CN104211635A - Piperidine compounds, and preparation method, pharmaceutical compositions and use thereof - Google Patents

Piperidine compounds, and preparation method, pharmaceutical compositions and use thereof Download PDF

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Publication number
CN104211635A
CN104211635A CN201310217590.9A CN201310217590A CN104211635A CN 104211635 A CN104211635 A CN 104211635A CN 201310217590 A CN201310217590 A CN 201310217590A CN 104211635 A CN104211635 A CN 104211635A
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piperidines
halogen
fluoro
replace
base
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沈建华
镇学初
段洪亮
郭琳
张立明
朱丽媛
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Shanghai Institute of Materia Medica of CAS
Suzhou University
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Shanghai Institute of Materia Medica of CAS
Suzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to piperidine compounds represented by the following general formula (I), and a preparation method and a use thereof in preparation of drugs for preventing or treating GlyT-1 mediated diseases.

Description

One class piperidines and preparation method thereof, pharmaceutical composition and purposes
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, be specifically related to class piperidines and preparation method thereof, the invention still further relates to described compound prevent in preparation or treat the purposes in the medicine of the disease mediated by GlyT-1, and the pharmaceutical composition containing described compound.
Background technology
Traditional viewpoint is thought, the schizoid cause of disease is due to the neural hyperfunction of Dopamine HCL (Dopamine, DA) in brain, make brain dopamine excessive or due to Dopamine Receptors super quick caused by.Therefore, the antipsychotic effect of initial medicine is mainly relevant with blocking-up Dopamine Receptors.DA hypothesis was once that research schizophrenia and the antipsychotics mechanism of action are the most theoretical.But due to DA dysfunction, schizoid neuropathologic change can not be explained completely, guide people to go to study the relation of other neurotransmitters exceptions and this disease.
Compare with traditional Dopamine Receptors hypothesis, thinking about schizoid neurochemistry hypothesis of current trend, schizophrenia is due to glutamic acid-type, especially caused by the L-glutamic acid neurotransmitter of the glutamate receptor mediation of NMDA (N-methyl-D-aspartate, NMDA) type is transported lowly.In vivo, nmda receptor regulates by glycine and D-Ser.Therefore, based on the hypothesis of nmda receptor function imbalance, for treatment schizophrenia, mainly strengthen the regulating power of nmda receptor.A kind of function strengthening nmda receptor is exactly the glycine and the D-Ser level that increase synaptic cleft to treat the approach of schizophrenia.The Glycine Levels of synaptic cleft mainly controls by glycine transport acceptor 1 (GlyT-1), Glycine Levels lower near the nmda receptor of this acceptor mainly regulating guarantee cynapse.Therefore, if glycine transport acceptor can be suppressed, and then synaptic cleft Glycine Levels can be increased, just can strengthen the turn-over capacity of nmda receptor.
In the recent period the research on function of mouse is found, block by effective inhibitor the activity that GlyT-1 can strengthen nmda receptor, and action time is longer.The physiological response of the GlyT-1 of these forebrain areas and clinical report all describe GlyT-1 inhibitor improving in the symptom of schizophreniac unusual effect.In addition, the research of a large amount of pharmacological evaluation and neural subject all demonstrates this discovery.Therefore, optionally GlyT-1 cell reabsorption inhibitor represents the antipsychotics of a new generation.
Summary of the invention
An object of the present invention is to provide the piperidines shown in following general formula (I) and pharmacy acceptable salt thereof:
Wherein, R 1for not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkoxyl group; Not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkylthio; Not replace or by C 1-7alkyl, C 3-7the amino of cycloalkyl substituted; C 3-7cycloalkyl oxy; C 4-7cycloalkenyl group; Not replace or by halogen, C 1-6the C6-C10 aryl that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heteroaryl be selected from containing 1-3 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heterocyclic radical be selected from containing 1-3 in N, O and S that alkyl replaces;
Preferably, R 1for not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-6alkoxyl group; Not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-6alkylthio; Not replace or by C 1-6alkyl, C 3-6the amino of cycloalkyl substituted; C 3-6cycloalkyl oxy; C 4-6cycloalkenyl group; Not replace or by halogen, C 1-4the phenyl that alkyl replaces; Not replace or by halogen, C 1-4the heteroatomic 5-6 unit heteroaryl be selected from containing 1-3 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-4the heteroatomic 5-6 unit heterocyclic radical be selected from containing 1-3 in N, O and S that alkyl replaces;
More preferably, R 1for not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkoxyl group; Not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkylthio; Not replace or by C 1-4alkyl, C 3-6the amino of cycloalkyl substituted; C 3-6cycloalkyl oxy; C 5-6cycloalkenyl group; Not replace or by halogen, C 1-2the phenyl that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heteroaryl be selected from containing 1-2 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heterocyclic radical be selected from containing 1-2 in N, O and S that alkyl replaces;
Most preferably, R1 is isopropoxy, isobutoxy, cyclo propyl methoxy, 1-trifluoromethyl oxyethyl group, 2,2,3, the fluoro-1-propoxy-of 3,3-five, isopropyisulfanyl, isopropylamino, i-butylamino, Cyclobutylamino, Cyclohexylamino, cyclopentyloxy, cyclopentenyl, cyclohexenyl, to fluorophenyl, thienyl, pyrrolidyl, 2-methylpyrrole alkyl, piperidyl, morpholinyl, thio-morpholinyl;
R 2for nitro, C 1-7alkyl sulphonyl, C 1-7alkylamino radical alkylsulfonyl; Preferably, R 2for nitro, C 1-4alkyl sulphonyl, C 1-4alkylamino radical alkylsulfonyl; More preferably, R 2for nitro, methylsulfonyl, methylamine alkylsulfonyl;
A, B, D, E and F are CH; Or one in A, B, D, E and F is N, and all the other are CH;
Z is O;
R 3for hydrogen, halogen, trifluoromethyl, cyano group, ethanoyl; Preferably, R 3for hydrogen, fluorine or trifluoromethyl;
R 4for hydrogen, halogen, trifluoromethyl, cyano group, ethanoyl; Preferably, R 4for hydrogen or fluorine;
Or, Z and R 4and adjacent atom is formed together
Preferably, the piperidines shown in general formula (I) and pharmacy acceptable salt thereof be following general formula (II), (III), (IV), (V), the piperidines shown in (VI) or (VII) and pharmacy acceptable salt thereof:
Wherein, R 1for not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkoxyl group; Not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkylthio; Not replace or by C 1-7alkyl, C 3-7the amino of cycloalkyl substituted; C 3-7cycloalkyl oxy; C 4-7cycloalkenyl group; Not replace or by halogen, C 1-6the C6-C10 aryl that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heteroaryl be selected from containing 1-3 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heterocyclic radical be selected from containing 1-3 in N, O and S that alkyl replaces;
Preferably, R 1for not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-6alkoxyl group; Not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-6alkylthio; Not replace or by C 1-6alkyl, C 3-6the amino of cycloalkyl substituted; C 3-6cycloalkyl oxy; C 4-6cycloalkenyl group; Not replace or by halogen, C 1-4the phenyl that alkyl replaces; Not replace or by halogen, C 1-4the heteroatomic 5-6 unit heteroaryl be selected from containing 1-3 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-4the heteroatomic 5-6 unit heterocyclic radical be selected from containing 1-3 in N, O and S that alkyl replaces;
More preferably, R 1for not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkoxyl group; Not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkylthio; Not replace or by C 1-4alkyl, C 3-6the amino of cycloalkyl substituted; C 3-6cycloalkyl oxy; C 5-6cycloalkenyl group; Not replace or by halogen, C 1-2the phenyl that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heteroaryl be selected from containing 1-2 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heterocyclic radical be selected from containing 1-2 in N, O and S that alkyl replaces;
Most preferably, R 1for isopropoxy, isobutoxy, ring third methoxyl group, 1-trifluoromethyl oxyethyl group, 2,2,3, the fluoro-1-propoxy-of 3,3-five, isopropyisulfanyl, isopropylamino, i-butylamino, ring butylamine base, cyclopentyloxy, cyclopentenyl, cyclohexenyl, to fluorophenyl, thienyl, pyrrolidyl, 2-methylpyrrole alkyl, piperidyl, morpholinyl, thio-morpholinyl;
R 2for nitro, C 1-7alkyl sulphonyl, C 1-7alkylamino radical alkylsulfonyl; Preferably, R 2for nitro, C 1-4alkyl sulphonyl, C 1-4alkylamino radical alkylsulfonyl; More preferably, R 2for nitro, methylsulfonyl, methylamine alkylsulfonyl;
R 3for hydrogen, halogen, trifluoromethyl, cyano group, ethanoyl; Preferably, R 3for hydrogen, fluorine or trifluoromethyl;
R 4for hydrogen or halogen; Preferably, R 4for hydrogen or fluorine.
Further preferably, the piperidines shown in general formula (II) and pharmacy acceptable salt thereof are the piperidines shown in following general formula (VIII) and pharmacy acceptable salt thereof:
Wherein, R 1for not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkoxyl group; Not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkylthio; Not replace or by C 1-7alkyl, C 3-7the amino of cycloalkyl substituted; C 3-7cycloalkyl oxy; C 4-7cycloalkenyl group; Not replace or by halogen, C 1-6the C6-C10 aryl that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heteroaryl be selected from containing 1-3 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heterocyclic radical be selected from containing 1-3 in N, O and S that alkyl replaces;
Preferably, R 1for not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-6alkoxyl group; Not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-6alkylthio; Not replace or by C 1-6alkyl, C 3-6the amino of cycloalkyl substituted; C 3-6cycloalkyl oxy; C 4-6cycloalkenyl group; Not replace or by halogen, C 1-4the phenyl that alkyl replaces; Not replace or by halogen, C 1-4the heteroatomic 5-6 unit heteroaryl be selected from containing 1-3 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-4the heteroatomic 5-6 unit heterocyclic radical be selected from containing 1-3 in N, O and S that alkyl replaces;
More preferably, R 1for not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkoxyl group; Not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkylthio; Not replace or by C 1-4alkyl, C 3-6the amino of cycloalkyl substituted; C 3-6cycloalkyl oxy; C 5-6cycloalkenyl group; Not replace or by halogen, C 1-2the phenyl that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heteroaryl be selected from containing 1-2 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heterocyclic radical be selected from containing 1-2 in N, O and S that alkyl replaces;
Most preferably, R 1for isopropoxy, isobutoxy, ring third methoxyl group, 1-trifluoromethyl oxyethyl group, 2,2,3, the fluoro-1-propoxy-of 3,3-five, isopropyisulfanyl, isopropylamino, i-butylamino, ring butylamine base, cyclopentyloxy, cyclopentenyl, cyclohexenyl, to fluorophenyl, thienyl, pyrrolidyl, 2-methylpyrrole alkyl, piperidyl, morpholinyl, thio-morpholinyl or piperazinyl;
R 2for nitro, C 1-7alkyl sulphonyl, C 1-7alkylamino radical alkylsulfonyl; Preferably, R 2for nitro, C 1-4alkyl sulphonyl, C 1-4alkylamino radical alkylsulfonyl; More preferably, R 2for nitro, methylsulfonyl, methylamine alkylsulfonyl;
R 3for hydrogen, halogen, trifluoromethyl, cyano group, ethanoyl; Preferably, R 3for hydrogen, fluorine or trifluoromethyl.
Further preferably, the piperidines shown in general formula (III) and pharmacy acceptable salt thereof are the piperidines shown in following general formula (IX) and pharmacy acceptable salt thereof:
Wherein, R 1for not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkoxyl group; Not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkylthio; Not replace or by C 1-7alkyl, C 3-7the amino of cycloalkyl substituted; C 3-7cycloalkyl oxy; C 4-7cycloalkenyl group; Not replace or by halogen, C 1-6the C6-C10 aryl that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heteroaryl be selected from containing 1-3 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heterocyclic radical be selected from containing 1-3 in N, O and S that alkyl replaces;
Preferably, R 1for not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-6alkoxyl group; Not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-6alkylthio; Not replace or by C 1-6alkyl, C 3-6the amino of cycloalkyl substituted; C 3-6cycloalkyl oxy; C 4-6cycloalkenyl group; Not replace or by halogen, C 1-4the phenyl that alkyl replaces; Not replace or by halogen, C 1-4the heteroatomic 5-6 unit heteroaryl be selected from containing 1-3 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-4the heteroatomic 5-6 unit heterocyclic radical be selected from containing 1-3 in N, O and S that alkyl replaces;
More preferably, R 1for not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkoxyl group; Not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkylthio; Not replace or by C 1-4alkyl, C 3-6the amino of cycloalkyl substituted; C 3-6cycloalkyl oxy; C 5-6cycloalkenyl group; Not replace or by halogen, C 1-2the phenyl that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heteroaryl be selected from containing 1-2 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heterocyclic radical be selected from containing 1-2 in N, O and S that alkyl replaces;
Most preferably, R 1for isopropoxy, isobutoxy, ring third methoxyl group, 1-trifluoromethyl oxyethyl group, 2,2,3, the fluoro-1-propoxy-of 3,3-five, isopropyisulfanyl, isopropylamino, i-butylamino, ring butylamine base, cyclopentyloxy, cyclopentenyl, cyclohexenyl, to fluorophenyl, thienyl, pyrrolidyl, 2-methylpyrrole alkyl, piperidyl, morpholinyl, thio-morpholinyl or piperazinyl;
R 2for nitro, C 1-7alkyl sulphonyl, C 1-7alkylamino radical alkylsulfonyl; Preferably, R 2for nitro, C 1-4alkyl sulphonyl, C 1-4alkylamino radical alkylsulfonyl; More preferably, R 2for nitro, methylsulfonyl, methylamine alkylsulfonyl;
R 3for hydrogen, halogen, trifluoromethyl, cyano group, ethanoyl; Preferably, R 3for hydrogen, fluorine or trifluoromethyl;
R 4for hydrogen or halogen; Preferably, R 4for hydrogen or fluorine.
Most preferably, compound shown in general formula (I) is specially following structure:
Another object of the present invention is to provide the preparation method of piperidines as shown in general formula (I) and pharmacy acceptable salt thereof.
Another object of the present invention is to provide a kind of prevention or treats the method for disease mediated by GlyT-1, and what it comprised the bacterium suffering from above-mentioned disease is selected from the piperidines as shown in general formula (I) and one or more compounds in pharmacy acceptable salt thereof.
An also object of the present invention is to provide the purposes in the disease that piperidines as shown in general formula (I) and pharmacy acceptable salt thereof mediate by GlyT-1 in prevention or treat, and what it comprised the bacterium suffering from above-mentioned disease is selected from the piperidines as shown in general formula (I) and one or more compounds in pharmacy acceptable salt thereof.
Another object of the present invention is to provide piperidines as shown in general formula (I) and pharmacy acceptable salt thereof in preparation as the purposes in the medicine of GlyT-1 inhibitor, and for the preparation of prevention or the application for the treatment of in the medicine of the disease mediated by GlyT-1.
The described disease mediated by GlyT-1 is such as schizophrenia, cognitive disorder etc.
Another object of the present invention is to provide a kind of pharmaceutical composition, and it comprises the piperidines that is selected from as shown in general formula (I) and one or more in pharmacy acceptable salt thereof as activeconstituents, and pharmaceutically acceptable auxiliary material.
The invention provides the piperidines shown in a class general formula (I) or its pharmacy acceptable salt, compound provided by the present invention can be enumerated particularly and mineral acid, organic acid etc. react the salt generated.These salt include, but is not limited to: the salt that (1) and following mineral acid are formed: example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; (2) salt formed with following organic acid, as acetic acid, oxalic acid, succinic acid, tartrate, methylsulfonic acid, toxilic acid or arginine etc.
The invention provides the preparation method of the piperidines shown in a class general formula (I) or its pharmacy acceptable salt.
Piperidines shown in formula of of the present invention (I) can by plurality of step and synthetic route preparation, representational step and synthetic method as follows, but be not limited to following method.
Formula a compound and formula c compound are obtained by reacting the piperidines shown in general formula (I) under condensing agent exists.
Wherein, R 1, R 2, R 3, R 4, Z, A, B, D, E and F definition the same.
Described condensing agent can be HATU etc.
Wherein, the aminated compounds in formula a or can buy, or known in chemical literature, or various method as known in the art can be utilized obtained.
