CN115160269A - Arylcarboxamide derivatives as positive allosteric modulators of NMDAR - Google Patents

Arylcarboxamide derivatives as positive allosteric modulators of NMDAR Download PDF

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CN115160269A
CN115160269A CN202110360498.2A CN202110360498A CN115160269A CN 115160269 A CN115160269 A CN 115160269A CN 202110360498 A CN202110360498 A CN 202110360498A CN 115160269 A CN115160269 A CN 115160269A
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methyl
pyrazol
carboxamide
dimethyl
furan
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张亮仁
黄卓
刘振明
李忠堂
蔡冠星
房凡
李文超
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Peking University
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Abstract

The invention discloses an aromatic formamide derivative as a positive allosteric regulator of NMDAR, wherein the aromatic formamide derivative is shown as a formula (I), and the definition of each substituent is shown in the specification. In addition, the invention also discloses a preparation method of the compound and a pharmaceutical composition containing the compound. The aryl formamide derivative has the pharmacological effect of positive allosteric regulation of NMDAR and the pharmacodynamic effects of depression resistance and the like.

Description

Arylcarboxamide derivatives as positive allosteric modulators of NMDAR
Technical Field
The present invention relates to, but is not limited to, pharmaceutical chemistry techniques, and in particular to the use of derivatives of arylcarboxamides as positive allosteric modulators of NMDAR.
Background
Major Depressive Disorder (MDD) is a mental disease with major symptoms of depressed mood, anhedonia, energy deficit, etc., and shows an increasing fatality rate and disability rate in recent years. However, the pathogenesis of MDD is not fully understood, and early, the hypothesis of monoamine transmitter deficiency predominates. However, the treatment means proposed based on this hypothesis has poor effect on clinically intractable patients at present, and a novel treatment mechanism is urgently needed.
The FDA recently approved a separate anesthetic, S-ketamine, for the treatment of resistant depression, an event that may be a milestone in the history of MDD treatment drug discovery because it was the antidepressant drug of the first new treatment mechanism in the last three decades. Ketamine is a blocker of the N-methyl-D-aspartate receptor (NMDARs) and can alleviate symptoms in treatment-resistant major depressive patients; it may also play a role by activating AMPA and mTOR of the prefrontal cortex and activating ERK phosphorylation at the molecular level.
However, ketamine also has major limitations such as potential addiction, side effects on the heart and urinary tract system, and severe narcotic-dissociating effects, requiring ketamine only as an antidepressant with limited use in hospitals. Therefore, finding a safe alternative to ketamine is an important goal in the development of current antidepressant drugs. NMDARs are an important target in the central nervous system and are involved in a variety of neurological disorders; at the same time, under different physiological conditions, the regulation of the NMDARs has high complexity, and the loss of function or the hyperactivity of the NMDARs can cause different diseases.
Complete blockade of NMDARs often leads to schizophreniform side effects and cognitive impairment, with appropriate activation contributing to an increase in cognitive levels; however, excessive activation of NMDARs can also lead to side effects such as epilepsy, neuronal damage and allodynia. In addition, there is increasing evidence that activation and reversal of NMDARs dysfunction through their glycine sites has shown good efficacy in both animal and human antidepressant trials. In a secondary clinical trial, a single intravenous injection of rapastinel (Glyx-13) at 5-10mg/kg showed a rapid and persistent reduction in depressive symptoms. A large number of experiments prove that rapastinel, as a partial agonist of a Gly site of an NMDARs, exerts its rapid and lasting antidepressant action by enhancing the long-term potentiating effect (LTP) and weakening the long-term inhibitory effect (LTD).
However, in the two recent clinical trials, the simultaneous use of rapastinel and oral antidepressant did not achieve different results from those in the placebo group (simultaneous oral antidepressant); rapastinel alone also failed to achieve superior results over placebo. Another rapastinel derivative, apimosinel, also tested in clinical phase two, is an orally effective partial agonist of NMDARs and has a stronger inhibitory effect on NMDARs than rapastinel. According to the current clinical test results related to the depression resistance of the NMDARs, although the results are poor, the rapid antidepressant activity and the cognitive improvement effect of rapastinel make people hope about the target of the NMDARs, and the receptor is activated or the sensitivity of the receptor is improved without obvious side effects such as psychoid side effects and the like.
NMDARs are a special dual ligand gated ion channel, co-regulated by the most major excitatory neurotransmitter in the brain, L-glutamate and its co-agonist, D-serine or glycine. As a heterotetrameric complex, NMDARs consist of two essential GluN1 subunits, with two GluN2 subunits (including four subtypes GluN 2A-D) or one GluN2 and one GluN3 subunit (including two subtypes GluN 3A-B). NMDARs on Ca 2+ ，Na + And K + Both are permeable and require that L-glutamate and glycine (or D-serine) bind to the GluN2 subunit and GluN1 subunit (or GluN3 subunit), respectively. Like other glutamate ionophores, NMDARs have a multi-domain molecular structure comprising: an extracellular amino-terminal region involved in subunit assembly, a ligand binding region that binds an endogenous ligand, and a transmembrane region that constitutes a heterotetrameric ionic void.
Allosteric modulators that alter receptor sensitivity have also gained increasing attention over the last two decades as compared to direct blocking or agonizing NMDARs. Positive allosteric modulators may increase the receptor's susceptibility to and activity of agonists, rather than directly activating the receptor. Therefore, positive allosteric modulators can reverse dysfunction due to decline in NMDARs function and avoid toxicity associated with over-activation.
Figure BDA0003005343500000031
NMDARs positive allosteric modulators
Recently, more and more studies have used positive allosteric modulators of NMDARs for the treatment of MDD, schizophrenia and even cognitive impairment. A neurosterone, 20-oxo-5-pregnene-3 β -sulfonate (PS, 1), was found to be both an orthosteric and a negative allosteric modulator of NMDARs; when present with agonists, PS enhances GluN2A and GluN2B subtype function, but has inhibitory effects on GluN2C and GluN 2D. More studies have found that PS achieves transient suppression and sustained functional enhancement by slowing the desensitization and inactivation of NMDAR ] . An endogenous compound 24 (S) -hydroxycholesterol (2) having a structure close to PS, acting on a different site of PS and having a better activity (EC) than PS 50 1 μ M); 24 (S) -hydroxycholesterol was found to exhibit better selectivity for NMDARs over AMPA and GABAA receptors, but not between subtypes of NMDAR.
Spermine (3), another endogenous compound, was found to be a GluN1/GluN2B selective NMDAR positive allosteric modulator. UBP512 (4), 9-iodophenanthrene-3-carboxylic acid, was found to be a GluN2A selective NMDAR allosteric modulator, while having no effect on GluN2B subtypes and exhibiting inhibitory effects on GluN2C and GluN2D subtypes; chemical modification of UBP512 at position 9 can alter the activity enhancement and subtype selectivity of the compound. UBP646 (5) showed PAM effect for all NMDAR subtypes, but UBP710 (6) showed function enhancement only for GluN2A and GluN2B subtypes. Further structure-activity relation research on phenanthrene mother nucleus series compounds finds that a 4-position isohexyl substituted compound UBP684 (7) has better activity, finds that a formic acid structure has a key effect on the activity, and the deletion of an alkyl chain can cause the compound to be converted from PAM to NAM. CIQ represents a class of NMDAR positive allosteric modulators with tetrahydroisoquinoline structures, with high selectivity for GluN2C and GluN2D subtypes; more intensive point mutation studies have found that compounds are able to interact with the M1 transmembrane helix of the transmembrane region, thereby reducing the difficulty of opening the channel, rather than stabilizing its open state. PYD-106 represents another series of PAMs acting on the binding pocket between the LDB domain and the ATD domain and shows high selectivity for the GluN2C subtype. Recently, a new class of GluN2A subtype-selective PAMs with thiazolopyrimidinone backbones has been discovered; further structure-activity relationship studies and X crystal derivation results indicated that compounds GNE-6901 (10) and GNE-8324 (11) can both bind to sites between the dimers of the GluN1-GluN2A LBD region; in addition, more medicinal works have been reported to optimize the activity and drug-forming property of the compound, such as replacing N-ethylaniline with 3-trifluoromethylpyrazole structure to enhance the metabolic stability of the compound, and introducing a cyclopropanecarbonitrile structure at the 3-position to optimize the drug-forming property; finally, a compound GNE-0723 (12) with the best selectivity to GluN2A is obtained; and the compound GNE-5729 (13) derived from GNE-0723 has a characteristic pyridopyrimidone parent nucleus and has good pharmacokinetic properties.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.
The invention provides an aromatic formamide derivative shown as a general formula (1), or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate or hydrate thereof, and application of the aromatic formamide derivative as a positive allosteric modulator of an N-methyl-D-aspartate receptor (NMDARs):
Figure BDA0003005343500000041
wherein, ar in the formula (I) 1 Is a group R 1 Substituted thienyl, by radicals R 1 Substituted furyl, by radicals R 1 Substituted imidazolyl, by the radical R 1 Substituted pyrrolyl, or by radicals R 1 Substituted phenyl; here, R 1 Each independently of the others hydrogen, halogen, unsubstituted C1-C6 alkylOr C1-C6 alkyl substituted by optionally substituted pyrazole;
ar in formula (I) 2 Is an optionally substituted aromatic hydrocarbon group, or an optionally substituted heteroaryl group.
In an embodiment of the present application, R in formula (I) 1 Is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or methyl substituted by optionally substituted pyrazole (may be optionally substituted pyrazole-1-methyl); here, the optionally substituted pyrazole means unsubstituted pyrazole, or pyrazole substituted by a group selected from: halogen, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted by one or more halogens, nitro, cyano.
In an embodiment of the present application, ar in formula (I) 2 Is an optionally substituted aromatic hydrocarbon group which is an optionally substituted phenyl group or an optionally substituted naphthyl group, wherein the optional substitution means being unsubstituted or substituted by one or more groups selected from:
unsubstituted C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy, phenyl, pyridine, pyrimidine, halogen, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, unsubstituted C1-C6 alkoxycarbonyl, mono-C1-C6 alkylaminocarbonyl, di-C1-C6 alkylaminocarbonyl, phenyl-substituted C1-C6 alkoxycarbonyl, or hydroxyl-substituted C1-C6 alkylaminocarbonyl.
In an embodiment of the present application, ar in formula (I) 2 Is an optionally substituted heteroaryl group which is an unsubstituted heteroaryl group or a substituted heteroaryl group; the heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, benzimidazolonyl, or quinolyl; here, the optional substitution means being unsubstituted or substituted by one or more groups selected from:
unsubstituted C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino.
In some embodiments, the compound of formula (I) is substituted with a group R 1 Substituted thienyl is of the formula:
Figure BDA0003005343500000051
here, R 1 Is as defined above; preferably, R 1 Is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, unsubstituted pyrazol-1-methyl or substituted pyrazol-1-methyl; here, the substituted pyrazole-1-methyl is substituted on the pyrazole with one or more groups selected from: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl.
In some embodiments, the compound of formula (I) is substituted with a group R 1 Substituted furyl is of the formula:
Figure BDA0003005343500000061
here, R 1 Is as defined above; preferably, R 1 Is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, unsubstituted pyrazol-1-methyl or substituted pyrazol-1-methyl; here, the substituted pyrazole-1-methyl is substituted on the pyrazole with one or more groups selected from: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl.
In some embodiments, the compound of formula (I) is substituted with a group R 1 Substituted phenyl is of the formula:
Figure BDA0003005343500000062
here, R 1 Is as defined above;preferably, R 1 Is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, unsubstituted pyrazol-1-methyl or substituted pyrazol-1-methyl; here, the substituted pyrazole-1-methyl is substituted on the pyrazole with one or more groups selected from: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl.
In some embodiments, ar in formula (I) 2 Is optionally substituted phenyl, or optionally substituted naphthyl, wherein the optional substitution means being unsubstituted or substituted by one or more groups selected from:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, phenyl, pyridine, amino, monomethylamino, monoethylamino, monopropylamino, monobutylamino, methoxycarbonyl, ethoxyformyl, propoxycarbonyl, butoxyformyl, monomethylcarbamoyl, monoethylcarbamoyl, monopropylcarbamoyl, monobutylamino, anilinoformyl, benzyloxyformyl, 2-hydroxyethylcarbamoyl, 3-hydroxypropylcarbamoyl, or 4-hydroxybutylcarbamoyl.
In some embodiments, ar in formula (I) 2 The following unsubstituted or substituted heteroaryl groups: pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, benzimidazolonyl, or quinolinyl; optionally, the substituents are one or more of the following groups:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, halogen, amino.
In a particularly preferred embodiment of the present application, there is provided the use of a derivative of the arylcarboxamides of formula (1) as a positive allosteric modulator of the N-methyl-D-aspartate receptor (NMDARs), said derivative being selected from the following compounds:
n- (2-methyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 00);
n- (2-ethyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 01);
n- (pyridin-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 02);
n- (2-methoxycarbonyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 03);
n- (4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 04);
n- (2-Methoxycarbonyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (Compound LF 05);
n- (2-methylphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 06);
n-phenyl-5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 07);
n- (2-hydroxymethyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 08);
n- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 09);
n- (2,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 10);
n- (pyridin-3-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 11);
n- ([ 1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 12);
n- (2- (2-hydroxyethyl) phenyl)) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 13);
n- (2-chloro-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 14);
n- (2-methylamino-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 15);
n- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 16);
n- [ (1,1' -biphenyl) -2-yl ] -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 17);
n- (2-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 18);
n- (2-anilinophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (compound LF 19);
n- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 20);
n- (pyridin-4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 21);
n- (2-butylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 22);
n- (2-phenylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 23);
n- (2- (3-hydroxypropyl) carbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 24);
n- (2-benzylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 27);
n- (2- (4-hydroxybutyl) carbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 28);
n- (2-methyl-4-bromophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (compound LF 29);
n- (2-methyl-4-chlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (compound LF 30);
n- (2-methyl-4-bromophenyl) -5- ((3, -trifluoromethyl-5-methyl-1H-pyrazol-1-methyl) furan-2-carboxamide (compound LF 31);
n- (2-methyl-4-chlorophenyl) -5- [ (3, -trifluoromethyl-5-methyl-1H-pyrazol-1-yl) methyl ] -furan-2-carboxamide (compound LF 32);
n- (2-methyl-4-bromophenyl) -furan-2-carboxamide (compound LF 33);
n- (2-methyl-4-bromophenyl) -5-methylfuran-2-carboxamide (compound LF 34);
n- (2-methyl-4-bromophenyl) -5-chlorofuran-2-carboxamide (compound LF 35);
n- (2-methyl-4-bromophenyl) -thiophene-2-carboxamide (compound LF 36);
n- (2-methyl-4-bromophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 37);
n- (2-methyl-4-chlorophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 38);
n- (2-methyl-4-fluorophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 39);
n- (2-methyl-4-bromophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 40);
n- (2-methyl-4-chlorophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 41);
n- (2-methyl-4-fluorophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 42);
n- (2-methyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 43);
n- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 44);
n- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 45);
n- (2-methyl-4-bromophenyl) -2- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 46);
n- (2-methoxycarbonyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 47);
n- (3,5-difluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 48);
n- (3,5-dimethoxyphenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 49);
n- (2-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 50);
n- (2-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 51);
n- (3-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 52);
n- (2,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 53);
n- (3,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 54);
n- (3,5-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 55);
n- (3-chloro-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 56);
n- (3-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 57);
n- (3,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 58);
n- (3,5-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 59);
n- (3,4-diethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 60);
n- (3,5-difluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 61);
n- (3-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 62);
n- (3,5-dimethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (Compound LF 63);
n- (isoquinolin-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 64);
n- (1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 65);
n- (1H-indol-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 66);
n- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 67);
n- (2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 68);
n- (quinolin-7-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 69);
n- ([ 1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 70);
n- (4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 71);
n- (3-methyl- [1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 72), and
n- (2-methyl-4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 73);
or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate or hydrate thereof.
