CN109912514B - (2-heteroarylaminophenyl) nitrogen heterocyclic derivative and application thereof - Google Patents
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Abstract
The invention discloses (2-heteroaryl aminophenyl) nitrogen heterocyclic derivatives, application thereof and a pharmaceutical composition containing the compounds, which can be used for inhibiting 5-hydroxytryptamine reuptake. The invention also relates to processes for the preparation of such compounds and pharmaceutical compositions, and their use in the treatment of central nervous system disorders, in particular affective disorders.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound and a pharmaceutical composition for treating central nervous system dysfunction, particularly affective disorder, and a using method and application thereof. In particular, the present invention relates to (2-heteroarylaminophenyl) azacyclic derivatives which are useful as 5-hydroxytryptamine reuptake inhibitors.
Background
5-hydroxytryptamine (5-HT), a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in Central Nervous System (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. The serotonin transporter (5-HT transporter, 5-HTT/serotonin transporter, SERT) is a transmembrane transporter with high affinity for 5-HT, which reuptakes serotonin from the synaptic cleft into presynaptic neurons, directly affecting the concentration of serotonin in the synaptic cleft.
Historically, the medical treatment of affective disorders began in the 50's of the 20 th century and included tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) which were mainly effective by blocking the action of neurotransmitters (dopamine, norepinephrine and 5-hydroxytryptamine). However, non-selective and undesirable side effects on targets limit their use. By the 80's of the 20 th century, the appearance of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) changed this situation. Such drugs are of comparable efficacy to TCAs, but have fewer side effects and less toxicity even when taken in excess (Sarko J. Andersessant, old and new. A review of the enzyme activities and toxicity in overdose. Emerg Med Clin North Am,2000 (4): 637-54). The selective 5-hydroxytryptamine reuptake inhibitor mainly has an inhibitory effect on 5-HT transporters, can effectively inhibit the presynaptic membrane of the central nervous system from absorbing 5-HT from synaptic clefts by combining with the 5-HT transporters, and increases the 5-HT which can be practically utilized in the gaps, thereby achieving the purpose of treatment.
Of all indications associated with 5-hydroxytryptamine dysfunction, depression is of prime importance, as it has been reported by the world health organization as the fourth most burdensome disease in humans. It is expected that disability from depression will jump to the second place in all diseases by the year 2020. (Bromet E, andlade LH, hwang I, et al, cross-national epidemic of DSM-IV major depressive epsilon. BMC Med.2011, 9.
However, clinical studies on depression have shown that the lack of response to known SSRIs is prominent, and another factor that is often ignored in antidepressant therapy is that the therapeutic effects of SSRIs are often delayed and sometimes symptoms worsen within the first few weeks of treatment. Furthermore, sexual dysfunction is a common side effect for SSRIs. Therefore, there is a need to develop compounds that can improve the treatment of depression and other 5-hydroxytryptamine related disorders.
The invention provides a new compound with 5-hydroxytryptamine reuptake inhibition activity, and the new compound has good clinical application prospect. Compared with the existing similar compounds, the compound of the invention has better drug effect, pharmacological property and/or toxicological property.
Disclosure of Invention
The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.
The present invention relates to a novel class of (2-heteroarylaminophenyl) nitrogen heterocycle derivatives having a strong binding affinity to the 5-HT transporter (SERT) and inhibiting 5-HT reuptake, and thus useful for the manufacture of a medicament for the treatment of disorders of the Central Nervous System (CNS), in particular for the treatment of affective disorders, including but not limited to depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorders, and post-traumatic stress disorder.
The compound has stable property, good safety and pharmacodynamic and pharmacokinetic advantages, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability and the like, thereby having good clinical application prospect.
The invention also provides processes for preparing such compounds and pharmaceutical compositions containing them.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 X and Y have the meanings given in the description.
In one embodiment, X may be CR x Or N.
In one embodiment of the process of the present invention,
is a single bond or a double bond.
In one embodiment, when
When it is a single bond, Y is N or CH.
In one embodiment, when
When it is a double bond, Y is C.
In one embodiment, R 1 、R 2 、R 3 And R x Each independently is H, D, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、 -SH、-COOH、-CONH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (= O) - (C) 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio radical, C 1 -C 6 Alkylamino or hydroxy substituted C 1 -C 6 An alkyl group.
In one embodiment, R 4 、R 5 、R 6 And R 7 Each independently of the other is H, D, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、 -COOH、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (= O) - (C) 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkoxy group.
In one embodiment, R 8 Is H, D, F, cl, br, I, -CN,-NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy or hydroxy substituted C 1 -C 6 An alkyl group.
In one embodiment, R 1 、R 2 、R 3 And R x Each independently of the other is H, D, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、 -SH、-COOH、-CONH 2 、-C(＝O)-(C 1 -C 4 Alkyl), -C (= O) - (C) 1 -C 4 Alkoxy group), C 1 -C 4 Alkyl radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkylthio radical, C 1 -C 4 Alkylamino or hydroxy substituted C 1 -C 4 An alkyl group.
In one embodiment, R 4 、R 5 、R 6 And R 7 Each independently is H, D, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、 -COOH、-C(＝O)NH 2 、C 1 -C 4 Alkyl radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy or C 1 -C 4 A haloalkoxy group.
In one embodiment, R 1 、R 2 、R 3 And R x Each independently of the other is H, D, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、 -SH、-COOH、-CONH 2 、-C(＝O)CH 3 、-C(＝O)OCH 3 Methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, R 4 、R 5 、R 6 And R 7 Each independently of the other is H, D, F, cl, br, I, -CN, -NO 2 、-NH 2 、-OH、 -COOH、-C(＝O)NH 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 or-CH 2 CF 3 。
In another embodiment, the compound of the present invention, which is a compound having one of the following structures or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of the compound having one of the following structures, or a prodrug thereof:
in another aspect, the invention relates to a pharmaceutical composition comprising a compound disclosed herein.
In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
In another embodiment, the pharmaceutical composition of the present invention further comprises a drug for treating central nervous system dysfunction, wherein the drug for treating central nervous system dysfunction is an antidepressant, an anxiolytic, a lithium salt drug as an affective stabilizer, an atypical antipsychotic, an antiepileptic, an anti-parkinson drug, a drug as a selective 5-hydroxytryptamine reuptake inhibitor, a central nervous stimulant, a nicotine antagonist, or any combination thereof.
In a still further embodiment of the process of the invention, the drug for treating the dysfunction of the central nervous system is amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), bupropion (bupapion), reboxetine (reboxetine), fluoxetine (fluoxetine), trazodone (trazodone), sertraline (sertraline), duloxetine (duloxetine), fluvoxamine (fluxamine), milnacipran (milnacipran), levomilnacipran (leflunomipran), desvenlafaxine (desvenlafaxine), vilazodone (vilazodone), venlafaxine (venlafafaxine), dapoxetine (dapoxetine), nefazodone (nefazodone), femoxetine (clomipramine), chlorpromazine (clomipramine), clomipramine (clomipramine) citalopram (citalopram), escitalopram (escitalopram), paroxetine (parooxetine), lithium carbonate (lithium carbonate), buspirone (buspirone), olanzapine (olanzapine), quetiapine (quetiapine), risperidone (risperidone), ziprasidone (zipasidone), aripiprazole (aripiprazole), piropiropirone (perospirrone), clozapine (clozapine), modafinil (modafinil), mecamylamine (mecamylamine), cabergoline (cabernine), adamantane (amantane), imipramine (imipramine), pramipexole (thyroxine), dextromethorphan (dextromethorphan), quinidine (quinaxdone), triptatridone (renone), and triptolide (risperidone) samimidophan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), pipamperone (pipamperone), vetipitant (vestipitant), chlordiazepoxide (chlorprizine), perphenazine (perphenazine) or any combination thereof.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction. For example, in one embodiment, the medicament is for preventing, treating or reducing central nervous system dysfunction in a mammal, and in another embodiment, the medicament is for preventing, treating or reducing central nervous system dysfunction in a human.
In one embodiment, the central nervous system disorder is depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, post-traumatic stress disorder, schizophrenia, sleep disorders, bipolar disorders, obsessive compulsive disorders, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction, and premenstrual tension syndrome.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for the prevention, treatment or alleviation of affective disorders.
In one embodiment, the affective disorder includes, but is not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, and post-traumatic stress disorder.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for inhibiting 5-hydroxytryptamine reuptake.
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Biological test results show that the compound has strong affinity to human 5-HT transporters (SERT), so that the compound provided by the invention can be used as a better selective 5-hydroxytryptamine reuptake inhibitor.
In addition, some of the compounds of the present invention have a combination of 5-hydroxytryptamine reuptake inhibition and norepinephrine reuptake inhibition, others of the compounds of the present invention have a combination of 5-hydroxytryptamine reuptake inhibition and dopamine reuptake inhibition, and still other compounds of the present invention have triple reuptake inhibition of 5-hydroxytryptamine, norepinephrine and dopamine.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
The following definitions as used herein should apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", thomas Sorrell, university Science Books, sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.
"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The term "optionally substituted with \8230; \8230, may be used interchangeably with the term" unsubstituted or substituted with \8230; \8230, i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, cl, br, I, N 3 ，-CN，-NO 2 ，-NH 2 ，-OH，-SH，-COOH，-CONH 2 ，-C(＝O)NHCH 3 ，-C(＝O)N(CH 3 ) 2 -C (= O) -alkyl, -C (= O) -alkoxy, alkyl, alkoxy, alkylthio, alkylamino, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxySubstituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.