Such as, the amine in formula a obtains by method as follows:
By the phenylformic acid series compound of formula d and N, O-dimethyl hydroxylamine reacts the midbody compound carrying out obtained formula e under the room temperatures such as condensing agent such as HATU, then the Grignard reagent that formula e compound and 1-methyl-Chloperastine obtain is obtained by reacting the midbody compound of formula f, then formula f compound reacts and removes methyl and obtain formula a compound in chloro-formic ester compounds such as 2-chloroethylchloroformate ester, wherein, R 3and R 4definition the same.
Or through type g prepares the Weinreb in formula h and then is obtained by reacting the midbody compound of formula i with a series of fragrant Grignard reagent, and then remove Boc in acid condition and obtain formula a compound.
Acid in formula c obtains by various methods as follows:
By by the fluorobenzene series compound in formula k and R 1 'oH reacts obtained formula c compound, wherein R under the alkaline conditions such as such as salt of wormwood, cesium carbonate, sodium hydride under heating or greenhouse 1 'c 1-8alkyl.
Or, by by the phenol series compound in formula 1 and R 1 'oH reacts the midbody compound obtaining formula m under Mitsunobu reaction conditions under the existence of phosphine such as triphenylphosphine and azodicarboxy acid dialkyl ester such as diethyl azodiformate, diisopropyl azo-2-carboxylic acid, then under the existence of alkali such as sodium hydroxide, lithium hydroxide, potassium hydroxide, hydrolysis carrys out obtained formula c compound, wherein R 1 'c 1-8alkyl.
Or, by the phenol series compound in formula 1 and trifluoromethyl sulfonic acid anhydride being obtained by reacting under alkali such as triethylamine condition the midbody compound of formula n, then reacted in palladium class catalyzer such as palladium by Buchwald-Hartwig, part is BINAP such as, with R under alkali such as cesium carbonate condition 1 'r 2 'n is obtained by reacting the midbody compound of formula o, and then under the existence of alkali such as sodium hydroxide, lithium hydroxide, potassium hydroxide, hydrolysis carrys out obtained formula c compound, wherein R 1 ', R 2 'c 1-8alkyl.
Or, by the fluorobenzene series compound in formula p being obtained by reacting under alkaline condition such as cesium carbonate, salt of wormwood, sodium hydride condition the midbody compound of formula q, then under the existence of alkali such as sodium hydroxide, lithium hydroxide, potassium hydroxide, hydrolysis carrys out obtained formula c compound, wherein R 1 ', R 2 'c 1-8alkyl.
Or by being reacted in palladium class catalyzer such as palladium by Suzuki by the benzene sulfonate series compound in formula n, part is triphenylphosphine such as, with R under alkali such as cesium carbonate condition 1the serial boric acid replaced or boric acid ester are obtained by reacting the midbody compound of formula r, and then under the existence of alkali such as sodium hydroxide, lithium hydroxide, potassium hydroxide, hydrolysis carrys out obtained formula c compound, wherein R 1' be substituted-phenyl, cycloalkenyl group.
Piperidines shown in formula of of the present invention (II) can synthesize by the following method:
Formula b compound and formula c compound are obtained by reacting by the piperidines shown in (II) under condensing agent exists, wherein, and R 1, R 2and R 3definition the same.
Described condensing agent can be HATU etc.
Formula b compound obtains by method as follows:
Series compound in a is reacted under alkali such as sodium hydroxide existence condition the midbody compound of obtained formula j with oxammonium hydrochloride, then obtain formula b compound at condition ShiShimonoseki rings such as alkali such as sodium hydroxide.
Unless otherwise, term used in the present invention has as given a definition:
Described " alkyl " represents saturated substituted or non-substituted straight chain, branched-chain alkyl, can enumerate particularly as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl etc.Described " C 2-5alkyl " represent that carbonatoms is saturated straight chain or the branched-chain alkyl of 2 to 5, can enumerate particularly as ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl etc.
Described " C 3-7cycloalkyl " represent that carbonatoms is the saturated cyclic alkyls of 3 to 7, can enumerate as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc. particularly.
Described " C 4-7cycloalkenyl group " represent that carbonatoms is the cyclic alkenyl radical with a double bond of 4 to 7, can enumerate particularly as cyclopentenyl, cyclohexenyl, cycloheptenyl etc.
Described " C 3-7alkoxyl group " represent that carbonatoms is the straight or branched alkoxyl group of 3 to 7, can enumerate particularly as positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, hexyloxy etc.
Described " C 1-6alkylthio " represent that carbonatoms is the straight or branched alkylthio of 1 to 6, can enumerate particularly as methylthio group, ethylmercapto group, positive rosickyite base, isopropyisulfanyl, positive butylthio etc.
Described " C 3-7cycloalkyl C 1-3alkoxyl group " expression carbonatoms to be the carbonatoms of the cycloalkyl substituted of 3 to 7 the be straight or branched alkoxyl group of 1 to 3, can enumerate particularly as cyclo propyl methoxy, cyclobutyl methoxyl group, cyclopentylmethoxy etc.
Described " C 3-7cycloalkyl C 1-3alkylthio " expression carbonatoms to be the carbonatoms of the cycloalkyl substituted of 3 to 7 the be straight or branched alkylthio of 1 to 3, can enumerate particularly as cyclopropyl methylthio group, cyclobutylmethyl sulfenyl, cyclopentyl methylthio group etc.
Described " halogen " represents fluorine, chlorine, bromine, iodine.
Described shortenings implication is:
HATU:2-(7-azepine-1H-benzotriazole-1-base)-1,1,3,3-tetramethyl-urea phosphofluoric acid ester,
DMF:N, dinethylformamide,
EDCI:1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate,
HOBt:1-hydroxybenzotriazole,
DIAD: diisopropyl azo-2-carboxylic acid.
Embodiment
Below will further illustrate the present invention by embodiment.These embodiments only for illustrating the present invention, but do not limit the present invention in any way.Not marked experimental technique in embodiment, conveniently condition is implemented usually.
Unless otherwise defined, in literary composition technical term used and those skilled in the art the same meaning be familiar with.
In all embodiments, 1h-NMR 300MHz or 400MHz nmr determination, chemical shift represents with δ (ppm).
Preparation embodiment
Embodiment 1:N-(2-isopropoxy-5-nitro benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
2-isopropoxy-5-nitrobenzene methyl
1g (5.08mmol) 5-NITROSALICYLIC ACID methyl esters is dissolved in 5mL N, in dinethylformamide, add 577 μ L (6.96mmol) isopropyl bromides and 1.15g (8.33mmol) salt of wormwood successively, react 4h under 70 ° of C after, reaction terminates, reaction solution is added in 40mL water, with extraction into ethyl acetate (30mL*3), after organic layer is merged, after (50mL*3 time) saturated common salt water washing separatory, organic layer, with after anhydrous sodium sulfate drying, is evaporated to dry, to obtain product 1.02g after quick preparative column purifying, yield is 80%. 1H?NMR(300MHz,CDCl 3)δ8.67(d,J=2.9Hz,1H),8.31(dd,J=9.3,2.9Hz,1H),7.03(d,J=9.4Hz,1H),4.75(dt,J=12.1,6.1Hz,1H),3.93(d,J=6.9Hz,3H),1.44(d,J=6.1Hz,6H).
N-(2-isopropoxy-5-nitro benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
0.8g (3.19mmol) 2-isopropoxy-5-nitrobenzene methyl is dissolved in the mixed solvent of 10mL methyl alcohol and 20mL water composition, add 153mg (3.83mmol) sodium hydroxide, react 3h under room temperature after, reaction terminates, removed under reduced pressure by methyl alcohol in reaction solution, the remaining aqueous solution regulates about pH to 2 with concentrated hydrochloric acid, separates out white solid, filtering drying obtains 2-isopropoxy-5-nitrobenzoic acid 0.68g, and yield is 95%.By 100mg (0.44mmol) 2-isopropoxy-5-nitrobenzoic acid; 100mg (0.44mmol) 4-(2; 4-difluoro benzoyl)-piperidines; 110mg (0.57mmol) EDCI, 77mg (0.57mmol) HOBt adds in 5mL methylene dichloride, adds 92 μ L (0.66mmol) triethylamines; react 3h under room temperature after; reaction terminates, and reaction solution is directly gone up quick preparative column purifying and obtain product 95mg, yield is 50%. 1H?NMR(300MHz,CDCl 3)δ8.24(dd,J=9.1,2.8Hz,1H),8.17(dd,J=12.1,2.8Hz,1H),7.94–7.82(m,1H),7.03–6.93(m,2H),6.87(ddd,J=11.1,4.9,2.5Hz,1H),4.71(ddd,J=16.4,11.5,5.2Hz,2H),3.58–3.43(m,1H),3.45–3.30(m,1H),3.23–2.92(m,2H),2.06(d,J=10.8Hz,1H),1.73(m,4H),1.45(d,J=6.0Hz,2H),1.41(dd,J=6.1,3.2Hz,4H),1.37(s,1H).
Embodiment 2:N-(2-ring third methoxyl group-5-nitro benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting except isopropyl bromide with cyclopropylmethyl bromide, other operations are with preparation embodiment 1. 1HNMR(300MHz,CDCl 3)δ8.28–8.22(m,1H),8.19(dd,J=9.2,2.7Hz,1H),7.87(dd,J=15.1,8.6Hz,1H),7.04–6.98(m,1H),6.98–6.91(m,1H),6.88(dd,J=11.1,2.5Hz,1H),4.73(dd,J=40.3,13.4Hz,1H),4.07–3.86(m,2H),3.55(d,J=13.2Hz,1H),3.37(t,J=10.6Hz,1H),3.14(m,2H),2.96(m,1H),2.07(d,J=12.1Hz,1H),1.89(d,J=18.5Hz,2H),1.79–1.66(m,1H),1.39–1.19(m,2H),0.70(dd,J=11.3,6.8Hz,2H),0.43–0.26(m,2H).
Embodiment 3:N-(2-cyclopentyloxy-5-nitro benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
2-cyclopentyloxy-5-nitrobenzene methyl
1.97g (1mmol) 2-hydroxyl-5-nitrobenzene methyl is dissolved in 30mL anhydrous tetrahydro furan, add 920 μ L (1mmol) cyclopentanol, 3.2g (1.2mmol) triphenylphosphine, 2.4mL (1.2mmol) DIAD, react under room temperature, after question response, reaction solution is directly obtained product 1.8g with quick preparative column purifying, yield is 68%. 1H?NMR(400MHz,CDCl 3)δ8.65(d,J=2.9Hz,1H),8.33–8.26(m,1H),7.03(d,J=9.3Hz,1H),4.95(tt,J=5.5,2.8Hz,1H),3.90(s,3H),2.00–1.90(m,4H),1.89–1.76(m,2H),1.74–1.61(m,2H).
Except substituting except 2-isopropoxy-5-nitrobenzene methyl with 2-cyclopentyloxy-5-nitrobenzene methyl, other operations are with preparation embodiment 1. 1H?NMR(400MHz,CDCl 3)δ8.25(dd,J=9.5,2.2Hz,1H),8.17(dd,J=21.7,2.7Hz,1H),7.90(dt,J=15.0,4.4Hz,1H),7.05–6.95(m,2H),6.95–6.86(m,1H),5.00–4.86(m,1H),4.72(m,1H),3.53(m,1H),3.39(m,1H),3.21–2.96(m,2H),2.15–2.00(m,2H),1.87(m,6H),1.77–1.59(m,4H).
Embodiment 4:N-(2-isobutoxy-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
2-isobutoxy-5-methylamine sulfonyl methyl benzoate
1.97g (1mmol) 2-hydroxy-5-methyl sulfamic methyl benzoate is dissolved in 30mL anhydrous tetrahydro furan; add 920 μ L (1mmol) isopropylcarbinols; 3.2g (1.2mmol) triphenylphosphine; 2.4mL (1.2mmol) DIAD; react under room temperature; after question response, obtain product 1.8g with quick preparative column purifying, yield is 68%. 1H?NMR(400MHz,CDCl 3)δ8.65(d,J=2.9Hz,1H),8.33–8.26(m,1H),7.03(d,J=9.3Hz,1H),4.95(tt,J=5.5,2.8Hz,1H),3.90(s,3H),2.00–1.90(m,4H),1.89–1.76(m,2H),1.74–1.61(m,2H).
N-(2-isobutoxy-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting 2-cyclopentyloxy-5-methylamine sulfonyl methyl benzoate, 4-(6-fluoro-1 with 2-isobutoxy-5-methylamine sulfonyl methyl benzoate; 2-benzoisoxazole-3-base) piperidines substitutes outside 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines, and other operations are with preparation embodiment 3. 1H?NMR(400MHz,CDCl 3)δ7.88–7.83(m,1H),7.78(dd,J=31.9,2.3Hz,1H),7.64(ddd,J=13.9,8.7,5.0Hz,1H),7.30–7.24(m,3H),7.09(tdd,J=8.8,4.8,2.1Hz,1H),7.00(dd,J=8.7,5.0Hz,1H),4.80(m,1H),4.32(m,1H),3.96–3.71(m,2H),3.62(m,1H),3.41–3.30(m,1H),3.29–3.04(m,2H),2.66(s,3H),2.31–2.18(m,1H),2.18–2.09(m,1H),2.01(m,3H),1.04(m,6H).
Embodiment 5:N-[2-(1-cyclohexenyl)-5-methylamine alkylsulfonyl benzoyl]-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except substituting 4-fluorobenzoic boric acid with tetrahydrobenzene-1-pinacol borate, 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines substitutes outside 4-(2,4 difluorobenzene formyl radical) piperidines, and other operations are with preparation embodiment 83. 1H?NMR(300MHz,)δ7.91–7.73(m),7.58(d,J=8.2Hz),7.41(d,J=8.1Hz),5.95(d,J=17.5Hz),4.77(dd,J=24.4,13.0Hz),3.46(dd,J=42.8,7.1Hz),3.25–3.00(m),2.67(s),2.52(d,J=15.2Hz),2.18(d,J=15.6Hz),2.08–1.90(m),1.83–1.62(m).
Embodiment 6:N-(2-isopropylamine base-5-nitro benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
2-isopropylamine base-5-nitrobenzoic acid
By 329mg (1mmol) 2-trifluoro-methanesulfonyl oxy-5-nitrobenzene methyl, 652mg (2mmol) cesium carbonate, 38.4mg (0.2mmol) palladium, 249mg (0.4mmol) BINAP, 130 μ L (1.5mmol) Isopropylamines add in 5mL toluene, are heated to backflow, after question response, reaction solution is directly obtained 2-isopropylamine base-5-nitrobenzene methyl 202mg with quick preparative column purifying, and yield is 86%.Except substituting except 2-isopropoxy-5-nitrobenzene methyl with 2-isopropylamine base-5-nitrobenzene methyl, other operations are with preparation 2-isopropoxy-5-nitrobenzoic acid. 1H?NMR(400MHz,CD 3OD)δ8.78(d,J=2.8Hz,1H),8.18(dd,J=9.5,2.8Hz,1H),6.85(d,J=9.7Hz,1H),3.89(hept,J=6.5Hz,1H),1.30(d,J=6.4Hz,7H).
N-(2-isopropylamine base-5-nitro benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-isopropylamine base-5-nitrobenzoic acid, other operations are with preparation embodiment 1. 1H?NMR(400MHz,CD 3OD)δ8.78(d,J=2.8Hz,1H),8.18(dd,J=9.5,2.8Hz,1H),6.85(d,J=9.7Hz,1H),3.89(d,J=6.5Hz,1H),1.30(d,J=6.4Hz,7H).
Embodiment 7:N-(2-cyclohexylamino-5-nitro benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting except Isopropylamine with hexahydroaniline, other operations are with preparation embodiment 6. 1H?NMR(300MHz,CDCl 3)δ8.11(dd,J=9.3,2.6Hz,1H),8.01(d,J=2.6Hz,1H),7.88(dd,J=15.2,8.5Hz,1H),7.04–6.94(m,1H),6.89(ddd,J=11.1,8.6,2.3Hz,1H),6.65(d,J=9.4Hz,1H),6.14(s,1H),4.44–4.05(m,2H),3.40(dd,J=11.8,8.5Hz,2H),3.17(t,J=11.5Hz,2H),2.01(d,J=14.2Hz,3H),1.88–1.56(m,4H),1.50–1.15(m,5H).
Embodiment 8:N-(2-piperidyl-5-nitro benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting except Isopropylamine with piperidines, other operations are with preparation embodiment 6. 1H?NMR(300MHz,CDCl 3)δ8.21–8.04(m,2H),7.95–7.81(m,1H),7.05–6.81(m,3H),4.70(m,1H),3.49(m,1H),3.33(m,3H),3.19–3.04(m,3H),3.04–2.87(m,1H),2.08(m,1H),1.83(m,2H).