In a second aspect, the present invention provides an arylcarboxamide derivative represented by general formula (I-1), or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate or hydrate thereof:
Figure BDA0003005343500000121
wherein, ar in the formula (I-1) 1 Is a group R 1 Substituted thienyl, by radicals R 1 Substituted furyl, by radicals R 1 Substituted imidazolyl by a radical R 1 Substituted pyrrolyl, or by radicals R 1 Substituted phenyl; here, R 1 Is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or methyl substituted by optionally substituted pyrazole (may be optionally substituted pyrazole-1-methyl); here, the optionally substituted pyrazole means unsubstituted pyrazole, or pyrazole substituted by a group selected from: halogen, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted by one or more halogens, nitro, cyano;
ar in the formula (I-1) 2 Is optionally substituted phenyl, or optionally substituted naphthyl, wherein the optional substitution means being unsubstituted or substituted by one or more groups selected from:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, phenyl, pyridine, amino, monomethylamino, monoethylamino, monopropylamino, monobutylamino, methoxycarbonylformyl, ethoxyformyl, propoxycarbonyl, butoxyformyl, monomethylcarbamoyl, monoethylcarbamoyl, monopropylcarbamoyl, monobutylaminoyl, anilinoyl, benzyloxyformyl, 2-hydroxyethylcarbamoyl, 3-hydroxypropylcarbamoyl, or 4-hydroxybutylcarbamoyl;
or, ar in the formula (I-1) 2 The following unsubstituted or substituted heteroaryl groups: pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, benzimidazolonyl, or quinolinyl; optionally, the substituents are one or more of the following groups:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, halogen, amino;
and that the derivatives represented by the formula (I-1) do not include the following compounds:
n- (2-methyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 00);
n- (2,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 10);
n- (pyridin-3-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 11);
n- (2-chloro-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 14);
n- (2-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 18);
n- (pyridin-4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 21);
n- (2-methyl-4-bromophenyl) -furan-2-carboxamide (compound LF 33);
n- (2-methyl-4-bromophenyl) -5-methylfuran-2-carboxamide (compound LF 34);
n- (2-methyl-4-bromophenyl) -5-chlorofuran-2-carboxamide (compound LF 35);
n- (2-methyl-4-bromophenyl) -thiophene-2-carboxamide (compound LF 36);
n- (2-methyl-4-chlorophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 38); and
n- (2-methyl-4-chlorophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 41).
In some embodiments of the present application, there is provided an arylcarboxamide derivative represented by the general formula (I-1), wherein Ar in formula (I-1) 1 Is a group R 1 Substituted thienyl, preferably, of the formula:
Figure BDA0003005343500000141
here, R 1 Is optionally substituted pyrazol-1-methyl; the optionally substituted pyrazole refers to unsubstituted pyrazole, or pyrazole substituted by a group selected from: halogen, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, nitro and cyano; preferably, the substituted pyrazole-1-methyl is substituted on the pyrazole by one or more groups selected from: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and trifluoromethyl; more preferably, the substituted pyrazole-1-methyl is 3,5-dimethyl-1H-pyrazole-1-methyl, 3,5-bistrifluoromethyl-1H-pyrazole-1-methyl, 3-trifluoromethyl-5-methyl-1H-pyrazole-1-methyl, or 3-methyl-5-trifluoromethyl-1H-pyrazole-1-methyl;
ar in the formula (I-1) 2 Is optionally substituted phenyl, or optionally substituted naphthyl, wherein the optional substitution means being unsubstituted or substituted by one or more groups selected from:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, phenyl, pyridine, amino, monomethylamino, monoethylamino, monopropylamino, monobutylamino, methoxycarbonylformyl, ethoxyformyl, propoxycarbonyl, butoxyformyl, monomethylcarbamoyl, monoethylcarbamoyl, monopropylcarbamoyl, monobutylaminoyl, anilinoyl, benzyloxyformyl, 2-hydroxyethylcarbamoyl, 3-hydroxypropylcarbamoyl, or 4-hydroxybutylcarbamoyl;
or, ar in the formula (I-1) 2 The following heteroaryl groups, unsubstituted or substituted: pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, benzimidazolonyl, or quinolinyl; optionally, the substituents are one or more of the following groups:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, halogen, amino.
In some embodiments of the present application, there is provided an arylcarboxamide derivative represented by the general formula (I-1), wherein Ar in formula (I-1) 1 Is a radical R 1 Substituted furanyl, preferably, of the formula:
Figure BDA0003005343500000151
here, R 1 Is substituted pyrazol-1-methyl; the substituted pyrazole refers to pyrazole substituted by groups selected from: halogen, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted by one or more halogens, nitro and cyano, and at least one group is defined as C1-C6 alkyl substituted by one or more halogens; preferably, the substituted pyrazole-1-methyl is substituted on the pyrazole with a trifluoromethyl group and one or more groups selected from: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and trifluoromethyl; more preferably, the substituted pyrazole-1-methyl is 3,5-bistrifluoromethyl-1H-pyrazole-1-methyl, 3-trifluoromethyl-5-methyl-1H-pyrazole-1-methyl, or 3-methyl-5-trifluoromethyl-1H-pyrazole-1-methyl;
ar in the formula (I-1) 2 Is optionally substituted phenyl, or optionally substituted naphthyl, wherein the optional substitution means being unsubstituted or substituted by one or more groups selected from:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, phenyl, pyridine, amino, monomethylamino, monoethylamino, monopropylamino, monobutylamino, methoxycarbonylformyl, ethoxyformyl, propoxycarbonyl, butoxyformyl, monomethylcarbamoyl, monoethylcarbamoyl, monopropylcarbamoyl, monobutylaminoyl, anilinoyl, benzyloxyformyl, 2-hydroxyethylcarbamoyl, 3-hydroxypropylcarbamoyl, or 4-hydroxybutylcarbamoyl;
or, ar in the formula (I-1) 2 The following unsubstituted or substituted heteroaryl groups: pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, benzimidazolonyl, or quinolinyl; optionally, the substituents are one or more of the following groups:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, halogen, amino.
In a particularly preferred embodiment, the present application provides an arylcarboxamide derivative represented by the general formula (I-1), which is selected from the following compounds:
n- (2-ethyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 01);
n- (pyridin-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 02);
n- (2-methoxycarbonyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 03);
n- (4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 04);
n- (2-Methoxycarbonyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (Compound LF 05);
n- (2-methylphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 06);
n-phenyl-5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 07);
n- (2-hydroxymethyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 08);
n- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 09);
n- ([ 1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 12);
n- (2- (2-hydroxyethyl) phenyl)) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 13);
n- (2-methylamino-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 15);
n- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 16);
n- [ (1,1' -biphenyl) -2-yl ] -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 17);
n- (2-anilinophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (compound LF 19);
n- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 20);
n- (2-butylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 22);
n- (2-phenylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 23);
n- (2- (3-hydroxypropyl) carbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 24);
n- (2-benzylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 27);
n- (2- (4-hydroxybutyl) carbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 28);
n- (2-methyl-4-bromophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (Compound LF 29)
N- (2-methyl-4-chlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (compound LF 30);
n- (2-methyl-4-bromophenyl) -5- ((3, -trifluoromethyl-5-methyl-1H-pyrazole-1-methyl) furan-2-carboxamide (compound LF 31);
n- (2-methyl-4-chlorophenyl) -5- [ (3, -trifluoromethyl-5-methyl-1H-pyrazol-1-yl) methyl ] -furan-2-carboxamide (compound LF 32);
n- (2-methyl-4-bromophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 37);
n- (2-methyl-4-fluorophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 39);
n- (2-methyl-4-bromophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 40);
n- (2-methyl-4-fluorophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 42);
n- (2-methyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 43);
n- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 44);
n- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 45);
n- (2-methyl-4-bromophenyl) -2- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide (compound LF 46);
n- (2-methoxycarbonyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 47);
n- (3,5-difluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 48);
n- (3,5-dimethoxyphenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 49);
n- (2-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 50);
n- (2-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 51);
n- (3-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 52);
n- (2,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 53);
n- (3,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 54);
n- (3,5-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (compound LF 55);
n- (3-chloro-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 56);
n- (3-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 57);
n- (3,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 58);
n- (3,5-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 59);
n- (3,4-diethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 60);
n- (3,5-difluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 61);
n- (3-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 62);
n- (3,5-dimethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 63);
n- (isoquinolin-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 64);
n- (1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 65);
n- (1H-indol-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 66);
n- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 67);
n- (2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 68);
n- (quinolin-7-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 69);
n- ([ 1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 70);
n- (4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 71);
n- (3-methyl- [1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (Compound LF 72)
N- (2-methyl-4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (compound LF 73);
or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate or hydrate thereof.
In a third aspect, the present invention also provides a process for preparing an aromatic carboxamide derivative represented by the general formula (I), comprising the steps of:
Figure BDA0003005343500000201
carrying out amidation reaction on the compound of the formula (II) and the compound of the formula (III) to obtain a compound of the formula (I);
here, the substituents Ar in the formulae (II) and (III) 1 And Ar 2 As defined above for the compounds of formula (I).
In a fourth aspect, the present invention provides a pharmaceutical composition comprising a pharmacologically effective amount of a benzamide derivative of the invention, or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier. The compound is mixed with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition. The pharmaceutical composition can be administered orally in the form of tablet, capsule, pill, powder, granule, powder, or syrup, or parenterally in the form of injection. The unit dose of the pharmaceutical composition is 0.1mg to 1g.
The pharmaceutical composition can be prepared by conventional pharmaceutical methods. Suitable pharmaceutically acceptable carriers include diluents or fillers, as well as binders, excipients, disintegrants, lubricants, stabilizers, sweeteners or flavoring agents, colors, dyes, and the like. Commonly used excipients include: saccharide derivatives, starch derivatives, cellulose derivatives, gum arabic and the like; binders such as gelatin, polyvinylpyrrolidone, polyethylene glycol; disintegrants such as sodium carboxymethyl cellulose, polyvinylpyrrolidone; lubricants such as talc, calcium stearate, magnesium stearate, spermaceti, etc.; stabilizers such as methyl paraben; and various sweetening or flavoring agents, coloring matter or dyes, and diluents such as water and various organic solvents, e.g., ethanol, propylene glycol, glycerin, and the like.
In a fifth aspect, the compounds of the present invention are novel compounds having positive allosteric modulating activity at the N-methyl-D-aspartate receptor (NMDARs) and can be used for the treatment of depression.
The arylcarboxamide derivatives provided by the present invention are useful for the treatment of depression associated with positive allosteric modulation of NMDARs, post-traumatic stress disorder, parkinson's disease, mild cognitive impairment and/or obsessive-compulsive disorder.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the example serve to explain the principles of the invention and not to limit the invention.
FIG. 1 shows the enhancement of the current of in vitro cultured neuronal cells (young neurons with fewer generations) by the compound LF00 of the invention;
FIG. 2 shows the effect of LF00 of the present invention on the enhancement of the current in cultured neuronal cells (more mature neurons) in vitro;
FIG. 3 shows a forced swimming test and a social failure model for evaluating the antidepressant effect of the compound LF00 of the present invention;
FIG. 4 shows the evaluation of the antidepressant action of the compounds LF45, LF55, LF58, LF77 according to the invention (single intraperitoneal administration);
FIG. 5 shows a forced swim test to evaluate the antidepressant effect of the compounds LF55 and LF58 of the present invention (administered twice in two consecutive days to the abdominal cavity).
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
In the present invention, abbreviations are:
NMDAR N-methyl-D-aspartate receptor
NMDA N-methyl-D-aspartic acid
PE Petroleum Ether
IC 50 Half the inhibitory amount
DIPEA diisopropylethylamine
HATU 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea
Hexafluorophosphate ester
MeOH methanol
FBS fetal bovine serum
PBS phosphate buffer
ATP adenosine triphosphate
Tris tromethamine
GTP guanosine triphosphate
EGTA ethylene glycol bis (2-aminoethyl ether) tetraacetic acid
HEPES 4-hydroxyethyl piperazine ethanesulfonic acid
The nuclear magnetic data were measured by a Bruker Avance model III 400 nuclear magnetic resonance apparatus with internal standard TMS (tertramethyl silane); nuclear magnetic data were processed by mestReNova (ver.6.1.0, mesrelab Research s.l.) software; high resolution mass spectrometry data (ESI-TOF) were determined by Bruker Apex IV FTMS type Fourier ion cyclotron transform mass spectrometry; thin layer chromatography silica gel plate (Shanghai Pongwu Co., ltd.); column chromatography silica gel (200-300 mesh, shanghai Pongkuai Co., ltd.).
All solvents, starting materials and reagents were, unless otherwise stated, commercially available in analytical pure form.
In an embodiment of the invention, the invention provides the following synthetic schemes:
synthesis scheme 1:
part of Ar in formula (I) 1 Is a group R 1 Synthetic routes to substituted furanyl compounds;
Figure BDA0003005343500000231
reagents and conditions (i) concentrated sulfuric acid, methanol; (ii) thionyl chloride, at 0 ℃ to room temperature, reacting for 1h; (iii) sodium iodide, acetone, heated to reflux for 0.5 hours; (iv) 3,5-dimethyl-1H-pyrazole or 3,5-bistrifluoromethyl-1H-pyrazole, potassium carbonate, acetonitrile, 60 ℃,7 hours; (v) sodium hydroxide, methanol, 40 ℃,3 hours; (vi) aniline, DIPEA, HATU, dichloromethane, 0 ℃ to r.t.,12h.
Synthesis scheme 2:
Figure BDA0003005343500000232
middle part of formula (I)Ar is divided 1 Is a group R 1 Synthetic routes to substituted furanyl compounds;
the reagent and the conditions are (i) 2-amino-5-chlorobenzoic acid methyl ester, DIPEA, HATU and dichloromethane, and the temperature is 0 ℃ to room temperature for 12 hours; (ii) sodium hydroxide, methanol, 40 ℃,3 hours; (iii) Methylamine, ethylamine, 4-hydroxybutylamine, aniline, benzylamine, etc., DIPEA, HATU, dichloromethane, 0 ℃ to r.t.,12 hours.
Synthesis scheme 3:
Figure BDA0003005343500000241
part of Ar in the formula (I) 1 Is a group R 1 Synthetic routes to substituted thienyl compounds; reacting the reagent with the conditions of (i) methyl iodide, sodium bicarbonate and N, N-dimethylformamide at room temperature; (ii) Reacting sodium tri (acetoxyl) borohydride and methanol at room temperature; (iii) thionyl chloride, dichloromethane, reacting at room temperature; (iv) heating and refluxing sodium iodide and acetone; (v) 2,4-dimethylpyrazole, potassium carbonate, acetonitrile, 70 degrees celsius; (vi) sodium hydroxide, methanol, 40 degrees celsius; (vii) (1) aniline, HATU, DIPEA, dichloromethane, at room temperature for compounds L43-45, L56, L57; (2) thionyl chloride, dichloromethane, 0 ℃; aniline, triethylamine; suitable for compound L58-73.
Example 1
Synthesis of methyl 5-hydroxymethylfurancarboxylate:
Figure BDA0003005343500000251
5-hydroxymethyl furan-2-carboxylic acid (2mmol, 284 mg) and concentrated sulfuric acid (0.125 mL) were added to a round bottom flask containing methanol (2.5 mL), refluxed at 70 ℃ for 3h, neutralized to pH =7 with saturated sodium bicarbonate, spun dry, added with 20mL water, extracted with ethyl acetate (20 mL × 3), the organic phases combined, dried over anhydrous sodium sulfate, column chromatographed (PE/EA = 2/1-1/1) to give 300mg of colorless oily liquid, yield: 96 percent. 1 H NMR(400MHz,CDCl 3 )δ7.09(d,J＝2.7Hz,1H),6.37(d,J＝2.7Hz,1H),4.63(d,J＝5.6Hz,2H),3.84(s,5H),3.19(t,J＝6.2Hz,1H)。 13 C NMR(101MHz,CDCl 3 ) δ 159.23,158.47,143.97,118.91,109.42,57.49,51.96.MS (ESI) theoretical value C 7 H 8 O 4 [M+H] + m/z 156.0, found 156.0.
Example 2
Synthesis of methyl 5-chlorofurancarboxylate:
Figure BDA0003005343500000252
methyl 5-hydroxymethylfurancarboxylate (1mmol, 156mg) was dissolved in 5ml CH 2 Cl 2 Adding SOCl at room temperature 2 (0.5 mL), stirred at room temperature for 0.5h, and the reaction solution was spin-dried and column chromatographed (PE/EA =3% -6%) with saturated sodium bicarbonate in a condensed water receiver to give 151mg of colorless oily liquid, yield: 86 percent. 1 H NMR(400MHz,CDCl 3 )δ7.12(d,J＝2.7Hz,1H),6.48(d,J＝2.7Hz,1H),4.58(s,2H),3.89(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 158.78,154.13,144.80,118.80,111.39,52.04,36.65.MS (ESI) theoretical value C 7 H 7 ClO 3 [M+H] + m/z 175.0, found 175.0.
Example 3
Synthesis of methyl 5-iodofurancarboxylate:
Figure BDA0003005343500000253
methyl 5-chlorofurancarboxylate (5mmol, 873mg) and sodium iodide (6mmol, 899mg) were added to a round-bottomed flask with acetone (30 mL) as a solvent, respectively, and reacted at 70 ℃ for 0.5h, and after the reaction liquid was dried by spinning, column chromatography (PE/EA =3% -6%) was performed to obtain 1307mg of colorless oily liquid, yield: 98 percent. 1 HNMR(400MHz,CDCl 3 ) δ 7.12 (d, J =2.7hz, 1h), 6.48 (d, J =2.7hz, 1h), 4.18 (s, 2H), 3.89 (s, 3H). MS (ESI) theoretical value C 7 H 7 IO 3 [M+H] + m/z 266.8, found 266.8.