In each part of this specification, substituents for the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C 1 -C 6 Alkyl "in particular denotes independently disclosed methyl, ethyl, C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 An alkyl group.
In each of the sections of the present invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
The term "alkyl" or "alkyl group" as used herein, means a saturated straight or branched chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms, wherein said alkyl radical may be optionally substituted with one or more substituents described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl group (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl group (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) Etc. etc。
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z".
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein the alkynyl radical may optionally be substituted with one or more substituents as described herein.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) And so on.
The term "alkylthio" denotes an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group has as defined in the present inventionThe above meanings are given. Unless otherwise specified, the alkylthio group contains 1 to 12 carbon atoms. In one embodiment, the alkylthio group contains 1 to 6 carbon atoms; in another embodiment, the alkylthio group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylthio group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein. Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH) 3 ) Ethylthio (EtS, -SCH) 2 CH 3 ) 1-propylthio (n-PrS, n-propylthio, -SCH) 2 CH 2 CH 3 ) 2-propylthio (i-PrS, i-propylthio, -SCH (CH) 3 ) 2 ) And so on.
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like. The alkylamino group is optionally substituted with one or more substituents described herein.
The term "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.
The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as set forth herein, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like. In one embodiment, C 1 -C 6 The haloalkyl group containing a fluorine-substituted C 1 -C 6 An alkyl group; in another embodiment, C 1 -C 4 Haloalkyl comprises fluorine-substituted C 1 -C 4 An alkyl group; in yet another embodiment, C 1 -C 2 Haloalkyl comprises fluorine-substituted C 1 -C 2 An alkyl group.
As described herein, the ring system (shown below) formed by the ring having substituent R attached to the center by a bond represents that substituent R may be substituted at any substitutable or reasonable position on the ring. For example, formula a represents the position of the substituent R at any possible position on the piperazine ring, such as formula a 1 -a 5 Shown in the figure:
the term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, which can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.
"metabolite" refers to the product of a particular compound or salt thereof that is metabolized in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: S.M. Berge et al, describe the descriptor of the pharmacological acceptable salts in detail in J. Pharmaceutical Sciences,1977, 66. The term "salts" refers to the term "salts" as used herein, unless otherwise specified. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valeric acid salts, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl radical) 4 A salt. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfationsSubstances, phosphates, nitrates, C 1 -C 8 Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in still other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of the disease or disorder.
The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and the severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.
The present invention relates to (2-heteroarylaminophenyl) azacyclic derivatives, pharmaceutically acceptable salts thereof, pharmaceutical formulations and compositions thereof which are useful as selective 5-hydroxytryptamine reuptake inhibitors, having potential use in the treatment of disorders of the central nervous system, particularly affective disorders including, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorders and post-traumatic stress disorders.
Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed within the scope of the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated and are encompassed by the present invention as disclosed compounds. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
The compounds of formula (I) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H、 3 H、 11 C、 13 C、 14 C、 15 N、 17 O、 18 O、 18 F、 31 P、 32 P、 35 S、 36 Cl and 125 I。
in another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or an individual stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic and/or prophylactic ingredients.
Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, ansel's pharmaceutical dosage Forms and Drug Delivery Systems (2004) Lippincott, williams & Wilkins, philidelphia; gennaro a.r.et al, remington: the Science and practice of Pharmacy (2000) Lippincott, williams & Wilkins, philadelphia; and Rowe R.C., handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, chicago.
It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.
Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) Parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppository; (5) inhalation, such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein can be formulated into an inhalation dosage form. In another embodiment, the disclosed compounds may be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.
The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets.
The pharmaceutical composition provided by the invention can be provided in a soft capsule or a hard capsule, and can be prepared from gelatin, methyl cellulose, starch or calcium alginate.
The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: the Science and Practice of Pharmacy, supra).
In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition.
Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3 (6), 318 (1986).
Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
Use of the Compounds and pharmaceutical compositions of the invention
The compounds and pharmaceutical compositions provided by the present invention can be used for preparing medicines for preventing, treating or relieving central nervous system dysfunction of mammals including human beings, and can also be used for preparing medicines for inhibiting reuptake of 5-hydroxytryptamine.
In particular, the amount of the compound in the pharmaceutical composition of the invention is effective to detectably and selectively inhibit reuptake of 5-hydroxytryptamine and the compounds of the invention are useful as medicaments for the treatment of Central Nervous System (CNS) disorders in humans, particularly affective disorders including, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, and post-traumatic stress disorder.
The compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment, or alleviation of central nervous system dysfunctional disorders by administering to a patient an effective amount of a compound or a pharmaceutical composition of the present invention. The central nervous system dysfunction responsive to 5-hydroxytryptamine regulation further includes, but is not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, post-traumatic stress disorder, schizophrenia, sleep disorders, bipolar disorders, obsessive-compulsive disorders, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms of drug addiction, premenstrual tension syndrome, and the like.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
In one embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these examples, but is provided only to practice the invention.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, guangdong Guanghua chemical reagent factory, guangzhou chemical reagent factory, tianjin Haojian Yunyu chemical Co., ltd, tianjin Shucheng chemical reagent factory, wuhan Xin Huayuan scientific and technological development Co., ltd, qingdao Tenglong chemical reagent Co., ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under a positive pressure of nitrogen or argon or by placing a drying tube over an anhydrous solvent (unless otherwise indicated), the reaction vial is stoppered with a suitable rubber stopper and the substrate is driven in by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao oceanic plants.
1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. 1 H NMR spectrum CDC1 3 、DMSO-d 6 、 CD 3 OD or acetone-d 6 TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad singleton), dd (doublet of doublets), dt (doublet of triplets). Coupling constant J, expressed in Hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: zorbax SB-C18, 2.1X 30mm,3.5 micron, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH with 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
Pure compounds were detected by UV at 210nm/254nm using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80 mm DAC).
The following acronyms are used throughout the invention:
BOC, boc tert-butoxycarbonyl min mmol, mM mmol
CH 2 Cl 2 DCM dichloromethane h hr μ M micromoles
CDC1 3 Deuterated chloroform 10% Pd/C10% palladium on carbon nM nanomolar
Micro g of DMSO dimethyl sulfoxide t-BuONa tert-butyl alcohol sodium
DMSO-d 6 Deuterated dimethyl sulfoxide Na 2 CO 3 Sodium carbonate, sodium acetate mg
EtOAc, EA ethyl acetate NaHCO 3 Sodium bicarbonate g
CH 3 OH, meOH methanol K 2 CO 3 Kg of Potassium carbonate
n-BuOH n-butanol Na 2 SO 4 Sodium sulfate PE Petroleum Ether (60-90 ℃ C.)
DMF N, N-dimethylformamide NaCl sodium chloride RT, RT, r.t. Room temperature
CF 3 Retention time of KCl potassium chloride Rt in COOH, TFA trifluoroacetic acid
Et 3 N Triethylamine HCl Saline hydrochloride normal Saline
(Boc) 2 O di-tert-butyl dicarbonate N 2 Nitrogen BSA bovine serum albumin
Toluene Toluene H 2 mL, mL of hydrogen
Tris (dibenzylideneacetone) dipalladium (0) Tris (dibenzylideneacetone) dipalladium Tris-HCl Tris (hydroxymethyl) aminomethane-hydrochloric acid
The following synthetic schemes describe the procedures for preparing the compounds disclosed herein, except as otherwise indicated, wherein each R is 1 、R 2 、R 3 、R 4 、R 5 、 R 6 、R 7 、R 8 X and Y have the definitions described herein.
Synthesis scheme 1
Formula (A), (B)4) The compounds shown can be prepared by synthesis scheme 1: containing different substituents 2-bromoaniline (a)1) By a coupling reaction to give a compound (2) Compound (A) to (B)2) Coupling with pyrimidinamines or pyridinamines having different substituents to give compounds3) Compound (A) to (B)3) Removing Boc protection under acidic condition to obtain target compound (4)。
Synthesis scheme 2
Wherein L is a leaving group: F. br is added.
Formula (A), (B) and4) The compounds shown can be prepared by synthesis scheme 2: anilines with different substituents (5) By coupling reaction to give a compound (6) Compound (A) to (B)6) Coupled with 2-chloropyrimidine or 2-chloropyridine with different substituents to obtain a compound (3) Compound (A) to (B)3) Removing Boc protection under acidic condition to obtain target compound (4)。
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated in the following examples.
Examples
Example 1 Synthesis of 4, 6-dimethyl-N- (2- (piperazin-1-yl) phenyl) pyrimidin-2-amine
Step 1) Synthesis of 1- (2-bromophenyl) piperazine
2-bromoaniline (10g, 58.13mmol), bis (2-chloroethyl) amine hydrochloride (10.37g, 58.13mmol) and potassium carbonate (16.05 g, 116.2 mmol) were added in this order to n-butanol (50 mL), and the reaction was warmed to 130 ℃ under a nitrogen atmosphere for 50 hours. The reaction was stopped, cooled to room temperature, the reaction solution was diluted with water (150 mL), extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 20) to give the title compound (brown oil, 7.01g, 50%).
MS(ESI,pos.ion)m/z:241.05[M+H] + ；
1 HNMR(600MHz,CDCl 3 )δ(ppm):7.62(dd,J＝7.9,1.3Hz,1H),7.29～7.21(m,1H),7.08(d,J＝7.2Hz,1H), 6.97～6.95(m,1H),3.48(t,4H),3.15～3.05(m,4H).