Embodiment 9:N-(2-piperidyl-5-nitro benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting except 2-isobutoxy-5-methylamine sulfonyl benzoic acid with 2-piperidyl-5-nitrobenzoic acid, other operations are with preparation embodiment 4. 1H?NMR(300MHz,CDCl 3)δ8.18(d,J=11.5Hz,2H),7.63(m,1H),7.29(m,1H),7.10(t,J=8.8Hz,1H),6.98(d,J=8.9Hz,1H),4.89(m,1H),4.62(m,1H),3.60(m,1H),3.34(m,4H),3.16(m,3H),2.27(m,1H),2.05(m,2H).
Embodiment 10:N-(2-cyclohexylamino-5-nitro benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting except piperidines with hexahydroaniline, other operations are with preparation embodiment 9. 1H?NMR(300MHz,CDCl 3)δ8.18–8.05(m,2H),7.65(dd,J=8.7,5.0Hz,1H),7.29(m,1H),7.10(td,J=8.8,2.0Hz,1H),6.68(d,J=9.3Hz,1H),6.23(s,1H),4.33(m,2H),3.49–3.36(m,2H),3.30(m,2H),2.22(m,2H),2.14–1.96(m,4H),1.78(m,2H),1.73–1.52(m,2H),1.35(m,6H).
Embodiment 11:N-(2-isopropylamine base-5-nitro benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting except piperidines with Isopropylamine, other operations are with preparation embodiment 9. 1H?NMR(300MHz,CDCl 3)δ8.16(dd,J=9.3,2.6Hz,1H),8.08(d,J=2.6Hz,1H),7.65(dd,J=8.7,5.0Hz,1H),7.32–7.28(m,1H),7.10(td,J=8.8,2.1Hz,1H),6.69(d,J=9.3Hz,1H),6.15(s,1H),4.33(m,2H),3.76(m,1H),3.49–3.36(m,1H),3.30(m,2H),2.22(m,2H),2.07(m,2H),1.29(m,6H).
Embodiment 12:N-(2-isopropoxy-5-nitro benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
N-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-)-N, O-dimethyl hydroxylamine
By fluoro-for 2g (9.6mmol) 2-4-trifluoromethylbenzoic acid, 1.4g (14.4mmol) N, O-dimethyl hydroxylamine, 2.2g (12.1mmol) EDCI, 1.56g (11.6mmol) HOBt is dissolved in 30mL methylene dichloride, adds 4mL (28.8mmol) triethylamine, react 5h under room temperature after, reaction terminates, and reaction solution is directly gone up quick preparative column purifying and obtain product 2.05g, yield is 85%. 1H?NMR(300MHz,CDCl 3)δ7.56(t,J=6.9Hz,1H),7.48(d,J=7.9Hz,1H),7.39(d,J=9.2Hz,1H),3.53(s,3H),3.37(s,3H).
4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-)-1-methyl piperidine
Chloro-for 2g (14.9mmol) 4-1-methyl piperidine is dissolved in 50mL anhydrous tetrahydro furan, adds 0.4g (16.7mmol) magnesium chips, 1 iodine grain, after adding thermal initiation, continue back flow reaction 1h, prepare Grignard reagent.Another by 2.5g (10mmol) N-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-)-N; O-dimethyl hydroxylamine is dissolved in 20mL anhydrous tetrahydro furan; above-mentioned obtained Grignard reagent is added to wherein; react 3h under room temperature after, react complete, under ice bath, 50mL saturated ammonium chloride solution is slowly added in reaction solution; with extraction into ethyl acetate separatory; organic layer, with after anhydrous sodium sulfate drying, obtains product 1.37g through quick preparative column purifying, and yield is 50%. 1H?NMR(300MHz,CD 3OD)δ7.91(t,J=7.5Hz,1H),7.63(s,1H),7.60(d,J=3.5Hz,1H),3.22–3.09(m,1H),2.90(d,J=12.0Hz,2H),2.29(s,3H),2.15(td,J=11.8,2.6Hz,2H),1.93(d,J=12.9Hz,2H),1.81–1.61(m,2H).
4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
222mg (1mmol) 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-)-1-methyl piperidine is dissolved in 5mL1; in 2-ethylene dichloride; add 167 μ L (1.5mmol) 2-chloroethylchloroformate esters; 213 μ L (1.5mmol) triethylamines; after question response; filter after adding acetic acid ethyl dissolution, filtrate is concentrated into dry, obtains product with recrystallizing methanol. 1H?NMR(300MHz,CD 3OD)δ7.99(t,J=7.4Hz,1H),7.66(d,J=9.3Hz,2H),3.56(t,J=10.6Hz,1H),3.44(d,J=13.0Hz,2H),3.15(t,J=13.0Hz,2H),3.04(dd,J=14.4,7.0Hz,2H),2.18(d,J=12.0Hz,2H),1.87(dd,J=22.6,11.3Hz,2H),1.30(t,J=7.3Hz,3H).
N-(2-isopropoxy-5-nitro benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting except 4-(2,4 difluorobenzene formyl radical) piperidines with 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines, other operations are with preparation embodiment 1. 1H?NMR(300MHz,CDCl 3)δ8.24(dd,J=9.1,2.6Hz,1H),8.17(d,J=11.5Hz,1H),7.90(t,J=7.6Hz,1H),7.53(d,J=8.2Hz,1H),7.45(d,J=10.7Hz,1H),6.97(dd,J=9.1,4.2Hz,1H),4.72(m,2H),3.45(m,2H),3.09(m,2H),2.07(m,1H),1.87(s,2H),1.65(m,3H),1.42(m,6H),0.93–0.77(m,3H).
Embodiment 13:N-(2-ring third methoxyl group-5-nitro benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-ring third methoxyl group-5-nitrobenzoic acid, other operations are with preparation embodiment 12. 1H?NMR(300MHz,CDCl 3)δ8.28–8.13(m,2H),7.89(t,J=7.5Hz,1H),7.53(d,J=8.1Hz,1H),7.44(d,J=10.6Hz,1H),6.94(d,J=9.1Hz,1H),4.72(m,1H),4.08–3.83(m,2H),3.62–3.31(m,2H),3.28–2.86(m,2H),2.15–1.81(m,3H),1.69(m,3H),0.93–0.80(m,1H),0.69(m,2H),0.46–0.26(m,2H).
Embodiment 14:N-(2-isopropylamine base-5-nitro benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-isopropylamine base-5-nitrobenzoic acid, other operations are with preparation embodiment 12. 1H?NMR(300MHz,CDCl 3)δ8.13(dd,J=9.3,2.6Hz,1H),8.02(d,J=2.6Hz,1H),7.90(t,J=7.5Hz,1H),7.53(d,J=8.2Hz,1H),7.44(d,J=10.7Hz,1H),6.66(d,J=9.4Hz,1H),6.09(s,1H),4.23(m,2H),3.73(s,1H),3.43(m,1H),3.18(m,2H),2.03(m,2H),1.88–1.60(m,3H),1.27(m,6H).
Embodiment 15:N-(2-cyclohexylamino-5-nitro benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-cyclohexylamino-5-nitrobenzoic acid, other operations are with preparation embodiment 12. 1H?NMR(300MHz,CDCl 3)δ8.12(dd,J=9.3,2.7Hz,1H),8.02(d,J=2.6Hz,1H),7.91(t,J=7.6Hz,1H),7.54(d,J=8.3Hz,1H),7.44(d,J=10.6Hz,1H),6.66(d,J=9.4Hz,1H),4.25(m,2H),3.41(m,2H),3.18(m,2H),2.02(m,4H),1.75(m,5H),1.49–1.19(m,6H).
Embodiment 16:N-(2-piperidyl-5-nitro benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-piperidyl-5-nitrobenzoic acid, other operations are with preparation embodiment 12. 1H?NMR(300MHz,CDCl 3)δ8.20–8.05(m,2H),7.90(dd,J=15.1,7.7Hz,1H),7.53(d,J=7.8Hz,1H),7.48–7.38(m,1H),7.00–6.88(m,1H),4.69(m,1H),3.58–2.90(m,8H),2.07(s,1H),1.84(m,2H).
Embodiment 17:N-(2-isopropylamine base-5-methylsulfonylbenzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
2-isopropylamine base-5-methyl sulfonylbenzoic acid methyl esters
130mg (0.56mmol) 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters is dissolved in 5mL anhydrous tetrahydro furan; add 67 μ L (0.73mmol) Isopropylamines; after reacting 1h with microwave heating to 120 ° C; react complete; reaction solution is directly obtained 62mg product with quick preparative column purifying, and yield is 41%. 1H?NMR(300MHz,DMSO)δ8.26(d,J=1.3Hz,1H),8.17(d,J=7.5Hz,1H),7.82(d,J=9.0Hz,1H),6.99(d,J=9.1Hz,1H),4.02–3.64(m,4H),3.12(s,3H),2.50(s,1H),1.19(dd,J=21.6,6.3Hz,7H).
2-isopropylamine base-5-methyl sulfonylbenzoic acid
1g (3.7mmol) 2-isopropylamine base-5-methyl sulfonylbenzoic acid methyl esters is dissolved in the mixed solvent of 10mL tetrahydrofuran (THF) and 3mL water composition; add 0.23g (0.74mmol) lithium hydroxide; after reacting 2h under room temperature; reaction terminates; steamed by tetrahydrofuran (THF) after removing, aqueous phase regulates about pH to 4 with concentrated hydrochloric acid, separates out solid; obtain product 0.93g after filtering drying, yield is 95%. 1H?NMR(300MHz,DMSO)δ8.39(d,J=7.3Hz,1H),8.25(d,J=2.2Hz,1H),7.78(dd,J=9.0,2.1Hz,1H),6.94(d,J=9.2Hz,1H),3.82(dt,J=12.6,6.5Hz,1H),3.10(s,3H),2.50(s,1H),1.20(t,J=7.4Hz,6H).
N-(2-isopropylamine base-5-methylsulfonylbenzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except substituting except 2-isopropoxy-5-methyl sulfonylbenzoic acid with 2-isopropylamine base-5-methyl sulfonylbenzoic acid, other operations are with preparation embodiment 27. 1H?NMR(300MHz,CDCl 3)δ7.87(s,1H),7.82(d,J=8.3Hz,1H),7.74(dd,J=8.9,2.2Hz,1H),7.65(d,J=2.2Hz,1H),7.57(d,J=8.3Hz,1H),6.75(d,J=8.9Hz,1H),5.73(s,1H),4.20(m,2H),3.71(m,1H),3.52–3.37(m,1H),3.27(m,2H),2.98(s,3H),2.22(m,2H),2.12–1.93(m,2H),1.33–1.21(m,6H).
Embodiment 18:N-(2-isopropoxy-5-nitro benzoyl)-4-(4-TRIFLUOROMETHYLBENZOYL) piperidines
Except substitute the fluoro-4-trifluoromethylbenzoic acid of 2-with 4-trifluoromethylbenzoic acid except, other operations are with preparation embodiment 12. 1H?NMR(300MHz,CDCl 3)δ8.66(s,1H),8.24(dd,J=9.2,2.8Hz,1H),8.18(dd,J=13.3,2.7Hz,1H),8.04(t,J=7.2Hz,2H),7.76(d,J=8.3Hz,2H),6.97(dd,J=9.2,4.2Hz,1H),5.63–5.52(m,1H),4.82–4.64(m,2H),4.02–3.87(m,2H),3.62–3.45(m,2H),3.12(m,2H),2.11–1.90(m,4H),1.88–1.74(m,4H),1.50–1.35(m,6H).
Embodiment 19:N-(2-ring third methoxyl group-5-nitro benzoyl)-4-(4-TRIFLUOROMETHYLBENZOYL) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-ring third methoxyl group-5-nitrobenzoic acid, other operations are with preparation embodiment 18. 1H?NMR(300MHz,CDCl 3)δ8.27–8.13(m,2H),8.04(m,2H),7.74(m,2H),6.94(d,J=9.1Hz,1H),5.62–5.48(m,1H),4.73(m,1H),4.04–3.84(m,4H),3.67–3.44(m,2H),3.13(m,2H),2.00(m,4H),1.90–1.66(m,5H),1.31(m,1H),0.70(m,2H),0.37(m,2H).
Embodiment 20:N-[2-(the fluoro-1-propoxy-of 1H, 1H-five)-5-nitro benzoyl]-4-(4-TRIFLUOROMETHYLBENZOYL) piperidines
Except substituting outside 2-isopropoxy-5-nitrobenzoic acid with 2-(the fluoro-1-propoxy-of 1H, 1H-five)-5-nitrobenzoic acid, other operations are with preparation embodiment 18. 1H?NMR(300MHz,CDCl 3)δ8.31(dd,J=9.0,2.4Hz,1H),8.23(dd,J=19.0,2.7Hz,1H),8.04(d,J=8.1Hz,2H),7.75(d,J=8.5Hz,2H),7.09–6.99(m,1H),4.78–4.47(m,3H),3.52(m,2H),3.28–3.00(m,2H),2.06(m,1H),1.77(m,3H).
Embodiment 21:N-(2-isopropylamine base-5-nitro benzoyl)-4-(4-TRIFLUOROMETHYLBENZOYL) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-isopropylamine base-5-nitrobenzoic acid, other operations are with preparation embodiment 18. 1H?NMR(300MHz,CDCl 3)δ8.14(d,J=9.3Hz,1H),8.05(m,3H),7.77(d,J=8.0Hz,2H),6.67(d,J=9.3Hz,1H),4.30(s,2H),3.75(s,1H),3.59(t,J=10.4Hz,1H),3.23(t,J=12.0Hz,2H),1.99(d,J=11.2Hz,2H),1.83(dd,J=21.4,10.7Hz,2H),1.28(t,J=7.2Hz,6H).
Embodiment 22:N-(2-cyclohexylamino-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with hexahydroaniline; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.67(dd,J=8.9,2.3Hz,1H),7.62(dt,J=8.6,4.3Hz,1H),7.60(d,J=2.3Hz,1H),7.29–7.24(m,2H),7.08(td,J=8.8,2.1Hz,1H),6.74(d,J=9.0Hz,1H),4.30(m,2H),3.38(m,2H),3.25(m,2H),2.61(s,3H),2.21(m,2H),2.01(m,4H),1.78(m,3H),1.71–1.58(m,2H),1.45–1.34(m,2H),1.29(m,3H).
Embodiment 23:N-(2-cyclohexylamino-5-nitro benzoyl)-4-(4-TRIFLUOROMETHYLBENZOYL) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-cyclohexylamino-5-nitrobenzoic acid, other operations are with preparation embodiment 18. 1H?NMR(300MHz,CDCl 3)δ8.11(dd,J=9.1,2.3Hz,1H),8.06(s,1H),8.03(d,J=1.8Hz,2H),7.75(d,J=8.2Hz,2H),6.65(t,J=8.1Hz,1H),6.18(d,J=7.4Hz,1H),4.27(s,2H),3.57(td,J=10.6,5.4Hz,1H),3.39(s,1H),3.22(t,J=11.2Hz,2H),2.79(t,J=4.0Hz,1H),1.98(d,J=10.8Hz,3H),1.88–1.72(m,4H),1.66(s,2H),1.33(dt,J=18.1,8.2Hz,5H),0.93–0.79(m,1H).
Embodiment 24:N-(2-isopropoxy-5-nitro benzoyl)-4-(4-fluoro benzoyl) piperidines
Except substituting except 4-(2,4 difluorobenzene formyl radical) piperidines with 4-(4-fluoro benzoyl) piperidines, other operations are with preparation embodiment 1. 1H?NMR(300MHz,CDCl 3)δ8.27–8.15(m,2H),7.98(dd,J=8.7,5.4Hz,2H),7.16(t,J=8.5Hz,2H),6.94(d,J=9.1Hz,1H),4.81(d,J=13.4Hz,1H),4.02–3.88(m,2H),3.64–3.43(m,2H),3.31–3.08(m,2H),3.08–2.94(m,1H),2.11–1.94(m,2H),1.87–1.73(m,2H),1.42–1.21(m,2H),0.81–0.62(m,2H),0.46–0.23(m,2H).