Example 4
Synthesis of methyl 5- ((3,5-dimethyl-1H-pyrazole) -1-methyl) furan 2-carboxylate:
Figure BDA0003005343500000261
the general method comprises the following steps: methyl 5-iodofurancarboxylate (1mmol, 266mg) was dissolved in acetonitrile (4 mL), followed by addition of potassium carbonate and 3,5-dimethyl-4-nitropyrazole, heating to 60 ℃, reaction for 7h, direct spin-drying, column chromatography (PE/EA =3% -15%) to give 155mg of white solid, yield: 66 percent. 1 HNMR(400MHz,CDCl 3 ) δ 7.07 (d, J =2.8hz, 1h), 6.17 (d, J =2.8hz, 1h), 5.82 (s, 1H), 5.20 (s, 2H), 3.85 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H). MS (ESI) theoretical value C 12 H 14 N 2 O 3 [M+H] + m/z 235.1, found 235.1.
Example 5
Synthesis of methyl 5- ((3,5-bistrifluoromethyl-1H-pyrazole) -1-methyl) furan 2-carboxylate:
Figure BDA0003005343500000262
the synthesis method is the same as example 4:3,5-ditrifluoromethylpyrazole as raw material. White solid was obtained, yield: and 64 percent. 1 H NMR(400MHz,CDCl 3 )δ7.05(d,J＝3.4Hz,1H),6.87(s,1H),6.38(d,J＝3.4Hz,1H),5.48(s,2H),3.79(s,3H). 13 C NMR(101MHz,CDCl 3 )δ158.71,150.94,145.02,(CF 3 )(143.20,142.81,142.41,142.02),(CF 3 )(134.21,133.80,133.40,133.00),(C 1 -CF 3 )(121.50,120.34),(C 2 -CF 3 ) (118.82,117.66),118.69,111.67,106.70,52.01,48.52. MS (ESI) theoretical value C 12 H 8 F 6 N 2 O 3 [M+H] + m/z 342.2, found 342.2.
Example 6
Synthesis of methyl 5- ((3-trifluoromethyl-5-methyl-1H-pyrazole) -1-methyl) furan 2-carboxylate:
Figure BDA0003005343500000263
the synthesis method is the same as example 4: 3-methyl-5-trifluoromethyl pyrazol is used as a raw material. White solid was obtained, yield: and 69 percent. 1 H NMR(400MHz,CDCl 3 ) δ 7.06 (d, J =3.5hz, 1h), 6.28 (s, 1H), 6.27 (d, J =3.5hz, 1h), 5.30 (s, 2H), 3.83 (s, 3H), 2.34 (s, 3H). MS (ESI) theoretical value C 12 H 11 F 3 N 2 O 3 [M+H] + m/z 288.2, found 288.2.
Example 7
Synthesis of 5- ((3,5-dimethyl-1H-pyrazole) -1-methyl) furan 2-carboxylic acid:
Figure BDA0003005343500000271
the corresponding methyl arylcarboxylate (1mmol, 234mg) was dissolved in methanol (5 mL), and 5N sodium hydroxide (3 eq.) was added and reacted at 30 ℃ for 3 hours. pH =3 adjusted with 1N hydrochloric acid, spin dried, added with 20mL water, extracted with ethyl acetate (20ml × 3), combined organic phases, dried with anhydrous sodium sulfate, filtered with suction, spin dried to give a white solid 205mg, yield: 93 percent. MS (ESI) theoretical value C 11 H 6 F 6 N 2 O 3 [M+H] + m/z 220.2, found 220.2.
Example 8
Synthesis of 5- ((3,5-bistrifluoromethyl-1H-pyrazole) -1-methyl) furan 2-carboxylic acid:
Figure BDA0003005343500000272
the synthesis method is the same as example 7:5- ((3,5-ditrifluoromethyl-1H-pyrazole) -1-methyl) furan 2-methyl formate is used as a raw material. A white solid was obtained. 1 H NMR(400MHz,CDCl 3 )δ9.90(s,3H),7.30(d,J＝3.5Hz,2H),6.96(s,2H),6.48(d,J＝3.5Hz,2H),5.57(s,4H)。 13 C NMR(101MHz,CDCl 3 )δ162.88,152.15,144.15,(CF 3 ) 1 (143.28,142.96,142.56,142.32),(CF 3 ) 2 (134.31,133.90,133.50,133.09),(C 1 -CF 3 )(121.47,120.32),120.90,(C 2 -CF 3 ) (118.79,117.64),112.02,106.81,48.51. MS (ESI) theoretical value C 11 H 6 F 6 N 2 O 3 [M+H] + m/z 328.1, found 328.1.
Example 9
Synthesis of N- (4-bromo-2-ethylphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 01):
Figure BDA0003005343500000273
5- ((3,5-dimethyl-1H-pyrazole) -1-methyl) furan 2-carboxylic acid (1 mmol), HATU (2 eq.) and DIPEA (2 eq.) were dissolved in dichloromethane (5 mL), stirred in an ice-water bath for 20min, then 2-ethyl-4-bromoaniline was added, and the reaction was allowed to warm to room temperature naturally for about 12H. Spin-drying, adding 30mL saturated saline solution, extracting with ethyl acetate (30mL × 3), mixing organic phases, adding anhydrous sodium sulfate, drying, filtering, spin-drying, and performing column chromatography (PE/EA =3% -36%) to obtain 273mg of white solid with a yield of 68%. M.p. 155-157 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.90(d,J＝8.7Hz,2H),7.33(d,J＝7.0Hz,2H),7.14(d,J＝3.4Hz,1H),6.34(d,J＝3.4Hz,1H),5.85(s,1H),5.22(s,2H),2.61(q,J＝7.6Hz,2H),2.29(s,3H),2.21(s,3H),1.25(t,J＝7.6Hz,4H). 13 C NMR(101MHz,CDCl 3 ) δ 155.80,152.45,148.33,147.43,139.10,136.35,133.62,131.38,129.75,124.27,118.32,116.28,110.63,105.94,45.80,24.07,13.57,13.51,11.09.MS (ESI) theoretical value C 19 H 21 N 3 O 2 Br[M+H] + m/z 402.0, found 402.0.
Example 10
Synthesis of N- (pyridin-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 02):
Figure BDA0003005343500000281
the synthesis method is the same as example 9: 192mg of a white solid are obtained, yield 65%. M.p. 98-100 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.54(s,1H),8.37(d,J＝4.7Hz,1H),8.11(d,J＝8.4Hz,1H),7.82(t,J＝7.8Hz,1H),7.57(d,J＝3.2Hz,1H),7.20-7.09(m,1H),6.49(d,J＝3.0Hz,1H),5.84(s,1H),5.27(s,2H),2.29(s,3H),2.07(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 156.77,154.64,152.10,148.41,146.83,146.64,139.56,138.67,120.24,116.72,114.82,110.79,105.66,45.43,13.74,11.09.MS (ESI) theoretical value C 16 H 17 N 4 O 2 [M+H] + m/z 297.1, found 297.1.
Example 11
Synthesis of N- (4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 04):
Figure BDA0003005343500000282
the synthesis method is the same as that of example 9: 209mg of a white solid was obtained in 56% yield. M.p. 168-170 ℃. 1 HNMR(400MHz,CDCl 3 )δ8.33(s,1H),7.53(d,J＝8.4Hz,2H),7.42(d,J＝8.5Hz,2H),7.12(d,J＝3.2Hz,1H),6.28(d,J＝2.9Hz,1H),5.85(s,1H),5.18(s,2H),2.26(s,3H),2.21(s,3H). 13 C NMR(101MHz,CDCl 3 ) δ 155.83,152.38,148.37,147.37,139.20,136.51,131.98 (2C), 121.62 (2C), 117.11,116.36,110.79,106.08,77.26,45.75,13.47,11.11.MS (ESI) theoretical value C 17 H 17 N 3 O 2 Br[M+H] + m/z374.0, found 374.0.
Example 12
Synthesis of N- (2-methylphenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 06):
Figure BDA0003005343500000291
the synthesis method is the same as that of example 9: yield 170mg of white solid55％。M.p.:98-100℃。 1 H NMR(400MHz,CDCl 3 )δ8.03-7.90(m,2H),7.32-7.20(m,2H),7.16-7.04(m,2H),6.32(s,1H),5.87(s,1H),5.22(s,2H),2.30(s,6H),2.23(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 155.80,152.31,148.28,147.64,139.16,135.15,130.49,128.55,126.87,125.12,122.41,115.94,110.48,105.94,45.81,17.57,13.51,11.08.MS (ESI) theoretical value C 18 H 20 N 3 O 2 [M+H] + m/z 310.1, found 310.1.
Example 13
Synthesis of N-phenyl-5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 07):
Figure BDA0003005343500000292
the synthesis method is the same as example 9: 195mg of a white solid are obtained, yield 66%. M.p. 124-126 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.10(s,1H),7.72(d,J＝8.6Hz,2H),7.41-7.28(m,3H),7.10(t,J＝7.4Hz,1H),6.46(d,J＝3.5Hz,1H),5.85(s,1H),5.28(s,2H),2.29(s,3H),2.09(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 156.53,154.08,147.37,146.83,139.57,138.93,129.10,124.21,120.84,115.77,110.62,105.69,45.54,13.75,11.10.MS (ESI) theoretical value C 17 H 18 N 3 O 2 [M+H]+ m/z 296.1, found 296.1.
Example 14
Synthesis of N- (2-hydroxymethyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 08):
Figure BDA0003005343500000301
the synthesis method is the same as that of example 9: 258mg of a white solid are obtained, yield 72%. M.p. 131-133 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.04(s,1H),7.75(d,J＝8.6Hz,1H),7.46(d,J＝2.3Hz,1H),7.35(dd,J＝8.6,2.4Hz,1H),7.23(d,J＝3.4Hz,1H),6.51(d,J＝3.4Hz,1H),5.84(s,1H),5.75(t,J＝5.5Hz,1H),5.27(s,2H),4.57(d,J＝5.4Hz,2H),2.31(s,3H),2.08(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 156.22,154.14,147.18,146.91,139.66,137.03,134.72,129.36,127.58,127.48,125.69,116.16,111.06,105.63,60.94,45.36,13.75,11.10.HRMS (ESI) theoretical value C 18 H 19 N 3 O 3 Cl[M+H] + m/z 360.1, found 360.1.
Example 15
Synthesis of N- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 09):
Figure BDA0003005343500000302
the synthesis method is the same as example 9: 155mg of a white solid was obtained, yield 45%. M.p. 138-140 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.32(s,1H),8.37(s,1H),7.96-7.74(m,4H),7.56-7.33(m,3H),6.49(d,J＝3.4Hz,1H),5.86(s,1H),5.31(s,2H),2.31(s,3H),2.09(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 156.73,154.21,147.36,146.86,139.60,136.61,133.74,130.46,128.68,127.92,127.82,126.89,125.31,121.31,117.10,115.93,110.69,105.71,45.56,13.76,11.11.MS (ESI) theoretical value C 21 H 20 N 3 O 2 [M+H] + m/z 346.1, found 346.1.
Example 16
Synthesis of N- (2,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 10):
Figure BDA0003005343500000311
the synthesis method is the same as that of example 9: 233mg of a white solid was obtained in 64% yield. M.p. 175-177 ℃. 1 H-NMR(400MHz,CDCl 3 )δ8.53(s,1H),8.47(d,J＝8.9Hz,1H),7.42(s,1H),7.19(d,J＝3.3Hz,1H),6.38(d,J＝3.2Hz,1H),5.87(s,1H),5.25(s,2H),2.35(s,3H),2.23(s,3H)。 13 C NMR(101MHz,CDCl 3 )δ155.48,153.06,148.45,146.93,139.20,133.00,129.18,128.77,128.02,123.24,121.88,116.87,110.75,105.96,45.72,13.50,11.10.MS (ESI) theoretical value C 17 H 16 N 3 O 2 C l2 [M+H] + m/z 364.0, found 364.0.
Example 17
Synthesis of N- (pyridin-3-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 11):
Figure BDA0003005343500000312
the synthesis method is the same as that of example 9: 172mg of a white solid are obtained, yield 58%. M.p. 144-146 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),8.90(s,1H),8.31(d,J＝4.3Hz,1H),8.14(d,J＝8.3Hz,1H),7.38(dd,J＝9.7,3.4Hz,2H),6.47(d,J＝2.5Hz,1H),5.85(s,1H),5.29(s,2H),2.28(s,3H),2.08(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 156.82,154.41,146.95,146.88,145.09,142.41,139.58,135.67,127.84,123.99,116.42,110.77,105.71,45.52,13.73,11.08.MS (ESI) theoretical value C 16 H 17 N 4 O 2 [M+H] + m/z 297.1, found 297.1.
Example 18
Synthesis of N- (1,1' -biphenyl-4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 12):
Figure BDA0003005343500000313
the synthesis method is the same as example 9: 208mg of a white solid are obtained, yield 56%. M.p. 178-180 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.23(s,1H),7.85(d,J＝8.6Hz,2H),7.67(d,J＝8.7Hz,4H),7.45(t,J＝7.6Hz,2H),7.40–7.29(m,2H),6.47(d,J＝3.3Hz,1H),5.86(s,1H),5.30(s,2H),2.30(s,3H),2.09(s,3H)。 13 C NMR(101MHz,DMSO-d 6 )δ156.55,154.15,147.38,146.87,140.13,139.57,138.48,135.86,129.35(2C),127.54,127.31(2C),126.75(2C),121.12(2C),115.90,110.66,105.72,45.56,13.75,11.10.HRMS (ESI) theoretical value C 23 H 22 N 3 O 2 [M+H] + m/z 372.1, found 372.1.
Example 19
Synthesis of N- (2- (2-hydroxyethyl) phenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 13):
Figure BDA0003005343500000321
the synthesis method is the same as example 9: 132mg of a white solid are obtained, yield 39%. M.p. 93-95 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.23(s,1H),7.60(d,J＝7.9Hz,1H),7.33-7.21(m,2H),7.18(d,1H),7.17-7.12(m,1H),6.56-6.45(m,1H),5.85(s,1H),5.53-5.33(m,1H),5.27(s,2H),3.70(t,J＝5.7Hz,2H),2.78(t,J＝5.6Hz,2H),2.31(s,3H),2.09(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 156.43,153.82,147.62,146.91,139.66,136.46,134.56,130.86,126.96,125.84,125.32,115.41,110.79,105.64,62.68,45.38,35.44,13.75,11.08.MS (ESI) theoretical value C 19 H 22 N 3 O 3 [M+H] + m/z 340.1, found 340.1.
Example 20
Synthesis of N- (2-chloro-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 14):
Figure BDA0003005343500000322
the synthesis method is the same as example 9: 311mg of a white solid was obtained in 76% yield. M.p. 186-188 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.51(s,1H),8.40(d,J＝8.9Hz,1H),7.53(s,1H),7.39(d,J＝8.9Hz,1H),7.16(d,J＝3.1Hz,1H),6.36(d,J＝2.9Hz,1H),5.86(s,1H),5.23(s,2H),2.33(s,3H),2.21(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 155.42,153.08,148.42,146.90,139.19,133.45,131.48,130.91,123.39,122.14,116.88,116.34,110.77,105.96,45.69,13.51,11.11.HRMS (ESI) theoretical value C 17 H 16 N 3 O 2 Cl[M+H] + m/z 408.0, found 408.0.
Example 21
Synthesis of N- (2-methylaminophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 15):
Figure BDA0003005343500000331
the synthesis method is the same as example 9: 181mg of white solid was obtained, yield 56%. M.p. 135-137 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.41(s,1H),7.26(s,1H),7.18-7.04(m,2H),6.68-6.55(m,2H),6.47(d,J＝2.9Hz,1H),5.85(s,1H),5.26(s,2H),5.13(d,J＝4.5Hz,1H),2.71(d,J＝4.8Hz,3H),2.30(s,3H),2.09(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 157.20,153.53,147.74,146.76,145.32,139.55,127.75,127.52,122.81,115.83,115.33,110.75,110.58,105.64,45.48,30.28,13.75,11.13.MS (ESI) theoretical value C 18 H 21 N 4 O 2 [M+H] + m/z 325.17, found 325.17.
Example 22
Synthesis of N- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 16):
Figure BDA0003005343500000332
the synthesis method is the same as that of example 9: 162mg of a white solid was obtained in 47% yield. M.p. 133-135 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝9.2Hz,1H),7.88(s,1H),7.28(s,0H),7.19(s,2H),7.14(d,J＝2.9Hz,1H),6.33(d,J＝2.7Hz,1H),5.87(s,1H),5.23(s,2H),2.30(s,3H),2.28(s,3H),2.23(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 155.72,152.46,148.32,147.38,139.12,133.77,130.34,130.24,130.03,126.82,123.56,116.22,110.54,105.97,45.80,17.43,13.49,11.07.HRMS (ESI) theoretical value C 18 H 19 N 3 O 2 Cl[M+H] + m/z 344.1, found 344.1.