Step 2) Synthesis of 4- (2-bromophenyl) piperazine-1-carboxylic acid tert-butyl ester
1- (2-bromophenyl) piperazine (12g, 50mmol) and triethylamine (21mL, 150mmol) were added successively to dichloromethane (50 mL), followed by slow addition of di-tert-butyl dicarbonate (21.8g, 100mmol), and after completion of the addition, the reaction was carried out at room temperature for 2 hours. The reaction was stopped, and the reaction solution was washed with water (50 mL) and saturated brine (50 mL) in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the resulting crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (V: V) = 50) to give the title compound (colorless transparent oil, 6.82g, 40%).
MS(ESI,pos.ion)m/z:341.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.59(dd,J＝7.9,1.3Hz,1H),7.33～7.23(m,1H),7.05(d,J＝7.2Hz,1H), 6.97～6.93(m,1H),3.63(t,4H),3.00(t,4H),1.50(s,9H).
Step 3) Synthesis of tert-butyl 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate
Tert-butyl 4- (2-bromophenyl) piperazine-1-carboxylate (280mg, 0.82mmol), 4, 6-dimethylpyrimidin-2-amine (151mg, 1.23 mmol), sodium tert-butoxide (0.1lg, 1.111mmol), tris (dibenzylideneacetone) dipalladium (75mg, 0.082mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (102mg, 0.164mmol) were added in this order to anhydrous toluene (20 mL), and the reaction was allowed to warm to 120 ℃ for 12 hours under a nitrogen atmosphere. The reaction was stopped, cooled to room temperature, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (40 mL × 3), the organic phases were combined, washed successively with water (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (white solid, 274mg, 87%).
MS(ESI,pos.ion)m/z:384.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.61(d,J＝8.2Hz,1H),8.17(s,1H),7.18(t,J＝7.8Hz,1H),7.12(d,J＝ 7.8Hz,1H),6.97(t,J＝7.6Hz,1H),6.50(s,1H),3.67(t,4H),2.87(t,4H),2.40(s,6H),1.51(s,9H).
Step 4) Synthesis of 4, 6-dimethyl-N- (2- (piperazin-1-yl) phenyl) pyrimidin-2-amine
Tert-butyl 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate (200mg, 0.52mmol) was added to methylene chloride (6 mL), followed by trifluoroacetic acid (3 mL), and after the addition was completed, the reaction was allowed to react at room temperature for 1 hour. The reaction was stopped, and the reaction was quenched with a saturated sodium bicarbonate solution, extracted with dichloromethane (6 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 119mg, 81%).
MS(ESI,pos.ion)m/z:284.10[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm):9.83(s,1H),9.36(s,2H),8.31(d,J＝8.0Hz,1H),7.28(d,J＝7.7Hz, 1H),7.23(t,J＝7.5Hz,1H),7.17(t,J＝7.3Hz,1H),7.03(s,1H),3.48～3.45(m,4H),3.13～3.03(m,4H),2.51(s, 6H)；
13 C NMR(151MHz,DMSO-d 6 )δ(ppm):153.6,142.3,132.7,125.8,125.1,121.6,120.9,112.5,49.2,43.3,40.2； HPLC:99.8％.
EXAMPLE 24, synthesis of 6-dimethoxy-N- (2- (piperazin-1-yl) phenyl) pyrimidin-2-amine
Step 1) Synthesis of tert-butyl 4- (2- ((4, 6-dimethoxypyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate
The title compound was prepared by the method described in example 1, step 3, namely tert-butyl 4- (2-bromophenyl) piperazine-1-carboxylate (280mg, 0.82mmol), 4, 6-dimethoxypyrimidin-2-amine (191mg, 1.23mmol), sodium tert-butoxide (0.1lg, 1.116mmol), tris (dibenzylideneacetone) dipalladium (75mg, 0.082mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (102mg, 0.164mmol) in dry toluene (20 mL) under nitrogen protection at 120 ℃ for 12 hours. The obtained crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (white solid, 238mg, 70%).
MS(ESI,pos.ion)m/z:416.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.52(d,J＝8.2Hz,1H),8.15(s,1H),7.18(t,J＝7.8Hz,1H),7.13(d,J＝ 7.8Hz,1H),6.99(t,J＝7.6Hz,1H),5.61(s,1H),3.97(s,6H),3.67(t,4H),2.88(t,J＝4.6Hz,4H),1.52(s,9H).
Step 2) Synthesis of 4, 6-dimethoxy-N- (2- (piperazin-1-yl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (2- ((4, 6-dimethoxypyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate (200mg, 0.48mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 1 hour. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 121mg, 80%).
MS(ESI,pos.ion)m/z:316.10[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm):8.26(dd,J＝8.0,1.0Hz,1H),8.18(s,1H),7.22～7.11(m,2H),7.03(t,J ＝12,1H),5.68(s,1H),3.87(s,6H),3.32～3.22(m,4H),3.06～2.98(m,4H)；
13 C NMR(151MHz,DMSO-d 6 )δ(ppm):172.1,159.1,141.5,134.4,125.4,123.0,120.7,120.5,81.0,54.3,48.8, 43.6；
HPLC:99.1％.
Example 3 Synthesis of 4- (piperazin-1-yl) -3- (pyrimidin-2-ylamino) benzonitrile
Step 1) Synthesis of 3-amino-4- (piperazin-1-yl) benzonitrile
3-amino-4-fluorobenzonitrile (3.0 g, 22mmol) and anhydrous piperazine (7.6 g, 88.2mmol) were added in this order to dimethyl sulfoxide (50 mL), and the reaction was heated to 130 ℃ under a nitrogen atmosphere for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was poured into water, extracted with dichloromethane, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 10) to give the title compound (brown oil, 1.56g, 35%).
MS(ESI,pos.ion)m/z:203.10[M+H] + ；
1 HNMR(600MHz,CDCl 3 )δ(ppm):7.59～7.51(m,1H),7.28～7.21(m,1H),,6.97～6.95(m,1H),6.28(s,2H), 3.47(t,4H),3.15～3.07(m,4H).
Step 2) Synthesis of 4- (2-amino-4-cyanophenyl) piperazine-1-carboxylic acid tert-butyl ester
The title compound was prepared as described in example 1, step 2 by reacting 3-amino-4- (piperazin-1-yl) benzonitrile (1.3 g,6.4 mmol), di-tert-butyl dicarbonate (2.2 g, 10mmol) and triethylamine (2.7mL, 19.2mmol) in dichloromethane (20 mL) at room temperature for 2 hours. The obtained crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (V: V) = 10) to give the title compound (white solid, 1.64g, 85%).
MS(ESI,pos.ion)m/z:247.20[M+H-56] + ；
1 HNMR(600MHz,CDCl 3 )δ(ppm):7.00(dd,J＝8.1,1.8Hz,1H),6.94(d,J＝1.8Hz,1H),6.92(d,J＝8.1Hz, 1H),3.55～3.50(m,4H),2.86～2.83(m,4H),1.46(s,9H).
Step 3) Synthesis of 4- (4-cyano-2- (pyrimidin-2-ylamino) phenyl) piperazine-1-carboxylic acid tert-butyl ester
The title compound of this step was prepared by the method described in step 3 of example 1, namely tert-butyl 4- (2-amino-4-cyanophenyl) piperazine-1-carboxylate (200mg, 0.66mmol), 2-chloropyrimidine (113mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (white solid, 131mg, 52%).
MS(ESI,pos.ion)m/z:381.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.94(s,1H),8.50(d,J＝4.8Hz,2H),8.16(s,1H),7.29(s,1H),7.15(d,J ＝8.2Hz,1H),6.84(t,J＝4.8Hz,1H),3.77～3.61(m,4H),3.02～2.82(m,4H),1.50(s,9H).
Step 4) Synthesis of 4- (piperazin-1-yl) -3- (pyrimidin-2-ylamino) benzonitrile
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (4-cyano-2- (pyrimidin-2-ylamino) phenyl) piperazine-1-carboxylate (200mg, 0.53mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (white solid, 119mg, 80%).
MS(ESI,pos.ion)m/z:281.20[M+H] + ；
1 HNMR(400MHz,CDCl 3 )δ(ppm):8.91(d,J＝1.2Hz,1H),8.48(d,J＝4.8Hz,2H),8.15(s,1H),7.27～7.25 (m,1H),7.16(d,J＝8.2Hz,1H),6.80(t,J＝4.8Hz,1H),3.10～3.05(m,4H),2.92～2.88(m,4H),2.34(s,1H)；
13 C NMR(100MHz,CDCl 3 )δ(ppm):159.5,158.0,145.2,135.1,125.9,121.3,120.7,119.5,113.4,108.1,52.7, 46.4；
HPLC:98.8％.
Example 4 Synthesis of 3- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (piperazin-1-yl) benzonitrile
Step 1) preparation of tert-butyl 4- (4-cyano-2- ((4, 6-dimethylpyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate
Synthesis of
The title compound of this step was prepared by the method described in step 3 of example 1, namely tert-butyl 4- (2-amino-4-cyanophenyl) piperazine-1-carboxylate (200mg, 0.66mmol), 2-chloro-4, 6-dimethylpyrimidine (141mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The obtained crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (white solid, 183mg, 68%).