Embodiment 25:N-(2-ring third methoxyl group-5-nitro benzoyl)-4-(4-fluoro benzoyl) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-ring third methoxyl group-5-nitrobenzoic acid, other operations are with preparation embodiment 24. 1H?NMR(300MHz,CDCl 3)δ8.29–8.20(m,1H),8.21–8.12(m,1H),8.07–7.91(m,2H),7.16(t,J=7.5Hz,2H),7.03–6.92(m,1H),4.76(m,2H),3.52(d,J=3.8Hz,3H),3.10(m,3H),1.99(m,2H),1.76(m,3H),1.43(m,6H).
Embodiment 26:N-(2-isopropoxy-5-nitro benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
2-fluoro-5-methyl sulfonylbenzoic acid methyl esters
Fluoro-for 4.5g (20.5mmol) 2-5-sulfonic benzoic acid is dissolved in 40mL DMF, add 9.18g (61.5mmol) salt of wormwood, 4.84mL (72mmol) methyl iodide, react 48h under room temperature after, reaction terminates, reaction solution is added in 200mL water, with ethyl acetate (100mL*3) extraction, after merging organic layer, with saturated common salt water washing, after anhydrous sodium sulfate drying, concentrate to obtain product. 1H?NMR(300MHz,CDCl 3)δ8.54(dd,J=6.5,2.5Hz,1H),8.11(ddd,J=8.7,4.2,2.5Hz,1H),7.41–7.30(m,1H),3.97(s,3H),3.08(s,3H).
The fluoro-5-methyl sulfonylbenzoic acid of 2-
2g (8.6mmol) 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters is dissolved in 20mL methyl alcohol; add 5mL water; 520mg (12.9mmol) sodium hydroxide; after stirred at ambient temperature 3h, react complete, the ethanol in reaction solution is steamed and removes; adjust about pH to 4; separate out solid, obtain product 1.78g after filtering drying, yield is 95%. 1H?NMR(400MHz,DMSO)δ8.34(dd,J=6.8,2.5Hz,1H),8.19–8.12(m,1H),7.60(dd,J=10.4,8.7Hz,1H),3.28(s,3H).
2-isopropoxy-5-methyl sulfonylbenzoic acid
Fluoro-for 500mg (2.3mmol) 2-5-methyl sulfonylbenzoic acid is dissolved in 15mL Virahol; add 2.25g (6.9mmol) cesium carbonate, react 67h under 80 ° of C after, stopped reaction; after reaction solution evaporate to dryness; in succession add 20mL methylene dichloride and 10mL water, after isolating water layer, pH is adjusted to 2; after 10mL*2 dichloromethane extraction; merge organic phase, dry concentrated evaporate to dryness obtains 430mg product, and yield is 72%. 1H?NMR(300MHz,CDCl 3)δ8.54(dd,J=6.5,2.5Hz,1H),8.11(ddd,J=8.7,4.2,2.5Hz,1H),7.41–7.30(m,1H),3.97(s,3H),3.08(s,4H).
N-(2-isopropoxy-5-nitro benzoyl)-4-(2-fluorine 4-TRIFLUOROMETHYLBENZOYL) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-isopropoxy-5-methyl sulfonylbenzoic acid, other operations are with preparation embodiment 12. 1H?NMR(400MHz,CDCl 3)δ7.88–7.84(m,2H),7.50(d,J=8.3Hz,1H),7.44–7.36(m,1H),6.99–6.94(m,2H),4.65(ddd,J=18.1,12.0,6.0Hz,3H),3.72(dq,J=14.0,7.0Hz,2H),3.33(td,J=13.9,7.0Hz,3H),1.20(t,J=6.5Hz,5H).
Embodiment 27:N-(2-isopropoxy-5-methylsulfonylbenzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except substituting outside 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines with 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, other operations are with preparation embodiment 26. 1H?NMR(400MHz,CDCl 3)δ7.91–7.86(m,2H),7.86–7.82(m,2H),7.81(d,J=2.4Hz,1H),7.55(d,J=8.4Hz,1H),7.03(dd,J=9.2,2.7Hz,1H),4.79(d,J=12.3Hz,1H),4.75–4.64(m,1H),3.58(d,J=13.7Hz,1H),3.47–3.35(m,1H),3.31–3.09(m,2H),2.23(dd,J=23.6,13.1Hz,1H),1.40(dd,J=14.2,8.3Hz,4H).
Embodiment 28:N-(2-isopropoxy-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substitute 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines with 4-(2,4 difluorobenzene formyl radical) piperidines except, other operations are with preparation embodiment 26. 1H?NMR(300MHz,CDCl 3)δ7.90(d,J=8.7Hz,2H),7.85–7.77(m,1H),7.02(m,2H),6.88(d,J=8.7Hz,1H),4.72(m,2H),3.47(m,1H),3.35(m,1H),3.10(m,1H),3.05(s,3H),2.96(m,1H),2.05(m,1H),1.83(m,2H),1.71(m,2H),1.40(m,6H).
Embodiment 29:N-(2-isopropoxy-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting outside 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines with 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines, other operations are with preparation embodiment 26. 1H?NMR(300MHz,CDCl 3)δ8.52–8.43(m,1H),7.89(m,2H),7.62(m,1H),7.28(m,1H),7.13–7.00(m,2H),4.73(m,2H),3.58(m,1H),3.35(m,1H),3.14(m,2H),3.07(s,3H),2.24(m,1H),2.07(s,1H),2.01–1.91(m,1H),1.41(m,4H),1.26(m,3H).
Embodiment 30:N-[2-(the fluoro-1-propoxy-of 1H, 1H-five)-5-methylsulfonylbenzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting outside 2-isopropoxy-5-methyl sulfonylbenzoic acid with 2-(the fluoro-1-propoxy-of 1H, 1H-five)-5-methyl sulfonylbenzoic acid, other operations are with preparation embodiment 28. 1H?NMR(300MHz,DMSO)δ7.98(dt,J=8.8,2.5Hz,1H),7.90(dd,J=10.0,7.8Hz,1H),7.79(dd,J=25.2,2.4Hz,1H),7.49–7.43(m,1H),7.43–7.36(m,1H),7.24(td,J=8.6,2.5Hz,1H),5.05(m,2H),4.58–4.37(m,1H),3.39(s,1H),3.23(d,J=2.0Hz,3H),3.17–2.78(m,2H),1.89(m,1H),1.70(m,1H),1.43(m,2H),1.23(m,1H).
Embodiment 31:N-[2-(1H, 1H-five fluoro-1-propoxy-)-5-methylsulfonylbenzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting outside 2-isopropoxy-5-methyl sulfonylbenzoic acid with 2-(the fluoro-1-propoxy-of 1H, 1H-five)-5-methyl sulfonylbenzoic acid, other operations are with preparation embodiment 29. 1H?NMR(400MHz,CDCl 3)δ8.01–7.94(m,1H),7.63(m,1H),7.24(m,1H),7.13–7.02(m,2H),4.75(m,1H),4.67–4.46(m,2H),3.63–3.49(m,1H),3.43–3.31(m,1H),3.30–3.09(m,2H),3.06(d,J=3.2Hz,3H),2.23(m,1H),2.01(m,2H).
Embodiment 32:N-[2-(1H, 1H-five fluoro-1-propoxy-)-5-methylsulfonylbenzoyl]-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting outside 2-isopropoxy-5-methyl sulfonylbenzoic acid with 2-(the fluoro-1-propoxy-of 1H, 1H-five)-5-methyl sulfonylbenzoic acid, other operations are with preparation embodiment 26. 1H?NMR(400MHz,CDCl 3)δ7.96–7.92(m,2H),7.75(d,J=8.3Hz,1H),7.44–7.39(m,1H),6.99–6.94(m,2H),5.03–4.48(m,3H),4.34(dd,J=19.0,11.2Hz,1H),3.44(d,J=26.4Hz,1H),3.01(dt,J=26.4,11.3Hz,1H),2.46(s,3H),2.13(d,J=10.5Hz,1H),1.91–1.73(m,4H).
Embodiment 33:N-[2-(the fluoro-1-propoxy-of 1H, 1H-five)-5-methylamine alkylsulfonyl benzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
Except with 1H; the fluoro-1-propyl alcohol of 1H-five substitutes Virahol; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(2,4 difluorobenzene formyl radical) piperidines substitutes other operations of 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines with preparation embodiment 26. 1H?NMR(300MHz,)δ7.91-7.77(m,3H),7.06-6.96(m,2H),6.88(ddd,J=11.0,8.6,2.4Hz,1H),4.74–4.61(m,3H),4.53(dd,J=19.5,11.4Hz,1H),3.41(d,J=25.6Hz,1H),3.08(dt,J=25.4,11.8Hz,1H),2.66(s,3H),2.06(d,J=10.5Hz,1H),1.92–1.74(m,4H).
Embodiment 34:N-(2-ring butylamine base-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with ring butylamine, 4-(2,4 difluorobenzene formyl radical) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.91–7.83(m,1H),7.71(dd,J=8.8,2.2Hz,1H),7.59(d,J=2.2Hz,1H),7.02–6.95(m,1H),6.88(ddd,J=11.0,8.6,2.3Hz,1H),6.61(d,J=8.9Hz,1H),3.94(m,1H),3.39(m,1H),3.14(m,2H),2.98(s,3H),2.45(m,2H),1.89(m,6H),1.79–1.63(m,4H).
Embodiment 35:N-(2-ring butylamine base-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with ring butylamine; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes the fluoro-5-methylsulfonyl of 2-, and 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines substitutes 4-(2; 4-difluoro benzoyl) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.87(s,1H),7.84(d,J=8.3Hz,1H),7.67(dd,J=8.8,1.9Hz,1H),7.60(d,J=2.0Hz,1H),7.58(d,J=8.3Hz,1H),6.61(dd,J=8.7,2.4Hz,1H),4.33(m,2H),4.01–3.89(m,1H),3.44(m,1H),3.27(m,2H),2.82(m,1H),2.59(d,J=4.4Hz,3H),2.45(m,2H),2.21(m,2H),2.13–1.98(m,2H),1.98–1.77(m,4H).
Embodiment 36:N-(2-isobutyl amine-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with isobutylamine; 2-fluoro-5-methylamine alkylsulfonyl-methyl benzoate substitutes 2-fluoro-5-methanesulfonyl-benzoic acid methyl esters; 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,DMSO)δ8.02(ddd,J=17.5,8.7,5.3Hz,1H),7.74–7.66(m,1H),7.52(dd,J=44.3,2.3Hz,1H),7.37–7.26(m,2H),7.17(dd,J=25.0,8.7Hz,1H),4.64(m,1H),3.61–3.43(m,1H),3.33(s,3H),3.28–3.13(m,2H),3.07(m,1H),3.01–2.83(m,2H),2.39(m,3H),2.20(m,1H),2.08–1.92(m,2H),1.86–1.70(m,1H),1.59–1.48(m,3H).
Embodiment 37:N-(2-ring butylamine base-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with ring butylamine, 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.73(dd,J=8.8,2.3Hz,1H),7.65(d,J=2.3Hz,1H),7.64–7.60(m,1H),7.27(m,1H),7.09(td,J=8.8,2.1Hz,1H),6.63(d,J=8.9Hz,1H),4.30(m,1H),3.96(m,1H),3.39(m,1H),3.26(m,2H),3.00(s,3H),2.47(m,2H),2.25–2.14(m,2H),2.09–1.77(m,7H).
Embodiment 38:N-(2-isopropyisulfanyl-5-methylamine alkylsulfonyl benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting 2-isopropoxy-5-nitrobenzene methyl with 2-isopropyisulfanyl-5-methylamine sulfonyl methyl benzoate; 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines substitutes 4-(2; 4-difluoro benzoyl) outside piperidines, other operations are with preparation embodiment 1. 1HNMR(400MHz,CD 3OD)δ7.98(s,1H),7.89(m,1H),7.77–7.67(m,3H),7.58–7.47(m,2H),4.46(m,1H),3.84–3.64(m,1H),3.47(m,2H),3.35(m,2H),3.24(m,1H),3.13(m,1H),2.98(m,1H),2.69–2.67(m,4H),2.53–2.47(m,1H),2.42(s,3H),1.99(m,1H),1.78(m,1H),1.27(m,6H).
Embodiment 39:N-(2-ring third methoxyl group-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting except Virahol with cyclopropyl-carbinol, other operations are with preparation embodiment 28. 1H?NMR(300MHz,CDCl 3)δ7.87(m,3H),6.99(m,2H),6.90(m,1H),4.89–4.58(m,1H),3.94(m,2H),3.50(s,1H),3.36(s,1H),3.14(m,1H),3.04(s,3H),3.02–2.88(m,1H),2.04(m,1H),1.86(m,2H),1.74(m,3H),1.28(m,1H),0.78–0.60(m,2H),0.36(m,2H).
Embodiment 40:N-(2-ring third methoxyl group-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting except 2-isopropoxy-5-methyl sulfonylbenzoic acid with 2-ring third methoxyl group-5-methyl sulfonylbenzoic acid, other operations are with preparation embodiment 29. 1H?NMR(300MHz,CDCl 3)δ7.92(m,1H),7.86(m,1H),7.68–7.59(m,1H),7.27(m,1H),7.14–7.05(m,1H),7.00(m,1H),4.93–4.72(m,2H),3.95(m,2H),3.69–3.55(m,1H),3.44–3.26(m,2H),3.06(s,3H),2.33–2.17(m,2H),2.08(m,2H),1.28(m,1H),0.66(m,2H),0.46–0.26(m,2H).
Embodiment 41:N-(2-isobutyl amine-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with isobutylamine; 2-fluoro-5-methylamine alkylsulfonyl-methyl benzoate substitutes 2-fluoro-5-methanesulfonyl-benzoic acid methyl esters; 4-(2; 4-difluoro benzoyl) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,)δ7.87(dd,J=15.2,8.5Hz),7.67(dd,J=8.8,2.2Hz),7.58–7.52(m),7.03–6.85(m),6.70(d,J=8.9Hz),4.23(s),3.39(s),3.15(s),2.98(d,J=6.9Hz),2.60(s),2.03–1.95(m),1.95–1.89(m),1.80–1.63(m),0.99(d,J=6.6Hz).
Embodiment 42:N-(2-cyclohexylamino-5-methylsulfonylbenzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except substituting except Isopropylamine with hexahydroaniline, other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.89(d,J=10.8Hz,1H),7.82(d,J=8.3Hz,1H),7.72(dd,J=8.9,2.3Hz,1H),7.64(d,J=2.3Hz,1H),7.57(dd,J=8.3,0.9Hz,1H),6.75(d,J=9.1Hz,1H),4.30(m,2H),3.44(m,1H),3.40–3.32(m,1H),3.27(m,2H),2.98(s,3H),2.21(m,2H),2.02(m,4H),1.77(m,2H),1.70–1.60(m,1H),1.45–1.34(m,2H),1.34–1.19(m,4H).
Embodiment 43:N-(2-cyclohexylamino-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with hexahydroaniline, 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(300MHz,CDCl 3)δ7.73(dd,J=8.9,2.2Hz,1H),7.67–7.58(m,2H),7.30–7.26(m,1H),7.09(td,J=8.8,2.1Hz,1H),6.76(d,J=8.9Hz,1H),4.30(m,2H),3.38(m,2H),3.26(m,2H),2.99(s,3H),2.19(m,2H),2.11–1.97(m,4H),1.78(m,2H),1.66(m,1H),1.48–1.19(m,5H).
Embodiment 44:N-(2-cyclohexylamino-5-methylsulfonylbenzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting Isopropylamine with hexahydroaniline, 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.89(t,J=7.5Hz,1H),7.70(dd,J=8.8,1.6Hz,1H),7.60(dd,J=6.4,2.3Hz,1H),7.48(m,1H),6.74(dd,J=8.9,2.9Hz,1H),4.20(s,1H),3.50–3.28(m,3H),3.15(s,1H),2.98(s,3H),1.99(m,3H),1.75(m,3H),1.64(s,1H),1.45–1.32(m,2H),1.19(m,4H).
Embodiment 45:N-(2-cyclohexylamino-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with hexahydroaniline, 4-(2,4 difluorobenzene formyl radical) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(300MHz,CDCl 3)δ7.88(dd,J=15.3,8.2Hz,1H),7.74(d,J=8.7Hz,1H),7.61(s,1H),6.99(t,J=8.1Hz,1H),6.89(t,J=10.0Hz,1H),6.75(d,J=8.8Hz,1H),4.22(m,2H),3.71(m,1H),3.39(m,1H),3.15(m,2H),2.99(s,3H),2.00(m,2H),1.72(m,3H),1.27(m,6H).