Example 23
Synthesis of N- (1,1' -biphenyl-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 17):
Figure BDA0003005343500000341
the synthesis method is the same as example 9: 241mg of white solid are obtained with a yield of 65%. M.p. 97-99 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.46(s,1H),7.63(d,J＝7.8Hz,1H),7.49-7.27(m,8H),7.10(d,J＝2.9Hz,1H),6.43(d,J＝3.2Hz,1H),5.84(s,1H),5.19(s,2H),2.21(s,3H),2.08(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 156.90,153.77,147.38,146.82,139.52,139.08,137.47,134.40,130.77,129.12 (2C), 128.92 (2C), 128.35,127.85,127.38,126.88,115.62,110.78,105.64,45.36,13.74,11.07.MS (ESI) theoretical value C 23 H 22 N 3 O 2 [M+H] + m/z 372.1, found 372.1.
Example 24
Synthesis of N- (2-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 18):
Figure BDA0003005343500000342
the synthesis method is the same as example 9: 264mg of a white solid was obtained, yield 76%. M.p. is 131-133 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.86(s,1H),7.79-7.40(m,2H),7.29(d,J＝10.7Hz,2H),6.50(s,1H),5.85(s,1H),5.28(s,2H),2.30(s,3H),2.08(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 160.14 (d, J =246.4 Hz), 156.69,154.22,146.91,146.86,139.60,131.31 (d, J =3.5 Hz), 130.72 (d, J =11.1 Hz), 129.87 (d, J =9.1 Hz), 117.20 (d, J =25.9 Hz), 116.28,115.14 (d, J =22.1 Hz), 110.83,105.66,45.43,13.75,11.11.MS (ESI) theoretical value C 17 H 16 N 3 O 2 ClF[M+H] + m/z 348.09, found 348.09.
Example 25
Synthesis of N- (2-anilinophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 19):
Figure BDA0003005343500000351
the synthesis method is the same as example 9: 131mg of a white solid are obtained, yield 34%. M.p. 64-66 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.41(s,1H),7.67(d,J＝7.8Hz,1H),7.51(s,1H),7.29(d,J＝7.9Hz,1H),7.26-7.10(m,4H),7.03(t,J＝7.5Hz,1H),6.90(d,J＝7.8Hz,2H),6.80(t,J＝7.3Hz,1H),6.47(d,J＝3.0Hz,1H),5.81(s,1H),5.23(s,2H),2.24(s,3H),2.06(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 156.63,153.85,147.42,146.82,144.82,139.55,136.60,129.65,129.56 (2C), 126.21,125.47,122.60,121.10,119.97,116.87 (2C), 115.92,110.84,105.64,45.39,13.73,11.05.HRMS (ESI) theoretical value C 23 H 23 N 4 O 2 [M+H] + m/z 387.1, found 387.1.
Example 26
Synthesis of N- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 20):
Figure BDA0003005343500000352
the synthesis method is the same as example 9: 147mg of a white solid are obtained, yield 45%. M.p. 120-122 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.73(s,1H),7.37-7.29(m,1H),7.26(d,J＝3.0Hz,1H),7.14(dd,J＝9.6,2.4Hz,1H),7.04(td,J＝8.6,2.7Hz,1H),6.47(d,J＝3.3Hz,1H),5.85(s,1H),5.27(s,2H),2.30(s,3H),2.21(s,3H),2.08(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 160.47 (d, J =242.0 Hz), 156.81,153.88,147.39,146.83,139.59,137.03 (d, J =8.3 Hz), 132.21 (d, J =2.8 Hz), 128.86 (d, J =8.8 Hz), 117.09 (d, J =22.2 Hz), 115.60,113.10 (d, J =22.0 Hz), 110.66,105.65,45.46,18.32,13.74,11.11.HRMS (ESI) theoretical value C 18 H 19 N 3 O 2 F[M+H] + m/z 328.15, found 328.1.
Example 27
Synthesis of N- (pyridin-4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 21):
Figure BDA0003005343500000361
the synthesis method is the same as that of example 9: 225mg of a white solid was obtained, yield 76%. M.p. 88-90 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.79(s,1H),8.57(d,J＝5.9Hz,2H),7.93(d,J＝6.2Hz,2H),7.47(d,J＝3.4Hz,1H),6.50(d,J＝3.2Hz,1H),5.86(s,1H),5.31(s,2H),2.28(s,3H),2.08(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 157.16,155.39,148.82,147.73 (2C), 146.95,146.32,139.62,117.89,114.79 (2C), 110.99,105.75,45.52,13.74,11.07.MS (ESI) theoretical value C 16 H 17 N 4 O 2 [M+H] + m/z 297.1, found 297.1.
Example 28
Synthesis of N- (2-methyl-4-bromophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 29):
Figure BDA0003005343500000362
the synthesis method is the same as example 9: 332mg of a white solid was obtained in 67% yield. M.p. 130-132 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.72(s,1H),7.65(s,1H),7.50(s,1H),7.40(d,1H),7.37-7.32(m,2H),6.72(d,J＝2.6Hz,1H),5.75(s,2H),2.21(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 156.38,150.46,148.07,141.26 (q, J =40.2 Hz), 136.39,135.32,133.26,133.20 (q, J =40.2 Hz), 129.34,128.40,120.86 (q, J =269.0 Hz), 119.38 (q, J =269.8 Hz), 118.76,115.79,112.69,108.22,48.88,17.86.MS (ESI) theoretical value C 18 H 13 N 3 O 2 F 6 [M+H] + m/z 496.0, found 496.0.
Example 29
Synthesis of N- (2-methyl-4-chlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 30):
Figure BDA0003005343500000363
the synthesis method is the same as example 9: 211mg of a white solid was obtained, yield 47%. M.p. 139-140 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.74(s,1H),7.65(d,J＝5.3Hz,1H),7.47-7.31(m,3H),7.26(d,J＝8.5Hz,1H),6.72(d,J＝2.7Hz,1H),5.75(s,2H),2.21(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 156.44,150.45,148.08 (d, J =1.9 Hz), 141.27 (q, J =38.8 Hz), 136.08 (d, J =3.6 Hz), 134.86,133.20 (q, J =40.4 Hz), 130.43,130.36,128.12 (d, J =3.8 Hz), 126.38,120.86 (q, J =268.6 Hz), 119.38 (q, J =269.6 Hz), 115.76,112.68,108.21,48.87,17.93.MS (ESI) theoretical value C 18 H 13 N 3 O 2 F 6 [M+H] + m/z 452.0, found 452.0.
Example 30
Synthesis of N- (2-methyl-4-bromophenyl) -5- ((3-trifluoromethyl-5-methyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 31):
Figure BDA0003005343500000371
the synthesis method is the same as example 9: 385mg of a white solid was obtained, yield 87%. M.p. 98-100 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.75(s,1H),7.57-7.46(m,1H),7.45-7.36(m,1H),7.37-7.25(m,2H),6.63(d,J＝3.4Hz,1H),6.56(s,1H),5.52(s,2H),2.43(s,3H),2.21(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 156.48,152.34,147.72,142.03,140.35 (q, J =37.2 Hz), 136.62,135.38,133.26,129.34,128.61,122.00 (q, J =268.1 Hz), 118.82,115.82,111.68,104.55,46.51,17.9,11.19.MS (ESI) theoretical value C 18 H 16 N 3 O 2 F 3 [M+H] + m/z 442.0, found 442.0.
Example 31
Synthesis of N- (2-methyl-4-chlorophenyl) -5- ((3-trifluoromethyl-5-methyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 32):
Figure BDA0003005343500000372
the synthesis method is the same as example 9: 230mg of a white solid are obtained, yield 58%. M.p. 127-129 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.76(s,1H),7.42-7.34(m,2H),7.34-7.24(m,2H),6.63(d,J＝3.4Hz,1H),6.57(s,1H),5.52(s,2H),2.43(s,3H),2.21(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 156.54,152.33,147.73,142.03,140.34 (q, J =37.2 Hz), 136.30,134.92,130.47,130.36,128.34,126.39,122.00 (q, J =268.2 Hz), 115.80,111.68,104.55 (d, J =2.5 Hz), 46.51,18.05,11.19.MS (ESI) theoretical value C 18 H 16 N 3 O 2 F 3 [M+H] + m/z 398.0, found 398.0.
Example 32
Synthesis of N- (3,5-difluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (LF 48):
Figure BDA0003005343500000381
the synthesis method is the same as example 9: 241mg of white solid are obtained with a yield of 41%. M.p. 116-118 ℃. 1 H NMR(400MHz,CDCl 3 )δ11.82(s,1H),8.84(dd,J＝5.0,19.0Hz 1H),7.76(dd,J＝4.0,8.0Hz 1H),7.33-7.28(m,1H),7.22(d,J＝4.0Hz,1H),6.97(s,1H),6.57(d,J＝4.0Hz,1H),5.60(s,2H),3.99(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 167.37,158.79,156.36,156.00,149.33,148.57,137.27,122.40,121.70,121.48,117.15,116.91,116.88,116.81,116.14,112.53,106.69,52.58,48.57. Theoretical value C 19 H 12 F 7 N 3 O 4 [M+H] + m/z 479.3, found 479.3.
Example 33
Synthesis of N- (3,5-dimethoxyphenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (LF 49):
Figure BDA0003005343500000382
the synthesis method is the same as example 9: 234mg of a white solid was obtained in 80% yield. M.p. is 123-125 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.00(s,1H),7.20(d,J＝4.0Hz,1H),6.98(s,1H),6.89(d,J＝4.0Hz,2H),6.60(d,J＝4.0Hz,1H),6.30(t,J＝4.0Hz,1H),5.55(s,2H),3.83(s,6H) 13 C NMR(101MHz,CDCl 3 ) δ 161.13 (2C), 155.42,148.62,148.34,138.84,124.68,121.45,116.02 (2C), 112.99,107.16,98.15 (2C), 97.25,77.22,55.41 (2C), 48.42. Theoretical value of C 19 H 15 F 6 N 3 O 4 [M+H] + m/z 463.3, found 463.3.
Example 34
Synthesis of N- (2-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (LF 50):
Figure BDA0003005343500000391
the synthesis method is the same as example 9: 206mg of a white solid are obtained, yield 78%. M.p.:162-164 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.94-7.90(m,2H),7.83(s,1H),7.21(d,J＝4.0Hz,1H),6.97-6.92(m,1H),6.63(d,J＝4.0Hz,1H),5.55(s,2H),2.32(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 161.15,158.72,155.50,148.61,148.48,130.88,130.85,124.42,124.34,117.24,117.02,115.96,113.50,113.28,113.00,106.86,77.33,77.02,76.70,48.36,48.34,17.47. Theoretical value: c 19 H 12 F 7 N 3 O 4 [M+H] + m/z 436.1, found 436.1.
Example 35
Synthesis of N- (2-methyl-4-chlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (LF 51):
Figure BDA0003005343500000392
the synthesis method is the same as example 9: 246mg of a white solid was obtained in 71% yield. M.p.:145-147 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.03(d,J＝6.0Hz,2H),7.90(s,1H),7.23(m,3H),6.97(s,1H),6.64(d,J＝4.0Hz,2H),5.55(s,2H),2.31(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 155.32,148.67,148.42,133.68,133.24,130.31,130.08,129.95,126.91,123.20,124.68,121.45,120.47,118.81,116.13,113.09,106.88,48.33,17.14. Theoretical value of C 18 H 12 ClF 6 N 3 O 2 [M+H] + m/z 452.5, found 452.5.
Example 36
Synthesis of N- (3-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (LF 52):
Figure BDA0003005343500000393
the synthesis method is the same as that of example 9: 250mg of white solid are obtained, yield 75%. M.p. is 132-134 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.97(s,1H),7.50(dd,J＝4.0,8.0Hz 1H),7.39(m,1H),7.20(d,J＝4.0Hz,1H),7.01(m,2H),6.60(d,J＝4.0Hz,1H),5.55(s,2H),2.31(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 159.48,155.39,148.57,148.37,132.72,125.70,125.52,123.23,123.18,120.49,119.10,119.02,115.97,115.47,115.24,113.01,48.40,14.70. Theoretical value of C 18 H 12 F 7 N 3 O 2 [M+H] + m/z 436.3, found 436.3.
Example 37
Synthesis of N- (2,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (LF 53):
Figure BDA0003005343500000401
the synthesis method is the same as example 9: 103mg of a white solid are obtained, yield 29%. M.p. 123-125 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.58(s,1H),8.50(d,J＝12.0Hz,1H),7.45(d,J＝4.0Hz,1H),7.3(dd,J＝2.0,9.0Hz,1H),7.25(d,J＝4.0Hz,1H),6.97(s,1H),6.65(d,J＝4.0Hz,1H),5.57(s,2H)。 13 C NMR(101MHz,CDCl 3 ) Delta 155.19,149.21,147.93,132.86,130.65,129.43,128.88,127.99,123.43,121.91,121.60,119.11,116.68,116.64,113.06,106.82,48.33 theoretical value C 17 H 9 Cl 2 F 6 N 3 O 2 [M+H] + m/z 473.1, found 473.1.
Example 38
Synthesis of N- (3,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (LF 54):
Figure BDA0003005343500000402
the synthesis method is the same as example 9: 200mg of white solid are obtained, yield 56%. M.p. 143-145 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.39(s,1H),8.07(d,J＝4.0Hz,1H),7.69(d,J＝8.0Hz,2H),7.62(d,J＝8.0Hz,1H),7.61,7.60,7.42(d,J＝4.0Hz,1H),6.72(d,J＝4.0Hz,1H),5.76(s,1H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 156.45,151.07,147.59,139.04,133.00,131.37,131.11,125.80,121.92,120.96,120.71,120.27,116.48,112.76,108.39,107.13,48.93. Theoretical value of C 17 H 9 Cl 2 F 6 N 3 O 2 ，[M+H] + m/z 473.1, found 473.0.
Example 39
Synthesis of N- (3,5-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide (LF 55):
Figure BDA0003005343500000411
synthesis methodThe same as example 9: 202mg of a white solid was obtained in 56% yield. M.p. 148-150 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.11(s,1H),7.62(d,J＝2.0Hz,2H),7.24(d,J＝4.0Hz,1H),7.16(t,J＝4.0Hz,1H),6.99(s,1H),6.62(d,J＝4.0Hz,1H),5.55(s,2H). 13 C NMR(101MHz,CDCl 3 ) δ 155.34,149.04,147.71,138.94,135.39 (2C), 133.64,133.24,124.68,121.45,120.47,118.16 (2C), 116.86,113.21,107.06,48.31. Theoretical value of C 17 H 9 Cl 2 F 6 N 3 O 2 [M+H] + m/z 473.1, found 473.1.
Example 40
Synthesis of N- (2-methoxycarbonyl-4-fluoro-phenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 47):
Figure BDA0003005343500000412
the synthesis method is the same as example 9: 217mg of a white solid was obtained, yield 56%. M.p.: 1 H NMR(400MHz,CDCl 3 )δ11.81(bs,1H),8.87-8.84(m,1H),7.76(d,J＝8.0Hz,1H),7.33-7.28(m,1H),7.19(s,1H),6.41(s,1H),5.86(s,1H),5.25(s,2H),3.99(s,3H),2.43(s,3H),2.24(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 167.59,156.34,153.19,148.34,147.64,139.68,137.52,122.38,121.85,121.63,117.09,116.85,116.43,110.86,105.75,52.61,45.66,13.48,11.04.MS (ESI) theoretical value C 19 H 18 FN 3 O 4 [M+H] + m/z 371.3, found 371.3.
EXAMPLE 41
Synthesis of N- (2-methoxycarbonyl-4-chloro-phenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 03):
Figure BDA0003005343500000421
the synthesis method is the same as example 9: 217mg of a white solid was obtained, yield 56%. M.p. 180-182 ℃. 1 H NMR(400MHz,CDCl 3 )δ11.86(s,1H),8.81(d,J＝9.1Hz,1H),8.02(s,1H),7.51(d,J＝9.1Hz,1H),7.17(d,J＝3.1Hz,1H),6.37(d,J＝2.6Hz,1H),5.84(s,1H),5.25(s,2H),3.97(s,3H),2.41(s,3H),2.21(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 167.53,156.36,153.36,148.33,139.73,139.60,134.50,130.49,127.80,121.87,116.63,116.46,110.86,105.72,77.23,52.63,45.69,13.54,11.05.MS (ESI) theoretical value C 19 H 19 N 3 O 4 Cl[M+H] + m/z 388.1, found 388.1.
Example 42
Synthesis of N- (4-bromo-6-methoxycarbonylphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 05):
Figure BDA0003005343500000422
the synthesis method is the same as example 9: this gave 201mg of a white solid in 45% yield. M.p. 174-176 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.92(s,1H),7.78(s,2H),7.29(d,J＝3.3Hz,1H),6.49(d,J＝3.4Hz,1H),5.85(s,1H),5.28(s,2H),3.71(s,3H),2.30(s,3H),2.24(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 165.67,156.66,154.08,147.25,146.84,139.73,139.61,136.84,134.65,130.43,130.39,119.06,115.98,110.77,105.66,52.79,45.46,13.75,11.12.HRMS (ESI) theoretical value C 20 H 21 N 3 O 4 Br[M+H] + m/z 432.07, found 432.07.