MS(ESI,pos.ion)m/z:409.30[M+H] + ；
1 HNMR(600MHz,CDCl 3 )δ(ppm):8.95(s,1H),7.28(d,J＝5.6Hz,1H),7.13(d,J＝8.1Hz,1H),6.60(s,1H), 3.70(s,4H),2.90(s,4H),2.44(s,6H),1.50(s,9H).
Step 2) Synthesis of 3- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (piperazin-1-yl) benzonitrile
The title compound of this step was prepared as described in example 1, step 4, by reacting 4- (4-cyano-2- ((4, 6-dimethylpyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.49mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (white solid, 139mg, 90%).
MS(ESI,pos.ion)m/z:309.25[M+H] + ；
1 HNMR(600MHz,DMSO-d 6 )δ(ppm):9.73(s,1H),9.58(s,2H),8.58(s,1H),7.61(d,J＝8.1Hz,1H),7.38(d, J＝8.2Hz,1H),7.08(s,1H),3.44～3.40(m,4H),3.17～3.15(m,4H),2.52(s,6H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm):154.4,146.8,133.0,129.1,124.3,122.3,119.3,113.2,107.1,48.2,42.9, 40.0；
HPLC:99.5％.
EXAMPLE 5 Synthesis of 3- ((4, 6-dimethoxypyrimidin-2-yl) amino) -4- (piperazin-1-yl) benzonitrile
Step 1) tert-butyl 4- (4-cyano-2- ((4, 6-dimethoxypyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate
Synthesis of (2)
The title compound of this step was prepared by the method described in step 3 of example 1, namely tert-butyl 4- (2-amino-4-cyanophenyl) piperazine-1-carboxylate (200mg, 0.66mmol), 2-chloro-4, 6-dimethoxypyrimidine (173mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (white solid, 145mg, 50%).
MS(ESI,pos.ion)m/z:441.25[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.87(d,J＝1.5Hz,1H),7.91(s,1H),7.27(dd,J＝8.1,1.6Hz,1H),7.13 (d,J＝8.2Hz,1H),5.65(s,1H),3.96(s,6H),3.67～3.63(m,4H),2.90～2.87(m,4H),1.50(s,9H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):172.0,158.1,154.7,144.5,135.2,125.7,121.8,120.6,119.4,108.3,82.0, 80.2,54.1,51.5,28.4.
Step 2) Synthesis of 3- ((4, 6-dimethoxypyrimidin-2-yl) amino) -4- (piperazin-1-yl) benzonitrile
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (4-cyano-2- ((4, 6-dimethoxypyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate (200mg, 0.45mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (white solid, 141mg, 92%).
MS(ESI,pos.ion)m/z:341.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.88(d,J＝1.8Hz,1H),7.93(s,1H),7.29～7.26(m,1H),7.17(d,J＝8.2 Hz,1H),5.66(s,1H),3.97(s,6H),3.16～3.12(m,4H),2.96～2.93(m,4H)；
13 C NMR(100MHz,CDCl 3 )δ(ppm):172.1,158.3,145.0,135.3,125.7,121.7,120.6,119.5,108.1,81.9,54.1, 52.4,46.2；
HPLC:98.5％.
Example Synthesis of 64- (piperazin-1-yl) -3- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) benzonitrile
Step 1) tert-butyl 4- (4-cyano-2- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate
Synthesis of (2)
The title compound of this step was prepared by the method described in step 3 of example 1, namely tert-butyl 4- (2-amino-4-cyanophenyl) piperazine-1-carboxylate (200mg, 0.66mmol), 2-chloro-4- (trifluoromethyl) pyrimidine (181mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (white solid, 175mg, 59%).
MS(ESI,pos.ion)m/z:449.15[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.84(d,J＝1.7Hz,1H),8.72(d,J＝4.9Hz,1H),8.37(s,1H),7.34(dd,J ＝8.2,1.8Hz,1H),7.18(d,J＝8.2Hz,1H),7.12(d,J＝4.9Hz,1H),3.68～3.65(m,4H),2.90～2.85(m,4H),1.49 (s,9H).
Step 2) Synthesis of 4- (piperazin-1-yl) -3- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) benzonitrile
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (4-cyano-2- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate (200mg, 0.45mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (white solid, 141mg, 90%).
MS(ESI,pos.ion)m/z:349.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.85(d,J＝1.5Hz,1H),8.73(d,J＝4.9Hz,1H),8.44(s,1H),7.36(dd,J ＝8.2,1.7Hz,1H),7.22(d,J＝8.2Hz,1H),7.12(d,J＝4.9Hz,1H),3.14～3.10(m,4H),3.00～2.84(m,4H)；
13 C NMR(100MHz,CDCl 3 )δ(ppm):160.6,159.6,156.7,145.57,134.4,126.8,121.6,120.9,119.2,118.9,114.0, 108.4,52.9,46.3；
HPLC:98.8％.
Example 7 Synthesis of 4- (piperazin-1-yl) -3- (pyridin-2-ylamino) benzonitrile
Step 1) Synthesis of 4- (4-cyano-2- (pyridin-2-ylamino) phenyl) piperazine-1-carboxylic acid tert-butyl ester
The title compound of this step was prepared by the method described in step 3 of example 1, namely tert-butyl 4- (2-amino-4-cyanophenyl) piperazine-1-carboxylate (200mg, 0.66mmol), 2-chloropyridine (112mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The obtained crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (white solid, 198mg, 79%).
MS(ESI,pos.ion)m/z:380.25[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.55(s,1H),8.27(d,J＝4.7Hz,1H),7.57(t,J＝7.8Hz,1H),7.40(s,1H), 7.21(d,J＝8.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.84～6.80(m,1H),6.79(d,J＝8.3Hz,1H),3.60～3.52(m,4H), 2.88～2.83(m,4H),1.47(s,9H).
Step 2) Synthesis of 4- (piperazin-1-yl) -3- (pyridin-2-ylamino) benzonitrile
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (4-cyano-2- (pyridin-2-ylamino) phenyl) piperazine-1-carboxylate (200mg, 0.53mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (white solid, 120mg, 81%).
MS(ESI,pos.ion)m/z:280.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.61(s,1H),8.30(d,J＝3.7Hz,1H),7.58(dd,J＝11.0,4.3Hz,1H),7.44 (s,1H),7.26～7.19(m,1H),7.13(d,J＝8.1Hz,1H),6.86～6.82(t,J＝11.9Hz,1H),6.81(d,J＝8.2Hz,1H), 3.08～3.02(m,4H),2.92～2.87(m,4H),2.30(s,1H)；
13 C NMR(151MHz,CDCl 3 )δ(ppm):154.5,148.2,145.2,137.8,136.2,125.2,120.5,120.2,119.6,116.0,110.8, 107.8,52.4,46.5；
HPLC 99.4％.
Example 8 Synthesis of 2- ((5-cyano-2- (piperazin-1-yl) phenyl) amino) nicotinonitrile
Step 1) Synthesis of tert-butyl 4- (4-cyano-2- ((3-cyanopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate
The title compound of this step was prepared by the method described in step 3 of example 1, namely tert-butyl 4- (2-amino-4-cyanophenyl) piperazine-1-carboxylate (200mg, 0.66mmol), 2-chloronicotinonitrile (137mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The obtained crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow solid, 187mg, 70%).
MS(ESI,pos.ion)m/z:349.15[M+H-56] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):9.12(d,J＝1.1Hz,1H),8.86(s,1H),8.52(dd,J＝4.9,1.8Hz,1H),7.87 (dd,J＝7.7,1.9Hz,1H),7.35(dd,J＝8.1,1.8Hz,1H),7.24(d,J＝8.2Hz,1H),6.93(dd,J＝7.7,5.0Hz,1H), 3.74～3.68(m,4H),2.90～2.81(m,4H),1.50(s,9H).
Step 2) Synthesis of 2- ((5-cyano-2- (piperazin-1-yl) phenyl) amino) nicotinonitrile
The title compound of this step was prepared by the method described in reference to example 1, step 4, namely 4- (4-cyano-2- ((3-cyanopyridin-2-yl) amino) phenyl) piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.49mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (white solid, 104 mg, 70%).
MS(ESI,pos.ion)m/z:305.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):9.10(d,J＝1.6Hz,1H),8.87(s,1H),8.51(dd,J＝4.9,1.7Hz,1H),7.86 (dd,J＝7.6,1.8Hz,1H),7.34(d,J＝1.8Hz,1H),7.31～7.24(m,1H),6.91(dd,J＝7.6,5.0Hz,1H),3.24～3.09 (m,4H),3.06～2.74(m,4H),1.96(s,1H)；
13 C NMR(151MHz,CDCl 3 )δ(ppm):155.2,152.2,145.5,141.6,135.2,126.5,121.4,121.3,119.4,116.3,114.7, 108.6,94.5,52.9,46.5；
HPLC:96.6％.
EXAMPLE 9 Synthesis of N- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Step 1) Synthesis of 2- (piperazin-1-yl) -5- (trifluoromethyl) aniline
The title compound of this step was prepared by the method described in step 1 of example 3, i.e., 2-fluoro-5- (trifluoromethyl) aniline (4.0 g,22.4 mmol) and anhydrous piperazine (9.0 g, 100mmol) were reacted in anhydrous dimethylsulfoxide (50 mL) under nitrogen at 135 ℃ for 48 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (brown oil, 1.65g, 30%).
