TWI619708B - Pyrazolyquinoline compounds and preparation methods and pharmaceutical compositions thereof - Google Patents

Abstract

The present invention provides a pyrazolylquinoline compound comprising: a quinolinyl group, a C6 position bonded to a substituent R ₁ , and R ₁ is a halogen atom; a pyrazolyl group; a first phenyl group; a diphenyl group, wherein: the C2 position of the quinolyl group is bonded to the C3 or C5 position of the pyrazolyl group; when in the first case, the C2 position of the quinolyl group is bonded to the C3 position of the pyrazolyl group, The C5 position of the pyrazolyl group is attached to the C4 position of the first phenyl group; and when in the second case, the C2 position of the quinolyl group is attached to the C5 position of the pyrazolyl group, the C3 of the pyrazolyl group The position is linked to the C4 position of the first phenyl group; and the N1 position of the pyrazole group is linked to the C4 position of the second phenyl group.

Description

Pyrazolylquinoline compound, preparation method thereof and pharmaceutical composition

The present invention relates to a pyrazolylquinoline compound, a preparation method thereof and a pharmaceutical composition, in particular to a pyrazolylquinoline compound against dengue virus, a preparation method thereof and a pharmaceutical composition.

The dengue virus (DENV) belongs to the family Flaviviridae , and West Nile virus (WNV), Yellow Fever virus (YFV), and Hepatitis C virus (HCV). )closely related. The dengue virus is transmitted by Aedes aegypti or Aedes albopictus , which causes dengue fever, dengue hemorrhagic fever (DHF) and dengue shock syndrome (dengue shock syndrome). , DSS).

Worldwide, between 50 and 100 million people are infected with dengue virus each year, and about half a million people suffer from hemorrhagic dengue fever, killing 20,000 people. At present, dengue fever is prevalent in 112 countries around the world, mostly in tropical and subtropical regions of Asia, Latin America and the Caribbean, and about 2.5 billion people are at risk of being infected. Taiwan is located in the subtropical region and there are many cases of dengue infection every year. The dengue fever epidemic has become a serious public health problem in Taiwan.

However, there is currently no effective drug for the treatment of diseases caused by dengue virus infection in the pharmaceutical market. Patients can only receive symptomatic or supportive treatment. Therefore, the development of a safe and effective drug for the treatment of diseases caused by dengue virus is It is imperative.

The first aspect of the present invention provides a pyrazolylquinoline compound comprising: a quinolinyl group, a C6 position bonded to a substituent R ₁ , and R ₁ is a halogen atom; a pyrazole group; a first benzene And a second phenyl group, wherein: the C2 position of the quinolyl group is bonded to the C3 or C5 position of the pyrazolyl group; when in the first case, the C2 position of the quinolinyl group is related to the pyrazolyl group When the C3 position is linked, the C5 position of the pyrazolyl group is linked to the C4 position of the first phenyl group; and when in the second case, the C2 position of the quinolyl group is linked to the C5 position of the pyrazolyl group, The C3 position of the pyrazolyl group is attached to the C4 position of the first phenyl group; and the N1 position of the pyrazole group is linked to the C4 position of the second phenyl group.

The second aspect of the present invention provides a pyrazolylquinoline compound comprising: a quinolinyl group, a C6 position bonded to a substituent R1, and R ₁ is a halogen atom; a pyrazolyl group; And a second phenyl group, wherein: the C2 position of the quinolyl group is bonded to a carbon atom position of the pyrazolyl group, and another carbon atom position of the pyrazolyl group is bonded to the C4 position of the second phenyl group, The N1 position of the pyrazolyl group is bonded to the C4 position of the first phenyl group.

The third aspect of the present invention provides a process for preparing a pyrazolylquinoline compound, comprising the steps of: providing 6-fluoro-2-methylquinoline; and oxidizing the 6-fluoro-2-methyl group with selenium dioxide Quinoline to form 6-fluoro-2-formylquinoline; condensing the 6-fluoro-2-quinolinecarboxaldehyde with monoacetophenone to form a carbonyl product; The carbonyl product is treated with a benzoquinone to form the pyrazolylquinoline compound.

The fourth aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a pyrazolylquinoline compound as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.

The first figure shows Synthesis Example 1 of the present invention: Preparation of quinolinyl chalcone compounds 3a-c.

The second figure shows Synthesis Example 2 of the present invention: Preparation of pyrazolylquinoline compound 4a-5c and Synthesis Example 3: Preparation of pyrazolylquinoline compound 6a-8c.

The third panel shows Experimental Example 1 of the present invention: 6-fluoro-2-[5-(4-methoxyphenyl)-1-phenyl- 1hydro -pyrazol-3-yl]quinoline) (Compound 4c) And the structure determination of 6-fluoro-2-[3-(4-methoxyphenyl)-1-phenyl-1 hydrogen -pyrazol-5-yl]quinoline (compound 5c).

The fourth panel shows the reverse transcriptase-instant quantitative polymerase chain reaction (RT-qPCR) of Experimental Example 6 of the present invention.

The fifth graph shows the Western blotting method of Experimental Example 6 of the present invention.

Fig. 6(a), Fig. 6(b) and Fig. 6(c) show Experimental Example 7 of the present invention: analysis of anti-DENV-2 activity in vivo.

The details of the present invention will be apparent from the following detailed description of the preferred embodiments.

A first embodiment of the present invention provides a pyrazolylquinoline compound comprising: a quinolinyl group, the C6 position is bonded to a substituent R ₁ , and R ₁ is a halogen atom, and the halogen atom may be a fluorine atom or a chlorine atom. An atom, a bromine atom, an iodine atom, but is not limited thereto; a pyrazolyl group; a first phenyl group; and a second phenyl group, wherein: the C2 position of the quinolyl group and the C3 or C5 position of the pyrazolyl group Linking; when in the first case, the C2 position of the quinolyl group is attached to the C3 position of the pyrazolyl group, the C5 position of the pyrazolyl group is linked to the C4 position of the first phenyl group; and when in the second In the case where the C2 position of the quinolyl group is bonded to the C5 position of the pyrazolyl group, the C3 position of the pyrazolyl group is bonded to the C4 position of the first phenyl group; and the N1 position of the pyrazolyl group and the first The C4 position of the diphenyl group is attached.

In the pyrazolylquinoline compound of the present embodiment, the C1 position of the first phenyl group may be bonded to a substituent R ₂ , and R ₂ may be a hydrogen atom, a halogen atom or an alkoxy group, wherein the halogen atom may be fluorine. The atom, the chlorine atom, the bromine atom, the iodine atom, but not limited thereto, the alkoxy group may be a methoxy group, an ethoxy group, a propoxy group or a butoxy group, but is not limited thereto; the C1 of the second phenyl group The position may be bonded to a substituent R ₃ , and R ₃ may be a hydrogen atom, a halogen atom, an alkoxy group or a sulfonamide group, wherein the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine. The atom is, but not limited to, the alkoxy group may be a methoxy group, an ethoxy group, a propoxy group or a butoxy group, but is not limited thereto.

The pyrazolylquinoline compound of the present embodiment may be selected from the group consisting of 6-fluoro-2-(1,5-diphenyl- 1hydro -pyrazol-3-yl)quinoline (6) -Fluoro-2-(1,5-diphenyl-1H-pyrazol-3-yl)quinoline), 6-fluoro-2-[5-(4-fluorophenyl)-1-phenyl-1 hydrogen -pyrazole 3-fluoro-2-[5-(4-fluorophenyl)-1-phenyl-1 H- pyrazol-3-yl]quinoline), 6-fluoro-2-[5-(4 - methoxyphenyl) -1-phenyl-1H - pyrazol-3-yl] quinoline (6-Fluoro-2- [5- (4-methoxyphenyl) -1-phenyl-1 H -pyrazol-3 -yl] quinoline), 6- fluoro-2- (1,3-diphenyl-1H - pyrazol-5-yl) - quinoline (6-fluoro-2- (1,3 -diphenyl-1H- pyrazol-5-yl) -quinoline) , 6- fluoro-2- [3- (4-fluorophenyl) -1-phenyl-1H - pyrazol-5-yl] quinoline (6-fluoro-2 -[3-(4-fluorophenyl)-1-phenyl-1 H -pyrazol-5-yl]quinoline), 6-fluoro-2-[3-(4-methoxyphenyl)-1-phenyl-1 Hydrogen -pyrazol-5-yl]quinoline (6-Fluoro-2-[3-(4-methoxyphenyl)-1-phenyl-1 H- pyrazol-5-yl]quinoline), 6-fluoro-2-[ 1- (4-fluorophenyl) -3-phenyl-1H - pyrazol-5-yl] quinoline (6-Fluoro-2- [1- (4-fluorophenyl) -3-phenyl-1 H - pyrazol-5-yl] quinoline) , 6- fluoro-2- [1,3-bis (4-fluorophenyl) -1H-- pyrazol-5-yl] Quinoline (6-Fluoro-2-[1,3-Bis(4-fluorophenyl)-1 H- pyrazol-5-yl]quinoline), 6-fluoro-2-(1-(4-fluorophenyl)- 3- (4-methoxyphenyl) -1H-- pyrazol-5-yl) quinoline (6-Fluoro-2- (1- (4-fluorophenyl) -3- (4-methoxyphenyl) -1 H - pyrazol-5-yl) quinoline) , 6- fluoro-2- [1- (4-methoxyphenyl) -3-phenyl-1H - pyrazol-5-yl] quinoline (6-fluoro-2 -[1-(4-methoxyphenyl)-3-phenyl-1 H -pyrazol-5-yl]quinoline), 6-fluoro-2-[3-(4-fluorophenyl)-1-(4-methoxy Phenyl)-1 hydrogen -pyrazol-5-yl]quinoline (6-Fluoro-2-[3-(4-fluorophenyl)-1-(4-methoxyphenyl)-1 H -pyrazol-5-yl]quinoline ), 6-fluoro-2- [1,3-bis (4-methoxyphenyl) -1H-- pyrazol-5-yl] quinoline (6-fluoro-2- [1,3 -bis (4 -methoxyphenyl) -1 H -pyrazol-5- yl] quinoline), 4- [5- (6- fluoro-quinolin-2-yl) -3-phenyl-1H - pyrazol-1-yl] benzenesulfonamide [amine (4-[5-(6-Fluoroquinolin-2-yl)-3-phenyl-1 H- pyrazol-1-yl]benzenesulfonamide), 4-[3-(4-fluorophenyl)-5-( 6-fluoro-quinolin-2-yl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [3- (4-Fluorophenyl ) -5- (6-fluoroquinolin-2-yl) -1 H- pyrazol-1-yl]benzenesulfonamide), and 4-[5-(6-fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 hydrogen -pyrazole 4-[5-(6-Fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 H- pyrazol-1-yl]benzenesulfonamide).