Example 43
Synthesis of 2- (5- ((3,5-dimethyl-1H-pyrazole) -1-methyl) furan-2-carboxamide) -5-chloro-benzoic acid:
Figure BDA0003005343500000423
dissolving LF03 (1 mmol) in methanol (10 mL), adding 5N sodium hydroxide (3 eq.) to react at 30 deg.C for 3h, adjusting pH =3 with 1N hydrochloric acid, spin-drying, adding 20mL water, extracting with ethyl acetate (20mL x 3), combining organic phases, adding anhydrous sodium sulfate to dry, suction-filtering, and spin-drying to obtain whiteSolid 318mg, yield: 85 percent. 1 H NMR(400MHz,CDCl 3 )δ8.81(d,J＝9.1Hz,1H),8.02(s,1H),7.51(d,J＝9.1Hz,1H),7.17(d,J＝3.1Hz,1H),6.37(d,J＝2.6Hz,1H),5.84(s,1H),5.25(s,2H),3.97(s,3H),2.41(s,3H),2.21(s,3H).ESI-MS m/z C 18 H 16 ClN 3 O 4 [M-H] + :372.08。
Example 44
Synthesis of N- (2- (N-butylcarbamoyl) -4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 22):
Figure BDA0003005343500000431
2- (5- ((3,5-dimethyl-1H-pyrazole) -1-methyl) furan-2-carboxamide) -5-chloro-benzoic acid (1 mmol), HATU (2 eq.) and DIPEA (2 eq.) were dissolved in dichloromethane (5 mL), stirred in an ice-water bath for 20min, then n-butylamine (1.5 eq.) was added, allowed to warm to room temperature naturally, and reacted for about 12H. Spin-drying, adding 30mL saturated saline solution, extracting with ethyl acetate (30mL × 3), mixing organic phases, adding anhydrous sodium sulfate, drying, filtering, spin-drying, and performing column chromatography (PE/EA =3% -50%) to obtain 372mg of white solid with yield of 87%. M.p. 175-177 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ12.44(s,1H),8.94(s,1H),8.60(d,J＝8.8Hz,1H),7.89(s,1H),7.59(d,J＝8.2Hz,1H),7.18(s,1H),6.61(s,1H),5.81(s,1H),5.26(s,2H),4.18–4.00(m,1H),3.18(d,J＝4.7Hz,2H),2.44(s,3H),2.05(s,3H),1.55(q,2H),1.37(q,2H),0.92(t,J＝6.9Hz,3H). 13 C NMR(101MHz,DMSO-d 6 ) Delta 167.32,155.81,154.36,147.45,139.92,138.19,132.19,128.18,127.12,122.28,122.14,116.67,111.66,105.41,49.05,45.12,39.52,31.23,20.15,14.11,13.71,11.05 HRMS (ESI) theoretical value C 22 H 26 N 4 O 3 Cl[M+H] + m/z 429.17, found 429.17.
Example 45
Synthesis of N- (2- (carboxanilido) -4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide (LF 23):
Figure BDA0003005343500000441
the synthesis method is the same as example 44: 305mg of a white solid was obtained in 68% yield. M.p. 190-192 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ11.60(s,1H),10.64(s,1H),8.51(d,J＝8.9Hz,1H),8.00(s,1H),7.75(d,J＝8.0Hz,2H),7.67(d,J＝9.0Hz,1H),7.43(t,J＝7.6Hz,2H),7.27–7.12(m,2H),6.63(d,J＝2.5Hz,1H),5.78(s,1H),5.25(s,2H),2.38(s,3H),2.03(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 166.28,155.79,154.40,147.26,146.96,139.87,138.68,137.52,132.43,129.09,129.02,127.45,124.98,123.97,122.96,121.54,116.99,111.82,105.40,45.04,13.74,11.15.MS (ESI) theoretical value C 24 H 22 N 4 O 3 Cl[M+H] + m/z 449.1, found 449.1.
Example 46
Synthesis of N- (2- (3-hydroxypropamoyl) -4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 24):
Figure BDA0003005343500000442
the synthesis method is the same as example 44: 272mg of a white solid are obtained, yield 63%. M.p. 228-230 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),9.08～8.84(m,1H),8.59(d,J＝9.0Hz,1H),7.89(s,1H),7.60(d,J＝9.0Hz,1H),7.18(d,J＝2.9Hz,1H),6.60(d,J＝2.8Hz,1H),5.83(s,1H),5.27(s,2H),4.53(t,J＝4.9Hz,1H),3.51(q,J＝5.7Hz,2H),3.41–3.35(m,2H),2.44(s,3H),2.06(s,3H),1.73(p,J＝6.4Hz,2H). 13 C NMR(101MHz,DMSO-d 6 ) δ 167.40,155.82,154.41,147.41,146.98,139.98,138.14,132.22,128.24,127.12,122.27,122.17,116.70,111.64,105.47,59.05,45.13,37.32,32.39,13.74,11.09.MS (ESI) theoretical value C 21 H 24 N 4 O 4 Cl[M+H] + m/z 431.15, found 431.15.
Example 47
Synthesis of N- (2-N-propylaminoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 25):
Figure BDA0003005343500000451
the synthesis method is the same as example 44: 216mg of a white solid are obtained, yield 52%. M.p. 179-181 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.97(d,J＝4.9Hz,1H),8.60(d,J＝9.0Hz,1H),7.90(s,1H),7.61(d,J＝11.1Hz,1H),7.19(d,J＝3.4Hz,1H),6.61(d,J＝3.3Hz,1H),5.83(s,1H),5.27(s,2H),3.27(q,J＝6.7Hz,2H),2.44(s,3H),2.06(s,3H),1.58(q,J＝7.3Hz,2H),0.93(t,J＝7.4Hz,3H). 13 C NMR(101MHz,DMSO-d 6 ) Delta 167.38,155.81,154.36,147.45,146.97,139.93,138.21,132.20,128.19,127.11,122.25,122.10,116.66,111.66,105.41,45.12,41.62,22.45,13.72,11.92,11.05 HRMS (ESI) theoretical value C 21 H 24 N 4 O 3 Cl[M+H] + m/z 415.1537, found 415.1519.
Example 48
Synthesis of N- (2-ethylcarbamyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 26):
Figure BDA0003005343500000452
the synthesis method is the same as example 44: 245mg of a white solid was obtained in 61% yield. M.p. 206-208 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ12.46(s,1H),8.97(t,J＝5.5Hz,1H),8.60(d,J＝9.0Hz,1H),7.90(d,J＝2.5Hz,1H),7.61(dd,J＝9.0,2.5Hz,1H),7.19(d,J＝3.5Hz,1H),6.61(d,J＝3.5Hz,1H),5.83(s,1H),5.27(s,2H),3.38-3.33(m,2H),2.44(s,3H),2.06(s,3H),1.17(t,J＝7.2Hz,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 167.20,155.83,154.41,147.41,146.96,139.95,138.20,132.25,128.21,127.12,122.27,122.10,116.71,111.66,105.46,45.14,34.76,14.76,13.74,11.07.MS (ESI) theoretical value C 20 H 22 N 4 O 3 Cl[M+H] + m/z 401.1, found 401.1.
Example 49
Synthesis of N- (2-benzylaminoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 27):
Figure BDA0003005343500000461
the synthesis method is the same as example 44: 259mg of white solid was obtained, yield 56%. M.p. 210-212 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),9.53(t,J＝5.2Hz,1H),8.62(d,J＝9.0Hz,1H),7.99(s,1H),7.62(d,J＝9.0Hz,1H),7.37(s,4H),7.28(s,1H),7.19(d,J＝2.5Hz,1H),6.72-6.52(m,1H),5.77(s,1H),5.25(s,2H),4.54(d,J＝5.4Hz,2H),2.38(s,3H),2.05(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) Delta 167.46,155.85,154.41,147.40,146.95,139.92,139.15,138.36,132.48,128.85 (2C), 128.30,127.81 (2C), 127.44,127.21,122.39,121.77,116.78,111.69,105.44,45.11,43.19,13.74,11.06.MS (ESI) theoretical value C 25 H 24 N 4 O 3 Cl[M+H] + m/z 463.1, found 463.1.
Example 50
Synthesis of N- (2- (4-hydroxybutylcarbamoyl) -4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) furan-2-carboxamide (LF 28):
Figure BDA0003005343500000462
the synthesis method is the same as example 44: 156mg of white solid was obtained, yield 35%. M.p. 142-144 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ12.45(s,1H),8.97(s,1H),8.60(d,J＝9.0Hz,1H),7.90(s,1H),7.61(d,J＝9.0Hz,1H),7.19(s,1H),6.61(s,1H),5.83(s,1H),5.27(s,2H),4.46(t,J＝4.6Hz,1H),3.45(q,J＝5.6Hz,2H),2.45(s,3H),2.06(s,3H),1.67-1.55(m,2H),1.55-1.43(m,2H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 167.31,155.82,154.40,147.40,146.97,139.97,138.18,132.25,128.20,127.11,122.26,122.10,116.74,111.70,105.44,60.89,45.10,30.48,30.48,25.87,13.75,11.08.MS (ESI) theoretical value C 22 H 26 N 4 O 4 Cl[M+H] + m/z 445.1, found 445.1.
Example 51
Synthesis of N- (2-methyl-4-bromophenyl) -furan-2-carboxamide (LF 33):
Figure BDA0003005343500000471
the synthesis method is the same as example 9: 243mg of white solid is obtained, yield 87%. M.p. 105-107 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.82(s,1H),7.94(d,1H),7.50(d,J＝2.0Hz,1H),7.45-7.37(m,1H),7.34-7.29(m,2H),6.70(dd,J＝3.4,1.7Hz,1H),2.23(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 156.73,147.86,146.12,136.77,135.50,133.23,129.30,128.78,118.79,115.16,112.58,18.06.HRMS (ESI) theoretical value C 12 H 11 NO 2 Br[M+H] + m/z 278.0, found 278.0.
Example 52
Synthesis of N- (2-methyl-4-bromophenyl) -5-methylfuran-2-carboxamide (LF 34):
Figure BDA0003005343500000472
the synthesis method is the same as example 9: 245mg of a white solid was obtained in 83% yield. M.p. is 138-140 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.67(s,1H),7.49(d,J＝2.0Hz,1H),7.39(dd,J＝8.5,2.2Hz,1H),7.30(d,J＝8.5Hz,1H),7.20(d,J＝3.3Hz,1H),6.32(d,J＝3.2Hz,1H),2.38(s,3H),2.22(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) Delta 156.74,155.51,146.33,136.75,135.66,133.19,129.26,128.72,118.64,116.33,108.94,18.09,14.03.HRMS (ESI) theoretical value C 13 H 13 NO 2 Br[M+H] + m/z 294.0, found 294.0.
Example 53
Synthesis of N- (2-methyl-4-bromophenyl) -5-chlorofuran-2-carboxamide (LF 35):
Figure BDA0003005343500000473
the synthesis method is the same as example 9: 257mg of white solid are obtained, yield 82%. M.p. 122-124 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.92(s,1H),7.51(d,J＝1.7Hz,1H),7.44～7.34(m,2H),7.27(d,J＝8.5Hz,1H),6.75(d,J＝3.6Hz,1H),2.21(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 155.69,147.42,138.28,137.02,135.22,133.29,129.35,128.96,119.07,117.45,109.95,18.07.HRMS (ESI) theoretical value C 12 H 10 NO 2 ClBr[M+H] + m/z 314.0, found 314.0.
Example 54
Synthesis of N- (2-methyl-4-bromophenyl) -thiophene-2-carboxamide (LF 36):
Figure BDA0003005343500000481
the synthesis method is the same as example 9: 231mg of a white solid are obtained, yield 78%. M.p. is 128-130 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.95(s,1H),7.99(d,J＝3.3Hz,1H),7.86(dd,J＝5.0,0.9Hz,1H),7.52(d,J＝2.0Hz,1H),7.42(dd,J＝8.4,2.3Hz,1H),7.33～7.20(m,2H),2.24(s,2H)。 13 C NMR(101MHz,DMSO-d 6 ) Delta 160.35,139.86,137.04,135.81,133.28,132.18,129.68,129.35,129.06,128.55,118.94,18.10 HRMS (ESI) theoretical value C 12 H 11 NOSBr[M+H] + m/z 296.2, found 296.2.
Example 55
Synthesis of N- (2-methyl-4-bromophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-methyl) benzamide (LF 37):
Figure BDA0003005343500000482
the synthesis method is the same as example 9: 183mg of a white solid were obtained, yield 46%. M.p. 160-162 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.86(s,1H),7.93(d,J＝7.7Hz,2H),7.50(s,1H),7.41(d,J＝8.5Hz,1H),7.33(d,J＝8.4Hz,1H),7.22(d,J＝7.8Hz,2H),5.88(s,1H),5.28(s,2H),2.23(s,3H),2.17(s,3H),2.12(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 165.53,146.73,142.12,139.33,136.80,136.35,133.76,133.21,129.27,128.77,128.43,127.26,118.65,105.60,51.71,18.08,13.82,11.10.MS (ESI) theoretical value C 20 H 21 N 3 OBr[M+H] + m/z 398.1, found 398.1.
Example 56
Synthesis of N- (2-methyl-4-chlorophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-methyl) benzamide (LF 38):
Figure BDA0003005343500000491
the synthesis method is the same as example 9: 269mg of a white solid are obtained, yield 76%. And M.p. 159-161 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.87(s,1H),7.93(d,J＝8.3Hz,2H),7.42-7.34(m,2H),7.30-7.25(m,1H),7.22(d,J＝8.3Hz,2H),5.88(s,1H),5.29(s,2H),2.23(s,3H),2.18(s,3H),2.12(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) Delta 165.57,146.73,142.11,139.33,136.46,135.90,133.77,130.31,128.47,128.43,127.26,126.32,105.60,51.72,18.15,13.82,11.09.MS (ESI) theoretical value C 20 H 21 N 3 OCl[M+H] + m/z354.1, found 354.1.
Example 57
Synthesis of N- (2-methyl-4-bromophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-methyl) benzamide (LF 39):
Figure BDA0003005343500000492
the synthesis method is the same as example 9: 222mg of a white solid was obtained in 66% yield. M.p. 166-168 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.85(s,1H),7.94(d,J＝8.2Hz,2H),7.39-7.30(m,1H),7.22(d,J＝8.2Hz,2H),7.14(dd,J＝9.7,2.8Hz,1H),7.05(td,J＝8.6,3.0Hz,1H),5.89(s,1H),2.23(s,3H),2.18(s,3H),2.13(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 165.63,160.42 (d, J =242.0 Hz), 146.73,142.01,139.33,137.07 (d, J =8.4 Hz), 133.85,133.13 (d, J =2.8 Hz), 128.90 (d, J =8.8 Hz), 128.37,127.24,117.04 (d, J =22.2 Hz), 113.02 (d, J =22.1 Hz), 105.61,51.73,18.36,13.81,11.09.MS (ESI) theoretical value C 20 H 21 N 3 OF[M+H] + m/z 338.1, found 338.1.
Example 58
Synthesis of N- (2-methyl-4-bromophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-methyl) benzamide (LF 40):
Figure BDA0003005343500000493
the synthesis method is the same as example 9: 147mg of a white solid are obtained, yield 37%. M.p. 122-124 ℃. 1 HNMR(400MHz,DMSO-d 6 )δ9.93(s,1H),7.89(d,J＝7.7Hz,1H),7.74(s,1H),7.56-7.46(m,2H),7.41(d,J＝10.1Hz,1H),7.32(d,J＝8.5Hz,1H),7.27(d,J＝7.6Hz,1H),5.88(s,1H),5.28(s,2H),2.23(s,3H),2.19(s,3H),2.11(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) Delta 165.65,146.68,139.30,138.86,136.82,136.31,135.03,133.22,130.56,129.28,129.12,128.81,126.94,126.86,118.71,105.58,51.75,18.08,13.83,11.17.MS (ESI) theoretical value C 20 H 21 N 3 OBr[M+H] + m/z 398.0, found 398.0.
Example 59
Synthesis of N- (2-methyl-4-chlorophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-methyl) benzamide (LF 41):
Figure BDA0003005343500000501
the synthesis method is the same as example 9: 198mg of a white solid are obtained, yield 56%. M.p. 119-121 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.95(s,1H),7.89(d,J＝7.8Hz,1H),7.74(s,1H),7.49(t,J＝7.7Hz,1H),7.42-7.34(m,2H),7.32-7.23(m,2H),5.88(s,1H),5.28(s,2H),2.24(s,3H),2.19(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 165.70,146.68,139.29,138.86,136.53,135.85,135.04,130.55,130.34 (2C), 129.12,128.51,126.94,126.86,126.33,105.58,51.76,18.16,13.82,11.16.MS (ESI) theoretical value C 20 H 21 N 3 OCl[M+H] + m/z354.1, found 354.1.
