WO2015085972A1 - Nouveaux sels de 3-(2-imidazo[1,2-b]pyridazin-3-yl-éthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl]benzamide - Google Patents

Nouveaux sels de 3-(2-imidazo[1,2-b]pyridazin-3-yl-éthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl]benzamide Download PDF

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Publication number
WO2015085972A1
WO2015085972A1 PCT/CZ2013/000163 CZ2013000163W WO2015085972A1 WO 2015085972 A1 WO2015085972 A1 WO 2015085972A1 CZ 2013000163 W CZ2013000163 W CZ 2013000163W WO 2015085972 A1 WO2015085972 A1 WO 2015085972A1
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Prior art keywords
methyl
salt
acid
ponatinib
salt according
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PCT/CZ2013/000163
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English (en)
Inventor
Violetta Kiss
Ludek Ridvan
Hana TOZICKOVA
Marcela Tkadlecova
Ondrej Dammer
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Zentiva, K.S.
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Priority to PCT/CZ2013/000163 priority Critical patent/WO2015085972A1/fr
Publication of WO2015085972A1 publication Critical patent/WO2015085972A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a novel salts of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl- N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide of Formula I
  • tyrosine kinase is a subclass of protein kinase and it plays an important role in the phosphate group transfer in form adenosine triphosphate (ATP) to a protein in the cell.
  • ATP adenosine triphosphate
  • the phosphate group is attached to the appropriate amino acid, tyrosine on the protein.
  • Tyrosine kinases act as an "on” and “off switch, however, can easily undergo mutation by sticking in the "on” position resulting in uncontrolled growth of the cell that leads to the development of cancer. Consequently, tyrosine kinase inhibitors are often used as effective agents for cancer treatments.
  • WO2007075869 describes protein kinase inhibitors with valuable pharmacological effect in the treatment of related diseases.
  • One example of the compounds disclosed is ponatinib; preparation of the base and the hydrochloride salt thereof are described.
  • the object of the present invention is to provide novel pharmaceutically acceptable salts of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-
  • ponatinib (trifluoromethyl)phenyl] benzamide
  • at least one acid component selected form the group consisting of benzoic acid, citric acid, fumaric acid, L-tartaric acid, maleic acid, phophoric acid, sulphuric acid, succinic acid and p-toluenesulphonic acid.
  • the novel salts of ponatinib are as follows:
  • the present invention further relates to pharmaceutical formulations comprising one of the novel salts of ponatinib and to the use thereof for the treatment of cancer.
  • An advantage of the newly prepared salts consists in their good physical and chemical characteristics, which make them suitable for preparation of a dosage form.
  • Figure 1 is a FTIR spectra of the salt of ponatinib and benzoic acid
  • Figure 2 is a ⁇ -NMR spectra the salt of ponatinib and benzoic acid
  • Figure 3 is a ssNMR spectra the salt of ponatinib and benzoic acid
  • Figure 4 is an XRPD pattern of the salt of ponatinib and benzoic acid
  • Figure 5 is a FTIR spectra of the salt of ponatinib and citric acid
  • Figure 6 is a ssNMR spectra the salt of ponatinib and citric acid
  • Figure 7 is an XRPD pattern of the salt of ponatinib and citric acid
  • Figure 8 is a FTIR spectra of the salt of ponatinib and fumaric acid
  • Figure 9 is a ⁇ -NMR spectra the salt of ponatinib and fumaric acid
  • Figure 10 is a ssNMR spectra the salt of ponatinib and fumaric acid
  • Figure 11 is an XRPD pattern of the salt of ponatinib and fumaric acid
  • Figure 12 is a FTIR spectra of the salt of ponatinib and phosphoric acid
  • Figure 13 is a ssNMR spectra the salt of ponatinib and phosphoric acid
  • Figure 14 is an XRPD pattern of the salt of ponatinib and phosphoric acid
  • Figure 15 is a FTIR spectra of the salt of ponatinib and sulphuric acid
  • Figure 16 is a ssNMR spectra the salt of ponatinib and sulphuric acid
  • Figure 17 is an XRPD pattern of the salt of ponatinib and sulphuric acid
  • Figure 18 is a FTIR spectra of the salt of ponatinib and succinic acid
  • Figure 19 is a ssNMR spectra the salt of ponatinib and succinic acid
  • Figure 20 is an XRPD pattern of the salt of ponatinib and succinic acid
  • Figure 21 is a FTIR spectra of the salt of ponatinib and p-toluenesulphonic acid
  • Figure 22 is a ⁇ -NMR spectra the salt of ponatinib and p-toluenesulphonic acid
  • Figure 23 is a ssNMR spectra the salt of ponatinib and p-toluenesulphonic acid
  • Figure 24 is an XRPD pattern of the salt of ponatinib and p-toluenesulphonic acid
  • Figure 25 is a FTIR spectra of the salt of ponatinib and L-tartaric acid
  • Figure 26 is a ssNMR spectra the salt of ponatinib and L-tartaric acid
  • Figure 27 is an XRPD pattern of the salt of ponatinib and L-tartaric acid
  • Figure 28 is a FTIR spectra of the salt of ponatinib and maleic acid
  • Figure 29 is a ssNMR spectra the salt of ponatinib and maleic acid
  • Figure 30 is an XRPD pattern of the salt of ponatinib and maleic acid.
  • the aim of the present invention is to provide novel pharmaceutically acceptable salts of ponatinib with advantegous properties for pharmaceutical use regarding their physico-chemical properties (e.g. stability, solubility) and which can be produced in a reproducible manner even in industrial scale.
  • physico-chemical properties e.g. stability, solubility
  • the above mentioned objects have been achieved by the novel pharmaceutically acceptable salts of ponatinib with benzoic acid, citric acid, fumaric acid, L-tartaric acid, maleic acid, phophoric acid, sulphuric acid, succinic acid and p-toluenesulphonic acid.
  • the invention also relates to a method of preparation of these salts. It has been surprisingly found that the above-mentioned chemically and morphologically stable salts of ponatinib can be prepared and have not been described in the literature and no analytical data (X-Ray Powder Diffraction patterns, Single-Crystal X-Ray Diffraction data etc.) serving to characterize the crystalline salt has been provided.
  • the present invention thus relates to a pharmaceutically acceptable salt of ponatinib and at least one acid component selected from the group consisting of benzoic acid, citric acid, fumaric acid, L- tartaric acid, maleic acid, phophoric acid, sulphuric acid, succinic acid and p-toluenesulphonic acid.
  • the inventive salts of ponatinib can be obtained with acceptable yields and high purity.
  • inventive salts may exist in different solid forms with different internal structures (polymorphism), which may have different physico-chemical properties, Therefore, crystalline modifications of the inventive salt cover individual crystals and/or mixtures thereof with another crystalline modification in any ratio.
  • Substantially pure crystalline forms and substantially pure amorphous form can be prepared, as well as mixtures of different crystalline forms in any ratio or mixtures of crystalline form(s) with the amorphous form.
  • the inventive salt formed from ponatinib and at least one pharmaceutically acceptable acid component can be present in a crystalline form or in an amorphous form. Preferably it is in a crystalline form.
  • inventively claimed salts may be in an anhydrous and/or a solvent-free form; or they may be in a hydrated or solvated form.
  • All said salts can be prepared by the reaction of ponatinib with an acid selected from the group consisting of benzoic acid, citric acid, fumaric acid, L-tartaric acid, maleic acid, phophoric acid, sulphuric acid, succinic acid and p-toluenesulphonic acid in a solvent selected from the group consisting of C1-C4 alkyl alcohols and any their mixtures, preferebly in methanol, ethanol and 2- propanol.
  • the selected solvents preferably methanol, ethanol and 2-propanol are suitable for the preparation of the salts of ponatinib in a yield and purity which is favorable from efficient and safe production point of view of a pharmaceutically active compound.
  • the reaction was carried out in the range of temperature 40-60°C, preferably at temperature 50°C.
  • the resulting salt was isolated from the reaction mixture at room temperature.
  • the salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and acid component selected from the group consisting of benzoic acid, citric acid, fumaric acid, L-tartaric acid, maleic acid, phophoric acid, sulphuric acid, succinic acid and p-toluenesulphonic acid can be obtained by a process comprising following steps: a/ dissolving the 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methy!]-3-(trifluoromethyl)phenyl] benzamide in a solvent selected from the group consisting of Cl-C4-alkyl alcohols and any their mixtures by heating
  • room temperature is defined as a temperature between 15 °C and 29 °C for the purpose of this invention; preferably it is between 20-23°C.
  • the term wornovernight as used in this patent application is related to the duration of the given process step.
  • the process that is to be carried out during comfortnight has to be performed for at least 10 hours, preferably 12-16 hours.
  • the novel salt s according to the invention can be used for preparation of ponatinib in a free form (Formula I).
  • the novel salts according to the present invention can be used for preparation of any other pharmaceutically acceptable salt of ponatinib.
  • Use of any of the novel salts of ponatinib for preparation of ponatinib in its free form is also part of the invention.
  • Use of any of the novel salts of ponatinib for conversion of any of the novel salts of ponatinib to other pharmaceutical acceptable salt thereof is also part of the invention.
  • Another aspect of the invention are novel crystalline salts of ponatinib with an acid component selected from the group consisting of benzoic acid, citric acid, fumaric acid, L-tartaric acid, maleic acid, phophoric acid, sulphuric acid, succinic acid and p-toluenesulphonic acid.
  • the salts according to this aspect of the invention are in a crystalline or a substantially crystalline state.
  • the word substantially is understood as comprising at least of 95% by weight of the respective solid form.
  • the crystalline salt of ponatinib and benzoic acid according to the present invention can be characterized by an FTIR spectroscopy and solid-state NMR investigation.
  • the crystalline salt of ponatinib and benzoic acid is characterised by a FTIR spectrum comprising characteristic peaks at 570, 678, 717, 838, 1109, 1142, 1387, 1659, 2217 and 3384 cm "1 wavenumbers, shown in Figure 1.
  • the solid-state NMR spectrum is shown in Figure 3.
  • the crystalline salt of ponatinib and benzoic acid according to the invention has the characteristic XRPD pattern as shown in Figure 4.
  • the salt of ponatinib and benzoic acid has the following most characteristic powder diffraction peaks illustrated in Table 1, below:
  • the crystalline salt ofponatinib and benzoic acid was prepared with excellent purity of 97.5%.
  • the crystalline salt of ponatinib and citric acid according to the present invention can be characterized by an FTIR spectroscopy and a solid-state NMR invesitgations.
  • the crystalline salt of ponatinib and citric acid is characterised by a FTIR spectrum spectrum comprising characteristic peaks at 593, 793, 1052, 1121, 1160, 1316, 1593, 1733, 2212 and 2839 cm "1 wavenumbers, shown in Figure 5.
  • the solid-state NMR spectrum is shown Figure 6.
  • the crystalline salt of ponatinib and citric acid according to the invention has the a characteristic XRPD pattern as shown in Figure 7.
  • the salt of ponatinib and citric acid has the following most characteristic powder diffraction peaks illustrated in Table 2, below:
  • the crystalline salt of ponatinib and citric acid was prepared with excellent purity of 99.1%.
  • the crystalline salt of ponatinib and fumaric acid according to the present invention can be characterized by an FTIR spectroscopy and a solid-state NMR invesitgations.
  • the crystalline salt of ponatinib and fumaric acid is characterised by a FTIR spectrum comprising characteristic peaks at 609, 670, 840, 1125, 1161, 1289, 1599, 1672, 2213 and 3067 cm "1 wavenumbers, shown in Figure 8.
  • the solid-state NMR spectrum is shown in Figure 10.
  • the crystalline salt of ponatinib and fumaric acid according to the invention has the characteristic XRPD pattern as shown in Figure 11.
  • the salt of ponatinib and fumaric acid has the following most characteristic powder diffraction peaks illustrated in Table 3, below:
  • the crystalline salt of ponatinib and fumaric acid was prepared with excellent purity of 99.1%.
  • the crystalline salt of ponatinib and phosphoric acid according to the present invention can be characterized by an FTIR spectroscopy and a solid-state NMR invesitgations.
  • the crystalline salt of ponatinib and phosphoric acid is characterised by a FTIR spectrum comprising characteristic peaks at 644, 803, 849, 904, 1083, 1121, 1250, 1423, 1652 and 2428 cm "1 wavenumbers, shown in Figure 12.
  • the solid-state NMR spectrum is shown in Figure 13.
  • the crystalline salt of ponatinib and phosphoric acid according to the invention has the characteristic XRPD pattern as shown in Figure 14.
  • the salt of ponatinib and phosphoric acid has the following most characteristic powder diffraction peaks illustrated in Table 4, below:
  • the crystalline salt of ponatinib and phosphoric acid was prepared with excellent purity of 99.4%.
  • the crystalline salt of ponatinib and sulphuric acid according to the present invention can be characterized by an FTIR spectroscopy and a solid-state NMR invesitgations.
  • the crystalline salt of ponatinib and sulphuric acid is characterised by a FTIR spectrum comprising characteristic peaks at 577, 745, 796, 1107, 1167, 1421, 1542, 1667, 2475 and 3018 cm "1 wavenumbers, shown in Figure 15.
  • the solid-state NMR spectrum is shown in Figure 16.
  • the crystalline salt of ponatinib and sulphuric acid according to the invention has the characteristic XRPD pattern as shown in Figure 17.
  • the salt of ponatinib and sulphuric acid has the following most characteristic powder diffraction peaks illustrated in Table 5, below: Pos. [°2Th.] d-spacing [A] Rel. Int. [%]
  • the crystalline salt of ponatinib and sulphuric acid was prepared withexcellent purity of 99.1%.
  • the crystalline salt of ponatinib and succinic acid according to the present invention can be characterized by an FTIR spectroscopy and a solid-state NMR invesitgations.
  • the crystalline salt of ponatinib and succinic acid is characterised by a FTIR spectrum comprising characteristic peaks at 570, 651, 747, 1113, 1141, 1317, 1538, 1663, 1715 and 3308 cm "1 wavenumbers, shown in Figure 18.
  • the solid-state NMR spectrum is shown in Figure 19.
  • the crystalline salt of ponatinib and succinic acid according to the invention has the characteristic XRPD pattern as shown in Figure 20.
  • the salt of ponatinib and succinic acid has the following most characteristic powder diffraction peaks illustrated in Table 6, below:
  • the crystalline salt of ponatinib and succinic acid o was prepared with excellent purity of 98.7%.
  • the crystalline salt of ponatinib and p-toluenesulphonic acid according to the present invention can be characterized by an FTIR spectroscopy and a solid-state NMR invesitgations.
  • the crystalline salt of ponatinib and p-toluenesulphonic acid is characterised by a FTIR spectrum comprising characteristic peaks at 567, 680, 749, 1000, 1141, 1161, 1231, 1420, 2217 and 3296 cm "1 wavenumbers, shown in Figure 21.
  • the solid-state NMR spectrum is shown in Figure 23.
  • the crystalline salt of ponatinib and p-toluenesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 24.
  • the salt of ponatinib and p-toluenesulphonic acid has the following most characteristic powder diffraction peaks illustrated in Table 7, below:
  • the crystalline salt of ponatinib and p-toluenesulphonic acid was prepared with excellent purity of 98.5%.
  • the novel salts of ponatinib with an acid component selected from the group consisting of benzoic acid, citric acid, fumaric acid, L-tartaric acid, maleic acid, phophoric acid, sulphuric acid, succinic acid and p-toluenesulphonic acid are in an amorphous state or in a substantially amorphous state.
  • the word substantially is understood as comprising at least of 95% by weight of the respective solid form.
  • the amorphous salt of ponatinib and L-tartaric acid can be characterized by an FTIR spectroscopy and solid-state NMR invesitgations.
  • Figure 25 shows the FTIR spectrum comprising characteristic peaks at 557, 648, 1052, 1113, 1294, 1317, 1535, 1600, 1722 and 2213 cm "1 wavenumbers and
  • Figure 26 shows the solid-state NMR spectrum.
  • the salt of ponatinib and L-tartaric acid according to the invention has the characteristic XRPD pattern as shown in Figure 27.
  • the salt of ponatinib and L-tartaric acid is an essentially amorhpous phase.
  • the amorphous salt of ponatinib and L-tartaric acid was prepared with excellent purity of 98.8%.
  • the salt of ponatinib and maleic acid can be characterized by an FTIR spectroscopy and solid-state NMR invesitgations.
  • Figure 28 shows the FTIR spectrum comprising characteristic peaks at 669, 746, 985, 1118, 1155, 1295, 1319, 1538, 1718 and 2947 cm 1 wavenumbers and
  • Figure 29 shows the solid-state NMR spectrum.
  • the salt of ponatinib and maleic acid according to the invention has the characteristic XRPD pattern as shown in Figure 30.
  • the salt of ponatinib and maleic acid is essentially amorphous phase.
  • the amorphous salt of ponatinib and maleic acid was prepared with purity of 96.7%.
  • novel salts according to the present invention can be used for preparation of pharmaceutical formulations which ca ben used for the treatment of leukaemia, especially chronic myeloid leukaemia (CML) as well as Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL).
  • CML chronic myeloid leukaemia
  • Ph+ Philadelphia chromosome positive acute lymphoblastic leukaemia
  • the formulations can be for oral or patenteral administration, or for any way of administration known in the state of the art.
  • the oral formulations can be e.g. in the form of tablets, capsules, minitablets, film-strips and any other known form, preferably in the form of tablets or capsules.
  • step time 0.5 s. Samples were measured as received on Si plate (zero background holder).
  • Incident beam optics programmable divergence slits (irradiated length 10 mm). 10 mm mask. 1/4 9 anti-scatter fixed slit, 0.02 rad Soller slits.
  • Diffracted beam optics X'Celerator detector, scanning mode, active length 2.1222. 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.
  • FTIR spectra were recorded by Nicolet Thermo 6700 spectrometer.
  • ⁇ - MR analysis showed a 2:1 stoichiometry of ponatinib and fumaric acid.
  • ponatinib 100 mg (0.188 mmol) of ponatinib was dissolved in 3 mL of methanol by heating to 50°C. 22 mg (0.190 mmol) of maleic acid was dissolved in 0.5 mL of methanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C.
  • ⁇ - MR analysis showed a 2:1 stoichiometry of ponatinib and maleic acid.

Abstract

Cette invention concerne un sel pharmaceutiquement acceptable de 3-(2-imidazo[1,2-b]pyridazin-3-yl-éthynyl)-4-méthyl-N-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl]benzamide (ponatinib) et au moins un composant acide, choisi dans le groupe constitué par l'acide benzoïque, l'acide citrique, l'acide fumarique, l'acide L-tartrique, l'acide maléique, l'acide phosphorique, l'acide sulfurique, l'acide succinique et l'acide p-toluènesulfonique.
PCT/CZ2013/000163 2013-12-09 2013-12-09 Nouveaux sels de 3-(2-imidazo[1,2-b]pyridazin-3-yl-éthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl]benzamide WO2015085972A1 (fr)

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PCT/CZ2013/000163 WO2015085972A1 (fr) 2013-12-09 2013-12-09 Nouveaux sels de 3-(2-imidazo[1,2-b]pyridazin-3-yl-éthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl]benzamide

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9725454B2 (en) 2013-07-04 2017-08-08 Sandoz Ag Crystalline forms of ponatinib hydrochloride
WO2019246479A1 (fr) 2018-06-22 2019-12-26 Johnson Matthey Public Limited Company Forme de ponatinib
WO2020223235A1 (fr) * 2019-04-29 2020-11-05 Incyte Corporation Formes pharmaceutiques de ponatinib du type mini-comprimés
US11072620B2 (en) 2017-06-20 2021-07-27 Apotex Inc. Crystalline forms of Ponatinib hydrochloride
CN113831344A (zh) * 2021-04-13 2021-12-24 暨南大学 炔苯基苯酰胺类化合物及其应用

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Publication number Priority date Publication date Assignee Title
WO2007075869A2 (fr) 2005-12-23 2007-07-05 Ariad Pharmaceuticals, Inc. Composes heteroaryles bicycliques
WO2011053938A1 (fr) * 2009-10-30 2011-05-05 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement du cancer

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Publication number Priority date Publication date Assignee Title
WO2007075869A2 (fr) 2005-12-23 2007-07-05 Ariad Pharmaceuticals, Inc. Composes heteroaryles bicycliques
WO2011053938A1 (fr) * 2009-10-30 2011-05-05 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement du cancer

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HUANG WEI-SHENG ET AL: "Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{ 4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 53, no. 12, 24 June 2010 (2010-06-24), pages 4701 - 4719, XP002615777, ISSN: 0022-2623, [retrieved on 20100601], DOI: 10.1021/JM100395Q *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9725454B2 (en) 2013-07-04 2017-08-08 Sandoz Ag Crystalline forms of ponatinib hydrochloride
US11072620B2 (en) 2017-06-20 2021-07-27 Apotex Inc. Crystalline forms of Ponatinib hydrochloride
WO2019246479A1 (fr) 2018-06-22 2019-12-26 Johnson Matthey Public Limited Company Forme de ponatinib
WO2020223235A1 (fr) * 2019-04-29 2020-11-05 Incyte Corporation Formes pharmaceutiques de ponatinib du type mini-comprimés
CN113831344A (zh) * 2021-04-13 2021-12-24 暨南大学 炔苯基苯酰胺类化合物及其应用
US11834454B2 (en) 2021-04-13 2023-12-05 Shenzhen Newdel Biotech Co., Ltd. Alkynylphenylbenzamide compounds and applications thereof

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