KR101947152B1 - Novel benzenesulfonamide derivatives and uses thereof - Google Patents
Novel benzenesulfonamide derivatives and uses thereof Download PDFInfo
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- KR101947152B1 KR101947152B1 KR1020170032080A KR20170032080A KR101947152B1 KR 101947152 B1 KR101947152 B1 KR 101947152B1 KR 1020170032080 A KR1020170032080 A KR 1020170032080A KR 20170032080 A KR20170032080 A KR 20170032080A KR 101947152 B1 KR101947152 B1 KR 101947152B1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/42—Benzene-sulfonamido pyrazoles
Abstract
The present invention relates to a novel benzenesulfonamide derivative or a pharmaceutically acceptable salt thereof and a use thereof, and more particularly to a novel benzenesulfonamide derivative having mTORC1 (Mammalian target of rapamycin complex 1) ≪ / RTI >
The benzenesulfonamide derivative of formula (I) according to the present invention inhibits the binding between LRS and RagD and thus has an excellent effect of inhibiting the activation of mTORC1. Therefore, the benzenesulfonamide derivative of formula (I) Neurodegenerative diseases such as autoimmune diseases, diabetes, obesity, respiratory-obstructive diseases, fibrosis, Pompe disease, lysosomal storage disease, Alzheimer's disease, Parkinson's disease and Huntington's disease, cardiovascular diseases and parasitic infections And can be very usefully used for the prevention or treatment of selected diseases.
Description
The present invention relates to a novel benzenesulfonamide derivative or a pharmaceutically acceptable salt thereof and a use thereof, and more particularly to a novel benzenesulfonamide derivative having mTORC1 (Mammalian target of rapamycin complex 1) A neurodegenerative disease such as cancer, epilepsy, inflammatory diseases, immune diseases, diabetes, obesity, respiratory-obstructive diseases, fibrosis, Pompe disease, lysosomal storage disease, Alzheimer's disease, Parkinson's disease and Huntington's disease , Cardiovascular diseases, and parasitic infections. The present invention also relates to a pharmaceutical composition for preventing or treating a disease selected from the group consisting of cardiovascular diseases and parasitic infections.
Amino acids act as nutrients to control protein metabolism as well as to be used as a source of protein synthesis. The activity of available amino acids in cells is mediated by the mTORC1 (mechanistic target of rapamycin complex 1), and mTORC1 not only regulates various intracellular responses such as protein synthesis, self-extinguishing action, cell growth, Diabetes, and neurodegeneration (Guertin and Sabatini, 2005; Zoncu et al., 2011; Laplante and Sabatini, 2012; Oddo, 2012).
MTOR (a mammalian target of rapamycin), also known as FRAP (FKBP12 and rapamycin related protein), has been shown to inhibit phosphorylation of the 289-kDa serine / threonine kinase of the PIKK (phosphoinositide 3-kinase-like kinase) to be.
This protein contains the C-terminal kinase domain, the FKBP12-rapamycin binding domain, the 20 N-terminal HEAT repeat, the FAT (FRAP-ATM-TRRAP) domain associated with protein- (Wullschleger et al. (2006) Cell, 124, 471-484).
mTOR kinase is a central regulator of cell growth and proliferation and plays an important role in cell metabolism and angiogenesis. mTOR is activated by the PI3K / Akt axis, which in turn is involved in downstream effects of the PI3K / Akt signaling pathway, in particular the two major regulators of cellular protein translation machinery, ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E binding protein (4E- ) (The mTOR signaling pathway is described in Zoncu et al. (2011) Nature Rev. Mol. Cell Biol. 12, 21-35).
The mTOR signaling pathway is mutated and deregulated in a variety of human cancers. Inhibition of protein kinase Akt, lipid kinase PI3K mutations and / or tumor suppressors PTEN and TSC2, and proliferation and / or mutations affecting growth factor receptors may result in constitutive inactivation of the PI3K / Akt / mTOR pathway, (See Guertin and Sabatini (2007) Cancer Cell 12, 9-22 for a review of the role of protein mTOR in cancer).
Genetic mutations and amplification affecting the mTOR pathway have been implicated in the formation of syngeneic, prostate, tuberous, lung (NSCLC), breast, ovarian, endometrial, colon, pancreatic, (Yuan and Cantley (2008) Oncogene 27, 5497-5510; Whittaker et al. (2010) Oncogene 29, 4989-5005).
mTOR employs several partners to form two multi-protein complexes essential for tumor growth. By phosphorylating the proteins s6K and 4E-BP1, the mTORC1 complex makes a link between tumor gene signal and protein synthesis, and the corresponding and lipid biosynthesis (Yecies and Manning (2011) J. Mol. Med. 89, 221-228). The mTORC2 complex recently phosphorylated Akt on the Ser-473 residue and was identified as a kinase that acts as an essential activator of kinase Akt. The role of the complex mTORC2 has recently been shown to be particularly linked to cellular changes (Sparks and Guertin (2010) Oncogene 29, 3733-3744).
Rapamycin and its analogs, rapalogues, bind to the protein FKBP12 and act as allosteric inhibitors of the mTORC1 complex. Several of these have been clinically developed for the treatment of certain cancers. Novartis and Temethorolimus (Wyeth) have recently been approved for the treatment of kidney cancer (renal cell carcinoma or RCC). However, the efficacy of rafalgog in cancer treatment seems to be underestimated and limited to subset cancer, despite certain promising results. This limitation is due to the fact that rapalog does not interact with the mTORC2 complex and that certain aspects of the mTORC1 complex activity and in particular the phosphorylation of 4E-BP1 are resistant to rapamycin and its analogues (Benjamin et al. (2011) Nature Reviews Drug Discovery 10, 868-880).
On the other hand, inhibitors of the mTOR kinase region have not been found to have this drawback (Feldman et al. (2009) PLoS Biology 7, 371-383) and are recognized as a new generation mTOR pathway regulator, Application. Several of these have been in clinical trials (Garcia-Echeverria (2011) Biochem. Soc. Trans., 39, 451-455, Richard et al., (2010) Curr Drug Opinion Disc. Dev. 13, 428-440).
Other potential therapeutic indications have been proposed for mTOR inhibitors (Tsang et al. (2007) Drug Discovery Today 12, 112-124). mTOR inhibitors may have neuroprotective actions in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease (Bov'e et al. (2011) Nature Reviews Neuroscience 12, 437-452). In addition, mTOR overactivity is associated with age-related diseases (Harrison et al. (2009) Nature 460, 392). Other indications include kidney, pulmonary and hepatic fibrosis (Lieberthal and Levine (2009), Shouval (2011)), inflammation and autoimmune diseases Opinion Pharmacol. 5, 418-423), diabetes, obesity (Dann et al., (2008) Am J Physiol Gastrointest Liver Physiol 295 G1237 G1245 Young and Nickerson- et al. (2010) Molecular Genetics and Metabolism 100, 309-315), cardiovascular disease (Hagenmueller et al., 2010). Neurobiology of Disease 40, 193-199), and parasitic diseases (Wang et al. (2002) (2010) 240th ACS National Meeting Boston, MEDI-152).
mTOR inhibition also activates autophagy and certain diseases, particularly metabolic diseases, neurodegenerative diseases, bacterial and viral infections, and cancers are susceptible to their inhibition (reviewed in Rubinsztein et al. (2007) Nature 6, 304-312 ).
On the other hand, mTORC1 regulates various upstream signals such as cell growth, protein synthesis, and growth factor regulation. The tuberous sclerosis complex (TSC), which transmits growth factors and energy signals to mTORC1, is a GTPase-activating protein (GAP) for Ras-like small GTPase, Rheb. Lt; RTI ID = 0.0 > mTORC1 < / RTI >
Rheb is able to migrate to the late endosomal / lysosomes and is required for mTORC1 activation induced by amino acids. In lysosomes, Rag GTPases and the Ragulator complex (MAPKSP1, ROBLD3 and c11orf59) act as amino acid-inducible docking sites for mTORC1.
Mammals express four Rag GTPases (RagA, RagB, RagC, RagD). Rag GTPases essentially form a heterodimer of RagA / C or RagB / D and mediate amino acid-induced mTORC1 activation. Amino acids induce mTORC1 to migrate to lysosomes, and in lysosomes, the Rag heterodimer, which contains GTP-bound RagB, interacts with mTORC1.
Leucine and glutamine can activate mTORC1 by Rag GTPase-dependent and non-dependent mechanisms, respectively. In RagA / B deficient cells, glutamine can still activate mTORC1 through ADP ribosylation factor 1 (ARF1) GTPase. Therefore, mTORC1 can be regulated differently by glutamine and leucine. However, the functional significance of the Rag GTPase-dependent leucine signal is not well known.
mTORC1 is activated in most human cancers and regulates cell growth and metabolism. Even though everolimus, the allosteric inhibitor of mTOR, is effective in treating carcinomas with alterations in the mTOR signal, its resistance appears. Acquired resistance due to activating mTOR mutations inhibits everolimus from binding to mTOR. Within the mTOR, the FRB domain, S2035, is essential for binding of FKBP12-rapamycin, and when mutations occur at this position, rapamycin resistance appears. If we can clearly understand the mechanism of acquisitive resistance, we will be able to use it to develop new therapies against mutations that are resistant to mTOR inhibitors.
On the other hand, aminoacyl-tRNA-synthetases (ARSs) are not only necessary for protein synthesis, but also for the physiological responses of various cells. ARS facilitates the binding of amino acids to the corresponding tRNA. In order to maintain protein homeostasis, ARS should sensitize amino acid availability. Leucine-tRNA-synthetase (LRS) functions as a leucine sensor for mTORC1 activation by interacting with RagD GTPase and acting as a GAP for RagD GTPase.
Therefore, if a substance that inhibits the leucine sensor function is searched without affecting the original function of binding the leucine to the tRNA, this substance inhibits the binding of LRS to RagD and inhibits the activation of mTORC1 And as a result will have an effect on potential therapeutic indications for mTOR inhibitors.
Accordingly, the inventors of the present invention have made an effort to find a compound that inhibits mTOR by inhibiting the binding of LRS and RagD. As a result, the benzenesulfonamide derivative defined in the present invention as shown by the formula (1) inhibits the binding of LRS and RagD, , Neurodegenerative diseases such as epilepsy, inflammatory diseases, immune diseases, diabetes, obesity, respiratory-obstructive diseases, fibrosis, Pompe disease, lysosomal storage disease, Alzheimer's disease, Parkinson's disease and Huntington's disease, An age-related disease or a parasitic infectious disease can be prevented or treated, and the present invention has been completed.
Accordingly, an object of the present invention is to provide a compound represented by the following general formula (1): < EMI ID =
[Chemical Formula 1]
In Formula 1,
R 1 is substituted or unsubstituted phenyl; Halo; Or straight or branched C 1 -C 6 alkyl, wherein when R 1 is substituted phenyl the substituent is selected from the group consisting of halogen atoms, unsubstituted linear or branched C 1 -C 6 alkyl and linear Or branched C 1 -C 6 alkyl,
R 2 is hydrogen; Or straight or branched C 1 -C 6 alkyl,
R 3 is hydrogen; Substituted or unsubstituted C 1 -C 6 straight or branched alkyl; C 5 -C 10 cycloalkyl; Substituted or unsubstituted C 5 -C 20 aryl; Dioxoanthracenyl; Or a heterocyclic or heteroaryl ring containing one or more heteroatoms in the ring, wherein when the substituents are substituted, they are straight or branched C 1 -C 6 alkyl; C 1 -C 6 alkyloxy; C 1 -C 6 alkyloxy substituted by a C 1 -C 6 alkylamino group; C 1 -C 6 alkyloxy substituted with morpholine; C 1 -C 6 alkyloxycarbonyl; Hydroxycarbonyl C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted by one or more fluoro atoms; C 1 -C 6 alkylamino; Phenyl; Linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkyloxy, linear or branched C 1 -C 6 alkyloxycarbonyl, halogen atoms and one or more fluoro atoms Phenyl substituted with one or more substituents selected from the group consisting of substituted alkyl; Phenoxy; Phenoxy substituted by one or more substituents selected from the group consisting of straight or branched C 1 -C 6 alkyl, halogen atoms and straight or branched C 1 -C 6 alkyloxy; Aminosulfonyl; Halo; Cyano; Acetyl; Nitro; Ethynyl; Hydroxy; Morpholino; Naphthyl; Teenyl; Pyridyl; Tetrahydrofuranyl; Carboxyl; Thiophenyl; C 1 -C 10 cycloalkyl; Benzodioxol; Indolyl substituted by straight or branched C 1 -C 6 alkyloxy; Dihydrobenzooxynil; And furylmethylsulfanyl, and the aryl, heterocyclic and heteroaryl rings may each be a heterocyclic structure fused with two or more rings, and may contain a carbonyl group in the ring There is,
R 2 and R 3 are bonded to each other to form a C 5 -C 20 heterocyclic ring or heteroaryl ring containing one or more heteroatoms in the ring.
Another object of the present invention is to provide a process for preparing the benzenesulfonamide derivative represented by the general formula (1).
Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
In order to accomplish the above object, the present invention provides a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
In Formula 1,
R 1 is substituted or unsubstituted phenyl; Halo; Or straight or branched C 1 -C 6 alkyl, wherein when R 1 is substituted phenyl the substituent is selected from the group consisting of halogen atoms, unsubstituted linear or branched C 1 -C 6 alkyl and linear Or branched C 1 -C 6 alkyl,
R 2 is hydrogen; Or straight or branched C 1 -C 6 alkyl,
R 3 is hydrogen; Substituted or unsubstituted C 1 -C 6 straight or branched alkyl; C 5 -C 10 cycloalkyl; Substituted or unsubstituted C 5 -C 20 aryl; Dioxoanthracenyl; Or a heterocyclic or heteroaryl ring containing one or more heteroatoms in the ring, wherein when the substituents are substituted, they are straight or branched C 1 -C 6 alkyl; C 1 -C 6 alkyloxy; C 1 -C 6 alkyloxy substituted by a C 1 -C 6 alkylamino group; C 1 -C 6 alkyloxy substituted with morpholine; C 1 -C 6 alkyloxycarbonyl; Hydroxycarbonyl C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted by one or more fluoro atoms; C 1 -C 6 alkylamino; Phenyl; Linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkyloxy, linear or branched C 1 -C 6 alkyloxycarbonyl, halogen atoms and one or more fluoro atoms Phenyl substituted with one or more substituents selected from the group consisting of substituted alkyl; Phenoxy; Phenoxy substituted by one or more substituents selected from the group consisting of straight or branched C 1 -C 6 alkyl, halogen atoms and straight or branched C 1 -C 6 alkyloxy; Aminosulfonyl; Halo; Cyano; Acetyl; Nitro; Ethynyl; Hydroxy; Morpholino; Naphthyl; Teenyl; Pyridyl; Tetrahydrofuranyl; Carboxyl; Thiophenyl; C 1 -C 10 cycloalkyl; Benzodioxol; Indolyl substituted by straight or branched C 1 -C 6 alkyloxy; Dihydrobenzooxynil; And furylmethylsulfanyl, and the aryl, heterocyclic and heteroaryl rings may each be a heterocyclic structure fused with two or more rings, and may contain a carbonyl group in the ring There is,
R 2 and R 3 are bonded to each other to form a C 5 -C 20 heterocyclic ring or heteroaryl ring containing one or more heteroatoms in the ring.
According to another aspect of the present invention, there is provided a process for preparing a benzenesulfonamide derivative represented by the general formula (1).
According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
Hereinafter, the present invention will be described in detail.
The present invention provides a compound represented by the following general formula (1): < EMI ID =
[Chemical Formula 1]
In Formula 1,
R 1 is substituted or unsubstituted phenyl; Halo; Or straight or branched C 1 -C 6 alkyl, wherein when R 1 is substituted phenyl the substituent is selected from the group consisting of halogen atoms, unsubstituted linear or branched C 1 -C 6 alkyl and linear Or branched C 1 -C 6 alkyl,
R 2 is hydrogen; Or straight or branched C 1 -C 6 alkyl,
R 3 is hydrogen; Substituted or unsubstituted C 1 -C 6 straight or branched alkyl; C 5 -C 10 cycloalkyl; Substituted or unsubstituted C 5 -C 20 aryl; Dioxoanthracenyl; Or a heterocyclic or heteroaryl ring containing one or more heteroatoms in the ring, wherein when the substituents are substituted, they are straight or branched C 1 -C 6 alkyl; C 1 -C 6 alkyloxy; C 1 -C 6 alkyloxy substituted by a C 1 -C 6 alkylamino group; C 1 -C 6 alkyloxy substituted with morpholine; C 1 -C 6 alkyloxycarbonyl; Hydroxycarbonyl C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted by one or more fluoro atoms; C 1 -C 6 alkylamino; Phenyl; Linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkyloxy, linear or branched C 1 -C 6 alkyloxycarbonyl, halogen atoms and one or more fluoro atoms Phenyl substituted with one or more substituents selected from the group consisting of substituted alkyl; Phenoxy; Phenoxy substituted by one or more substituents selected from the group consisting of straight or branched C 1 -C 6 alkyl, halogen atoms and straight or branched C 1 -C 6 alkyloxy; Aminosulfonyl; Halo; Cyano; Acetyl; Nitro; Ethynyl; Hydroxy; Morpholino; Naphthyl; Teenyl; Pyridyl; Tetrahydrofuranyl; Carboxyl; Thiophenyl; C 1 -C 10 cycloalkyl; Benzodioxol; Indolyl substituted by straight or branched C 1 -C 6 alkyloxy; Dihydrobenzooxynil; And furylmethylsulfanyl, and the aryl, heterocyclic and heteroaryl rings may each be a heterocyclic structure fused with two or more rings, and may contain a carbonyl group in the ring There is,
R 2 and R 3 are bonded to each other to form a C 5 -C 20 heterocyclic ring or heteroaryl ring containing one or more heteroatoms in the ring.
&Quot; Alkyl " means an aliphatic hydrocarbon group, which may be straight or branched, containing from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain from about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups include about 1, 2, 3, 4, 5 or 6 carbon atoms in the chain. The side chain means that at least one lower alkyl group, e. G. Methyl, ethyl or propyl, is attached to the linear alkyl chain. &Quot; Lower alkyl " means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. &Quot; Alkyl " may be unsubstituted or optionally substituted by one or more substituents which may be the same or different and each substituent is independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, Thio, amino, carboxy, and the like. Preferably alkyl is butyl or isobutyl.
&Quot; Aryl " means an aromatic hydrocarbon ring system, examples of which include phenyl, indenyl, indanyl, naphthyl and fluorenyl, preferably (6C) aryl.
The " halogen " may include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.
&Quot; Cycloalkyl " means an otherwise saturated hydrocarbon ring.
&Quot; Heteroaryl " means an aromatic cycloalkyl (also referred to as heteroaryl) in some embodiments of a compound of formula (II) or a heteroatom selected from solvates wherein one to four of the ring carbon atoms are comprised of O, S, Non-aromatic cycloalkyl. In some embodiments, the heterocyclyl group contains 3 to 10 ring members, while such other groups have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclyl may also be combined with other groups at any ring atom (i. E., Any carbon atom or heteroatom of the heterocyclic ring). The heterocycloalkyl group may be substituted or unsubstituted. Heterocyclyl groups include unsaturated, partially saturated and saturated cyclic groups such as imidazolyl, imidazolinyl and imidazolidinyl groups. The term heterocyclyl includes fused ring species such as those containing fused aromatic and nonaromatic groups such as, for example, benzotriazolyl, 2,3-dihydrobenzo [1,4] dioxinyl, and Benzo [1,3] dioxolyl. The term also includes, but is not limited to, bridged polycyclic ring systems containing, for example, quinuclidil, containing heteroatoms. Representative examples of heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl , Pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazole (E.g., tetrahydrothiopyranyl, tetrahydrothiopyranyl, oxathiene, tetrahydrothiopyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl, , Dioxolyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiunyl, dihydrodithioyl, homopiperazinyl, quinuclidyl , Indolyl, indolinyl, isoindolyl, Benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithianyl, benzothiazolyl, benzothiazolyl, benzoxazolyl, benzodiazolyl, benzothiazolyl, benzothiazolyl, Benzothiazyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzo [1,3] dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl, for example, Imidazo [4,5-b] pyridyl or 1H-imidazo [4,5-b] pyridin-2 (3H) -one), triazolopyridyl, isoxazolopyridyl, Thienyl, adeninyl, guanidinyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, Dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindolyl, tetrahydrothiopyranyl, A tetrahydroimidazolyl group, a tetrahydrothiopyrimidinyl group, a tetrahydrothiazolopyridyl group, a tetrahydrothiopyrimidinyl group, a tetrahydrothiazolopyridyl group, and a tetrahydroquinolinyl group, But is not limited thereto.
&Quot; Cycloalkylalkyl " group is a radical of formula-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. In some embodiments of compounds of formula (II), the cycloalkylalkyl group may be substituted in the alkyl, cycloalkyl, or alkyl and cycloalkyl moiety of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl.
When the groups disclosed herein are referred to as " substituted ", these groups may be substituted with any suitable substituents or substituents. Illustrative examples of substituents include those exemplified in the present invention and those exemplified in the embodiments, and halogen (chloro, uretho, bromo or fluoro group); Alkyl; Hydroxyl; Alkoxy; Alkoxyalkyl; Amino; Alkylamino; Carboxy; Nitro; Cyano; Thiol; Thioether; immigrant; Imide; Amidine; Guanidine; Enamin; Aminocarbonyl; Acylamino; Phosphoneate; Phosphine; Thiocarbonyl; Sulfonyl; Sulfone; Sulfonamide; Ketones; Aldehyde; ester; Urea; urethane; Oxime; Hydroxylamine; Alkoxyamine; Aralcoxyamine; N-oxide; Hydrazine; Hydrazide; Hydrazone; Azide; Isocyanate; Isothiocyanate; Cyanate; Thiocyanate; Oxygen (= O); B (OH) 2, O (alkyl) aminocarbonyl; (E.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which may be monocyclic or fused or non-fused polycyclic, or heterocyclyl which may be monocyclic or fused or non-fused polycyclic, (E.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thiazinyl); Monocyclic or fused or unfused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, Pyridyl, pyrazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl or benzofuranyl) aryl Oxy; Aralkyloxy; Heterocyclyloxy; And heterocyclylalkoxy. ≪ / RTI > Preferably, straight or branched C 1 -C 6 alkyl; C 1 -C 6 alkyloxy; C 1 -C 6 alkyloxy substituted by a C 1 -C 6 alkylamino group; C 1 -C 6 alkyloxy substituted with morpholine; C 1 -C 6 alkyloxycarbonyl; Hydroxycarbonyl C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted by one or more fluoro atoms; C 1 -C 6 alkylamino; Phenyl; Linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkyloxy, linear or branched C 1 -C 6 alkyloxycarbonyl, halogen atoms and one or more fluoro atoms Phenyl substituted with one or more substituents selected from the group consisting of substituted alkyl; Phenoxy; Phenoxy substituted by one or more substituents selected from the group consisting of straight or branched C 1 -C 6 alkyl, halogen atoms and straight or branched C 1 -C 6 alkyloxy; Aminosulfonyl; Halo; Cyano; Acetyl; Nitro; Ethynyl; Hydroxy; Morpholino; Naphthyl; Teenyl; Pyridyl; Tetrahydrofuranyl; Carboxyl; Thiophenyl; C 1 -C 10 cycloalkyl; Benzodioxol; Indolyl substituted by straight or branched C 1 -C 6 alkyloxy; Dihydrobenzooxynil; ≪ / RTI > and furylmethylsulfanyl.
More preferably, the compound of formula (1) may be selected from the following.
N-cyclohexyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
Ethyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzoate;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-phenyl-benzenesulfonamide;
N-cyclohexyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N-methyl-benzenesulfonamide;
N- (4-tert-butylphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (4-methoxyphenyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (4-morpholinophenyl) benzenesulfonamide;
N - [(3,4-dimethoxyphenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(2-methoxyphenyl) methyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (p-tolyl) benzenesulfonamide;
N- (4-chlorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (2-methoxyphenyl) ethyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (2-methoxyphenoxy) ethyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (3-methoxyphenyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-methoxyphenyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (3-phenylpropyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (3-nitrophenyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (4-nitrophenyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2-phenylethyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (4-phenylbutyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (5-quinolyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (3-quinolyl) benzenesulfonamide;
N- (4-fluorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
Tert-butyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] piperidine-1-carboxylate;
N- [2- (4-chlorophenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2-thienylmethyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (3-pyridylmethyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (2-pyridyl) ethyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2-naphthylmethyl) benzenesulfonamide;
N- [2- (3-fluorophenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (5-fluoro-2-pyridyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(4-methoxyphenyl) methyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (6-quinolyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfone amides;
N- [4- (dimethylamino) phenyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
Methyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzoate;
Ethyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzoate;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [3- (trifluoromethyl) phenyl] benzenesulfonamide;
N- [2- (4-fluorophenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (4-isopropylphenyl) benzenesulfonamide;
N- (3-fluorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (3-fluorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-methyl- benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (1-naphthyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(3-methoxyphenyl) methyl] benzenesulfonamide;
N - [(3-fluorophenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (tetrahydrofuran-2-ylmethyl) benzenesulfonamide;
N- [2- (2-furylmethylsulfanyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (p-tolyl) ethyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (4-methoxyphenyl) -N- methyl- benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (4-methoxyphenyl) ethyl] benzenesulfonamide;
N - [(2-chlorophenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2-fluorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N - [(2-fluorophenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (p-tolylmethyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (m-tolylmethyl) benzenesulfonamide;
N- (2,5-dimethylphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (m-tolyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (o-tolyl) benzenesulfonamide;
N- (4-cyanophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [2- (trifluoromethyl) phenyl] benzenesulfonamide;
N- (2,4-dimethylphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (6-methoxy-3-pyridyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (p-tolyl) benzenesulfonamide;
N- (2,2-dimethylpropyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-pyridylmethyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-pyridyl) benzenesulfonamide;
N- (3-bromophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2-bromophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2,4-dibromophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2,5-dibromophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (3-ethylphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (1,1-dimethylpropyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (3,5-dimethoxyphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N-cyclopentyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4-isopropyl-2- [4- [4- (4-methoxyphenyl) piperazin-1-yl] sulfonylphenyl] -1,5-dimethyl-pyrazol-3-one;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (4-sec-butylphenyl) benzenesulfonamide;
Ethyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] piperidine-1-carboxylate;
N-indan-5-yl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N-indan-2-yl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N-cycloheptyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [3- (trifluoromethyl) phenyl] benzenesulfonamide;
N- (4-acetylphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
Methyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzoate;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-pyrimidin-2-yl-benzenesulfonamide;
N - [(2,4-dimethoxyphenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2-chloro-4-pyridyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
2- [4- (4-ethylpiperazin-1-yl) sulfonylphenyl] -4-isopropyl-l, 5-dimethyl-pyrazol-3-one;
N- [3,5-bis (trifluoromethyl) phenyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (4-pyridylmethyl) benzenesulfonamide;
N- (9-ethylcarbazol-3-yl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (4-bromo-1-naphthyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2-phenylphenyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-methyl-1-naphthyl) benzenesulfonamide;
N- [2- (4-bromophenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
- [2- (5-methoxy-lH-indol-3-yl) ethyl] benzenesulfonamide ;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2-methyl-lH-indol-5-yl) benzenesulfonamide;
N- (lH-indol-5-ylmethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (6-methoxy-1,3-benzothiazol-2-yl) benzenesulfonamide;
N- [2- (1H-indol-3-yl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-methyl-8-quinolyl) benzenesulfonamide;
N- (4-ethoxy-2-nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (3,4-dichlorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- [2- (2-chlorophenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N - [(4-chlorophenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (3,5-dichlorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (1,2-dimethoxypropyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (5-chloro-2-fluoro-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (4-ethynylphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N - [(4-fluorophenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2,4-dimethyl-6-nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2,5-Dichloro-4-nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (4-chloro-3-nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2,3-dimethyl-6-nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (1-naphthylmethyl) benzenesulfonamide;
N - [(3-bromophenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- [2- (3-bromophenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N - [(2-bromophenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- [2- (3-chlorophenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [[3- (trifluoromethyl) phenyl] methyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [[2- (trifluoromethyl) phenyl] methyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [[4- (trifluoromethyl) phenyl] methyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (o-tolylmethyl) benzenesulfonamide;
N- (3-chlorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2-chlorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N - [(3-chlorophenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2-phenoxyethyl) benzenesulfonamide;
N- [2- (2-fluorophenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N - [(4-bromophenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- [2- (2-bromophenyl) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (o-tolyl) ethyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (3-methoxyphenyl) ethyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [2- [2- (trifluoromethyl) phenyl] ethyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [2- [3- (trifluoromethyl) phenyl] ethyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [2- [4- (trifluoromethyl) phenyl] ethyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [4- (trifluoromethyl) phenyl] benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzene Sulfonamide;
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2-phenoxyethyl) benzenesulfonamide;
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(2-fluorophenyl) methyl] benzenesulfonamide;
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(3-fluorophenyl) methyl] benzenesulfonamide;
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(4-fluorophenyl) methyl] benzenesulfonamide;
4- (4-Chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (3,4-dichlorophenyl) benzenesulfonamide;
4- (4-Chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (5-chloro-2-fluoro-phenyl) benzenesulfonamide;
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [4- (dimethylamino) phenyl] benzenesulfonamide;
4- (4-Chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-pyridylmethyl) benzenesulfonamide;
Methyl 3 - [[4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzoate;
4- (4-Chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (lH-indol-5-ylmethyl) benzenesulfonamide;
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (1-naphthylmethyl) benzenesulfonamide;
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(3,4-dimethoxyphenyl) methyl] benzenesulfonamide;
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (5-quinolyl) benzenesulfonamide;
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(2,4-dimethoxyphenyl) methyl] benzenesulfonamide;
4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N - [(3,4-dimethoxyphenyl) methyl] benzenesulfonamide;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (5-quinolyl) benzenesulfonamide;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [4- (dimethylamino) phenyl] benzenesulfonamide;
Methyl 3 - [[4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzoate;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(3-fluorophenyl) methyl] benzenesulfonamide;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N - [(2-fluorophenyl) methyl] benzenesulfonamide;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2-pyridylmethyl) benzenesulfonamide;
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2,3- amides;
N- [3,5-bis (trifluoromethyl) phenyl] -4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (3,4-dichlorophenyl) benzenesulfonamide;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (5-chloro-2-fluoro-phenyl) benzenesulfonamide;
N- [3,5-bis (trifluoromethyl) phenyl] -4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2,3-dihydro-1, 4-benzodioxin-6-yl) benzenesulfonamide ;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-cyclopentyl-benzenesulfonamide;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-cycloheptyl-benzenesulfonamide;
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-phenyl-benzenesulfonamide;
4- (2,3-dimethyl-5-oxo-4-phenyl-pyrazol-l-yl) -N- (2-phenoxyethyl) benzenesulfonamide;
4- [4- (4-chlorophenyl) -2,3-dimethyl-5-oxo-pyrazol-1-yl] -N- (2-phenoxyethyl) benzenesulfonamide;
2- [3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] phenyl] acetic acid;
N- (2-hydroxyphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (4-hydroxyphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- [2,3-dimethyl-5-oxo-4- [4- (trifluoromethyl) phenyl] pyrazol-1-yl] -N- (2-phenoxyethyl) benzenesulfonamide;
N- [3- (hydroxymethyl) phenyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (6-hydroxy-1-naphthyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-phenoxypropyl) benzenesulfonamide;
N- [2- (2-fluorophenoxy) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- [4- [2- (dimethylamino) ethoxy] phenyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
Methyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] propanoate;
N- (4-hydroxy-3-methyl-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (6-acetyl-1,3-benzodioxol-5- yl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (1,3,5-trimethylpyrazol-4-yl) benzenesulfonamide;
2- (4-indolin-1-ylsulfonylphenyl) -4-isopropyl-l, 5-dimethyl-pyrazol-3-one;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N-tetralin-1-yl-benzenesulfonamide;
N, N-diethyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-methyl-N-phenyl-benzenesulfonamide;
N-benzyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
Methyl 2 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] -2-phenyl-acetate;
N- (2-ethoxyethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (2,6-dimethylphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (9-oxothioxanthen-2-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (4-methoxy-3,5-dimethyl-phenyl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide ;
Ethyl 5 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzothiophene-2-carboxylate;
4- [4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonyl-1,3-dihydroquinoxalin-2-one;
N-tert-butyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N- (3-fluoro-2-methyl-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzenesulfonamide;
4-isopropyl-l, 5-dimethyl-2- [4- [4- (3-phenylquinoxalin-2-yl) piperazin-l-yl] sulfonylphenyl] pyrazol-3-one;
4-isopropyl-2- [4 - [[4- [4- (4-isopropyl-2,3- dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonyl- Yl] sulfonyl] phenyl] -1,5-dimethyl-pyrazol-3-one;
Carbonyl) -2-nitro-phenyl] piperazin-1-yl] sulfonylphenyl] pyrazine Lt; / RTI >
4-isopropyl-l, 5-dimethyl-2- [4- [4- (2-pyridyl) piperazin-l-yl] sulfonylphenyl] pyrazol-3-one;
N- (2,2-dimethylpropyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4-isopropyl-2- [4- [4- (4-methoxyphenyl) piperazin-1-yl] sulfonylphenyl] -1,5-dimethyl-pyrazol-3-one;
2 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonyl Amino] benzamide;
Dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] -4,5,6,7-tetrahydrobenzothiophene -3-carboxylate;
2- [4- [4- (7-Chloro-4-quinolyl) piperazin-1-yl] sulfonylphenyl] -4-isopropyl-l, 5-dimethyl-pyrazol-3-one;
4-isopropyl-l, 5-dimethyl-2- [4- (l-piperidylsulfonyl) phenyl] pyrazol-3-one;
N-isopropyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
N-cyclopropyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4-isopropyl-l, 5-dimethyl-2- (4-morpholinosulfonylphenyl) pyrazol-3-one;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-phenoxyethyl) benzenesulfonamide;
N- [2- (3,5-dimethylphenoxy) ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide;
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-
4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H- Pyrazol-1-yl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1- yl) benzenesulfonamide
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) benzenesulfone amides
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1 -yl) -N- (2,4-dimethylphenyl) benzenesulfonamide
Pyrazol-1-yl) -N- (4- (2-morpholinoethoxy) phenyl) -2,3- Benzenesulfonamide
Dihydroxyphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
(4-bromo-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- amides
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) benzene Sulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro- amides
3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) phenylsulfonamido) benzoic acid
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- (2- methoxy-5-nitrophenyl) amides
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- amides
Benzo [b] thiophen-5-yl) -4- (4-isopropyl-2,3-dimethyl- Sulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
(Benzofuran-5-ylmethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
Methyl-5- (4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 2-carboxylate
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) phenylsulfonamido) methyl) benzoate
Methyl-6- (4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) phenylsulfonamido) -2-
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-mesitylbenzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H- Pyrazol-1-yl) benzenesulfonamide
5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- (isoquinolin-5-yl) benzenesulfonamide
4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazole- 1-yl) benzenesulfonamide
4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazole -1-yl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- amides
(4-bromo-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- amides
Pyrazol-1-yl) -N- (2- (thiophen-2-yl) ethyl) Benzenesulfonamide
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- (3,4,5-trimethoxyphenyl) benzene Sulfonamide
(Cyclohexylmethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
(Cycloheptylmethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
Preparation of N- (2-cyclohexylethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
N- (3,4-dimethoxyphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamide.
The structural formulas of the compounds of the present invention are summarized in Table 1 below.
The benzosulfonamide derivative of formula (I) of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salts, acid addition salts formed by various organic acids or inorganic acids which are pharmaceutically or physiologically acceptable are useful. Suitable organic acids include, for example, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, And the like. Examples of suitable inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, and the like, such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like, for example, hydrochloric acid, sulfuric acid or phosphoric acid Can be used.
The benzosulfonamide derivative of formula (I) of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.
The present invention provides a method for preparing a benzosulfonamide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.
The process for preparing a derivative of formula (I) according to the present invention, as shown in Scheme 1,
1) reacting a pyrazolone compound of formula (2) with chlorosulfonic acid to produce a compound of formula (3)
2) reacting the compound of formula 2 with a secondary amine in step 1) to prepare a compound of formula 1, which comprises reacting a benzene sulfonamide derivative represented by the following formula 1 .
[Reaction Scheme 1]
In the above Reaction Scheme 1,
R1, R2 and R3 are the same as defined in the above formula (1).
The benzosulfonamide derivative or its pharmaceutically acceptable salt of the present invention inhibits the binding between LRS and RagD and thus inhibits the activity of mTOR. Therefore, it is possible to prevent or prevent various diseases in which a therapeutic effect is attained by inhibiting mTOR, Can be treated. Non-limiting examples of diseases in which the therapeutic effect is attained by inhibiting mTOR in the present invention include cancer, epilepsy, inflammatory diseases, immune diseases, diabetes, obesity, respiratory-obstructive diseases, fibrosis, lupus, lysosomal storage neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease, cardiovascular diseases or parasitic infections, preferably cancerous or epileptic.
Specifically, according to one embodiment of the present invention, the compounds of the present invention are highly effective in inhibiting the activity of mTORC1, which is known to be highly active in cancer cells, and exhibit cytotoxicity against various cancer cells, It was confirmed that it did not show any cytotoxicity.
Accordingly, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the benzosulfonamide derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
LRS (leucyl tRNA synthetase) functions as a key mediator of amino acid signaling to mTORC1. That is, LRS directly binds to Rag GTPase, which is an amino acid-dependent signaling mediator to mTORC1, and acts as a GTPase-activating protein (GAP) for Rag GTPase, and Rag GTPase activates mTORC1. In addition, leucyl-tRNA synthetase (LRS) plays an important role in the activation of mTORC1, which is derived from amino acid, and LRS detects intracellular leucine concentration and affects the activation of mTORC1 induced in leucine . Rag proteins belong to the Rag subfamily of Ras small GTPase and there are four kinds of RagA, RagB, RagC and RagD. A and B are orthologs of Gtr1p GTPase of yeast and C and D are east and east Gtr2p orthologs. RagD binds with A or B to form a dimer, which mediates mTORC1 activity by amino acids. (Trends in Biochemical Sciences, 33: 565-568, 2008). Therefore, inhibition of the binding between LRS and RagD may inhibit the activation of mTORC1, thereby preventing or treating cancer.
More specifically, the cancer includes, but is not limited to, melanoma, leukemia, colon cancer, lung cancer, liver cancer, stomach cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, renal cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, Cancer, ovarian cancer, breast cancer, thyroid cancer, brain cancer, head and neck cancer, skin cancer, lymphoma, aplastic anemia and the like. The lymphoma includes both Hodgkin's lymphoma and non-Hodgkin's lymphoma. B-cell neoplasms such as precursor B-cell neoplasm, precursor T-cell neoplasm, cell neoplasm), Hodgkin lymphoma (Hodgkin's disease) such as T-cell and NK-cell neoplasm, and classical Hodgkin's lymphoma.
According to one embodiment of the present invention, it has been confirmed that the benzosulfonamide derivative of Formula 1 of the present invention can exhibit an effective therapeutic effect also for a cancer showing resistance to rapamycin.
That is, the benzosulfonamide derivative of Formula 1 of the present invention has an effect of inhibiting the leucine-sensing activity of LRS without affecting the enzymatic activity of LRS. The expression level of LRS was positively correlated with the activation of Rag GTPase and mTORC1 in colorectal cancer tissues and cells, and the migration tendency of the cells was found to be influenced. The benzosulfonamide derivative of formula (1) of the present invention binds to the site of interaction with RagD in LRS, specifically inhibiting LRS to be a lysosome, inhibits the activity of RagD GTPase and mTORC1, Growth inhibition effect. These results are also shown in cancer cells showing resistance to rapamycin. The benzosulfonamide derivative of the formula 1 of the present invention shows an effect of effectively preventing or treating cancer showing mTOR mutation and showing resistance to rapamycin .
(I) hydrolysis of RagD GTP and lysosomal translocation of LRS were inhibited, and (ii) inhibition of lysosomal translocation of LRS was inhibited. ) mTORC1 was also inhibited. As a result of administering the compound of the present invention to the animal model of epilepsy, it was confirmed that the number of epileptic seizures was remarkably reduced compared with the control group. In particular, the compound of the present invention has a high blood-brain barrier (BBB) permeability, and thus is highly likely to be developed as a preventive treatment for brain diseases.
The pharmaceutical composition according to the present invention may be formulated variously according to the route of administration by a method known in the art together with a pharmaceutically acceptable carrier. &Quot; Pharmaceutically acceptable " refers to a nontoxic composition which is physiologically acceptable and which, when administered to humans, does not inhibit the action of the active ingredient and does not normally cause an allergic reaction such as a gastrointestinal disorder, dizziness, or the like . Such carriers include all kinds of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads and microsomes.
When the composition of the present invention is administered parenterally, the composition of the present invention may be formulated together with a suitable parenteral carrier according to methods known in the art in the form of injections, transdermal administrations and nasal inhalants. In the case of the injections, they must be sterilized and protected from contamination of microorganisms such as bacteria and fungi. Examples of suitable carriers for injectables include, but are not limited to, solvents or dispersion media containing water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and / or vegetable oils . More preferred examples of suitable carriers include Hank's solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine or isotonic solutions such as sterilized water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose Can be used. In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like may be further included. In addition, the injections may in most cases additionally include isotonic agents, such as sugars or sodium chloride.
Examples of transdermal dosage forms include ointments, creams, lotions, gels, solutions for external use, pastes, liniments, and air lozenges. By " transdermal administration " as used herein, it is meant that the composition of the present invention is locally administered to the skin, whereby an effective amount of the active ingredient contained in the composition is delivered into the skin. For example, the composition of the present invention may be prepared in a spiral form and administered by pricking the skin lightly with a 30 gauge thin needles or by directly applying it to the skin. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975, Mack Publishing Company, Easton, Pennsylvania, which is a commonly known formulary in pharmaceutical chemistry.
In the case of an inhalation dosage form, the compositions according to the present invention can be prepared from a pressurized pack or sprayer using a suitable propellant, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. It can be conveniently delivered in aerosol spray form. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges used in inhalers or insufflators may be formulated to contain the compound and a powder mixture of a suitable powder base such as lactose or starch.
Other pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).
The composition according to the invention may also contain one or more buffers (e.g., saline or PBS), a carbohydrate (e.g., glucose, mannose, sucrose or dextran), an antioxidant, a bacteriostatic, (E.g., EDTA or glutathione), an adjuvant (e.g., aluminum hydroxide), a suspending agent, a thickening agent, and / or a preservative.
The compositions of the present invention may also be formulated variously using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. The composition of the present invention can also be administered in combination with a known compound having an effect of preventing or treating cancer.
The benzenesulfonamide derivative of formula (I) according to the present invention inhibits the binding between LRS and RagD and thus has an excellent effect of inhibiting the activation of mTORC1. Therefore, the benzenesulfonamide derivative of formula (I) Neurodegenerative diseases such as autoimmune diseases, diabetes, obesity, respiratory-obstructive diseases, fibrosis, Pompe disease, lysosomal storage disease, Alzheimer's disease, Parkinson's disease and Huntington's disease, cardiovascular diseases and parasitic infections And can be very usefully used for the prevention or treatment of selected diseases.
FIG. 1 shows the cytotoxicity of benzenesulfonamide derivatives to normal normal epithelial cells (FHC) (Rap: rapamycin, 5-FU: 5-fluoro uracil).
2 is a graph showing the EC50 of cytotoxicity of benzenesulfonamide derivatives to various cancer cells.
Figure 3 shows the hydrolysis of RagD GTP and the lysosomal translocation of LRS (Figure 3B) when LRS was deleted in NIH3T3 cells expressing the mTOR mutation (L2427P) associated with epilepsy (Figure 3A) This is the result of Western blot analysis.
FIG. 4 shows Western blotting (FIG. 4A) that the activity of mTORC1 was reduced when NIH3T3 cells expressing the mTOR mutation associated with epilepsy (L2427P) were treated with the compound of the present invention (FIG. 4A) (Fig. 4B).
FIG. 5 shows the results of measurement of the frequency of epileptic seizures after administering the compound of the present invention, rapamycin or a comparative substance to an epileptic animal model.
FIG. 6 shows the results of analysis of the blood-brain barrier (BBB) permeability of the compounds according to the present invention using the in vitro Pion BBB-PAMPA assay kit.
Hereinafter, the present invention will be described in detail.
However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.
< Example 1>
Preparation of the compounds of the invention
< Example 1-1> N- Cyclohexyl -4- (4-isopropyl-2, 3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
1. Preparation of 4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonyl chloride
Isopropyl-1,5-dimethyl-2-phenylpyrazolone (15 g, 65.1 mmol) was added to a 250 ml round bottom flask at 0 ° C in the presence of chlorosulfonic acid (43.3 mL, 651 mmol) Gt; 40 C < / RTI > After cooling to room temperature, the product is slowly poured into ice water, extracted with dichloromethane (100 ml) and dried using anhydrous magnesium sulfate. The primary compound thus obtained was purified by silica gel column chromatography (100% dichloromethane) to obtain 53% yield of 4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazole -1-yl) benzenesulfonyl chloride (11.3 g).
2. Preparation of N-cyclohexyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
To a 10 ml round bottom flask was added cyclohexanamine (91.53 mg, 0.547 mmol) and the resulting product 4- (4-isopropyl-2,3-dimethyl- 5-oxo-pyrazol-1-yl) benzenesulfonyl chloride (150 mg, 0.456 mmol) was reacted at room temperature for about 3 hours. The reaction is terminated using TLC (EA / HX = 1), the solvent is removed using a vacuum pump, and the residue is purified by silica gel column chromatography (EA / HX = 1). Further recrystallization using dichloromethane and hexane or ethyl ether and hexane afforded N-cyclohexyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1-yl) benzenesulfonamide (209.64 mg).
ESI (m / z) 392 (MH < + >) 390 (MH &
< Example 1-2> Ethyl 4 - [[4- (4-isopropyl-2,3-dimethyl- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Benzoate Produce
Ethyl 4-aminobenzoate was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 458 (MH @ +) 480 (MNa @ +) 456 (MH @ -)
< Example 1-3> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N-phenyl- Benzenesulfonamide Produce
Aniline was used as a starting material to carry out the reaction in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 386 (MH +) 408 (MNa < + >) 384 (MH &
< Example 1-4> N- Cyclohexyl -4- (4-isopropyl-2, 3-dimethyl-5-oxo- Pyrazole -1-yl) -N- methyl - Benzenesulfonamide Produce
The objective compound was obtained by reacting N-methylcyclohexaneamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 406 (MH < + >) 428 (MNa &
< Example 1-5> N- (4- Rat - Butylphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 4-tert-butyl-aniline as starting materials in the same manner as in Example 1-1.
ESI (m / z) 442 (MH < + >) 440 (MH &
< Example 1-6> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (4- Methoxyphenyl ) Benzenesulfonamide Produce
4-methoxyaniline was used as a starting material, the reaction was conducted in the same manner as in Example 1-1 to give the target compound. (Yield: 81.3%)
ESI (m / z) 416 (MH < + >) 438 (MNa < + >) 414 (MH-); 2H, J = 8.8 Hz), 7.52 (d, 2H, 8.4 Hz), 7.01 (d, 2H, J = 8.8 Hz, 3H), 2.79 (s, 3H), 2.79 (s, 3H), 2.82 (d, 2H, J = J = 6.8 Hz); 13.9 (m, DMSO-d6) δ peak 165.1, 156.9, 155.6, 139.3, 135.8, 130.5, 128.1, 123.7, 122.0, 144.7, 144.6, 55.5, 37.2, 23.9, 21.2, 11.2
< Example 1-7> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (4- Morpholinophenyl ) Benzenesulfonamide Produce
4-morpholinoaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound. (Yield: 84.5%)
ESI (m / z) 471 (MH < + >) 493 (MNa < + >) 469 (MH-); 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.4 Hz), 6.98 (d, 2H, J = 4H), 2.93 (s, 3H), 2.77-2.70 (m, IH), 3.70 (d, 2H, J = , 2.19 (s, 3H), 1.17 (d, 6H, J = 6.8 Hz); 13.3 NMR (100 MHz, DMSO-d6)? Peak 165.1, 155.6, 148.1, 139.2, 136.0, 129.7, 128.1, 123.2, 122.0, 116.3, 114.6, 66.3, 49.1, 37.2, 23.9, 21.3, 11.3
< Example 1-8 > N - [(3,4- Dimethoxyphenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(3,4-dimethoxyphenyl) methanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1. (Yield: 75.9%)
ESI (m / z) 460 (MH +) 482 (MNa < + >) 458 (MH-); (D, 2H, J = 8.4Hz), 6.81-6.72 (d, 2H, J = (s, 3H), 2.96 (s, 3H), 2.81-2.70 (m, 1H), 2.22 s, 3H), 1.19 (d, 6H, J = 6.8 Hz); (100 MHz, DMSO-d6)? Peak 165.1, 155.5, 148.8, 148.3, 138.9, 137.2, 130.0, 127.9, 122.0, 120.2, 114.5, 111.8, 111.7, 55.8, 55.7, 49.0, 46.5, 37.1, 21.3, 11.2
< Example 1-9 > N- [2- (3,4- Dimethoxyphenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting the title compound with 2- (3,4-dimethylmethoxyphenyl) ethanamine as a starting material in the same manner as in Example 1-1. (Yield: 94.7%)
ESI (m / z) 474 (MH < + >) 496 (MNa < + >) 472 (MH-); 1H NMR (400 MHz, DMSO-d6)? 7.85 (d, 2H, J = 8.4 Hz), 7.70 J = 8.0 Hz), 6.81 (s, 1H), 6.65 (d, 1H, J = 8.4 Hz), 3.70 (d, 6H, J = 5.6 Hz), 3.00-2.95 2.70 (m, 1H), 2.62 (t, 2H, J = 7.4 Hz), 2.21 (s, 3H), 1.19 (d, 6H, J = 6.8 Hz); 137.9, 127.9, 122.2, 120.9, 114.5, 112.9, 112.2, 55.8, 55.7, 44.6, 37.1, 35.3, 23.9, 21.3, 11.2
< Example 1-10> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(2- Methoxyphenyl ) methyl ] Benzenesulfonamide Produce
(2-methoxyphenyl) methanamine as starting materials, the desired compounds were obtained. (Yield: 86.9%)
ESI (m / z) 430 (MH < + >) 452 (MNa < + >) 428 (MH-); (D, 2H, J = 8.4Hz), 7.25-7.17 (d, 2H, J = (m, 2H), 6.89-6.84 (m, 2H), 3.97 (d, 2H, J = 6.0 Hz), 3.70 (s, 3H), 2.97 2.22 (s, 3H), 1.20 (d, 6H, J = 6.8 Hz); 137.1, 128.9, 128.98, 127.84, 125.4, 122.1, 120.3, 114.5, 110.7, 55.5, 49.0, 41.4, 37.1, 23.9, 21.3, 11.2
< Example 1-11> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (p- Tolyl ) Benzenesulfonamide Produce
The objective compound was obtained by reacting p-toluidine as a starting material in the same manner as in Example 1-1.
2H, J = 7.2 Hz), 6.99 (s, 4H), 2.93 (d, 2H, J = (s, 3H), 2.80-2.77 (m, IH), 2.25 (s, 3H)
< Example 1-12> N- (4- Chlorophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
4-chloroaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound.
< Example 1-13> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) -N- [2- (2- < / RTI > < Methoxyphenyl )ethyl] Benzenesulfonamide Produce
The objective compound was obtained by reacting the title compound with 2- (2-methoxyphenyl) ethanamine as a starting material in the same manner as in Example 1-1. (Yield: 55.5%)
ESI (m / z) 444 (MH +) 466 (MNa < + >) 442 (MH &
< Example 1-14> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) -N- [2- (2- < / RTI > < Methoxyphenoxy )ethyl] Benzenesulfonamide Produce
The objective compound was obtained by reacting the title compound with 2- (2-methoxyphenoxy) ethanamine as a starting material in the same manner as in Example 1-1. (Yield: 92.4%)
ESI (m / z) 460 (MH < + >) 482 (MNa &
< Example 1-15> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (3- Methoxyphenyl ) Benzenesulfonamide Produce
3-methoxyaniline was used as a starting material in the same manner as in Example 1-1 to give the desired compound. (Yield: 86.9%)
ESI (m / z) 416 (MH +) 438 (MNa < + >) 414 (MH-)
< Example 1-16> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Methoxyphenyl ) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2-methoxyaniline as a starting material in the same manner as in Example 1-1. (Yield: 83.3%)
ESI (m / z) 416 (MH +) 438 (MNa < + >) 414 (MH-)
< Example 1-17> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (3- Phenylpropyl ) Benzenesulfonamide Produce
3-phenylpropan-1-amine as a starting material, the desired compound was obtained. (Yield: 62.6%)
ESI (m / z) 428 (MH +) 450 (MNa < + >) 426 (MH-)
< Example 1-18> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (3- Nitrophenyl ) Benzenesulfonamide Produce
By using 3-nitroaniline as a starting material, the objective compound was obtained by the same procedure as in Example 1-1. (Yield: 73.0%)
ESI (m / z) 431 (MH +) 453 (MNa < + >) 429 (MH-)
< Example 1-19> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (4- Nitrophenyl ) Benzenesulfonamide Produce
The objective compound was obtained by reacting 4-nitroaniline as a starting material in the same manner as in Example 1-1. (Yield: 72.9%)
ESI (m / z) 431 (MH +) 453 (MNa < + >) 429 (MH-)
< Example 1-20> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Phenylethyl ) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2-phenylethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 414 (MH +) 436 (MNa < + >) 412 (MH-)
< Example 1-21> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (4- Phenylbutyl ) Benzenesulfonamide Produce
4-phenylbutan-1-amine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1.
ESI (m / z) 442 (MH +) 464 (MNa < + >) 440 (MH-)
< Example 1-22> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (5- Quinolyl ) Benzenesulfonamide Produce
Quinolin-5-amine as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-1.
ESI (m / z) 437 (MH +) 459 (MNa < + >) 435 (MH-)
< Example 1-23> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (3- Quinolyl ) Benzenesulfonamide Produce
Quinolin-3-amine as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-1.
ESI (m / z) 437 (MH +) 459 (MNa < + >) 435 (MH-)
< Example 1-24> N- (4- Fluorophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 4-fluoroaniline in the same manner as in the above-mentioned Example 1-1 using the starting material.
ESI (m / z) 404 (MH < + >) 402 (MH &
< Example 1-25> Rat -Butyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Piperidine-1-carboxylate
Tert-butyl 4-aminopiperidine-1-carboxylate as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1.
ESI (m / z) 493 (MH < + >) 491 (MH &
< Example 1-26> N- [2- (4- Chlorophenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The target compound was obtained by reacting the title compound with 2- (4-chlorophenyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 448 (MH < + >) 446 (MH &
< Example 1-27> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Thienylmethyl ) Benzenesulfonamide Produce
Thiophen-2-ylmethanamine was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 406 (MH +) 428 (MNa < + >) 404 (MH-)
< Example 1-28> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (3- Pyridyl methyl ) Benzenesulfonamide Produce
Pyridin-3-ylmethanamine as a starting material, the desired compound was obtained.
ESI (m / z) 401 (MH +) 423 (MNa < + >) 399 (MH &
< Example 1-29> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) -N- [2- (2- < / RTI > < Pyridyl )ethyl] Benzenesulfonamide Produce
The target compound was obtained by reacting the title compound with 2- (pyridin-2-yl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 415 (MH +) 437 (MNa < + >) 413 (MH-)
< Example 1-30> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Naphthylmethyl ) Benzenesulfonamide Produce
Naphthalen-2-ylmethanamine was used as a starting material in the same manner as in Example 1-1 to give the desired compound.
ESI (m / z) 450 (MH +) 472 (MNa < + >) 448 (MH-)
< Example 1-31 > N- [2- (3- Fluorophenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (3-fluorophenyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 432 (MH +) 454 (MNa < + >) 430 (MH &
< Example 1-32 > N- (5- Fluoro -2- Pyridyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The target compound was obtained by reacting 5-fluoropyridin-2-amine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 405 (MH +) 427 (MNa < + >) 403 (MH-)
< Example 1-33] 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(4- Methoxyphenyl ) methyl ] Benzenesulfonamide Produce
(4-methoxyphenyl) methanamine as starting materials, the desired compounds were obtained.
ESI (m / z) 430 (MH @ +) 452 (MNa @ +) 428 (MH @ -)
< Example 1-34> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (6- Quinolyl ) Benzenesulfonamide Produce
Quinolin-6-amine as a starting material, the desired compound was obtained.
ESI (m / z) 437 (MH +) 459 (MNa < + >) 435 (MH-)
< Example 1-35 > N- (2,3- Dihydro -1,4- Benzodioxine Yl) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) benzenesulfonamide < / RTI >
2,3-dihydro-1,4-benzodioxin-6-amine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1.
ESI (m / z) 444 (MH +) 466 (MNa < + >) 442 (MH &
< Example 1-36> N- [4- (Dimethylamino) phenyl] -4- (4-isopropyl-2,3- Pyrazole -1 day) Benzenesulfonamide Produce
N, N-dimethylbenzene-1,4-diamine as starting materials, the desired compounds were obtained.
ESI (m / z) 429 (MH +) 451 (MNa < + >) 427 (MH-)
< Example 1-37> methyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Benzoate Produce
Methyl 3-aminobenzoate was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 444 (MH +) 466 (MNa < + >) 442 (MH &
< Example 1-38> Ethyl 3 - [[4- (4-isopropyl-2,3-dimethyl- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Benzoate Produce
Ethyl 3-aminobenzoate was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 458 (MH @ +) 480 (MNa @ +) 456 (MH @ -)
< Example 1-39> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [3- ( Trifluoromethyl ) Phenyl] Benzenesulfonamide Produce
The objective compound was obtained by carrying out the reaction in the same manner as in the above-mentioned Example 1-1, using 3- (trifluoromethyl) aniline as a starting material.
ESI (m / z) 454 (MH +) 476 (MNa < + >) 452 (MH &
< Example 1-40> N- [2- (4- Fluorophenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (4-fluorophenyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 432 (MH +) 454 (MNa < + >) 430 (MH &
< Example 1-41> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (4- Isopropylphenyl ) Benzenesulfonamide Produce
4-isopropylaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 428 (MH +) 450 (MNa < + >) 426 (MH-)
< Example 1-42 > N- (3- Fluorophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
3-fluoroaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 404 (MH +) 426 (MNa < + >) 402 (MH &
< Example 1-43> N- (3- Fluorophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- methyl - Benzenesulfonamide Produce
The target compound was obtained by reacting 3-fluoro-N-methylaniline as a starting material in the same manner as in Example 1-1.
ESI (m / z) 418 (MH < + >).
< Example 1-44> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (1- Naphthyl ) Benzenesulfonamide Produce
Naphthalen-1-amine as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-1.
ESI (m / z) 436 (MH +) 458 (MNa < + >) 434 (MH-)
< Example 1-45> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(3- Methoxyphenyl ) methyl ] Benzenesulfonamide Produce
(3-methoxyphenyl) methanamine as starting materials, the desired compounds were obtained.
ESI (m / z) 430 (MH @ +) 452 (MNa @ +) 428 (MH @ -)
< Example 1-46> N - [(3- Fluorophenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(3-fluorophenyl) methanamine as starting materials, the desired compounds were obtained.
ESI (m / z) 418 (MH +) 440 (MNa < + >) 416 (MH-)
< Example 1-47> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- ( Tetrahydrofuran -2- Yl methyl ) Benzenesulfonamide Produce
(Tetrahydrofuran-2-yl) methanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1.
ESI (m / z) 394 (MH +) 416 (MNa < + >) 392 (MH &
< Example 1-48 > N- [2- (2- Furylmethylsulfanyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
2 - ((furan-2-ylmethyl) thio) ethanamine as a starting material, the desired compound was obtained.
ESI (m / z) 450 (MH +) 472 (MNa < + >) 448 (MH-)
< Example 1-49> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [2- (p- Tolyl )ethyl] Benzenesulfonamide Produce
The target compound was obtained by reacting the title compound with 2- (p-tolyl) ethanamine as starting materials in the same manner as in Example 1-1.
ESI (m / z) 428 (MH +) 450 (MNa < + >) 426 (MH-)
< Example 1-50> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (4- Methoxyphenyl ) -N- methyl - Benzenesulfonamide Produce
Methoxy-N-methylaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 430 (MH < + >) 452 (MNa &
< Example 1-51> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [2- (4- Methoxyphenyl )ethyl] Benzenesulfonamide Produce
The target compound was obtained by reacting the title compound with 2- (4-methoxyphenyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 444 (MH +) 466 (MNa < + >) 442 (MH &
< Example 1-52 > N - [(2- Chlorophenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(2-chlorophenyl) methanamine as starting materials, the desired compounds were obtained.
ESI (m / z) 434 (MH +) 456 (MNa < + >) 432 (MH-)
< Example 1-53 > N- (2- Fluorophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The target compound was obtained by reacting 2-fluoroaniline in the same manner as in the above-mentioned Example 1-1 using the starting material.
ESI (m / z) 404 (MH +) 426 (MNa < + >) 402 (MH &
< Example 1-54> N - [(2- Fluorophenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(2-fluorophenyl) methanamine as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-1.
ESI (m / z) 418 (MH < + >) 416 (MH &
< Example 1-55> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (p- Tolylmethyl ) Benzenesulfonamide Produce
The objective compound was obtained by reacting p-tolylmethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 414 (MH +) 436 (MNa < + >) 412 (MH-)
< Example 1-56> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) -N- (m- Tolylmethyl ) Benzenesulfonamide Produce
m-tolylmethanamine was used as a starting material to carry out the reaction in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 414 (MH +) 436 (MNa < + >) 412 (MH-)
< Example 1-57> N- (2,5- Dimethylphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
2,5-dimethylaniline was used as a starting material to carry out the reaction in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 414 (MH +) 436 (MNa < + >) 412 (MH-)
< Example 1-58> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) -N- (m- Tolyl ) Benzenesulfonamide Produce
m-toluidine was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 400 (MH +) 422 (MNa < + >) 398 (MH-)
< Example 1-59> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (o- Tolyl ) Benzenesulfonamide Produce
o-toluidine was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 400 (MH +) 422 (MNa < + >) 398 (MH-)
< Example 1-60 > N- (4- Cyanophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
4-aminobenzonitrile was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 411 (MH +) 433 (MNa < + >) 409 (MH &
< Example 1-61> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [2- ( Trifluoromethyl ) Phenyl] Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (trifluoromethyl) aniline as a starting material in the same manner as in Example 1-1.
ESI (m / z) 454 (MH +) 476 (MNa < + >) 452 (MH &
< Example 1-62> N- (2,4- Dimethylphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
2,4-dimethylaniline was used as a starting material and reacted in the same manner as in Example 1-1 to obtain the target compound.
ESI (m / z) 414 (MH +) 436 (MNa < + >) 412 (MH-)
< Example 1-63> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (6- Methoxy -3- Pyridyl ) Benzenesulfonamide Produce
6-methoxypyridin-3-amine as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-1.
ESI (m / z) 417 (MH +) 439 (MNa < + >) 415 (MH-)
< Example 1-64> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (p- Tolyl ) Benzenesulfonamide Produce
The objective compound was obtained by reacting p-toluidine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 400 (MH +) 422 (MNa < + >) 398 (MH-)
< Example 1-65 > N- (2,2- Dimethylpropyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
2-dimethylpropan-1-amine as a starting material, the target compound was obtained.
ESI (m / z) 380 (MH +) 402 (MNa < + >) 378 (MH-)
< Example 1-66> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Pyridyl methyl ) Benzenesulfonamide Produce
Pyridin-2-ylmethanamine as starting materials, the desired compounds were obtained.
ESI (m / z) 401 (MH +) 423 (MNa < + >) 399 (MH &
< Example 1-67> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Pyridyl ) Benzenesulfonamide Produce
Pyridine-2-amine as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-1.
ESI (m / z) 387 (MH +) 409 (MNa < + >) 385 (MH-)
< Example 1-68> N- (3- Bromophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
3-Bromoaniline was used as a starting material to carry out the reaction in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 464 (M @ +) 466 (M + 2)
< Example 1-69> N- (2- Bromophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
2-Bromoaniline was used as a starting material to carry out the reaction in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 464 (M @ +) 466 (M + 2)
< Example 1-70> N- (2,4- Dibromophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
2,4-dibromoaniline was used as a starting material to carry out the reaction in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 544 (MH +) 546 (M + 2) 542 (MH-)
< Example 1-71> N- (2,5- Dibromophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
2,5-dibromoaniline was used as a starting material to carry out the reaction in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 544 (MH +) 546 (M + 2) 542 (MH-)
< Example 1-72> N- (3- Ethyl phenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 3-ethylaniline as a starting material in the same manner as in Example 1-1.
ESI (m / z) 414 (MH +) 436 (MNa < + >) 412 (MH-)
< Example 1-73> N- (1,1- Dimethylpropyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
2-methylbutan-2-amine as a starting material, the objective compound was obtained.
ESI (m / z) 380 (MH < + >).
< Example 1-74> N- (3,5- Dimethoxyphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
3,5-dimethoxyaniline was used as a starting material and reacted in the same manner as in Example 1-1 to obtain the target compound.
ESI (m / z) 446 (MH @ +) 468 (MNa @ +) 444 (MH @ -)
< Example 1-75> N- Cyclopentyl -4- (4-isopropyl-2, 3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting cyclopentanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 378 (MH < + >) 376 (MH &
< Example 1-76> 4-Isopropyl-2- [4- [4- (4- Methoxyphenyl ) Piperazin-1-yl] Sulfonylphenyl ] -1, 5-dimethyl- Pyrazole -3-one
The objective compound was obtained by reacting it with 1- (4-methoxyphenyl) piperazine as starting materials in the same manner as in Example 1-1.
ESI (m / z) 485 (MH < + >) 507 (MNa &
< Example 1-77> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (4-sec- Butylphenyl ) Benzenesulfonamide Produce
The objective compound was obtained by reacting 4- (sec-butyl) aniline as starting materials in the same manner as in Example 1-1.
ESI (m / z) 442 (MH +) 464 (MNa < + >) 440 (MH-)
< Example 1-78> Ethyl 4 - [[4- (4-isopropyl-2,3-dimethyl- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Piperidine-1-carboxylate
The objective compound was obtained by reacting ethyl 4-aminopiperidine-1-carboxylate as a starting material in the same manner as in Example 1-1.
ESI (m / z) 465 (MH +) 487 (MNa < + >) 463 (MH &
< Example 1-79> N- indan-5-yl-4- (4-isopropyl-2,3-dimethyl- Pyrazole -1 day) Benzenesulfonamide Produce
2,3-dihydro-1H-inden-5-amine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1.
ESI (m / z) 426 (MH +) 448 (MNa < + >) 424 (MH-)
< Example 1-80> N-Indan-2-yl-4- (4-isopropyl-2,3- Pyrazole -1 day) Benzenesulfonamide Produce
2,3-dihydro-1H-inden-2-amine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1.
ESI (m / z) 426 (MH < + >) 424 (MH &
< Example 1-81> N- Cycloheptyl -4- (4-isopropyl-2, 3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
Cycloheptanamine was used as a starting material and reacted in the same manner as in Example 1-1 to obtain the target compound.
ESI (m / z) 406 (MH < + >) 404 (MH &
< Example 1-82> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [3- ( Trifluoromethyl ) Phenyl] Benzenesulfonamide Produce
The objective compound was obtained by carrying out the reaction in the same manner as in the above-mentioned Example 1-1, using 3- (trifluoromethyl) aniline as a starting material.
ESI (m / z) 454 (MH +) 476 (MNa < + >) 452 (MH &
< Example 1-83> N- (4- Acetylphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 1- (4-aminophenyl) ethanone as a starting material in the same manner as in Example 1-1.
ESI (m / z) 428 (MH +) 450 (MNa < + >) 426 (MH-)
< Example 1-84> methyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Benzoate Produce
Methyl 4-aminobenzoate was used as a starting material to carry out the reaction in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 444 (MH +) 466 (MNa < + >) 442 (MH &
< Example 1-85> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) -N-pyrimidin-2-yl- Benzenesulfonamide Produce
Pyrimidin-2-amine as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-1.
ESI (m / z) 388 (MH < + >) 386 (MH &
< Example 1-86> N - [(2,4- Dimethoxyphenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(2,4-dimethoxyphenyl) methanamine as a starting material, the desired compound was obtained.
ESI (m / z) 460 (MH < + >).
< Example 1-87> N- (2- Chloro -4- Pyridyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2-chloropyridin-4-amine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 421 (MH +) 443 (MNa < + >) 419 (MH-)
< Example 1-88 > 2- [4- (4- Ethylpiperazine -1 day) Sulfonylphenyl ] -4-isopropyl-l, 5-dimethyl- Pyrazole -3-one
Ethylpiperazine was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 407 (MH < + >).
< Example 1-89> N- [3,5- Bis (trifluoromethyl) phenyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) benzenesulfonamide < / RTI >
The objective compound was obtained by reacting 3,5-bis (trifluoromethyl) aniline as a starting material in the same manner as in Example 1-1.
ESI (m / z) 522 (MH < + >) 520 (MH &
< Example 1-90> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (4- Pyridyl methyl ) Benzenesulfonamide Produce
Pyridin-4-ylmethanamine as starting materials, the desired compounds were obtained.
ESI (m / z) 420 (MH +) 423 (MNa < + >) 399 (MH-)
< Example 1-91> N- (9- Ethylcarbazole Yl) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
9-ethyl-9H-carbazole-3-amine as a starting material, the target compound was obtained.
ESI (m / z) 503 (MH < + >) 525 (MNa &
< Example 1-92 > N- (4- Bromo -One- Naphthyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
4-Bromonaphthalene-1-amine as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-1.
ESI (m / z) 514 (M @ +) 516 (M + 2)
< Example 1-93> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Phenyl phenyl ) Benzenesulfonamide Produce
[1,1'-biphenyl] -2-amine as a starting material, the desired compound was obtained.
ESI (m / z) 462 (MH < + >) 460 (MH-); 1H NMR (400 MHz, DMSO-d6)? 8.27 (s, IH), 8.04 (t, IH, J = 2.0Hz) 8.02-7.99 7.94 (t, 1H, J = 8.0Hz, Jb (J = 2.0Hz), 7.80 (t, 1H, J = 6.0Hz, 2H), 1.67 (d, 6H), 7.60 (d, 1H, J = 8.0 Hz, J = 1.6 Hz) , J = 6.8 Hz); 128.9, 128.6, 128.1, 127.8, 126.2, 124.9, 121.7, 115.9, 37.2, 24.5 (dd, , 20.7, 10.7
< Example 1-94> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- methyl -One- Naphthyl ) Benzenesulfonamide Produce
2-methylnaphthalen-1-amine as a starting material, the desired compound was obtained.
ESI (m / z) 450 (MH < + >) 448 (MH-); (M, 3H), 8.12 (d, 2H, J = 8.8 Hz), 7.96 (d, 2H, J = 8.8 Hz) , 7.81 (d, 2H, J = 8.4 Hz), 7.77 (t, 1H, J = 7.4 Hz), 7.68 1H), 2.75 (s, 3H), 2.68 (s, 3H), 1.67 (d, 6H, J = 6.8 Hz)
< Example 1-95 > N- [2- (4- Bromophenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The target compound was obtained by reacting the title compound with 2- (4-bromophenyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 492 (M @ +) 494 (M + 2); (D, 2H, J = 8.8 Hz), 7.82 (d, 2H, 8.4 Hz), 7.54 (d, 2H 2H), 3.48 (s, 3H), 3.28-3.18 (m, 3H), 2.69 (s, 3H) , 1.67 (d, 6H, J = 7.2 Hz)
< Example 1-96> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [2- (5- Methoxy -1H-indol-3-yl) ethyl] benzenesulfonamide
The target compound was obtained by reacting the title compound with 2- (5-methoxy-1H-indol-3-yl) ethanamine as starting materials in the same manner as in Example 1-1.
ESI (m / z) 483 (MH @ +) 481 (MH @ -); 1H NMR (400 MHz, DMSO-d 6)? 10.26 (s, 1H), 8.27 (d, 2H, J = 8.8 Hz), 8.00 ), 7.43-7.41 (m, 2H), 7.14 (dd, 1H, Jao = 8.0 Hz, Jb = 2.4 Hz), 6.93 (t, 1H, J = 5.8 Hz) (m, 2H), 3.33 (t, 2H, J = 7.4 Hz), 3.27-3.19
< Example 1-97> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- methyl Indol-5-yl) Benzenesulfonamide Produce
Methyl-1H-indole-5-amine as starting materials, the target compound was obtained by carrying out the reaction in the same manner as in Example 1-1.
ESI (m / z) 439 (MH < + >) 437 (MH-); (D, 2H, J = 8.4 Hz), 7.69 (d, 2H, J = (s, 3H), 3.24-3.15 (m, IH), 7.55 (d, 2H, 8.8 Hz), 7.29 (m, 1H), 2.78 (s, 3H), 2.64 (s, 3H), 1.63 (d, 6H, J = 7.2 Hz); (100 MHz, DMSO-d6) [delta] 165.6, 155.7, 139.9, 137.1, 136.9, 136.3, 134.9, 129.7, 129.4, 128.4, 121.4, 117.3, 115.9, 114.5, 110.8, 100.0, 37.1, 24.4, 20.7, 13.0 , 10.7
< Example 1-98> N- (1H-indole-5- Yl methyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(1H-indol-5-yl) methanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1.
ESI (m / z) 439 (MH < + >).
< Example 1-99> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (6- Methoxy -1,3- Benzothiazole -2-yl) benzenesulfonamide
6-methoxybenzo [d] thiazole-2-amine as a starting material, the target compound was obtained.
ESI (m / z) 473 (MH +) 495 (MNa < + >) 471 (MH-)
< Example 1-100> N- [2- (1H-Indol-3-yl) ethyl] -4- (4- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (1H-indol-3-yl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 453 (MH +) 475 (MNa < + >) 451 (MH-)
< Example 1-101> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- methyl -8- Quinolyl ) Benzenesulfonamide Produce
Methyl-8-quinolylamine was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 451 (MH < + >) 473 (MNa &
< Example 1-102> N- (4- Ethoxy Nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 4-ethoxy-2-nitroaniline as a starting material in the same manner as in Example 1-1.
ESI (m / z) 475 (MH +) 497 (MNa < + >) 473 (MH-)
< Example 1-103> N- (3,4- Dichlorophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
3,4-dichloroaniline was used as a starting material to carry out the reaction in the same manner as in Example 1-1, to give the target compound.
ESI (m / z) 454 (M @ +) 456 (M + 2)
< Example 1-104> N- [2- (2- Chlorophenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide
The objective compound was obtained by reacting 2- (2-chlorophenyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 448 (MH < + >) 446 (MH &
< Example 1-105> N - [(4- Chlorophenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(4-chlorophenyl) methanamine as starting materials, the desired compounds were obtained.
ESI (m / z) 434 (MH +) 456 (MNa < + >) 432 (MH-)
< Example 1-106> N- (3,5- Dichlorophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
3,5-dichloroaniline was used as a starting material and reacted in the same manner as in Example 1-1 to obtain the target compound.
ESI (m / z) 454 (M @ +) 456 (M + 2)
< Example 1-107> N- (1,2- Dimethoxypropyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
1,2-dimethoxypropan-1-amine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1.
ESI (m / z) 412 (MH < + >).
< Example 1-108> N- (5- Chloro -2- Fluoro -Phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
5-chloro-2-fluoroaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 438 (MH < + >) 436 (MH &
< Example 1-109> N- (4- Ethynyl phenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
4-ethynylaniline was used as a starting material to carry out the reaction in the same manner as in Example 1-1 to give the target compound. (Yield: 79.4%)
ESI (m / z) 410 (MH @ +) 408 (MH @ -); J = 8.0 Hz), 7.32 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 3H), 2.74-2.63 (m, 1H), 2.14 (s, 3H), 1.12 (d, 2H), 7.09 (d, 2H, J = 8.8 Hz) 6H, J = 7.2 Hz); 137.2, 23.9, 21.2, 11.2 (1H, dd, < RTI ID = 0.0 >
< Example 1-110> N - [(4- Fluorophenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(4-fluorophenyl) methanamine as starting materials, the desired compounds were obtained. (Yield: 67.9%)
ESI (m / z) 418 (MH < + >) 416 (MH &
< Example N- (2,4-dimethyl-6-nitro-phenyl) -4- (4-isopropyl- Pyrazole -1 day) Benzenesulfonamide Produce
2,4-dimethyl-6-nitroaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound. (Yield: 38.0%)
ESI (m / z) 459 (MH @ +) 457 (MH @ +); 1H NMR (400 MHz, DMSO-d6)? 10.02 (s, 1H), 7.59 (d, 2H, J = 8.8 Hz), 7.50-7.47 3H), 1.77 (s, 3H), 1.15 (d, 6H, J = 7.2 Hz); 2.77 (s, 3H). 13.5 NMR (100 MHz, DMSO-d6)? Peak 165.0, 155.7, 149.4, 139.57,139.52,138.7,138.8,135.8,127.8,24.4,123.4,122.3,114.7,37.2,12.9,21.3,20.5,17.6,11.3
< Example 1-112> N- (2,5- Dichloro -4-nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl- Pyrazole -1-yl) benzenesulfonamide < / RTI >
Dichloro-4-nitroaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound. (Yield: 42.6%)
ESI (m / z) 499 (M) < RTI ID = 0.0 >
< Example 1-113> N- (4- Chloro Nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
Chloro-3-nitroaniline as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-1. (Yield: 86.0%)
1H NMR (400 MHz, DMSO-d6)? 11.01 (s, 1H), 7.87 (d, 2H, J = 8.8 Hz), 7.73 1H, J = 8.8 Hz), 7.54 (d, 2H, J = 8.4 Hz), 7.38 (dd, IHJa = 12.0 Hz, Jb = 2.4 Hz), 2.89 (s, 3H), 1.12 (d, 6H, J = 7.2 Hz); 14.9, 128.2, 124.4, 122.2, 120.0, 116.0, 114.6, 37.3, 23.9, 21.2, 11.3 (d,
< Example 1-114> N- (2,3-Dimethyl-6-nitro-phenyl) -4- (4-isopropyl-2,3- Pyrazole -1 day) Benzenesulfonamide Produce
By using 2,3-dimethyl-6-nitroaniline as a starting material, the objective compound was obtained by the same procedure as in Example 1-1. (Yield: 35.9%)
ESI (m / z) 459 (MH @ +) 457 (MH @ +); 1H NMR (400 MHz, DMSO-d6)? 10.16 (s, IH), 7.64 (d, IH, J = 8.4 Hz), 7.60 (D, 2H, J = 8.4 Hz), 7.33 (d, 1H, J = 8.4 Hz), 2.96 (s, 3H), 2.97-2.72 , 1.19 (d, 6H, J = 7.2 Hz); 137.9, 139.9, 138.9, 136.5, 129.5, 127.8, 126.8, 122.4, 122.3, 114.7, 37.1, 23.9, 21.3, 20.8, 14.7, 11.3
< Example 1-115> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (1- Naphthylmethyl ) Benzenesulfonamide Produce
Naphthalen-1-ylmethanamine was used as a starting material in the same manner as in Example 1-1 to give the target compound. (Yield: 9.21%).
ESI (m / z) 450 (MH +) 472 (MNa < + >) 448 (MH-)
< Example 1-116> N - [(3- Bromophenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(3-bromophenyl) methanamine as starting materials, the desired compounds were obtained. (Yield: 76.7%)
ESI (m / z) 478 (M @ +) 480 (M + 2)
< Example 1-117> N- [2- (3- Bromophenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (3-bromophenyl) ethanamine as a starting material in the same manner as in Example 1-1. (Yield: 61.8%)
ESI (m / z) 492 (M @ +) 494 (M + 2)
< Example 1-118 > N - [(2- Bromophenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(2-bromophenyl) methanamine as starting materials, the desired compounds were obtained by the reaction in the same manner as in Example 1-1. (Yield: 95.8%)
ESI (m / z) 478 (M @ +) 480 (M + 2)
< Example 1-119> N- [2- (3- Chlorophenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (3-chlorophenyl) ethanamine as a starting material in the same manner as in Example 1-1. (Yield: 73.1%)
ESI (m / z) 448 (MH @ +) 470 (MNa @ +) 446 (MH @ -)
< Example 1-120> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [[3- ( Trifluoromethyl ) Phenyl] methyl] benzenesulfonamide < / RTI >
(3- (trifluoromethyl) phenyl) methanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-1. (Yield: 78.9%)
ESI (m / z) 468 (MH +) 490 (MNa < + >) 466 (MH &
< Example 1-121> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [[2- ( Trifluoromethyl ) Phenyl] methyl] benzenesulfonamide < / RTI >
(2- (trifluoromethyl) phenyl) methanamine as starting materials, the desired compounds were obtained. (Yield: 77.3%)
ESI (m / z) 468 (MH +) 490 (MNa < + >) 466 (MH &
< Example 1-122> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [[4- ( Trifluoromethyl ) Phenyl] methyl] benzenesulfonamide < / RTI >
(4- (trifluoromethyl) phenyl) methanamine as starting materials, the desired compounds were obtained. (Yield: 74.6%)
ESI (m / z) 468 (MH +) 490 (MNa < + >) 466 (MH &
< Example 1-123> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (o- Tolylmethyl ) Benzenesulfonamide Produce
o-tolylmethanamine as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-1. (Yield: 84.2%)
ESI (m / z) 414 (MH +) 436 (MNa < + >) 412 (MH-)
< Example 1-124> N- (3- Chlorophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
3-chloroaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound. (Yield: 88.8%)
ESI (m / z) 420 (MH < + >) 418 (MH &
< Example 1-125> N- (2- Chlorophenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
2-chloroaniline was used as a starting material and reacted in the same manner as in Example 1-1 to give the target compound. (Yield: 80.6%)
ESI (m / z) 420 (MH < + >) 418 (MH &
< Example 1-126> N - [(3- Chlorophenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
3-Chlorophenylmethanamine was used as a starting material in the same manner as in Example 1-1 to give the target compound. (Yield: 96.4%)
ESI (m / z) 434 (MH +) 456 (MNa < + >) 432 (MH-)
< Example 1-127> 4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Phenoxyethyl ) Benzenesulfonamide Produce
1. Preparation of 4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonyl chloride
By using 4-isopropyl-1,5-dimethyl-2-phenylpyrazolone as a starting material, the reaction was carried out in the same manner as in the step 1-1 of Example 1-1 to give the target compound as a pale yellow solid.
2. Preparation of 4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-phenoxyethyl) benzenesulfonamide
The target compound was obtained by reacting 2-phenoxyethanamine as a starting material in the same manner as in Example 1-1-2. (Yield: 80.6%)
ESI (m / z) 466 (M @ +) 468 (M + 2); 2H, J = 8.4 Hz), 7.56 (d, 2H, J = 8.8 Hz), 7.25 (t, 2H, J = 8.0 Hz), 3.91 (t, 2H, J = 8.0 Hz), 6.91 (t, 1H, J = 8.8 Hz) ), 3.13 (s, 3 H), 2.33 (s, 3 H); 129.9, 129.6, 121.1, 114.79, 114.77, 88.4, 66.6, 42.4, 37.1, 12.7 (dd,
< Example 1-128> N- [2- (2- Fluorophenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (2-fluorophenyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 432 (MH +) 454 (MNa < + >) 430 (MH &
< Example 1-129> N - [(4- Bromophenyl ) methyl ] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(4-bromophenyl) methanamine as starting materials, the desired compounds were obtained.
ESI (m / z) 478 (M @ +) 480 (M + 2)
< Example 1-130> N- [2- (2- Bromophenyl ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (2-bromophenyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 492 (M @ +) 494 (M + 2)
< Example 1-131> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [2- (o- Tolyl )ethyl] Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (o-tolyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 428 (MH < + >) 450 (MNa &
< Example 1-132> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [2- (3- Methoxyphenyl )ethyl] Benzenesulfonamide Produce
The objective compound was obtained by reacting 2- (3-methoxyphenyl) ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 444 (MH < + >) 466 (MNa &
< Example 1-133> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [2- [2- ( Trifluoromethyl ) Phenyl] ethyl] benzenesulfonamide < / RTI >
The objective compound was obtained by reacting the title compound with 2- [2- (trifluoromethyl) phenyl] ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 482 (MH +) 504 (MNa < + >) 480 (MH-)
< Example 1-134> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [2- [3- ( Trifluoromethyl ) Phenyl] ethyl] benzenesulfonamide < / RTI >
The target compound was obtained by reacting 2- [3- (trifluoromethyl) phenyl] ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 482 (MH +) 504 (MNa < + >) 480 (MH-)
< Example 1-135> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [2- [4- ( Trifluoromethyl ) Phenyl] ethyl] benzenesulfonamide < / RTI >
The objective compound was obtained by reacting 2- [4- (trifluoromethyl) phenyl] ethanamine as a starting material in the same manner as in Example 1-1.
ESI (m / z) 482 (MH +) 504 (MNa < + >) 480 (MH-)
< Example 1-136> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [4- ( Trifluoromethyl ) Phenyl] Benzenesulfonamide Produce
The objective compound was obtained by reacting 4- (trifluoromethyl) aniline as starting materials in the same manner as in Example 1-1.
ESI (m / z) 454 (MH +) 476 (MNa < + >) 452 (MH &
< Example 1-137> N- (2,3- Dihydro -1,4- Benzodioxine -6- Yl methyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) benzenesulfonamide < / RTI >
(2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methanamine as starting materials, the target compound was obtained.
ESI (m / z) 458 (MH @ +) 480 (MNa @ +) 456 (MH @ -)
< Example 1-138> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Phenoxyethyl ) Benzenesulfonamide Produce
1. Preparation of 4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonyl chloride
Using 4-chloro-1,5-dimethyl-2-phenylpyrazolone as a starting material, the reaction was conducted in the same manner as in the step 1 of Example 1-1 to obtain the target compound as a pale yellow solid. (Yield: 40.5%)
2. Preparation of 4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2-phenoxyethyl) benzenesulfonamide
The target compound was obtained by reacting 2-phenoxyethanamine as a starting material in the same manner as in Example 1-1-2. (Yield: 51.94%)
ESI (m / z) 422 (MH < + >) 444 (MNa < + >) 420 (MH-); (D, 2H, J = 8.8 Hz), 7.25 (t, 2H, J = 8.4 Hz) (D, 2H, J = 8.0 Hz), 6.91 (t, 1H, J = 7.4 Hz), 6.83 = 5.6 Hz), 3.11 (s, 3H), 2.32 (s, 3H); 138.1, 129.8, 128.0, 123.6, 121.1, 114.7, 100.6, 66.6, 42.4, 37.0, 11.5 (dd,
< Example 1-139 > 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(2- Fluorophenyl ) methyl ] Benzenesulfonamide Produce
(2-fluorophenyl) methanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-138. (Yield: 50.8%)
ESI (m / z) 410 (MH < + >) 432 (MNa < + >) 408 (MH-); 1H NMR (400 MHz, DMSO-d6) 8.29 (t, IH, J = 6.2 Hz), 7.90 (d, 2H, J = 8.4 Hz), 7.53 2H, J = 7.6 Hz), 7.30-7.25 (m, 1H), 7.13-7.07 (m, 2H), 4.09
< Example 1-140> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(3- Fluorophenyl ) methyl ] Benzenesulfonamide Produce
(3-fluorophenyl) methanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-138. (Yield: 17.3%)
ESI (m / z) 410 (MH < + >) 432 (MNa < + >) 408 (MH-); (D, 2H, J = 8.4Hz), 7.31 (q, 1H, J = 6.0Hz) 2H, J = 6.4 Hz), 3.13 (s, 3H), 2.33 (s, 3H)
< Example 1-141> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(4- Fluorophenyl ) methyl ] Benzenesulfonamide Produce
(4-fluorophenyl) methanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-138. (Yield: 40.9%)
ESI (m / z) 410 (MH < + >) 432 (MNa < + >) 408 (MH-); (D, 2H, J = 8.8Hz), 7.28-7.25 (m, 1H), 7.89 2H), 7.08 (t, 2H, J = 8.8 Hz), 4.04 (d, 2H, J = 6.4 Hz), 3.13 (s, 3H), 2.33 (s, 3H); 138.9, 138.1, 134.2, 134.1, 130.1, 130.0, 128.1, 123.6, 115.5, 115.2, 100.6, 45.8, 37.0, 11.5,
< Example 1-142> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (3,4- Dichlorophenyl ) Benzenesulfonamide Produce
3,4-dichloroaniline was used as a starting material to carry out the reaction in the same manner as in Example 1-138 to give the target compound. (Yield: 91.4%)
ESI (m / z) 447 (MH < + >) 489 (MNa < + >) 445 (MH-); 1H NMR (400 MHz, DMSO-d6) 7.85 (d, 2H, J = 8.8 Hz), 7.51 (d, 2H, J = 8.8 Hz), 7.45 , J = 2.4 Hz), 7.06 (dd, 1H, J = 2.6 Hz), 3.03 (s, 3H), 2.23 (s, 3H); 138.9, 138.2, 136.4, 131.9, 131.7, 128.3, 126.5, 123.5, 121.3, 120.0, 100.7, 37.2, 11.5 (dd,
< Example 1-143> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (5- Chloro -2- Fluoro - phenyl) Benzenesulfonamide Produce
Chloro-2-fluoroaniline as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-138. (Yield: 88.2%)
ESI (m / z) 431 (MH < + >) 453 (MNa < + >) 429 (MH-); (D, 2H, J = 8.8Hz), 7.25-7.15 (m, 3H), 3.04 (s, 3H), 2.24 (s, 3 H);
< Example 1-144> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [4- (dimethylamino) phenyl] Benzenesulfonamide Produce
N, N-dimethylbenzene-1,4-diamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-138. (Yield: 13.7%)
ESI (m / z) 421 (MH < + >) 443 (MNa < + >) 419 (MH-); 8.84 (d, 2H, J = 8.8 Hz), 7.48 (d, 2H, J = 8.4 Hz), 6.84 ), 6.54 (d, 2H, J = 9.2 Hz), 3.06 (s, 3H), 2.76 (s, 6H), 2.26 (s, 3H); 13C NMR (100 MHz, DMSO-d6)? 161.0, 155.4, 148.6, 138.2, 137.5, 128.3, 126.1, 124.5, 123.3, 113, 100.6, 37.1,
< Example 1-145> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Pyridyl methyl ) Benzenesulfonamide Produce
Pyridin-2-ylmethanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-138. (Yield: 64.9%)
ESI (m / z) 393 (MH < + >) 415 (MNa < + >) 491 (MH-); (T, 1H, J = 6.4 Hz), 7.83 (d, 2H, J = 8.8 Hz), 7.64 (t, 1H, J = J = 7.8 Hz), 7.46 (d, 2H, J = 8.8 Hz), 7.27 (d, 1H, J = 8.9 Hz), 7.15 = 6.0 Hz), 4.07 (d, 2H, J = 6.0 Hz), 3.06 (s, 3H), 2.25 (s, 3H); 138.0, 137.0, 128.1, 123.6, 122.8, 122.0, 100.6, 48.3, 37.0, 11.5 (dd,
< Example 1-146> methyl 3 - [[4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Benzoate Produce
Methyl-3-aminobenzoate as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-138. (Yield: 27.2%)
ESI (m / z) 436 (MH +) 458 (MNa < + >) 434 (MH-); 1H NMR (400MHz, DMSO-d6)? 10.58 (s, 1H), 7.82 (d, 2H, J = 8.8 Hz), 7.66-7.62 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 4.4 Hz), 3.74 (s, 3H), 3.01 (s, 3H), 2.22 (s, 3H);
< Example 1-147> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (lH-indol-5- Yl methyl ) Benzenesulfonamide Produce
1H-indole-5-ylmethanamine was used as a starting material to carry out the reaction in the same manner as in Example 1-138 to give the target compound. (Yield: 15.2%)
ESI (m / z) 431 (MH < + >) 453 (MNa < + >) 429 (MH-); (D, 2H, J = 8.8 Hz), 7.85 (d, 2H, J = 8.8 Hz) 2H, J = 8.4 Hz), 7.29 (s, 1H), 7.21 (d, 2H, J = 8.8 Hz), 6.88 Hz), 3.01 (s, 3H), 2.25 (s, 3H); 127.9, 127.8, 126.0, 123.6, 121.6, 119.7, 111.5, 101.3, 100.5, 47.3, 36.9, 11.4 (d,
< Example 1-148> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (1- Naphthylmethyl ) Benzenesulfonamide Produce
Naphthalen-1-ylmethanamine as a starting material, the desired compound was obtained by the reaction in the same manner as in Example 1-138. (Yield: 5.6%)
ESI (m / z) 442 (MH +) 464 (MNa < + >) 440 (MH-)
< Example 1-149> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(3,4- Dimethoxyphenyl ) methyl ] Benzenesulfonamide Produce
(3,4-dimethoxyphenyl) methanamine as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-138. (Yield: 5.4%)
ESI (m / z) 452 (MH +) 474 (MNa < + >) 450 (MH &
Example 1-150 Preparation of 4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (5-quinolyl) benzenesulfonamide
Quinolin-5-amine as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-138. (Yield: 38.5%)
ESI (m / z) 429 (MH < + >) 451 (MNa < + >) 427 (MH-); 8.84 (d, 1H, J = 8.4 Hz), 8.30 (d, 1H, J = 2H, J = 8.4 Hz), 7.38 (t, 1H, J = 4.2 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.62 (t, , 7.21 (d, IH, J = 7.6 Hz), 2.99 (s, 3H), 2.23 (s, 3H); 128.0, 128.3, 125.1, 124.1, 123.4, 121.6, 100.7, 37.0, 11.4 (1H, dd,
Example 1-151 Preparation of 4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (5-quinolyl) benzenesulfonamide
Quinolin-5-amine as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-138. (Yield: 7.3%)
ESI (m / z) 452 (MH +) 474 (MNa < + >) 450 (MH &
< Example 1-152> 4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(3,4- Dimethoxyphenyl ) methyl ] Benzenesulfonamide Produce
(3,4-dimethoxyphenyl) methanamine as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-138.
ESI (m / z) 496 (M +) 498 (M + 2)
Example 1-153 Preparation of 4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (5-quinolyl) benzenesulfonamide
Quinolin-5-amine as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-127.
ESI (m / z) 473 (M @ +) 475 (M + 2)
< Example 1-154 > 4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- [4- (dimethylamino) phenyl] Benzenesulfonamide Produce
N, N-dimethylbenzene-1,4-diamine as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-127.
ESI (m / z) 465 (M @ +) 467 (M + 2)
< Example 1-155> methyl 3 - [[4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Benzoate Produce
Methyl-3-aminobenzoate as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-127.
< Example 1-156 > 4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(3- Fluorophenyl ) methyl ] Benzenesulfonamide Produce
(3-fluorophenyl) methanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-127.
< Example 1-157> 4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N - [(2- Fluorophenyl ) methyl ] Benzenesulfonamide Produce
(2-fluorophenyl) methanamine as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-127.
< Example 1-158> 4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Pyridyl methyl ) Benzenesulfonamide Produce
Pyridin-2-ylmethanamine as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-127.
ESI (OT / Z) 437 (M @ +) 439 (M + 2); 1H NMR (400 MHz, DMSO-d6)? 8.38 (d, 1H, J = 4.4 Hz), 8.34 J = 7.6 Hz), 7.48 (d, 2H, J = 8.4 Hz), 7.31 (d, 1H, J = 7.6 Hz), 7.20-7.16 6.4 Hz), 3.10 (d, 3H, J = 9.2 Hz), 2.29 (s, 3H)
< Example 1-159 > 4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2,3- Dihydro -1,4- Benzodioxine -6-yl) benzenesulfonamide
The objective compound was obtained by reacting 2,3-dihydro-1,4-benzodioxin-6-amine as a starting material in the same manner as in Example 1-127.
ESI (m / z) 480 (M @ +) 482 (M + 2); 1H NMR (400 MHz, DMSO-d 6)? 10.05 (s, 1H), 7.83 (d, 2H, J = 8.4 Hz), 7.55-7.53 , 6.60 (d, 1H, J = 2.0 Hz), 6.56-6.54 (m, 1H), 4.16 (s, 4H)
< Example 1-160> N- [3,5- Bis (trifluoromethyl) phenyl ] -4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) benzenesulfonamide < / RTI >
The target compound was obtained by reacting 3,5-bis (trifluoromethyl) aniline as a starting material in the same manner as in Example 1-127.
ESI (m / z) 558 (M @ +) 560 (M + 2); 2H), 7.61 (dd, 2H, J = 8.8 Hz), 7.79 (s, J = 8.0 Hz, Jb = 2.0 Hz), 3.11 (d, 3H, J = 8.8 Hz), 2.32 (s,
< Example 1-161> 4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (3,4- Dichlorophenyl ) Benzenesulfonamide Produce
3,4-dichloroaniline was used as a starting material to carry out the reaction in the same manner as in Example 1-127, to give the target compound.
ESI (m / z) 492 (MH < + >) 514 (MNa < + >) 490 (MH-); J = 8.8 Hz), 7.58 (d, 2H, 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz) (D, 1H, J = 8.0 Hz, Jb = 2.4 Hz), 3.12 (d, 3H, J = 9.2 Hz), 2.31
< Example 1-162> 4- (4- Bromo -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (5- Chloro -2- Fluoro - phenyl) Benzenesulfonamide Produce
Chloro-2-fluoroaniline as starting materials, the target compound was obtained by a reaction in the same manner as in Example 1-127.
ESI (OT / Z) 474 (M @ +) 476 (M + 2); J = 8.8 Hz), 7.32-7.26 (m, 3H), 7.58 (d, 2H, J = , 3.13 (d, 3H, J = 9.2 Hz), 2.32 (s, 3H)
< Example 1-163> N- [3,5- Bis (trifluoromethyl) phenyl ] -4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) benzenesulfonamide < / RTI >
The objective compound was obtained by reacting 3,5-bis (trifluoromethyl) aniline as a starting material in the same manner as in Example 1-138. (Yield: 82.4%)
ESI (m / z) 514 (MH < + >) 536 (MNa < + >) 512 (MH-); 2H NMR (400 MHz, DMSO-d6)? 11.30 (s, IH), 7.97 (d, 2H, J = 8.8 Hz), 7.79 = 8.4 Hz), 3.11 (s, 3H), 2.32 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) 161.096, 155.964, 140.214, 139.225, 136.019, 131.914, 131.586, 128.378, 124.605, 123.636, 121.893, 119.325, 117.498, 100.842, 37.156, 31.077, 11.509
< Example 1-164> 4- (4- Chloro -2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2,3- Dihydro -1,4- Benzodioxine -6-yl) benzenesulfonamide
By using 2,3-dihydro-1,4-benzodioxin-6-amine as a starting material, the desired compound was obtained by the same procedure as in Example 1-138. (Yield: 10.3%)
ESI (m / z) 436 (MH +) 458 (MNa < + >) 434 (MH-)
Example 1-165 Preparation of 4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N-cyclopentyl-benzenesulfonamide
The objective compound was obtained by reacting cyclopentanamine as a starting material in the same manner as in Example 1-127. (Yield: 4.9%)
ESI (m / z) 414 (M @ +) 416 (M + 2); 1H, J = 7.2 Hz), 7.57 (q, 2H, J = 2.4 Hz), 3.15 (d, 2H, J = 3H, J = 9.2 Hz), 2.33 (s, 3H), 1.66-1.60
Example 1-166 Preparation of 4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N-cycloheptyl-benzenesulfonamide
Cycloheptanamine was used as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-127. (Yield: 3.7%)
ESI (OT / Z) 442 (M @ +) 444 (M + 2); 1H NMR (400MHz, DMSO-d6)? 10.39 (s, 1H), 7.91-7.89 (m, 2H), 7.57-7.54 J = 8.0 Hz), 7.05 (t, 1H, J = 7.4 Hz), 3.12 (d,
Example 1-167 Preparation of 4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N-phenyl-benzenesulfonamide
Aniline was used as a starting material to carry out the reaction in the same manner as in Example 1-127 to give the target compound. (Yield: 4.4%)
ESI (m / z) 422 (M +) 424 (M + 2)
< Example 1-168> 4- (2,3-Dimethyl-5-oxo-4-phenyl- Pyrazole -1-yl) -N- (2- Phenoxyethyl ) Benzenesulfonamide Produce
A 2-5 ml microwave reactor tube was charged with the resultant product 4- (4-bromo-2,3-dimethyl-5- (dimethylamino) (2-phenoxyethyl) benzenesulfonamide (150 mg, 0.322 mmol), phenylboronic acid (39.22 mg, 0.322 mmol), dichlorobis (triphenylphosphine) Palladium (II) (11.29 mg, 0.016 mmol) and sodium carbonate (68.18 mg, 0.643 mmol) were added and reacted at 120 ° C for 40 minutes using a microwave reactor. After confirming the reaction, water is added to terminate the reaction, and extraction is carried out using dichloromethane. The extraction solution is extracted with a vacuum pump and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1). Additional crystals were obtained using dichloromethane and hexane to give 4- (2,3-dimethyl-5-oxo-4-phenyl-pyrazol-1 -yl) -N- Ethyl) benzenesulfonamide.
ESI (m / z) 464 (MH @ +) 462 (MH @ +); J = 8.8 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = J = 8.0 Hz), 7.42 (t, 2H, J = 7.8 Hz), 7.31-7.23 (m, 3H), 6.91 (t, 8.0 Hz), 3.95 (t, 2H, J = 5.4 Hz), 3.21-3.15 (m, 5H), 2.40
< Example 1-169> 4- [4- (4- Chlorophenyl ) -2,3-dimethyl-5-oxo- Pyrazole -1-yl] -N- (2- Phenoxyethyl ) Benzenesulfonamide Produce
(4-chlorophenyl) boronic acid as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-168.
ESI (m / z) 498 (MH < + >) 497 (MH &
< Example 1-170> 2- [3 - [[4- (4-Isopropyl-2,3-dimethyl- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Phenyl] acetic acid
The objective compound was obtained by reacting 2- (3-aminophenyl) acetic acid as a starting material in the same manner as in Example 1-127.
ESI (m / z) 444 (MH +) 466 (MNa < + >) 442 (MH &
< Example 1-171> N- (2- Hydroxyphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 2-aminophenol as a starting material in the same manner as in Example 1-127.
ESI (m / z) 402 (MH +) 424 (MNa < + >) 400 (MH &
< Example 1-172> N- (4- Hydroxyphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 4-aminophenol as a starting material in the same manner as in Example 1-127.
ESI (m / z) 402 (MH +) 424 (MNa < + >) 400 (MH &
< Example 1-173> 4- [2,3-Dimethyl-5-oxo-4- [4- ( Trifluoromethyl ) Phenyl] Pyrazole -1-yl] -N- (2- Phenoxyethyl ) ≪ / RTI > benzenesulfonamide
(4- (trifluoromethyl) phenyl) boronic acid as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-168.
1H NMR (400MHz, DMSO-d6)? 7.98 (d, 2H, J = 8.8 Hz), 7.67-7.58 (m, 6H), 7.24-7.21 2H), 6.78 (d, 2H, J = 8.0 Hz), 5.25 (t, 1H, J = 6.2 Hz), 3.96 3.16 (s, 3 H), 2.40 (s, 3 H)
< Example 1-174> N- [3- ( Hydroxymethyl ) Phenyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
(3-aminophenyl) methanol as starting materials, the target compound was obtained by the reaction in the same manner as in Example 1-127.
1H NMR (400MHz, DMSO-d6) d 10.30 (s, 1H), 7.84 (d, 2H, J = 8.8 Hz), 7.52 (d, 2H, J = 8.4 Hz), 7.19-7.12 2H), 5.17 (t, 1H, J = 5.8 Hz), 4.39 (d, 2H, J = 4.0 Hz), 2.93 (s, 3H), 2.78-2.68 (s, 3H), 1.16 (d, 6H, J = 6.8 Hz)
< Example 1-175> N- (6-Hydroxy-1- Naphthyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting 5-aminonaphthalen-2-ol as a starting material in the same manner as in Example 1-127.
ESI (m / z) 452 (MH < + >) 450 (MH < - >); 1H, J = 9.2 Hz), 7.73 (d, 2H, J = 8.4 Hz), 7.53 (d, (d, IH, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.27 (d, 1H, J = 12.0 Hz, Jb = 2.4 Hz), 6.92 (d, 1H, J = 7.6), 2.90 (s, 3H), 2.78-2.68 (d, 6H, J = 7.2)
< Example 1-176> 4- (4-Isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) -N- (2- Phenoxypropyl ) Benzenesulfonamide Produce
2-phenoxypropan-1-amine as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-127.
ESI (m / z) 444 (MH +) 466 (MNa < + >) 442 (MH &
< Example 1-177> N- [2- (2- Fluorophenoxy ) Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
The objective compound was obtained by reacting the title compound with 2- (2-fluorophenoxy) ethanamine as a starting material in the same manner as in Example 1-127.
ESI (m / z) 448 (MH < + >) 446 (MH < " >); (D, 2H, J 8.8 Hz), 7.52 (d, 2H, 8.8 Hz), 7.22-7.17 (m, 2H, J = 5.6 Hz), 2.96 (s, 2H), 4.08 (m, 3H), 1.19 (d, 6H, J = 6.8 Hz), 2.79 (s,
< Example 1-178> N- [4- [2- (dimethylamino) Ethoxy ] Phenyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1-yl) benzenesulfonamide < / RTI >
The objective compound was obtained by reacting 4- (2- (dimethylamino) ethoxy) aniline as starting materials in the same manner as in Example 1-127.
ESI (m / z) 473 (MH < + >) 471 (MH-); 2H, J = 8.8 Hz), 7.51 (d, 2H, J = 8.8 Hz), 7.02 (d, 2H, J = 2H, J = 8.8 Hz), 6.84 (d, 2H, J = 8.8 Hz), 4.06 (t, 2H, J = 5.6 Hz), 2.93 (s, 3H), 1.17 (d, 6H, J = 6.8 Hz)
< Example 1-179> methyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole Yl) phenyl] < RTI ID = 0.0 & Sulfonylamino ] Propanoate Produce
The objective compound was obtained by reacting methyl 3-aminopropanoate as a starting material in the same manner as in Example 1-127.
ESI (m / z) 396 (MH < + >) 418 (MNa < + >); 1H NMR (400 MHz, DMSO-d6)? 7.87 (d, 2H, J = 6.6 Hz), 7.77 (t, 1H, J = 5.8 Hz), 7.58 2H, J = 6.8 Hz), 2.22 (s, 3H), 1.19 (d, 6H, J = 6.8 Hz)
< Example 1-180> N- (4-Hydroxy-3- methyl -Phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo- Pyrazole -1 day) Benzenesulfonamide Produce
By using 4-amino-2-methylphenol as a starting material, the objective compound was obtained by the same procedure as in Example 1-127.
2H NMR (400 MHz, DMSO-d6) d 9.70 (s, 1H), 9.21 (s, 1H), 7.73 (d, 2H, J = 8.8 Hz), 7.51 3H), 2.93 (s, 3H), 2.93 (s, 3H), 2.79-2.69 (m, 1H), 2.19 (s, 3H), 2.00 (s, 3H), 1.17 (d, 6H, J = 6.8 Hz); (2), 125.55, 124.76, 121.99 (2), 121.43, 115.14, 114.59, 37.19, 23.92, 21.30 (2) , 16.44, 11.29
< Example 1-217> N- (4-Hydroxy- [1,1'- Biphenyl ] -3- yl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H-pyrazol-1-yl) benzenesulfonamide
Amino] - [1,1'-biphenyl] -4-ol as starting materials, the reaction was carried out in the same manner as in Example 1-1 to give the target compound in a yield of 81.45%.
ESI (m / z) 478 (MH < + >); J = 8.6 Hz), 7.42 (t, 2H, J = 8.8 Hz), 7.65 (d, 2H, J = 1H, J = 7.6 Hz), 7.33 (t, 1H, J = 7.4), 7.02-6.99 (m, 2H), 6.78 (dd, s, 3H), 2.79-2.73 (m, 1H), 2.22 (s, 3H), 1.19 (d, 6H, J = 8.0 Hz); 123.9, 165.2, 156.5, 141.6, 141.1, 140.0 (2), 135.4, 130.7, 130.0, 129.2 (2), 127.8, 126.8 (2), 123.6, 123.0, 121.7, 114.8 , 73.9, 37.4, 31.1, 23.9, 21.2 (2), 11.3
< Example 1-218> N- (2- Hydroxyphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) benzenesulfonamide < / RTI >
The objective compound was obtained in a yield of 55.04% by the same procedure as in Example 1-1 above using 2-aminophenol as a starting material.
ESI (m / z) 402 (MH < + >); J = 8.8 Hz), 6.98-6.92 (m, 2H), 6.70 (dd, 1H, J < RTI ID = 0.0 > 2H), 2.97 (s, 3H), 2.81 (s, 3H), 2.31 (s, 6H, J = 7.2 Hz); (2), (2), 116.1, 116.1, 114.8, 37.4, 23.9, 21.2 (2) , 11.3
< Example 1-219> N- (5-hydroxynaphthalen-2-yl) -4- (4-isopropyl-2,3-dimethyl- Dihydro -1H-pyrazol-1-yl) benzenesulfonamide
Aminonaphthalen-1-ol as a starting material, the desired compound was obtained in a yield of 5.03%.
ESI (m / z) 452 (MH < + >) 450 (MH < - >); 1H NMR (400MHz, DMSO-d6) d 7.98 (d, 2H, J = 8.4 Hz), 7.61 (d, 2H, J = 8.4 Hz), 7.50 1H, J = 8.4 Hz), 7.23 (t, 1H, J = 7.8 Hz), 6.90 (d, 1H, J = 8.8 Hz), 6.81-6.78 s, 3H), 2.79-2.72 (m, 1H), 2.22 (s, 3H), 1.19 (d, 6H, J = 6.8 Hz); 129.9, 122.3, 122.0 (2), 119.5, 119.5, 114.8, 113.44, 105.8, 37.4, 23.9, 21.2 (2), 11.3
< Example 1-220> 4- (4- Bromo -2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (2,4- Dimethylphenyl ) ≪ / RTI > benzenesulfonamide
2,4-dimethylaniline was used as a starting material in the same manner as in Example 1-127 to give the target compound in a yield of 29.13%.
ESI (m / z) 451 (MH < + >) 449 (MH-); 2H, J = 8.8, 2.4 Hz), 6.95 (s, 1H), 7.76 (dd, 2H, J = ), 6.90 (d, 1H, J = 8.4 Hz), 6.83 (d, 1H, J = 8.4 Hz), 3.13 ), 1.96 (s, 3H); 12.3, 134.7, 132.3, 131.7, 128.1, 127.2, 123.5, 100.7, 88.5, 37.1, 20.8, 17.9, 12.7, 11.5 (d,
< Example 1-221> 4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole Yl) -N- (4- (2- < / RTI > < Morpholinoethoxy ) Phenyl) benzenesulfonamide < / RTI >
The objective compound was obtained by reacting 4- (2-morpholinoethoxy) aniline as a starting material in the same manner as in Example 1-1.
< Example 1-222> N- (2,4- Dihydroxyphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) benzenesulfonamide < / RTI >
The objective compound was obtained in a yield of 17.01% by the same procedure as in Example 1-1 above using 4-aminobenzene-1,3-diol as a starting material.
ESI (m / z) 418 (MH < + >) 416 (MH-); J = 8.8 Hz), 6.84 (d, 1H, J = 8.4 Hz), 6.18 (d, 2H, J = 1H, J = 2.8 Hz), 6.12 (dd, 1H, J = 8.4, 2.4 Hz), 2.94 (s, 3H), 2.78-2.71 , J = 6.8 Hz); 128.1 (2), 121.6 (2), 115.1, 114.6, 106.4, 103.0, 37.2, 23.9, 21.3 (2) , 11.2
< Example 1-223> 4- (4- Bromo -2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (4- ( Trifluoromethyl ) Phenyl) benzenesulfonamide < / RTI >
The target compound was obtained in a yield of 32.9% by the same procedure as in Example 1-127 using 3- (trifluoromethyl) aniline as a starting material.
ESI (m / z) 490 (M); 138.9, (2), 101.0, 88.8, 37.5, 12.8, 11.6 (2), < RTI ID = 0.0 >
< Example 1-224> N- (3- Fluoro -4- Hydroxyphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H-pyrazol-1-yl) benzenesulfonamide
4-amino-2-fluorophenol was used as a starting material in the same manner as in Example 1-1 to give the target compound.
< Example 1-225> 4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (2- Methoxy -4-nitrophenyl) benzenesulfonamide < / RTI >
Using 2-methoxy-4-nitroaniline as a starting material, the target compound was reacted in the same manner as in Example 1-1 to obtain 92.68% of the target compound.
ESI (m / z) 461 (MH @ +) 459 (MH @ -); 1H NMR (400MHz, DMSO-d6) d 10.34 (s, 1H), 7.97 (d, 2H, J = 8.8 Hz), 7.84 = 2.4 Hz), 7.59-7.53 (m, 3H), 3.83 (s, 3H), 2.95 (s, 3H), 2.79-2.69 7.2 Hz); 128.2 (2), 122.0 (2), 120.1, 117.1, 114.5, 106.9, 56.8, 37.2, 23.9, 21.2 (d, 2), 11.3
< Example 1-226> 3- (4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1 day) Phenyl sulfonamido ) Preparation of benzoic acid
3-Aminobenzoic acid was used as a starting material and reacted in the same manner as in Example 1-1 to give the target compound.
< Example 1-227> 4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (2- Methoxy -5-nitrophenyl) benzenesulfonamide < / RTI >
Methoxy-5-nitroaniline as starting materials, the target compound was obtained in a yield of 32.04% by the same procedure as in Example 1-1.
ESI (m / z) 461 (MH @ +) 459 (MH @ -); (M, 2H), 7.85 (d, 2H, J = 8.8 Hz), 8.12 (d, 1H, J = 2.4 Hz) 3H), 2.78-2.71 (m, 1H), 2.21 (s, 2H), 7.55 (d, 2H, J = 8.8 Hz), 7.16 , ≪ / RTI > 3H), 1.17 (d, 6H, J = 6.8 Hz); 137.9, 137.1, 128.9 (2), 126.5, 122.9, 122.0 (2), 119.3, 114.5, 112.2, 56.9, 37.1, 23.9, 21.2 (2), 11.2
< Example 1-228> 4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (2- Methylbenzofuran -5-yl) benzenesulfonamide
2-methoxybenzofuran-5-amine as a starting material, the target compound was obtained by a reaction in the same manner as in Example 1-1.
< Example 1-229> N- ( Benzo [b] thiophene Yl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) benzenesulfonamide < / RTI >
Benzo [b] thiophen-5-amine as starting materials, the target compound was obtained.
ESI (m / z) 442 (MH < + >) 440 (MH &
< Example 1-230> N- ( Benzofuran Yl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) benzenesulfonamide < / RTI >
Benzofuran-5-amine as starting materials, the target compound was obtained.
ESI (m / z) 426 (MH < + >) 424 (MH &
< Example 1-231> N- ( Benzofuran -5- Yl methyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) benzenesulfonamide < / RTI >
Benzofuran-5-ylmethanamine as starting materials, the desired compounds were obtained.
ESI (m / z) 440 (MH +) 438 (MH-)
< Example 1-232> methyl 5-oxo-2,5-dihydro-1H-pyrazol-1-yl) phenylsulfonamido) benzo [b] thiophen- - Preparation of carboxylate
The objective compound was obtained by reacting methyl 5-aminobenzo [b] thiophene-2-carboxylate as a starting material in the same manner as in Example 1-1.
ESI (m / z) 500 (MH < + >) 498 (MH &
< Example 1-233> methyl 4 - ((4- (4-isopropyl-2,3-dimethyl-5-oxo- Dihydro -1H- Pyrazole -1 day) Phenyl sulfonamido ) ≪ / RTI > methyl) benzoate
The objective compound was obtained in a yield of 27.25% by reacting methyl 4- (aminomethyl) benzoate as a starting material in the same manner as in Example 1-1.
ESI (m / z) 458 (MH @ +) 480 (MNa @ +) 456 (MH @ +); (D, 2H, J = 2.0 Hz), 7.53 (d, 2H, J = 2H, J = 8.8 Hz), 7.40 (d, 2H, J = 8.4 Hz), 4.11 (d, 2H, J = 5.6 Hz), 3.83 m, 1 H), 2.22 (s, 3 H), 1.19 (d, 6 H, J = 6.8 Hz); 128.18 (2), 127.92 (2), 122.15 (2), 114.56, 52.49, 46.15, 37.12, 23.95, 21.30, 11.29
< Example 1-234> methyl 6- (4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1 day) Phenyl sulfonamido ) -2-naphthoate
Methyl 6-amino-2-naphthoate was used as a starting material in the same manner as in Example 1-1 to give the target compound in a yield of 20.03%.
ESI (m / z) 494 (MH @ +) 492 (MH @ +); 1H, J = 8.8 Hz), 7.97 (d, 2H, J = 8.4 Hz), 7.91 (d, (s, 2H), 7.70 (s, 1H), 7.55 (d, 2H, J = 8.4 Hz), 7.43 2.74 - 2.67 (m, 1H), 2.17 (s, 3H), 1.14 (d, 6H, J = 7.2 Hz); 136.93, 135.55, 131.31, 130.73, 129.14, 128.23 (2), 128.10, 126.12, 125.95, 122.09 (2), 120.91, 114.76, 114.59, 52.57, 37.25, 23.88, 21.23 (2), 11.26
< Example 1-235> 4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- Of mesitylbenzenesulfonamide Produce
By using 2,4,6-trimethylaniline as a starting material, a reaction was conducted in the same manner as in Example 1-1 to obtain the target compound in 60.81%.
ESI (m / z) 428 (MH < + >) 426 (MH-); 2H NMR (400 MHz, DMSO-d6) d 9.24 (s, 1H), 7.73 (d, 2H, J = 8.4 Hz), 7.55 s, 3H), 2.95-2.73 (m, 1H), 2.20 (d, 6H, J = 11.6 Hz), 1.92 (s, 6H), 1.20 (d, 6H, J = 6.8 Hz); (2), 129.73 (2), 127.86 (2), 122.28 (2), 114.71, 37.17, 23.94, 21.33 (dd, 2), 20.83, 18.74 (2), 11.30
< Example 1-236> N- (9,10- Dioxo -9,10- Dihydroanthracene -2-yl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamide
Amino-4a, 9a-dihydroanthracene-9,10-dione as starting materials, the target compound was obtained.
ESI (m / z) 516 (MH < + >) 514 (MH &
< Example 1-237> 4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (isoquinolin-5-yl) benzenesulfonamide
Isoquinolin-5-amine as a starting material, the desired compound was obtained.
ESI (m / z) 437 (MH < + >) 435 (MH &
< Example 1-238> N- ( Benzo [d] [1,3] < / RTI > Yl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H-pyrazol-1-yl) benzenesulfonamide
Benzo [d] [1,3] dioxol-5-amine as starting materials, the target compound was obtained.
ESI (m / z) 430 (MH < + >) 428 (MH &
< Example 1-239> N- ( Benzo [d] [1,3] < / RTI > -5- Yl methyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H-pyrazol-1-yl) benzenesulfonamide
Benzo [d] [1,3] dioxol-5-ylmethanamine as starting materials, the target compound was obtained.
ESI (m / z) 443 (MH < + >) 442 (MH &
< Example 1-240> 4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (2- Oxoindoline -5-yl) benzenesulfonamide
Aminoindolin-2-one was used as a starting material in the same manner as in Example 1-1 to give the target compound.
ESI (m / z) 441 (MH < + >) 439 (MH &
< Example 1-241> 4- (4- Bromo -2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (4- ( Trifluoromethyl ) Phenyl) benzenesulfonamide < / RTI >
4-trifluoroaniline was used as a starting material in the same manner as in Example 1-127 to give the target compound in a yield of 49.27%.
ESI (m / z) 491 (MH < + >) 489 (MH-); (D, 2H, J = 8.0Hz), 7.96 (d, 2H, J = 7.6Hz), 7.63-7.56 3.10 (d, 3H, J = 9.2 Hz), 2.29 (s, 3H);
< Example 1-242> 4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (2- (thiophen-2-yl) ethyl) benzenesulfonamide
2-thiophen-2-yl) ethan-1-amine as a starting material, the target compound was obtained in a yield of 25.13%.
ESI (m / z) 420 (MH < + >) 418 (MH-); 1H NMR (400MHz, DMSO-d6) d 7.88-7.81 (m, 3H), 7.57 (d, 2H, J = 8.4 Hz), 7.32 ), 3.01-2.93 (m, 7H), 2.79-2.72 (m, 1H), 2.22 (s, 3H), 1.19 (d, 6H, J = 6.8 Hz); (2), 127.3, 125.9, 124.5, 122.2 (2), 114.5, 44.5, 37.2, 30.0, 23.9, 21.3 (2) , 11.2
< Example 1-243> 4- (4-Isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) -N- (3,4,5- Trimethoxyphenyl ) ≪ / RTI > benzenesulfonamide
3,4,5-trimethoxyaniline as starting materials, the target compound was obtained in a yield of 51.17% by the same procedure as in Example 1-1.
ESI (m / z) 476 (MH < + >) 498 (MNa < + >) 474 (MH-); (D, 2H, J = 8.4 Hz), 6.40 (s, 2H), 3.65 (d, s, 6H), 3.56 (s, 3H), 2.93 (s, 3H), 2.77-2.70 (m, 1H), 2.19 (s, 3H), 1.17 (d, 6H, J = 6.4 Hz); (2), 145.4, 135.3, 134.6, 133.9, 128.3 (2), 122.1 (2), 114.6, 98.4 (2), 60.4, 56.1 (2) , 37.2, 23.9, 21.2 (2), 11.2
< Example 1-244> N- ( Cyclohexylmethyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) benzenesulfonamide < / RTI >
Cyclohexylmethanamine was used as a starting material in the same manner as in Example 1-1 to give the target compound in a yield of 45.59%.
ESI (m / z) 406 (MH < + >) 404 (MH-); 1H NMR (400MHz, DMSO-d6) d 7.86 (d, 2H, J = 8.4 Hz), 7.60-7.56 (m, 3H), 2.97 1H, J = 6.0 Hz), 2.22 (s, 3H), 1.66-1.59 (m, 5H), 1.33 (br s, , 3H), 0.85-0.79 (m, 2H); (2), 122.9 (2), 114.5, 49.1, 37.7, 37.1, 30.5 (2), 26.3, 25.6 (2), 23.9, 21.3 (2), 11.2
< Example 1-245> N- ( Cycloheptylmethyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) benzenesulfonamide < / RTI >
Cycloheptylmethyl as a starting material, the target compound was obtained in a yield of 53.50%.
ESI (m / z) 420 (MH < + >) 418 (MH-); (D, 2H, J = 8.4 Hz), 2.96 (s, 1H), 7.62 (d, 2H, J = 3H), 1.66-1.61 (m, 2H), 1.54-1.36 (m, 7H), 1.34 (m, - 1.26 (m, 2H), 1.19 (d, 6H, J = 6.8 Hz), 1.11 - 1.03 (m, 2H); 38.1 (2), 26.1 (2), 38.2 (2), 41.5, 49.3, 39.1, 37.1, 31.6 (2) , 23.9, 21.3 (2), 11.2
< Example 1-246> N- (2- Cyclohexylethyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) benzenesulfonamide < / RTI >
2-cyclohexylethan-1-amine as a starting material, the target compound was obtained in a yield of 50.31% by the same procedure as in Example 1-1.
ESI (m / z) 420 (MH < + >) 418 (MH-); 3H), 2.78-2.75 (m, 3H), 2.22 (s, 3H), 2.78 (d, , 3H), 1.57 (t, 5H, J = 11.8 Hz), 1.25-1.24 (m, 3H), 1.19 (d, 6H, J = 6.8 Hz), 1.14-1.04 m, 2H); (2), < / RTI > (2), < RTI ID = 0.0 > 23.9, 21.2 (2), 11.2
< Example 1-247> N- (3,4- Dimethoxyphenyl ) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5- Dihydro -1H- Pyrazole -1-yl) benzenesulfonamide < / RTI >
3,4-methoxyaniline was used as a starting material in the same manner as in Example 1-1 to give the target compound in a yield of 18.06%.
ESI (m / z) 446 (MH < + >) 468 (MNa < + >) 444 (MH-); 1H NMR (400 MHz, DMSO-d6) d 9.92 (s, 1H), 7.78 (d, 2H, J = 8.4 Hz), 7.52 (D, 1H, J = 8.8 Hz), 6.68 (d, 1H, J = 1.6 Hz), 6.58 m, 1 H), 2.19 (s, 3 H), 1.17 (d, 6 H, J = 6.8 Hz)
< Example 2>
Benzenesulfonamide Derivative mTORC1 Evaluation of inhibitory activity
<2-1> Benzenesulfonamide Derivative mTORC1 Evaluation of the activity inhibition effect
In order to evaluate the inhibitory effect of the benzenesulfonamide derivatives according to the present invention on mTORC1 activity, experiments were conducted as follows.
The colorectal cancer cell line SW620 was purchased from the American Type Culture Collection (ATCC). The cell line was divided into 24-well plates, cultured for 24 hours, treated with a medium containing no leucine amino acid for 1 hour 30 minutes, and then cultured for 15 minutes in a leucine-containing medium. Benzenesulfonamide derivatives were added at the final concentration of 20 uM in culture medium containing leucine. 20 ug of cell lysate was separated by electrophoresis and analyzed by Western blot method using phospho-p70 S6 Kinase (Thr380) antibody (# 9206, Cell Signaling Technology) to examine mTORC1 activity. The mTORC1 activity inhibitory effect was evaluated by comparing the negative control group treated with DMSO alone to the compound treated group.
As shown in Tables 2 and 3, it can be seen that the benzenesulfonamide derivative according to the present invention significantly inhibits the activity of mTORC1 at 20 uM. Examples 1-35 to 38, 1-62, 1-85, 1-86, 1-89, 1-97, 1-98, 1-103, 1-108, 1-115, 1-130, 1- 131, 1-133, 1-134, 1-136 to 1-138, 1-158 to 1-161, 1-164, 1-166, 1-167, 1-220, 1-229, 1-230, 1-239, and 1-240 showed excellent inhibitory effects of 70% or more.
Accordingly, the benzenesulfonamide derivative of formula (I) according to the present invention inhibits the activity of mTORC1, which is known to be highly active in cancer cells, and thus can be useful for the treatment of cancer.
<2-2> Benzenesulfonamide Derivative mTORC1 Assessment of activity inhibition (IC50)
In order to evaluate the inhibitory effect (IC50) on the mTORC1 of the benzenesulfonamide derivatives according to the present invention, experiments were conducted as follows.
The colorectal cancer cell line SW620 was purchased from the American Type Culture Collection (ATCC). The cell lines were divided into 24-well plates and cultured for 24 hours. The benzenesulfonamide derivatives were then added (at final concentrations of 0.1, 0.5, 1, 2, 5, 10, 20 uM) for 6 hours in medium supplemented with 10% FBS . 20 ug of cell lysate was separated by electrophoresis and analyzed by Western blot method using phospho-p70 S6 Kinase (Thr380) antibody (# 9206, Cell Signaling Technology) to examine mTORC1 activity. The mTORC1 activity inhibitory effect was evaluated by comparing the negative control group treated with DMSO alone to the compound treated group.
Among the compounds evaluated for mTORC1 inhibitory activity above, compounds showing excellent inhibitory activity (inhibitory activity of 70% or more) were further selected and the inhibitory activity of mTORC1 was further evaluated. As shown in Table 5, it can be seen that the benzenesulfonamide derivative according to the present invention significantly inhibits the activity of mTORC1 below 1 uM. In particular, it was found that the compounds of Examples 1-62 and 1-166 exhibit excellent effects at a concentration of IC50 of 100 nM or less
Accordingly, the benzenesulfonamide derivative of formula (I) according to the present invention inhibits the activity of mTORC1, which is known to be highly active in cancer cells, and thus can be used for the treatment of cancer.
< Example 3>
Benzenesulfonamide Evaluation of Growth Inhibitory Effect of Derivatives on Colorectal Cancer Cells (SW620)
<3-1> Production of RFP Expressing Cell Lines
To evaluate the effect of the benzenesulfonamide derivatives of the present invention on the growth of colorectal cancer cell SW620, RFP fluorescently labeled cell lines were prepared. The colorectal cancer cell line SW620 was purchased from the American Type Culture Collection (ATCC). NucLight Red Lentivirus Reagent (EF1a, Puro) (# 4476, Essen Bioscience) was purchased for RFP fluorescently labeled SW620 cell line. NucLight Red Lentivirus Reagent was added to the SW620 cell line for 24 hours, and the cells were cultured in RPMI 1640 medium containing 10% FBS and 1% penicillin / streptomycin at 37 ° C and 5% CO 2. Subsequently, puromycin was added to the medium at a concentration of 0.5 ug / ml and then cultured for 4 days at 37 ° C and 5% CO 2.
<3-2> Inhibitory effect of compound on SW620 cell growth
RFP fluorescently labeled SW620 cell line was divided into 96-well plates and cultured for 24 hours. Then, the benzenesulfonamide derivatives according to the present invention were treated for 24 hours in a medium containing 10% FBS (final concentration 0.000282, 0.000847, 0.00254, 0.0076 , 0.0229, 0.0686, 0.206, 0.617, 1.85, 5.56, 16.67, 50 uM). Cellular phase contrast images and red fluorescence images were obtained at 2-hour intervals after compound treatment using an Incucyte Zoom (Essen Bioscience) long-term cell observation and analysis system. Quantitative analysis of RFP fluorescence was performed using Incucyte Zoom basic analyzer (Essen Bioscience) Respectively. GI50 (50% growth inhibition) values were calculated using the GraphPad Prism tool program for RFP fluorescence values of each compound concentration. The effect of inhibiting SW620 cell growth was evaluated by comparing the RFP fluorescence of each well with the negative control group treated with DMSO alone and the group treated with the compound.
As shown in Table 6, it can be seen that the benzenesulfonamide derivatives according to the present invention significantly inhibited the growth of SW620 cells. Examples 1-35, 1-62, 1-89, 1-103, 1-108, 1-115, 1-131, 1-133, 1-136 to 1-138, 1-158, 1-159, 1-164, 1-166, 1-174 to 1-177, 1-179, 1-204, 1-214, 1-220, 1-222, 1-229, 1-230, 1-231, 1- 239, 1-240, 1-243, and 1-247 exhibit excellent inhibitory effects of GI50 100 nM or less.
Accordingly, the benzenesulfonamide derivatives of formula (I) according to the present invention are excellent in the effect of inhibiting the growth of cancer cells, and thus can be usefully used for the treatment of cancer.
<3-3> Benzenesulfonamide Evaluation of cytotoxicity of derivatives against colorectal cancer cells (SW620)
In order to evaluate the cytotoxic effect of the benzenesulfonamide derivatives according to the present invention on colon cancer cells, experiments were conducted as follows.
RFP fluorescently labeled SW620 cell line was divided into 96-well plates and cultured for 24 hours. Then, the benzenesulfonamide derivatives according to the present invention were treated for 24 hours in a medium containing 10% FBS (final concentration 0.000282, 0.000847, 0.00254, 0.0076 , 0.0229, 0.0686, 0.206, 0.617, 1.85, 5.56, 16.67, 50 uM). To observe cytotoxicity in real time during the compound treatment, CellTox Green (# G8741, Promega) with green fluorescence was added upon cell death. Green fluorescence images were obtained at 2-hour intervals after compound treatment using Incucyte Zoom (Essen Bioscience) long-term observation system and quantitation of green fluorescence was performed using Incucyte Zoom basic analyzer (Essen Bioscience). EC50 (50% cell death) was calculated using the GraphPad Prism tool program. The green fluorescence of each well was compared with the negative control group treated with DMSO alone and the compound treated group to evaluate the SW620 cell growth inhibitory effect.
As shown in Table 7, it was found that the benzenesulfonamide derivatives according to the present invention significantly induce the death of SW620 cells. Examples 1-62, 1-103, 1-108, 1-115, 1-131, 1-133, 1-136, 1-137, 1-138, 1-158, 1-159, 1-164, 1-166, 1-174, 1-176, 1-177, 1-179, 1-214, 1-220, 1-229, 1-230, 1-231, 1-239, 1-240, 1- 243, and 1-247 showed excellent inhibitory effects of
Accordingly, the benzenesulfonamide derivatives of Formula 1 according to the present invention are excellent in the effect of inducing cancer cell death, and thus can be usefully used as therapeutic agents for cancer.
<3-4> Evaluation of cytotoxicity of the benzenesulfonamide derivative according to the present invention on a normal cell line
To evaluate the effect of the benzenesulfonamide derivative according to the present invention on the normal cell line, the cytotoxicity test was conducted as described above. The benzenesulfonamide derivatives according to the present invention were tested on the basis of the compounds of Examples 1-214.
FHC (colon normal epithelial cell) was purchased from American Type Culture Collection (ATCC).
The results are shown in Fig. As shown in Fig. 1, the benzenesulfonamide derivatives according to the present invention did not show cytotoxicity against normal colon cell lines at 100 uM. That is, the compound according to the present invention selectively exhibits cytotoxicity selectively only in the colon cancer cell line, suggesting that the compound has anti-cancer activity.
That is, the benzenesulfonamide derivative of Formula 1 according to the present invention has no toxicity to normal cells and selectively acts on cancer cells, and thus can be safely used for prevention and treatment of cancer.
<3-5> Evaluation of cytotoxicity of the benzenesulfonamide derivatives according to the present invention on six cancer cell lines
To evaluate the effects of the benzenesulfonamide derivatives according to the present invention on six cancer cell lines, cytotoxicity tests were carried out in the same manner as in Example 3-3. The benzenesulfonamide derivatives according to the present invention were tested on the basis of the compounds of Examples 1-214.
Thirteen cell lines of COLO201, WiDr, HCT-15, SW620, SW480, DLD-1, HCT-116, HT-29, LS1034, LoVo, NCI-H508, COLO205 and LS174T were used as colon cancer cell lines.
The lung cancer cell line contained 11 phenol groups of NCI-H1975, A549, NCI-H226, NCI-H1793, NCI-H1650, NCI-H596, NCI-H460, NCI-H1299, NCI-H358, HCC-44 and HCC- Respectively.
Pancreatic cancer cell lines used five phenol-like strains: Panc-1, MIA-Paca-2, BxPC-3, AsPC-1 and Panc10.05.
Five breast cancer cell lines were used: MDM-MB-231, HCC1569, HCC70, HCC1937 and HCC1395.
Five ovarian cancer cell lines, NIH: OVCAR-3, SK-OV-3, Caov-3, SNU119 and UWB1.289 were used.
Five brain tumor cell lines were used: U343, T98G, SNB-19, A-172 and U87.
All the cancer cell lines were purchased from the American Type Culture Collection (ATCC).
The results are shown in Fig. As shown in FIG. 2, the benzenesulfonamide derivatives according to the present invention show cytotoxicity against six solid carcinomas, indicating that they have anticancer activities against various carcinomas.
<Example 4>
Epilepsy improvement effect
<4-1> Inhibition activity of RagD GTP hydrolysis and lysosomal translocation of LRS
NIH3T3 cells harboring the mTOR wild type or L2427P mutation were transfected with si-control or si-LRS for 48 hours, leucine deficient for 90 minutes and re-stimulated with leucine for 15 minutes. The cell lysate was incubated with GTP-agarose beads to pull-down the GTP-binding protein. The precipitate was immunoblotted with anti-RagD or ARF1 antibody, respectively. ARF1 was used as a negative control. The lysosomal fraction was obtained using a lysosome concentration kit (Thermo Fisher Scientific, # 89839). The effect of Examples 1-214 on S6K phosphorylation was analyzed by immunoblotting with anti-phospho S6K antibody (Cell Signaling Technology, # 9205). The results are shown in Fig. 3A.
As shown in Fig. 3A, transfection of NIH3T3 cells harboring the mTOR L2427P mutation with si-LRS inhibited the GTP degradation of RagD by leucine treatment and blocked the lysosomal transport of Raptor, one of the components of mTORC1, . ≪ / RTI >
In addition, NIH3T3 cells bearing the mTOR wild type or L2427P mutation were treated with 20 microM of the compound of Example 1-214 for 6 hours, leucine deficient for 90 minutes, and re-stimulated with leucine for 15 minutes. The cell lysate was incubated with GTP-agarose beads to pull-down the GTP-binding protein. The precipitate was immunoblotted with anti-RagD or ARF1 antibody, respectively. ARF1 was used as a negative control. The lysosomal fraction was obtained using a lysosome concentration kit (Thermo Fisher Scientific, # 89839). The effect of the compound of Example 1-186 on S6K phosphorylation was analyzed by immunoblotting with anti-phospho S6K antibody (Cell Signaling Technology, # 9205). The results are shown in Fig. 3B.
As shown in Figure 3B, treatment of NIH3T3 cells harboring the mTOR L2427P mutation with the compound of Example 1-214 inhibited the GTP degradation of RagD by leucine treatment and blocked the lysosomal transfer of Raptor, one of the components of mTORC1 S6K phosphorylation is inhibited.
<4-2> Inhibition of mTORC1 activity in cells expressing mTOR mutation (L2427P) associated with epilepsy
NIH3T3 cells expressing the L2427P mutation were treated with the corresponding concentrations of the compounds of Examples 1-214 for 6 hours. The effect of compounds on S6K phosphorylation was analyzed by immunoblotting with anti-phospho S6K antibody (Cell Signaling Technology, # 9205). The results are shown in Fig.
As shown in FIG. 4, when the compound of Example 1-214 was treated at different concentrations in NIH3T3 cells harboring the mTOR L2427P mutation, a pattern in which the phosphorylation of S6K decreased with increasing concentration can be seen. When the degree of phosphorylation of S6K is quantified and plotted, the IC50 value of the compound of Example 1-186 for the S6K phosphorylation inhibition effect is analyzed to be about 54.99 nM.
<4-3> Inhibition effect of seizure on epileptic animal model
C57BL / 6 mice were purchased and maintained in an incubator at 23 ° C for 12 h. Three animals were used in each group of the test substance, and three groups were used in total, and each group was the compound of Example 1-214, rapamycin (positive control group), vehicle (control group). To establish the epileptic animal model, the pregnant mouse (embryonic day 14) was anesthetized with isoflurane (oxygen and isoflurane vaporizer gauge 3, 0.4 L / min) over time. The cervix was exposed and injected into the lateral ventricle of each embryo using a glass capillary with 2 μg / ml Fast Green (F7252, Sigma, USA) combined with 2-3 mg of the mTOR mutant plasmid. When the mouse was born, GFP screening was performed. At 30 days after birth, the epileptic seizure state was confirmed to select the epileptic animal model. The epileptic animal model of the present invention was performed by the method described in Nature Medicine, 21 (4): 395-400 (2015).
Example 1-214 Compound (TID, 10 mg / kg, IP injection), rapamycin (QD, 10 mg / kg, IP injection) or a control substance (4% DMAC, 5% PEG, 5% Tween- After two weeks of administration to mice with the L2427P mTOR mutation, the frequency of behavioral seizures was measured.
The results are shown in Fig.
As shown in Fig. 5, in the epileptic animal model with the mTOR L2427P mutation, the control substance showed an average of 18 behavioral seizures for 24 hours, whereas when the compound of Example 1-214 was administered, the average of 3.3 hours And the frequency of the seizures was observed.
<4-4> Blood-brain barrier (BBB) permeability
The Pion BBB-PAMPA assay kit was used as an in vitro model of passive, intercellular permeability. An artificial membrane immobilized on the filter was placed between the donor and the receptor compartment. Each drug was introduced into the donor compartment and then the drug concentration in the donor and receptor compartments was measured. The results are shown in Fig.
As shown in FIG. 6, the compound of Example 1-214 showed superior porosity and permeability compared to hydroxychloroquine, progesterone, corticosterone, rivastigmine, and carbamazepine, which are used as therapeutic agents for brain diseases, and mTOR inhibitors (rapamycin, temsirolimus, INK128), which shows the highest transmittance.
On the other hand, the in vivo permeability test of BBB was performed according to the following method.
The test compound was dissolved in dimethylacetamide / Tween 80/20% 2-hydroxypropyl-β-cyclodextrin (10/10/80 v / v%) and injected intravenously (iv, 5 ml / kg) and then euthanized in a CO2 chamber at 0, 30, 60, and 90 minutes. Blood was collected through cardiac collection and the brain was excised (n = 3 / each time point). The blood was centrifuged at 4 ° C for 5 minutes at 4 ° C and then centrifuged at 4 ° C for 5 minutes. Plasma was separated and the brain was weighed and homogenized by adding 3 volumes of water. Blood and brain homogenate was subjected to protein precipitation by adding acetonitrile containing 3 times volume of internal standard. The supernatant was diluted 1: 1 with water and quantitatively analyzed by LC-MS / MS method.
The results are shown in Table 8.
As shown in Table 8, when the amounts of compounds present in brain and plasma were compared to determine the amount of BBB permeation measured, the brain / plasma ratio of the compound of Example 1-214 was measured, 20% of the compounds migrated to the brain.
As described above, the compounds of the present invention effectively inhibit the activity of mTORC1 in cells expressing an epilepsy-related mutation and remarkably reduce the frequency of epileptic seizures in an epileptic animal model, The permeability of the brain barrier is also very high, indicating that it is very likely to be developed as a treatment for epilepsy.
The benzenesulfonamide derivative of formula (I) according to the present invention inhibits the binding between LRS and RagD and thus has an excellent effect of inhibiting the activation of mTORC1. Therefore, the benzenesulfonamide derivative of formula (I) Neurodegenerative diseases such as autoimmune diseases, diabetes, obesity, respiratory-obstructive diseases, fibrosis, Pompe disease, lysosomal storage disease, Alzheimer's disease, Parkinson's disease and Huntington's disease, cardiovascular diseases and parasitic infections It can be very usefully used for the prevention of a selected disease or the development of a therapeutic agent, and thus it is highly industrially applicable.
Claims (12)
[Chemical Formula 1]
In Formula 1,
R 1 is substituted or unsubstituted phenyl; Halo; Or straight or branched C 1 -C 6 alkyl, wherein when R 1 is substituted phenyl the substituent is selected from the group consisting of halogen atoms, unsubstituted linear or branched C 1 -C 6 alkyl and linear Or branched C 1 -C 6 alkyl,
R 2 is hydrogen; Or straight or branched C 1 -C 6 alkyl,
R 3 is hydrogen; Substituted or unsubstituted C 1 -C 6 straight or branched alkyl; C 5 -C 10 cycloalkyl; Substituted or unsubstituted C 5 -C 20 aryl; Dioxoanthracenyl; Or a heterocyclic or heteroaryl ring containing one or more heteroatoms in the ring, wherein when the substituents are substituted, they are straight or branched C 1 -C 6 alkyl; C 1 -C 6 alkyloxy; C 1 -C 6 alkyloxy substituted by a C 1 -C 6 alkylamino group; C 1 -C 6 alkyloxy substituted with morpholine; C 1 -C 6 alkyloxycarbonyl; Hydroxycarbonyl C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted by one or more fluoro atoms; C 1 -C 6 alkylamino; Phenyl; Linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkyloxy, linear or branched C 1 -C 6 alkyloxycarbonyl, halogen atoms and one or more fluoro atoms Phenyl substituted with one or more substituents selected from the group consisting of substituted alkyl; Phenoxy; Phenoxy substituted by one or more substituents selected from the group consisting of straight or branched C 1 -C 6 alkyl, halogen atoms and straight or branched C 1 -C 6 alkyloxy; Aminosulfonyl; Halo; Cyano; Acetyl; Nitro; Ethynyl; Hydroxy; Morpholino; Naphthyl; Teenyl; Pyridyl; Tetrahydrofuranyl; Carboxyl; Thiophenyl; C 1 -C 10 cycloalkyl; Benzodioxol; Indolyl substituted by straight or branched C 1 -C 6 alkyloxy; Dihydrobenzooxynil; And furylmethylsulfanyl, and the aryl, heterocyclic and heteroaryl rings may each be a heterocyclic structure fused with two or more rings, and may contain a carbonyl group in the ring There is,
Wherein R 2 and R 3 are bonded to each other to form a C 5 -C 20 heterocyclic or heteroaryl ring containing one or more heteroatoms in the ring,
With the proviso that the following compounds are excluded:
N-cyclohexyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide,
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- (6-acetyl-
Dimethyl-5-oxo-pyrazol-1-yl) -N- (1,3,5-trimethylpyrazol-4-yl) benzenesulfonamide,
2- (4-indolin-1-ylsulfonylphenyl) -4-isopropyl-l, 5-dimethyl-pyrazol-
Dimethyl-5-oxo-pyrazol-1-yl) -N-tetralin-1-yl-benzenesulfonamide,
N, N-diethyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide,
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide,
Dimethyl-5-oxo-pyrazol-l-yl) -N-methyl-N-phenyl-benzenesulfonamide,
Benzyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide,
Phenyl] sulfonylamino] -2-phenyl-acetate, < / RTI >
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- (2-ethoxyethyl)
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- (2,6-
Dimethyl-5-oxo-pyrazol-1-yl) -N- (9-oxothioxanthene-2-yl) benzenesulfonamide,
(4-methoxy-3,5-dimethyl-phenyl) benzenesulfonamide, 4- (4-isopropyl-
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide ,
Ethyl 5 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzothiophene-
Phenyl] sulfonyl-1,3-dihydroquinoxalin-2-one, 4- [4- (4-isopropyl-2,3-
Butyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide,
Methyl-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide, N- (3-fluoro-
4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] benzenesulfonamide,
Yl] piperazin-1-yl] sulfonylphenyl] pyrazol-3-one, 4-
4-isopropyl-2- [4 - [[4- [4- (4-isopropyl-2,3- dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonyl- Yl] sulfonyl] phenyl] -1,5-dimethyl-pyrazol-3-one,
Carbonyl) -2-nitro-phenyl] piperazin-1-yl] sulfonylphenyl] pyrazine Lt; / RTI >
Dimethyl-2- [4- [4- (2-pyridyl) piperazin-1-yl] sulfonylphenyl] pyrazol-
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- (2,2-
1-yl] sulfonylphenyl] -1,5-dimethyl-pyrazol-3-one,
2 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonyl Amino] benzamide,
Dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] -4,5,6,7-tetrahydrobenzothiophene -3-carboxylate,
1-yl] sulfonylphenyl] -4-isopropyl-l, 5-dimethyl-pyrazol-3-one,
4-isopropyl-1,5-dimethyl-2- [4- (1-piperidylsulfonyl) phenyl] pyrazol-
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide,
N-cyclopropyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide,
4-isopropyl-l, 5-dimethyl-2- (4-morpholinosulfonylphenyl) pyrazol-
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2-phenoxyethyl) benzenesulfonamide,
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, and
4- (4-Isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-propyl-benzenesulfonamide.
Ethyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] benzoate
4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- phenyl- benzenesulfonamide
N-cyclohexyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- l-yl) -N-
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (4-methoxyphenyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (4- morpholinophenyl) benzenesulfonamide
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1-yl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
-N- [(2-methoxyphenyl) methyl] benzenesulfonamide < / RTI >
Dimethyl-5-oxo-pyrazol-1-yl) -N- (p-tolyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (2- methoxyphenyl) ethyl] benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (2-methoxyphenoxy) ethyl] benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (3-methoxyphenyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2-methoxyphenyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (3-phenylpropyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (3-nitrophenyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (4-nitrophenyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2- phenylethyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (4- phenylbutyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (5-quinolyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (3-quinolyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Butyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] piperidine-
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2- thienylmethyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (3-pyridylmethyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (2-pyridyl) ethyl] benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2-naphthylmethyl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
-N- [(4-methoxyphenyl) methyl] benzenesulfonamide < / RTI >
Dimethyl-5-oxo-pyrazol-1-yl) -N- (6-quinolyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfone amides
Phenyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Methyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] benzoate
Ethyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] benzoate
3- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [3- (trifluoromethyl) phenyl] benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (4-isopropylphenyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
N- (3-fluorophenyl) -4- (4-isopropyl-2,3-dimethyl-5- oxo-pyrazol- l-yl) -N- methyl- benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (1-naphthyl) benzenesulfonamide
-N- [(3-methoxyphenyl) methyl] benzenesulfonamide < / RTI >
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (tetrahydrofuran-2-ylmethyl) benzenesulfonamide
Ethyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (p- tolyl) ethyl] benzenesulfonamide
N- (4-methoxyphenyl) -N-methyl-benzenesulfonamide < / RTI >
Dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (4-methoxyphenyl) ethyl] benzenesulfonamide
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (p-tolylmethyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-l-yl) -N- (m-tolylmethyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (m-tolyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (o-tolyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-l-yl) -N- [2- (trifluoromethyl) phenyl] benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (6-methoxy-3-pyridyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (p-tolyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2-pyridylmethyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2- pyridyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
(2,4-dibromophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
N- (1,1-dimethylpropyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
N-cyclopentyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (4-sec-butylphenyl) benzenesulfonamide
Ethyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] piperidine-
N-indan-5-yl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
N-indan-2-yl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
N-cycloheptyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
3- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [3- (trifluoromethyl) phenyl] benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Methyl 4 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] benzoate
Dimethyl-5-oxo-pyrazol-l-yl) -N-pyrimidin-2- yl- benzenesulfonamide
N - [(2,4-dimethoxyphenyl) methyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
2- [4- (4-ethylpiperazin-1-yl) sulfonylphenyl] -4-isopropyl-1,5-dimethyl-pyrazol-
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (4-pyridylmethyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2, 3-dimethyl-5-oxo-pyrazol- 1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2-phenylphenyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2-methyl- 1 -naphthyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
- [2- (5-methoxy-lH-indol-3-yl) ethyl] benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl)
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
(4-isopropyl-2, 3-dimethyl-5-oxo-pyrazol-1-yl) -N- (6-methoxy-1,3- benzothiazol-
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2-methyl-8- quinolyl) benzenesulfonamide
N- (4-ethoxy-2-nitro-phenyl) -4- (4-isopropyl-2,3- dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
N- (3,4-dichlorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
N- (1,2-dimethoxypropyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
N- (2,4-Dimethyl-6-nitro-phenyl) -4- (4-isopropyl-2,3- dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
(4-chloro-3-nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl-
N- (2,3-dimethyl-6-nitro-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (1-naphthylmethyl) benzenesulfonamide
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide < / RTI >
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Yl) -N - [[3- (trifluoromethyl) phenyl] methyl] benzenesulfonamide as a colorless oil
Yl) -N - [[2- (trifluoromethyl) phenyl] methyl] benzenesulfonamide as a colorless oil,
Yl) -N - [[4- (trifluoromethyl) phenyl] methyl] benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (o- tolylmethyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2-phenoxyethyl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Methyl-4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (o- tolyl) ethyl] benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (3- methoxyphenyl) ethyl] benzenesulfonamide
Pyrazol-1-yl) -N- [2- [2- (trifluoromethyl) phenyl] ethyl] benzenesulfonamide
Pyrazol-1-yl) -N- [2- [3- (trifluoromethyl) phenyl] ethyl] benzenesulfonamide
-N- [2- [4- (trifluoromethyl) phenyl] ethyl] benzenesulfonamide < / RTI >
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [4- (trifluoromethyl) phenyl] benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzene Sulfonamide
4- (4-Chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2- phenoxyethyl) benzenesulfonamide
-N- [(2-fluorophenyl) methyl] benzenesulfonamide < / RTI >
-N- [(3-fluorophenyl) methyl] benzenesulfonamide < / RTI >
N- (4-fluoro-phenyl) methyl] benzenesulfonamide
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (3,4- dichlorophenyl) benzenesulfonamide
N- (5-chloro-2-fluoro-phenyl) -benzenesulfonamide < / RTI >
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [4- (dimethylamino) phenyl] benzenesulfonamide
4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2- pyridylmethyl) benzenesulfonamide
Methyl 3 - [[4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] benzoate
(4-chloro-2, 3-dimethyl-5-oxo-pyrazol-l-yl) -N- (lH-indol-5- ylmethyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (1-naphthylmethyl) benzenesulfonamide
-N- [(3,4-dimethoxyphenyl) methyl] benzenesulfonamide < / RTI >
4- (4-Chloro-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (5- quinolyl) benzenesulfonamide
-N- [(2,4-dimethoxyphenyl) methyl] benzenesulfonamide < / RTI >
Dimethyl-5-oxo-pyrazol-1-yl) -N - [(3,4-dimethoxyphenyl) methyl] benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (5-quinolyl) benzenesulfonamide
4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [4- (dimethylamino) phenyl] benzenesulfonamide
Methyl 3 - [[4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] benzoate
N- (3-fluorophenyl) methyl] benzenesulfonamide < / RTI >
-N- [(2-fluorophenyl) methyl] benzenesulfonamide < / RTI >
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2-pyridylmethyl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2,3- amides
Phenyl] -4- (4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (3,4- dichlorophenyl) benzenesulfonamide
N- (5-chloro-2-fluoro-phenyl) -benzenesulfonamide < / RTI >
Phenyl] -4- (4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
N- (2,3-dihydro-1, 4-benzodioxin-6-yl) benzenesulfonamide
Dimethyl-5-oxo-pyrazol-l-yl) -N-cyclopentyl-benzenesulfonamide
Dimethyl-5-oxo-pyrazol-l-yl) -N-cycloheptyl-benzenesulfonamide
4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-phenyl-benzenesulfonamide
4- (2,3-dimethyl-5-oxo-4-phenyl-pyrazol-l-yl) -N- (2- phenoxyethyl) benzenesulfonamide
Pyrazol-1-yl] -N- (2-phenoxyethyl) benzenesulfonamide < / RTI >
Phenyl] sulfonylamino] phenyl] acetic acid < RTI ID = 0.0 >
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
4- [2,3-dimethyl-5-oxo-4- [4- (trifluoromethyl) phenyl] pyrazol- 1- yl] -N- (2- phenoxyethyl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
N- (6-hydroxy-1-naphthyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2- phenoxypropyl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Phenyl] -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide
Methyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1-yl) phenyl] sulfonylamino] propanoate
Methyl-phenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H- Pyrazol-1-yl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1- yl) benzenesulfonamide
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) benzenesulfone amides
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1 -yl) -N- (2,4-dimethylphenyl) benzenesulfonamide
Pyrazol-1-yl) -N- (4- (2-morpholinoethoxy) phenyl) -2,3- Benzenesulfonamide
Dihydroxyphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
(4-bromo-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- amides
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) benzene Sulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro- amides
3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) phenylsulfonamido) benzoic acid
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- (2- methoxy-5-nitrophenyl) amides
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- amides
Benzo [b] thiophen-5-yl) -4- (4-isopropyl-2,3-dimethyl- Sulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
(Benzofuran-5-ylmethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
Methyl-5- (4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 2-carboxylate
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) phenylsulfonamido) methyl) benzoate
Methyl-6- (4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) phenylsulfonamido) -2-
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-mesitylbenzenesulfonamide
4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H- Pyrazol-1-yl) benzenesulfonamide
5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- (isoquinolin-5-yl) benzenesulfonamide
4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazole- 1-yl) benzenesulfonamide
4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazole -1-yl) benzenesulfonamide
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- amides
(4-bromo-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- amides
Pyrazol-1-yl) -N- (2- (thiophen-2-yl) ethyl) Benzenesulfonamide
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- (3,4,5-trimethoxyphenyl) benzene Sulfonamide
(Cyclohexylmethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
(Cycloheptylmethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- 1- yl) benzenesulfonamide
(2-cyclohexylethyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamide as a colorless amorphous material was obtained from N- (3,4- dimethoxyphenyl) -4- ≪ / RTI >
[Reaction Scheme 1]
In the above Reaction Scheme 1,
R 1, R 2, and R 3 are the same as defined in claim 1.
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- [4-
Methyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] benzoate,
Ethyl 3 - [[4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) phenyl] sulfonylamino] benzoate,
(2,4-dimethylphenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol- 1- yl) benzenesulfonamide,
4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N - [(2,4- dimethoxyphenyl) methyl] -4-
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- [3,5-
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl)
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- (lH-
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- (3,4-
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N-
Dimethyl-5-oxo-pyrazol-1-yl) -N- (1-naphthylmethyl) benzenesulfonamide,
(4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- [2-
Dimethyl-5-oxo-pyrazol-1-yl) -N- [2- (o- tolyl) ethyl] benzenesulfonamide,
Yl] -N- [2- [2- (trifluoromethyl) phenyl] ethyl] benzenesulfonamide, 4-
Pyrazol-1-yl) -N- [2- [3- (trifluoromethyl) phenyl] ethyl] benzenesulfonamide, 4-
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- [4- (trifluoromethyl) phenyl] benzenesulfonamide,
4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzene Sulfonamide,
(4-chloro-2,3-dimethyl-5-oxo-pyrazol-1-yl) -N- (2- phenoxyethyl) benzenesulfonamide,
(4-bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N- (2- pyridylmethyl) benzenesulfonamide,
Dimethyl-5-oxo-pyrazol-1-yl) -N- (2,3- amides,
(4-bromo-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide, N- [3,5-
Dimethyl-5-oxo-pyrazol-1-yl) -N- (3,4-dichlorophenyl) benzenesulfonamide,
N- (2,3-dihydro-1, 4-benzodioxin-6-yl) benzenesulfonamide ,
Dimethyl-5-oxo-pyrazol-1-yl) -N-cycloheptyl-benzenesulfonamide, 4-
4-bromo-2,3-dimethyl-5-oxo-pyrazol-l-yl) -N-
(4-bromo-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- (2,4-dimethylphenyl) benzenesulfonamide,
Benzo [b] thiophen-5-yl) -4- (4-isopropyl-2,3-dimethyl- Sulfonamide,
Dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamide, N- (benzofuran-
4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazole -1-yl) benzenesulfonamide and
(4-isopropyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol- Amide, or a pharmaceutically acceptable salt thereof, as an active ingredient.
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