Example 60
Synthesis of N- (2-methyl-4-fluorophenyl) -3- ((3,5-dimethyl-1H-pyrazole-1-methyl) benzamide (LF 42):
Figure BDA0003005343500000502
the synthesis method is the same as example 9: 155mg of a white solid were obtained, yield 46%. M.p. 107-109 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.91(s,1H),7.90(d,J＝7.6Hz,1H),7.75(s,1H),7.49(t,J＝7.6Hz,1H),7.38-7.29(m,1H),7.26(d,J＝7.5Hz,1H),7.15(d,J＝9.6Hz,1H),7.05(t,J＝8.4Hz,1H),5.87(s,1H),5.28(s,2H),2.23(s,3H),2.19(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 165.75,160.43 (d, J =241.9 Hz), 146.68,139.28,138.84,137.07 (d, J =8.5 Hz), 135.11,133.08 (d, J =2.7 Hz), 130.47,129.09,128.92 (d, J =8.8 Hz), 126.92,126.79,117.05 (d, J =22.1 Hz), 113.04 (d, J =22.0 Hz), 105.57,51.78,18.35,13.82,11.16.Ms (ESI) theoretical value C 20 H 21 N 3 OF[M+H] + m/z 338.1, found 338.1.
Example 61
Synthesis of methyl 5-formylthiophene-2-carboxylate:
Figure BDA0003005343500000511
adding 2-carboxyl-5-aldehyde thiophene (64.0 mmol,10.0 g) and iodomethane (1.2 eq.,10.9 g) into a round-bottom flask, stirring at room temperature for 10h, neutralizing with saturated sodium bicarbonate until pH =7, spin-drying, adding 80mL of water, extracting with ethyl acetate (80mL × 3), combining organic phases, drying with anhydrous sodium sulfate, spin-drying the reaction solution, and separating by column chromatography (PE/EA = 50%) to obtain 10.5g of colorless oily liquid, and obtaining the productRate: 96 percent. 1 H NMR(400MHz,CDCl 3 )δ9.99(s,1H),7.86(d,J＝4.0Hz,1H),7.75(d,J＝3.9Hz,1H),3.96(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 183.31,161.95,147.78,140.96,135.03,133.36,52.79.MS (ESI) theoretical value C 7 H 6 O 3 S[M+H] + m/z 170.2, found 170.2.
Example 62
Synthesis of methyl 5-hydroxymethylthiophene-2-carboxylate:
Figure BDA0003005343500000512
dissolving 5-aldehyde thiophene-2-methyl formate (5.9mmol, 1.0 g) in methanol, adding sodium borohydride acetate (4 eq.,4.99 g) into a round-bottom flask, adding acetic acid (1 eq.,0.35 g), stirring at room temperature for 24h, neutralizing with saturated sodium bicarbonate until the pH is =7, spinning, adding 80mL of water, extracting with ethyl acetate (80mL × 3), combining organic phases, drying with anhydrous sodium sulfate, spinning the reaction solution, and separating by column chromatography (PE/EA = 80%) to obtain 0.96g of colorless oily liquid, wherein the yield is as follows: 95 percent. Nuclear magnetism: 1 H NMR(400MHz,CDCl 3 )δ7.13(d,J＝3.4Hz,1H),6.42(dd,J＝3.4,0.7Hz,1H),4.70-4.65(m,2H),3.89(s,3H),2.69(s,1H)。 13 C NMR(101MHz,CDCl 3 ) δ 159.23,158.47,143.97,118.91,109.42,57.49,51.96.MS (ESI) theoretical value C 7 H 8 O 3 S[M+H] + m/z 172.0, found 172.0.
Example 63
Synthesis of methyl 5-chloro-thiophene-2-carboxylate:
Figure BDA0003005343500000521
5-Hydroxythiophene-2-carboxylic acid methyl ester (74.9 mmol,12.9 g) was dissolved in 40mL of dichloromethane, thionyl chloride (1.2 eq.,10.7 g) was added, the reaction was carried out at room temperature for 1h, saturated sodium bicarbonate was neutralized to pH =7, the solution was spun dry, 80mL of water was added, ethyl acetate was extracted (80mL. Multidot.3), the organic phases were combined, anhydrous sodium sulfate was added and the reaction solution was dried, and then the reaction solution was spun dryColumn chromatography (PE/EA = 40%) separation gave 11.7g of oily liquid, yield: 82 percent. Nuclear magnetism: 1 H NMR(400MHz,CDCl 3 )δ7.67(d,J＝3.8Hz,1H),7.09(dt,J＝3.8,0.8Hz,1H),4.78(d,J＝0.8Hz,2H),3.90(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 162.30,147.14,134.14,133.30,127.88,52.28,39.82.MS (ESI) theoretical value C 7 H 7 ClO 2 S[M+H] + m/z 190.6, found 190.6.
Example 64
Synthesis of methyl 5-iodothiophene-2-carboxylate:
Figure BDA0003005343500000522
methyl 5-chloromethylthiophene-2-carboxylate (61.4 mmol,11.7 g) and sodium iodide (2 eq, 18.5 g) were added to a round-bottomed flask in acetone (30 mL) as a solvent, and the reaction was stirred at 70 ℃ for 0.5h, and the reaction solution was dried and directly subjected to the next step. To give 17.0g of an oily liquid, yield: 98 percent. MS (ESI) theoretical value C 7 H 7 IO 2 S[M+H] + m/z 283.1, found 283.1.
Example 65
Synthesis of methyl 5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxylate:
Figure BDA0003005343500000523
dissolving 5-iodomethylthiophene-2-carboxylic acid methyl ester (60.3 mmol,17.0 g) in acetonitrile (30 mL), adding potassium carbonate (1.5 eq.,12.6 g) and 3,5-dimethylpyrazole (1.4 eq.,8.1 g), heating to 60 ℃, reacting for 7h, directly spin-drying, and separating by column chromatography (PE/EA =10% -15%) to obtain 14.6g of a white solid, yield: 97 percent. Nuclear magnetism: 1 H NMR(400MHz,CDCl 3 )δ7.62(dd,J＝3.8,1.0Hz,1H),6.85(dd,J＝3.8,0.9Hz,1H),5.84(s,1H),5.33(d,J＝1.0Hz,2H),3.84(d,J＝1.1Hz,3H),2.23(d,J＝1.0Hz,6H)。 13 C NMR(101MHz,CDCl 3 )δ162.40,148.33,147.42,138.95,133.48,132.99,125.87,106.01,52.12,47.78,13.51,11.04.MS (ESI) theoretical value C 7 H 7 ClO 2 S[M+H] + m/z 190.6, found 190.6.
Example 66
Synthesis of 5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxylic acid:
Figure BDA0003005343500000531
dissolving methyl 5- ((3,5-dimethylpyrazol-1-yl) methylthiophene-2-carboxylate (58.3mmol, 14.6 g) in methanol (40 mL), adding sodium hydroxide (3 eq.,7.0 g), reacting at 50 ℃ for 3h, adjusting the pH with hydrochloric acid =3, spin-drying, adding 40mL of water, extracting with ethyl acetate (40ml × 3), combining the organic phases, adding anhydrous sodium sulfate, drying, suction filtering, spin-drying to obtain a white solid 12.8g, yield: 93%. Nuclear magnetic: 1 H NMR(400MHz,DMSO-d 6 )δ13.05(s,1H),7.58(d,J＝3.7Hz,1H),7.02(dd,J＝3.8,1.0Hz,1H),5.84(s,1H),5.39(d,J＝0.9Hz,2H),2.21(d,J＝0.8Hz,3H),2.10(s,3H)。 13 C NMR(101MHz,DMSO)δ163.17,148.14,147.11,139.20,134.40,133.46,127.06,105.78,47.33,13.79,11.03。
example 67
Synthesis of N- (3-chloro-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 56):
Figure BDA0003005343500000532
5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carboxylic acid (1.27mmol, 300mg), HATU, DIPEA (2 eq.) were dissolved in dichloromethane (5 mL), stirred in an ice-water bath for 20min, then 3-chloro-4-fluoroaniline (1.2 eq.) was added, and the reaction was allowed to warm to room temperature naturally for about 12h. Spin-dry, add 30mL of saturated saline, ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, pump-filter, spin-dry, column-chromatographe (PE: PA = 2-5%) to obtain 204mg of white solid with a yield of 44%. M.p. 163-165 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.34(s,1H),7.98(dd,J＝4.0,8.0Hz 1H),7.84(d,J＝4.0Hz,1H),7.65(m,1H),7.41(t,J＝8.0Hz,1H),7.08(d,J＝4.0Hz,1H),5.85(s,1H),5.41(s,2H),2.23(s,3H),2.11(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 160.26,152.66,147.07 (d, J =28 Hz), 139.16 (d, J =36 Hz), 136.42,129.82,126.99,122.18,121.00 (d, J =28 Hz), 119.62,119.43,117.45,117.23,105.79,47.37,13.81,11.06. Theoretical value of C 17 H 15 ClFN 3 OS[M+H] + m/z 363.8, found 363.8.
Example 68
Synthesis of N- (2-methyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) thiophene-2-carboxamide (LF 43):
Figure BDA0003005343500000541
the synthesis method is the same as example 67: 149mg of a white solid was obtained in 37% yield. M.p. 97-99 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.90(s,1H),7.81(d,J＝3.1Hz,1H),7.50(s,1H),7.40(d,J＝8.4Hz,1H),7.25(d,J＝8.4Hz,1H),7.07(d,J＝2.7Hz,1H),5.85(s,1H),5.40(s,2H),2.23(s,3H),2.21(s,3H),2.11(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) Delta 160.17,147.03,146.52,139.22,139.12,137.03,135.76,133.27,129.47,129.33,129.03,126.94,118.94,105.76,47.36,18.05,13.81,11.07 HRMS (ESI) theoretical value C 18 H 19 N 3 OSBr[M+H] + m/z 404.0, found 404.0.
Example 69
Synthesis of N- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) thiophene-2-carboxamide (LF 44):
Figure BDA0003005343500000542
the synthesis method is the same as example 67: white solid 262mg, 73% yield, was obtained. M.p. 110-112 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.90(s,1H),7.81(d,J＝3.6Hz,1H),7.36(s,1H),7.34～7.24(m,2H),7.07(d,J＝3.5Hz,1H),5.85(s,1H),5.40(s,2H),2.24(s,3H),2.21(s,3H),2.11(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) Delta 160.23,147.04,146.52,139.23,139.11,136.68,135.31,130.57,130.37,129.45,128.72,126.93,126.39,105.76,47.36,18.12,13.81,11.07 HRMS (ESI) theoretical value C 18 H 19 N 3 OSCl[M+H] + m/z 360.0, found 360.0.
Example 70
Synthesis of N- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazole-1-methyl) thiophene-2-carboxamide (LF 45):
Figure BDA0003005343500000551
the synthesis method is the same as example 67: 154mg of a white solid was obtained in 45% yield. M.p. 124-126 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.88(s,1H),7.80(d,J＝3.3Hz,1H),7.34-7.23(m,1H),7.19～7.10(m,1H),7.11～6.98(m,2H),5.85(s,1H),5.40(s,2H),2.24(s,3H),2.21(s,3H),2.11(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 160.53 (d), 160.35,147.03,146.35,139.37,139.10,137.28 (d, J =8.4 Hz), 132.54 (d, J =2.7 Hz), 129.26,129.11 (d, J =8.9 Hz), 126.91,117.09 (d, J =22.1 Hz), 113.11 (d, J =22.1 Hz), 105.75,47.36,18.32,13.80,11.06.MS (ESI) theoretical value C 18 H 19 N 3 OSF[M+H] + m/z 344.1, found 344.1.
Example 71
Synthesis of N- (3-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 57):
Figure BDA0003005343500000552
the synthesis method is the same as example 67: 206mg of a white solid are obtained, yield 47%. M.p. 154-156 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.74(s,1H),7.45(m,2H),7.44,7.32(m,1H),6.98(d,J＝4.0Hz,1H),6.88(d,J＝4.0Hz,1H),5.88(s,1H),5.35(s,2H),2.28(s,6H),2.26(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 159.72,148.43,145.54,139.08,138.60,133.22,128.63,126.01,125.56,125.37,123.64,119.43,115.36,106.08,47.68,14.69,14.65,13.52,11.09. Theoretical value of C 18 H 18 FN 3 OS[M+H] + m/z 343.4, found 343.4.
Example 72
Synthesis of 5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carbonyl chloride:
Figure BDA0003005343500000561
dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carboxylic acid (0.85mmol, 200mg) in dichloromethane (5 mL), adding thionyl chloride (1.5 eq, 152 mg) dropwise, heating to 45 ℃, reacting for 2h, and spin-drying to obtain 177mg of white solid for the next reaction.
Example 73
Synthesis of N- (3,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 58):
Figure BDA0003005343500000562
dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), stirring and dropwise adding 3,4-dichloroaniline (1.2 eq.,135 mg) and triethylamine (1.5 eq.,105 mg) under the condition of an ice-water bath, reacting for 2h, spin-drying, and performing column chromatography (PE: PA =2% -5%) to obtain 197mg of white solid with the yield of 75%. M.p. 162-164 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.41(s,1H),8.06(d,J＝3.2Hz,1H),7.86(d,J＝4.0Hz,1H),7.70(dd,J＝4.0,8.0Hz 1H),7.62(d,J＝8.0Hz,1H),7.07(d,J＝4.0Hz,1H),5.86(s,1H),5.41(s,2H),2.23(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 160.38,147.39,139.33,139.17,138.94,131.36,131.09,130.04,127.03,125.64,121.82,120.62,113.46,105.79,47.36,13.81,11.07. Theoretical value of C 17 H 15 Cl 2 N 3 OS[M+H] + m/z 380.2, foundThe value 380.2.
Example 74
Synthesis of N- (3,5-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 59):
Figure BDA0003005343500000563
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), stirring and dropwise adding 3,5-dichloroaniline (1.2 eq.,135 mg) and triethylamine (1.5 eq.,105 mg) under the condition of an ice-water bath, reacting for 2h, spin-drying, and performing column chromatography (PE: PA =2% -5%) to obtain a white solid 205mg with the yield of 78%. M.p. 246-248 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.42(bs,1H),7.86(d,J＝4.0Hz,1H)7.82(d,J＝2.0Hz,1H),7.32-7.(m,1H),7.09(d,J＝4.0Hz,1H),5.86(s,1H),5.41(s,2H),2.23(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 160.51,147.63,147.10,141.57,139.18,138.70,134.46,130.23,127.07,123.31,118.65,105.80,47.36,13.81,11.06. Theoretical value of C 17 H 15 Cl 2 N 3 OS[M+H] + m/z 380.2, found 380.2.
Example 75
Synthesis of N- (3,4-diethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 60):
Figure BDA0003005343500000571
the synthesis method is the same as example 73: 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) was dissolved in dichloromethane (5 mL), stirred and added with 3,4-diethoxyaniline (1.2 eq.,151 mg) and triethylamine (1.5 eq.,105 mg) dropwise under ice-water bath conditions, reacted for 2h, spin-dried, and column chromatographed (PE: PA =2% -5%) to give 208mg of white solid in 75% yield. M.p. 146-148 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.77(bs,2H),7.43(dd,J＝2.0,12.0Hz,1H),6.93(dd,J＝4.0,8.0Hz,1H),6.87-6.83(m,2H),5.88(s,1H),5.35(s,2H),4.15-4.06(m,4H),2.28(s,3H),2.26(s,3H),1.47-1.43(m,6H)。 13 C NMR(101MHz,CDCl 3 ) δ 159.69,148.92,148.38,145.58,145.29,139.11,139.03,131.44,128.35,125.99,113.90,112.33,106.86,106.05,64.95,64.45,47.68,14.86,14.71,13.51,11.08. Theoretical value of C 21 H 25 N 3 O 3 S[M+H] + m/z 399.1, found 399.1.
Example 76
Synthesis of N- (3,5-difluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 61):
Figure BDA0003005343500000572
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), stirring and dropwise adding 3,5-difluoroaniline (1.2 eq.,108 mg) and triethylamine (1.5 eq.,105 mg) under the condition of an ice-water bath, reacting for 2h, spin-drying, and performing column chromatography (PE: PA =2% -5%) to obtain 203mg of white solid with the yield of 78%. M.p. 223-225 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),7.86(d,J＝4.0Hz,1H),7.50-7.44(m,2H),7.09(d,J＝4.0Hz,1H),6.99-6.93(m,1H),5.86(s,1H),5.41(s,2H),2.23(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 160.52,147.57,147.10,141.75,139.18,138.78,130.17,127.03,105.80,103.50,103.21,101.07,47.36,13.81,11.06. Theoretical value of C 17 H 15 F 2 N 3 OS[M+H] + m/z 347.3, found 347.3.
