (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate is dissolved in methylene dichloride (30mL); add trifluoroacetic acid (1.98mL at 0 ℃; 26mmol), with this mixture in stirred overnight at room temperature.Slowly add NaHCO
3Until pH9, with this mixture with methylene dichloride and ethyl acetate extraction 3 times.Evaporating solvent obtains 0.812gg (24.4mmol, 75.5%) white solid, its not purified next step that namely is used for.MS(m/e)：333.2(M+H
+)。
4-chloro-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide
With 4-chloro-benzoic acid (0.014g, 0.09mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate (0.029g, 0.09mmol) and (0.06mL, 0.270mmol) the N-ethyl diisopropyl amine stirs 0.5h in room temperature in 0.3mLDMF, add trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) (0.030g, 0.09mmol).This mixture was stirred 12 hours in stirring at room.This mixture is concentrated into drying, resistates is placed methyl alcohol, with preparation type reversed-phase HPLC, through acetonitrile/water wash-out purifying.Product fraction vapourisation under reduced pressure with merging obtains 0.015g pale solid (0.032mmol, 36%).MS(m/e)：471.3(M+H
+)。
According to the synthetic described method of embodiment 1, synthesized other derivative from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and corresponding acid respectively.They comprise that embodiment 1 is to 30A63.
| The embodiment numbering | Systematic name | MW | Initial substance | MW surveys (M+H) + |
| 1 | 4-chloro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 471.0 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-chloro-benzoic acid | 471.3 |
| 2 | Cyclopropane-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 400.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and cyclopropane-carboxylic acid | 401.3 |
| 3 | 4-(3,5-dimethyl ,-Yi Evil azoles-4-ylmethoxies)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 561.7 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-(3,5-dimethyl ,-isoxazole-4-base methoxyl groups)-phenylformic acid | 562.3 |
| 4 | Tetrahydrochysene-pyrans-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 444.59 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and tetrahydrochysene-pyrans-4-formic acid | 445.3 |
| 5 | N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-trifluoromethyl-benzamide | 504.57 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-(trifluoromethyl) phenylformic acid | 505.2 |
| 6 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide | 418.55 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 3-methoxyl group-propionic acid | 419.3 |
| 7 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide | 521.68 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-morpholino phenylformic acid | 522.5 |
| 8 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-(5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide | 518.3 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 3-(5-methyl isophthalic acid, 2,4-Evil diazole-3-yl)-phenylformic acid | 519.4 |
| 9 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyrroles-1-base-benzamide | 501.65 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-(1H-pyrroles-1-yl) phenylformic acid | 502.1 |
| 10 | 4-oxyethyl group-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 480.62 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-ethoxybenzoic acid | 481.4 |
| 11 | Tetrahydrochysene-furans-3-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 430.56 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and tetrahydrochysene-furans-3-formic acid | 431.4 |
| 12 | 4-acetylamino-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 493.2 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-acetylamino phenylformic acid | 494.1 |
| 13 | 2-methyl-2H-indazole-3-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 490.62 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 2-methyl-2H-indazole-3-formic acid | 491.4 |
| 14 | 2-(4-chloro-phenyl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-isobutyramide | 513.1 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-chloro-α, the alpha-alpha-dimethyl phenylacetic acid | 514.5 |
| 15 | N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-(3-methyl-5-oxo-4,5-dihydro-pyrazoles-1-yl)-benzamide | 532.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-phenylformic acid | 533.2 |
| 16 | 6-chloro-2-methyl-quinoline-3-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 536.09 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 6-chloro-2-methyl-quinoline-3-formic acid | 536.2 |
| 17 | 5-chloro-1-(3,4-, two chloro-benzyls)-6-oxo-1,6-dihydro-Nicotinicum Acidum is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 647.02 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 5-chloro-1-(3,4-, two chloro-benzyls)-6-oxo-1,6-dihydro-Nicotinicum Acidum | 648.1 |
| 18 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-6-methyl-niacinamide | 451.59 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 6-methylnicotinic acid | 452.7 |
| 19 | 4-cyano group-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 461.58 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-cyanobenzoic acid | 462.2 |
| 20 | [1,8] naphthyridines-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 488.61 | Trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and [1,8] naphthyridines-4-formic acid are trans | 489.2 |
| 21 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyrazol-1-yl-benzamide | 502.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-(1H-pyrazol-1-yl-phenylformic acid | 503.1 |
| 22 | 2,4-, two chloro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 505.46 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 2,4 dichloro benzene formic acid | 507.1 |
| 23 | 4-(4-chloro-benzenesulfonyl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 611.18 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-(4-4-(4-chloro-benzenesulfonyl)-phenylformic acid | 611.8 |
| 24 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-trifluoromethoxy-benzamide | 520.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-trifluoromethoxy-phenylformic acid | 521.3 |
| 25 | 3-oxyethyl group-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-propionic acid amide | 432.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 3-oxyethyl group-propionic acid | 433.3 |
| 26 | 3,3,3-, three fluoro-N-are trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-propionic acid amide | 442.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 3,3,3-, three fluoro-propionic acid | 443.1 |
| 27 | N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-(1,1,2,2-tetrafluoro-oxyethyl group)-benzamide | 552.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-(1,1,2,2-tetrafluoro-oxyethyl group)-phenylformic acid | 553.2 |
| 28 | N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-propionic acid amide | 388.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and propionic acid | 389.3 |
| 29 | Naphthenic acid is trans-(4-{2-[4-(4-fluoro-benzene first | 442.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4- | 443.5 |
| Acyl group)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | The fluoro-phenyl)-ketone (trifluoroacetate) and naphthenic acid | |||
| 30 | Diamantane-1-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 494.7 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and diamantane-1-formic acid | 495.4 |
| 30A1 | 2,2,2-, three fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide | 450.9 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and trifluoroacetic acid | 453.0 |
| 30A2 | 5-fluoro-1H-indole-2-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 493.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 5-fluoro-1H-indole-2-carboxylic acid | 494.0 |
| 30A3 | 5-trifluoromethoxy-1H-indole-2-carboxylic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 559.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) 5-trifluoromethoxy-1H-indole-2-carboxylic acid | 560 |
| 30A4 | 5-methoxyl group-1H-indole-2-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 505.3 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 5-methoxyl group-1H-indole-2-carboxylic acid | 506.0 |
| 30A5 | 2-cyclopropyl-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide | 414.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and the acid of 2-cyclopropyl | 416 |
| 30A6 | Trans (4-{2-[4-(the 4-fluorine of N- | 402.5 | Trans-{ 1-[2-(4-amino-hexamethylene | 403.0 |
| -benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-butyramide | Base)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and butyric acid | |||
| 30A7 | Thiophene-2-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 442.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and thiophene-2-carboxylic acid | 443.2 |
| 30A8 | 3H-imidazo [4,5-b] pyridine-6-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 477.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 3H-imidazo [4,5-b] pyridine-6-formic acid | 478.3 |
| 30A9 | 2-methyl-cyclopropane-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 414.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 2-methyl-cyclopropane-carboxylic acid | 415.4 |
| 30A10 | 5-methylsulfonyl-thiophene-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 520.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 5-methylsulfonyl-thiophene-2-carboxylic acid | 521.3 |
| 30A11 | 6-fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-niacinamide | 455.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 6-fluorine nicotinic acid | 456.2 |
| 30A12 | 4-methoxyl group-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)- | 472.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-methoxyl group-hexanaphthene | 473.3 |
| Acid amides | Formic acid | |||
| 30A13 | 4-hydroxyl-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 458.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (trifluoroacetate) and 4-hydroxyl-naphthenic acid | 459.5 |
| 30A14 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-butyramide | 432.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3-methoxyl group-butyric acid (saponification by ester obtains) | 433.5 |
| 30A15 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyridin-3-yl-benzamide | 513.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-pyridin-3-yl-phenylformic acid | 514.1 |
| 30A16 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyridin-4-yl-benzamide | 513.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-pyridin-4-yl-phenylformic acid | 514.1 |
| 30A17 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyridine-2-base-benzamide | 513.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-pyridine-2-base-phenylformic acid | 514.1 |
| 30A18 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-(4-methyl-piperazine | 534.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-(4-methylpiperazine subbase) phenylformic acid | 535.1 |
| -1-yl)-benzamide | ||||
| 30A19 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-6-morpholine-4-base-niacinamide | 522.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-(4-methylpiperazine subbase) phenylformic acid | 523.7 |
| 30A20 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-phthalazines-1-base-benzamide | 564.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-phthalazines-1-base-phenylformic acid | 565.0 |
| 30A21 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-4-pyridine-2-base-benzamide | 543.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3-methoxyl group-4-pyridine-2-base-phenylformic acid | 544.0 |
| 30A22 | Xenyl-4-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 512.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-xenyl carbonic acid | 513.5 |
| 30A23 | 3-methyl-chroman-3-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 506.7 | Trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3-methyl-chroman-3-formic acid (as preparation as described in the WO200386288) | 507.3 |
| 30A24 | 2-morpholine-4-base-pyrimidine-5-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)- | 523.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 2-morpholine-4-base-pyrimidine-5-formic acid | 524.2 |
| Acid amides | ||||
| 30A25 | 6-morpholine-4-base-pyridazine-3-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 523.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 6-morpholine-4-base-pyridazine-3-formic acid | 524.0 |
| 30A26 | 5-morpholine-4-base-pyrazine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 523.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 5-morpholine-4-base-pyrazine-2-formic acid | 524.2 |
| 30A27 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-phenoxy group-propionic acid amide | 480.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3-phenoxy propionic acid | 481.2 |
| 30A28 | 3-phenyl-propynoic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 460.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and phenyl propynoic acid | 461.2 |
| 30A29 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-hydroxyl-2,2-dimethyl-propionic acid amide | 432.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 2,2-dimethyl-3-hydroxy-propionic acid | 433.4 |
| 30A30 | 2-fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide | 539.7 | Trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 2-fluoro-4-morpholine-4-base-phenylformic acid are (according to Biorganicaland Medicinal chemistry | 540.1 |
| Letters (2005), 15 (5), the 1529-1534 preparation) | ||||
| 30A31 | Benzo [1,3] dioxole-5-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 480.57 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 2-fluoro-4-morpholine-4-base-phenylformic acid | 481.1 |
| 30A32 | 3-methyl-isoxazoles-5-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 441.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3-methyl-isoxazole-5-formic acid | 442.5 |
| 30A33 | 4-(3,3-dimethyl-2-oxo-azetidine-1-yl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 533.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-(3,3-dimethyl-2-oxo-azetidine-1-yl)-phenylformic acid | 534.2 |
| 30A34 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-ylmethyl-benzamide | 535.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-(morpholino methyl) phenylformic acid | 536.2 |
| 30A35 | The 2-benzo [d] isoxazole-3-base-N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide | 491.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 2-(1,2-benzoisoxazole-3-yl) acetic acid | 492.4 |
| 30A36 | Trans (4-{2-[4-(the 4-fluorine of N- | 455.6 | Trans { 1-[2-(4-amino-hexamethylene | 456.3 |
| -benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-2-(3-methyl-Yi Evil azoles-5-yls)-ethanamide | Base)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3-methyl-5-isoxazole acetic acid | |||
| 30A37 | 2-(3,5-dimethoxy-phenyl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide | 510.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3,5-dimethoxy benzene guanidine-acetic acid | 511.5 |
| 30A38 | 2-benzo [1,3] dioxole-5-base-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide | 494.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3,4-methylenedioxyphenyl guanidine-acetic acid | 495.4 |
| 30A39 | Trans N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-2-methoxyl group-Isonicotinamide | 467.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 2-methoxyl group-Yi Yansuan | 468.4 |
| 30A40 | 4-tert.-butoxy-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 508.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-tert.-butoxy phenylformic acid | 509.5 |
| 30A41 | 4-dimethylamino-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 479.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-dimethylaminobenzoic acid | 480.3 |
| 30A42 | 4-(1,1-dioxo-6-sulphur | 569.7 | Trans { 1-[2-(4-amino-hexamethylene | 570.4 |
| Morpholine-4-yl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | Base)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-(1,1-dioxo-4-thiazan-4-yl) phenylformic acid | |||
| 30A43 | 3-fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide | 539.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3-fluoro-4-morpholine-4-base-phenylformic acid | 540.1 |
| 30A44 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-(3-hydroxyl-tetramethyleneimine-1-yl)-benzamide | 521.7 | Trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-(3-hydroxyl-tetramethyleneimine-1-yl)-phenylformic acid are (according to Biorganic and Medicinal Chemistry Letters (2005), 15 (5), 1529 preparations) | 522.5 |
| 30A45 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-(4-hydroxy-piperdine-1-yl)-benzamide | 535.7 | Trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-(4-hydroxy-piperdine-1-yl)-phenylformic acid are (according to Biorganic and Medicinal Chemistry Letters (2005), 15 (5), 1529 preparations). | 536.4 |
| 30A46 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-parathiazan-4-base- | 537.8 | Trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-parathiazan-4-base-phenylformic acid (according to | 538.4 |
| Benzamide | Biorganic and Medicinal Chemistry Letters (2005), 15 (5), 1529 preparations) | |||
| 30A47 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-piperidines-1-base-benzamide | 519.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-piperidines-1-base-phenylformic acid | 520.3 |
| 30A48 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-6-morpholine-4-base-niacinamide | 522.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-morpholino nicotinic acid | 523.7 |
| 30A49 | 2,3-dihydro-benzo [1,4] dioxine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 494.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 1,4-benzodioxan-2-formic acid | 495.3 |
| 30A50 | (1S, 4R)-two the ring [2.2.1] heptane-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 494.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and (1S, 4R)-two ring [2.2.1] heptane-2-formic acid | 495.3 |
| 30A51 | (1R, 4R)-7,7-dimethyl-2-oxo-two ring [2.2.1] heptane-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 496.6 | Trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and (1R, 4R)-7,7-dimethyl-2-oxo-two ring [2.2.1] heptane-1-formic acid | 497.4 |
| 30A52 | 4-trifluoromethyl-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 510.62 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-trifluoromethyl-naphthenic acid | 511.5 |
| 30A53 | 1-methyl-cyclohexyl alkane formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 456.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 1-methyl-naphthenic acid | 457.5 |
| 30A54 | 4-methyl-cyclohexyl alkane formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 456.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-methyl-naphthenic acid | 457.5 |
| 30A55 | 6-hydroxyl-two ring [2.2.2] octane-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 484.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 6-hydroxyl-two ring [2.2.2] octane-2-formic acid | 485.4 |
| 30A56 | 1-trifluoromethyl-cyclopropane-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 456.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 1-trifluoromethyl-cyclopropane-carboxylic acid | 457.5 |
| 30A57 | 3-chloro-cyclobutane formate trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 449.01 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 3-chloro-cyclobutane formate | 449.5 |
| 30A58 | Trans (4-{2-[4-(the 4-of acetic acid | 432.5 | Trans { 1-[2-(4-amino-hexamethylene | 433.4 |
| The fluoro-benzoyl)-piperidines-1-yl]-ethyl }-the cyclohexyl carboxyamide base)-methyl ester | Base)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and ethoxyacetic acid | |||
| 30A59 | 1-hydroxyl-cyclopropane-carboxylic acid (trans-4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 416.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 1-hydroxyl-cyclopropane-carboxylic acid | 417.4 |
| 30A60 | Cyclobutane formate trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 414.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and cyclobutane formate | 415.5 |
| 30A61 | 4-hydroxyl-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 458.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 4-hydroxyl-naphthenic acid | 459.4 |
| 30A62 | 2,2-, two fluoro-cyclopropane-carboxylic acids trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 436.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 2,2-, two fluoro-cyclopropane-carboxylic acids | 437.2 |
| 30A63 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-2-morpholine-4-base-benzamide | 522.4 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 2-morpholino phenylformic acid | 521.6 |
Embodiment 30A64
Trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-Urethylane
With trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(30mg 0.082mmol) is dissolved in the 1ml methylene dichloride (4-fluoro-phenyl)-ketone (trifluoroacetate).Reactant is cooled to 0 ℃.Add coke acid dimethyl esters (10.9mg, 0.082mmol) and triethylamine (8.3mg, 0.082mmol).With reaction mixture in stirred overnight at room temperature.Add sodium bicarbonate aqueous solution, until pH8, with the water dichloromethane extraction.Carry out chromatography with methylene chloride (1/0 to 8/2), obtain required compound, be white solid (24mg, 69.1%).