MS(ESI,pos.ion)m/z:246.15[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.01～6.97(m,2H),6.95(s,1H),3.58(brs,4H),2.78(brs,4H).
Step 2) preparation of tert-butyl 4- (2-amino-4- (trifluoromethyl) phenyl) piperazine-1-carboxylateSynthesis of
The title compound was prepared as described in example 1, step 2, by reacting 2- (piperazin-1-yl) -5- (trifluoromethyl) aniline (1.6 g,6.5 mmol), di-tert-butyl dicarbonate (1.7g, 7.8mmol) and triethylamine (1.4mL, 10mmol) in dichloromethane (20 mL) at room temperature for 2 hours. The obtained crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (V: V) = 10) to give the title compound (yellow solid, 1.35g, 60%).
MS(ESI,pos.ion)m/z:290.20[M+H-56] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.01～6.97(m,2H),6.95(s,1H),3.58(brs,4H),2.88(brs,4H),1.48(s, 9H).
Step 3) Synthesis of 4- (2- (pyrimidine) -2-ylamino) -4- (trifluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester
The title compound was prepared by the method described in step 3 of example 1, namely tert-butyl 4- (2-amino-4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (200mg, 0.58mmol), 2-chloropyrimidine (100mg, 0.87mmol), sodium tert-butoxide (127mg, 0.87mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow oil, 184mg, 75%).
MS(ESI,pos.ion)m/z:424.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.90(s,1H),8.49(d,J＝4.8Hz,2H),8.29(s,1H),7.24(d,J＝8.1Hz,1H), 7.18(d,J＝8.2Hz,1H),6.79(t,J＝4.8Hz,1H),3.67(brs,4H),2.89(brs,4H),1.50(s,9H).
Step 4) Synthesis of N- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (2- (pyrimidin-2-ylamino) -4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (200mg, 0.47mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 137mg, 90%).
MS(ESI,pos.ion)m/z:324.20[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm):9.54(s,2H),9.28(s,1H),8.70(d,J＝4.9Hz,1H),8.54(d,J＝1.4Hz, 1H),7.47～7.42(m,1H),7.38(d,J＝8.3Hz,1H),7.09(t,J＝4.9Hz,1H),3.33～3.21(m,4H),3.21～3.06(m,4H)； 13 C NMR(151MHz,DMSO-d 6 )δ(ppm):158.5,157.7,145.6,133.8,125.3,124.7,121.7,120.8,117.5,113.7, 48.3,43.2；
HPLC:98.7％.
Example 10 Synthesis of 4, 6-dimethyl-N- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Step 1) tert-4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) piperazine-1-carboxylic acid
Synthesis of butyl ester
The title compound of this step was prepared by the method described in step 3 of example 1, namely tert-butyl 4- (2-amino-4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (200mg, 0.58mmol), 2-chloro-4, 6-dimethylpyrimidine (124mg, 0.87mmol), sodium tert-butoxide (127mg, 0.87 mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132 mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (pale yellow solid, 222mg, 85%).
MS(ESI,pos.ion)m/z:452.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):9.01(s,1H),8.15(s,1H),7.23(dd,J＝8.3,1.5Hz,1H),7.17(d,J＝8.3Hz, 1H),6.57(s,1H),3.70～3.59(m,4H),2.90～2.85(m,4H),2.43(s,6H),1.51(s,9H).
Step 2) Synthesis of 4, 6-dimethyl-N- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (200mg, 0.44mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 139mg, 90%).
MS(ESI,pos.ion)m/z:352.20[M+H] + ；
1 H NMR(400MHz,MeOD)δ(ppm):8.80(s,1H),7.57(d,J＝1.6Hz,2H),7.13(s,1H),3.71～3.63(m,4H), 3.29～3.21(m,4H),2.66(s,6H)；
13 C NMR(100MHz,MeOD)δ(ppm):152.4,145.1,132.5,127.5,124.0,122.0,121.9,118.0,112.6,48.8,43.3； HPLC:99.4％.
EXAMPLE 11 Synthesis of 4, 6-dimethoxy-N- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Step 1) 4- (2- ((4, 6-dimethoxypyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) piperazine-1-carboxylic acid
Synthesis of tert-butyl ester
The title compound of this step was prepared by the method described in example 1, step 3, i.e., tert-butyl 4- (2-amino-4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (200mg, 0.58mmol), 2-chloro-4, 6-dimethoxypyrimidine (152mg, 0.87mmol), sodium tert-butoxide (127mg, 0.87 mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132 mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow solid, 210mg, 75%).
MS(ESI,pos.ion)m/z:484.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):9.00(d,J＝1.7Hz,1H),8.07(s,1H),7.25(dd,J＝8.3,1.5Hz,1H),7.18 (d,J＝8.2Hz,1H),5.65(s,1H),3.98(s,6H),3.69～3.61(m,4H),2.90～2.82(m,4H),1.52(s,9H).
Step 2) Synthesis of 4, 6-dimethoxy-N- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (200mg, 0.41mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 141mg, 90%).
MS(ESI,pos.ion)m/z:384.15[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.62(s,2H),8.67(s,2H),7.39(dd,J＝8.4,1.6Hz,1H),7.35(d,J＝8.4 Hz,1H),5.83(s,1H),3.90(s,6H),3.34～3.26(m,4H),3.18～3.05(m,4H)；
13 C NMR(100MHz,DMSO-d 6 )δ(ppm):171.8,158.0,145.0,134.4,125.3,124.8,121.5,120.0,117.5,81.6,54.7, 48.3,43.2；
HPLC:99.6％.
EXAMPLE 12 Synthesis of N- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenyl) -4- (trifluoromethyl) pyrimidin-2-amine
Step 1) 4- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylic acid
Synthesis of tert-butyl ester
The title compound of this step was prepared by the method described in step 3 of example 1, i.e., tert-butyl 4- (2-amino-4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (200mg, 0.58mmol), 2-chloro-4- (trifluoromethyl) pyrimidine (159mg, 0.87mmol), sodium tert-butoxide (127mg, 0.87 mmol), tris (dibenzylideneacetone) dipalladium (60mg, 0.066 mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (82mg, 0.132 mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow solid, 131mg, 46%).
MS(ESI,pos.ion)m/z:492.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.89(s,1H),8.71(d,J＝4.8Hz,1H),8.52(s,1H),7.31(d,J＝8.0Hz,1H), 7.23(d,J＝8.2Hz,1H),7.10(d,J＝4.9Hz,1H),3.69(brs,4H),2.91(brs,4H),1.51(s,9H).
Step 2) Synthesis of N- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenyl) -4- (trifluoromethyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate (200mg, 0.41mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The obtained crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 144mg, 90%).
MS(ESI,pos.ion)m/z:392.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.89(s,1H),8.72(d,J＝4.9Hz,1H),8.58(s,1H),7.35～7.30(m,1H),7.27 (d,J＝8.2Hz,1H),7.10(d,J＝4.9Hz,1H),3.16～3.11(m,4H),2.95～2.89(m,4H)；
13 C NMR(151MHz,CDCl 3 )δ(ppm):160.6,159.7,156.5,144.3,134.2,127.2,124.2,120.6,120.4,119.5,115.4, 108.1,53.1,46.5；
HPLC:99.8％.
EXAMPLE 13 Synthesis of N- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) pyrimidin-2-amine
Step 1) Synthesis of 4- (2-aminophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
2-bromoaniline (2.0g, 11.6 mmol), 4- (cross-linked-ester-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (4.33g, 14.0 mmol), sodium acetate (1.7g, 17.4 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (490mg, 0.6 mmol) were added in this order to a mixed solvent of N, N-dimethylformamide (30 mL) and water (3 mL), and the temperature was raised to 95 ℃ under the protection of nitrogen for 12 hours. The reaction was stopped, the reaction solution was poured into water (100 mL), dichloromethane (30 mL × 3) was extracted, organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow solid, 2.39g, 75%).
MS(ESI,pos.ion)m/z:175.20[M+H-100] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.14～7.04(m,1H),7.00(d,J＝7.5Hz,1H),6.76(t,J＝7.4Hz,1H),6.72 (d,J＝8.0Hz,1H),5.78(s,1H),4.06(d,2H),3.65(t,J＝5.3Hz,2H),2.42(t,2H),1.52(s,9H).
Step 2) Synthesis of 4- (2- (pyrimidin-2-ylamino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
The title compound was prepared by the method described in step 3 of example 1, namely 4- (2-aminophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (130mg, 0.40mmol), 2-chloropyrimidine (100mg, 0.64mmol), sodium tert-butoxide (62mg, 0.64mmol), tris (dibenzylideneacetone) dipalladium (37mg, 0.04mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (50mg, 0.08mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow oil, 116mg, 82%).
MS(ESI,pos.ion)m/z:353.25[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.95(s,1H),8.45(d,J＝4.7Hz,2H),7.11～7.05(m,1H),7.00(d,J＝7.5 Hz,1H),6.75(t,J＝7.4Hz,1H),6.73(d,J＝8.0Hz,1H),5.76(s,1H),4.05(d,2H),3.65(t,J＝5.3Hz,2H),2.43 (t,2H),1.50(s,9H).
Step 3) Synthesis of N- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared as described in example 1, step 4, by reacting 4- (2- (pyrimidin-2-ylamino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (200mg, 0.57mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow oil, 137mg, 95%).