Example 77
Synthesis of N- (3-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 62):
Figure BDA0003005343500000581
the synthesis method is the same as example 73:dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), stirring and dropwise adding 4-chloro-3-fluoroaniline (1.2 eq.,121 mg) and triethylamine (1.5 eq.,105 mg) under the condition of an ice-water bath, reacting for 2h, spin-drying, and performing column chromatography (PE: PA =2% -5%) to obtain 187mg of white solid with the yield of 72%. M.p. 239-241 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.44(s,1H),7.87-7.84(m,2H),7.58-7.51(m,2H),7.09(d,J＝4.0Hz,1H),5.85(s,1H),5.41(s,2H),2.23(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 160.41,147.38,147.09,139.17,138.95,130.94,130.03,127.00,117.48,113.94,108.83,108.58,105.80,101.81,47.37,13.81,11.06. Theoretical value of C 17 H 15 ClFN 3 OS[M+H] + m/z 363.8, found 363.8.
Example 78
Synthesis of N- (3,5-dimethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 63):
Figure BDA0003005343500000582
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), stirring and dropwise adding 3,5-dimethoxyaniline (1.2 eq.,128 mg) and triethylamine (1.5 eq.,105 mg) under the condition of an ice-water bath, reacting for 2h, spin-drying, and performing column chromatography (PE: PA =2% -5%) to obtain 201mg of white solid with the yield of 78%. And M.p. 194-196 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.76(s,1H),7.45(d,J＝4.0Hz,1H),6.88(d,J＝4.0Hz,1H),6.86(d,J＝2.0Hz,2H),6.28(t,J＝2.0Hz,1H),5.88(s,1H),5.36(s,2H),3.80(s,6H),2.28(s,3H),2.26(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 161.05 (2C), 159.80,148.43,145.69,139.52,139.12,138.90,128.53,126.01,106.08,98.29 (2C), 97.14,55.38 (2C), 47.67,13.52,11.08. Theoretical value of C 19 H 21 N 3 O 3 S[M+H] + m/z 371.4, found 371.4.
Example 79
Synthesis of N- (isoquinolin-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 64):
Figure BDA0003005343500000591
the synthesis method is the same as example 73: 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) was dissolved in dichloromethane (5 mL), and 6-aminoisoquinoline (1.2 eq.,120 mg) and triethylamine (1.5 eq.,105 mg) were added dropwise with stirring under ice-water bath conditions, reacted for 2h, spin-dried, and column chromatographed (PE: PA =2% -5%) to give 176mg of white solid in 70% yield. M.p. 197-199 ℃. 1 H NMR(400MHz,DMSO)δ10.56(s,1H),9.21(s,1H),8.43(m,2H)8.12(d,J＝8.0Hz,1H),7.97(d,J＝4.0Hz,1H),7.94(dd,J＝2.0,10.0Hz,1H),7.7(d,J＝6.0Hz,1H),7.11(d,J＝4.0Hz,1H),5.86(s,1H),5.43(s,2H),2.25(s,3H),2.12(s,3H)。 13 C NMR (101MHz, DMSO). Delta. 160.68,151.96,147.35,147.09,143.52,140.85,139.31,139.18,136.55,130.09,128.93,127.06,125.64,122.39,120.67,114.66,105.80,47.13.82,11.08 theoretical value C 20 H 18 N 4 OS[M+H] + m/z 362.4, found 362.4.
Example 80
Synthesis of N- (1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 65):
Figure BDA0003005343500000601
the synthesis method is the same as example 73: 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) was dissolved in dichloromethane (5 mL), and 6-amino-1H-benzimidazole (1.2 eq, 120 mg) and triethylamine (1.5 eq, 105 mg) were added dropwise with stirring under ice-water bath conditions, reacted for 2H, spin-dried, and column chromatographed (PE: PA =2% -5%) to give 176mg of white solid in 70% yield. M.p. 195-198 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ12.40(bs,1H),10.19(s,1H),8.18(s,1H),8.07(s,1H),7.88(d,J＝4.0Hz,1H),7.56(d,J＝8.0Hz,1H),7.43(d,J＝8.0Hz,1H),7.07(d,J＝4.0Hz,1H),5.86(s,1H),5.40(s,2H),2.24(s,3H),2.12(s,3H). 13 C NMR(101MHz,DMSO-d 6 ) δ 160.01,147.02,146.30,142.71,140.22,139.13,133.75,129.05,126.87,116.41,105.77,49.07,47.41,13.82,11.08. Theoretical value of C 18 H 17 N 5 OS[M+H] + m/z 351.4, found 351.4.
Example 81
Synthesis of N- (1H-indol-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 66):
Figure BDA0003005343500000602
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), adding 6-aminoindole (1.2 eq.,111 mg) and triethylamine (1.5 eq.,105 mg) dropwise under stirring in an ice-water bath, reacting for 2h, spin-drying, and performing column chromatography (MeOH: CH) 2 Cl 2 = 3%) to give 184mg of a white solid in 75% yield. M.p. 285-287 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ11.06(bs,1H),10.09(s,1H),7.96(s,1H),7.87(d,J＝4.0Hz,1H),7.48(d,J＝8.0Hz,1H),7.29(t,J＝2.0Hz,1H)7.21(dd,J＝2.0,80Hz,1H),7.06(d,J＝4.0Hz,1H),6.38-6.37(m,1H),5.86(s,1H),5.40(s,2H),2.24(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 159.85,147.00,146.10,140.49,139.12,136.24,133.07,128.83,126.86,125.71,124.79,120.15,113.83,105.77,103.95,101.41,47.41,13.83,11.09. Theoretical value of C 19 H 18 N 4 OS[M+H] + m/z 350.44, found 350.44.
Example 82
Synthesis of N- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 67):
Figure BDA0003005343500000611
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), adding 2-naphthylamine (1.2 eq.,120 mg) and triethylamine (1.5 eq.,105 mg) dropwise with stirring under ice-water bath conditions, reacting for 2h, spin-drying, column chromatography (MeOH: CH) 2 Cl 2 = 2.5%) to give 202mg of a white solid, yield 80%. M.p. 191-194 ℃ C.1H NMR (400MHz, DMSO-d) 6 )δ10.39(s,1H),8.34(s,1H),7.93-7.77(m,5H),7.51-7.41(m,2H),7.09(d,J＝4.0Hz,1H),5.87(s,1H),5.42(s,2H),2.25(s,3H),2.12(s,3H).13C NMR(101MHz,DMSO-d 6 ) δ 160.36,147.05,146.79,139.80,139.16,136.77,133.75,130.45,129.53,128.71,127.93,127.85,127.01,126.91,125.33,121.28,117.09,105.79,47.39,13.83,11.09. Theoretical value of C 21 H 19 N 3 OS[M+H] + m/z 361.4, found 361.4.
Example 83
Synthesis of N- (2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 68):
Figure BDA0003005343500000612
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-formyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), adding 5-amino-2-benzimidazolone (1.2 eq.,125 mg) and triethylamine (1.5 eq.,105 mg) dropwise under stirring in an ice-water bath, reacting for 2h, spin-drying, and performing column chromatography (MeOH: CH) 2 Cl 2 = 4%) to give 179mg of white solid in 68% yield. M.p. 304-306 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.62(s,1H),10.55(s,1H),10.09(s,1H),7.85(d,J＝4.0Hz,1H),7.48(s,1H),7.20(dd,J＝2.0,8.0Hz,1H),7.04(d,J＝4.0Hz,1H),6.86(d,J＝12.0Hz,1H),5.85(s,1H),5.39(s,2H)2.23(s,3H),2.11(s,3H)。 13 C NMR (101MHz, DMSO). Delta. 160.16,147.05,146.76,140.11,139.80,139.15,138.64,135.82,129.48,129.38,127.33,126.94,126.76,121.08,105.79,47.40,13.83,11.08. Theoretical value of C 18 H 17 N 5 O 2 S[M+H] + m/z 367.4, found 367.4.
Example 84
Synthesis of N- (quinolin-7-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 69):
Figure BDA0003005343500000621
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), adding 7-aminoquinoline (1.2 eq.,121 mg) and triethylamine (1.5 eq.,105 mg) dropwise with stirring under ice-water bath conditions, reacting for 2h, spin-drying, and performing column chromatography (MeOH: CH) 2 Cl 2 = 3%) to give 183mg of white solid, yield 72%. M.p. 199-201 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.51(s,1H),8.86(dd,J＝2.0,4.0Hz,1H),8.48(s,1H),8.29(d,J＝8.0Hz,1H),7.97-7.90(m,3H),7.47(dd,J＝2.0,4.0Hz,1H),7.11(d,J＝4.0Hz,1H),5.87(s,1H),5.43(s,2H),2.25(s,3H),2.12(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 160.54,151.43,148.77,147.15,147.09,140.04,139.51,139.18,136.01,129.88,128.83,127.01,125.11,121.47,120.75,117.75,105.80,47.40,13.83,11.09. Theoretical value of C 20 H 18 N 4 OS[M+H] + m/z 362.4, found 362.4.
Example 85
Synthesis of N- ([ 1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 70):
Figure BDA0003005343500000622
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-formyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), stirring and dropwise adding 4-aminobiphenyl (1.2 eq.,142 mg) and triethylamine (1.5 eq.,105 mg) under the condition of ice-water bath, reacting for 2h, spin-drying, and performing column Chromatography (CH) 2 Cl 2 ) Get whiteSolid 222mg, yield 82%. M.p. 188-190 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.14(bs,1H),7.70-7.67(m,2H),7.60-7.57(m,4H),7.49(d,J＝4.0Hz,1H),7.45(t,J＝8.0Hz,2H),7.35(t,J＝8.0Hz,1H),6.85(d,J＝4.0Hz,1H),5.89(s,1H),5.35(s,2H),2.29(s,3H),2.27(s,3H)。 13 C NMR(101MHz,CDCl 3 ) δ 159.75,148.45,145.63,140.43,139.11,138.80,137.38,137.01,128.79,128.68,127.66,127.16,126.84,126.04,120.50,106.10,77.35,77.03,76.71,47.71,13.54,11.11. Theoretical value of C 23 H 21 N 3 OS[M+H] + m/z 387.5, found 387.5.
Example 86
Synthesis of N- (4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 71):
Figure BDA0003005343500000631
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), adding 3- (4-aminophenyl) pyridine (1.2 eq, 143 mg) and triethylamine (1.5 eq, 105 mg) dropwise with stirring under ice-water bath conditions, reacting for 2h, spin-drying, and performing column chromatography (MeOH: CH) 2 Cl 2 = 4%) to give 163mg of a white solid in 60% yield. M.p. 191-193 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.32(s,1H),8.91(d,J＝4.0Hz,1H),8.55(dd,J＝2.0,4.0Hz,1H),8.08(m,1H),7.90(d,J＝4.0Hz,1H),7.80(dd,J＝8.0,48.0Hz,1H),7.47(dd,J＝2.0,4.0Hz,1H),7.09(d,J＝4.0Hz,1H),5.86(s,1H),5.76(s,1H),5.41(s,2H),2.24(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 160.24,148.59,147.81,147.07,146.87,139.69,139.31,139.16,135.51,134.08,132.62,129.59,127.59,126.95,124.30,121.16,105.79,55.38,47.40,13.82,11.08. Theoretical value of C 22 H 20 N 4 OS[M+H] + m/z 388.5, found 388.5.
Example 87
Synthesis of N- (3-methyl- [1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 72):
Figure BDA0003005343500000632
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), adding 4-amino-3-methylbiphenyl (1.2 eq, 154 mg) and triethylamine (1.5 eq, 105 mg) dropwise under stirring in an ice-water bath, reacting for 2h, spin-drying, and performing column chromatography (MeOH: CH) 2 Cl 2 = 2%) to give 191mg of white solid in 68% yield. M.p. 70-72 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.92(s,3H),7.84(d,J＝4.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.58(s,1H),7.52-7.45(m,2H),7.39-7.36(m,2H),7.09(d,J＝4.0Hz,1H),5.86(s,1H),5.40(s,2H),2.29(s,3H),2.25(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 160.25,147.04,146.38,140.17,139.56,139.13,138.35,135.75,134.65,129.37,129.31,129.10,127.79,127.50,127.03,126.95,124.77,105.77,47.37,18.50,13.82,11.09. Theoretical value of C 24 H 23 N 3 OS[M+H] + m/z 401.5, found 401.5.
Example 88
Synthesis of N- (2-methyl-4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide (LF 73):
Figure BDA0003005343500000641
the synthesis method is the same as example 73: dissolving 5- ((3,5-dimethylpyrazol-1-yl) methyl) thiophene-2-carbonyl chloride (0.70mmol, 177mg) in dichloromethane (5 mL), adding 3- (3-methyl-4-aminophenyl) pyridine (1.2 eq, 155 mg) and triethylamine (1.5 eq, 105 mg) dropwise under stirring in an ice-water bath, reacting for 2h, spin-drying, and performing column chromatography (MeOH: CH) 2 Cl 2 = 4%) to give 155mg of a white solid, yield 55%. M.p. 74-76 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.94(s,1H),8.92(d,J＝2.0Hz,1H),8.57(dd,J＝2.0,4.0Hz,1H),8.10(d,J＝8.0Hz,1H),7.84(d,J＝4.0Hz,1H),7.66(s,1H),7.58(d,J＝12.0Hz,1H),7.50-7.47(m 1H),7.42(d,J＝12.0Hz,1H),7.10(d,J＝4.0Hz,1H),5.86(s,1H),5.41(s,2H),2.30(s,3H),2.24(s,3H),2.11(s,3H)。 13 C NMR(101MHz,DMSO-d 6 ) δ 160.25,148.83,148.02,147.05,146.47,139.47,139.14,136.44,135.57,135.14,134.87,134.41,129.40,129.31,127.60,126.96,124.97,124.31,105.77,47.37,18.47,13.82,11.09. Theoretical value of C 23 H 22 N 4 OS[M+H] + m/z 402.5, found 402.5.
Test example 1
The compound of the invention is discovered by evaluating the enhancement effect of the NMDAR current of the mouse brain slice; intensive research on a compound LF00 shows that the compound can also have an enhancement effect on NMDAR current on primary culture neurons cultured in vitro; and further determining the EC thereof 50 It was found to be 3.2. Mu.M. The effect of the derivatives of the invention on NMDAR current was tested on primary cultured neurons cultured in vitro. The specific test method is as follows:
primary neuron culture
Taking pregnant mouse with gestational age of eighteen days, and taking cerebral cortex of pregnant mouse after sacrifice. After removal of hippocampal tissue, the remaining tissue was ground, then digested with 0.25% pancreatic enzyme at 37 ℃ for 30min, and the culture was continued with DMEM medium containing 10% FBS. Take 1X 10 6 Individual neuronal cells in polylysine coated 35 mm dishes; after 4 hours of culture, the medium was replaced with neuronal medium containing 2% B27 and 0.5mmol/L GlutaMAX-I. Placed in 37% and 5% carbon dioxide incubators and 50% medium was changed every three days. After 11-14 days of culture, cortical neurons were taken for electrophysiological experiments.
Electrophysiological experiments
For current changes in either the primary neurons or the high expressing cell lines, the current changes were measured by a HEKA EPC10 amplifier (PatchMaster software, HEKA Elektronik) using whole cell patch clamp at room temperature and-70 mV voltage. The patch-clamp pipettes were filled with solutions containing the following ingredients (122 mM cesium chloride, 1mM calcium chloride, 5mM magnesium chloride, 10mM EGTA,10mM HEPES,4mM ATP sodium, 0.3mM Tris-GTP,14mM Tris-inosine phosphate, cesium hydroxide adjusted to pH 7.3), and the resistances were adjusted to 4-6 M.OMEGA.. The cells were then perfused through the extracellular fluid (containing 140mM sodium chloride, 2.5mM potassium chloride, 2mM calcium chloride, 10mM HEPES, and 10mM glucose, pH 7.4). NMDA and other compounds were administered via gravity dosing tubes until the current reached steady state (5-10 s).
Data was recorded by the PatchMaster software.
Figure BDA0003005343500000651
Figure BDA0003005343500000661
Figure BDA0003005343500000671
In fig. 1, a: the enhancement effect of the compound on the current of in vitro cultured neuron cells (young neurons with less generation) is measured by patch clamp, and the result shows that the compound can stimulate the current with certain intensity when 20 mu M NMDA is externally supplied; it is shown that glycine is present in extremely trace concentration around younger neurons, but 10 μ M LF00 is given simultaneously on the basis of 20 μ M NMDA, and there is no significant increase relative to 20 μ M NMDA, probably because LF00 cannot increase the current of cells due to too low concentration of endogenous glycine remaining around the cells; when 30 μ M glycine was supplemented on the basis of 20 μ M NMDA, the plateau of the excitation current was significantly elevated compared to 20 μ M NMDA administered alone; however, when 30 μ M glycine and 10 μ M LF00 were given simultaneously on the basis of 20 μ M NMDA, there was a significant increase in the plateau phase of the current relative to the 30 μ M glycine alone. Given that NMDAR is a dual ligand gated ion channel, we further investigated the allosteric modulation of two endogenous ligands by LF00 on cultured neuronal cells in vitro. B: first, on the basis of 30. Mu.M glycine, NMDA was added in a concentration gradient, and the excitation of the current was foundMotility increases with increasing NMDA concentration; when 30. Mu.M LF00 was added exogenously, the current was found to shift left with increasing NMDA concentration, but the maximal effect was unchanged. Indicating that LF00 can reduce EC in NMDA 50 . C: similarly, a concentration gradient of glycine was added based on the addition of 30 μ M NMDA, and it was found that the agonistic effect on current increased with increasing glycine concentration; when 30 mu M LF00 is exogenously added at the same time, the plateau phase of the curve maximum effect of the current increasing along with the concentration of glycine is greatly improved, but the curve is not moved left and right totally, and the curves are superposed after normalization; that is, LF00 can promote E of glycine max 。
Figure BDA0003005343500000672
In fig. 2, a: the enhancement effect of the compound on the current of in vitro cultured neuron cells (aged neurons with long culture time) is measured by patch clamp, and the fact that when 100 mu M NMDA is externally applied, an excitation current can be generated shows that the endogenous glycine level of the neurons is high; when the single administration of 30 mu M LF00 is carried out, basically no exciting current can be generated; however, when 30. Mu.M LF00 and 100. Mu.M NMDA were given simultaneously, a significant increase in current was found. B: adding exogenous 100 μ M NMDA to the system, and applying LF00 with concentration gradient to obtain dose-effect relationship curve, and calculating EC of LF00 for current increase 50 。
Test example 2
The anti-depression effect of the compound LF00 is researched on a mouse model, the compound LF00 shows a certain anti-stress effect in a forced swimming experiment, and shows a certain anti-depression effect in a mouse chronic social failure stress model. The compound of the invention shows good anti-stress effect in forced swimming experiments, such as compounds LF45, LF55, LF58, LF66 and LF71 (intraperitoneal injection; 30 mg/kg) are basically equivalent to a positive drug fluoxetine (intraperitoneal injection; 30 mg/kg), wherein the compounds LF55 and LF58 are mixed with duloxetine (intraperitoneal injection; 15 mg/kg) under lower dosage conditions (intraperitoneal injection; 3mg/kg and 10 mg/kg).
Forced swimming experiment
LF00 and fluoxetine were dissolved in artificially prepared cerebrospinal fluid to make up a 10. Mu.M/ml solution, which was then injected into the lateral ventricles (distance anterior cranial: AP, +0.8 ML, -1.5 DV, -2.5. After 30 minutes of injection, the mice were placed in a clean cylindrical jar (40cm x 20cm) containing water at a water level of 30cm at a water temperature of 24 + -2 deg.C. The mice were allowed to swim freely for 6 minutes and the time for the last quarter Zhong Xiaoshu to swim motionless was recorded. After each animal was tested, the water was replaced.
The screened compounds/fluoxetine/duloxetine etc. were dissolved in PBS solution (5% DMSO; 2% Tween 80) at the designed dose. The ICR mice were randomly grouped into ten groups, and vehicle was administered to the placebo group by intraperitoneal injection at a dose of 30mg per kg. After 20 minutes of injection, the mice were placed in a clean cylindrical jar (40cm x 20cm) containing water 30cm high at 24 + -2 deg.C. The mice were allowed to swim freely for 6 minutes and the time for the last quarter Zhong Xiaoshu to swim motionless was recorded. After each animal was tested, the water was replaced.
In fig. 3, a: the potential antidepressant activity of LF00 is tested by a forced swimming experiment, and the LF00 can be found to remarkably reduce the immobility time of mouse swimming by ventricular administration;
in fig. 4, a: the potential antidepressant activity of the LF00 derivative is evaluated by a forced swimming experiment, and the compounds LF45, LF55, LF58 and LF77 (single administration in abdominal cavity) are found to be capable of obviously reducing the immobility time of swimming of mice.
In fig. 5, a: the potential antidepressant activity of compounds LF55 and LF58 (administered twice in two consecutive days to the abdominal cavity) was further evaluated by forced swim tests and was found to reach levels comparable to the positive drug duloxetine.
Chronic social failure stress and social contact experiments
LF00 or fluoxetine was dissolved in artificially prepared cerebrospinal fluid to make a 10. Mu.M/ml solution, which was then injected into the lateral ventricles of C57BL/6N mice (AP, +0.8 ML, -1.5 DV, -2.5 from the anterior cranium at a rate of 0.4. Mu.l per minute over ten minutes. Eleven days in succession, one C57BL/6 mouse and one CD-1 mouse were placed in a cage after each day of administration, and the CD-1 mice were allowed to invade the C57BL/6 mice for 5 minutes and then kept separated from each other by a transparent perforated barrier for 24 hours; CD-1 mice were replaced daily. On the eleventh day, the drugs were injected, and thirty minutes later, social contact experiments were performed. The degree of depression in mice was assessed by measuring social contact rate.
In fig. 3, B: through a chronic social failure model, LF00 is found to be capable of remarkably reducing the avoidance behavior of mice and achieving the strength equivalent to that of a positive drug fluoxetine.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.

Claims (10)

1. Use of an arylcarboxamide derivative of formula (I), or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate or hydrate thereof, as a positive allosteric modulator of N-methyl-D-aspartate receptors (NMDARs):
Figure FDA0003005343490000011
here, ar in the formula (I) 1 Is a group R 1 Substituted thienyl, by radicals R 1 Substituted furyl, by radicals R 1 Substituted imidazolyl or by radicals R 1 A substituted phenyl group; here, R 1 Each independently of the others is hydrogen, halogen, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted by optionally substituted five-membered heteroaryl, or C1-C6 alkyl substituted by optionally substituted six-membered heteroarylA group;
ar in formula (I) 2 Is an optionally substituted aromatic hydrocarbon group, or an optionally substituted heteroaryl group.
2. The use according to claim 1, wherein the use of a positive allosteric modulator of the N-methyl-D-aspartate receptor (NMDARs) is the treatment or prevention of a disease or disorder selected from the group consisting of: depression, post-traumatic stress disorder, parkinson's disease, mild cognitive impairment and obsessive-compulsive disorder.
3. The use according to claim 1, wherein R in formula (I) 1 Is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or methyl substituted by optionally substituted pyrazole (may be optionally substituted pyrazole-1-methyl); here, the optionally substituted pyrazole means unsubstituted pyrazole, or pyrazole substituted by a group selected from: halogen, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted by one or more halogens, nitro, cyano.
4. Use according to any one of claims 1 to 3, wherein Ar in formula (I) 2 Is an optionally substituted aromatic hydrocarbon group which is an optionally substituted phenyl group or an optionally substituted naphthyl group, wherein the optional substitution means being unsubstituted or substituted by one or more groups selected from:
unsubstituted C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy, phenyl, pyridine, pyrimidine, halogen, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, unsubstituted C1-C6 alkoxy formyl, mono-C1-C6 alkylamino carbamoyl, di-C1-C6 alkylamino formyl, phenyl-substituted C1-C6 alkoxy formyl, or hydroxy-substituted C1-C6 alkylamino formyl;
or, ar in formula (I) 2 Is an optionally substituted heteroaryl group which is an unsubstituted heteroaryl group orSubstituted heteroaryl; the heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, benzimidazolonyl, or quinolinyl; here, the optional substitution means being unsubstituted or substituted by one or more groups selected from:
unsubstituted C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino.
5. The use according to claim 4, wherein in the formula (I) is substituted by a group R 1 Substituted thienyl is of the formula:
Figure FDA0003005343490000021
or, in the formula (I), by the radical R 1 Substituted furyl is of the formula:
Figure FDA0003005343490000022
or, in the formula (I), by the radical R 1 Substituted phenyl is of the formula:
Figure FDA0003005343490000023
here, R 1 Is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, unsubstituted pyrazol-1-methyl or substituted pyrazol-1-methyl; here, the substituted pyrazole-1-methyl is substituted on the pyrazole with one or more groups selected from: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl.
6. Use according to claim 1, wherein the derivatives of the arylcarboxamides are selected from:
n- (2-methyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-ethyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (pyridin-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methoxycarbonyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methoxycarbonyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methylphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n-phenyl-5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-hydroxymethyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (pyridin-3-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- ([ 1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2- (2-hydroxyethyl) phenyl)) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-chloro-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methylamino-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- [ (1,1' -biphenyl) -2-yl ] -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-anilinophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide;
n- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (pyridin-4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-butylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-phenylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2- (3-hydroxypropyl) carbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-benzylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2- (4-hydroxybutyl) carbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methyl-4-bromophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide;
n- (2-methyl-4-chlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide;
n- (2-methyl-4-bromophenyl) -5- ((3, -trifluoromethyl-5-methyl-1H-pyrazol-1-methyl) furan-2-carboxamide;
n- (2-methyl-4-chlorophenyl) -5- [ (3, -trifluoromethyl-5-methyl-1H-pyrazol-1-yl) methyl ] -furan-2-carboxamide;
n- (2-methyl-4-bromophenyl) -furan-2-carboxamide;
n- (2-methyl-4-bromophenyl) -5-methylfuran-2-carboxamide;
n- (2-methyl-4-bromophenyl) -5-chlorofuran-2-carboxamide;
n- (2-methyl-4-bromophenyl) -thiophene-2-carboxamide;
n- (2-methyl-4-bromophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-chlorophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-fluorophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-bromophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-chlorophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-fluorophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (2-methyl-4-bromophenyl) -2- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methoxycarbonyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3,5-difluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3,5-dimethoxyphenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3,5-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3-chloro-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,5-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,4-diethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,5-difluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,5-dimethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (isoquinolin-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (1H-indol-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (quinolin-7-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- ([ 1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3-methyl- [1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide; and
n- (2-methyl-4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate or hydrate thereof.
7. An aromatic formamide derivative shown as a general formula (I-1), or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate or hydrate thereof:
Figure FDA0003005343490000061
wherein, ar in the formula (I-1) 1 Is a group R 1 Substituted thienyl, by radicals R 1 Substituted furyl, by radicals R 1 Substituted imidazolyl by a radical R 1 Substituted pyrrolyl, or by radicals R 1 Substituted phenyl; here, R 1 Is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or methyl substituted by optionally substituted pyrazole (may be optionally substituted pyrazole-1-methyl); here, the optionally substituted pyrazole means unsubstituted pyrazole, or pyrazole substituted by a group selected from: halogen, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted by one or more halogens, nitro, cyano;
ar in the formula (I-1) 2 Is optionally substituted phenyl, or optionally substituted naphthyl, wherein the optional substitution means being unsubstituted or substituted by one or more groups selected from:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, phenyl, pyridine, amino, monomethylamino, monoethylamino, monopropylamino, monobutylamino, methoxycarbonyl, ethoxyformyl, propoxycarbonyl, butoxyformyl, monomethylcarbamoyl, monoethylcarbamoyl, monopropylcarbamoyl, monobutylaminoyl, anilinoformyl, benzyloxyformyl, 2-hydroxyethylcarbamoyl, 3-hydroxypropylcarbamoyl, or 4-hydroxybutylcarbamoyl;
or, ar in the formula (I-1) 2 The following unsubstituted or substituted heteroaryl groups: pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, benzimidazolonyl, or quinolinyl; optionally, the substituents are one or more of the following groups:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, halogen, amino;
and that the derivatives represented by the formula (I-1) do not include the following compounds:
n- (2-methyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (pyridin-3-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-chloro-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (pyridin-4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methyl-4-bromophenyl) -furan-2-carboxamide;
n- (2-methyl-4-bromophenyl) -5-methylfuran-2-carboxamide;
n- (2-methyl-4-bromophenyl) -5-chlorofuran-2-carboxamide;
n- (2-methyl-4-bromophenyl) -thiophene-2-carboxamide;
n- (2-methyl-4-chlorophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide; and
n- (2-methyl-4-chlorophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide.
8. The arylcarboxamide derivative according to claim 7, wherein Ar in formula (I-1) 1 Is a group R 1 Substituted thienyl, preferably, of the formula:
Figure FDA0003005343490000071
here, R 1 Is optionally substituted pyrazol-1-methyl; the optionally substituted pyrazole refers to unsubstituted pyrazole, or pyrazole substituted by a group selected from: halogen, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, nitro and cyano; preferably, the substituted pyrazole-1-methyl is substituted on the pyrazole by one or more groups selected from: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and trifluoromethyl; more preferably, the substituted pyrazole-1-methyl is 3,5-dimethyl-1H-pyrazole-1-methyl, 3,5-bistrifluoromethyl-1H-pyrazole-1-methyl, 3-trifluoromethyl-5-methyl-1H-pyrazole-1-methyl, or 3-methyl-5-trifluoromethyl-1H-pyrazole-1-methyl;
or, ar in the formula (I-1) 1 Is a group R 1 Substituted furyl, preferably, of the formula:
Figure FDA0003005343490000081
here, R 1 Is substituted pyrazol-1-methyl; the substituted pyrazole refers to pyrazole substituted by groups selected from: halogen, unsubstitutedC1-C6 alkyl substituted by one or more halogens, nitro and cyano, and at least one group is defined as C1-C6 alkyl substituted by one or more halogens; preferably, the substituted pyrazole-1-methyl is substituted on the pyrazole with trifluoromethyl and one or more groups selected from: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and trifluoromethyl; more preferably, the substituted pyrazole-1-methyl is 3,5-bistrifluoromethyl-1H-pyrazole-1-methyl, 3-trifluoromethyl-5-methyl-1H-pyrazole-1-methyl, or 3-methyl-5-trifluoromethyl-1H-pyrazole-1-methyl;
ar in the formula (I-1) 2 Is optionally substituted phenyl, or optionally substituted naphthyl, wherein said optionally substituted means unsubstituted or substituted by one or more groups selected from:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, phenyl, pyridine, amino, monomethylamino, monoethylamino, monopropylamino, monobutylamino, methoxycarbonyl, ethoxyformyl, propoxycarbonyl, butoxyformyl, monomethylcarbamoyl, monoethylcarbamoyl, monopropylcarbamoyl, monobutylaminoyl, anilinoformyl, benzyloxyformyl, 2-hydroxyethylcarbamoyl, 3-hydroxypropylcarbamoyl, or 4-hydroxybutylcarbamoyl;
or, ar in the formula (I-1) 2 The following unsubstituted or substituted heteroaryl groups: pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, benzimidazolonyl, or quinolinyl; optionally, the substituents are one or more of the following groups:
fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl, halogen, amino.
9. The arylcarboxamide derivative according to claim 7 or 8, which is selected from the following compounds:
n- (2-ethyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (pyridin-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methoxycarbonyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methoxycarbonyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methylphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n-phenyl-5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-hydroxymethyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- ([ 1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2- (2-hydroxyethyl) phenyl)) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methylamino-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- [ (1,1' -biphenyl) -2-yl ] -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-anilinophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-methyl) furan-2-carboxamide;
n- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-butylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-phenylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2- (3-hydroxypropyl) carbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-benzylcarbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2- (4-hydroxybutyl) carbamoyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methyl-4-bromophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide;
n- (2-methyl-4-chlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazole-1-methyl) furan-2-carboxamide;
n- (2-methyl-4-bromophenyl) -5- ((3, -trifluoromethyl-5-methyl-1H-pyrazol-1-methyl) furan-2-carboxamide;
n- (2-methyl-4-chlorophenyl) -5- [ (3, -trifluoromethyl-5-methyl-1H-pyrazol-1-yl) methyl ] -furan-2-carboxamide;
n- (2-methyl-4-bromophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-fluorophenyl) -4- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-bromophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-fluorophenyl) -3- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methyl-4-bromophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (2-methyl-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (2-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (2-methyl-4-bromophenyl) -2- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) benzamide;
n- (2-methoxycarbonyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3,5-difluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3,5-dimethoxyphenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3-methyl-4-fluorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (2,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3,4-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3,5-dichlorophenyl) -5- ((3,5-bistrifluoromethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide;
n- (3-chloro-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3-methyl-4-fluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,4-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,5-dichlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,4-diethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,5-difluorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3-fluoro-4-chlorophenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3,5-dimethoxyphenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (isoquinolin-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (1H-indol-6-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (naphthalen-2-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (quinolin-7-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- ([ 1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
n- (3-methyl- [1,1' -biphenyl ] -4-yl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide; and
n- (2-methyl-4- (pyridin-3-yl) phenyl) -5- ((3,5-dimethyl-1H-pyrazol-1-yl) methyl) thiophene-2-carboxamide;
or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate or hydrate thereof.
10. A pharmaceutical composition comprising the benzamide derivative of any one of claims 7 to 9.
CN202110360498.2A 2021-04-02 2021-04-02 Arylcarboxamide derivatives as positive allosteric modulators of NMDAR Pending CN115160269A (en)

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