Embodiment 30A65
5-(4-methyl-piperazine-1-yl)-pyridine-2-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-second
Base }-cyclohexyl)-acid amides
Step 1:5-bromo-pyridine-2-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-hexamethylene
Base)-acid amides
According to embodiment 1 synthetic described method, from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-(embodiment 1 for ketone, intermediate F) and 5-bromo-2-carboxyl pyridine prepare this title compound, MS:m/e=515.9/517.9 (M+H
+).
Step 2:5-(4-methyl-piperazine-1-yl)-pyridine-2-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-
Base]-ethyl }-cyclohexyl)-acid amides
With 5-bromo-pyridine-2-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-(80mg, 0.15mmol) (31 μ l 0.28mmol) are dissolved in the 2ml diox acid amides with the 1-methylpiperazine.Add 4,5-two (diphenylphosphine)-9,9-dimethyl xanthene (9mg, 0.016mmol), cesium carbonate (76mg, 0.23mmol), water (1 μ l, 0.078mmol) and three (dibenzalacetone) two palladium chloroform mixture (8mg, 0.008mmol), reaction mixture is stirred 16hr at 110 ℃.Then with the reaction mixture evaporation, by flash chromatography purifying (methylene chloride 100: 0-＞90: 10 gradients) on silica gel.Obtain required product, be incarnadine solid (33mg, 40%), MS:m/e=536.0 (M+H
+).
Embodiment 30A66
5-morpholine-4-base-pyridine-2-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-hexamethylene
Base)-acid amides
According to the general method of embodiment 30A65 step 2, from 5-bromo-pyridine-2-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides and morpholine prepare this title compound, MS:m/e=523.2 (M+H
+).
Embodiment 30A67
5-phenyl-pyridine-2-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acyl
Amine
With 5-bromo-pyridine-2-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides (embodiment 30A66; step 1) (80mg; 0.155mmol) and phenyl for boric acid (27mg; 0.22mmol) under argon gas, be dissolved in 0.4ml 2M sodium carbonate solution and 1.6ml 1, in the 2-glycol dimethyl ether.Add triphenyl phosphine (16mg, 0.062mmol) and acid chloride (II) (7mg, 0.03mmol), with this mixture at 85 ℃ of stirring 16hr.With this reaction mixture water extraction, use dichloromethane extraction 2 times.With organic extract water and salt water washing, use dried over sodium sulfate, filter evaporation.With crude product by flash chromatography purifying (methylene dichloride/methane 100: 0-＞90: 10 gradients) on silica gel.Obtain required compound, be brown solid (36mg, 45%), MS:m/e=514.1 (M+H
+).
Embodiment 31
Quinoline-4-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides
Intermediate B
Trans-(4-amino-cyclohexyl)-ethyl acetate
Step 1.
(0.005g 276mmol) adds in the solution of 22.08g 50% sodium hydroxide solution in the 450mL deionized water of stirring with (4-nitro-phenyl)-acetic acid.This clear yellow solution is transferred in the autoclave, and this autoclave is equipped with the sponge nickel catalyst of 30g (511mmol) water-wet.With autoclave sealing, purge with nitrogen, then with pressurized with hydrogen to 115bar.Reaction mixture stirred and be heated to 125 ℃ reach 48h.This moment is with this autoclave cooling, ventilation, other 30g (511mmol) sponge nickel catalyst of packing under nitrogen.This autoclave is used nitrogen purging again, be forced into 115bar then, under stirring this container is heated to 130 ℃ (observing the 130bar peak pressure).Continuous hydrogenation 5 days to 130 ℃.With the autoclave cooling, nitrogen purging is used in ventilation, and content is removed, and filters to remove catalyzer through flocculating aids then.After the desolventizing, obtain thick material.The not purified next step that namely is directly used in of this intermediate.MS(m/e)：158.3(M+H
+)。
Step 2
With gained trans-(74g, solution 476mmol) is adjusted to pH5 with 25%HCl to (4-amino-cyclohexyl)-acetic acid.This mixture is evaporated to drying, dried overnight under vacuum.Resistates is suspended in the 146mL 6.5N HCl ethanolic soln, 0.6L ethanol is added in this mixture.After the backflow 4h, with this mixture cooling, filter, under vacuum, filtrate is concentrated into drying.Resistates is dissolved in the ethanol, handles with ether, but spend the night in refrigerator and cooled, obtain trans-(4-amino-cyclohexyl)-ethyl acetate hydrochloride (19.7g, 32%, through two steps), be white solid, with its filtration, dry under vacuum.MS(m/e)：186.1(M+H
+)。
Intermediate G
Step 1
Trans-4-[(quinoline-4-carbonyl)-amino]-cyclohexyl }-ethyl acetate hydrochloride
With trans-(4-amino-cyclohexyl)-ethyl acetate hydrochloride (3.63g, 17mmol) mixture is dissolved in the methylene dichloride (115mL), and adding quinoline-4-carbonyl villaumite hydrochlorate (4.184g, 18mmol), then 0 ℃ slowly add triethylamine (11.3mL, 81mmol).This mixture in stirred overnight at room temperature, is removed by filter the salt of gained, extraction filtrate.Organic layer NaHCO
3With the salt water washing.With the organic phase drying, concentrate, obtain the 3.8g crude product.After AcOEt carries out flash chromatography, obtain solid with heptane/AcOEt 4: 1, it with EtOAc and normal heptane recrystallization, is obtained title compound, be pink solid (2.72g, 42% productive rate).MS(m/e)：341.3(M+H
+)。
Step 2
Trans-4-[(quinoline-4-carbonyl)-amino]-cyclohexyl }-acetic acid
With 4-[(quinoline-4-carbonyl)-amino]-cyclohexyl }-ethyl acetate hydrochloride (2.7g, 8mmol) with lithium hydroxide monohydrate (3.33g, 79mmol) in the mixture of water (65mL) and THF (130mL), react, this mixture was heated 5 hours under refluxing.With the evaporation of 2/3 mixture, add HCl37%, until pH7.Then this mixture is evaporated to drying, adds water 30mL, filter this suspension, obtain solid, with its recrystallization (2.2g, 88.6% productive rate) in toluene.MS(m/e)：313.1(M+H
+)。
Intermediate H
Trans-4-[(quinoline-4-carbonyl)-amino]-cyclohexyl }-thioacetic acid S-ethyl ester
With 2.19g trans-4-[(quinoline-4-carbonyl)-amino]-cyclohexyl-acetic acid (7mmol) adds in the 1300mL methylene dichloride.Add 1.8mL oxalyl chloride (21mmol) then.This suspension is heated to backflow reaches 3 hours, the mixture with muddiness concentrates under vacuum then.This resistates is placed 500mL methylene dichloride and (1.28g, 21mmol) in the suspension of sulfur alcohol sodium, this sulfur alcohol sodium by 1.45mL sulfur alcohol and 12.07mL butyllithium (1.6M is in toluene) 0 ℃ and in glycol dimethyl ether (20mL) at stirring at room 1h and prepared fresh.The reaction mixture stirring is spent the night.Add NaHCO
3, organic phase dichloromethane extraction 3 times.With the organic phase drying, concentrate, resistates is carried out chromatography with heptane/AcOEt 1: 1 to AcOEt, obtain title compound, be solid (1.97g, 78.9% productive rate).MS(m/e)：357.3(M+H
+)。
Intermediate compound I
Quinoline-4-formic acid is trans-[4-(2-oxo-ethyl)-cyclohexyl]-acid amides
With trans-4-[(quinoline-4-carbonyl)-amino]-cyclohexyl-(1.87g 5mmol) is dissolved in acetone/methylene dichloride (40/40mL) to thioacetic acid S-ethyl ester, the 0.8g molecular sieve is added in this mixture, with this solution stirring 0.5h.Add 0.558g (1mmol) then and drape over one's shoulders palladium activated carbon 10%, then add 1.25mL (8mmol) triethyl-silicane.Reactant at stirring at room 1.5h, is added other 0.558g (1mmol) and drapes over one's shoulders palladium activated carbon 10% and 1.25mL (8mmol) triethyl-silicane, continuously stirring 1 hour in addition.This mixture by diatomite filtration, is concentrated mother liquor, use heptane/AcOEt1: after 1 to the AcOEt chromatography, obtain the final compound of 1.1 (37.1mmol, 70.8% productive rates).MS(m/e)：297.3(M+H
+)。
Quinoline-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides
With 4-(4-fluoro benzoyl) piperidines (trifluoroacetate) (0.020g 0.062mmol) is dissolved in the 1.2-methylene dichloride (0.300mL), add quinoline-4-formic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-acid amides (0.020g, 0.067mmol).Methyl alcohol (0.200mL) is added in this mixture, its stirring is spent the night.With sodium triacetoxy borohydride (0.024,0.11mmol) add in this settled solution, stirring at room 10 hours.This mixture is concentrated into drying, resistates is placed methyl alcohol, use preparation type reversed-phase HPLC, use acetonitrile/water wash-out purifying.Product fraction vapourisation under reduced pressure with merging obtains 0.03g white solid (0.06mmol, 99%).MS(m/e)：488.3(M+H
+)。
According to the synthetic described method of embodiment 31, from quinoline-4-formic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-acid amides and corresponding phenyl or heteroaryl piperidine-4-base-ketone (be obtained commercially, by means known in the art obtain or by the described method acquisition of this patent) synthesized other derivative.
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 31 | Quinoline-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 487.6 | Quinoline-4-formic acid is trans-[4-(2-oxo-ethyl)-cyclohexyl]-acid amides and 4-(4-fluoro benzoyl) piperidines (trifluoroacetate) | 488.3 |
| 32 | Quinoline-4-formic acid is trans-(4-{2-[4-(4-methoxyl group-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 499.6 | Quinoline-4-formic acid is trans-[4-(2-oxo-ethyl)-cyclohexyl]-acid amides and (4-p-methoxy-phenyl) (4-piperidyl) ketone hydrochloride | 500.3 |
| 33 | Quinoline-4-formic acid is trans-4-[2-(4-benzoyl-4-hydroxy-piperdine-1-yl)-ethyl]-cyclohexyl }-acid amides | 485.6 | Quinoline-4-formic acid is trans-[4-(2-oxo-ethyl)-cyclohexyl]-acid amides and 4-hydroxy-4-piperidinyl base phenyl ketone hydrochloride | 486.4 |
| 34 | Quinoline-4-formic acid is trans-4-[2-(4-benzoyl-4-fluoro-piperidine-1-yl)-ethyl]-cyclohexyl }-acid amides | 487.6 | Quinoline-4-formic acid is trans-[4-(2-oxo-ethyl)-cyclohexyl]-acid amides and (4-fluoro-piperidine-4-yl)-phenyl-ketone (trifluoroacetate) | 488.4 |
| 35 | Quinoline-4-formic acid is trans-(4-{2-[4-(3,4-, two chloro-benzoyls)-piperidines-1-yl]-second | 538.52 | Quinoline-4-formic acid is trans-[4-(2-oxo-ethyl)-cyclohexyl]-acid amides and (3,4-, two chloro-phenyl)-piperazine | 538.4 |
| Base }-cyclohexyl)-acid amides | Pyridine-4-base-ketone |
Embodiment 36
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
With trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (intermediate F, embodiment 1) (0.03g, 0.09mmol) be suspended in methylene dichloride (0.300mL), add triethylamine (0.01mL, 0.094mmol), then add Acetyl Chloride 98Min. (0.010mL, 0.094mL), this mixture stirring at room 2 hours, is shown that up to TLC reaction finishes.Desolventizing adds DMF (0.8mL), with this solution usefulness preparation type reversed-phase HPLC, usefulness acetonitrile/water (0.05%Et
3N) wash-out purifying.Product fraction vapourisation under reduced pressure with merging obtains 0.008g pale solid (0.02mmol, 22.2%).MS(m/e)：375.3(M+H
+)。
According to the synthetic described method of embodiment 36, synthesized other derivative from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and corresponding acyl chlorides.They comprise embodiment 36 and 37.
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 36 | N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide | 374.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(4-fluoro-phenyl)-ketone and Acetyl Chloride 98Min. | 375.2 |
| 37 | Morpholine-4-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 445.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(4-fluoro-phenyl)-ketone and 4-morpholinyl carbonyl chloride | 446.3 |
Embodiment 38
Anti-form-1-(2.4-two chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-hexamethylene
Base)-urea
With trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-(embodiment 1 for ketone, intermediate F) (0.03g, 0.09mmol) be suspended in the acetonitrile (0.300mL), add isocyanic acid 2,4-dichlorophenyl ester (0.019g, 0.1mmol), this mixture stirring at room 2 hours, is shown that until TLC reaction finishes.Desolventizing, with chromatography with methylene chloride (1/0 to 9/1) wash-out with this purifying crude.Product fraction vapourisation under reduced pressure with merging obtains 0.001g white solid (0.019mmol, 21%).MS(m/e)：375.3(M+H
+)。
According to the synthetic described method of embodiment 38, synthesized other derivative from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and corresponding isocyanic ester.They comprise embodiment 38 to 41.
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 38 | Anti-form-1-(2,4-, two chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea | 520.4 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and isocyanic acid 2,4 dichloro benzene base ester | 520.5 |
| 39 | Anti-form-1-(4-chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea | 520.4 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and isocyanic acid 4-chloro-phenyl-ester | 520.5 |
| 40 | Anti-form-1-(4-oxyethyl group-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea | 486.03 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and isocyanic acid 4-ethoxyl phenenyl ester | 486.5 |
| 41 | Anti-form-1-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-p-methylphenyl-urea | 465.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and isocyanic acid p-methylphenyl ester | 466.1 |
Embodiment 42
Anti-form-1-(4-chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-1-
Methyl-urea
With trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-(embodiment 1 for ketone, intermediate F) (0.05g, 0.1mmol) be suspended in the acetonitrile (1mL), add (4-chloro-phenyl) methyl carbamic acid 4-nitro-phenylester (methylene dichloride, preparing with triethylamine from 4-chloro-methylphenylamine and chloroformic acid 4-nitrophenyl ester under the stirring at room) (0.034g, 0.1mmol), then add N, N-diisopropylethylamine (0.04mL, 0.2mmol), this mixture was stirred 24 hours at 75 ℃, show that until TLC reaction finishes.Desolventizing, with chromatography with methylene chloride (1/0 to 9/1) wash-out with this purifying crude.Product fraction vapourisation under reduced pressure with merging obtains 0.02g white solid (0.04mmol, 40%).MS(m/e)：501.2(M+H
+)。
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 42 | Anti-form-1-(4-chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-1-methyl-urea | 500.1 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and (4-chloro-phenyl) methyl carbamic acid 4-nitro-phenylester | 501.2 |
Embodiment 42A1
2,3-dihydro-indoles-1-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acyl
Amine
With trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (embodiment 1, intermediate F) (80mg 0.24mmol) is dissolved in the 1.5ml methylene dichloride, add the N-ethyl diisopropyl amine (0.33mL, 1.93mmol).Careful add triphosgene (79mg, 0.27mmol), in room temperature with this solution stirring 30 minutes.Add indoline (32mg, 0.27mmol), stirring at room 30 minutes.With the saturated NaHCO of this reaction mixture
3-solution and dichloromethane extraction.With the salt water washing of this organic extract, use dried over sodium sulfate, filter evaporation.With crude product by flash chromatography purifying (methylene chloride 100: 0-＞90: 10 gradients) on silica gel.Obtain required compound, be white solid (51mg, 44%), MS:m/e=478.2 (M+H
+).
According to the synthetic described method of embodiment 42A1, synthesized other derivative from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone (embodiment 1, intermediate F) and corresponding amine.They comprise embodiment 42A2 to 42A7.
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 42A2 | 6-trifluoromethyl-2,3-dihydro-indoles-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 545.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 6-(trifluoromethyl) indoline | 546.2 |
| 42A3 | 1,3-dihydro-isoindole-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 477.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and isoindole | 478.2 |
| 42A4 | 3,4-dihydro-1H-isoquinoline 99.9-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 491.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and 1,2,3,4-tetrahydroisoquinoline | 492.1 |
| 42A5 | 3-phenoxy group-tetramethyleneimine-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 521.7 | Trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and (RS)-3-phenoxy group-tetramethyleneimine | 522.2 |
| 42A6 | 1,1-dioxo-parathiazan-4-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 493.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and (1,1-dioxo-parathiazan-4-formic acid | 494.4 |
| 42A7 | Trans-3-(4-{2-[4-(4-fluoro- | 403.5 | Trans { 1-[2-(4-amino-hexamethylene | 404.4 |
| Benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-1,1-dimethyl-urea | Base)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and dimethylamine |
Embodiment 43
N-{ (trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-3-(5-methyl
-[1,2,4] oxadiazole-3-yls)-benzamide
Intermediate K
Trans-2-[tert-butoxycarbonyl amino-(toluene-4-alkylsulfonyl)-methyl]-the cyclopropane-carboxylic acid ethyl ester
(2.9g 20.4mmol) is dissolved in the methyl alcohol, adds 2.4g (20.49mmol) t-butyl carbamate, then is added in the SPTS (40mL) in the water with 2-formyl radical-cyclopropane-carboxylic acid ethyl ester (88-90% trans-isomer(ide)).After stirring at room, add 5mL (132.5mmol) formic acid, this mixture was stirred 70 minutes, precipitate until product.With solid filtering, water and heptane wash, dry under high vacuum, obtain 3.6g (44.5% productive rate) title compound (only being trans-isomer(ide)), be white solid.MS(m/e)：384.5(M+H
+)。
Intermediate L
Trans-2-(tert-butoxycarbonyl amino-methyl)-cyclopropane-carboxylic acid ethyl ester
(2.3g 58.55mol) is suspended in the tetrahydrofuran (THF) (150mL), adds 4mL water with sodium borohydride.Add (13.3g, 33.46mmol) trans-2-[tert-butoxycarbonyl amino-(toluene-4-alkylsulfonyl)-methyl]-cyclopropane-carboxylic acid ethyl ester (every crowd of 0.8g), make temperature remain on 18-30 ℃. in batches1.5h add water afterwards, (4mL) and 0.4g (10.15mmol) sodium borohydride again.With gained mixture ammonium chloride 2M (300mL) and 100mL1M K
2CO
3Cancellation continues to stir 0.5h.Separate organic layer, water is with ethyl acetate (300mL) extraction, with the organic layer MgSO that merges
4Drying, under vacuum, be concentrated into dried, with column chromatography at silica gel with heptane/AcOEt (9/1) purifying, obtain 7.5g (92.1% productive rate) title compound, be white solid.MS(m/e)：244.1(M+H
+)。
Intermediate M
Trans-(2-formyl radical-cyclopropyl methyl)-t-butyl carbamate
-78 ℃ to trans-2-(tert-butoxycarbonyl amino-methyl)-cyclopropane-carboxylic acid ethyl ester (0.320g, 1.3mmol) add in the solution in toluene (5mL) solution of 1.2M DIBAL-H in toluene (1.86mL, 2.2mmol).-78 ℃ of stirrings, the TLC demonstration reacts completely behind 0.5h with this mixture.The saturated solution that adds sodium tartrate is with water dichloromethane extraction 3 times.With organic layer water and the salt water washing that merges, use dried over mgso, filter evaporation.The not purified next step that namely is used for of crude product.MS(m/e)：200.3(M+H
+)。
Intermediate N
Trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-t-butyl carbamate
With 4-(4-fluoro benzoyl) piperidines (0.300g; 1.2mmol), trans-(2-formyl radical-cyclopropyl methyl)-t-butyl carbamate (0.294g; 1.2mmol) 1; mixture in the 2-ethylene dichloride (2mL) is at stirring at room 4h; add sodium triacetoxy borohydride (0.470g; 2.2mmol), with gained solution stirring 12 hours, show up to TLC to react completely.This mixture is filtered, be concentrated into driedly, use CH with column chromatography at silica gel
2Cl
2-CH
2Cl
2/ MeOH (1-9: 1) purifying.The product fraction is concentrated, obtain 0.288g (0.74mmol, 60% productive rate) white solid.MS(m/e)：391.3(M+H
+)。
[1-(trans-2-amino methyl-cyclopropyl methyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate
0.288g (0.74mmol) { trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclopropyl methyl }-t-butyl carbamate is dissolved in the methylene dichloride (5mL); add trifluoroacetic acid (0.757mL at 0 ℃; 6.6mmol), with this mixture in stirred overnight at room temperature.Slowly add NaHCO
3Until pH9, with this mixture with methylene dichloride and ethyl acetate extraction 3 times.Evaporating solvent obtains 0.308g (0.76mmol, 100%) white solid, its not purified next step that namely is used for.MS(m/e)：291.2(M+H
+)。
N-{ (trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-3-(5-methyl
-[1,2,4] oxadiazole-3-yls)-benzamide
With 3-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) phenylformic acid (0.015g, 0.074mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate (0.024g, 0.074mmol) and (0.04mL, 0.224mmol) the N-ethyl diisopropyl amine is in 0.3mL DMF, at stirring at room 0.5h, adding [1-(trans-2-amino methyl-cyclopropyl methyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate (0.030g, 0.074mmol).With this mixture stirring at room 12 hours.This mixture is concentrated into dried, resistates is used methylene dichloride and methyl alcohol (9: 1) purifying with chromatography.Product fraction vapourisation under reduced pressure with merging obtains 0.02g light brown solid (0.04mmol, 56.6%).MS(m/e)：477.0(M+H
+)。
According to the synthetic described method of embodiment 43, from [1-(trans-2-amino methyl-cyclopropyl methyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone (trifluoroacetate) and synthetic other amide derivatives of the acid that respectively is obtained commercially.Use preparation HPLC on the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains amide compound separately, and they comprise embodiment 43 to 45.
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 43 | N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide | 476.5 | [1-(trans-2-amino methyl-cyclopropyl methyl)-piperidines-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and 3-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) phenylformic acid | 477.0 |
| 44 | 2-(4-chloro-phenyl)-N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-isobutyramide | 471.02 | [1-(trans-2-amino methyl-cyclopropyl methyl)-piperidines-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and 4-chloro-α, α-dimethyl phenyl acetic acid | 471.3 |
| 45 | 4-chloro-N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-benzamide | 428.9 | [1-(trans-2-amino methyl-cyclopropyl methyl)-piperidines-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and 4-chloro-benzoic acid | 429.5 |
Embodiment 46
1-(4-chloro-phenyl)-3-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-
Urea
This title compound from [1-(trans-2-amino methyl-cyclopropyl methyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate and isocyanic acid 4-chloro-phenyl-ester, acetonitrile, synthetic according to embodiment 21 described methods.MS(m/e)：444.0(M+H
+)
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 46 | 1-(4-chloro-phenyl)-3-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-urea | 443.95 | [1-(trans-2-amino methyl-cyclopropyl methyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone, trifluoroacetate and isocyanic acid 4-chloro-phenyl-ester | 444.0 |
Embodiment 47
2-(4-chloro-phenyl)-N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-
Isobutyramide
Intermediate P
Trans-2-hydroxymethyl-cyclobutane formate methyl esters
With trans-tetramethylene-1, (24.6g 142.9mmol) is dissolved in the 310mL methyl alcohol 2-formic acid dimethyl ester, and (12.7g, 322mmol), keeping temperature is 0 ℃ to divide 5 parts of each 40 minutes adding sodium borohydrides.After last the interpolation, this mixture was stirred 2 hours.Add 2M aqueous ammonium chloride solution (500mL) and sulfuric acid 2M (76ml), until pH7.With water 150mL dichloromethane extraction 3 times, with the purifying mixture of organic layer with column chromatography, use methylene dichloride and TBME (4+1), obtain 15.3g title compound (106mmol, 74% productive rate), be colourless liquid.MS(m/e)：167.2(M+Na
+)。
Intermediate Q
Trans-2-formyl radical-cyclobutane formate methyl esters
At-78 ℃, (9.2mL 106.5mmol) is dissolved in the methylene dichloride (250mL), is added in (15.5mL, 218mmol) dimethyl sulfoxide (DMSO) in the 20mL methylene dichloride with oxalyl chloride.After-78 ℃ were stirred 15 minutes, (14g 95.17mmol) joined in the 78mL methylene dichloride, and after 10 minutes, (67mL 479mmol), stirs 2h with this mixture at-78 ℃ to add triethylamine with trans-2-hydroxymethyl-cyclobutane formate methyl esters.Add the 150mL methylene dichloride, add 200mL water, water 200mL dichloromethane extraction, the organic phase that merges is used normal heptane/AcOEt (4+1) purifying with column chromatography at silica gel, obtain 11.1g (78mmol, 82% productive rate) title compound, be colourless liquid.MS(m/e)：165.2(M+Na
+)。
Intermediate R
Trans-2-[tert-butoxycarbonyl amino-(toluene-4-alkylsulfonyl)-methyl]-the cyclobutane formate methyl esters
According to trans-2-[tert-butoxycarbonyl amino-(toluene-4-alkylsulfonyl)-methyl]-cyclopropane-carboxylic acid ethyl ester (intermediate K; embodiment 43) synthetic; from trans-2-formyl radical-cyclobutane formate methyl esters (11.1g; 73.4mmol), t-butyl carbamate (12.4g; 105.8mmol), the SPTS in water (19.1g, 104.6mmol) and formic acid (24mL 636.1mol) prepares this title compound; obtain 29.17g (73.4mmol, 84.3% productive rate).MS(m/e)：384.5(M+H
+)。
Intermediate S
Trans-(2-hydroxymethyl-cyclobutylmethyl)-t-butyl carbamate
Step 1
Trans-2-(tert-butoxycarbonyl amino-methyl)-cyclobutane formate methyl esters
According to trans-2-(tert-butoxycarbonyl amino-methyl)-cyclopropane-carboxylic acid ethyl ester (intermediate L; embodiment 43) synthetic; from trans-2-[tert-butoxycarbonyl amino-(toluene-4-alkylsulfonyl)-methyl]-cyclobutane formate methyl esters (17.7g; 44.53mmol), sodium borohydride (3.3g; 83.74mmol) prepare this title compound; obtain 8.2g (33.7mmol, 73.4% productive rate).MS(m/e)：244.0(M+H
+)。
Step 2
Trans-(2-hydroxymethyl-cyclobutylmethyl)-t-butyl carbamate
0 ℃ to trans-2-(tert-butoxycarbonyl amino-methyl)-cyclobutane formate methyl esters (4.1g, 16.8mmol) add in the solution in methyl alcohol (20mL) in batches sodium borohydride (1.3g, 33.6mmol).This mixture is stirred 4h, show until TLC to react completely.Add the ammonium chloride saturated solution, under vacuum, remove methyl alcohol, with the water dichloromethane extraction.With organic layer water and the salt water washing that merges, use dried over mgso, to filter, evaporation is used normal heptane-EtOAc (1: 1) purifying with column chromatography at silica gel.The product fraction is concentrated, obtain 2.8g (16.8mmol, 80% productive rate) title compound, be white solid.MS(m/e)：216.3(M+H
+)。
Intermediate T
Methylsulfonic acid is trans-2-(tert-butoxycarbonyl amino-methyl)-cyclobutylmethyl ester
At 0 ℃, (1g 4.6mmol) is dissolved in the 10mL methylene dichloride, and (0.585g 4.6mmol), then adds (1.19mL, 7mmol) N, N-diisopropylethylamine to add methylsulfonyl chloride with trans-(2-hydroxymethyl-cyclobutylmethyl)-t-butyl carbamate.Mixture is stirred 1h at 0 ℃, add aqueous ammonium chloride solution, with water 200mL dichloromethane extraction, the organic phase that merges is used normal heptane/AcOEt (1/1) purifying with column chromatography at silica gel, obtain 1.27g (4.4mmol, 94.5% productive rate) title compound, be weak yellow liquid.MS(m/e)：294.2(M+H
+)。
Intermediate N
Trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-t-butyl carbamate
With 4-(4-fluoro benzoyl) piperidines (0.500g; 2.0mmol), methylsulfonic acid is trans-2-(tert-butoxycarbonyl amino-methyl)-cyclobutyl methyl esters (0.662g; 2.2mmol) and triethylamine (0.71mL, 5mol) mixture in acetonitrile (4mL) stirs 12h at 80 ℃.This mixture is concentrated into dried, uses the 10mL dichloromethane extraction, use methylene chloride-methanol (9: 1) purifying with column chromatography at silica gel.The product fraction is concentrated, obtain 0.759g (1.9mmol, 91.5% productive rate) light brown solid.MS(m/e)：405.5(M+H
+)。
[1-(trans-2-amino methyl-cyclobutylmethyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate
Synthetic according to [1-(trans-2-amino methyl-cyclopropyl methyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate (embodiment 43) is from trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-t-butyl carbamate and trifluoroacetic acid prepare this title compound.MS(m/e)：291.2(M+H
+)。
Embodiment 47
N-{ (trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl }-3-(5-methyl
-[1,2,4] oxadiazole-3-yls)-benzamide
According to N-{ (trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-the cyclopropyl methyl-3-(5-methyl-[1; 2; 4] oxadiazole-3-yl)-the synthetic described method of benzamide (embodiment 43); from [1-(trans-2-amino methyl-cyclobutylmethyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate and 3-(5-methyl-[1; 2,4] oxadiazole-3-yl)-phenylformic acid prepares this title compound (m/e): 491.2 (M+H
+).
Other amide derivatives is from [1-(trans-2-amino methyl-cyclobutylmethyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate, N-ethyl diisopropyl amine and the listed acid that respectively is obtained commercially of table C are synthetic.
Use preparation HPLC in the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains amide compound separately, and they comprise embodiment 47 to embodiment 48.
| Embodiment | Systematic name | MW | Initial substance | MW surveys (M+H) + |
| 47 | N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide | 490.5 | [1-(trans-2-amino methyl-cyclobutylmethyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and 3-(the 5-methyl-[1,2,4] Evil diazole-3-yls)-phenylformic acid | 491.2 |
| 48 | 2-(4-chloro-phenyl)-N-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-isobutyramide | 485.04 | [1-(trans-2-amino methyl-cyclobutylmethyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and 4-chloro-α, the alpha-alpha-dimethyl phenylacetic acid | 485.4 |
Embodiment 49
1-(4-chloro-phenyl)-3-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-
Urea
This title compound is from 1-(trans-2-amino methyl-cyclobutylmethyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate and isocyanic acid 4-chloro-phenyl-ester, acetonitrile, synthetic according to embodiment 38 described methods.MS(m/e)：458.1(M+H
+)。
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 49 | 1-(4-chloro-phenyl)-3-{ is trans-2-[4-(4-fluoro-benzoyl)-piperidines-1-ylmethyl]-cyclobutylmethyl }-urea | 457.9 | 1-(trans-2-amino methyl-cyclobutylmethyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and isocyanic acid 4-chloro-phenyl-ester | 458.1 |
Embodiment 50
N-is trans-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-the 3-methoxyl group-
Propionic acid amide
Intermediate A A
4-(4-fluoro-benzoyl)-piperidines-1-t-butyl formate
With 4-(4-fluoro benzoyl) piperidine hydrochlorate (1.5g; 6.16mmol) be suspended in the acetonitrile (30mL); add triethylamine (0.940mL at 0 ℃; 6.8mmol), dimethyl aminopyridine (0.150g; 1.2mmol) and a contracting two dimethyl dicarbonate butyl ester (1.6g; 7.4mmol), with this mixture at stirring at room 3h.Evaporating solvent adds the 1M HCl aqueous solution (20mL), and water with ethyl acetate (100mL) extraction, is used normal heptane-EtOAc (1: 1) purifying with column chromatography at silica gel.The product fraction is concentrated, obtain 1.87g (6.08mmol, 99% productive rate) white solid.MS(m/e)：307.3(M+H
+)。
Intermediate A B
4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-t-butyl formate
With the 4-among the 0.5mL DMF (4-fluoro-benzoyl)-piperidines-1-t-butyl formate add to 0 ℃, contain 0.5mL tBuOH, (0.109mg is 0.651mmol) in the solution of tBuOK and 2mL DMF.After 0 ℃ is stirred 20min, add in batches N-fluorine BBI (0.246g, 0.781mmol).Reactant is stirred 45min at 0 ℃, and (0.55g adds (0.123g, 0.390mmol) N-fluorine BBI after the 0.33mmol) tBuOK, 10min 0 ℃ of adding.Each 0.5h repeats to add (0.55g, 0.33mmol) tBuOK and (0.123g, 0.390mmol) N-fluorine BBI twice again.The last interpolation after the 1h with the quencher of 4mL water, removed DMF with reactant under vacuum.With this water ethyl acetate extraction, the organic phase that merges is used normal heptane-EtOAc (3: 1) purifying with column chromatography at silica gel.The product fraction is concentrated, obtain 0.122g (0.375mmol, 58% productive rate) yellow oil.MS(m/e)：326.1(M+H
+)。
Intermediate D
4-fluoro-4-(4-fluoro-benzoyl)-piperidines
With 4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-t-butyl formate (0.122g 0.375mmol) is dissolved in the methylene dichloride (2mL), 0 ℃ add trifluoroacetic acid (0.258mL, 3.37mmol).Slowly add NaHCO
3The aqueous solution is until pH9, with this mixture with methylene dichloride and ethyl acetate extraction 3 times.Evaporating solvent obtains g (0.mmol, 100%) white solid, its not purified next step that namely is used for.MS(m/e)：226.1(M+H
+)。
Intermediate E
Trans-4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-the carboxylamine uncle
Butyl ester
This title compound from 4-fluoro-4-(4-fluoro-benzoyl)-piperidines and trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate, according to trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate (intermediate E; embodiment 1) synthetic described method in 1,2-ethylene dichloride, use triacetoxy boron hydride thing preparation.MS(m/e)：451.1(M+H
+)。
Intermediate F
Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone trifluoro second
Hydrochlorate
This title compound from trans-4 (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate and trifluoroacetic acid, according to the synthetic described method preparation of trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate (intermediate F, embodiment 1).MS(m/e)：351.3(M+H
+)。
N-is trans-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-the 3-methoxyl group-
Propionic acid amide
According to 4-chloro-N-trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-the synthetic described method of benzamide (embodiment 1); from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate, 2-(1H-benzotriazole-1-yl)-1; 1; 3,3-tetramethyl-urea a tetrafluoro borate, N-ethyl diisopropyl amine and 3-methoxyl group-propionic acid synthesize this title compound.MS(m/e)：437.0(M+H
+)。
Other amide derivatives is from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate, N-ethyl diisopropyl amine and the listed acid that each is obtained commercially of table D are synthetic.Use preparation HPLC in the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains amide compound separately, they comprise embodiment 50 to
Embodiment 53.
| Embodiment | Systematic name | MW | Initial substance | MW survey (M+H)+ |
| 50 | N-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide | 436.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone; Trifluoroacetate and 3-methoxyl group-propionic acid | 437.0 |
| 51 | 4-oxyethyl group-N-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-second | 498.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone; Trifluoro | 499.0 |
| Base }-cyclohexyl)-benzamide | Acetate and 4-ethoxybenzoic acid | |||
| 52 | Tetrahydrochysene-furans-3-formic acid is trans-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 448.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone; Trifluoroacetate and tetrahydrochysene-furans-3-formic acid | 449.0 |
| 53 | N-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide | 392.4 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone; Trifluoroacetate and acetic acid | 393.2 |
Embodiment 54
1-(4-chloro-phenyl)-3-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea
This title compound from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate and isocyanic acid 4-chloro-phenyl-ester, acetonitrile, synthetic according to embodiment 38 described methods.MS(m/e)：504.3(M
+)。
According to the synthetic described method of embodiment 54, other urea derivatives is synthetic from { 1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate and the isocyanic ester that respectively is obtained commercially.Use preparation HPLC in the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains carbamide compound separately, and they comprise embodiment 54 and embodiment 55.
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 54 | 1-(4-chloro-phenyl)-3-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-urea | 504.0 | 1-[2-(4-amino-cyclohexyl)-ethyl]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone; Trifluoroacetate and isocyanic acid 4-chloro-phenyl-ester | 504.3 |
| 55 | 1-(4-oxyethyl group-phenyl)-3- | 513.6 | { 1-[2-(4-amino-cyclohexyl)-second | 514.5 |
| Trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea | Base]-4-fluoro-piperidine-4-yl }-(4-fluoro-phenyl)-ketone; Trifluoroacetate and isocyanic acid 4-ethoxyl phenenyl ester |
Embodiment 56
Quinoline-4-formic acid (4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl }-cyclohexyl)-acyl
Amine
Intermediate W
(1-benzyl-piperidin-4-yl)-(4-fluoro-phenyl)-ketone
Will (3g, 12.3mmol) 4-(4-fluoro benzoyl) piperidine hydrochlorate be suspended in acetonitrile (60mL) and triethylamine (4.29mL, 31mmol) in, the adding bromotoluene (1.61mL, 14mmol) and sodium iodide (2.8g, 18mol).This mixture is spent the night 80 ℃ of stirrings, after the cooling, this mixture is filtered, add water, with water 100mL dichloromethane extraction.With the organic phase dried over mgso that merges, filter, concentrate, use methylene chloride (95/0.5) purifying with column chromatography at silica gel, obtain 3.6g (12mmol, 99% productive rate) title compound, be brown solid.MS(m/e)：298.4(M+H
+)。
Intermediate X
(1-benzyl-4-bromo-piperidin-4-yl)-(4-fluoro-phenyl)-ketone
(2g 6.73mmol) is dissolved in the 500mL chloroform, and (2.14g, 13.4mmol), with this mixture backflow 1h, stirring is spent the night to add bromine with (1-benzyl-piperidin-4-yl)-(4-fluoro-phenyl)-ketone.When cooling, this mixture is filtered, obtain the 1.4g title compound, for white solid (3.83mol, 3.8mmol).MS(m/e)：376.1(M
+)。
Intermediate Y
6-benzyl-2-(4-fluoro-phenyl)-2-methoxyl group-1-oxa--6-azepine-spiral shell [2.5] octane
With (1-benzyl-4-bromo-piperidin-4-yl)-(4-fluoro-phenyl)-ketone (1g 2.66mmol) is dissolved in the methyl alcohol (11mL), add sodium (0.300g, 13.04mmol), with this mixture backflow 2h.Add water, under vacuum, methyl alcohol is concentrated, water is extracted with ethyl acetate (50mL).With the organic phase dried over mgso that merges, filter, concentrate, obtain 0.644g (2mmol, 75% productive rate) title compound, be yellow oil, its not purified next step that namely is used for.MS(m/e)：328.4(M+H
+)。
Intermediate Z
(1-benzyl-4-hydroxy-piperdine-4-yl)-(4-fluoro-phenyl)-ketone
With 6-benzyl-2-(4-fluoro-phenyl)-2-methoxyl group-1-oxa--6-azepine-spiral shell [2.5] octane (0.600g 1.83mmol) is dissolved in the ether (6mL), adds the 0.6mL HCl aqueous solution (37%), with this reaction mixture in stirring at room.0.5h afterwards, reaction is finished, and adds water, and product is precipitated.This mixture is filtered, make solid recrystallization from ethanol/ether, obtain title compound, be white solid (0.550g, 1.76mmol, 96%).MS(m/e)：314.0(M+H
+)。
Intermediate D
(4-fluoro-phenyl)-(4-hydroxy-piperdine-4-yl)-ketone
With (0.550g, 1.76mmol) (1-benzyl-4-hydroxy-piperdine-4-yl)-(4-fluoro-phenyl)-ketone uses the hydrogenation of 0.065g (0.61mmol) palladium on carbon in 4mL ethyl acetate and 2mL methyl alcohol, filtering catalyst and under vacuum after the desolventizing, obtain 0.392g title compound (1.76mmol, 100% productive rate), be pale solid.MS(m/e)：314.0(M+H
+)。
Intermediate E
(4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl }-cyclohexyl)-carboxylamine uncle fourth
Ester
This title compound from ((4-fluoro-phenyl)-(4-hydroxy-piperdine-4-yl)-ketone and trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate, basis (4-{2-is trans-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate (intermediate E; embodiment 1) synthetic described method, in 1,2-ethylene dichloride, use the preparation of triacetoxy boron hydride thing.MS(m/e)：451.1(M+H
+)。
Intermediate F
Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-4-hydroxy-piperdine-4-yl }-(4-fluoro-phenyl)-ketone trifluoro
Acetate
This title compound from (4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate and trifluoroacetic acid, according to the synthetic described method preparation of trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate (intermediate F, embodiment 1).MS(m/e)：351.3(M+H
+)。
Quinoline-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl }-hexamethylene
Base)-acid amides
According to N-trans-chloro-N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-the synthetic described method of benzamide (embodiment 1); from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-4-hydroxy-piperdine-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate and quinoline-4-formic acid, use 2-(1H-benzotriazole-1-yl)-1; 1; 3,3-tetramethyl-urea a tetrafluoro borate, N-ethyl diisopropyl amine be synthetic this title compound in DMF.MS(m/e)：504.2(M+H
+)。
Other amide derivatives is synthetic from { 1-[2-(4-amino-cyclohexyl)-ethyl]-4-hydroxy-piperdine-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate and the acid that respectively is obtained commercially.Use preparation HPLC in the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains amide compound separately, and they comprise embodiment 56 to embodiment 57.
| Embodiment | Systematic name | MW | Initial substance | MW surveys (M+H) + |
| 56 | Quinoline-4-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl-cyclohexyl)-acid amides | 503.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-4-hydroxy-piperdine-4-yl }-(4-fluoro-phenyl)-ketone; Trifluoroacetate and quinoline-4-formic acid | 504.2 |
| 57 | N-trans (4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl-hexamethylene | 534.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-4-hydroxy-piperdine-4-yl }-(4-fluoro-phenyl)-ketone; Three | 535.2 |
| Base)-3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide | Fluoroacetate and 3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-phenylformic acid |
Embodiment 57A1
Trans N-(4-{2-[4-(4-fluoro-benzoyl)-4-methyl-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
Intermediate D
(4-fluoro-phenyl)-(4-methyl-piperidin-4-yl)-ketone
Step 1
With N-boc-4-methyl-4-piperidine carboxylic acid (4g, 16mol), the 4-bromobenzene for boric acid (2.7g, 20mol), the PIVALIC ACID CRUDE (25) acid anhydride (4.6g, 25mmol), Pd (OAc)
2(0.111g, 0.4mol), 1,1 '-two (diphenylphosphine) ferrocene (0.319g, 0.1mol) and (0.7mL, 41mmol) water is mixed together in the 20mL tetrahydrofuran (THF), with this mixture 60 ℃ of heated overnight.Reaction mixture is filtered desolventizing under vacuum.Resistates uses normal heptane-EtOAc (4: 1) purifying with column chromatography at silica gel, obtains 0.216g (5%) title compound.MS(m/e)：322.0(M+H
+)。
The mixture of (4-fluoro-phenyl)-(4-methyl-piperidin-4-yl)-ketone and trifluoroacetic acid
This title compound from (4-fluoro-phenyl)-(4-methyl-piperidin-4-yl)-ketone (0.215g, 0.6mmol) and trifluoroacetic acid (1.4mL, 6mmol) synthetic in the 5mL methylene dichloride, obtain the 0.328g yellow solid, its not purified next step that namely is used for.MS(m/e)：222.3(M+H
+)。
Step 2
(4-fluoro-phenyl)-(4-methyl-piperidin-4-yl)-ketone
Intermediate E
Trans (4-{2-[4-(4-fluoro-benzoyl)-4-methyl-piperidines-1-yl]-ethyl }-cyclohexyl)-carboxylamine
The tert-butyl ester
According to trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate (intermediate E; embodiment 1) synthetic described method, from synthetic this title compound of (4-fluoro-phenyl)-(4-methyl-piperidin-4-yl)-ketone and trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate.MS(m/e)：447.4(M+H
+)。
Intermediate F
{ 1-trans-[2-(4-amino-cyclohexyl)-ethyl]-4-methyl-piperidin-4-yl }-(4-fluoro-phenyl)-ketone
According to { 1-trans-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate (intermediate F; embodiment 1) synthetic described method, from trans (4-{2-[4-(4-fluoro-benzoyl)-4-methyl-piperidines-1-yl]-ethyl-cyclohexyl)-synthetic this title compound of t-butyl carbamate and trifluoroacetic acid.MS(m/e)：347.4(M+H
+)。
Trans N-(4-{2-[4-(4-fluoro-benzoyl)-4-methyl-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
According to the synthetic described method of embodiment 36, from { 1-trans-[2-(4-amino-cyclohexyl)-ethyl]-4-methyl-piperidin-4-yl }-(4-fluoro-phenyl)-ketone and synthetic this title compound of corresponding Acetyl Chloride 98Min..MS(m/e)：389.4(M+H
+)。
Embodiment 58
N-is trans-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-the 3-methoxyl group-
Propionic acid amide
Intermediate E
Trans-(4-{2-[4-(2,4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-t-butyl carbamate
According to trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate (intermediate E; embodiment 1) synthetic described violating the law; from 4-(2,4-fluoro benzoyl) piperidines and synthetic this title compound of trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate.MS(m/e)：451.5(M+H
+)。
Intermediate F
{ 1-trans-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone and trifluoro
The mixture of acetic acid
According to { 1-trans-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate (intermediate F; embodiment 1) synthetic described method; from trans-(4-{2-[4-(2,4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-synthetic this title compound of t-butyl carbamate and trifluoroacetic acid.MS(m/e)：351.5(M+H
+)。
N-is trans-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-the 3-methoxyl group-
Propionic acid amide
According to 4-chloro-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-the synthetic described method of benzamide (embodiment 1); from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2; 4-two fluoro-phenyl)-(embodiment 58 for ketone; intermediate F) and 3-methoxyl group-propionic acid, use 2-(1H-benzotriazole-1-yl)-1; 1; 3,3-tetramethyl-urea a tetrafluoro borate and N-ethyl diisopropyl amine be synthetic this title compound in DMF.MS(m/e)：437.0(M+H
+)。
According to the synthetic described method of embodiment 58, from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone (embodiment 58, intermediate F) and synthetic other derivative of corresponding acid.Use preparation HPLC on the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains amide compound separately, and they comprise embodiment 58 to embodiment 63A18.
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 58 | N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide | 436.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 3-methoxyl group-propionic acid | 437.0 |
| 59 | N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-oxyethyl group-benzamide | 498.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 4-oxyethyl group-phenylformic acid | 499.2 |
| 60 | N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-3-(5-methyl-[1,2,4] oxadiazole-3-yl)- | 536.6 | Trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 3-(5-methyl-[1,2,4] oxadiazole-3-yl)- | 537.3 |
| Benzamide | Phenylformic acid | |||
| 61 | Tetrahydrochysene-furans-3-formic acid trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 448.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and tetrahydrochysene-furans-3-formic acid | 449.0 |
| 62 | N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide | 392.4 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and acetic acid | 393.4 |
| 63 | Tetrahydrochysene-pyrans-4-formic acid trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 462.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and tetrahydrochysene-pyrans-4-formic acid | 463.4 |
| 63A1 | N is trans-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-propionic acid amide | 406.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and propionic acid | 407.3 |
| 63A2 | 4-chloro-N-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide | 406.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and propionic acid and 4-chloro-benzoic acid | 407.3 |
| 63A3 | Cyclopropane-carboxylic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 418.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and propionic acid and cyclopropane-carboxylic acid | 419.4 |
| 63A4 | Cyclobutane formate (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-second | 432.5 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-first | 433.3 |
| Base }-cyclohexyl)-acid amides | Ketone and propionic acid and cyclobutane formate | |||
| 63A5 | 5-methylsulfonyl-thiophene-2-carboxylic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 538.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and propionic acid and 5-methylsulfonyl-thiophene-2-carboxylic acid | 538.5 |
| 63A6 63A7 63A8 | Chroman-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 510.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and propionic acid and chroman-3-formic acid (annotate: chiral separation obtains two kinds of enantiomers) | 511.5 |
| 63A9 | Xenyl-4-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 530.7 | 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone and xenyl-4-formic acid | 530.9 |
| 63A10 | N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-6-morpholine-4-base-niacinamide | 540.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone 2-morpholino nicotinic acid | 541.0 |
| 63A11 | N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-2-(3-methyl-isoxazole-5-base)-ethanamide | 473.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 3-methyl 5-isoxazole acetic acid | 474.6 |
| 63A12 | 4-trifluoromethyl-naphthenic acid trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acyl | 528.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 4-trifluoromethyl-hexamethylene | 529.2 |
| Amine | Alkane formic acid | |||
| 63A13 | N-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-morpholine-4-base-benzamide | 539.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 4-morpholino phenylformic acid | 540.3 |
| 63A14 | N-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-2-hydroxyl-ethanamide | 408.4 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 2-hydroxyl-acetic acid | 409.4 |
| 63A15 | (R)-N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-2-methoxyl group-propionic acid amide | 436.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 2-methoxyl group-propionic acid amide | 437.4 |
| 63A16 | 2-benzyloxy-N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide | 498.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 2-benzyloxy acetic acid | 499.3 |
| 63A17 | (S)-tetrahydrochysene-furans-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 448.5 | Trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and (S)-tetrahydrochysene-furans-3-formic acid | 449.4 |
| 63A18 | (R)-tetrahydrochysene-furans-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 448.5 | Trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and (R)-tetrahydrochysene-furans-3-formic acid | 449.3 |
Embodiment 64
Anti-form-1-(4-chloro-phenyl)-3-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-hexamethylene
Base)-urea
This title compound from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone (embodiment 58, intermediate F) and isocyanic acid 4-chloro-phenyl-ester, in acetonitrile, synthetic according to embodiment 38 described methods.MS(m/e)：504.3(M+H
+)。
According to the synthetic described method of embodiment 64, from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone (embodiment 58, intermediate F) and synthetic other urea derivatives of isocyanic ester of respectively being obtained commercially.Use preparation HPLC on the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains carbamide compound separately, and they comprise embodiment 64 and embodiment 65.
| Embodiment | Systematic name | MW | Initial substance | MW surveys (M+H) + |
| 64 | 1-(4-chloro-phenyl)-3-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-urea | 504.02 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and isocyanic acid 4-chloro-phenyl-ester | 504.3 |
| 65 | 1-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl] trans-ethyl-cyclohexyl)-3-(4-oxyethyl group-phenyl)-urea | 513.6 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and isocyanic acid 4-ethoxyl phenenyl ester | 514.5 |
According to the synthetic described method of embodiment 42A1, from trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone (embodiment 58, intermediate F) and synthetic other derivative of corresponding amine.They comprise embodiment 65A1 to 65A4.
| Implement | Systematic name | MW | Initial substance | The MW actual measurement |
| Example | (M+H)+ | |||
| 65A1 | 4-phenyl-Piperazine-1-formic acid trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 538.7 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone hydrochloride and 1-phenylpiperazine | 539.0 |
| 65A2 | 2,3-dihydro-indoles-1-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 495.6 | 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone hydrochloride and indoline | 496.2 |
| 65A4 | Morpholine-4-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 463.6 | 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone hydrochloride and morpholine | 464.2 |
| 65A4 | Tetramethyleneimine-1-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 447.6 | 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone hydrochloride and tetramethyleneimine | 448.3 |
Embodiment 65A5
Quinoline-4-formic acid trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acyl
Amine
This title compound obtains white solid according to embodiment 1, from trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone and quinoline-4-formic acid preparation.(m/e)：506.3(M+H
+)。
Other amide derivatives is synthetic from trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two fluoro-phenyl)-ketone and each acid.Use preparation HPLC on the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains amide compound separately, and they comprise embodiment 65A5 to embodiment 65A17.
| Embodiment | Systematic name | MW | Initial substance | MW surveys (M+H) + |
| 65A5 | Quinoline-4-formic acid trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 505.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and quinoline-4-formic acid | 506.3 |
| 65A6 | Tetrahydrochysene-furans-3-formic acid trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 448.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone tetrahydrochysene-furans-3-formic acid | 449.4 |
| 65A7 | Cyclopropane-carboxylic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 418.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and cyclopropane-carboxylic acid | 419.3 |
| 65A8 | 5-methylsulfonyl-thiophene-2-carboxylic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 538.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 5-methylsulfonyl-thiophene-2-carboxylic acid | 539.5 |
| 65A9 | N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-butyramide | 420.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and butyric acid | 421.1 |
| 65A10 | 2,2-, two fluoro-cyclopropane-carboxylic acids (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 454.3 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 2,2-, two fluoro-cyclopropane-carboxylic acids | 455.3 |
| 65A11 | Tetrahydrochysene-pyrans-4-formic acid | 462.5 | Trans { 1-[2-(4-amino-hexamethylene | 463.4 |
| (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | Base)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and tetrahydrochysene-pyrans-4-formic acid | |||
| 65A12 | 2-cyclopropyl-N-(4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide | 432.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 2-cyclopropyl ethanamide | 433.2 |
| 65A13 | Chroman-3-formic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 510.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and chroman-3-formic acid | 511.5 |
| 65A14 | 4-cyano group-N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 479.5 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 4-cyanobenzoic acid | 480.5 |
| 65A15 | N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyrroles-1-base-benzamide | 519.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 4-pyrroles's phenylformic acid | 520.2 |
| 65A16 | N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyrroles-1-base-benzamide | 519.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 4-pyrroles's phenylformic acid | 520.2 |
| 65A17 | N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide | 539.6 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2,4-, two fluoro-phenyl)-ketone and 4-morpholine phenylformic acid | 540.5 |
Embodiment 65A18
2-benzyloxy-N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-
Ethanamide
Step 1
1-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl ketone
(5g 19mmol) is dissolved among the THF (3mL), drips isopropylmagnesium chloride-lithium chloride (2M is in THF) at-10 ℃, and this mixture was stirred 30 minutes at 0 ℃ with 2-chloro-4-fluoro-1-iodobenzene (benzol).(3.3g 18mmol), stirs this mixture 10 minutes at-10 ℃, stirs 4h at 0 ℃ to be dissolved in 1-ethanoyl-piperidines-4-formyl chloride (1-acetyl-isonipecotoyl chloride) among the THF (2mL)-10 ℃ of addings.Add water, with the reactant dichloromethane extraction.With heptane/EtOAc (2: 1) chromatography, obtain required compound, be clarification orange liquid (1.8g, 33% productive rate).(m/e)：284.3(M+H
+)。
Step 2
(2-chloro-4-fluoro-phenyl)-piperidin-4-yl-ketone hydrochloride
With 1-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-(1.8g 6.5mmol) is dissolved among the 6N HCl (17mL) ethyl ketone, adds water 17mL.This mixture stirred under refluxing spend the night.Add diethyl ether (20mL), reactant is extracted.Abandon organic phase, in this water, add aqueous sodium hydroxide solution (10%), until pH11, use dichloromethane extraction.Desolventizing obtains 1.1g, 5mmol title compound (66% productive rate).(m/e)：242.3(M+H
+)。
Intermediate E and F
Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone
According to the step of in embodiment 1, having described, from (2-chloro-4-fluoro-phenyl)-piperidin-4-yl-ketone and trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate, then remove the Boc protecting group and prepare this title compound by handling with trifluoroacetic acid.(m/e)：367.4(M+H
+)。
2-benzyloxy-N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-
Ethanamide
As described in the embodiment 1 from trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate, N-ethyl diisopropyl amine and 2-benzyloxy acetic acid prepare this title compound in DMF.(m/e)：515.3(M+H
+)。
According to the synthetic described method of embodiment 65A18, from trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and synthetic other derivative of corresponding acid.Use preparation HPLC on the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains amide compound separately, and they comprise embodiment 65A18 to embodiment 65A28.
| Embodiment | Systematic name | MW | Initial substance | MW surveys (M+H) + |
| 65A18 | 2-benzyloxy-N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide | 515.1 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and 2-benzyloxy acetic acid | 515.3 |
| 65A19 | N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide | 556.1 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and 4-morpholine phenylformic acid | 556.1 |
| 65A20 | Tetrahydrochysene-furans-3-formic acid trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 465.1 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and tetrahydrochysene-furans-3-formic acid | 465.3 |
| 65A21 | Cyclopropane-carboxylic acid trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides | 434.9 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and cyclopropane-carboxylic acid | 435.4 |
| 65A22 | N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-butyramide | 437.0 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and butyric acid | 437.4 |
| 65A23 | N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-2-cyclopropyl-ethanamide | 449.0 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and 2-cyclopropyl-acetic acid | 449.4 |
| 65A24 | N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-propionic acid amide | 437.0 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and propionic acid | 437.4 |
| 65A25 | Tetrahydrochysene-pyrans-4-formic acid (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 479.0 4 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and tetrahydrochysene-pyrans-4-formic acid | 479.3 |
| 65A26 | 5-methylsulfonyl-thiophene-2-carboxylic acid (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 555.1 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and 5-methylsulfonyl-thiophene-2-carboxylic acid | 555.3 |
| 65A27 | N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide | 453.0 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and 3-methoxyl group-propionic acid | 453.2 |
| 65A28 | 4-chloro-N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide | 505.1 | Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidines-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and 4-chloro-benzoic acid | 505.4 |
Embodiment 65A29
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide
As described in the embodiment 36 from trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone and Acetyl Chloride 98Min. preparation.MS(m/e)：409.4(M+H
+)
Embodiment 66
4-oxyethyl group-N{4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-benzamide
Intermediate A C
4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-t-butyl carbamate
With 4-(4-fluoro benzoyl) piperidine hydrochlorate (0.5g 2.01mmol) is suspended in the acetonitrile (5mL), add 4-(Boc-amino) butyl bromide (0.569g, 2.01mmol) and sodium iodide (0.461g 3.02mmol), spends the night this mixture 80 ℃ of stirrings.Add water, with water 30mL dichloromethane extraction.With the organic phase dried over mgso that merges, filter, concentrate, use methylene chloride (95/0.5) purifying with column chromatography at silica gel, obtain 0.830g (2.1mmol, 100% productive rate) title compound, be brown solid.MS(m/e)：379.2(M+H
+)。
Intermediate A D
[1-(4-amino-butyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate
According to the synthetic described method of trans-{ 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate (intermediate F), from 4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-t-butyl carbamate and synthetic this title compound of trifluoroacetic acid.MS(m/e)：279.2(M+H
+)。
4-oxyethyl group-N-{4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-benzamide
According to 4-chloro-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-the synthetic described method of benzamide (embodiment 1); from trans-[1-(4-amino-butyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate and 4-ethoxybenzoic acid, use 2-(1H-benzotriazole-1-yl)-1; 1; 3,3-tetramethyl-urea a tetrafluoro borate and N-ethyl diisopropyl amine be synthetic this title compound in DMF.MS(m/e)：427.3(M+H
+)。
According to the synthetic described method of embodiment 66, from [1-(4-amino-butyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate and synthetic other amide derivatives of the acid that respectively is obtained commercially.Use preparation HPLC on the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains amide compound separately, and they comprise embodiment 66 and embodiment 68.
| Embodiment | Systematic name | MW | Initial substance | MW survey (M+H)+ |
| 66 | 4-oxyethyl group-N-{4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-benzamide | 426.5 | [1-(4-amino-butyl)-piperidines-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and 4-ethoxybenzoic acid | 427.3 |
| 67 | N-{4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-benzamide | 464.5 | [1-(4-amino-butyl)-piperidines-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and 3-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-phenylformic acid | 465.1 |
| 68 | Tetrahydrochysene-furans-3-formic acid 4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-acid amides | 376.4 | [1-(4-amino-butyl)-piperidines-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and tetrahydrochysene-furans-3-formic acid | 377.2 |
Embodiment 69
1-(4-chloro-phenyl)-3-{4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-urea
This title compound from trans-[1-(4-amino-butyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone trifluoroacetate and isocyanic acid 4-chloro-phenyl-ester, acetonitrile, synthetic according to embodiment 38 described methods.MS(m/e)：432.05(M
+)。
According to the synthetic described method of embodiment 59, use synthetic other carbamide compound of the isocyanic ester that respectively is obtained commercially.Use preparation HPLC on the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains carbamide compound separately.
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 69 | 1-(4-chloro-phenyl)-3-{4-[4-(4-fluoro- | 431.9 | [1-(4-amino-butyl)-piperidin-4-yl]-(4-fluoro-phenyl)-first | 432.5 |
| Benzoyl)-piperidines-1-yl]-butyl }-urea | Ketone; Trifluoroacetate and isocyanic acid 4-chloro-phenyl-ester | |||
| 70 | 1-(4-oxyethyl group-phenyl)-3-{4-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-butyl }-urea | 491.5 | [1-(4-amino-butyl)-piperidin-4-yl]-(4-fluoro-phenyl)-ketone; Trifluoroacetate and isocyanic acid 4-ethoxyl phenenyl ester | 492.4 |
Embodiment 71
Quinoline-4-formic acid is trans-(4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides
Intermediate E
Trans-(4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-t-butyl carbamate
According to trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate (intermediate E; embodiment 1) synthetic described method, from 4-{2-[4-(2-chloro-benzoyl)] synthetic this title compound of piperidines and trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate.MS(m/e)：450.1(M+H
+)。
Intermediate F
Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2-chloro-phenyl)-ketone trifluoroacetate
According to { 1-trans-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-phenyl)-ketone trifluoroacetate (intermediate F; embodiment 1) synthetic described method, from trans-(4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-synthetic this title compound of t-butyl carbamate and trifluoroacetic acid.MS(m/e)：349.5(M+H
+)。
Quinoline-4-formic acid is trans-(4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides
According to 4-chloro-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-the synthetic described method of benzamide (embodiment 1), from
Trans-1-[2-(4-amino-cyclohexyl)-ethyl]- Piperidin-4-yl-(2-chloro-phenyl)-ketone trifluoroacetate and quinoline-4-formic acid,Use 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate and N-ethyl diisopropyl amine be synthetic this title compound in DMF.MS(m/e)：504.4(M+H
+)。
Other amide derivatives from
Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl-(2-chloro- Phenyl)-the ketone trifluoroacetate andThe acid that respectively is obtained commercially is synthetic.Use preparation HPLC on the reversed-phase column material with by acetonitrile/water (0.05%Et
3N) gradient elution of Xing Chenging carries out purifying.The evaporate fraction obtains amide compound separately, and they comprise embodiment 71 to embodiment 72.
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 71 | Quinoline-4-formic acid is trans-(4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 504.07 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2-chloro-phenyl)-ketone; Trifluoroacetate and quinoline-4-formic acid | 504.4 |
| 72 | N-trans (4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide | 390.9 | Trans-1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2-chloro-phenyl)-ketone; Trifluoroacetate and acetic acid | 391.3 |
Embodiment 73
N-trans (4-{2-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base
-benzamide
Step 1
1-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl ketone
With 1-ethanoyl-piperidines-4-formyl chloride (8g 42mmol) is dissolved in the dichlorobenzene, add in batches aluminum chloride (11.2g, 894mmol).After reactant cooperates, with this mixture at 90 ℃ of backflow 4h.In this mixture, add ice/water, use dichloromethane extraction.After chromatography, obtain product from heptane to EtOAc, be yellow oil (6.3g, 50%).MS(m/e)：300.2(M+H
+)
Step 2
(2,4-, two chloro-phenyl)-piperidin-4-yl-ketone
Removing as refluxing in 6NHCl as described in the embodiment 65A18 of ethanoyl protecting group finished.MS(m/e)：258.0(M+H
+)。
Intermediate E
Trans (4-{2-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-carboxylamine uncle fourth
Ester
This title compound prepares from (2,4-, two chloro-phenyl)-piperidin-4-yl-ketone and trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate as described in embodiment 1.(m/e)：483.4(M+H
+)。
Intermediate F
Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two chloro-phenyl)-ketone
This title compound as described in the embodiment 1 from trans (4-{2-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate and trifluoroacetic acid preparation.(m/e)：383.3(M+H
+)。
N-trans (4-{2-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base
-benzamide
This title compound as described in the embodiment 1 from trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-two chloro-phenyl)-ketone and 4-morpholino phenylformic acid, use 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate and N-ethyl diisopropyl amine prepare in DMF.(m/e)：572.3(M+H
+)
Embodiment 74
N-trans (4-{2-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide
As described in the embodiment 36 from trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two chloro-phenyl)-ketone and Acetyl Chloride 98Min. preparation.MS(m/e)：425.3(M+H
+)。
Embodiment 75
N-trans (4-{2-[4-(2,5-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide
1-[4-(2,5-, two chloro-benzoyls)-piperidines-1-yl]-ethyl ketone
This title compound is described from 2,5-, two chloro-1-iodobenzenes, isopropylmagnesium chloride-lithium chloride (2M is in THF) and 1-ethanoyl-piperidines-4-formyl chloride preparation according to embodiment 65A18.(m/e)：301.1(M+H
+)。
(2,5-, two chloro-phenyl)-piperidin-4-yl-ketone
Removing as refluxing in 6N HCl as described in the embodiment 65A18 of ethanoyl protecting group finished.MS(m/e)：258.1(M+H
+)
Intermediate E
Trans (4-{2-[4-(2,5-, two chloro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-carboxylamine uncle fourth
Ester
This title compound prepares from (2,5-, two chloro-phenyl)-piperidin-4-yl-ketone and trans-[4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate as described in embodiment 1.(m/e)：483.5(M+H
+)。
Intermediate F
Trans 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,5-, two chloro-phenyl)-ketone
This title compound as described in the embodiment 1 from trans (4-{2-[4-(2,5-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-t-butyl carbamate and trifluoroacetic acid preparation.(m/e)：383.0(M+H
+)。
N-trans (4-{2-[4-(2,5-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide
As described in the embodiment 36 from trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2,4-, two chloro-phenyl)-ketone and Acetyl Chloride 98Min. preparation.MS(m/e)：425.3(M+H
+)。
Embodiment 76
N-trans (4-{2-[4-(4-fluoro-2-methyl-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide
As preparing from trans { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-fluoro-2-methyl-phenyl)-ketone (as trans as described in the embodiment 65A18 { 1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(2-chloro-4-fluoro-phenyl)-ketone preparation) and Acetyl Chloride 98Min. as described in the embodiment 36.MS(m/e)：389.1(M+H
+)。
The general method of reductive amination A.1
At l, the mixture in the 2-ethylene dichloride (ca.0.2M) is in stirred overnight at room temperature with amine hydrochlorate (1.0 equivalent) and aldehyde (1.1 equivalent).Add Na (AcO)
3BH (1.5 equivalent) is by TLC and MS monitoring reaction.After finishing, add saturated NHCO
3The aqueous solution is with product CH
2Cl
2Extraction.Dry (Na
2SO
4Or MgSO
4) afterwards, evaporating solvent, product passes through purified by flash chromatography.
The general method of reductive amination A.2
With amine hydrochlorate (1.0 equivalent), aldehyde (1.1 equivalent) and the mixture of AcOH (2.0 equivalent) in 1,2-ethylene dichloride (ca.0.2M) in stirred overnight at room temperature.Add Na (AcO)
3BH (1.5 equivalent) is by TLC and MS monitoring reaction.After finishing, add saturated NHCO
3The aqueous solution is with product CH
2Cl
2Extraction.Dry (Na
2SO
4Or MgSO
4) afterwards, evaporating solvent, product passes through purified by flash chromatography.
The general method that Boc dissociates B.1
Amine (1.0 equivalent), MeOH (10 equivalent) and the 4.6M HCl mixture in EtOAc (15 equivalent) of Boc protection is stirred, until monitoring less than initial substance by TLC and MS.The solid collected by filtration product, dry under HV.
The general method that Boc dissociates B.2
To the amine (1.0 equivalent) of Boc protection at CH
2Cl
2(ca.0.2M) add HCl in the mixture at Et
2Saturated solution among the O (CH of 1/2 volume
2Cl
2).This mixture is stirred, until monitoring less than initial substance by TLC and MS.Add Et
2O precipitates product, filters and collects, and uses more Et
2The O washing, dry under HV.
The general method C that acid amides forms
To N
2Under the solution (ca.0.1M) of acid (1.1 equivalent) in DMF of stirring in add TBTU (1.1 equivalent) and Et
3N (3.1 equivalent).After stirring at room 1h, add amine hydrochlorate (1.0 equivalent).Continue to stir, by TLC and MS monitoring reaction.After finishing, add saturated NHCO
3The aqueous solution extracts product with 3 parts of EtOAc.Dry (Na
2SO
4Or MgSO
4) afterwards, evaporating solvent, crude product passes through purified by flash chromatography.
General method D
Inert atmosphere and-78 ℃, the solution of 1.6M n-BuLi (1.1 equivalent) in Hex is added in the solution (0.1M) of thiophene (1.1 equivalent) in THF in batches.After-78 ℃ are stirred 2h, add the 4-formyl radical-piperidines-1-t-butyl formate (1.0 equivalent) that is dissolved among a small amount of THF.Continue to stir 2.5h at-78 ℃, make reaction mixture be warmed to room temperature then, be poured among the EtOAc, use saturated NaHCO
3Solution washing.Water layer extracts with more EtOAc.With the organic layer drying (Na that merges
2SO
4Or MgSO
4), evaporating solvent, crude product passes through purified by flash chromatography.
Alcohols is to the MnO of ketone
2
The general method of oxidation E.1
With MnO
2(20 equivalent) adds to alcohol (1.0 equivalent) at CH
2Cl
2In solution (0.1M) in.The gained mixture is spent the night 30 ℃ of stirrings.Filter with Dicalite, evaporating solvent obtains crude product, and it passes through purified by flash chromatography.
Alcohols to the general method of the TPAP oxidation of ketone E.2
Alcohol (1.0 equivalent) is dissolved in CH
2Cl
2(0.25M), add powdered
Molecular sieve (500mg/mmol) adds NMO, then adds shackles acid tetrapropyl ammonium (0.05 equivalent).This reaction mixture in stirring at room, is monitored by TLC.After finishing, use CH
2Cl
2The diluted mixture thing is used 1M Na then
2SO
3The aqueous solution, salt solution, use 1M CuSO at last
4Solution washing.Dry (Na
2SO
4Or MgSO
4), evaporating solvent obtains crude product, and it passes through purified by flash chromatography.
Embodiment 77
N-{ is trans-4-[2-(4-benzoyl-piperidine-1-yl)-ethyl]-cyclohexyl }-ethanamide
Step 1
Trans-4-[2-(4-benzoyl-piperidine-1-yl)-ethyl]-cyclohexyl }-t-butyl carbamate
From 4-benzoyl piperidine hydrochlorate (200mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate (intermediate C, 235mg), A.2 prepare via method.Output: 181mg (49%).Pale solid.MS(m/z)：415.3([M+H
+)。
Step 2
1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-phenyl-ketone dihydrochloride
From { trans-4-[2-(4-benzoyl-piperidine-1-yl)-ethyl]-cyclohexyl }-t-butyl carbamate (172mg), B.1 prepare via method.Output: 148mg (92%).White solid.MS(m/z)：315.1([M+H]
+)。
Step 3
N-{ is trans-4-[2-(4-benzoyl-piperidine-1-yl)-ethyl]-cyclohexyl }-ethanamide
From { 1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-phenyl-ketone dihydrochloride (138mg) and acetic acid (23mg), prepare via method C.Output: 85mg (66%).White solid.357.3([M+H]
+)。
Embodiment 78
N-(trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-morpholine-4-base-benzene
Methane amide
Step 1
(trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-t-butyl carbamate
From (4-chloro-phenyl-) (4-piperidyl) ketone hydrochloride (100mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate (intermediate C, 102mg), A.1 prepare via method.Output: 128mg (74%).Faint yellow solid.MS(m/z)：449.3([M+H]
+)。
Step 2
1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-chloro-phenyl)-ketone dihydrochloride
From (4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-t-butyl carbamate, B.2 prepare via method.Output: 100mg (84%).White solid.MS(m/z)：349.3([M+H]
+)。
Step 3
N-(trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-morpholine-4-base-benzene
Methane amide
From 1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-chloro-phenyl)-ketone dihydrochloride (100mg) and 4-morpholine-4-base-phenylformic acid preparation.Output: 56mg (40%).MS(m/z)：538.5([M+H]
+)。
Embodiment 79 and 80
Be similar to embodiment 78 preparation embodiment 79 and 80:
| Embodiment | Systematic name | MW | Initial substance | MW actual measurement (M+H)+ |
| 79 | Tetrahydrochysene-pyrans-4-formic acid (trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 461.05 | Start from 1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-chloro-phenyl)-ketone dihydrochloride and tetrahydrochysene-pyrans-4-formic acid | 461.5 |
| 80 | (R, S)-chroman-3-formic acid (trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides | 509.09 | Start from { 1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(4-chloro-phenyl)-ketone dihydrochloride and (R, S)-3-chroman formic acid | 509.3 |
Intermediate A G
N-[is trans-4-(2-oxo-ethyl)-cyclohexyl]-ethanamide
AE (trans-4-acetylamino-cyclohexyl)-ethyl acetate
(trans-4-amino-cyclohexyl)-ethyl acetate hydrochloride (10.0g, 45mmol, intermediate B) is dissolved in CH
2Cl
2(150mL), add Et
3N and AcCl (3.89g, 50mmol).Reaction mixture at stirring at room 3h, is used H then
2O and salt water washing.Dry (Na
2SO
4) afterwards, evaporating solvent, obtain 8.42g (82%, 37mmol) white solid.MS(m/z)：228.3([M+H
+)。
AFN-[is trans-4-(2-hydroxyl-ethyl)-cyclohexyl]-ethanamide
With LiAlH
4(2.10g, 55mmol) and THF (150mL) place dry balloon.This mixture is cooled to after 0 ℃, drips (trans-4-acetylamino-cyclohexyl)-ethyl acetate (8.42g, 37mmol) solution in a small amount of THF.Reactant is stirred 1h, carefully use H then
2O (5.6mL), 1N NaOH (3 * 5.6mL) and more H
2O (5.6mL) neutralization.The stirring of gained mixture is spent the night, leach solid then.Evaporating solvent, dry under high vacuum, obtain 5.25g (76%, 28mmol) light brown solid.MS(m/z)：186.4([M+H
+)。
AG N-[is trans-4-(2-oxo-ethyl)-cyclohexyl]-ethanamide
Will be at CH at-78 ℃
2Cl
2(3.68g, (2.9g is 23mmol) at CH 47mmol) to add to oxalyl chloride for DMSO (20mL)
2Cl
2In the solution of the stirring (100mL).After-78 ℃ are stirred 1h, add N-[trans-4-(2-hydroxyl-ethyl)-cyclohexyl]-(2.18g is 12mmol) at CH for ethanamide
2Cl
2Add Et after the solution (80mL), 2h
3N (7.14g, 71mmol).Make this mixture reach room temperature, use H then
2CH is used in the O dilution
2Cl
2Extraction.With the organic layer drying (Na that merges
2SO
4), evaporating solvent obtains crude product.Chromatography (CH
2Cl
2/ MeOH 95: 5), obtain 1.75g (81%, 9.5mmol) light brown solid.MS(m/z)：184.3([M+H]
+)。
Embodiment 81
N-(trans-4-{2-[4-(thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
Step 1
4-(hydroxyl-thiophene-2-base-methyl)-piperidines-1-t-butyl formate
From thiophene (130mg) and 4-formyl radical-piperidines-1-t-butyl formate (300mg), prepare via method D.Output: 167mg (40%).Yellow oil.MS(m/z）：298.1([M+H]
+)。
Step 2
4-(thiophene-2-carbonyl)-piperidines-1-t-butyl formate
From 4-(hydroxyl-thiophene-2-base-methyl)-piperidines-1-t-butyl formate (127mg), E.1 prepare via method.Output: 117mg (93%).Yellow oil.MS(m/z)：296.2([M+H]
+)。
Step 3
Piperidin-4-yl-thiophene-2-base-ketone hydrochloride
From 4-(thiophene-2-carbonyl)-piperidines-1-t-butyl formate (115mg), B.2 prepare via method.Output: 74mg (82%).Yellow solid.MS(m/z)：196.0([M+H]
+)。
Step 4
N-(trans-4-{2-[4-(thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
From piperidin-4-yl-thiophene-2-base-ketone hydrochloride (74mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-ethanamide (64mg, intermediate A G) preparation.Output: 75mg (65%).Faint yellow solid.MS(m/z)：363.4([M+H]
+)。
Embodiment 82
(R, S)-chroman-3-formic acid (trans-4-{2-[4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-hexamethylene
Base)-acid amides
Step 1
4-[(3-chloro-thiophene-2-yl)-hydroxyl-methyl]-piperidines-1-t-butyl formate
From 3-chlorothiophene 612mg) and 4-formyl radical-piperidines-1-t-butyl formate (1.00g), prepare via method D.Output: 420mg (27%).Yellow solid.MS(m/z)：332.2([M+H]
+)。
Step 2
4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-t-butyl formate
From 4-[(3-chloro-thiophene-2-yl)-hydroxyl-methyl]-piperidines-1-t-butyl formate (420mg), E.2 prepare via method.Output: 255mg (61%).Light yellow oil.MS(m/z)：330.2([M+H]
+)。
Step 3
(3-chloro-thiophene-2-yl)-piperidin-4-yl-ketone hydrochloride
From 4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-t-butyl formate (255mg), B.2 prepare via method.Output: 178mg (86%).White solid.MS(m/z)：230.4([M+H]
+)。
Step 4
(trans-4-{2-[4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-carboxylamine uncle fourth
Ester
From (3-chloro-thiophene-2-yl)-piperidin-4-yl-ketone hydrochloride (100mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate (intermediate C, 91mg), A.1 prepare via method.Output: 85mg (50%).White foam shape thing.MS(m/z)：455.3([M+H]
+)。
Step 5
1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(3-chloro-thiophene-2-yl)-ketone two hydrochloric acid
Salt
From (trans-4-{2-[4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-t-butyl carbamate (85mg), B.2 prepare via method.Output: 60mg (75%).White solid.MS(m/z)：355.3([M+H]
+)。
Step 6
(R.S)-chroman-3-formic acid (trans-4-{2-[4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-hexamethylene
Base)-acid amides
From { 1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(3-chloro-thiophene-2-yl)-ketone dihydrochloride (30mg) and (R, S)-chroman formic acid, prepare via method C.Output: 1mg (2.7%).White solid.MS(m/z)：515.3([M+H]
+)。
Embodiment 83
N-(trans-4-{2-[4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
From (3-chloro-thiophene-2-yl)-piperidin-4-yl-ketone hydrochloride (78mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-ethanamide (54mg, intermediate A G), A.1 prepare via method.Output: 52mg (45%).White solid.MS(m/z)：397.1([M+H]
+)。
Embodiment 84
N-(trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
Step 1
4-[(5-chloro-thiophene-2-yl)-hydroxyl-methyl]-piperidines-1-t-butyl formate
From 2-chlorothiophene (183mg) and 4-formyl radical-piperidines-1-t-butyl formate (300mg), prepare via method D.Output: 180mg (38%).Brown oil.MS(m/z)：332.1([M+H]
+)。
Step 2
4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-t-butyl formate
From 4-[(5-chloro-thiophene-2-yl)-hydroxyl-methyl]-piperidines-1-t-butyl formate (20mg), E.1 prepare via method.Output: 18mg (90%).Yellow oil.MS(m/z)：330.2([M+H]
+)。
Step 3
(5-chloro-thiophene-2-yl)-piperidin-4-yl-ketone hydrochloride
From 4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-t-butyl formate (12mg), B.2 prepare via method.Output: 10mg (100%).White solid.MS(m/z)：230.3([M+H]
+)。
Step 4
N-(trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
From (5-chloro-thiophene-2-yl)-piperidin-4-yl-ketone hydrochloride (10mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-ethanamide (7mg, intermediate A G), A.1 prepare via method.Output: 9mg (59%).White solid.MS(m/z)：397.4([M+H]
+)。
Embodiment 85
Benzo [1,3] dioxole-5-formic acid (trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-
Base]-ethyl }-cyclohexyl)-acid amides
Step 1
(trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-carboxylamine uncle fourth
Ester
From (5-chloro-thiophene-2-yl)-piperidin-4-yl-ketone hydrochloride (585mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-t-butyl carbamate (intermediate C, 530mg), A.2 prepare via method.Output: 513mg (51%).Faint yellow solid.MS(m/z)：455.2([M+H]
+)。
Step 2
1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(5-chloro-thiophene-2-yl)-ketone two hydrochloric acid
Salt
From (trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-t-butyl carbamate (1.14g), B.1 prepare via method.Output: 970mg (91%).The light gray solid.MS(m/z)：355.1([M+H]
+)。
Step 3
Benzo [1,3] dioxole-5-formic acid (trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-
Base]-ethyl }-cyclohexyl)-acid amides
From { 1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl }-(5-chloro-thiophene-2-yl)-ketone dihydrochloride (100mg) and benzo [1,3] dioxole-5-formic acid (45mg), prepare via method C.Output: 62mg (52%).Pale solid.MS(m/z)：503.2([M+H]
+)。
Embodiment 86
N-(trans-4-{2-[4-(5-fluoro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
Step 1
4-[(5-fluoro-thiophene-2-yl)-hydroxyl-methyl]-piperidines-1-t-butyl formate
(3.71mL, (500mg is 5.9mmol) in the solution in THF (15mL) 5.9mmol) to add to (78 ℃) thiophene of cooling with the solution of 1.6M n-BuLi in Hex under argon gas.After-78 ℃ are stirred 30min, add N-fluorine BBI (1.87g, 5.9mmol) solution in THF (10mL).At-78 ℃ of continuously stirring 10min, slowly be warming up to 0 ℃ through 15min then.Form solid precipitation.This mixture is cooled to-78 ℃, add the solution of 1.6M n-BuLi in Hex (3.71mL 0.59mL), stirs 10min with it then, be added on then 4-formyl radical-piperidines-1-t-butyl formate among the THF (5mL) (836mg, 3.9mmol).After-78 ℃ are stirred 30min, this solution slowly is warmed to room temperature.Add saturated NH
4The Cl aqueous solution (5mL) with EtOAc (100mL) dilution, is used saturated NH with this mixture
4The Cl aqueous solution (100mL), saturated NaHCO
3The aqueous solution (2 * 100mL) and salt solution (100mL) washing.Dry (Na
2SO
4) afterwards, evaporating solvent by chromatogram (amido modified silica gel, heptane is to EtOAc) purifying, obtains 971mg (79%) brown oil with crude product.MS(m/z)：316.1([M+H]
+)。
Step 2
4-(5-fluoro-thiophene-2-carbonyl)-piperidines-1-t-butyl formate
From 4-[(5-fluoro-thiophene-2-yl)-hydroxyl-methyl]-piperidines-1-t-butyl formate (968mg), E.2 prepare via method.MeCN (0.6mL) is added in the reaction mixture.Output: 577mg (60%).The light brown jelly.MS(m/z)：336.4([M+Na]
+)。
Step 3
(5-fluoro-thiophene-2-yl)-piperidin-4-yl-ketone hydrochloride
From 4-(5-fluoro-thiophene-2-carbonyl)-piperidines-1-t-butyl formate (51mg), B.1 prepare via method.Output: 20mg (49%).Pale solid.MS(m/z)：214.1([M+H]
+)。
Step 4
N-(trans-4-{2-[4-(5-fluoro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide
From (5-fluoro-thiophene-2-yl)-piperidin-4-yl-ketone hydrochloride (17mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-ethanamide (20mg, intermediate A G), A.2 prepare via method.Output: 19mg (73%).White solid.MS(m/z)：381.3([M+H]
+)。
Embodiment A
The thin membrane coated tablet that contains following component can prepare in a usual manner:
| Component | Every | |
| Label: | ||
| Formula (I) compound | 10.0mg | 200.0mg |
| Microcrystalline Cellulose | 23.5mg | 43.5mg |
| Lactose hydrate | 60.0mg | 70.0mg |
| 30 POVIDONE K 30 BP/USP 30 | 12.5mg | 15.0mg |
| Sodium starch glycolate | 12.5mg | 17.0mg |
| Magnesium Stearate | 1.5mg | 4.5mg |
| (label weight) | 120.0mg | 350.0mg |
| Film-coat: | ||
| Vltra tears | 3.5mg | 7.0mg |
| Polyethylene glycol 6000 | 0.8mg | 1.6mg |
| Talcum powder | 1.3mg | 2.6mg |
| Ferric oxide (yellow) | 0.8mg | 1.6mg |
| Titanium dioxide | 0.8mg | 1.6mg |
Activeconstituents is sieved, mix with Microcrystalline Cellulose, this mixture is granulated with the solution of polyvinylpyrrolidone in water.This particle is mixed with sodium starch glycolate and Magnesium Stearate, and compression obtains 120 or the 350mg label respectively.With the aqueous solution/suspension coating of this label with above-mentioned film-coat.
Embodiment B
The capsule that contains following component can prepare in a usual manner:
Component
Every capsules
Formula (I) compound 25.0mg
Lactose 150.0mg
W-Gum 20.0mg
Talcum powder 5.0mg
Each component is sieved, mix, be filled in No. 2 capsules.
Embodiment C
Injection solution can have following component:
Formula (I) compound 3.0mg
Gelatin 150.0mg
Phenol 4.7mg
It is 7 that yellow soda ash obtains final pH
The injection solution water adds to 1.0ml
Embodiment D
The soft gelatin capsule that contains following component can prepare in a usual manner:
Capsule 's content
Formula (I) compound 5.0mg
Yellow wax 8.0mg
Hydrogenated soybean oil 8.0mg
Partially hydrogenated vegetable oil 34.0mg
Soybean oil 110.0mg
Capsule 's content weight 165.0mg
Gelatine capsule
Gelatin 75.0mg
Glycerine 85% 32.0mg
Karion83 8.0mg (dry-matter)
Titanium dioxide 0.4mg
Zh 1 1.1mg
Activeconstituents is dissolved in the hot melt thing of other component, this mixture is filled in the soft capsule that is fit to size.The soft capsule of filling is handled according to conventional methods.
Embodiment E
The sachet (Sachets) that contains following component can prepare in a usual manner:
Formula (I) compound 50.0mg
Lactose, fine powder 1015.0mg
Microcrystalline Cellulose (AVICELPH102) 1400.0mg
Xylo-Mucine 14.0mg
Polyvinylpyrrolidone K30 10.0mg
Magnesium Stearate 10.0mg
Aromatic additive 1.0mg
Activeconstituents is mixed with lactose, Microcrystalline Cellulose and Xylo-Mucine, with the granulating mixture of polyvinylpyrrolidone in water.This particle is mixed with Magnesium Stearate and aromatic additive, be filled in the sachet.
Claims (23)
1. formula (Ia) compound:
Wherein:
A is optional by 1 to 5 aryl that is selected from down the substituting group replacement of group: cyano group, halo;
R
1The C that is replaced by aryl
2-6-alkynyl or C
2-6-alkenyl,
Or it is optional by 1 to 5 C that is selected from down the substituting group replacement of group
1-6-alkyl:
Halo,
Hydroxyl,
C
1-6-alkyl,
C
1-6-haloalkyl,
-CO (O)-C
1-6-alkyl,
C
1-6-alkoxyl group,
Optional by halo or C
1-6The aryl that-alkoxyl group replaces,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl replaces and
Phenoxy group,
Or C
1-6-alkoxyl group,
Or it is optional by one or more R
aThe C that replaces
3-10-cycloalkyl,
Or 4 to 10 yuan of Heterocyclylalkyls,
Or it is optional by one or more R
aThe aryl that replaces,
Or it is optional by one or more R
a5 to 10 yuan of heteroaryls that replace,
Or-NR
bR
c, R wherein
bBe H or C
1-6-alkyl, and R wherein
cBe H, C
1-6-alkyl or optional by one or more R
aThe aryl that replaces,
R wherein
aBe selected from:
Halo,
Cyano group,
Hydroxyl,
The halogeno-benzene alkylsulfonyl,
C
1-6-alkyl,
C
1-6-alkoxyl group,
4 to 10 yuan of Heterocyclylalkyls,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl replaces;
R
2Be H, OH, C
1-6-alkyl or halo;
Wherein said aryl is phenyl,
With and pharmacologically acceptable salts.
2. according to formula (Ia) compound of claim 1, wherein:
A is the optional aryl that is replaced by 1 to 5 halo;
R
1Be C
1-6-alkyl, it is optional by 1 to 5 halo, C
1-6-alkoxyl group or the optional aryl that is replaced by halo replace,
Or it is optional by one or more R
aThe C that replaces
3-10-cycloalkyl,
Or 5 to 10 yuan of Heterocyclylalkyls,
Or it is optional by one or more R
aThe aryl that replaces,
Or it is optional by one or more R
a5 to 10 yuan of heteroaryls that replace,
Or-NR
bR
c, R wherein
bBe H or C
1-6-alkyl, and R wherein
cBe optional by one or more R
aThe aryl that replaces,
R wherein
aBe selected from:
Halo,
Cyano group,
The halogeno-benzene alkylsulfonyl,
C
1-6-alkyl,
C
1-6-alkoxyl group,
5 to 6 yuan of Heterocyclylalkyls and
Optional by C
1-65 to 6 yuan of heteroaryls that-alkyl replaces;
R
2Be H, OH or halo;
With and pharmacologically acceptable salts.
3. the formula of claim 1 (Ia) compound, wherein:
A is optional by 1 to 5 aryl that is selected from the substituting group replacement of halo;
R
1The C that is replaced by aryl
2-6-alkynyl,
Or it is optional by 1 to 5 C that is selected from down the substituting group replacement of group
1-6-alkyl:
Halo,
Hydroxyl,
-CO (O)-C
1-6-alkyl,
C
1-6-alkoxyl group,
Optional by halo or C
1-6The aryl that-alkoxyl group replaces,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl replaces and
Phenoxy group,
Or C
1-6-alkoxyl group,
Or it is optional by one or more R
aThe C that replaces
3-10-cycloalkyl, and R
aBe selected from 1,2,3 hydroxyl,
Or 4 to 10 yuan of Heterocyclylalkyls,
Or it is optional by one or more R
aThe aryl that replaces, and R
aBe selected from:
Cyano group,
Halo,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl replaces,
The halogeno-benzene alkylsulfonyl,
Or it is optional by one or more R
a5 to 10 yuan of heteroaryls that replace, and R
aBe selected from:
5 to 6 yuan of Heterocyclylalkyls,
Or-NR
bR
c, R wherein
bBe H or C
1-6-alkyl, and R wherein
cBe H, C
1-6-alkyl or optional by one or more R
aThe aryl that replaces, and R
aBe selected from: halo, C
1-6-alkyl and C
1-6-alkoxyl group;
R
2Be H, OH or halo;
With and pharmacologically acceptable salts.
4. according to formula (Ia) compound of claim 3, R wherein
1Be optional by one or more R
a5 to 10 yuan of heteroaryls that replace.
5. formula (Ia) compound, it is selected from down group:
2-methyl-2H-indazole-3-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
6-chloro-2-methyl-quinoline-3-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-chloro-1-(3,4-, two chloro-benzyls)-6-oxo-1,6-dihydro-Nicotinicum Acidum trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-6-methyl-niacinamide;
[1,8] naphthyridines-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-fluoro-1H-indole-2-carboxylic acid (trans-4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-trifluoromethoxy-1H-indole-2-carboxylic acid (trans-4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-methoxyl group-1H-indole-2-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Thiophene-2-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
3H-imidazo [4,5-b] pyridine-6-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-methylsulfonyl-thiophene-2-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
6-fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-niacinamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-6-morpholine-4-base-niacinamide;
3-methyl-chroman-3-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
2-morpholine-4-base-pyrimidine-5-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
6-morpholine-4-base-pyridazine-3-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-morpholine-4-base-pyrazine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Benzo [1,3] dioxole-5-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
3-methyl-different
Azoles-5-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Trans N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-2-methoxyl group-Isonicotinamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-6-morpholine-4-base-niacinamide;
2,3-dihydro-benzo [1,4] two
Alkene-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-(4-methyl-piperazine-1-yl)-pyridine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-morpholine-4-base-pyridine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-phenyl-pyridine-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Quinoline-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Quinoline-4-formic acid is trans-(4-{2-[4-(4-methoxyl group-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Quinoline-4-formic acid is trans-4-[2-(4-benzoyl-4-hydroxy-piperdine-1-yl)-ethyl]-cyclohexyl }-acid amides;
Quinoline-4-formic acid is trans-4-[2-(4-benzoyl-4-fluoro-piperidine-1-yl)-ethyl]-cyclohexyl }-acid amides;
Quinoline-4-formic acid is trans-(4-{2-[4-(3,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
2,3-dihydro-indoles-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
6-trifluoromethyl-2,3-dihydro-indoles-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1,3-dihydro-isoindole-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
3,4-dihydro-1H-isoquinoline 99.9-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Quinoline-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-methylsulfonyl-thiophene-2-carboxylic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Chroman-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
(R)-chroman-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
(S)-chroman-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-6-morpholine-4-base-niacinamide;
2,3-dihydro-indoles-1-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Quinoline-4-formic acid trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
5-methylsulfonyl-thiophene-2-carboxylic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Chroman-3-formic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
5-methylsulfonyl-thiophene-2-carboxylic acid (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Quinoline-4-formic acid (4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Chroman-3-formic acid (trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Chroman-3-formic acid (trans-4-{2-[4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides; With
Benzo [1,3] dioxole-5-formic acid (trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides.
6. according to formula (Ia) compound of claim 3, R wherein
1Be-NR
bR
c, R wherein
bBe H or C
1-6-alkyl and R wherein
cBe H, C
1-6-alkyl or optional by one or more R
aThe aryl that replaces.
7. formula (Ia) compound, it is selected from down group:
Trans 1-(2,4-, two chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea;
Trans 1-(4-chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea;
Trans 1-(4-oxyethyl group-phenyl)-3-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea;
Trans 1-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-hexamethylene)-3-p-methylphenyl-urea;
Trans 1-(4-chloro-phenyl)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-1-methyl-urea;
Trans-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-1,1-dimethyl-urea;
Trans 1-(4-chloro-phenyl)-3-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea;
Trans 1-(4-chloro-phenyl)-3-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-urea; With
Trans 1-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-(4-oxyethyl group-phenyl)-urea.
8. according to formula (Ia) compound of claim 3, R wherein
1Be optional by one or more R
aThe aryl that replaces.
9. formula (Ia) compound, it is selected from down group:
4-chloro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
4-(3,5-dimethyl-different
Azoles-4-ylmethoxy)-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-trifluoromethyl-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-morpholine-4-base-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-(5-methyl-[1,2,4]
Diazole-3-yl)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-pyrroles-1-base-benzamide;
4-oxyethyl group-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
4-acetylamino-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;
4-cyano group-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-pyrazol-1-yl-benzamide;
2,4-, two chloro-N-are trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
4-(4-chloro-benzenesulfonyl)-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-trifluoromethoxy-benzamide;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-(1,1,2,2-tetrafluoro-oxyethyl group)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyridin-3-yl-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyridin-4-yl-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyridine-2-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-(4-methyl-piperazine-1-yl)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-phthalazines-1-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-4-pyridine-2-base-benzamide;
Xenyl-4-formic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
2-fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide;
4-(3,3-dimethyl-2-oxo-azetidine-1-yl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-ylmethyl-benzamide;
4-tert.-butoxy-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
4-dimethylamino-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
4-(1,1-dioxo-6-parathiazan-4-yl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
3-fluoro-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-(3-hydroxyl-tetramethyleneimine-1-yl)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-(4-hydroxy-piperdine-1-yl)-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-parathiazan-4-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-piperidines-1-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-2-morpholine-4-base-benzamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-4-hydroxy-piperdine-1-yl]-ethyl-cyclohexyl)-3-(5-methyl-[1,2,4]
Diazole-3-yl)-benzamide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-oxyethyl group-benzamide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-3-(5-methyl-[1,2,4]
Diazole-3-yl)-benzamide;
4-chloro-N-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-benzamide;
Xenyl-4-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
N-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-morpholine-4-base-benzamide;
4-cyano group-N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-pyrroles-1-base-benzamide;
N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide;
4-chloro-N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide;
N-trans (4-{2-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-4-morpholine-4-base-benzamide; With
N-(trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-4-morpholine-4-base-benzamide.
10. according to formula (Ia) compound of claim 3, R wherein
1Be optional by one or more R
aThe C that replaces
3-10-cycloalkyl.
11. formula (Ia) compound, it is selected from down group:
Cyclopropane-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Diamantane-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl-acid amides;
2-cyclopropyl-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
2-methyl-cyclopropane-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-methoxyl group-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-hydroxyl-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
(1S, 4R)-two the ring [2.2.1] heptane-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
(1R, 4R)-7,7-dimethyl-2-oxo-two ring [2.2.1] heptane-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-trifluoromethyl-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1-methyl-cyclohexyl alkane formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-methyl-cyclohexyl alkane formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
6-hydroxyl-two ring [2.2.2] octane-2-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1-trifluoromethyl-cyclopropane-carboxylic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
3-chloro-cyclobutane formate trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1-hydroxyl-cyclopropane-carboxylic acid (trans-4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Cyclobutane formate trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
4-hydroxyl-naphthenic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
2,2-, two fluoro-cyclopropane-carboxylic acids trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Cyclopropane-carboxylic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Cyclobutane formate (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
4-trifluoromethyl-naphthenic acid trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Cyclopropane-carboxylic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
2,2-, two fluoro-cyclopropane-carboxylic acids (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides; With
Cyclopropane-carboxylic acid trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides.
12. according to formula (Ia) compound of claim 3, wherein R
1Be 5 to 10 yuan of Heterocyclylalkyls.
13. formula (Ia) compound, it is selected from down group:
Tetrahydrochysene-pyrans-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Morpholine-4-formic acid is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
3-phenoxy group-tetramethyleneimine-1-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
1,1-dioxo-parathiazan-4-formic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid is trans-(4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid is trans-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
(S)-tetrahydrochysene-furans-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
(R)-tetrahydrochysene-furans-3-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
4-phenyl-Piperazine-1-formic acid trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Morpholine-4-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetramethyleneimine-1-formic acid (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Tetrahydrochysene-pyrans-4-formic acid (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides;
Tetrahydrochysene-furans-3-formic acid trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides;
Tetrahydrochysene-pyrans-4-formic acid (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides; With
Tetrahydrochysene-pyrans-4-formic acid (trans-4-{2-[4-(4-chloro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-acid amides.
14. according to formula (Ia) compound of claim 3, wherein R
1Be optional by 1 to 5 C that is selected from down the substituting group replacement of group
1-6-alkyl:
Halo,
Hydroxyl,
C
1-6-alkyl,
-CO (O)-C
1-6-alkyl,
C
1-6-alkoxyl group,
Optional by halo or C
1-6The aryl that-alkoxyl group replaces,
Optional by C
1-65 to 10 yuan of heteroaryls that-alkyl replaces and
Phenoxy group.
15. formula (Ia) compound, it is selected from down group:
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide;
2-(4-chloro-phenyl)-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-isobutyramide;
3-oxyethyl group-N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-propionic acid amide;
3,3,3-, three fluoro-N-are trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-propionic acid amide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-propionic acid amide;
2,2,2-, three fluoro-N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-butyramide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-butyramide;
N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-phenoxy group-propionic acid amide;
N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-3-hydroxyl-2,2-dimethyl-propionic acid amide;
[d] is different for the 2-benzo
Azoles-3-base-N-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-2-(3-methyl-different
Azoles-5-yl)-ethanamide;
2-(3,5-dimethoxy-phenyl)-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
2-benzo [1,3] dioxole-5-base-N-trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
Acetic acid trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-the cyclohexyl carboxyamide base)-methyl ester;
N-is trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide;
Trans N-(4-{2-[4-(4-fluoro-benzoyl)-4-methyl-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide;
N is trans-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-propionic acid amide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-2-(3-methyl-different
Azoles-5-yl)-ethanamide;
N-(4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-2-hydroxyl-ethanamide;
(R)-N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-2-methoxyl group-propionic acid amide;
2-benzyloxy-N-trans (4-{2-[4-(2,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-butyramide;
2-cyclopropyl-N-(4-{2-[4-(3,4-, two fluoro-benzoyls)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
2-benzyloxy-N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-butyramide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-2-cyclopropyl-ethanamide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-propionic acid amide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-3-methoxyl group-propionic acid amide;
N-trans (4-{2-[4-(2-chloro-4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2-chloro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2,4-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(2,5-, two chloro-benzoyls)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-trans (4-{2-[4-(4-fluoro-2-methyl-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-ethanamide;
N-{ is trans-4-[2-(4-benzoyl-piperidine-1-yl)-ethyl]-cyclohexyl }-ethanamide;
N-(trans-4-{2-[4-(3-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-(trans-4-{2-[4-(5-chloro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide;
N-(trans-4-{2-[4-(5-fluoro-thiophene-2-carbonyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-ethanamide.
16. according to formula (Ia) compound of claim 3, wherein R
1Be C
1-6-alkoxyl group.
17. formula (Ia) compound, it is selected from down group:
Trans (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl }-cyclohexyl)-Urethylane; With
4-oxyethyl group-N-trans (4-{2-[4-fluoro-4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-benzamide.
18. according to formula (Ia) compound of claim 3, wherein R
1Be C
2-6-alkynyl or the C that is replaced by aryl
2-6-alkynyl.
19. formula (Ia) compound, its be 3-phenyl-propynoic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidines-1-yl]-ethyl-cyclohexyl)-acid amides.
20. medicine, it contains one or more as any described compound of claim 1 to 19 and the acceptable vehicle of pharmacy, is used for the treatment of and/or prevents cognitive disorder, drug habit, depression, anxiety, pharmacological dependence, dementia, memory defects and psychosis.
21. according to the medicine of claim 20, be used for the treatment of and/or prevent schizophrenia, dissociation of sensibility sexual dysfunction, two-phase sexual dysfunction, mania, psychotic depression, paranoia and vain hope.
22. according to claim 1 to 19 each compound and pharmacologically acceptable salts in the purposes of preparation in the medicine, described medicine is used for the treatment of and/or prevents cognitive disorder, drug habit, depression, anxiety, pharmacological dependence, dementia, memory defects and psychosis.
23. according to the purposes of claim 22, wherein said medicine is used for the treatment of and/or prevents schizophrenia, dissociation of sensibility sexual dysfunction, two-phase sexual dysfunction, mania, psychotic depression, paranoia and vain hope.
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| EP06110112 | 2006-02-17 | ||
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| EP06112464.0 | 2006-04-11 | ||
| PCT/EP2007/051160 WO2007093540A1 (en) | 2006-02-17 | 2007-02-07 | Benzoyl-piperidine derivatives as 5ht2/d3 modulators |
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| WO2010031735A1 (en) * | 2008-09-22 | 2010-03-25 | F. Hoffmann-La Roche Ag | Piperazine d3 and 5-ht2a receptor modulators |
| TW201039825A (en) | 2009-02-20 | 2010-11-16 | Astrazeneca Ab | Cyclopropyl amide derivatives 983 |
| MX2012009473A (en) * | 2010-02-18 | 2012-09-12 | Astrazeneca Ab | Processes for making cyclopropyl amide derivatives and intermediates associated therewith. |
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Non-Patent Citations (4)
| Title |
|---|
| Jeff L. Herndon et al.Ketanserin analogues: structure-affinity relationships for 5HT2 and 5-HT1C serotonin receptor binding.《Journal of Medicinal Chemistry》.1992,第35卷(第26期),4903-4910. * |
| Pharmaceutical Bulletin》.1990,第38卷(第10期),2726-2732. * |
| Yoshifumi Watanabe et al.Synthesis of monocyclic and bicyclic 2,4(1H,3H)-pyrimidinediones and their serotonin 2 antagonist activities.《Chemical & Pharmaceutical Bulletin》.1990,第38卷(第10期),2726-2732. |
| Yoshifumi Watanabe et al.Synthesis of monocyclic and bicyclic 2,4(1H,3H)-pyrimidinediones and their serotonin 2 antagonist activities.《Chemical & * |
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