MS(ESI,pos.ion)m/z:253.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.40(d,J＝4.8Hz,1H),8.27(d,J＝8.2Hz,1H),7.44(s,1H),7.33～7.29 (m,1H),7.14(dd,J＝7.5,1.2Hz,1H),7.05(dd,J＝10.7,4.1Hz,1H),6.70(t,J＝4.8Hz,1H),5.84(s,1H),3.53 (d,J＝2.5Hz,2H),3.11(t,J＝5.6Hz,2H),2.33(d,J＝1.8Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):160.2,158.0,135.8,135.1,133.7,128.4,127.6,127.3,122.8,120.5,112.5, 45.0,43.2,30.0；
HPLC:96.2％.
Example 14 Synthesis of 4, 6-dimethyl-N- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) pyrimidin-2-amine
Step 1) 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) phenyl) -5, 6-dihydropyridine-1 (2H) -one-Carboxylic acid tert-butyl
Synthesis of butyl esters
The title compound of this step was prepared by the method described in reference to example 1, step 3, namely 4- (2-aminophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (130mg, 0.40mmol), 2-chloro-4, 6-dimethylpyrimidine (91mg, 0.64mmol), sodium tert-butoxide (62mg, 0.64mmol), tris (dibenzylideneacetone) dipalladium (37mg, 0.04mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (50mg, 0.08mmol) in anhydrous toluene (20 mL) under nitrogen at 120 ℃ for 12 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow oil, 126mg, 83%).
MS(ESI,pos.ion)m/z:381.25[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.34(d,J＝8.2Hz,1H),7.35～7.25(m,1H),7.20(s,1H),7.12(dd,J＝7.6, 1.6Hz,1H),7.03(td,J＝7.5,1.0Hz,1H),6.50(s,1H),5.80(s,1H),4.09(d,J＝2.3Hz,2H),3.66(t,J＝5.6Hz, 2H),2.41(t,2H),2.38(s,6H),1.52(s,9H).
Step 2) Synthesis of 4, 6-dimethyl-N- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (200mg, 0.53mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 134mg, 90%).
MS(ESI,pos.ion)m/z:281.25[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.68(s,1H),9.51(s,1H),7.94(d,J＝8.1Hz,1H),7.45～7.34(m,1H), 7.29～7.17(m,1H),7.02(s,1H),5.75(s,1H),3.70(d,2H),3.35～3.28(m,2H),2.57～2.49(m,2H),2.46(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):154.0,135.3,133.9,133.8,128.9,128.6,125.9,124.1,122.3,112.4, 41.7,40.7,39.6,26.2；
HPLC:95.1％.
EXAMPLE 15 Synthesis of 4, 6-dimethoxy-N- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) pyrimidin-2-amine
Step 1) 4- (2- ((4, 6-Dimethoxypyridin-2-yl) amino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid
Synthesis of tert-butyl esters
The title compound was prepared by the method described in example 1, step 3, namely 4- (2-aminophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (130mg, 0.40mmol), 2-chloro-4, 6-dimethoxypyrimidine (112mg, 0.64mmol), sodium tert-butoxide (62mg, 0.64 mmol), tris (dibenzylideneacetone) dipalladium (37mg, 0.04mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (50mg, 0.08mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (white solid, 155mg, 94%).
MS(ESI,pos.ion)m/z:413.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.35(d,J＝8.2Hz,1H),7.36～7.24(m,2H),7.13(dd,J＝7.6,1.6Hz,1H), 7.05(dd,J＝7.4,1.0Hz,1H),5.82(s,1H),5.60(s,1H),4.12(d,J＝2.4Hz,2H),3.93(s,6H),3.68(t,J＝5.5Hz, 2H),2.41(s,2H),1.53(s,9H).
Step 2) Synthesis of 4, 6-dimethoxy-N- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared as described in example 1, step 4, i.e. 4- (2- ((4, 6-dimethoxypyrimidin-2-yl) amino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (200mg, 0.64mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 190mg, 95%).
MS(ESI,pos.ion)m/z:313.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.33(d,J＝8.3Hz,1H),7.33～7.29(m,1H),7.18(s,1H),7.14(d,J＝7.5 Hz,1H),7.05(t,J＝7.4Hz,1H),5.85(s,1H),5.59(s,1H),3.92(s,6H),3.70(d,J＝34.1Hz,2H),3.30～3.22(m, 2H),2.51～2.45(m,2H)；
13 C NMR(100MHz,CDCl 3 )δ(ppm):172.1,159.1,136.2,135.5,132.4,128.2,127.8,124.1,122.5,121.1,80.8, 54.0,43.6,42.2,29.7；
HPLC:96.7％.
EXAMPLE 16 Synthesis of N- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -4- (trifluoromethyl) pyrimidin-2-amine
Step 1) 4- (2- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid
Synthesis of tert-butyl esters
The title compound of this step was prepared by the method described in reference to example 1, step 3, namely 4- (2-aminophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (130mg, 0.40mmol), 2-chloro-4- (trifluoromethyl) pyrimidine (117mg, 0.64mmol), sodium tert-butoxide (62mg, 0.64 mmol), tris (dibenzylideneacetone) dipalladium (37mg, 0.04mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (50mg, 0.08mmol) in anhydrous toluene (20 mL) under nitrogen atmosphere at 120 ℃ for 12 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow oil, 80mg, 44%).
MS(ESI,pos.ion)m/z:365.20[M+H-56] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.63(d,J＝4.8Hz,1H),8.22(d,J＝8.2Hz,1H),7.42(s,1H),7.38～7.32 (m,1H),7.21～7.15(m,1H),7.13(t,J＝7.4Hz,1H),7.03(d,J＝4.9Hz,1H),5.82(s,1H),4.10(s,2H),3.66(t,J ＝5.2Hz,2H),2.41(t,2H),1.53(s,9H).
Step 2) Synthesis of N- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -4- (trifluoromethyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, namely 4- (2- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (200mg, 0.48mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 138mg, 90%).
MS(ESI,pos.ion)m/z:321.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.61(d,J＝4.8Hz,1H),8.26(d,J＝8.2Hz,1H),7.73(s,1H),7.36～7.29 (m,1H),7.17(dd,J＝7.6,1.3Hz,1H),7.10～7.03(m,1H),7.00(d,J＝4.9Hz,1H),5.86(s,1H),3.57(d,J＝2.6 Hz,2H),3.13(t,J＝5.6Hz,3H),2.36(d,J＝1.9Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):160.5,160.2,156.4,135.0,134.9,133.9,128.5,127.8,127.4,123.5,120.7, 120.4,107.5,44.9,43.1,29.9；
HPLC:96.7％.
Example 17 Synthesis of 4, 6-dimethyl-N- (2- (piperidin-4-yl) phenyl) pyrimidin-2-amine
Step 1) Synthesis of tert-butyl 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) phenyl) piperidine-1-carboxylate
4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (500mg, 1.31mmol) and 10% palladium on charcoal (100 mg) were successively added to anhydrous methanol (10 mL), and the system was left under a hydrogen atmosphere to react at room temperature for 16 hours. The reaction was stopped, suction filtration was performed, the filtrate was collected, the solvent was removed by distillation under the reduced pressure, and the resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50).
MS(ESI,pos.ion)m/z:383.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.71(d,J＝7.9Hz,1H),7.21～7.16(m,3H),7.13(t,J＝7.1Hz,1H),6.42 (s,1H),4.33～3.98(m,2H),2.89～2.83(m,1H),2.72～2.65(m,2H),2.27(s,6H),1.79～1.72(m,2H),1.57～1.49(m, 2H),1.46(s,9H).
Step 2) Synthesis of 4, 6-dimethyl-N- (2- (piperidin-4-yl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) phenyl) piperidine-1-carboxylate (200mg, 0.52mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 103mg, 70%).
MS(ESI,pos.ion)m/z:283.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.80(d,J＝7.9Hz,1H),7.31(d,J＝7.6Hz,1H),7.22(t,J＝7.4Hz,1H), 7.14(t,J＝7.5Hz,1H),7.05(s,1H),6.45(s,1H),3.19(t,J＝12.0Hz,2H),2.90～2.86(m,1H),2.73(t,J＝11.7 Hz,2H),2.31(s,6H),1.84～1.78(m,2H),1.71～1.65(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):167.7,160.9,138.6,136.3,126.6,126.4,124.8,124.1,111.4,47.0,37.0, 33.3,23.9；
HPLC:98.6％.
EXAMPLE 18 Synthesis of 4, 6-dimethoxy-N- (2- (piperidin-4-yl) phenyl) pyrimidin-2-amine
Step 1) Synthesis of tert-butyl 4- (2- ((4, 6-dimethoxypyrimidin-2-yl) amino) phenyl) piperidine-1-carboxylate
The title compound of this step was prepared by the method described in step 1 of example 17, namely 4- (2- ((4, 6-dimethoxypyrimidin-2-yl) amino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (500mg, 1.21mmol) and 10% palladium on carbon (100 mg) in anhydrous methanol (10 mL) under a hydrogen atmosphere at room temperature for 16 hours. The obtained crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (white solid, 451mg, 90%).
MS(ESI,pos.ion)m/z:415.25[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.79(d,J＝7.8Hz,1H),7.20～7.15(m,2H),7.11(dd,J＝10.9,4.0Hz,1H), 6.79(s,1H),5.52(s,1H),4.22(d,J＝5.1Hz,2H),3.82(s,6H),2.90～2.86(m,1H),2.79～2.72(m,2H),1.77～1.70 (m,2H),1.61～1.53(m,2H),1.46(s,9H).