The pyrazolylquinoline compound of the present embodiment is more preferably selected from the group consisting of 4-[5-(6-fluoroquinolin-2-yl)-3-phenyl-1 hydrogen -pyrazole -1-yl]benzenesulfonamide (4-[5-(6-Fluoroquinolin-2-yl)-3-phenyl-1 H- pyrazol-1-yl]benzenesulfonamide), 4-[3-(4-fluoro phenyl) -5- (6-fluoro-quinolin-2-yl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [3- (4-Fluorophenyl ) -5- (6-fluoroquinolin -2-yl)-1 H- pyrazol-1-yl]benzenesulfonamide), and 4-[5-(6-fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 hydrogen- pyrazol-1-yl] benzenesulfonamide Amides (4- [5- (6-Fluoroquinolin -2-yl) -3- (4-methoxyphenyl) -1 H -pyrazol-1-yl] benzenesulfonamide).

Pyrazolyl quinoline compounds of the present Example is the best embodiment of 4- [5- (6-fluoro-quinolin-2-yl) -3- (4-methoxyphenyl) -1H-- pyrazol-1-yl ] 4-[5-(6-Fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 H- pyrazol-1-yl]benzenesulfonamide).

A second embodiment of the present invention provides a pyrazolylquinoline compound comprising: an oxazoline group, a C6 position bonded to a substituent R1, and R ₁ is a halogen atom, the halogen atom may be a fluorine atom; An azolyl group; a first phenyl group; and a second phenyl group, wherein: the C2 position of the quinolyl group is bonded to a carbon atom position of the pyrazolyl group, and the other carbon atom position of the pyrazolyl group is The C4 position of the diphenyl group is bonded, and the N1 position of the pyrazole group is bonded to the C4 position of the first phenyl group.

In the pyrazolylquinoline compound of the present embodiment, the C1 position of the first phenyl group may be bonded to a substituent R ₂ , and R ₂ may be a hydrogen atom, a halogen atom or an alkoxy group, wherein the halogen atom may be fluorine. The atom, the chlorine atom, the bromine atom, the iodine atom, but not limited thereto, the alkoxy group may be a methoxy group, an ethoxy group, a propoxy group or a butoxy group, but is not limited thereto; the C1 of the second phenyl group The position may be bonded to a substituent R ₃ , and R ₃ may be a hydrogen atom, a halogen atom, an alkoxy group or a sulfonamide group, wherein the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine. The atom is, but not limited to, the alkoxy group may be a methoxy group, an ethoxy group, a propoxy group or a butoxy group, but is not limited thereto.

The pyrazolylquinoline compound of the present embodiment may be selected from the group consisting of 6-fluoro-2-(1,5-diphenyl- 1hydro -pyrazol-3-yl)quinoline (6) -Fluoro-2-(1,5-diphenyl-1H-pyrazol-3-yl)quinoline), 6-fluoro-2-[5-(4-fluorophenyl)-1-phenyl-1 hydrogen -pyrazole 3-fluoro-2-[5-(4-fluorophenyl)-1-phenyl-1 H- pyrazol-3-yl]quinoline), 6-fluoro-2-[5-(4 - methoxyphenyl) -1-phenyl-1H - pyrazol-3-yl] quinoline (6-Fluoro-2- [5- (4-methoxyphenyl) -1-phenyl-1 H -pyrazol-3 -yl] quinoline), 6- fluoro-2- (1,3-diphenyl-1H - pyrazol-5-yl) - quinoline (6-fluoro-2- (1,3 -diphenyl-1H- pyrazol-5-yl) -quinoline) , 6- fluoro-2- [3- (4-fluorophenyl) -1-phenyl-1H - pyrazol-5-yl] quinoline (6-fluoro-2 -[3-(4-fluorophenyl)-1-phenyl-1 H -pyrazol-5-yl]quinoline), 6-fluoro-2-[3-(4-methoxyphenyl)-1-phenyl-1 Hydrogen -pyrazol-5-yl]quinoline (6-Fluoro-2-[3-(4-methoxyphenyl)-1-phenyl-1 H- pyrazol-5-yl]quinoline), 6-fluoro-2-[ 1- (4-fluorophenyl) -3-phenyl-1H - pyrazol-5-yl] quinoline (6-Fluoro-2- [1- (4-fluorophenyl) -3-phenyl-1 H - pyrazol-5-yl] quinoline) , 6- fluoro-2- [1,3-bis (4-fluorophenyl) -1H-- pyrazol-5-yl] Quinoline (6-Fluoro-2-[1,3-Bis(4-fluorophenyl)-1 H- pyrazol-5-yl]quinoline), 6-fluoro-2-(1-(4-fluorophenyl)- 3- (4-methoxyphenyl) -1H-- pyrazol-5-yl) quinoline (6-Fluoro-2- (1- (4-fluorophenyl) -3- (4-methoxyphenyl) -1 H - pyrazol-5-yl) quinoline) , 6- fluoro-2- [1- (4-methoxyphenyl) -3-phenyl-1H - pyrazol-5-yl] quinoline (6-fluoro-2 -[1-(4-methoxyphenyl)-3-phenyl-1 H -pyrazol-5-yl]quinoline), 6-fluoro-2-[3-(4-fluorophenyl)-1-(4-methoxy Phenyl)-1 hydrogen -pyrazol-5-yl]quinoline (6-Fluoro-2-[3-(4-fluorophenyl)-1-(4-methoxyphenyl)-1 H -pyrazol-5-yl]quinoline ), 6-fluoro-2- [1,3-bis (4-methoxyphenyl) -1H-- pyrazol-5-yl] quinoline (6-fluoro-2- [1,3 -bis (4 -methoxyphenyl) -1 H -pyrazol-5- yl] quinoline), 4- [5- (6- fluoro-quinolin-2-yl) -3-phenyl-1H - pyrazol-1-yl] benzenesulfonamide [amine (4-[5-(6-Fluoroquinolin-2-yl)-3-phenyl-1 H- pyrazol-1-yl]benzenesulfonamide), 4-[3-(4-fluorophenyl)-5-( 6-fluoro-quinolin-2-yl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [3- (4-Fluorophenyl ) -5- (6-fluoroquinolin-2-yl) -1 H- pyrazol-1-yl]benzenesulfonamide), and 4-[5-(6-fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 hydrogen -pyrazole 4-[5-(6-Fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 H- pyrazol-1-yl]benzenesulfonamide).

The pyrazolylquinoline compound of the present embodiment is more preferably selected from the group consisting of 4-[5-(6-fluoroquinolin-2-yl)-3-phenyl-1 hydrogen -pyrazole -1-yl]benzenesulfonamide (4-[5-(6-Fluoroquinolin-2-yl)-3-phenyl-1 H- pyrazol-1-yl]benzenesulfonamide), 4-[3-(4-fluoro phenyl) -5- (6-fluoro-quinolin-2-yl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [3- (4-Fluorophenyl ) -5- (6-fluoroquinolin -2-yl)-1 H- pyrazol-1-yl]benzenesulfonamide), and 4-[5-(6-fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 hydrogen- pyrazol-1-yl] benzenesulfonamide Amides (4- [5- (6-Fluoroquinolin -2-yl) -3- (4-methoxyphenyl) -1 H -pyrazol-1-yl] benzenesulfonamide).

Pyrazolyl quinoline compounds of the present Example is the best embodiment of 4- [5- (6-fluoro-quinolin-2-yl) -3- (4-methoxyphenyl) -1H-- pyrazol-1-yl ] 4-[5-(6-Fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 H- pyrazol-1-yl]benzenesulfonamide).

A third embodiment of the present invention provides a process for the preparation of a pyrazolylquinoline compound, comprising the steps of: providing 6-fluoro-2-methylquinoline, and oxidizing the 6-fluoro-2-methyl group with selenium dioxide Quinoline to form 6-fluoro-2-formylquinoline; condensing the 6-fluoro-2-quinolinecarboxaldehyde with monoacetophenone to form a carbonyl product; The carbonyl product is treated with a benzoquinone to form the pyrazolylquinoline compound.

The method of the present embodiment, wherein the acetophenone may be acetophenone, 4-fluoroacetophenone or 4-methoxyacetophenone, but is not limited thereto.

In the method of the present embodiment, the benzoquinone may be phenylhydrazine, 4-fluorophenylhydrazine, 4-methoxybenzoquinone or 4-hydrazinobenzenesulfonamide, but is not limited thereto.

The method of the present embodiment, wherein the acetophenone is 4-methoxyacetophenone, and the carbonyl product is ( E )-3-(6-fluoroquinolin-2-yl)-1-(4- Methoxyphenyl)prop-2-quin-1-one (( E )-3-(6-Fluoroquinolin-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one) The benzoquinone is 4-fluorophenylhydrazine, 4-methoxybenzoquinone or 4-hydrazinobenzenesulfonamide, but is not limited thereto.

In the method of the present embodiment, when the benzoquinone is benzoquinone, the carbonyl product may be treated with the benzoquinone to carry out oxidation of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).

A fourth embodiment of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a pyrazolylquinoline compound according to the first embodiment or the second embodiment of the present invention or a pharmaceutically acceptable salt thereof, and Its pharmaceutically acceptable carrier.

Synthesis Example 1: Preparation of quinolinyl chalcone compound 3a-c:

Please refer to the first figure to oxidize 6-fluoro-2-methylquinoline (compound 1) with selenium dioxide to form 6-fluoro-2-quinoline formaldehyde (6-fluoro- 2-formylquinoline) (Compound 2) by compound 1 (0.48 g, 3.0 mmol) and selenium dioxide (SeO ₂ ) (0.66 g, 6.0 mmol) in 1,4-dioxane (1) , 4-dioxane) (50 ml) was heated at 100 ° C for 2 hours (monitored by thin layer chromatography (TLC)). After cooling, 5% sodium bicarbonate and dried (NaHCO ₃₎ solution (80 mL), dichloromethane (CH ₂ Cl ₂₎ (50 mL × 3), the organic layer was collected, dried over (MgSO ₄₎ And evaporated. The crude product was crystallized from EtOAc (EtOAc) Compound 2 is condensed with acetophenone to give the trans conjugated carbonyl product ( E )-3-(6-fluoroquinolin-2-yl)-1-phenylprop-2-ene-1 exclusively - Ketone (( E )-3-(6-Fluoroquinolin-2-yl)-1-phenylprop-2-en-1-one) (Compound 3a) by Compound 2 (0.36 g, 2.0 mmol) The acetophenone (2.0 mmol) was stirred at 0 °C for 15 min. EtOAc (EtOAc) (EtOAc) After completion of the reaction, 1 M hydrochloric acid (HCl) was added to the obtained mixture until pH was 3, and extracted with ethyl acetate (50 ml × 3). The organic layer was collected, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified and crystallized from alcohol to give quinolinylchalcone compound 3a. Correspondingly, compound 2 forms ( E )-1-(4-fluorophenyl)-3-(6-fluoro) with 4-fluoroacetophenone and 4-methoxyacetophenone, respectively, under the same reaction conditions. Quinoline-2-yl)prop-2-yl-1-one (( E )-1-(4-Fluorophenyl)-3-(6-fluoroquinolin-2-yl)prop-2-en-1-one) (Compound 3b) and ( E )-3-(6-fluoroquinolin-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (( E )-3-( 6-Fluoroquinolin-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one)) (Compound 3c).