Embodiment 46:N-(2-isopropylamine base-5-methylsulfonylbenzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines with 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines, other operations are with preparation embodiment 17. 1H?NMR(300MHz,CDCl 3)δ7.89(t,J=7.5Hz,1H),7.72(d,J=8.8Hz,1H),7.64–7.57(m,1H),7.48(m,1H),6.73(d,J=8.8Hz,1H),4.28(m,1H),3.77–3.62(m,1H),3.41(m,3H),3.14(m,1H),2.98(s,3H),2.01(m,1H),1.71(m,1H),1.30–1.18(m,6H).
Embodiment 47:N-(2-isopropylamine base-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines with 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines, other operations are with preparation embodiment 17. 1H?NMR(300MHz,CDCl 3)δ7.74(d,J=8.8Hz,1H),7.63(m,2H),7.27(m,1H),7.09(t,J=8.8Hz,1H),6.76(d,J=9.0Hz,1H),5.70(m,1H),4.30(m,1H),3.72(m,1H),3.37(m,1H),3.26(m,2H),3.00(s,3H),2.19(m,2H),2.02(m,2H),1.27(m,6H).
Embodiment 48:N-(2-isopropylamine base-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substitute 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines with 4-(2,4 difluorobenzene formyl radical) piperidines outside, other operations are with preparation embodiment 17. 1H?NMR(300MHz,CDCl 3)δ7.75(d,J=8.6Hz,1H),7.66(d,J=2.1Hz,1H),7.64–7.60(m,1H),7.28(m,1H),7.09(dd,J=9.8,8.0Hz,1H),6.76(d,J=8.9Hz,1H),5.72(s,1H),4.30(m,2H),3.72(m,1H),3.39(m,1H),3.26(m,2H),3.00(s,3H),2.20(m,2H),2.02(m,2H),1.31–1.24(m,6H).
Embodiment 49:N-(2-cyclopentyloxy-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
2-hydroxy-5-methyl sulfamic methyl benzoate
4.5g (18.4mmol) 2-hydroxy-5-methyl sulfamic phenylformic acid is dissolved in 200mL methyl alcohol; the 10mL vitriol oil is dripped under ice bath; react 24h under room temperature after, reaction terminates, and is steamed by the methyl alcohol in reaction solution and removes; add 100mL water; with extraction into ethyl acetate, organic layer with saturated common salt water washing, after anhydrous sodium sulfate drying; steaming desolventizes and obtains product 4g, and yield is 90%. 1H?NMR(400MHz,CDCl 3)δ8.65(d,J=2.9Hz,1H),8.33–8.26(m,1H),7.03(d,J=9.3Hz,1H),4.95(tt,J=5.5,2.8Hz,1H),3.90(s,3H),2.00–1.90(m,4H),1.89–1.76(m,2H),1.74–1.61(m,2H).
N-(2-cyclopentyloxy-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting 2-cyclopentyloxy-5-nitrobenzoic acid with 2-cyclopentyloxy-5-methylamine sulfonyl benzoic acid, other operations are with preparation embodiment 3. 1H?NMR(400MHz,DMSO)δ7.91(dd,J=15.4,8.6Hz,1H),7.78–7.71(m,1H),7.52(m,1H),7.43(dd,J=11.4,9.4Hz,1H),7.39–7.32(m,1H),7.25(td,J=8.9,2.9Hz,2H),4.97(s,1H),4.50(m,1H),3.51–3.38(m,1H),3.34(s,4H),3.29(s,1H),3.10(m,1H),2.91(m,1H),2.44–2.34(m,3H),2.07–1.84(m,3H),1.79–1.52(m,7H),1.49–1.33(m,2H).
Embodiment 50:N-(2-piperidyl-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with piperidines; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.69(dd,J=8.8,2.0Hz,1H),7.65–7.61(m,1H),7.60(d,J=2.3Hz,1H),7.29–7.23(m,1H),7.08(td,J=8.8,2.0Hz,1H),6.72(d,J=8.9Hz,1H),4.30(s,2H),3.39(t,J=10.9Hz,1H),3.27(t,J=11.5Hz,2H),3.00(d,J=6.9Hz,2H),2.61(s,3H),2.19(m,2H),1.95(ddd,J=20.0,15.5,8.7Hz,4H),1.01(m,6H).
Embodiment 51:N-(2-cyclopentyloxy-5-methylamine alkylsulfonyl benzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except substituting outside 4-(2,4 difluorobenzene formyl radical) piperidines with 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, other operations are with preparation embodiment 49. 1H?NMR(400MHz,DMSO)δ8.26(m,2H),7.76(m,2H),7.58(m,1H),7.36(q,J=4.7Hz,1H),7.28(d,J=8.8Hz,1H),4.99(m,1H),4.61(m,1H),3.60(m,1H),3.40(m,1H),3.23(m,1H),3.04(m,1H),2.40(dd,J=7.7,5.1Hz,3H),2.21(dd,J=26.4,12.4Hz,1H),2.10–1.81(m,4H),1.79–1.55(m,7H).
Embodiment 52:N-(2-ring third methoxyl group-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except with except cyclopropyl-carbinol displaced loop amylalcohol, other operations are with preparation embodiment 49. 1H?NMR(300MHz,)δ7.85(ddd,J=11.8,11.0,5.4Hz),7.75(dd,J=7.8,2.2Hz),7.05–6.84(m),4.72(dd,J=42.5,13.5Hz),4.42(s),4.01–3.84(m),3.36(t,J=10.7Hz),2.64(s),2.00(dd,J=37.2,13.6Hz),1.78(dd,J=28.1,12.1Hz),1.30(d,J=4.9Hz),0.68(s),0.36(d,J=4.8Hz).
Embodiment 53:N-(2-isopropoxy-5-methylamine alkylsulfonyl benzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except with except Virahol alcohol displaced loop amylalcohol, other operations are with preparation embodiment 51. 1H?NMR(400MHz,DMSO)δ8.26(m,2H),7.75(m,2H),7.58(m,1H),7.37(d,J=4.9Hz,1H),7.31(d,J=8.9Hz,1H),4.89–4.74(m,1H),4.62(s,1H),3.68–3.52(m,1H),3.41(m,1H),3.24(m,1H),3.04(s,1H),2.40(dd,J=7.9,5.0Hz,3H),2.30–2.14(m,1H),2.11–1.91(m,2H),1.75–1.62(m,1H),1.37–1.20(m,6H).
Embodiment 54:N-(2-isopropoxy-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except with except Virahol displaced loop amylalcohol, other operations are with preparation embodiment 49. 1H?NMR(400MHz,DMSO)δ7.97–7.86(m,1H),7.74(d,J=8.9Hz,1H),7.52(m,1H),7.44(t,J=10.4Hz,1H),7.38–7.32(m,1H),7.26(m,2H),4.78(m,1H),4.51(m,1H),3.44(m,1H),3.29(s,1H),3.22–3.03(m,1H),2.92(m,1H),2.69(s,3H),2.39(t,J=4.5Hz,3H),1.99(m,2H),1.71(m,2H),1.53–1.34(m,2H),1.35–1.19(m,6H).
Embodiment 55:N-[2-(2-methylpyrrole alkyl)-5-methylamine alkylsulfonyl benzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with 2-crassitude; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) piperidines substitute outside, other operation with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.80–7.55(m,3H),7.30–7.22(m,2H),7.14–7.03(m,1H),6.78(d,J=7.4Hz,1H),4.92–4.55(m,1H),4.41(s,1H),4.14–3.86(m,2H),3.45(m,2H),3.41–3.04(m,3H),2.62(m,3H),2.23(m,2H),2.12–1.78(m,4H),1.22(m,4H).
Embodiment 56:N-(2-ring butylamine base-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with ring butylamine; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes the fluoro-5-methylsulfonyl of 2-; 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.72–7.56(m,3H),7.27(m,2H),7.09(t,J=8.0Hz,1H),6.61(d,J=8.8Hz,1H),4.31(s,2H),3.94(m,1H),3.37(m,1H),3.25(m,2H),2.61(s,3H),2.51–2.38(m,2H),2.19(m,2H),2.10–1.76(m,7H).
Embodiment 57:N-(2-piperidyl-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with piperidines, 4-(2,4 difluorobenzene formyl radical) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(400MHz,DMSO)δ7.97–7.85(m,1H),7.85–7.77(m,1H),7.60(dd,J=27.4,2.2Hz,1H),7.48–7.37(m,1H),7.25(t,J=7.0Hz,1H),7.17(dd,J=27.2,8.8Hz,1H),4.65–4.44(m,1H),3.46(m,1H),3.31–3.08(m,7H),3.06–2.86(m,4H),2.50(s,1H),2.03–1.85(m,2H),1.72(m,2H),1.52(m,8H),1.30(m,1H).
Embodiment 58:N-(2-piperidyl-5-methylsulfonylbenzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting Isopropylamine with piperidines, 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(400MHz,DMSO)δ8.26(s,1H),8.34–8.17(m,2H),7.98(dd,J=8.8,2.2Hz,1H),7.86(ddd,J=8.0,5.0,2.4Hz,1H),7.78–7.72(m,1H),7.56(t,J=9.8Hz,1H),5.54(m,1H),4.61(m,1H),3.57(m,1H),3.39(mz,1H),3.25(m,4H),3.14–2.98(m,1H),2.22(m,1H),2.02(m,2H),1.79(m,2H),1.45(m,3H).
Embodiment 59:N-(2-piperidyl-5-methylsulfonylbenzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except substituting except Isopropylamine with piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,DMSO)δ8.25(dd,J=17.6,8.6Hz,2H),7.83(ddd,J=8.7,6.5,2.3Hz,1H),7.76(t,J=8.8Hz,1H),7.66(dd,J=41.9,2.3Hz,1H),7.20(dd,J=23.5,8.7Hz,1H),4.65(dd,J=31.9,12.8Hz,1H),3.71–3.49(m,1H),3.36(d,J=17.5Hz,2H),3.17(t,J=14.0Hz,3H),3.11–3.02(m,1H),3.02–2.89(m,2H),2.24(dd,J=28.1,11.5Hz,1H),2.03(dd,J=17.8,9.3Hz,2H),1.90–1.73(m,1H),1.71–1.48(m,6H).
Embodiment 60:N-(2-piperidyl-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with piperidines, 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(400MHz,DMSO)δ8.03(ddd,J=20.5,8.7,5.3Hz,1H),7.83(ddd,J=8.8,6.7,2.4Hz,1H),7.71–7.67(m,1H),7.74–7.58(m,2H),7.30(ddd,J=18.4,9.2,2.1Hz,1H),7.19(dd,J=23.5,8.7Hz,1H),4.64(dd,J=29.4,13.0Hz,1H),3.07–2.89(m,3H),2.68(s,3H),2.20(m,1H),2.07–1.90(m,2H),1.70–1.47(m,7H).
Embodiment 61:N-[2-(1-trifluoromethyl oxyethyl group)-5-methylsulfonylbenzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
N-(2-(1-trifluoromethyl oxyethyl group)-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Fluoro-for 500mg (2.3mmol) 2-5-methyl sulfonylbenzoic acid is dissolved in 10mL DMF; add 990mg (6.9mmol) salt of wormwood; 1.07mL (11.5mmol) 1; 1; 1-Trifluoroisoproanol, after reacting 2.5h under microwave heating to 150 ° C, reaction terminates; reaction solution is directly gone up quick preparative column purifying and obtain 2-(1-trifluoromethyl oxyethyl group)-5-methyl sulfonylbenzoic acid 490mg, yield is 69%.Subsequent operations is except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-(1-trifluoromethyl oxyethyl group)-5-methyl sulfonylbenzoic acid, and other operations are with preparation embodiment 1. 1H?NMR(400MHz,DMSO)δ7.95(dt,J=6.9,3.4Hz,1H),7.94–7.86(m,1H),7.84–7.73(m,1H),7.54(t,J=9.0Hz,1H),7.43(ddd,J=11.7,5.2,2.6Hz,1H),7.25(t,J=8.4Hz,1H),5.63–5.43(m,1H),4.51(m,1H),3.44(m,1H),3.30(s,1H),3.24(s,3H),3.11(m,1H),3.01–2.84(m,1H),2.69(s,1H),1.96(m,1H),1.73(m,1H),1.46(m,2H),1.39(m,2H).
Embodiment 62:N-[2-(1H, 1H-five fluoro-1-propoxy-)-5-methylamine alkylsulfonyl benzoyl]-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting Virahol with the fluoro-1-propyl alcohol of 1H, 1H-five, 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters, and other operations are with preparation embodiment 26. 1H?NMR(400MHz,DMSO)δ7.91(ddd,J=14.9,8.6,6.5Hz,1H),7.74(dd,J=8.2,1.6Hz,1H),7.65–7.57(m,1H),7.56–7.48(m,2H),7.47–7.38(m,1H),7.24(td,J=8.5,2.3Hz,1H),4.61–4.40(m,1H),3.42(m,1H),3.24(m,1H),3.04(m,1H),2.88(m,1H),2.68(s,3H),2.42(m,3H),2.12(m,3H),1.94(m,1H),1.70(m,3H),1.64–1.53(m,2H),1.47(m,1H),1.35(m,1H).
Embodiment 63:N-[2-(1-trifluoromethyl oxyethyl group)-5-methylsulfonylbenzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting except 2-isopropylamine base-5-nitrobenzoic acid with 2-(1-trifluoromethyl oxyethyl group)-5-methyl sulfonylbenzoic acid, other operations are with preparation embodiment 11. 1H?NMR(400MHz,DMSO)δ8.13–7.99(m,1H),7.99–7.94(m,1H),7.85(ddd,J=7.8,5.0,2.4Hz,1H),7.70(d,J=8.9Hz,1H),7.56(t,J=9.4Hz,1H),7.30(t,J=7.9Hz,1H),5.53(dt,J=12.3,6.2Hz,1H),4.59(s,1H),3.61–3.35(m,1H),3.25(s,3H),3.04(m,2H),2.69(s,1H),2.18(m,1H),2.07–1.91(m,3H),1.90–1.57(m,3H),1.44(m,4H).
Embodiment 64:N-(2-pyrrolidyl-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting except 2-isopropoxy-5-nitrobenzoic acid with 2-pyrrolidyl-5-methylamine sulfonyl benzoic acid, other operations are with preparation embodiment 1. 1H?NMR(400MHz,CDCl 3)δ7.88(dd,J=15.3,8.5Hz,1H),7.73–7.67(m,1H),7.64(dd,J=8.9,2.1Hz,1H),7.57–7.48(m,2H),7.03–6.95(m,1H),6.93–6.82(m,1H),6.69(t,J=8.7Hz,1H),4.66(m,1H),4.41–4.27(m,1H),4.27–4.14(m,1H),3.75(m,1H),3.53–3.09(m,6H),2.80(s,1H),2.59(s,3H),2.05(m,6H),1.87(m,2H),1.76–1.58(m,3H),1.49–1.19(m,8H),0.99–0.78(m,4H).
Embodiment 65:N-[2-(4-fluorophenyl)-5-methylamine alkylsulfonyl benzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
2-(4-fluorophenyl)-5-methyl sulfonylbenzoic acid methyl esters
The preparation method of 2-trifluoro-methanesulfonyl oxy-5-methylamine sulfonyl methyl benzoate is with preparation 2-trifluoro-methanesulfonyl oxy-5-nitrobenzene methyl.By 50mg (0.13mmol) 2-trifluoro-methanesulfonyl oxy-5-methylamine sulfonyl methyl benzoate; 36mg (0.16mmol) 4-fluorobenzoic boric acid; 10mg (0.007mmol) tetra-triphenylphosphine palladium; 36mg (0.26mmol) salt of wormwood adds in 5mL toluene; backflow is heated under nitrogen protection; after completion of the reaction, obtain product 21mg with quick preparative column purifying, yield is 50% in TLC display. 1H?NMR(400MHz,CDCl 3)δ7.98–7.94(m,2H),7.94–7.89(m,2H),7.70(dd,J=5.6,3.4Hz,1H),7.60–7.55(m,5H),7.53(dd,J=5.7,3.4Hz,1H),7.49(dd,J=8.5,5.3Hz,1H),7.21(ddd,J=15.8,10.5,6.4Hz,5H),7.12–7.05(m,1H),4.79–4.50(m,3H),3.31(dd,J=22.1,13.7Hz,2H),3.14(dd,J=15.9,7.6Hz,2H),3.03–2.86(m,2H),2.73(d,J=4.8Hz,5H),1.75–1.54(m,5H).
N-[2-(4-fluorophenyl)-5-methylamine alkylsulfonyl benzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting 2-isopropoxy-5-nitrobenzene methyl with 2-(4-fluorophenyl)-5-methylamine sulfonyl methyl benzoate; 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines substitutes 4-(2; 4-difluoro benzoyl) outside piperidines, other operations are with preparation embodiment 1. 1H?NMR(400MHz,CDCl 3)δ7.98–7.94(m,2H),7.94–7.89(m,2H),7.70(dd,J=5.6,3.4Hz,1H),7.60–7.55(m,3H),7.53(dd,J=5.7,3.4Hz,1H),7.49(dd,J=8.5,5.3Hz,1H),7.21(ddd,J=15.8,10.5,6.4Hz,3H),7.12–7.05(m,1H),4.79–4.50(m,3H),3.31(dd,J=22.1,13.7Hz,2H),3.14(dd,J=15.9,7.6Hz,2H),3.03–2.86(m,2H),2.73(d,J=4.8Hz,5H),1.75–1.54(m,5H).
Embodiment 66:N-[2-(2-methylpyrrole alkyl)-5-methylsulfonylbenzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with 2-crassitude, 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1HNMR(400MHz,CDCl 3)δ7.73(d,J=9.0Hz,2H),7.67–7.58(m,1H),7.30–7.22(m,1H),7.09(tt,J=8.8,2.3Hz,1H),6.82(d,J=8.8Hz,1H),4.00(s,1H),3.43–3.28(m,2H),3.05–2.97(m,3H),2.32–2.16(m,2H),2.13–1.95(m,5H),1.89(m,2H),1.69(m,2H),1.24(m,4H).
Embodiment 67:N-(2-thio-morpholinyl-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with thiomorpholine, 4-(2,4 difluorobenzene formyl radical) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.90(d,J=8.8Hz,1H),7.86(dd,J=8.6,2.3Hz,1H),7.83–7.72(m,1H),7.08(s,1H),6.99(t,J=7.5Hz,1H),6.88(t,J=9.2Hz,1H),4.86–4.47(m,1H),3.57(m,1H),3.45–3.22(m,3H),3.04(m,3H),2.73(s,3H),2.15–2.01(m,1H),1.81(d,J=7.8Hz,1H),1.78–1.64(m,2H).
Embodiment 68:N-(2-thio-morpholinyl-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting Isopropylamine with thiomorpholine, 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.89(s,1H),7.84(d,J=32.6Hz,1H),7.64(dd,J=8.5,4.9Hz,1H),7.27(d,J=11.0Hz,1H),7.11(m,2H),3.69–3.53(m,2H),3.47(m,1H),3.42–3.22(m,4H),3.16–3.07(m,1H),3.04(m,3H),2.77(m,4H),2.24(m,1H),2.14–1.94(m,3H),1.92–1.78(m,1H).
Embodiment 69:N-(2-cyclopentyloxy-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting outside 4-(2,4 difluorobenzene formyl radical) piperidines with 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines, other operations are with preparation embodiment 49. 1H?NMR(400MHz,CDCl 3)δ7.85(dd,J=6.6,4.2Hz,1H),7.74(d,J=2.3Hz,1H),7.65(ddd,J=16.9,8.7,5.1Hz,1H),7.31–7.22(m,1H),7.13–7.04(m,1H),7.01(dd,J=8.6,5.2Hz,1H),4.95–4.85(m,1H),4.77(m,1H),3.60(m,1H),3.35(m,1H),3.17(m,2H),2.87(s,1H),2.65(s,3H),2.24(m,1H),2.10–1.73(m,8H),1.73–1.57(m,2H).
Embodiment 70:N-(2-isobutoxy-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except with isopropylcarbinol displaced loop amylalcohol, 2-hydroxy-5-methyl sulfonyl methyl benzoate substitutes outside 2-hydroxyl-5-nitrobenzene methyl, and other operations are with preparation embodiment 3. 1H?NMR(400MHz,CDCl 3)δ7.93–7.83(m,2H),7.80(dd,J=18.3,2.3Hz,1H),7.07–6.94(m,2H),6.93–6.82(m,1H),4.75–4.61(m,1H),3.93(dd,J=8.7,6.2Hz,1H),3.83(dt,J=11.4,5.9Hz,1H),3.80–3.70(m,1H),3.49(m,1H),3.42–3.26(m,1H),3.20–3.05(m,1H),3.01(s,3H),2.14(m,1H),2.09–1.98(m,1H),1.76(m,3H),1.02(m,6H).
Embodiment 71:N-(2-isobutoxy-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except with isopropylcarbinol displaced loop amylalcohol; 2-hydroxy-5-methyl sulfonyl methyl benzoate substitutes 2-hydroxyl-5-nitrobenzene methyl; 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines substitutes 4-(2; 4-difluoro benzoyl) outside piperidines, other operations are with preparation embodiment 3. 1H?NMR(400MHz,CDCl 3)δ7.97–7.90(m,1H),7.86(dd,J=32.3,2.2Hz,1H),7.63(ddd,J=13.7,8.6,4.9Hz,1H),7.27(d,J=5.0Hz,1H),7.13–7.00(m,2H),4.79(m,1H),3.99–3.73(m,2H),3.60(m,1H),3.35(m,1H),3.21(m,2H),3.07–2.99(m,3H),2.81(s,2H),2.31–2.18(m,1H),2.18–2.10(m,1H),2.03(m,3H),1.04(m,5H).
Embodiment 72:N-(2-ring butylamine base-5-methylamine alkylsulfonyl benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting Isopropylamine with ring butylamine; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.90–7.81(m,1H),7.73(dd,J=8.8,2.2Hz,1H),7.57(d,J=2.2Hz,1H),7.04–6.89(m,1H),6.85(ddd,J=11.0,8.6,2.3Hz,1H),6.60(d,J=8.9Hz,1H),3.94(m,1H),3.37(m,1H),3.13(m,2H),2.97(s,3H),2.44(m,2H),1.88(m,6H),1.79–1.60(m,4H).
Embodiment 73:N-(2-isobutoxy-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except with isopropylcarbinol displaced loop amylalcohol, 2-hydroxy-5-methyl sulfamic methyl benzoate substitutes outside 2-hydroxyl-5-nitrobenzene methyl, and other operations are with preparation embodiment 3. 1H?NMR(300MHz,CDCl 3)δ7.86(m,2H),7.72(d,J=12.8Hz,1H),7.03–6.93(m,2H),6.87(m,1H),4.67(m,1H),4.59(m,1H),3.96–3.88(m,1H),3.82(m,1H),3.74(m,1H),3.51(m,1H),3.34(s,1H),3.11(dd,J=28.8,15.2Hz,2H),2.80(s,2H),2.62(s,3H),2.25–1.96(m,2H),1.88–1.56(m,4H),1.00(m,6H).
Embodiment 74:N-[2-(1-trifluoromethyl oxyethyl group)-5-methylsulfonylbenzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting except the fluoro-5-methyl sulfonylbenzoic acid of 2-with 2-fluoro-5-methylamine sulfonyl benzoic acid, other operations are with preparation embodiment 61. 1H?NMR(300MHz,CDCl 3)δ7.94–7.82(m),7.77(dd,J=11.6,2.1Hz),7.13–6.95(m),6.88(ddd,J=8.6,6.8,2.4Hz),4.86–4.61(m),3.41(dd,J=32.3,8.8Hz),3.11(dt,J=28.2,16.5Hz),2.67(d,J=4.5Hz),2.06(d,J=10.1Hz),1.83(s),1.76(d,J=10.3Hz),1.62(d,J=6.3Hz),1.54(dd,J=13.4,6.4Hz).
Embodiment 75:N-(2-isobutyl amine-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with isobutylamine, 4-(2,4 difluorobenzene formyl radical) piperidines substitutes outside 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, and other operations are with preparation embodiment 17. 1H?NMR(400MHz,DMSO)δ7.91(td,J=8.6,6.8Hz,1H),7.64(dd,J=8.8,2.3Hz,1H),7.46(d,J=2.3Hz,1H),7.45–7.39(m,1H),7.25(td,J=8.5,2.5Hz,1H),6.81(d,J=9.0Hz,1H),6.22(t,J=5.9Hz,1H),3.43(m,1H),3.10(s,3H),2.99(m,2H),2.72–2.64(m,2H),1.99(m,1H),1.92–1.78(m,3H),1.51(m,2H),0.88(m,6H).
Embodiment 76:N-(2-isobutyl amine-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting outside 4-(2,4 difluorobenzene formyl radical) piperidines with 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines, other operations are with preparation embodiment 75. 1H?NMR(400MHz,CDCl 3)δ7.72–7.56(m,3H),7.27(m,2H),7.09(t,J=8.0Hz,1H),6.61(d,J=8.8Hz,1H),4.31(s,2H),3.94(m,1H),3.37(m,1H),3.25(m,2H),2.61(s,3H),2.51–2.38(m,2H),2.19(m,2H),2.10–1.76(m,7H).
Embodiment 77:N-(2-isopropyisulfanyl-5-methylsulfonylbenzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substitute 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines with 4-(2,4 difluorobenzene formyl radical) piperidines outside, other operations are with preparation embodiment 93. 1H?NMR(400MHz,CDCl 3)δ7.92–7.80(m,2H),7.70(m,1H),7.48(d,J=8.4Hz,1H),7.02–6.94(m,1H),6.87(t,J=9.4Hz,1H),4.66(s,1H),3.69–3.56(m,1H),3.48–3.28(m,2H),3.07(m,1H),3.04(s,3H),2.06(m,1H),1.92–1.67(m,3H),1.38(m,6H).
Embodiment 78:N-(2-morpholinyl-5-methylamine alkylsulfonyl benzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except substituting Isopropylamine with morpholine, 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes outside 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters, and other operations are with preparation EXAMPLE Example 17. 1H?NMR(300MHz,CDCl 3)δ7.94–7.78(m,3H),7.60(dd,J=8.3,3.3Hz,1H),7.08(d,J=6.6Hz,1H),4.79(m,2H),3.41(m,4H),3.16–3.06(m,1H),2.94(m,2H),2.70–2.61(m,3H),2.24(m,2H),2.04(m,3H),0.12–0.02(m,2H).
Embodiment 79:N-(2-morpholinyl-5-methylamine alkylsulfonyl benzoyl)-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting Isopropylamine with morpholine; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation EXAMPLE Example 17. 1H?NMR(300MHz,CDCl 3)δ7.90(t,J=7.5Hz,1H),7.84–7.75(m,1H),7.70(dd,J=6.9,1.9Hz,1H),7.48(dd,J=29.3,9.4Hz,1H),7.04(d,J=8.6Hz,1H),4.67(m,1H),3.79(m,4H),3.55(m,1H),3.42(m,1H),3.12(m,5H),2.62(s,3H),2.08(m,1H),1.92–1.63(m,2H),1.25(m,2H),1.04(m,2H).
Embodiment 80:N-(2-morpholinyl-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with morpholine; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(2; 4-difluoro benzoyl) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation EXAMPLE Example 17. 1H?NMR(400MHz,CDCl 3)δ7.89(d,J=7.0Hz,1H),7.81(dd,J=8.6,2.3Hz,1H),7.71(d,J=2.3Hz,1H),7.05(d,J=8.5Hz,1H),7.02–6.96(m,1H),6.92–6.85(m,1H),4.67(s,1H),4.50(q,J=5.3Hz,1H),3.82(m,4H),3.41(m,3H),2.98(m,3H),2.65(d,J=5.3Hz,3H),2.08(m,1H),1.99(s,1H),1.83(m,1H),1.71(m,1H).
Embodiment 81:N-[2-(1-cyclopentenyl)-5-methylamine alkylsulfonyl benzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting except 4-fluorobenzoic boric acid with cyclopentenes-1-pinacol borate, other operations are with preparation embodiment 65. 1H?NMR(300MHz,CDCl 3)δ7.85–7.73(m,2H),7.70–7.56(m,2H),7.48(m,1H),7.30–7.22(m,1H),7.09(td,J=8.8,1.9Hz,1H),6.19(d,J=28.3Hz,1H),4.76(m,1H),3.59–3.42(m,1H),3.31(m,2H),3.26–3.00(m,3H),2.68(s,3H),2.63–2.51(m,2H),2.26(m,1H),2.15–1.87(m,4H).
Embodiment 82:N-[2-(4-fluorophenyl)-5-methylsulfonylbenzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting 2-trifluoro-methanesulfonyl oxy-5-methylamine sulfonyl methyl benzoate with 2-trifluoro-methanesulfonyl oxy-5-methyl sulfonylbenzoic acid methyl esters; 4-(2; 4-difluoro benzoyl) piperidines substitutes 4-(6-fluoro-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 65. 1H?NMR(400MHz,CDCl 3)δ8.00(dd,J=8.2,2.2Hz,1H),7.98–7.93(m,1H),7.85–7.73(m,1H),7.63–7.56(m,1H),7.48(ddd,J=16.8,8.6,5.2Hz,2H),7.17(dd,J=15.4,8.5Hz,2H),7.00–6.91(m,1H),6.87–6.78(m,1H),4.52(dd,J=43.4,13.3Hz,1H),3.18(dd,J=28.7,12.4Hz,1H),3.14–3.07(m,3H),2.96–2.83(m,1H),2.75–2.64(m,1H),2.38(dt,J=13.8,8.0Hz,1H),1.87(d,J=13.7Hz,1H),1.47(t,J=10.8Hz,2H).
Embodiment 83:N-[2-(4-fluorophenyl)-5-methylamine alkylsulfonyl benzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
Except substitute 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines with 4-(2,4 difluorobenzene formyl radical) piperidines outside, other operations are with preparation embodiment 65. 1H?NMR(400MHz,CDCl 3)δ7.95–7.90(m,1H),7.90–7.85(m,1H),7.85–7.74(m,1H),7.54(dd,J=15.0,6.4Hz,1H),7.47(ddd,J=16.3,8.6,5.2Hz,2H),7.16(dd,J=15.3,8.5Hz,2H),6.99–6.91(m,1H),6.83(ddd,J=11.0,8.6,2.3Hz,1H),4.89(s,1H),4.51(m,1H),3.29–3.16(m,1H),3.12(m,1H),2.94–2.82(m,1H),2.79(m,4H),2.66(s,3H),2.45–2.30(m,1H),1.86(m,2H),1.72–1.56(m,1H),1.46(m,2H),0.33(m,1H).
Embodiment 84:N-[2-(4-fluorophenyl)-5-methylsulfonylbenzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting except 2-trifluoro-methanesulfonyl oxy-5-methylamine sulfonyl methyl benzoate with 2-trifluoro-methanesulfonyl oxy-5-methyl sulfonylbenzoic acid methyl esters, other operations are with preparation embodiment 65. 1H?NMR(400MHz,CDCl 3)δ8.08–7.97(m,2H),7.65–7.54(m,2H),7.50(dd,J=8.7,5.2Hz,1H),7.21(dt,J=11.6,6.3Hz,3H),7.13–7.02(m,1H),4.65(m,1H),3.29(m,1H),3.13(m,3H),3.04–2.86(m,2H),2.05–1.92(m,2H),1.63(m,2H),1.51(m,1H).
Embodiment 85:N-[2-(3-thienyl)-5-methylamine alkylsulfonyl benzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting 4-fluorobenzoic boric acid with 3 thienylboronic acid, 4-(2,4 difluorobenzene formyl radical) piperidines substitutes outside 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines, and other operations are with preparation embodiment 65. 1H?NMR(400MHz,CDCl 3)δ7.88(ddd,J=10.4,5.2,2.3Hz,1H),7.84–7.81(m,1H),7.81–7.74(m,1H),7.62(d,J=8.2Hz,1H),7.51(ddd,J=18.6,5.6,4.1Hz,1H),7.44(ddd,J=10.2,5.0,2.9Hz,1H),7.28(dt,J=11.2,1.8Hz,1H),6.95(t,J=8.2Hz,1H),6.83(ddd,J=11.1,8.6,2.4Hz,1H),4.97(s,1H),4.71(m,1H),3.29–3.04(m,3H),2.97–2.83(m,2H),2.65(s,3H),2.53–2.39(m,1H),1.88(m,1H),1.54–1.39(m,2H),1.33(m,1H).
Embodiment 86:N-[2-(3-thienyl)-5-methylamine alkylsulfonyl benzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting except 4-fluorobenzoic boric acid with 3 thienylboronic acid, other operations are with preparation embodiment 65. 1H?NMR(400MHz,CDCl 3)δ7.95–7.90(m,1H),7.90–7.85(m,1H),7.64(dd,J=8.1,2.4Hz,1H),7.59(dt,J=4.4,2.3Hz,1H),7.59–7.52(m,1H),7.45(ddd,J=13.6,6.8,3.9Hz,2H),7.32(ddd,J=19.7,5.0,1.2Hz,1H),7.23(dd,J=8.4,1.9Hz,1H),7.06(tt,J=8.8,2.3Hz,1H),4.86–4.69(m,2H),3.33(m,1H),3.14(m,1H),3.08–2.87(m,2H),2,83(s,3H),2.69(m,3H),2.08(m,1H),1.89–1.88(m,1H),1.84(s,1H),1.87–1.75(m,1H),1.73–1.54(m,2H),0.71(m,1H).
Embodiment 87:N-[2-(the fluoro-1-propoxy-of 1H, 1H-five)-5-methylamine alkylsulfonyl benzoyl]-4-(6-methyl fluoride-1,2-benzoisoxazole-3-base) piperidines
Except with 1H; the fluoro-1-propyl alcohol of 1H-five substitutes Virahol; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(6-methyl fluoride-1; 2-benzoisoxazole-3-base) piperidines substitutes outside 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines, and other operations are with preparation embodiment 26. 1H?NMR(400MHz,DMSO)δ7.90(ddd,J=17.1,15.6,8.7Hz,1H),7.82(ddd,J=8.6,6.3,2.3Hz,1H),7.61(dd,J=33.0,2.2Hz,1H),7.49–7.38(m,3H),7.24(td,J=8.5,2.4Hz,1H),4.99(m,2H),4.47(m,1H),3.44(m,1H),3.29(m,1H),3.09(m,1H),2.91(m,1H),2.69(m,3H),2.40(m,3H),1.91(m,1H),1.73(m,1H),1.57–1.34(m,2H).
Embodiment 88:N-(2-ring third methoxyl group-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except with cyclopropyl-carbinol displaced loop amylalcohol; 2-hydroxy-5-methyl sulfamic methyl benzoate substitutes 2-hydroxyl-5-nitrobenzene methyl; 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines substitutes 4-(2; 4-difluoro benzoyl) outside piperidines, other operations are with preparation embodiment 3. 1H?NMR(400MHz,CDCl 3)δ7.88–7.73(m,2H),7.70–7.59(m,1H),7.27(d,J=4.7Hz,1H),7.08(dd,J=15.7,7.0Hz,1H),6.97(d,J=8.5Hz,1H),4.81(dd,J=24.7,13.5Hz,1H),4.51(s,1H),3.91(m,2H),3.63(m,1H),3.44–3.26(m,2H),3.14(m,2H),2.65(s,3H),2.21(m,2H),2.05(m,3H),1.69(m,2H),0.87(m,1H),0.65(m,2H),0.43–0.24(m,2H).
Embodiment 89:N-(2-isopropylamine base-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting except 2-fluorine-5-nitro benzoic acid methyl esters with 2-fluoro-5-methylamine sulfonyl methyl benzoate, other operations are with preparation embodiment 6. 1H?NMR(400MHz,CDCl 3)δ7.87(td,J=8.6,6.6Hz,1H),7.67(dd,J=8.9,2.2Hz,1H),7.54(d,J=2.2Hz,1H),7.03–6.94(m,1H),6.88(ddd,J=11.1,8.6,2.4Hz,1H),6.71(d,J=8.9Hz,1H),4.17(m,2H),3.68(m,1H),3.38(m,1H),3.13(m,2H),2.80(m,3H),2.60(s,3H),1.99(m,2H),1.80–1.61(m,2H),1.25(m,6H).
Embodiment 90:N-(2-isopropylamine base-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting outside 4-(2,4 difluorobenzene formyl radical) piperidines with 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines, other operations are with preparation embodiment 89. 1H?NMR(400MHz,CDCl 3)δ7.72–7.66(m,2H),7.63(dd,J=8.7,5.0Hz,1H),7.60(d,J=2.2Hz,1H),7.55–7.50(m,1H),7.27(q,J=2.2Hz,1H),7.09(td,J=8.8,2.1Hz,1H),6.73(d,J=8.9Hz,1H),4.28(m,1H),4.26–4.13(m,2H),3.70(m,1H),3.45–3.32(m,1H),3.25(m,2H),2.61(s,3H),2.26–2.09(m,2H),2.01(m,3H),1.73–1.57(m,2H),1.48–1.37(m,2H),1.33(m,4H),1.25(m,6H),0.95–0.81(m,4H).
Embodiment 91:N-[2-(2-methylpyrrole alkyl)-5-methylamine alkylsulfonyl benzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with 2-crassitude; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(2; 4-difluoro benzoyl) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.94–7.81(m,1H),7.66(d,J=8.9Hz,2H),6.99(dd,J=10.7,8.5Hz,1H),6.89(dd,J=11.1,8.7Hz,1H),6.81(s,1H),4.64(s,1H),4.30(s,1H),3.95(m,1H),3.59(m,1H),3.04(s,2H),2.79(m,1H),2.62(s,3H),2.27–2.14(m,1H),2.00(m,3H),1.71(s,3H),1.26–1.16(m,4H).
Embodiment 92:N-[2-(2-methylpyrrole alkyl)-5-methylsulfonylbenzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
Except substitute 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines with 4-(2,4 difluorobenzene formyl radical) piperidines outside, other operations are with preparation embodiment 66. 1H?NMR(300MHz,CDCl 3)δ7.95–7.83(m,1H),7.72(m,1H),7.00(m,1H),6.88(m,1H),6.82–6.70(m,1H),4.84–4.52(m,1H),4.14–3.86(m,2H),3.56–3.20(m,3H),3.01(s,3H),2.29–2.15(m,1H),2.04(s,2H),1.82(s,2H),1.68(m,3H),1.33–1.24(m,2H),1.21(m,3H).
Embodiment 93:N-(2-isopropyisulfanyl-5-methylsulfonylbenzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting 2-isopropoxy-5-nitrobenzene methyl with 2-isopropyisulfanyl-5-methyl sulfonylbenzoic acid methyl esters; 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines substitutes outside 4-(2,4 difluorobenzene formyl radical) piperidines, and other operations are with preparation embodiment 1. 1H?NMR(400MHz,CDCl 3)δ7.87(dd,J=8.3,2.1Hz,1H),7.67(s,1H),7.52(d,J=8.3Hz,1H),7.29–7.23(m,1H),7.07(s,1H),4.80(s,1H),3.68(s,1H),3.53(s,1H),3.38(td,J=11.1,5.7Hz,1H),3.19(dd,J=26.1,11.3Hz,2H),3.06(s,3H),2.82(s,1H),2.32–2.15(m,2H),2.03(s,2H),1.41(t,J=7.7Hz,6H).
Embodiment 94:N-(2-isopropyisulfanyl-5-methylamine alkylsulfonyl benzoyl)-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting except 2-fluoro-5-methanesulfonyl-benzoic acid methyl esters with 2-fluoro-5-methylamine alkylsulfonyl-methyl benzoate, other operations are with preparation embodiment 93. 1H?NMR(400MHz,CDCl 3)δ7.79(d,J=7.8Hz,1H),7.69(s,2H),7.48(d,J=8.1Hz,1H),7.27(d,J=7.0Hz,1H),7.07(s,1H),4.81(s,1H),4.54(s,1H),3.61(m,2H),3.29(m,3H),2.86(s,1H),2.71(s,3H),2.23(s,2H),2.02(s,2H),1.36(m,6H),0.06(s,1H).
Embodiment 95:N-(2-piperidyl-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with piperidines; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(2; 4-difluoro benzoyl) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(300MHz,CDCl 3)δ7.86(s,1H),7.78–7.62(m,2H),6.97(m,2H),6.87(t,J=10.0Hz,1H),4.67(m,2H),3.42(mz,1H),3.27(m,3H),2.92(m,3H),2.79(s,3H),2.62(d,J=5.3Hz,3H),2.02(m,1H),1.77(m,2H),1.64(m,6H).
Embodiment 96:N-(2-isopropyisulfanyl-5-methylamine alkylsulfonyl benzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except with 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) piperidines substitutes 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines; 2-isopropyisulfanyl-5-methylamine sulfonyl benzoic acid replaces outside 2-isopropyisulfanyl-5-methyl sulfonylbenzoic acid, and other operations are with preparation embodiment 93. 1H?NMR(400MHz,CDCl 3)δ7.88(m,2H),7.78(m,1H),7.72(m,1H),7.57(m,1H),7.49(d,J=8.3Hz,1H),4.78(m,2H),3.72–3.38(m,3H),3.23(m,2H),2.65(s,3H),2.33–2.18(m,2H),2.08(m,2H),1.43–1.33(m,6H).
Embodiment 97:N-(2-isopropyisulfanyl-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except with 4-(2; 4-difluoro benzoyl) piperidines substitutes 4-(6-fluoro-1; 2-benzoisoxazole-3-base) piperidines, 2-isopropyisulfanyl-5-methylamine sulfonyl benzoic acid replaces outside 2-isopropyisulfanyl-5-methyl sulfonylbenzoic acid, and other operations are with preparation embodiment 93. 1H?NMR(400MHz,DMSO)δ7.91(dd,J=15.7,8.1Hz,1H),7.75–7.67(m,2H),7.53(m,2H),7.43(m,1H),7.25(td,J=8.4,2.3Hz,1H),4.48(m,1H),3.75(m,1H),3.43(m,1H),3.25(m,1H),3.14(m,1H),2.97(m,1H),2.74(s,3H),2.42(m,3H),2.02–1.89(m,1H),1.76(m,1H),1.51(m,2H),1.26(m,6H).
Embodiment 98:N-(2-isopropylamine base-5-methylamine alkylsulfonyl benzoyl)-4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines
Except substituting outside 4-(2,4 difluorobenzene formyl radical) piperidines with 4-(6-Trifluoromethyl-1,2-benzoisoxazole-3-base) piperidines, other operations are with preparation embodiment 89. 1H?NMR(400MHz,CDCl 3)δ7.88(s,1H),7.83(d,J=8.3Hz,1H),7.69(dd,J=8.9,2.2Hz,1H),7.61(d,J=2.2Hz,1H),7.58(d,J=8.4Hz,1H),6.74(d,J=8.9Hz,1H),4.32(m,2H),3.70(m,1H),3.49–3.39(m,1H),3.27(m,2H),2.62(s,3H),2.28–2.15(m,2H),2.04(m,3H),1.25(m,6H).
Embodiment 99:N-[2-(1-cyclohexenyl)-5-methylamine alkylsulfonyl benzoyl]-4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines
Except substituting 4-fluorobenzoic boric acid with tetrahydrobenzene-1-pinacol borate, 4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-) piperidines substitutes outside 4-(2,4 difluorobenzene formyl radical) piperidines, and other operations are with preparation embodiment 83. 1H?NMR(300MHz,CDCl 3)δ7.79(m,2H),7.67(m,1H),7.62–7.51(m,1H),7.50–7.44(m,1H),7.41(dd,J=8.4,3.3Hz,1H),7.27(d,J=5.6Hz,1H),7.09(td,J=8.8,2.1Hz,1H),5.95(d,J=17.3Hz,1H),4.76(m,1H),4.48(m,1H),3.51(m,1H),3.31(m,1H),3.21–2.94(m,2H),2.69(s,3H),2.49(m,1H),2.17(m,3H),1.97(m,2H),1.75(m,2H),1.67(m,2H).
Embodiment 100:N-[2-(1-cyclohexenyl)-5-methylamine alkylsulfonyl benzoyl]-4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines
Except substituting 4-fluorobenzoic boric acid with tetrahydrobenzene-1-pinacol borate, 4-(the fluoro-4-TRIFLUOROMETHYLBENZOYL of 2-) piperidines substitutes outside 4-(2,4 difluorobenzene formyl radical) piperidines, and other operations are with preparation embodiment 83. 1HNMR(300MHz,CDCl 3)δ7.88(dd,J=17.4,10.9Hz),7.76(dd,J=20.6,8.2Hz),7.45–7.34(m),7.05–6.82(m),5.93(d,J=26.6Hz),4.68(d,J=9.6Hz),3.39(s),3.11–2.87(m),2.68(s),2.49(s),2.20(s),2.03(s),1.88–1.59(m).
Embodiment 101:N-(2-ring butylamine base-5-methylamine alkylsulfonyl benzoyl)-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting Isopropylamine with ring butylamine; 2-fluoro-5-methylamine sulfonyl methyl benzoate substitutes outside 2-fluoro-5-methyl sulfonylbenzoic acid methyl esters; 4-(2; 4-difluoro benzoyl) piperidines substitutes 4-(6-Trifluoromethyl-1; 2-benzoisoxazole-3-base) outside piperidines, other operations are with preparation embodiment 17. 1H?NMR(400MHz,CDCl 3)δ7.87(td,J=8.5,6.7Hz,1H),7.65(dd,J=8.8,2.2Hz,1H),7.54(d,J=2.2Hz,1H),7.02–6.95(m,1H),6.88(ddd,J=11.1,8.6,2.3Hz,1H),6.58(d,J=8.9Hz,1H),4.41(s,1H),3.98–3.85(m,1H),3.38(m,1H),3.13(m,2H),2.58(s,3H),2.48–2.37(m,2H),2.05–1.78(m,6H),1.77–1.64(m,3H).
Embodiment 102:N-[2-(1-cyclohexenyl)-5-methylamine alkylsulfonyl benzoyl]-4-(2,4 difluorobenzene formyl radical) piperidines
Except substituting except 4-fluorobenzoic boric acid with tetrahydrobenzene-1-pinacol borate, other operations are with preparation embodiment 83. 1H?NMR(300MHz,CDCl 3)δ7.88(dd,J=17.4,10.9Hz),7.76(dd,J=20.6,8.2Hz),7.45–7.34(m),7.05–6.82(m),5.93(d,J=26.6Hz),4.68(d,J=9.6Hz),3.39(s),3.11–2.87(m),2.68(s),2.49(s),2.20(s),2.03(s),1.88–1.59(m).
Embodiment 103:N-(2-trifluoro isopropoxy-5-methylsulfonyl benzoyl)-4-(5-fluorine pyridine-2-formyl radical) piperidines
4-(formyl radical-N, O-dimethyl hydroxyl-N-(tertiary butyl acyl group) piperidines
By 5g (21.8mmol) N-tertiary butyl oxygen base formyl piperidine-4-formic acid; 2.4g (24.0mmol) N; O-dimethyl hydroxylamine; 10.8g (28.4mmol) HATU, is dissolved in 40mL methylene dichloride, adds 9.1mL (65.4mmol) triethylamine; react 5h under room temperature after; reaction terminates, and reaction solution is directly gone up quick preparative column purifying and obtain product 5.05g, yield is 85%. 1H?NMR(400MHz,CDCl 3)δ4.16–4.05(m,2H),3.68(s,3H),2.80(s,3H),2.74-2.50(m,3H),1.72–1.57(m,4H),1.42(s,9H).
2-trifluoro isopropoxy-5-methyl sulfonylbenzoic acid
Fluoro-for 2.18g (10.0mmol) 2-5-methyl sulfonylbenzoic acid is dissolved in 30mL N; in N-N,N-DIMETHYLACETAMIDE; add 5.7g (50mmol) Trifluoroisoproanol and 9.8g (30mmol) cesium carbonate; react 4h under 150 ° of C after; reaction terminates; by the N in reaction solution; N-N,N-DIMETHYLACETAMIDE removes under reduced pressure; add water with concentrated hydrochloric acid adjustment about pH to 2; separate out white solid; filtering drying obtains 2-trifluoro isopropoxy-5-methyl sulfonylbenzoic acid 2.5g, and yield is 80%. 1H?NMR(300MHz,DMSO-d6)δ7.73(dd,J=7.6,2.2Hz,1H),7.36(m,1H),6.95(dd,J=10.4,8.2,Hz,1H)
4-(5-fluorine pyridine-2-formyl radical)-N-(tertiary butyl oxygen base formyl radical) piperidines
By iodo-for 500mg (2.24mmol) 2-5 fluorine pyridines in 8mL tetrahydrofuran (THF), nitrogen protection is taken a breath 3 times, is cooled to-78oC, and drip 1.0mL (2.0mmol, 2.0M) isopropylmagnesium chloride and drip off for 15 minutes, temperature keeps below-75 ° of C.Then reaction is raised to-60 ° of C in 30 minutes.1.5h is reacted again at normal temperature.487mg (1.78mmol) 4-(formyl radical-N, O-dimethyl hydroxylamine)-N-(tertiary butyl oxygen base formyl radical) piperidines drips in 2mL tetrahydrofuran (THF).At normal-temperature reaction 1.5h.Add saturated ammonium chloride cancellation, extraction into ethyl acetate, saturated common salt is washed, and dried over mgso, the quick preparative column purifying of evaporate to dryness obtains product 115m g, and yield is 12%.
1H?NMR(300MHz,CDCl 3)δ8.50(d,J=2.8Hz，2H),,8.11(dd,J=8.7,4.7Hz,1H),7.53(td,J=8.3,2.8Hz,1H),4.17(d,J=13.3Hz,2H),4.03–3.89(m,1H),2.91(td,J=13.3,2.7Hz，2H),1.88(d,J=11.0Hz,2H),1.72–1.57(m,2H),1.47(s,9H).
N-(2-trifluoro isopropoxy-5-methylsulfonyl benzoyl)-4-(5-fluorine pyridine-2-formyl radical) piperidines
By 110mg4-(5-fluorine pyridine-2-formyl radical)-N-(tertiary butyl oxygen base formyl radical) piperidines in methylene dichloride/trifluoroacetic acid=9:1 (10mL), normal-temperature reaction 1.5h.Evaporate to dryness obtains the trifluoroacetate of 4-(5-fluorine pyridine-2-formyl radical) piperidines.Get the trifluoroacetate of 68mg (0.21mmol) 4-(5-fluorine pyridine-2-formyl radical) piperidines; add 66mg (0.21mmol) 2-trifluoro isopropoxy-5-methyl sulfonylbenzoic acid and 104mg (0.27mmol) HATU in 6mL N; in dinethylformamide, then add 88uL (0.68mmol) triethylamine.Normal-temperature reaction 3 hours.Add saturated ammonium chloride and water, extraction into ethyl acetate, salt is washed, dried over mgso.The quick preparative column purifying of evaporate to dryness obtains product 90mg, and yield is 85%
1HNMR(300MHz,CDCl 3)δ8.50(d,J=2.7Hz，1H),8.12(dd,J=8.7,4.6Hz,1H),8.02–7.82(m,2H),7.53(td,J=8.4,2.7Hz,2H),7.20–7.03(m,1H),4.85-4.72(m,,2H),4.16–4.02(m,1H),3.56–3.40(m，1H),3.18-3.22(m,1H),3.06(d,J=1.8Hz,3H),2.07(d,J=11.0Hz,1H),1.89–1.71(m,3H),1.68–1.49(m,3H).
Embodiment 104:N-(2-trifluoro isopropoxy-5-methylsulfonyl benzoyl)-4-(4-5-flumethiazine-2-formyl radical) piperidines
Except substituting except 2-iodo-5-fluorine pyridine with 2-bromo-4-5-flumethiazine, other operations are with preparation embodiment 103. 1HNMR(300MHz,CDCl 3)δ8.88(d,J=4.9Hz，1H),8.28(s,1H),7.93(dd,J=15.8,8.7Hz,2H),7.72(d,J=4.8Hz,1H),7.12(dd,J=9.6,5.6Hz,1H),4.92–4.68(m,2H),4.11(dd,J=9.0,5.3Hz,1H),3.50(d,J=10.5Hz,1H),3.34–2.98(m,5H),2.10(d,J=12.4Hz,1H),1.82(d,J=18.8Hz,3H),1.60–1.47(m,3H).
Embodiment 105:N-(2-trifluoro isopropoxy-5-methylsulfonyl benzoyl)-4-(5-5-flumethiazine-2-formyl radical) piperidines
4-(5-5-flumethiazine-2-first)-N-(tertiary butyl formyl radical) piperidines
By bromo-for 500mg (2.21mmol) 2-5-5-flumethiazine in 8mL ether, nitrogen protection is taken a breath 3 times, is cooled to-78 ° of C, and drip 1.1mL (2.2mmol, 2.2M) n-Butyl Lithium and drip off for 15 minutes, temperature keeps below-75 ° of C.Then react 15 minutes.481mg (1.77mmol) 4-(formyl radical-N, O-dimethyl hydroxylamine)-N-(tertiary butyl oxygen base formyl radical) piperidines drips in 2mL ether, and temperature keeps below-75 ° of C.React after 90 minutes, be raised to ambient temperature overnight.Add saturated ammonium chloride cancellation, extraction into ethyl acetate, saturated common salt is washed, and dried over mgso, the quick preparative column purifying of evaporate to dryness obtains product 150m g, and yield is 26%. 1hNMR (300MHz, CDCl 3) δ 8.97 – 8.92 (m, 1H), 8.11 (dt, J=8.2,5.0Hz, 2H), 4.18 (d, J=13.0Hz, 2H), 4.00 (ddd, J=15.1,7.5,3.6Hz, 2H), 2.93 (t, J=11.6Hz, 2H), 1.90 (d, J=12.7Hz, 2H), 1.64 (dd, J=13.0,4.2Hz, 2H), 1.47 (d, J=2.6Hz, 9H).
N-(2-trifluoro isopropoxy-5-methylsulfonyl benzoyl)-4-(5-5-flumethiazine-2-formyl radical) piperidines
Except substituting except 4-(5-fluorine pyridine-2-formyl radical)-N-(tertiary butyl oxygen base formyl radical) piperidines with 4-(5-5-flumethiazine-2-formyl radical)-N-(tertiary butyl oxygen base formyl radical) piperidines, other operations are with preparation embodiment 103. 1HNMR(400MHz,CDCl 3)δ8.94(s,1H),8.14(dd,J=25.1,8.2H,2H),8.01–7.83(m,2H),7.13(dd,J=18.2,8.6Hz,1H),4.88–4.70(m,2H),4.11(d,J=10.2Hz,1H),3.47(s,1H),3.20(d,J=12.7Hz,1H),3.10-3.05m,4H),2.10(d,J=12.6Hz,1H),1.87(d,J=13.9Hz,1H),1.74(d,J=9.6Hz,2H),1.66–1.47(m,3H).
Embodiment 106:N-(2-trifluoro isopropoxy-5-methylsulfonyl benzoyl)-4-(6-5-flumethiazine-2-formyl radical) piperidines
Except substituting except the iodo-5 fluorine pyridines of 2-with 2-iodo-6-5-flumethiazine, other operations are with preparation embodiment 103. 1HNMR(400MHz,CDCl 3)δ8.22(d,J=7.9Hz，1H),8.06(t,J=7.9Hz,1H),7.98–7.92(m,1H),7.92–7.84(m,2H),7.18–7.05(m,1H),4.86-4.72(m,2H),4.16–4.06(m,1H),3.47(d,J=7.7Hz，1H),3.29–3.16(m,1H),3.12-3.06(m,4H),2.12-2.09(m,1H),1.96–1.85(m,2H),1.81–1.70(m，1H),1.65–1.51(m,3H).
Embodiment 107:N-(2-trifluoro isopropoxy-5-methylsulfonyl benzoyl)-4-(6-5-flumethiazine-3-formyl radical) piperidines
Except substituting except 2-iodo-5-fluorine pyridine with 3-bromo-6-5-flumethiazine, other operations are with preparation embodiment 103. 1HNMR(400MHz,CDCl 3)δ9.23(d,J=5.5Hz,1H),8.40(d,J=8.1Hz,1H),8.00–7.81(m,3H),7.18–7.05(m,1H),4.82-4.70(m,2H),3.59–3.46(m,2H),3.29–3.01(m,2H),2.96(s,3H),,2.06(d,J=14.4Hz,1H),1.86-1.80(m,3H),1.67–1.49(m,3H).
Embodiment 108:N-(2-trifluoro isopropoxy-5-methylsulfonyl benzoyl)-4-(2-5-flumethiazine-4-formyl radical) piperidines
Except substituting except 2-iodo-5-fluorine pyridine with 2-trifluoromethyl-4-iodine pyridine, other operations are with preparation embodiment 103. 1HNMR(300MHz,CDCl 3)δ8.96(d,J=4.9Hz,1H),8.08(s,1H),8.05–7.85(m,3H),7.20–7.06(m,1H),4.81-4.78(m,2H),3.58–3.45(m,2H),3.30–3.11(m,2H),3.08(d,J=4.6Hz,3H),2.04(d,J=13.6Hz,1H),1.84(d,J=9.4Hz,2H),1.72-1.68(m,1H),1.65–1.50(m,3H).
Pharmacological experiment:
The GlyT-1 inhibit activities test of the piperidines shown in general formula of the present invention (I) is as follows:
1, experiment material
(1) isotropic substance: [ 3h] Glycine;
(2) the rat C 6 cells system of natural expression glycine transporter;
(3) other: GF/C glass fiber filter paper; Fat-soluble scintillation solution.
2, sample preparation
Take about 1mg compound, add the DMSO of corresponding dosage respectively, concentration is 10 -2m.Before use, dilute for corresponding concentration with HS damping fluid.Most of sample dissolves completely in DMSO, and after adding damping fluid, diluent is clarified, without obviously muddiness, precipitation produce.
3, experimental system detects and positive compound related data mensuration
(1) C6 cell is inoculated in 24 orifice plates respectively;
Etc. (2), after cytogamy degree reaches 80-90%, experiment is started;
(3) liquid in plate is discarded;
(4) each hole adds 160 μ L HB damping fluids.Then (final concentration is respectively: 10 to add the positive drug of 20 μ L different concns -10, 10 -9, 10 -8, 10 -7, 10 -6, 10 -5m).20 μ L HB are added in total picked-up hole;
(5) 20 μ L radio isotope (about cpm:20000) are added again;
(6), after vibrating a little, 30 ° of C hatch 30 minutes;
(7) liquid in plate is discarded.Twice is washed with ice-cold HB.Suck all liquid in plate;
(8) every hole adds 100 μ L2M NaOH, makes lysis.And all split products, be placed in GF/C glass fiber filter paper;
(9) after filter paper is dried, be placed in 0.5mL centrifuge tube, add the fat-soluble scintillation solution of 500 μ L, measure intensity of radioactivity by MicroBeta liquid scintillation counter.The multiple pipe of each concentration determination 3, carries out 2 independent experiments;
(10) test-compound screening
Be tested concentration with 10 μm of ol/L, each experiment positive compound provided arranges contrast (10 μm of ol/L).Laboratory operating procedures is identical with above-mentioned steps;
(11) inhibiting rate calculates
Inhibiting rate=(total intake-testing compound intake) × 100%/(total intake-non-specific uptake amount).
The GlyT-1 inhibit activities of part of compounds
Embodiment IC 50(nM) Embodiment IC 50(nM) Embodiment IC 50(nM)
12 471310 4951 26817 7980 7680
3 87 52 172 83 2068
4 38 53 506 84 741
5 162 54 72 85 272
9 85 55 311 86 363
12 1855 56 608 88 122
24 2790 57 955 89 117
25 461 61 572 91 409
30 30 62 526 92 916
31 185 63 496 96 585
32 2870 64 109 97 115
36 533 70 501 100 9
38 499 71 159 101 736
41 161 72 1419 ? ?
Test result explanation in above table, piperidines shown in general formula of the present invention (I) and acceptable salt pair GlyT-1 thereof have good restraining effect, and the clinical treatment of this compounds to the symptom such as schizophrenia, cognitive disorder has good application prospect.

Claims (10)

1. the piperidines shown in the following general formula of a class (I) or its pharmacy acceptable salt:
Wherein, R 1for not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkoxyl group; Not replace or by halogen, C 3-7the C of cycloalkyl substituted 1-7alkylthio; Not replace or by C 1-7alkyl, C 3-7the amino of cycloalkyl substituted; C 3-7cycloalkyl oxy; C 4-7cycloalkenyl group; Not replace or by halogen, C 1-6the C6-C10 aryl that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heteroaryl be selected from containing 1-3 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-6the heteroatomic 5-7 unit heterocyclic radical be selected from containing 1-3 in N, O and S that alkyl replaces;
R 2for nitro, C 1-7alkyl sulphonyl, C 1-7alkylamino radical alkylsulfonyl;
R 3for hydrogen, halogen, trifluoromethyl, cyano group, ethanoyl;
R 4for hydrogen, halogen, trifluoromethyl, cyano group, ethanoyl;
Z is O;
A, B, D, E and F are CH; Or one in A, B, D, E and F is N, and all the other are CH;
Or, Z and R 4and adjacent atom is formed together
2. piperidines according to claim 1 or its pharmacy acceptable salt, wherein,
R 1for not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkoxyl group; Not replace or by halogen, C 3-6the C of cycloalkyl substituted 1-4alkylthio; Not replace or by C 1-4alkyl, C 3-6the amino of cycloalkyl substituted; C 3-6cycloalkyl oxy; C 5-6cycloalkenyl group; Not replace or by halogen, C 1-2the phenyl that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heteroaryl be selected from containing 1-2 in N, O and S that alkyl replaces; Not replace or by halogen, C 1-2the heteroatomic 5-6 unit heterocyclic radical be selected from containing 1-2 in N, O and S that alkyl replaces;
R 2for nitro, C 1-4alkyl sulphonyl, C 1-4alkylamino radical alkylsulfonyl;
R 3for hydrogen, halogen, trifluoromethyl, cyano group, ethanoyl;
R 4for hydrogen, halogen, trifluoromethyl, cyano group, ethanoyl;
Z is O;
A, B, D, E and F are CH; Or one in A, B, D, E and F is N, and all the other are CH;
Or, Z and R 4and adjacent atom is formed together
3. piperidines according to claim 2 or its pharmacy acceptable salt, wherein,
R 1for isopropoxy, isobutoxy, cyclo propyl methoxy, 1-trifluoromethyl oxyethyl group, 2,2,3, the fluoro-1-propoxy-of 3,3-five, isopropyisulfanyl, isopropylamino, i-butylamino, Cyclobutylamino, Cyclohexylamino, cyclopentyloxy, cyclopentenyl, cyclohexenyl, to fluorophenyl, thienyl, pyrrolidyl, 2-methylpyrrole alkyl, piperidyl, morpholinyl, thio-morpholinyl;
R 2for nitro, methylsulfonyl, methylamine alkylsulfonyl;
R 3for hydrogen, fluorine or trifluoromethyl;
R 4for hydrogen or fluorine;
Z is O;
A, B, D, E and F are CH; Or one in A, B, D, E and F is N, and all the other are CH;
Or, Z and R 4and adjacent atom is formed together
4. the piperidines according to any one of claim 1-3 or its pharmacy acceptable salt, wherein, the piperidines shown in general formula (I) be following general formula (II), (III), (IV), (V), the piperidines shown in (VI) or (VII):
Wherein, R 1, R 2, R 3and R 4definition require with respective right in definition identical.
5. piperidines according to claim 4 or its pharmacy acceptable salt, wherein,
Piperidines shown in described general formula (II) is the piperidines shown in following general formula (VIII):
Piperidines shown in described general formula (III) is the piperidines shown in following general formula (IX):
Wherein, R 1, R 2, R 3and R 4definition identical with the definition in claim 4.
6. piperidines according to claim 1 or its pharmacy acceptable salt, wherein, the piperidines shown in general formula (I) is selected from following compounds:
7. prepare a method for the piperidines according to any one of claim 1-6, described method comprises the steps:
Formula a compound and formula c compound are obtained by reacting the piperidines shown in general formula (I) under condensing agent exists,
Wherein, R 1, R 2, R 3, R 4, Z, A, B, D, E require with respective right with the definition of F in definition identical.
8. the piperidines according to any one of claim 1-6 or its pharmacy acceptable salt as the purposes in the medicine of GlyT-1 inhibitor in preparation, especially prevent in preparation or treat the purposes in the medicine of the disease mediated by GlyT-1.
9. purposes according to claim 9, the described disease mediated by GlyT-1 is schizophrenia or cognitive disorder.
10. a pharmaceutical composition, it comprises one or more and the pharmaceutically acceptable auxiliary material that are selected from piperidines according to any one of claim 1-6 and its pharmacy acceptable salt for the treatment of significant quantity.
CN201310217590.9A 2013-06-03 2013-06-03 Piperidine compounds, and preparation method, pharmaceutical compositions and use thereof Pending CN104211635A (en)

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