Step 2) Synthesis of 4, 6-dimethoxy-N- (2- (piperidin-4-yl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (2- ((4, 6-dimethoxypyrimidin-2-yl) amino) phenyl) piperidine-1-carboxylate (200mg, 0.48mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 h. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow oil, 136 mg, 90%).
MS(ESI,pos.ion)m/z:315.20[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm):8.77(s,1H),7.44～7.36(m,1H),7.25(dd,J＝6.6,2.5Hz,1H),7.18(dd, J＝6.4,2.9Hz,2H),5.52(s,1H),3.74(s,7H),3.23(d,J＝11.7Hz,2H),3.15～3.04(m,1H),2.80(t,J＝11.8Hz, 2H),1.79(d,J＝12.4Hz,2H),1.74～1.64(m,2H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm):172.1,161.3,140.8,137.0,127.6,126.5,126.4,125.8,79.6,53.9,45.3, 34.9,31.0；
HPLC:96.8％.
EXAMPLE 19 Synthesis of N- (2- (piperidin-4-yl) phenyl) -4- (trifluoromethyl) pyrimidin-2-amine
Step 1) Synthesis of tert-butyl 4- (2- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperidine-1-carboxylate
The title compound of this step was prepared by the method described in example 17, step 1, i.e., 4- (2- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (500mg, 1.19mmol) and 10% palladium on carbon (100 mg) in dry methanol (10 mL) under a hydrogen atmosphere at room temperature for 16 hours. The obtained crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow oil, 402mg, 80%).
MS(ESI,pos.ion)m/z:423.25[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.59(d,J＝4.7Hz,1H),7.67～7.59(m,1H),7.36(dd,J＝6.7,2.5Hz,1H), 7.25～7.21(m,2H),7.18(s,1H),6.99(d,J＝4.9Hz,1H),3.23(t,2H),2.91～2.83(m,1H),2.76(t,J＝11.4Hz, 2H),1.82～1.75(m,2H),1.73～1.69(m,2H),1.49(s,9H).
Step 2) Synthesis of N- (2- (piperidin-4-yl) phenyl) -4- (trifluoromethyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (2- ((4- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperidine-1-carboxylate (200mg, 0.47mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 121mg, 80%).
MS(ESI,pos.ion)m/z:323.15[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.57(d,J＝4.8Hz,1H),7.66～7.55(m,1H),7.38(dd,J＝6.6,2.5Hz,1H), 7.27～7.20(m,2H),7.19(s,1H),6.99(d,J＝4.9Hz,1H),3.22(t,2H),2.90～2.82(m,1H),2.75(t,J＝11.4Hz, 2H),1.82～1.78(m,2H),1.73～1.63(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):161.6,160.7,156.7,140.2,134.8,127.0,126.7,126.5,125.3,120.4,107.3, 47.0,37.2,33.5；
HPLC:98.6％.
EXAMPLE 20 Synthesis of N- (2- (1, 2,3, 6-tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Step 1) Synthesis of 4- (2-amino-4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
2-bromo-5- (trifluoromethyl) aniline (2.0g, 8.3mmol), 4- (pinacol ester-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (3.1g, 10mmol), potassium acetate (1.23g, 12.5mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (343mg, 0.42mmol) were sequentially added to a mixed solvent of N, N-dimethylformamide (30 mL) and water (2 mL), and the reaction was heated to 90 ℃ for 16 hours under a nitrogen atmosphere. The reaction was stopped, cooled to room temperature, the reaction solution was poured into water (100 mL), extracted with dichloromethane (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50).
MS(ESI,pos.ion)m/z:243.15[M+H-100] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.08(d,J＝7.9Hz,1H),6.99(d,J＝7.8Hz,1H),6.94(s,1H),5.82(s,1H), 4.08(d,2H),3.66(t,J＝5.4Hz,2H),2.40(t,2H),1.52(s,9H).
Step 2) 4- (2- (pyrimidin-2-ylamino) -4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid
Synthesis of tert-butyl ester
The title compound was prepared by the method described in example 1, step 3, namely 4- (2-amino-4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (400mg, 1.17mmol), 2-chloropyrimidine (148mg, 1.29mmol), sodium tert-butoxide (1699 mg,1.76 mmol), tris (dibenzylideneacetone) dipalladium (110mg, 0.12mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (149mg, 0.24 mmol) in anhydrous toluene (20 mL) at 120 ℃ for 12 hours under a nitrogen atmosphere. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow oil, 394mg, 80%).
MS(ESI,pos.ion)m/z:421.25[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.75(s,1H),8.47(d,J＝4.7Hz,2H),7.31(d,J＝13.5Hz,1H),7.23(d,J ＝7.9Hz,1H),6.81(t,J＝4.8Hz,1H),5.86(s,1H),4.12(d,2H),3.68(t,J＝5.0Hz,2H),2.41(t,2H),1.53(s, 9H).
Step 3) Synthesis of N- (2- (1, 2,3, 6-tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared as described in example 1, step 4, by reacting 4- (2- (pyrimidin-2-ylamino) -4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (200mg, 0.48mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow oil, 138mg, 90%).
MS(ESI,pos.ion)m/z:321.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.78(s,1H),8.46(d,J＝4.6Hz,2H),7.54(s,1H),7.28(d,J＝8.7Hz,1H), 7.23(d,J＝7.8Hz,1H),6.79(t,J＝4.6Hz,1H),5.91(s,1H),3.59(d,J＝1.6Hz,2H),3.16(t,J＝5.4Hz,2H), 2.35(s,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):159.7,158.1,150.7,136.6,135.9,134.2,129.9,128.7,128.2,118.8,116.5, 113.2,44.9,43.0,29.7；
HPLC:92.1％.
Example 21 Synthesis of 4, 6-dimethyl-N- (2- (1, 2,3, 6-tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Step 1) 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) -5, 6-dihydropir
Synthesis of pyridine-1 (2H) -carboxylic acid tert-butyl ester
The title compound of this step was prepared by the method described in example 1, step 3, namely 4- (2-amino-4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (400mg, 1.17mmol), 2-chloro-4, 6-dimethylpyrimidine (184mg, 1.29mmol), sodium tert-butoxide (1699 mg, 1.76mmol), tris (dibenzylideneacetone) dipalladium (110mg, 0.12mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (149 mg, 0.24mmol) in dry toluene (20 mL) at 120 ℃ under a nitrogen atmosphere for 12 hours. The obtained crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow solid, 367mg, 70%).
MS(ESI,pos.ion)m/z:449.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.95(s,1H),7.35(s,1H),7.22(d,J＝7.7Hz,1H),7.21(d,J＝7.9Hz,1H), 5.91(s,1H),3.55(d,2H),3.14(t,J＝5.0Hz,2H),2.39(s,6H),2.34(t,2H),1.49(s,9H).
Step 2) preparation of 4, 6-dimethyl-N- (2- (1, 2,3, 6-tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Synthesis of
The title compound of this step was prepared by the method described in example 1, step 4, i.e. 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (200mg, 0.44mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2H. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 123mg, 80%).
MS(ESI,pos.ion)m/z:349.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.94(s,1H),7.36(s,1H),7.24(d,J＝7.8Hz,1H),7.20(d,J＝7.9Hz,1H), 6.56(s,1H),5.91(s,1H),3.63(d,2H),3.20(t,J＝5.0Hz,2H),2.40(s,6H),2.38(t,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):167.8,159.3,137.0,135.3,134.4,129.8,128.6,127.6,124.3,118.2,116.3, 112.4,44.6,42.8,29.7,23.9；
HPLC:99.4％.
EXAMPLE 22 Synthesis of 4, 6-dimethoxy-N- (2- (1, 2,3, 6-tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Step 1) 4- (2- ((4, 6-dimethoxypyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) -5, 6-dihydropir-ine
Synthesis of pyridine-1 (2H) -carboxylic acid tert-butyl ester
The title compound of this step was prepared by the method described in example 1, step 3, namely 4- (2-amino-4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (400mg, 1.17mmol), 2-chloro-4, 6-dimethoxypyrimidine (225mg, 1.29mmol), sodium tert-butoxide (1699 mg, 1.76mmol), tris (dibenzylideneacetone) dipalladium (110mg, 0.12mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (149 mg, 0.24mmol) in dry toluene (20 mL) at 120 ℃ under nitrogen for 12 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (yellow solid, 281mg, 50%).
MS(ESI,pos.ion)m/z:481.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.79(s,1H),7.39(s,1H),7.26～7.21(m,1H),7.18(d,J＝7.9Hz,1H),5.91 (s,1H),5.64(s,1H),3.90(s,6H),3.75(d,J＝1.9Hz,2H),3.36(t,J＝5.8Hz,2H),2.52～2.38(m,2H),1.50(s, 9H).
Step 2) 4, 6-dimethoxy-N- (2- (1, 2,3, 6-tetrahydropyridine)) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Synthesis of (2)
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (2- ((4, 6-dimethoxypyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (200mg, 0.42mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2H. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (white solid, 128mg, 80%).
MS(ESI,pos.ion)m/z:381.15[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.91(s,1H),7.38(s,1H),7.28～7.24(m,1H),7.22(d,J＝7.9Hz,1H),5.90 (s,1H),5.63(s,1H),5.37(s,1H),3.92(s,6H),3.78(d,J＝1.9Hz,2H),3.36(t,J＝5.7Hz,2H),2.54～2.48(m, 2H)；
13 C NMR(100MHz,CDCl 3 )δ(ppm):172.0,158.5,136.9,134.5,130.1,128.6,124.6,124.2,118.5,117.5,81.8, 54.1,53.4,43.2,41.8；
HPLC:99.4％.