Analytical Example 1: ( E )-3-(6-Fluoroquinolin-2-yl)-1-phenylprop-2-en-1-one (Compound 3a):

Yield: 50% yellow solid. Melting point: 156.7-157.7 ° C. UV λ _max nm (log ε): 327 (4.23), 264 (4.67), 218 (4.69) in methanol. _{^{1 H NMR (400MHz, CDCl 3}} ): 7.45 (dd, 1H, J = 8.4,2.8Hz, Ar-H), 7.51-7.56 (m, 3H, Ar-H), 7.60-7.64 (m, 1H, Ar -H), 7.68 (d, 1H, J = 8.4 Hz), 7.93 (d, 1H, J = 15.6 Hz), 8.10-8.17 (m, 5H, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 110.61 (d, J = 22.0 Hz), 120.50 (d, J = 25.8 Hz), 122.20, 127.02, 128.71 (2C), 128.77 (2C), 128.83 (d, J = 9.7 Hz), 132.43 (d, J = 9.1 Hz), 133.12, 136.14 (d, J = 5.3 Hz), 137.78, 143.18, 145.50, 152.87 (d, J = 3.0 Hz), 160.95 (d, J = 248.7 Hz) ), 190.58. ESIMS [M+H] ⁺ :278. C ₁₈ H ₁₂ FNO. Analysis calculated for 0.5 H ₂ O: C 75.51, H 4.58, N 4.89; found: C 75.50, H 4.38, N 4.65.

Analysis Example 2: ( E )-1-(4-fluorophenyl)-3-(6-fluoroquinolin-2-yl)prop-2-en-1-one (Compound 3b)

Yield: 69% yellow solid. Melting point: 194.7-195.4 °C. UV λ _max nm (log ε): 327 (4.07), 263 (4.65), 218 (4.70) in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 7.18-7.24 (m, 2H, Ar-H), 7.45 (dd, 1H, J = 8.4, 2.8 Hz, Ar-H), 7.54 (ddd, 1H, J = 9.2 , 8.4, 2.8 Hz, Ar-H), 7.67 (d, 1H, J = 8.4 Hz, Ar-H), 7.93 (d, 1H, J = 15.6 Hz, CH=), 8.12-8.18 (m, 5H, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 110.66 (d, J = 21.9 Hz), 115.86 (2C, d, J = 21.3 Hz), 120.58 (d, J = 25.7 Hz), 122.37, 126.49, 128.91 (d, J = 9.8 Hz), 131.41 (2C, d, J = 9.8 Hz), 132.42 (d, J = 9.1 Hz), 134.12 (d, J = 2.8 Hz), 136.20 (d, J = 6.1 Hz), 143.28, 145.49, 152.66 (d, J = 3.1 Hz), 160.97 (d, J = 248.6 Hz), 165.82 (d, J = 253.1 Hz), 188.84. ESIMS [M+H] ⁺ :296. C ₁₈ H ₁₁ F ₂ NO. Analysis calculated for 0.4 H ₂ O: C 71.47, H 3.93, N 4.63; Found: C 71.57, H 3.96, N 4.65.

Analytical Example 3: ( E )-3-(6-Fluoroquinolin-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (Compound 3c):

Yield: 79% yellow solid. Melting point: 157.7-158.6 °C. UV λ _max nm (log ε): 333 (4.43), 264 (4.71), 218 (4.74) in MeOH in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 3.91 (s, 3H, OH H ₃ ), 7.01 (d, 2H, J = 8.8 Hz, Ar-H), 7.44 (dd, 1H, J = 8.8, 2.8 Hz, Ar-H), 7.52 (ddd, 1H, J = 9.2, 8.4, 2.8 Hz, Ar-H), 7.67 (d, 1H, J = 8.4 Hz, Ar-H), 7.92 (d, 1H, J =15.6) Hz, CH=), 8.12-8.19 (m, 5H, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 55.51, 110.62 (d, J = 21.9 Hz), 113.92 (2C), 120.43 (d, J = 25.7 Hz), 122.29, 126.92, 128.80 (d, J = 9.8 Hz) , 130.76, 131.14 (2C), 132.37 (d, J = 9.1 Hz), 136.09 (d, J = 5.3 Hz), 142.30, 145.48, 153.05 (d, J = 3.0 Hz), 160.87 (d, J = 248.7 Hz) ), 163.70, 188.66. ESIMS [M+H] ⁺ :308. C ₁₉ H ₁₄ FNO ₂ . Analysis calculated for 0.5 H ₂ O: C 72.14, H 4.78, N 4.43; found: C 72.15, H 4.51, N 4.18.

Synthesis Example 2: Preparation of pyrazolylquinoline compounds 4a-5c by cyclocondensation of quinoline chalcone compounds 3a-c and phenylhydrazine:

Please refer to the second figure for the treatment of ( E )-3-(6-fluoroquinolin-2-yl)-1-phenylprop-2-en-1-one (compound 3a) with phenylhydrazine followed by 2,3 -Dichloro-5,6-dicyanobenzoquinone (DDQ) is oxidized to give a yield of 21% of 6-fluoro-2-(1,5-diphenyl- hydrogen 1 - pyrazol-3-yl) quinoline (6-fluoro-2- (1,5 -diphenyl-1H-pyrazol-3-yl) quinoline) ( compound 4a), and 20% of 6-fluoro-2- (1,3-diphenyl-1 hydrogen-pyrazol-5-yl)-quinoline (6-Fluoro-2-(1,3-Diphenyl-1H-pyrazol-5-yl)-quinoline) (Compound 5a ). The procedure was benzoquinone (2.1 mmol) to quinolinyl chalcone compound 3a (2.1 mmol) in alcohol (10 ml), and the resulting solution was refluxed until the reaction was completed and monitored by TLC (approximately 18 hour). The solvent was evaporated in vacuo then EtOAc EtOAc (EtOAc) ×3) Extraction. The organic layer was collected, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, using dichloromethane/methanol (20:1) as solvent and recrystallized from methanol. The pyrazolylquinoline compounds 4a and 5a are obtained. Correspondingly, ( E )-1-(4-fluorophenyl)-3-(6-fluoroquinolin-2-yl)prop-2-en-1-one (compound 3b) under the same reaction conditions Pian with benzene to give 6-fluoro-2- [5- (4-fluorophenyl) -1-phenyl-1H - pyrazol-3-yl] quinoline (6-fluoro-2- [5- (4 -fluorophenyl) -1-phenyl-1 H -pyrazol-3-yl] quinoline) ( compound 4b) and 6-fluoro-2- [3- (4-fluorophenyl) -1-phenyl-1H - pyrazol a mixture of 6-Fluoro-2-[3-(4-fluorophenyl)-1-phenyl-1 H- pyrazol-5-yl]quinoline) (compound 5b) from ( E -3-(6-fluoroquinolin-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (compound 3c) with phenylhydrazine to give compound 6-fluoro-2- [5- (4-methoxyphenyl) -1-phenyl-1H - pyrazol-3-yl] quinoline (6-Fluoro-2- [5- (4-methoxyphenyl) -1-phenyl-1 H -pyrazol-3-yl] quinoline ) ( compound 4c) and 6-fluoro-2- [3- (4-methoxyphenyl) -1-phenyl-1H - pyrazol-5-yl] quinoline (6-Fluoro-2-[3-(4-methoxyphenyl)-1-phenyl-1 H- pyrazol-5-yl]quinoline) (Compound 5c). Compounds 4a, 4b and 4c have the formula of formula Ia; and compounds 5a, 5b and 5c have the formula of formula Ib.

Analytical Example 4: 6-Fluoro-2-(1,5-diphenyl- 1hydro -pyrazol-3-yl)quinoline (Compound 4a):

Compound 4a was obtained as a yellow solid in a yield of 21% (0.16 g). Melting point: 153.4-154.4 °C. UV λ _max nm (log ε): 331 (4.10), 260 (4.78), 218 (4.78) in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 7.33 - 7.51 (m, 13H, Ar-H), 8.14 - 8.17 (m, 2H, Ar-H), 8.30 (d, 1H, J = 8.8 Hz, Ar-H ). ¹³ C NMR (100 MHz, CDCl ₃ ): 106.83, 110.68 (d, J = 21.2 Hz), 119.55 (d, J = 25.0 Hz), 119.56, 125.41 (2C), 127.75, 128.34 (d, J = 10.6 Hz) , 128.39, 128.48 (2C), 128.77 (2C), 128.98 (2C), 130.33, 131.88 (d, J = 9.1 Hz), 135.77 (d, J = 5.3 Hz), 140.07, 144.87, 145.20, 151.62, 152.30, 160.30 (d, J = 246.3 Hz). ESIMS [M+H] ⁺ :366. C ₂₄ H ₁₆ FN ₃ . Analysis calculated for 0.1 H ₂ O: C 78.50, H 4.45, N 11.44; found: C 78.37, H 4.52, N 11.45.

Analysis Example 5: 6-fluoro-2-(1,3-diphenyl- 1hydro -pyrazol-5-yl)-quinoline) (Compound 5a):

Compound 5a was obtained as a pink solid in 20% (0.15 g). Melting point: 114.5-115.2 °C. UV λ _max nm (log ε): 258 (4.78), 219 (4.78) in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 7.25-7.30 (m, 2H, ar-H), 7.34-7.51 (m, 10H, ar-H), 7.96-8.01 (m, 4H, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 106.62, 110.57 (d, J = 22.0 Hz), 120.26 (d, J = 25.8 Hz), 121.87, 125.54 (2C), 125.88 (2C), 127.68 (d, J = 9.8 Hz), 127.80, 128.11, 128.65 (2C), 128.93 (2C), 133.14 (d, J = 9.1 Hz), 132.82, 135.55 (d, J = 5.3 Hz), 140.48, 143.56, 144.99, 148.81 (d, J = 3.0 Hz), 152.23, 160.77 (d, J = 247.8 Hz). ESIMS [M+H] ⁺ :366. C ₂₄ H ₁₆ FN ₃ . 0.1 H ₂ O Calcd: C 78.50, H 4.45, N 11.44; Found: C 78.22, H 4.54, N 11.37.

Analytical Example 6: 6-Fluoro-2-[5-(4-fluorophenyl)-1-phenyl- 1hydro -pyrazol-3-yl]quinoline (Compound 4b):

Compound 4b was obtained as a yellow solid in 22% (0.17 g). Melting point: 178.0-178.9 °C. UV λ _max nm (log ε): 330 (4.12), 259 (4.80), 219 (4.81) in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 7.01 - 7.06 (m, 2H, Ar-H), 7.27 - 7.51 (m, 10H, Ar-H), 8.13 - 8.17 (m, 2H, Ar-H), 8.29 (d, 1H, J = 9.2 Hz, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 106.81, 110.69 (d, J = 22.0 Hz), 115.65 (2C, d, J = 21.2 Hz), 119.50, 119.60 (d, J = 25.0 Hz), 125.41 (2C) , 126.45 (d, J = 2.8 Hz), 127.89, 128.36 (d, J = 9.8 Hz), 129.07 (2C), 130.59 (2C, d, J = 7.6 Hz), 131.86 (d, J = 9.1 Hz), 135.80 (d, J = 5.3 Hz), 139.87, 143.84, 145.18, 151.47 (d, J = 3.0 Hz), 152.34, 160.26 (d, J = 234.0 Hz), 162.33 (d, J = 234.1 Hz). ESIMS [M+H] ⁺ :384. C ₂₄ H ₁₅ F ₂ N ₃ . Analysis calculated for 0.1 H ₂ O: C 74.83, H 3.98, N 10.91; found: C 74.68, H 4.16, N 10.87.

Analytical Example 7: 6-Fluoro-2-[3-(4-fluorophenyl)-1-phenyl- 1hydro -pyrazol-5-yl]quinoline (Compound 5b):

Compound 5b was obtained as a yellow solid in 25% (0.19 g). Melting point: 68.8-69.8 °C. UV λ _max nm (log ε): 323 (4.07), 260 (4.81), 219 (4.81) in methanol. _{^{1 H NMR (400MHz, CDCl 3}} ): 7.11-7.15 (m, 2H, Ar-H), 7.20 (s, 1H), 7.34-7.52 (m, 8H, Ar-H), 7.92-8.01 (m, 4H , Ar-H), 8.00 (d, 2H, J = 8.4 Hz, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 106.38, 110.59 (d, J = 22.0 Hz), 115.59 (2C, d, J = 21.2 Hz), 120.33 (d, J = 25.0 Hz), 121.82, 125.51 (2C) , 127.57 (d, J = 9.8 Hz), 127.70 (2C, d, J = 9.9 Hz), 127.89, 128.98 (2C), 132.13 (d, J = 9.1 Hz), 135.59 (d, J = 6.0 Hz), 135.82 (d, J = 2.8 Hz), 140.36, 143.69, 144.99, 148.69 (d, J = 2.8 Hz), 151.36, 160.78 (d, J = 247.8 Hz), 162.82 (d, J = 244.7 Hz). ESIMS [M+H] ⁺ :384. C ₂₄ H ₁₅ F ₂ N ₃ . Analysis calculated for 0.1 H ₂ O: C 74.83, H 3.98, N 10.91; found: C 74.99, H 4.33, N 10.61.

Analytical Example 8: 6-Fluoro-2-[5-(4-methoxyphenyl)-1-phenyl- 1hydro -pyrazol-3-yl]quinoline) (Compound 4c):

Compound 4c was obtained in a yield of 23% (0.18 g) as a white solid. Melting point: 175.3-176.0 ° C. UV λ _max nm (log ε): 331 (4.12), 261 (4.81), 219 (4.81) in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 3.82 (s, 3H, OH H ₃ ), 6.86 (d, 2H, J = 8.8 Hz, ArH), 7.25 (d, 2H, J = 8.8 Hz, Ar-H) , 7.30 (s, 1H), 7.32 - 7.51 (m, 7H, Ar-H), 8.13-8.17 (m, 2H, Ar-H), 8.29 (d, 1H, J = 8.4 Hz, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 55.25, 106.28, 110.67 (d, J = 22.0 Hz), 113.93 (2C), 119.52 (d, J = 25.7 Hz), 119.57, 122.73, 125.41 (2C), 127.66, 128.32 (d, J = 9.1 Hz), 128.96 (2C), 130.07 (2C), 131.86 (d, J = 9.1 Hz), 135.73 (d, J = 5.3 Hz), 140.18, 144.73, 145.19, 151.71 (d, J = 2.3 Hz), 152.19, 159.63, 160.28 (d, J = 246.2 Hz). ESIMS [M+H] ⁺ : 396. C ₂₅ H ₁₈ FN ₃ O Calcd: C 75.93, H 4.59, N 10.63; Found: C 75.63, H 4.61, N 10.96.

Analytical Example 9: 6-Fluoro-2-[3-(4-methoxyphenyl)-1-phenyl- 1hydro -pyrazol-5-yl]quinoline (Compound 5c):

Compound 5c was obtained as a white solid in 40% (0.32 g). Melting point: 142.8-143.5 °C. UV λ _max nm (log ε): 260 (4.81), 219 (4.82) in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 3.86 (s, 3H, OC H ₃ ), 6.98 (d, 2H, J = 8.8 Hz, Ar-H), 7.18 (s, 1H), 7.27 (d, 1H, J = 9.2 Hz, Ar-H), 7.33 - 7.51 (m, 7H, Ar-H), 7.89 (d, 2H, J = 8.8 Hz, Ar-H), 7.98 - 8.01 (m, 2H, ArH). ¹³ C NMR (100 MHz, CDCl ₃ ): 55.31, 106.22, 110.57 (d, J = 21.9 Hz), 114.06 (2C), 120.24 (d, J = 25.7 Hz), 121.90, 125.51 (2C), 125.59, 127.16 ( 2C), 127.61, 127.70, 128.92 (2C), 132.13 (d, J = 9.1 Hz), 135.51 (d, J = 5.3 Hz), 140.49, 143.46, 144.99, 148.90 (d, J = 3.1 Hz), 152.08, 159.67, 160.74 (d, J = 247.8 Hz). ESIMS [M+H] ⁺ : 396. C ₂₅ H ₁₈ FN ₃ O Calcd: C 75.93, H 4.59, N 10.63; Found: C 75.95, H 4.61, N 10.83.

Synthesis Example 3: Cyclization of condensed quinolinyl chalcone compounds 3a-c and 4-substituted Preparation of pyrazolylquinoline compound 6a-8c from phenylhydrazine:

Please refer to the second figure to reflux ( E )-3-(6-fluoroquinolin-2-yl)-1-phenylprop-2-en-1-one with 4-fluorophenylhydrazine 3a) Exclusively obtained the single product 6-fluoro-2-[1-(4-fluorophenyl)-3-phenyl- 1hydro -pyrazol-5-yl]quinoline (6-Fluoro-2-[1 -(4-fluorophenyl)-3-phenyl-1 H- pyrazol-5-yl]quinoline) (6a). The procedure was the addition of 4-fluorophenylhydrazine (2.1 mmol) to the quinolinyl chalcone compound 3a (2 mmol) in alcohol (10 mL). The resulting solution was refluxed until the reaction was completed and was monitored by TLC (about 12 hours). The solvent was evaporated in vacuo and purified by flash chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) Correspondingly, ( E )-1-(4-fluorophenyl)-3-(6-fluoroquinolin-2-yl)prop-2-en-1-one (compound 3b) under the same reaction conditions And ( E )-3-(6-fluoroquinolin-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (compound 3c) and 4-fluorophenylhydrazine give 6 - fluoro-2- [1,3-bis (4-fluorophenyl) -1H-- pyrazol-5-yl] quinoline (6-fluoro-2- [1,3 -bis (4-fluorophenyl) - 1 H -pyrazol-5-yl]quinoline) (Compound 6b) and 6-fluoro-2-(1-(4-fluorophenyl)-3-(4-methoxyphenyl)-1 hydrogen -pyrazole- 5-(6-Fluoro-2-(1-(4-fluorophenyl)-3-(4-methoxyphenyl)-1 H- pyrazol-5-yl)quinoline) (Compound 6c). Reducing compound 3a with 4-methoxyphenylhydrazine to give a single product, 6-fluoro-2-[1-(4-methoxyphenyl)-3-phenyl-1 hydrogen -pyrazole, exclusively -5-yl]quinoline (6-Fluoro-2-[1-(4-methoxyphenyl)-3-phenyl-1H-pyrazol-5-yl]quinoline) (7a). 6-fluoro-2-[3-(4-fluorophenyl)-1-(4-methoxyphenyl)-1 was obtained from compounds 3b and 3c and 4-methoxyphenylhydrazine under the same reaction conditions. Hydrogen -pyrazol-5-yl]quinoline (6-Fluoro-2-[3-(4-fluorophenyl)-1-(4-methoxyphenyl)-1 H- pyrazol-5-yl]quinoline) (Compound 7b) and 6-fluoro-2- [1,3-bis (4-methoxyphenyl) -1H-- pyrazol-5-yl] quinoline (6-fluoro-2- [1,3 -bis (4- Methoxyphenyl)-1 H -pyrazol-5-yl]quinoline) (Compound 7c). Compound 3a was refluxed with 4-sulfazinobenzenesulfonamide to give a single product 4-[5-(6-fluoroquinolin-2-yl)-3-phenyl-1 hydrogen -pyrazole- 1-[5-(6-Fluoroquinolin-2-yl)-3-phenyl-1 H- pyrazol-1-yl]benzenesulfonamide) (8a). 4-[3-(4-Fluorophenyl)-5-(6-fluoroquinolin-2-yl)-1 hydrogen was obtained from compounds 8b and 8c and 4-sulfonamidophenylhydrazine under the same reaction conditions. -pyrazol-1-yl]benzenesulfonamide (Compound 8b) and 4-[5-(6-fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 hydrogen -pyrazole 4-[5-(6-Fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 H- pyrazol-1-yl]benzenesulfonamide) (Compound 8c). Compounds 6a-8c have the formula of formula Ib.

Analytical Example 10: 6-Fluoro-2-[1-(4-fluorophenyl)-3-phenyl- 1hydro -pyrazol-5-yl]quinoline (Compound 6a):

Yield 29% as a yellow solid. Melting point: 151.2-152.8 °C. UV λ _max nm (log ε): 323 (4.17), 246 (4.59) 222 (4.52) in methanol. _{^{1 H NMR (400MHz, CDCl 3}} ): 7.05-7.10 (m, 2H, Ar-H), 7.23 (s, 1H), 7.35-7.51 (m, 8H, Ar-H), 7.92-7.96 (m, 3H , Ar-H), 8.04 (d, 1H, J = 8.4 Hz, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 106.45, 110.60 (d, J = 22.0 Hz), 115.73 (2C, d, J = 22.7 Hz), 120.39 (d, J = 25.8 Hz), 121.66, 125.88 (2C) , 127.47 (d, J = 8.3 Hz), 127.69 (d, J = 9.9 Hz), 128.21, 128.70 (2C), 132.12 (2C, d, J = 9.1 Hz), 132.69, 135.76, 136.87, 143.56, 144.92, 148.48,152.26,160.83 (d, J = 247.9Hz) , 161.92 (d, J = 245.7Hz). ESIMS [M+H] ⁺ :384. Analysis Calculated for C ₂₄ H ₁₅ F ₂ N ₃ of: C 75.19, H 3.94, N 10.96; Found: C 75.30, H 3.63, N 10.87.

: - quinoline (Compound 6b) 6- Fluoro-2- [pyrazol-5-yl 1,3-bis (4-fluorophenyl) -1H-]: Analysis Example 11

Yield 28% as a yellow solid. Melting point: 188.2-189.8 ° C. UV λ _max nm (log ε): 326 (4.08), 262 (4.61) 220 (4.51) in MeOH in methanol. _{^{1 H NMR (400MHz, CDCl 3}} ): 7.06-7.16 (m, 4H, ArH), 7.18 (s, 1H), 7.35 (d, 1H, J = 8.8Hz, ArH), 7.40-7.52 (m, 4H, ArH), 7.90-7.96 (m, 3H, Ar-H), 8.04 (d, 1H, J = 8.8 Hz, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 106.23, 110.61 (d, J = 21.9 Hz), 115.64 (2C, d, J = 21.3 Hz), 115.78 (2C, d, J = 22.7 Hz), 120.45 (d, J = 25.7Hz), 121.61,127.39 (2C , d, J = 9.1Hz), 127.55 (2C, d, J = 8.4Hz), 127.69 (d, J = 10.6Hz), 128.87 (d, J = 3.1Hz ), 132.08 (d, J = 9.1 Hz), 135.83 (d, J = 5.3 Hz), 136.67 (d, J = 3.0 Hz), 143.65, 144.88, 148.29 (d, J = 3.1 Hz), 151.35, 160.82 ( d, J = 247.8 Hz), 161.91 (d, J = 246.3 Hz), 162.84 (d, J = 245.6 Hz). ESIMS [M+H] ⁺ :402. Analysis Calculated for C ₂₄ H ₁₄ F ₃ N ₃ of: C 71.82, H 3.52, N 10.47; Found: C 71.98, H 3.21, N 10.40.

Analysis of Example 12: 6-fluoro-2- (1- (4-fluorophenyl) -3- (4-methoxyphenyl) -1H-- pyrazol-5-yl) quinoline) (Compound 6C):

Yield 29% as a yellow solid. Melting point: 180.4-181.6 °C. UV λ _max nm (log ε): 326 (4.17), 262 (4.62), 221 (4.51) in methanol. _{^{1 H NMR (400MHz, CDCl 3}} ): 3.86 (s, 3H, OC H 3), 6.96-7.10 (m, 4H, Ar-H), 7.16 (s, 1H), 7.35 (d, 1H, J = 8.8 Hz, Ar-H), 7.39-7.51 (m, 4H, Ar-H), 7.86-7.89 (m, 2H, Ar-H), 7.94 (dd, 1H, J = 9.2, 5.2 Hz, Ar-H) , 8.03 (d, 1H, J = 8.4 Hz, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 55.31, 106.05, 110.59 (d, J = 21.2 Hz), 114.07 (2C), 115.72 (2C, d, J = 22.7 Hz), 120.36 (d, J = 25.9 Hz) , 121.68, 125.39, 127.13 (2C), 127.39 (2C, d, J = 9.1 Hz), 127.65 (d, J = 9.9 Hz), 132.08 (d, J = 9.1 Hz), 135.74 (d, J = 5.3 Hz) ), 136.80 (d, J = 3.1 Hz), 143.44, 144.88, 148.51 (d, J = 3.0 Hz), 152.07, 159.71, 160.77 (d, J = 247.8 Hz), 161.82 (d, J = 246.3 Hz). ESIMS [M+H] ⁺ :414. _{C 25 H 17 F 2 N 3} O Calcd: C 72.63, H 4.14, N 10.16; Found: C 72.86, H 4.23, N 9.94.

Analytical Example 13: 6-Fluoro-2-[1-(4-methoxyphenyl)-3-phenyl- 1hydro -pyrazol-5-yl]quinoline (Compound 7a):

Yield 18% as a brown solid. Melting point: 203.6-204.5 °C. UV λ _max nm (log ε): 258 (4.72), 215 (4.81) in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 3.83 (s, 3H, OC H ₃ ), 6.88-6.91 (m, 2H, Ar-H), 7.25-7.27 (m, 2H, Ar-H), 7.33-7.53 (m, 7H, Ar-H), 7.95-8.05 (m, 4H, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 55.52, 106.17, 110.55 (d, J = 21.9 Hz), 114.11 (2C), 120.24 (d, J = 25.0 Hz), 121.80, 125.84 (2C), 126.95 (2C) , 127.63 (d, J = 9.9 Hz), 128.01, 128.63 (2C), 132.12 (d, J = 9.1 Hz), 132.89, 133.67, 135.51 (d, J = 5.3 Hz), 143.56, 144.98, 148.83 (d, J = 3.0 Hz), 151.91, 159.15, 160.73 (d, J = 247.8 Hz). ESIMS [M+H] ⁺ : 396. C ₂₅ H ₁₈ FN ₃ O. Analysis calculated for 0.1 H ₂ O: C 75.59, H 4.62, N 10.58; found: C 75.49, H 4.47, N 10.54.

Analysis of Example 14: 6-fluoro-2- [3- (4-fluorophenyl) -1- (4-methoxyphenyl) -1H-- pyrazol-5-yl] quinoline (Compound 7B):

Yield 19% as a brown solid. Melting point: 167.5-168.3 ° C. UV λ _max nm (log ε): 259 (4.84), 219 (4.84) in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 3.83 (s, 3H, OC H ₃ ), 6.88-6.92 (m, 2H, ar-H), 7.10-7.15 (m, 2H, Ar-H), 7.19 (s , 1H, Ar-H), 7.24 (d, 1H, J = 8.8 Hz, Ar-H), 7.33 - 7.36 (m, 2H, Ar-H), 7.40 (dd, 1H, J = 8.8, 2.8 Hz, Ar-H), 7.47-7.52 (m, 1H, Ar-H), 7.90-7.94 (m, 2H, Ar-H), 7.98 (d, 1H, J = 8.8 Hz, Ar-H), 8.03 (dd , 1H, J = 9.2, 5.6 Hz, Ar-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 55.53, 105.91 (d, J = 22.0 Hz), 114.15 (2C), 114.19, 115.55 (d, J = 22.0 Hz), 120.28 (d, J = 25.7 Hz), 121.74 , 126.91 (2C), 127.52 (2C, d, J = 8.4 Hz), 127.65 (d, J = 9.9 Hz), 129.13 (d, J = 3.0 Hz), 132.13 (d, J = 9.1 Hz), 133.55, 135.53 (d, J = 5.3 Hz), 143.72, 144.99, 148.71 (d, J = 3.0 Hz), 151.03, 159.20, 160.75 (d, J = 247.8 Hz), 162.76 (d, J = 245.5 Hz). ESIMS [M+H] ⁺ :414. C ₂₅ H ₁₇ F ₂ N ₃ O. Analysis calculated for 0.2 H ₂ O: C 72.00, H 4.21., N 10.08. Found: C 71.90, H 4.33, N 9.79.

Analysis of Example 15: 6-Fluoro-2- [1,3-bis (4-methoxyphenyl) -1H-- pyrazol-5-yl] quinoline (Compound 7C):

Yield 22% as a brown solid. Melting point: 63.5-63.9 ° C. UV λ _max nm (log ε): 261 (4.85), 218 (4.86) in methanol. ¹ H NMR (400 MHz, CDCl ₃ ): 3.83 (s, 3H, OC H ₃ ), 3.86 (s, 3H, OC H ₃ ), 6.88-6.90 (m, 2H, Ar-H), 6.96-6.99 (m , 2H, Ar-H), 7.17 (s, 1H, Ar-H), 7.25 (d, 1H, J = 8.8 Hz, Ar-H), 7.334-7.37 (m, 2H, Ar-H), 7.40 ( Dd,1H, J = 8.8, 2.8 Hz, Ar-H), 7.47-7.52 (m, 1H, Ar-H), 7.88-7.90 (m, 2H, Ar-H), 7.98 (d, 1H, J = 8.8 Hz, Ar-H), 8.03 (dd, 1H, J = 8.8, 5.2 Hz, Ar-H). _{^{13 C NMR (100MHz, CDCl 3}} ): 55.30,55.53,105.71,110.54 (d, J = 22.0Hz), 114.04 (2C), 114.11 (2C), 120.19 (d, J = 25.0Hz), 121.82,125.71, 126.94(2C), 127.12(2C), 127.58 (d, J = 9.8 Hz), 132.15 (d, J = 9.1 Hz), 133.75, 135.45 (d, J = 5.3 Hz), 143.53, 145.03, 148.96, 151.78, 159.10, 159.60, 160.72 (d, J = 247.9 Hz). ESIMS [M+H] ⁺ : 426. C ₂₆ H ₂₀ FN ₃ O ₂ Calcd: C 73.40, H 4.74, N 9.88; Found: C 73.29, H 4.95, N 9.84.

Analytical Example 16: 4-[5-(6-Fluoroquinolin-2-yl)-3-phenyl- 1hydro -pyrazol-1-yl]benzenesulfonamide (Compound 8a):

The yield was 25% and was a brown solid. Melting point: 244.5~245.3 °C. UV λ _max nm (log ε): 260 (4.86), 219 (4.86) in methanol. ^{1 H NMR (400MHz, DMSO- d} 6): 7.39-7.44 (m, 1H, Ar-H), 7.49-7.52 (m, 4H, Ar-H), 7.61-7.75 (m, 5H, Ar-H) , 7.82-7.89 (m, 4H, Ar-H), 7.99-8.01 (m, 2H, ar-H), 8.46 (d, 1H, J = 8.4 Hz, Ar-H). ¹³ C NMR (100 MHz, DMSO- d ₆ ): 107.58, 111.11 (d, J = 22.0 Hz), 120.37 (d, J = 25.8 Hz), 121.94, 125.53 (2C), 125.70 (2C), 126.27 (2C) , 127.67 (d, J = 9.8 Hz), 128.45, 128.88 (2C), 131.62 (d, J = 9.1 Hz), 132.12, 136.74 (d, J = 5.3 Hz), 142.90, 142.95, 143.29, 144.02, 147.97 ( d, J = 2.3 Hz), 151.65, 160.24 (d, J = 244.8 Hz). ESIMS [M+H] ⁺ :445. Analysis Calculated for C ₂₄ H ₁₇ FN ₄ O ₂ S of: C 64.85, H 3.86, N 12.60; Found: C 64.60, H 3.94, N 12.45.

17 cases: 4- [3- (4-fluorophenyl) -5- (6-fluoro-quinolin-2-yl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (compound 8B):

The yield was 28% and was a green solid. Melting point: 236.5-237.7 °C. UV λ _max nm (log ε): 332 (4.10), 260 (4.61), 224 (4.52) in methanol. ^{1 H NMR (400MHz, DMSO- d} 6): 7.32-7.37 (m, 2H, Ar-H), 7.49 (s, 2H, N H 2), 7.60-7.75 (m, 5H, Ar-H), 7.82 -7.88 (m, 4H, Ar-H), 8.02 - 8.05 (m, 2H, Ar-H), 8.46 (d, 1H, J = 8.8 Hz, Ar-H). ¹³ C NMR (100 MHz, DMSO- d ₆ ): 107.50, 111.10 (d, J = 22.0 Hz), 115.79 (2C, d, J = 21.3 Hz), 120.38 (d, J = 25.8 Hz), 121.90, 125.68 ( 2C), 126.27 (2C), 127.59 (2C, d, J = 8.3 Hz), 127.67 (d, J = 9.1 Hz), 128.70 (d, J = 3.0 Hz), 131.61 (d, J = 9.8 Hz), 136.74 (d, J = 5.3 Hz), 142.87, 142.93, 143.37, 144.01, 147.92, 150.76, 160.04 (d, J = 244.8 Hz), 162.25 (d, J = 244.0 Hz). ESIMS [M+H] ⁺ : 463. C ₂₄ H ₁₆ F ₂ N ₄ O ₂ S. Analysis calculated for 0.5 H ₂ O: C 61.14, H 3.63, N 11.88; found: C 61.43, H 3.40, N 11.76.

Analysis of Example 18: 4- [5- (6-fluoro-quinolin-2-yl) -3- (4-methoxyphenyl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (compound 8c) :

The yield was 23% as a yellow solid. Melting point: 233.1-2234 ° C. UV λ _max nm (log ε): 262 (4.89), 219 (4.89) in methanol. ¹ H NMR (400 MHz, DMSO- d ₆ ): 3.37 (s, 3H, OH H ₃ ), 7.05-7.07 (m, 2H, Ar-H), 7.49 (s, 2H, N H ₂ ), 7.58-7.76 (m, 5H, Ar-H), 7.82-7.93 (m, 6H, Ar-H), 8.46 (d, 1H, J = 8.8 Hz, Ar-H). ¹³ C NMR (100 MHz, DMSO- d ₆ ): 55.20, 107.21, 111.11 (d, J = 22.0 Hz), 114.27 (2C), 120.36 (d, J = 25.7 Hz), 121.95, 124.70, 125.58 (2C), 126.27(2C), 126.92(2C), 127.66(d, J = 11.3Hz), 131.63(d, J = 9.9Hz), 136.71(d, J = 5.3Hz), 142.73, 143.00, 143.18, 144.05, 148.09 ( d, J = 3.0 Hz), 151.59, 159.52, 160.04 (d, J = 244.8 Hz). ESIMS [M+H] ⁺ : 475. C ₂₅ H ₁₉ FN ₄ O ₃ S. Analysis calculated for 0.5 H ₂ O: C 62.10, H 4.17, N 11.59; found: C 61.72, H 3.85, N 11.51.

In the analysis example of the present invention, the melting point was measured by an electrothermal IA9100 melting point apparatus. Infrared light spectra were measured using a Perkin Elmer System-2000 spectrometer (Perkin Elmer System-2000 spectrometer). The UV spectrum was recorded on a UV-160A UV-vis spectrophometer in a spectral grade of MeOH. Nuclear magnetic resonance ( ¹ H and ¹³ C) were recorded on a Varian Gemini 200 spectrometer or a Varian-Unity-400 spectrometer. Chemical shifts are expressed in parts per million (δ) and tetramethylsilane (TMS) is used as an internal standard. Thin layer chromatography was carried out on a silica gel 60 F-254 plate purchased from E. Merck and Co. Mass spectra were recorded on a Bruker APEX II (ESI) mass spectrometer (Bruker APEX II (ESI) mass spectrometer). Elemental analysis was performed using EA's Heraeus CHN-O-RAPID Elemental Analyzer (Heraeus CHN-O Rapid EA) at the National Science Council and National Taiwan University National Science Council Instrument Center, and all values were theoretically ±0.4 Less than %.

In the experimental example of the present invention, the compound was dissolved in 10 mM DMSO, followed by dilution with a medium. Human liver cancer Huh-7 cells were purchased from the Bioresources Collection and Research Center. Huh-7-DV-Fluc cells and C6/36 cells were provided by Dr. Wu Huinan from the Institute of Molecular Biology, Academia Sinica. DENV-2 strain 16681 was isolated from a Thai patient with hemorrhagic dengue fever and expanded in C6/36 mosquito cells.

Experimental Example 1: 6-Fluoro-2-[5-(4-methoxyphenyl)-1-phenyl- 1hydro -pyrazol-3-yl]quinoline) (Compound 4c) and 6-Fluoro-2 -Structural determination of [3-(4-methoxyphenyl)-1-phenyl-1 hydrogen -pyrazol-5-yl]quinoline (Compound 5c):

Referring to the third figure, the structures of the compound 4c and the compound 5c were determined by X-ray crystallographic analysis. The structure by the method Shelx 97 ⁴² Program group (Shelx 97 ⁴² suite ^of programs) parsing (Solve) and finishing (refine). A white single crystal of compound 4c was obtained by slow evaporation from a methanol/dichloromethane (30/70) solution: triclinic, space group P-1, a = 6.262(3) Å, b = 11.961 (5) Å , c = 13.502 (6) Å, α = 68.380 (11) °, β = 87.617 (13) °, γ = 83.998 (12) °, V = 935.0 (8) Å ³ , Z = 2, δ (calcd) =1.405Mg.m ^-3 , C ₂₅ H ₁₈ FN3O FW=395.42, F (000)=412. Complete crystallographic data for structural analysis has been deposited at the Cambridge Crystallographic Data Centre and compound 4c is CCDC 1054761. A white single crystal of compound 5c was obtained by slow evaporation from a methanol/dichloromethane (30/70) solution: monoclinic system, space group P21/c, a = 12.8551 (14) Å, b = 14.15552 (15) Å , c =10.8351(13)Å, α=90°, β=98.879(2)°, γ=90°, V =1948.0(4)Å ³ , Z=4, δ(calcd)=1.348Mg.m ^{- 3} , C ₂₅ H ₁₈ FN3O FW = 395.42 for, F (000) = 824. Complete crystallographic data for structural analysis has been deposited at the Cambridge Crystallography Data Center and compound 5c is CCDC 1054760. A copy of this information is available from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK, fax: +44-1223-336033, e-mail: deposit@ccdc.cam.ac.uk , www.ccdc.cam.ac.uk) Get it for free.

Experimental Example 2: Cytotoxicity analysis:

See Table 2, cytotoxicity assay starting density of 5x10 ³ Huh-7 cells/well in maintenance medium, with or without sequence dilution (20 and 200 μM) of compounds 4a-8c. After 3 days, 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2 H -tetrazole-5 was added to the humidified CO ₂ (5%) atmosphere at 37 ° C. - Determination of cell viability anilino-formyl (2,3-bis [2-methyloxy -4-nitro-5-sulfophenyl] -2 H -tetrazolium-5-carboxanilide, XTT) method. Results Compounds 6C, 7c and 8c showed low cytotoxicity with a survival rate of greater than 50% at a concentration of 200 μM.

Experimental Example 3: Analysis of anti-DENV-2 virus:

Referring to Table 2, Huh-7-DV-Fluc cells were seeded at a density of 2×10 ⁴ cells/well in 24-well plates and treated with two concentrations (1 and 10 μM) of compound 4a-8c as negative controls. The group was treated with 0.1% DMSO or ribavirin as a positive control group. After three days of culture, luciferase activity assays were performed using the Bright-Glo Luciferase Assay System (Promega) according to the manufacturer's instructions.

A compound exhibiting >32% inhibition of DENV-2 at a concentration of 10 μM was considered to be active. The results in Table 2 indicate that Compound 4a showed 15% inhibition of DENV-2 at a concentration of 10 μM, which was more active than the fluorine-substituted counterpart 4b and the methoxy-substituted counterpart 4c. Compound 4a is also more active than its positional isomer 5a. However, Compound 5b showed 25% inhibition of DENV-2 at a concentration of 10 μM, which was more active than its positional isomer 4b. Introduction of a 4-methoxy or 4-sulfonamide group to the N-1 phenyl ring promotes activity against DENV-2, compounds 7a and 8a are more active than compound 5a, while compounds 7c and 8c are more potent than compounds. 5c is more active. However, compound 5b is more active against DENV-2 than 7a and 8a. Among these compounds, compounds 6c, 7c, and 8c were the most active, showing 55%, 65%, and 85% inhibition of DENV-2 replication in Huh-7-DV-Fluc cells at a concentration of 10 μM, respectively, while the positive control group Ribavirin showed only 33% inhibition.

Table 2 Antiviral activity and cytotoxicity of pyrazolylquinoline compound 4a-8c

Experimental Example 4: 50% inhibition concentration of DENV-2 replication of compounds 6c, 7c and 8c (IC ₅₀ ), 50% cytotoxic concentration of cell growth (CC) ₅₀ And selectivity index (SI: CC) ₅₀ /IC ₅₀ ):

See Table 3, Compounds 6c, 7c, and 8c for inhibition of DENV-2 replication by 50% inhibitory concentration (IC ₅₀ ), inhibition of uninfected Huh-7 cell growth by 50% cytotoxicity (CC ₅₀ ), and selectivity index (selectivity index, SI: CC ₅₀ /IC ₅₀ ) was determined and listed in Table 3. The results indicated that compounds 6c, 7c and 8c (IC ₅₀ of 1.36, 1.0 and 0.81 μM, respectively) showed an anti-DENV-2 activity about 10 times higher than that of ribavirin (IC ₅₀ of 12.61 μM), and they were respectively greater than The SI values of 147, 183 and 247 were higher than ribavirin (SI 4.47) and had good selectivity.

Experimental Example 5: DENV-2 infection:

Huh-7 cells were seeded at a density of 4 x 10 ⁴ cells/well in 24-well plates for 16-20 hours, and then infected with 0.1 MOI of DENV-2 (16681 virus strain) for 2 hours at 37 °C. The cells were washed once with PBS and then re-added to DMEM plus 2% FBS medium containing various indicated concentrations of 8c.

Experimental Example 6: Compound 8c reduces DENV-2 infection in Huh-7 cells Copy of DENV-2:

In order to confirm that the luciferase activity in Huh-7-DV-Fluc cells dose-dependently reduced the decrease in DENV-2 replication, specific antibodies were used and specific antibodies against NS2B protein against DENV-2 were used. Transcriptase-instant quantitative polymerase chain reaction (RT-qPCR) and western blotting method, in which the endogenous reference gene glyceraldehydes-3-phosphate dehydrogenase (GAPDH) is used as Control group (loading control).

After three days of treatment with compound 8c in RT-qPCR, Total RNA was extracted by Total RNA Miniprep Purification Kit (GMbiolab, Taiwan) according to the manufacturer's instructions. The mRNA expression of NS5 of DENV was determined by quantitative real-time PCR using a specific primer corresponding to the NS gene of DENV, forward primer: 5-AAG GTG AGA AGC AAT GCA GC-3 (SEQ ID NO: 1); Primer: 5-CCA CTC AGG GAG TTC TCT CT-3 (SEQ ID NO: 2). The NS5 copy number of each sample was normalized with GAPDH, forward primer: 5-GTC TTC ACC ACC ATG GAG AA-3 (SEQ ID NO: 3); reverse primer: 5-ATG GCA TGG ACT GTG GTC AT-3 (SEQ ID NO: 4). The CT value of each sample was determined by ABI Step One Real-Time PCR-System (ABI Warrington, UK).

In the western blotting method, the membrane is an anti-NS2B rabbit polyclonal antibody (1:3000) (Genetex, Irvine, CA, USA) and GAPDH (1:10000) (Genetex, as a control group). Irvine, CA, USA) culture overnight.

Please refer to the fourth and fifth figures. The results of reverse transcriptase-instant quantitative polymerase chain reaction and Western blotting showed that after 8 days of treatment, compound 8c was reduced. Replication of dengue virus in Huh-7-DV-Fluc cells. In the inhibition of DENV-2 replication, treatment with 0.1% DMSO was used as a mock control.

Experimental Example 7: Analysis of anti-DENV-2 activity in vivo:

Please refer to Figure 6 (a), Figure 6 (b) and Figure 6 (c). In order to investigate whether compound 8c exerts protective effects against dengue virus infection in vivo, six-day-old ICR lactating mice were randomized. Divided into 3 groups (n=5/group): Group 1: Intracerebral injection of 2.5× ^{10 5} PFU heat-inactivated DENV-2 (iDENV) at 60 ° C (as a simulated control group). Group 2: Intracerebral injection of 2.5 x ^{10 5} PFU of DENV-2 virus + intraperitoneal injection of physiological saline (DENV). Group 3; intracerebral injection of 2.5x10 ⁵ PFU virus + DENV-2, 5, 10 and 20 mg intraperitoneal injection / kg of compound 8c. Mice were given physiological saline, 1, 5, 10 and 20 mg/kg of compound 8c by intraperitoneal injection 1, 3, 5 days after infection (DPI). Survival, body weight and clinical scores were measured daily after DENV-2 injection for a total of 6 days. . Disease symptom scores were as follows: 0 asymptomatic; 1 mild weight loss and disordered hair; 2 activity slowed; 3 weak; 4 paralysis and mortally ill causing death; 5 death. Results are expressed as mean ± SD. Differences in mean values between groups were analyzed by analysis of variance (ANOVA) and Student's t-test. The septic shock analysis used a log-rank test. Statistical significance was evaluated as p < 0.05 [* P <0.05; ** P < 0.01].

Referring to Figure 6 (a), Figure 6 (b), and Figure 6 (c), mice infected with DENV-2 without Compound 8c were infected with infection in mice infected with iDENV. After 6 days (dpi) develop into a serious disease leading to death. In contrast, various concentrations of Compound 8c protected mice from the life-threatening effects of DENV-2 infection compared to mice not treated with Compound 8c. DENV-2 infected mice that did not receive Compound 8c showed severe paralysis, anorexia, and weakness compared to control group mice infected with iDENV 6 days after infection (dpi). Conversely, after 6 days of infection Post-dpi (dpi) mice infected with compound 8c infected with DENV-2 showed only mild paralysis, anorexia and weakness compared to control group mice infected with iDENV.

Example

A pyrazolylquinoline compound comprising: a quinolinyl group, a C6 position bonded to a substituent R ₁ , and R ₁ is a halogen atom; a pyrazolyl group; a first phenyl group; and a second a phenyl group, wherein: the C2 position of the quinolyl group is bonded to the C3 or C5 position of the pyrazolyl group; when in the first case, the C2 position of the quinolyl group is bonded to the C3 position of the pyrazolyl group, a C5 position of the pyrazolyl group attached to the C4 position of the first phenyl group; and when in the second case, the C2 position of the quinolyl group is attached to the C5 position of the pyrazolyl group, the C3 position of the pyrazolyl group Attached to the C4 position of the first phenyl group; and the N1 position of the pyrazole group is linked to the C4 position of the second phenyl group.

2. The pyrazolylquinoline compound according to embodiment 1, wherein the C1 position of the first phenyl group is bonded to a substituent R ₂ and R ₂ is a hydrogen atom, a halogen atom or an alkoxy group; The C1 position of the group is bonded to a substituent R ₃ and R ₃ is a hydrogen atom, a halogen atom, an alkoxy group or a sulfonamide group.

3. The pyrazolylquinoline compound according to the embodiment 1-2, wherein R ₁ is a fluorine atom, R ₂ is a hydrogen atom, a fluorine atom or a methoxy group, and R ₃ is a hydrogen atom, a fluorine atom or a methoxy group. Base or sulfonamide group.

4. The pyrazolylquinoline compound of any of embodiments 1-3, wherein the pyrazolylquinoline compound is selected from the group consisting of 6-fluoro-2-(1,5-diphenyl) -1- hydrogen -pyrazol-3-yl)quinoline (6-Fluoro-2-(1,5-diphenyl-1H-pyrazol-3-yl)quinoline), 6-fluoro-2-[5-(4 - fluorophenyl) -1-phenyl-1H - pyrazol-3-yl] quinoline (6-fluoro-2- [5- (4-fluorophenyl) -1-phenyl-1 H -pyrazol-3- Yl]quinoline), 6-fluoro-2-[5-(4-methoxyphenyl)-1-phenyl- 1hydro -pyrazol-3-yl]quinoline (6-Fluoro-2-[5- (4-methoxyphenyl) -1-phenyl -1 H -pyrazol-3-yl] quinoline), 6- fluoro-2- (1,3-diphenyl-1H - pyrazol-5-yl) - quinoline (6-Fluoro-2-(1,3-Diphenyl-1H-pyrazol-5-yl)-quinoline), 6-fluoro-2-[3-(4-fluorophenyl)-1-phenyl-1 hydrogen -6-Fluoro-2-[3-(4-fluorophenyl)-1-phenyl-1 H- pyrazol-5-yl]quinoline), 6-fluoro-2-[3 - (4-methoxyphenyl) -1-phenyl-1H - pyrazol-5-yl] quinoline (6-Fluoro-2- [3- (4-methoxyphenyl) -1-phenyl-1 H - pyrazol-5-yl] quinoline) , 6- fluoro-2- [1- (4-fluorophenyl) -3-phenyl-1H - pyrazol-5-yl] quinoline (6-fluoro-2- [1-(4-fluorophenyl)-3-phenyl-1 H -pyrazol-5-yl]quinoline), 6- Fluoro-2- [1,3-bis (4-fluorophenyl) -1H-- pyrazol-5-yl] quinoline (6-Fluoro-2- [1,3 -Bis (4-fluorophenyl) -1 H -pyrazol-5-yl] quinoline ), 6- fluoro-2- (1- (4-fluorophenyl) -3- (4-methoxyphenyl) -1H-- pyrazol-5-yl) quinolin 6-Fluoro-2-(1-(4-fluorophenyl)-3-(4-methoxyphenyl)-1 H -pyrazol-5-yl)quinoline), 6-fluoro-2-[1-(4-A oxyphenyl) -3-phenyl-1H - pyrazol-5-yl] quinoline (6-Fluoro-2- [1- (4-methoxyphenyl) -3-phenyl-1 H -pyrazol-5-yl ] quinoline), 6- fluoro-2- [3- (4-fluorophenyl) -1- (4-methoxyphenyl) -1H-- pyrazol-5-yl] quinoline (6-fluoro-2 -[3-(4-fluorophenyl)-1-(4-methoxyphenyl)-1 H -pyrazol-5-yl]quinoline), 6-fluoro-2-[1,3-bis(4-methoxyphenyl) -1H - pyrazol-5-yl] quinoline (6-Fluoro-2- [1,3 -Bis (4-methoxyphenyl) -1 H -pyrazol-5-yl] quinoline), 4- [5- ( 6-fluoro-quinolin-2-yl) -3-phenyl-1H - pyrazol-1-yl] benzenesulfonamide Amides (4- [5- (6-Fluoroquinolin -2-yl) -3-phenyl- 1 H -pyrazol-1-yl] benzenesulfonamide), 4- [3- (4- fluorophenyl) -5- (6-fluoro-quinolin-2-yl) -1H-- pyrazol-1-yl] benzene 4-[3-(4-Fluorophenyl)-5-(6-fluoroquinolin-2-yl)-1 H- pyrazol-1-yl]benzenesulfonamide), and 4-[5-(6- Fluoro-quinolin-2-yl) -3- (4-methoxyphenyl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [5- (6-Fluoroquinolin -2-yl) - 3-(4-methoxyphenyl)-1 H -pyrazol-1-yl]benzenesulfonamide).

5. The pyrazolylquinoline compound of any of embodiments 1-4, wherein the pyrazolylquinoline compound is selected from the group consisting of 4-[5-(6-fluoroquinoline-2) - yl) -3-phenyl-1H - pyrazol-1-yl] benzenesulfonamide Amides (4- [5- (6-Fluoroquinolin -2-yl) -3-phenyl-1 H -pyrazol-1- yl] benzenesulfonamide), 4- [3- (4- fluorophenyl) -5- (6-fluoro-quinolin-2-yl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [ 3-(4-Fluorophenyl)-5-(6-fluoroquinolin-2-yl)-1 H- pyrazol-1-yl]benzenesulfonamide), and 4-[5-(6-fluoroquinolin-2-yl)- 3- (4-methoxyphenyl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [5- (6-Fluoroquinolin -2-yl) -3- (4-methoxyphenyl) -1 H- pyrazol-1-yl]benzenesulfonamide).

A pyrazolylquinoline compound comprising: a quinolinyl group, a C6 position bonded to a substituent R1, and R ₁ is a halogen atom; a pyrazolyl group; a first phenyl group; and a second benzene group a group, wherein: the C2 position of the quinolyl group is bonded to a carbon atom position of the pyrazolyl group, and another carbon atom position of the pyrazolyl group is bonded to the C4 position of the second phenyl group, and the pyridyl group is N1. The position is linked to the C4 position of the first phenyl group.

7. A process for the preparation of a pyrazolylquinoline compound comprising the steps of providing 6-fluoro-2-methyl Quinoline, oxidizing the 6-fluoro-2-methylquinoline with selenium dioxide to form 6-fluoro-2-formylquinoline; 6-fluoro-2-quinoline The morpholine is condensed with a monoacetophenone to form a carbonyl product; and the carbonyl product is treated with a benzoquinone to form the pyrazolylquinoline compound.

8. The method of embodiment 7, wherein the acetophenone is acetophenone, 4-fluoroacetophenone or 4-methoxyacetophenone.

9. The method of any of embodiments 7-8, wherein the benzoquinone is benzoquinone, 4-fluorophenylhydrazine, 4-methoxyphenylhydrazine or 4-hydrazinobenzenesulfonamide.

10. The method of any of embodiments 7-9 wherein the acetophenone is 4-methoxyacetophenone and the carbonyl product is ( E )-3-(6-fluoroquinolin-2-yl) 1-(4-methoxyphenyl)prop-2-en-1-one (( E )-3-(6-Fluoroquinolin-2-yl)-1-(4-methoxyphenyl)prop-2-en- 1-one), and the benzoquinone is 4-fluorophenylhydrazine, 4-methoxybenzoquinone or 4-hydrazinobenzenesulfonamide.

11. The method of any of embodiments 7-10, wherein the benzoquinone is phenylhydrazine, and after treating the carbonyl product with the phenylhydrazine, 2,3-dichloro-5,6-dicyanazoquinone is carried out. (DDQ) oxidation.

A pharmaceutical composition comprising a therapeutically effective amount of the pyrazolylquinoline compound according to any one of embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

<110> Kaohsiung Medical University

<120> Pyrazolyquinoline Compounds and Preparation Methods and Pharmaceutical Compositions thereof

<160> 4

<210> 1

<211> 20

<212> DNA

<213> Dengue virus

<400> 1

<210> 2

<211> 20

<212> DNA

<213> Dengue virus

<400> 2

<210> 3

<211> 20

<212> DNA

<213> Homo sapiens

<400> 1

<210> 4

<211> 20

<212> DNA

<213> Homo sapiens

<400> 1

Claims (11)

A pyrazolylquinoline compound having the structural formula shown in Formula Ia or Formula Ib: The pyrazolylquinoline compound comprises: a quinolyl group, a C6 position bonded to a substituent R ₁ , and R ₁ is a halogen atom; a pyrazolyl group; a first phenyl group; and a second phenyl group, Wherein: the C2 position of the quinolyl group is bonded to the C3 or C5 position of the pyrazolyl group, the C1 position of the first phenyl group is bonded to a substituent R ₂ , and the C1 position of the second phenyl group and a substituent R ₃ linked, and: when in the first case, the C2 position of the quinolyl group is attached to the C3 position of the pyrazolyl group, the C5 position of the pyrazolyl group is linked to the C4 position of the first phenyl group, the pyridyl The N1 position of the azolyl group is bonded to the C4 position of the second phenyl group; and when in the second case, the C2 position of the quinolyl group is bonded to the C5 position of the pyrazolyl group, the C3 position of the pyrazolyl group is The C4 position of the first phenyl group is bonded, and the N1 position of the pyrazole group is bonded to the C4 position of the second phenyl group, wherein R ₂ is a hydrogen atom, a halogen atom or an alkoxy group, and R ₃ is a hydrogen atom or a halogen. Atom, alkoxy or sulfonamide group. The pyrazolylquinoline compound according to claim 1, wherein R ₁ is a fluorine atom, R ₂ is a hydrogen atom, a fluorine atom or a methoxy group, and R ₃ is a hydrogen atom, a fluorine atom or a methoxy group. Or a sulfonamide group. The pyrazolylquinoline compound according to claim 1, wherein the pyrazolylquinoline compound is selected from the group consisting of 6-fluoro-2-(1,5-diphenyl) -1H - pyrazol-3-yl) quinoline (6-fluoro-2- (1,5 -diphenyl-1H-pyrazol-3-yl) quinoline), 6- fluoro-2- [5- (4- fluorophenyl) -1-phenyl-1H - pyrazol-3-yl] quinoline (6-fluoro-2- [5- (4-fluorophenyl) -1-phenyl-1 H -pyrazol-3-yl ]quinoline), 6-fluoro-2-[5-(4-methoxyphenyl)-1-phenyl- 1hydro -pyrazol-3-yl]quinoline (6-Fluoro-2-[5-( 4-methoxyphenyl) -1-phenyl- 1 H -pyrazol-3-yl] quinoline), 6- fluoro-2- (1,3-diphenyl-1H - pyrazol-5-yl) - quinoline ( 6-Fluoro-2-(1,3-Diphenyl-1H-pyrazol-5-yl)-quinoline), 6-fluoro-2-[3-(4-fluorophenyl)-1-phenyl-1 hydrogen- 6-Fluoro-2-[3-(4-fluorophenyl)-1-phenyl-1 H- pyrazol-5-yl]quinoline), 6-fluoro-2-[3- (4-methoxyphenyl) -1-phenyl-1H - pyrazol-5-yl] quinoline (6-Fluoro-2- [3- (4-methoxyphenyl) -1-phenyl-1 H -pyrazol -5-yl]quinoline), 6-fluoro-2-[1-(4-fluorophenyl)-3-phenyl- 1hydro -pyrazol-5-yl]quinoline (6-Fluoro-2-[ 1-(4-fluorophenyl)-3-phenyl-1 H -pyrazol-5-yl]quin oline), 6- fluoro-2- [1,3-bis (4-fluorophenyl) -1H-- pyrazol-5-yl] quinoline (6-Fluoro-2- [1,3 -Bis (4 -fluorophenyl)-1 H- pyrazol-5-yl]quinoline), 6-fluoro-2-(1-(4-fluorophenyl)-3-(4-methoxyphenyl)-1 hydrogen -pyrazole- 5-fluororo-2-(1-(4-fluorophenyl)-3-(4-methoxyphenyl)-1 H- pyrazol-5-yl)quinoline), 6-fluoro-2-[1 - (4-methoxyphenyl) -3-phenyl-1H - pyrazol-5-yl] quinoline (6-Fluoro-2- [1- (4-methoxyphenyl) -3-phenyl-1 H - pyrazol-5-yl] quinoline) , 6- fluoro-2- [3- (4-fluorophenyl) -1- (4-methoxyphenyl) -1H-- pyrazol-5-yl] quinoline ( 6-Fluoro-2-[3-(4-fluorophenyl)-1-(4-methoxyphenyl)-1 H -pyrazol-5-yl]quinoline), 6-fluoro-2-[1,3-bis(4- methoxyphenyl) -1H-- pyrazol-5-yl] quinoline (6-Fluoro-2- [1,3 -Bis (4-methoxyphenyl) -1 H -pyrazol-5-yl] quinoline), 4 - [5- (6-fluoro-quinolin-2-yl) -3-phenyl-1H - pyrazol-1-yl] benzenesulfonamide Amides (4- [5- (6-Fluoroquinolin -2-yl) -3-phenyl-1 H -pyrazol-1-yl]benzenesulfonamide), 4-[3-(4-fluorophenyl)-5-(6-fluoroquinolin-2-yl)-1 hydrogen -pyrazole- 1-[3-(4-Fluorophenyl)-5-(6-fluoroquinolin-2-yl)-1 H- pyrazol-1-yl]benzenesulfonamide) And 4- [5- (6-fluoro-quinolin-2-yl) -3- (4-methoxyphenyl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [5- ( 6-Fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1 H- pyrazol-1-yl]benzenesulfonamide). The pyrazolylquinoline compound according to claim 1, wherein the pyrazolylquinoline compound is selected from the group consisting of 4-[5-(6-fluoroquinolin-2- 3-phenyl-1- hydro -pyrazol-1-yl]benzenesulfonamide (4-[5-(6-Fluoroquinolin-2-yl)-3-phenyl-1 H- pyrazol-1-yl ] benzenesulfonamide), 4- [3- ( 4- fluorophenyl) -5- (6-fluoro-quinolin-2-yl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [3 -(4-Fluorophenyl)-5-(6-fluoroquinolin-2-yl)-1 H- pyrazol-1-yl]benzenesulfonamide), and 4-[5-(6-fluoroquinolin-2-yl)-3 - (4-methoxyphenyl) -1H-- pyrazol-1-yl] benzenesulfonamide Amides (4- [5- (6-Fluoroquinolin -2-yl) -3- (4-methoxyphenyl) -1 H -pyrazol-1-yl]benzenesulfonamide). A pyrazolylquinoline compound having the structural formula shown below: The pyrazolylquinoline compound comprises: a quinolyl group, a C6 position bonded to a substituent R ₁ , and R ₁ is a halogen atom; a pyrazolyl group; a first phenyl group; and a second phenyl group, Wherein: the C2 position of the quinolyl group is bonded to a carbon atom position of the pyrazolyl group, and another carbon atom position of the pyrazolyl group is bonded to the C4 position of the second phenyl group, and the N1 position of the pyrazolyl group or The N2 position is linked to the C4 position of the first phenyl group. A method for preparing a pyrazolylquinoline compound, comprising the steps of: providing 6-fluoro-2-methylquinoline; oxidizing the 6-fluoro-2-methylquinoline with selenium dioxide to form 6-fluoro 6-fluoro-2-formylquinoline; condensing the 6-fluoro-2-quinolinecarboxaldehyde with monoacetophenone to form a carbonyl product; and treating the carbonyl group with a benzoquinone a product to form the pyrazolylquinoline compound, wherein the pyrazolylquinoline compound has a structural formula as shown in Formula Ia or Formula Ib: Wherein R ₁ is a halogen atom, R ₂ is a hydrogen atom, a halogen atom or an alkoxy group, and R ₃ is a hydrogen atom, a halogen atom, an alkoxy group or a sulfonamide group. The method of claim 6, wherein the acetophenone is acetophenone, 4-fluoroacetophenone or 4-methoxyacetophenone. The method of claim 6, wherein the benzoquinone is benzoquinone, 4-fluorophenylhydrazine, 4-methoxyphenylhydrazine or 4-hydrazinobenzenesulfonamide. The method of claim 6, wherein the acetophenone is 4-methoxyacetophenone and the carbonyl product is ( E )-3-(6-fluoroquinolin-2-yl)- 1-(4-methoxyphenyl)prop-2-en-1-one (( E )-3-(6-Fluoroquinolin-2-yl)-1-(4-methoxyphenyl)prop-2-en-1 -one), and the benzoquinone is 4-fluorophenylhydrazine, 4-methoxybenzoquinone or 4-hydrazinobenzenesulfonamide. The method of claim 6, wherein the benzoquinone is benzoquinone, and after the carbonyl product is treated with the benzoquinone, 2,3-dichloro-5,6-dicyanobenzoquinone is carried out ( DDQ) oxidation. A pharmaceutical composition comprising a therapeutically effective amount of a pyrazolylquinoline compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof a.