EXAMPLE 23 Synthesis of N- (2- (piperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Step 1) Synthesis of 4- (2- (pyrimidin-2-ylamino) -4- (trifluoromethyl) phenyl) piperidine-1-carboxylic acid tert-butyl ester
The title compound of this step was prepared by the method described in example 17, step 1, i.e. 4- (2- (pyrimidin-2-ylamino) -4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (500mg, 0.95mmol) and 10% palladium on carbon (100 mg) in dry methanol (10 mL) under hydrogen at room temperature for 16H. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (colorless oil, 301mg, 75%).
MS(ESI,pos.ion)m/z:423.25[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.42(d,J＝4.8Hz,1H),8.13(s,1H),7.43(d,J＝8.1Hz,1H),7.39(d,J＝ 8.2Hz,1H),7.05(s,1H),6.78(t,J＝4.8Hz,1H),4.27～4.19(m,2H),2.96～2.88(m,1H),2.80～2.72(m,2H), 1.91～1.77(m,2H),1.66～1.51(m,2H),1.50(s,9H).
Step 2) Synthesis of N- (2- (piperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. 4- (2- (pyrimidin-2-ylamino) -4- (trifluoromethyl) phenyl) piperidine-1-carboxylic acid tert-butyl ester (200mg, 0.47mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow solid, 121mg, 80%).
MS(ESI,pos.ion)m/z:323.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.39(d,1H),8.10(s,1H),7.41(d,1H),7.39(d,1H),7.16(s,1H),6.74(t, 1H),4.26～4.18(m,2H),3.24～3.18(m,2H),2.94～2.86(m,2H),2.74～2.62(m,2H),1.80～1.72(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):160.9,158.3,142.0,136.4,129.0,127.2,124.1,121.7,121.2,113.0,46.6, 36.9,32.6；
HPLC:91.1％.
Example 24 Synthesis of 4, 6-dimethyl-N- (2- (piperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
Step 1) tert-4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) piperidine-1-carboxylic acid
Synthesis of butyl esters
The title compound was prepared by the method described in example 17, step 1, i.e., 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (500mg, 1.11mmol) and 10% palladium on charcoal (100 mg) in dry methanol (10 mL) under hydrogen at room temperature for 16 hours. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 50) to give the title compound (colorless oil, 400mg, 80%).
MS(ESI,pos.ion)m/z:451.20[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.32(s,1H),7.37～7.29(m,2H),7.08(s,1H),6.54(s,1H),4.25(s,2H), 2.94～2.88(m,1H),2.83～2.72(m,2H),2.36(s,6H),1.83～1.76(m,2H),1.72～1.55(m,2H),1.48(s,9H).
Step 2) Synthesis of 4, 6-dimethyl-N- (2- (piperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2-amine
The title compound of this step was prepared by the method described in example 1, step 4, i.e. tert-butyl 4- (2- ((4, 6-dimethylpyrimidin-2-yl) amino) -4- (trifluoromethyl) phenyl) piperidine-1-carboxylate (200mg, 0.44mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) at room temperature for 2 h. The resulting crude product was isolated and purified by column chromatography (dichloromethane: methanol (V: V) = 15) to give the title compound (yellow oil, 139mg, 90%).
MS(ESI,pos.ion)m/z:351.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.39(s,1H),7.39(d,J＝8.0Hz,1H),7.34(d,J＝7.9Hz,1H),7.08(s,1H), 6.53(s,1H),3.22(t,2H),2.93～2.84(m,1H),2.79(t,J＝11.8Hz,2H),2.67(s,1H),2.35(s,6H),1.85～1.79(m, 2H),1.76～1.63(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):167.8,160.2,140.5,139.8,136.9,128.6,126.9,124.3,120.4,119.7,112.2, 46.9,37.0,33.1,23.8；
HPLC:98.7％.
Biological assay
Example A: evaluation of the affinity of Compounds for humanized 5-HT transporters expressed in CHO cells
Experimental methods
Homogenizing protein (12. Mu.g), 2nM [ mu.g ] to the cell membrane at 22 ℃, [ 3 H]Imipramine and buffer (50 mM Tris-HCl (pH 7.4), 120mM NaCl, 5mM KCl and 0.1% BSA) were incubated for 60 minutes with or without test compound.
And in the mixed system of the above conditions, 10 μ M imipramine was added for measuring the non-specific binding value.
The incubated samples were rapidly filtered through a glass fiber filter (GF/B, packard) pre-soaked with 0.3% PEI using a 96-sample cell harvester (Unifilter, packard) under vacuum and repeatedly rinsed several times with ice-cold 50mM Tris-HCl and 150mM NaCl. The filters were dried and the residual radioactivity was counted in scintillation cocktail (Microscint 0, packard) in a scintillation counter (Topcount, packard). The results of the experiment are expressed as the percentage inhibition of the specific binding of the radioligand relative to the control.
The standard reference compound is imipramine, and IC is calculated by obtaining competitive curve through experimental test of series concentration 50 . Results see Table A for the results of affinity experiments on humanized 5-HT transporters (SERTs) for compounds of the present invention.
TABLE A affinity assay for human 5-HT transporters (SERT) for the Compounds of the invention
| Example No. 2 | IC 50 (nM) |
| Example 1 | 15.0 |
| Example 2 | 10.9 |
| Example 3 | 20.0 |
| Example 4 | 10.6 |
| Example 5 | 8.9 |
| Example 6 | 13.2 |
The experimental result shows that the compound has stronger affinity to human 5-HT transporters (SERT).
Example B pharmacokinetic evaluation of the Compounds of the invention after intravenous or intragastric dosing of rats
The present invention evaluates the pharmacokinetic studies of the compounds of the invention in rats and the animal information is detailed in table B.
Table B information sheet of the subject animals of the present invention
Test method
The compounds of the invention were administered to the test animals as 5% DMSO +5% Kolliphor HS 15+2% (2% HCl) +88% saline solution or 10% DMSO +10% aqueous saline solution, as follows. For the group administered by intravenous injection, the dose was 1mg/kg or 2mg/kg, followed by intravenous blood (0.3 mL) at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration and centrifugation at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃. For the gavage group, the dose was 2.5mg/kg or 5mg/kg, and then blood was taken intravenously (0.3 mL) at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃.
The plasma solutions collected from the above groups were analyzed by LC/MS/MS. The analysis result shows that the compound of the invention measured by intravenous injection administration and intragastric administration in rat body has better pharmacokinetic properties of large exposure value, low clearance rate, high bioavailability, and the like. The compound of the invention has better drugability and better clinical application prospect.
The experimental result shows that the compound has better pharmacokinetic property in the rat body.
In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A compound which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt of a compound of formula (I),
wherein:
x may be CR x Or N;
y is N or CH;
R 1 、R 3 and R x Each independently of the other is H, D, F, cl, br, I, -CN, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkoxy group;
R 2 is H or D;
R 5 is H, D, F, cl, br, I, -CN, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkoxy group;
R 4 、R 6 and R 7 Each independently is H or D; and
R 8 is H or D.
2. The compound of claim 1, wherein R 1 、R 3 And R x Each independently is H, D, F, cl, br, I, -CN, C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy or C 1 -C 4 A haloalkoxy group.
3. The compound of claim 1, wherein R 5 Is H, D, F, cl, br,I、-CN、C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy or C 1 -C 4 A haloalkoxy group.
4. The compound of claim 1 or 2, wherein R 1 、R 3 And R x Each independently of the others is H, D, F, cl, br, I, -CN, methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy.
5. A compound according to claim 1 or 3, wherein R 5 Is H, D, F, cl, br, I, -CN, methyl, ethyl, n-propyl, isopropyl, -CF 3 or-CH 2 CF 3 。
6. The compound of claim 1, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt of a compound having one of the following structures:
7. a pharmaceutical composition comprising a compound of any one of claims 1-6; and
the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
8. The pharmaceutical composition of claim 7, further comprising a central nervous system dysfunction treating agent that is amitriptyline, desipramine, mirtazapine, bupropion, reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, milnacipran, levomilnacipran, desvenlafaxine, vilazone, venlafaxine, dapoxetine, nefazodone, femoxetine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate, buspirone, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, pipapine, clozapine, modafinib, mecamylamine, cabergoline, adamantane, imipramipexole, pramipexole, dextromethorphan, quinidine, naloxone, midorzopran, buprenorphine, buproprion, milnacipranole, fluazurin, milnacipranole, sertraline, pramipexole, or any combination thereof.
9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 8 in the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction.
10. Use according to claim 9, for the prevention, treatment or alleviation of affective disorders.
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| CN105294554A (en) * | 2015-11-18 | 2016-02-03 | 乳源瑶族自治县大众药品贸易有限公司 | Phenylpiperazine derivative, use method and uses thereof |
| CN105348204A (en) * | 2015-11-18 | 2016-02-24 | 乳源瑶族自治县大众药品贸易有限公司 | 1-heterocyclyl-2-(heteroarylthio) benzene derivative and use method and application |
| CN105461635A (en) * | 2015-11-18 | 2016-04-06 | 乳源瑶族自治县大众药品贸易有限公司 | Phenylpiperazine derivatives, using method thereof and uses of the derivatives |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |