KR102278691B1 - Novel pyrimidine sulfonamide derivatives - Google Patents

Abstract

The present invention relates to a pyrimidine sulfonamide derivative in which a trifluoroethoxy group is disubstituted at a specific position. By introducing the trifluoroethoxy group into pyrimidine sulfonamide, CD73 inhibitory activity, metabolic stability, and drug efficacy are excellent. Thus, it is possible to provide a compound with increased drug usefulness.

Description

Novel pyrimidine sulfonamide derivatives

The present invention relates to novel pyrimidine sulfonamide derivatives.

ATP (adenosine triphosphate) exists in the cells of all living things and plays a very important role in energy metabolism, and one ATP molecule releases a large amount of energy through hydrolysis to be used for biological activities. Under normal physiological conditions, the intracellular ATP concentration is maintained at the mM concentration, whereas the extracellular concentration is tightly regulated in the nM concentration range. However, under certain conditions, such as tissue damage, inflammation, ischemia, or the tumor microenvironment (TME), the concentration of extracellular ATP is increased by ATP secreted from inflammatory cells, apoptotic cells or necrotic cells. Signals by extracellular ATP are widely expressed in immune and non-immune cells in the body through one of the purinergic receptors, the P2 receptor (P2R), and are involved in several physiological and pathological processes.

The current paradigm of purinergic signaling for immune responses can be explained by a balance between pro-inflammatory and anti-inflammatory signaling from the respective extracellular ATP and adenosine. During the physiologically acute inflammatory response, ATP secretion from stressed, apoptotic and necrotic cells can act as a ‘danger signal’, which is essential for intracellular bacterial, parasite and viral clearance. In addition, ATP can induce immunogenic cell death in cancer cells, which promotes immune surveillance in the tumor microenvironment.

Conversely, adenosine is a major anti-inflammatory agent and promotes cell protection, wound healing and suppression of the immune system. Adenosine is present in nM concentrations in normal tissues, but increases to μM concentrations in solid tumors and is more present in hypoxic tumor centers. A greater increase in the amount of adenosine is observed in inflammation, ischemia, hypoxia and organ trauma, which is an important component of immune cell regulation in bacterial/viral sepsis or renal dysfunction or injury.

Due to the high concentration of adenosine in the tumor microenvironment and the expression of adenosine receptors in cancer cells and immune cells, the role of adenosine in cancer progression and anticancer immune response has been intensively studied, and CD39, CD73, A2AR (adenosine receptor 2A) and A2BR ( This has led to the clinical development of antibodies and small molecule inhibitors targeting various components of the adenosine pathway, including the denosine receptor 2B).

CD73 (5'-nucleotidase, ecto-5'-nucelotidase) is an ectonucleotidase belonging to the E-NTPDase (ectonucleoside triphosphate diphosphohydrolase) family, and irreversibly dephosphorylates AMP to adenosine.

CD73 has been considered to be pivotal in the formation of an immune-suppressive environment through adenosine production. The produced adenosine has anti-inflammatory activity when released from the extracellular environment, and interacts with specific receptors on T cells, contributing to anti-tumor immune suppression. This role of CD73 in inflammation and tumorigenesis is supported by the fact that CD73-deficient mice are susceptible to inflammation/autoimmunity and exhibit resistance to tumor growth following adenosine-mediated remission of immunosuppression. In addition, CD73 has been shown to be a biomarker in patients with several tumor types, and most studies have shown that high expression of CD73 is present in patients with triple negative breast cancer, lung cancer, ovarian cancer, kidney cancer, gastric cancer and melanoma. It has been shown to be associated with a lower treatment response.

Accordingly, recently, a number of studies are being conducted to develop an antibody or inhibitory compound that inhibits the enzymatic activity of CD73 as a cancer treatment (Geoghegan, JC et al, MABS, 8(3), 454-467, 2016; Rahimova, R. et al., PLoS Comput. Biol., 14(1), e1005943, 2018).

Meanwhile, as a prior document related to pyrimidine sulfonamide derivatives, International Patent Publication No. 2011-072243 discloses a pyrimidine sulfonamide derivative having histone acetyl transferase (HAT) activity and its use, and International Patent Publication No. 2002-090348 Ho, disclosed a sulfonamide derivative and its use as an antagonist of urotensin II, and a previous paper [Elderfield, RC et al., The Journal of Organic Chemistry, 26(10), 1961] 6-methyluracil 5-sulfonic acid , derivatives and their anticancer uses have been disclosed. However, as in the present invention, there is no previous report mentioning the usefulness of a compound in which a trifluoroethoxy group is disubstituted at a specific position of the pyrimidine sulfonamide compound and the drug according to the introduction of the substituent.

Accordingly, in the process of researching pyrimidine sulfonamide derivatives, the present inventors studied pyrimidine sulfonamide (4,6-bis ( 2,2,2-trifluoroethoxy) - N - ( 3,4,5-trifluorophenyl) pyrimidine-5-sulfonamide) compound is trifluoromethyl as International Patent Publication No. 2011-072243 and International Publication Patent No. 2002-090348 A pyrimidine sulfonamide compound in which a trifluoromethoxy group is disubstituted instead of an ethoxy group (4,6-bis(2,2,2-trifluoromethoxy)- N -(3,4,5-trifluorophenyl)pyrimidine-5-sulfonamide) , Pyrimidine sulfonamide compound in which the trifluoroethoxy group is not disubstituted and only one trifluoroethoxy group is substituted (4-(2,2,2-trifluoromethoxy) -N -(3,4,5-trifluorophenyl) )pyrimidine-5-sulfonamide), a pyrimidine sulfonamide compound in which an ethoxy group is disubstituted instead of a trifluoroethoxy group (4,6-diethoxy- N -(3,4,5-trifluorophenyl)pyrimidine-5-sulfonamide) and Talk time trifluoroethoxy group is introduced, but benzenesulfonamide including a benzene ring instead of the pyrimidine compound (4,6-bis (2,2,2-trifluoroethoxy ) - N - (3,4,5-trifluorophenyl) benzene- 5-sulfonamide), the present invention was completed by confirming that the bioavailability of the drug was excellently improved, including the CD73 inhibitory activity, metabolic stability, and longevity of drug effect.

International Patent Publication No. 2011-072243, HISTONE ACETYLTRANSFERASE ACTIVATORS AND USES THEREOF, June 16, 2011, published. International Patent Publication No. 2002-090348, SULFONAMIDES, published on November 14, 2002.

Elderfield, R. C. et al., Synthesis of Potential Anticancer Agents. XI. Synthesis and Reactions of Derivatives of 6-Methyluracil-5-sulfonic Acid, The Journal of Organic Chemistry, 26(10), 1961. Geoghegan, J. C. et al, Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action, MABS, 8(3), 454-467, 2016. Rahimova, R. et al., Identification of allosteric inhibitors of the ecto-5'-nucleotidase (CD73) targeting the dimer interface, PLoS Comput. Biol., 14(1), e1005943, 2018.

It is an object of the present invention to provide a novel pyrimidine sulfonamide derivative with improved CD73 inhibitory activity, metabolic stability, and drug durability.

The present invention relates to a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ₁ is substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₁₀ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₀ aryl or substituted or unsubstituted C ₄ - substituted with one or more substituents selected from the group consisting of C _{10 heteroaryl,}

In this case, the substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl is hydrogen, halogen, hydroxy, CF ₃ , NO ₂ , S-(C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₁ substituted with one or more substituents selected from the group consisting of -C ₆ alkynyl, C ₁ -C ₆ alkylphenyl, C ₁ -C ₁₀ alkoxy, C ₄ -C ₁₀ aryl or C ₄ -C _{10 heterocycloalkyl.}

More preferably, in Formula 1,

R ₁ is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C ₄ -C ₁₀ aryl or substituted or unsubstituted C ₄ -C _{10 heteroaryl,}

In this case, the substituted aryl or heteroaryl is hydrogen, halogen, hydroxy, CF ₃ , NO ₂ , S-(C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkylphenyl, C ₁ -C ₁₀ alkoxy, C ₄ -C ₁₀ aryl or C ₄ -C ₁₀ a compound represented by Formula 1 substituted with one or more substituents selected from the group consisting of heterocycloalkyl, or a compound thereof It relates to a pharmaceutically acceptable salt.

When the compound of Formula 1 of the present invention is more specifically illustrated,

N- (3-phenoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 1);

N- (3-(methylthio)phenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 2);

N- (3,5-di-tert-butylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 3);

N- (benzo[ d ][1,3]dioxol-5-yl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 4);

4,6-bis (2,2,2-trifluoroethoxy-ethoxy) - N - (3,4,5- trifluorophenyl) pyrimidin-5-sulfonamide (compound 5);

4,6-bis (2,2,2-trifluoroethoxy) - N - (3,4,5- trimethoxyphenyl) pyrimidine-5-sulfonamide (compound 6);

N- (3,4-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 7);

N- (3-Chloro-4-iodophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 8);

N- (4-fluoro-3-(trifluoromethyl)phenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 9);

N- (3,5-dinitrophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 10);

N- (3-isopropylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 11);

N- (3-fluorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 12);

N- (3-Chloro-4-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 13);

N- (4-ethynylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 14);

N- (2-Chloro-5-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 15);

N- (2-Fluoro-4-morpholinophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 16);

N- (3-Methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 17);

N- (1-Benzyl-1 H -pyrazol-4-yl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 18);

N- (2,6-dimethoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 19);

N- (2-Methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 20);

N- (4-iodo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 21);

N- ( o -Tolyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 22);

N- ( p -Tolyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 23);

N- (2,3-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 24);

N- (4-Methoxy-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 25);

N- (3-Chloro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 26);

N- (4-Chloro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 27);

N- (3-Bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 28);

N- (4-Bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 29);

N- (5-Bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 30);

N- (2,4-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 31);

N- (4-Chloro-2,6-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 32);

N- (2,4,5-trichlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 33);

N- (3-Fluoro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 34);

N- (4-Fluoro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 35);

N- (3-Chlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 36);

N- (4-Chlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 37); and

N- (5-Methoxy-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 38); is selected from the group consisting of

In addition, the following terms in the present invention have the following meanings unless otherwise indicated. Any terms not defined have the meanings understood in the art.

The term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

The term “alkyl” refers to a single-bonded straight-chain or branched hydrocarbon group. Examples include methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl and the like.

The term “alkoxy” refers to an oxygen group to which a single bond straight or branched saturated hydrocarbon is bonded. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy and the like.

The term “cycloalkyl” refers to a saturated hydrocarbon group having a single cyclic bond. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. are mentioned.

The term “aryl” refers to an aromatic substituent having at least one ring having a shared pi electron system, for example, phenyl, naphthyl, and the like.

The term “arylalkyl” refers to an aryl group substituted with an alkyl group, and aryl and alkyl are as described above.

The term “heterocycloalkyl” refers to a saturated hydrocarbon group of a single cyclic bond containing one or more heteroatoms such as N, O, or S, and may vary depending on the number and type of heteroatoms included in the ring and the number of carbon atoms. ridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

The term “heteroaryl” refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and pyrrolyl, furanyl, pyridine according to the number and type of heteroatoms included in the ring, and carbon number yl, pyrimidinyl, and pyranyl.

In the present invention, the pharmaceutically acceptable salt refers to a salt or complex of Formula 1 having desirable biological activity. Examples of such salts include, but are not limited to, inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) ], and acetic acid, oxalic acid, tartari acid, succinic acid, malic acid, fumaric acid, maleic acid ), ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene salts formed with organic acids such as naphthalene disulfonic acid, and poly-galacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carbohydrate. Voxylates (e.g., benzoates, succinates, acetates, glycorates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinnamoates, mandeloates and diphenylacetate). The compound of Formula 1 of the present invention may include all salts, hydrates, solvates and prodrugs that can be prepared by conventional methods as well as pharmaceutically acceptable salts.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).

Furthermore, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of this invention.

The present invention relates to a pyrimidine sulfonamide derivative in which a trifluoroethoxy group is disubstituted at a specific position. By introducing the trifluoroethoxy group into pyrimidine sulfonamide, CD73 inhibitory activity, metabolic stability, and drug efficacy are excellent. Thus, it is possible to provide a compound with increased drug usefulness.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided so that this disclosure will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

<Example 1. Synthesis of novel pyrimidine sulfonamide derivative compound and confirmation of physicochemical properties>

_{Compounds 1 to 38 of the present invention were synthesized pyrimidine sulfonamide derivatives including various substituents R 1} with reference to the following [Scheme], and their physicochemical properties are as follows.

[reaction formula]

Compound 1. N -(3-phenoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-phenoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3-phenoxyaniline (25mg, 1.0eq. , 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45 wt%) (0.02ml, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 36% (25.4 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.45 (s, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.1 Hz, 1H), 7.13 (t, J = 7.4) Hz, 1H), 6.92 (d, J = 7.7 Hz, 2H), 6.90 - 6.86 (m, 1H), 6.83 (s, 1H), 6.73 (dd, J = 8.3, 2.4 Hz, 1H), 6.68 (t) , J = 2.4 Hz, 1H), 4.87 (q, J = 8.1 Hz, 4H).

compound 2. N -(3-(methylthio)phenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-(methylthio)phenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-(methylthio)aniline (0.02 ml, 1.0) in a 7 ml vial eq., 0.133 mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45 wt%) (0.02ml, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 51% (32.3 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.44 (s, 1H), 7.14 (t, J = 8.1 Hz, 1H), 6.96 (d, J = 6.6 Hz, 2H), 6.89 (dt, J = 11.1) , 2.6 Hz, 2H), 4.94 (q, J = 8.2 Hz, 4H), 2.42 (s, 3H).

compound 3. N -(3,5-di-tert-butylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3,5-di-tert-butylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3,5-di-tert-butylaniline (27 mg, 1.0 eq., 0.133 mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a white solid in a yield of 47% (34 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.42 (s, 1H), 7.16 (t, J = 1.8 Hz, 1H), 6.95 (d, J = 1.7 Hz, 2H), 6.81 (s, 1H), 4.93 - 4.86 (m, 4H), 1.23 (s, 18H).

compound 4. N -(benzo[ d ][1,3]dioxol-5-yl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(benzo[ d ][1,3]dioxol-5-yl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3,4-methylenedioxyaniline (18mg, 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 27% (17.1 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.45 (s, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.71 (s, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.49 (dd, J = 8.4, 2.1 Hz, 1H), 5.92 (s, 2H), 4.95 (q, J = 8.1 Hz, 4H).

Compound 5. 4,6-bis(2,2,2-trifluoroethoxy)- N -(3,4,5-trifluorophenyl)pyrimidine-5-sulfonamide (4,6-bis(2,2,2-trifluoroethoxy)- N -(3,4,5-trifluorophenyl)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3,4,5-trifluoroaniline (20 mg, 1.0 eq., 0.133 mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 17% (10.8 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.49 (s, 1H), 6.89 (s, 1H), 6.85 - 6.76 (m, 2H), 4.98 (q, J = 8.1 Hz, 4H).

Compound 6. 4,6-bis(2,2,2-trifluoroethoxy)- N -(3,4,5-trimethoxyphenyl)pyrimidine-5-sulfonamide (4,6-bis(2,2,2-trifluoroethoxy)- N -(3,4,5-trimethoxyphenyl)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3,4,5-trimethoxyaniline (24 mg, 1.0 eq., 0.133 mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 39% (27.3 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.46 (s, 1H), 6.77 (s, 1H), 6.39 (s, 2H), 4.95 (q, J = 8.2 Hz, 4H), 3.76 (d, J) = 1.5 Hz, 9H).

compound 7. N -(3,4-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3,4-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3,4-dimethylaniline (16mg, 1.0eq) in a 7ml vial ., 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product with a yield of 46% (28.3 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.41 (s, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 6.83 (dd, J = 8.1) , 2.4 Hz, 1H), 6.75 (s, 1H), 4.93 (q, J = 8.1 Hz, 4H), 2.16 (d, J = 2.7 Hz, 6H).

compound 8. N -(3-chloro-4-iodophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-chloro-4-iodophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis (2,2,2-trifluoroethoxy) pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-chloro-4-iodoaniline (34 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 35% (27.7 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.47 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 6.90 (d, J = 4.6) Hz, 1H), 6.77 (dd, J = 8.7, 2.6 Hz, 1H), 4.96 (q, J = 8.1 Hz, 1H).

compound 9. N -(4-fluoro-3-(trifluoromethyl)phenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(4-fluoro-3-(trifluoromethyl)phenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-fluoro-3-(trifluoromethyl) in a 7 ml vial ) Add aniline (0.02ml, 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 42% (28.6 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (s, 1H), 7.39 - 7.33 (m, 2H), 7.12 (t, J = 9.0 Hz, 1H), 6.97 (s, 1H), 4.97 (q) , J = 8.2 Hz, 4H).

compound 10. N -(3,5-dinitrophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3,5-dinitrophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3,5-dinitroaniline (20 mg, 1.0) in a 7 ml vial eq., 0.133 mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a yellow solid in a yield of 12% (8.3 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.74 (t, J = 1.9 Hz, 1H), 8.52 (s, 1H), 8.31 (d, J = 2.0 Hz, 2H), 5.02 (q, J = 8.1) Hz, 4H).

compound 11. N -(3-isopropylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-isopropylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3-isopropylaniline (18mg, 1.0eq. , 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 44% (27.6 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.42 (s, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.98 - 6.93 (m, 3H), 6.83 (s, 1H), 4.93 (q) , J = 8.1 Hz, 5H), 1.16 (d, J = 7.0 Hz, 6H).

compound 12. N -(3-fluorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-fluorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3-fluoroaniline (0.013ml, 1.0eq. , 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 16% (9.8 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.45 (s, 1H), 7.20 (td, J = 8.3, 6.3 Hz, 1H), 6.98 (s, 1H), 6.93 (dt, J = 10.1, 2.3 Hz) , 1H), 6.85 - 6.81 (m, 1H), 6.81 - 6.76 (m, 1H), 4.96 (q, J = 8.1 Hz, 4H).

compound 13. N -(3-chloro-4-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-chloro-4-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-chloro-4-methoxyaniline (17.5 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 18% (11.9 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.45 (d, J = 1.2 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.04 (dt, J = 8.8, 1.9 Hz, 1H), 6.83 - 6.78 (m, 2H), 4.99 - 4.92 (m, 4H), 3.84 (d, J = 1.1 Hz, 3H).

compound 14. N -(4-ethynylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(4-ethynylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 4-ethynylaniline (13mg, 1.0eq. , 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 28% (17 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.44 (s, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.96 (s, 1H), 4.95 (q, J = 8.2 Hz, 4H), 3.03 (s, 1H).

compound 15. N -(2-chloro-5-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(2-chloro-5-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 2-chloro-5-methoxyaniline (17.5 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 12% (7.6 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.46 (s, 1H), 7.46 (s, 1H), 7.27 (d, J = 3.2 Hz, 1H), 7.17 (d, J = 8.9 Hz, 1H), 6.59 (dd, J = 8.9, 2.9 Hz, 1H), 4.91 (q, J = 8.1 Hz, 4H), 3.75 (s, 3H).

compound 16. N -(2-fluoro-4-morpholinophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(2-fluoro-4-morpholinophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 2-fluoro-4-morpholinoaniline ( 22 mg, 1.0 eq., 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 45% (32.2 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.36 (dd, J = 9.0, 5.4 Hz, 1H), 6.86 (dd, J = 9.6, 2.8 Hz) , 1H), 6.74 (td, J = 8.7, 2.8 Hz, 1H), 4.97 (q, J = 8.2 Hz, 4H), 3.89 - 3.83 (m, 4H), 2.85 (t, J = 4.6 Hz, 4H) .

compound 17. N -(3-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3-methoxyaniline (14mg, 1.0eq. , 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product with a yield of 33% (20.4 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.43 (s, 1H), 7.13 (t, J = 8.1 Hz, 1H), 6.89 (s, 1H), 6.72 - 6.66 (m, 2H), 6.66 - 6.62 (m, 1H), 4.93 (q, J = 8.1 Hz, 5H), 3.74 (s, 3H).

compound 18. N -(1-benzyl-1 H -Pyrazol-4-yl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(1-benzyl-1 H -pyrazol-4-yl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 1-benzyl-1H-pyrazol-4-amine in a 7ml vial (14 mg, 1.0 eq., 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a white solid in a yield of 37% (25.5 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.45 (s, 1H), 7.42 (s, 1H), 7.31 (dd, J = 5.1, 1.9 Hz, 3H), 7.17 (s, 1H), 7.13 (dd , J = 6.6, 2.8 Hz, 2H), 6.59 (s, 1H), 5.17 (s, 2H), 4.91 (q, J = 8.1 Hz, 4H).

compound 19. N -(2,6-dimethoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(2,6-dimethoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 2,6-dimethoxyaniline (17 mg, 1.0) in a 7 ml vial eq., 0.133 mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 39% (25.7 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (s, 1H), 7.14 (t, J = 8.4 Hz, 1H), 6.56 (s, 1H), 6.51 (d, J = 8.5 Hz, 2H), 4.93 (q, J = 8.2 Hz, 4H), 3.63 (s, 6H).

compound 20. N -(2-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(2-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and o-anisidine (14mg, 1.0eq., 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45 wt%) (0.02ml, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 20% (12.3 mg), and the NMR results thereof are as follows.

1H NMR (400 MHz, Chloroform- d ) δ 8.41 (s, 1H), 7.61 - 7.53 (m, 2H), 7.01 (td, J = 7.8, 1.5 Hz, 1H), 6.86 (td, J = 7.8, 1.3) Hz, 1H), 6.80 (dd, J = 8.2, 1.3 Hz, 1H), 4.90 (q, J = 8.1 Hz, 4H), 3.78 (s, 3H).

compound 21. N -(4-iodo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(4-iodo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-iodo-2-methylaniline (26 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 28% (21.4 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (s, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 8.5, 2.1 Hz, 1H), 7.04 (d, J) = 8.6 Hz, 1H), 6.72 (s, 1H), 4.94 (q, J = 8.1 Hz, 4H), 2.18 (s, 3H).

compound 22. N -( o -Tolyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -( o -tolyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and o -toluidine (13 mg, 1.0 eq., 0.133) in a 7 ml vial mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 19% (9.6 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.42 (s, 1H), 7.05 - 6.99 (m, 4H), 6.82 (s, 1H), 4.93 (q, J = 8.2 Hz, 4H), 2.25 (s) , 3H).

compound 23. N -( p -Tolyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -( p -tolyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and p -toluidine (13 mg, 1.0 eq., 0.133) in a 7 ml vial mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, extraction was performed with aqueous sodium hydrogen carbonate solution (10 ml) and ethyl acetate (10 ml×2), and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 17% (8.6 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.47 (s, 1H), 7.24 (d, J = 1.3 Hz, 1H), 7.18 - 7.12 (m, 1H), 7.06 (dtd, J = 23.0, 7.5, 1.6 Hz, 2H), 6.75 (s, 1H), 4.94 (q, J = 8.2 Hz, 4H), 2.24 (s, 3H).

compound 24. N -(2,3-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(2,3-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 2,3-dimethylaniline (14 mg, 1.0 eq) in a 7 ml vial ., 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 33% (16.7 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.47 (s, 1H), 7.02 - 6.92 (m, 3H), 6.73 (s, 1H), 4.93 (q, J = 8.1 Hz, 4H), 2.26 (s) , 3H), 2.18 (s, 3H).

compound 25. N -(4-methoxy-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(4-methoxy-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-methoxy-2-methylaniline (15 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 13% (6.8 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 2.9 Hz, 1H), 6.59 (dd, J = 8.8) , 3.0 Hz, 1H), 6.54 (s, 1H), 4.93 (q, J = 8.1 Hz, 4H), 3.74 (s, 3H), 2.26 (s, 3H).

compound 26. N -(3-chloro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-chloro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3-chloro-2-methylaniline (16mg, 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product with a yield of 18% (9.5 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.49 (s, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.02 (t, J = 8.1 Hz, 1H), 6.81 (s, 1H), 4.95 (q, J = 8.1 Hz, 4H), 2.30 (s, 3H).

compound 27. N -(4-chloro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(4-chloro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 4-chloro-2-methylaniline (16mg, 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product with a yield of 18% (9.7 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 7.06 (dd, J = 8.7) , 2.5 Hz, 1H), 6.72 (s, 1H), 4.94 (q, J = 8.2 Hz, 5H), 2.22 (s, 3H).

compound 28. N -(3-Bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-bromo-2-methylaniline (21 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 23% (13.2 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.49 (s, 1H), 7.39 - 7.33 (m, 2H), 7.21 (d, J = 8.1 Hz, 1H), 6.94 (t, J = 8.1 Hz, 1H) ), 6.84 (s, 1H), 4.94 (q, J = 8.1 Hz, 5H), 2.35 (s, 3H).

compound 29. N -(4-Bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(4-bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-bromo-2-methylaniline (21 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 11% (6 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (s, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.21 (dd, J = 8.6, 2.3 Hz, 1H), 7.15 (d, J) = 8.7 Hz, 1H), 6.72 (s, 1H), 4.94 (q, J = 8.1 Hz, 5H), 2.21 (s, 3H).

compound 30. N -(5-Bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(5-bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 5-bromo-2-methylaniline (21 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 13% (8.5 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.50 (s, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 8.1, 2.0 Hz, 1H), 7.01 (d, J) = 8.2 Hz, 1H), 6.76 (s, 1H), 4.95 (q, J = 8.1 Hz, 5H), 2.18 (s, 3H).

compound 31. N -(2,4-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(2,4-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 2,4-dimethylaniline (13mg, 1.0eq) in a 7ml vial ., 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 22% (11.1 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.47 (s, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.2) , 2.1 Hz, 1H), 6.66 (s, 1H), 4.93 (q, J = 8.1 Hz, 4H), 2.24 (s, 3H).

compound 32. N -(4-chloro-2,6-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(4-chloro-2,6-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-chloro-2,6-dimethylaniline (17 mg, 1.0 eq., 0.133 mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 18% (9.6 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.52 (s, 1H), 7.05 (s, 2H), 6.32 (s, 1H), 4.97 (q, J = 8.2 Hz, 4H), 2.17 (s, 6H) ).

compound 33. N -(2,4,5-trichlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(2,4,5-trichlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 2,4,5-trichloroaniline (22 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 20% (12.1 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.49 (s, 1H), 7.19 (s, 2H), 4.98 (q, J = 8.1 Hz, 4H).

compound 34. N -(3-fluoro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-fluoro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-fluoro-2-methylaniline (14 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 40% (20.7 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (s, 1H), 7.05 (dd, J = 3.8, 1.8 Hz, 2H), 6.85 - 6.81 (m, 1H), 6.80 (d, J = 8.0 Hz) , 1H), 4.95 (q, J = 8.1 Hz, 5H), 2.15 (d, J = 2.0 Hz, 3H).

compound 35. N -(4-fluoro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(4-fluoro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-fluoro-2-methylaniline (14 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 46% (23.6 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.49 (s, 1H), 7.10 (dd, J = 8.9, 5.1 Hz, 1H), 6.89 (dd, J = 9.1, 3.0 Hz, 1H), 6.80 - 6.75 (m, 1H), 6.62 (s, 1H), 4.94 (q, J = 8.1 Hz, 4H), 2.26 (s, 3H).

compound 36. N -(3-chlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(3-chlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3-chloroaniline (14mg, 1.0eq., 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 40% (20.5 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.45 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 2.1 Hz, 1H), 7.07 (ddd, J = 8.1) , 2.0, 1.0 Hz, 1H), 7.01 (ddd, J = 7.9, 2.2, 0.9 Hz, 1H), 6.92 (s, 1H), 4.96 (q, J = 8.1 Hz, 5H).

compound 37. N -(4-chlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(4-chlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 4-chloroaniline (14mg, 1.0eq., 0.133 mmol) is added. Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product in a yield of 41% (21.3 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.45 (s, 1H), 7.24 - 7.19 (m, 2H), 7.07 - 7.04 (m, 2H), 6.89 (s, 1H), 4.95 (q, J = 8.1 Hz, 4H).

compound 38. N -(5-Methoxy-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide ( N -(5-methoxy-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide)

4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 2-methoxy-5-methylaniline (15 mg) in a 7 ml vial , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25 mL) was added at 0°C. After that, potassium hydroxide (45wt%) (0.02㎖, 1.6eq,, 0.213mmol) was added and reacted at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL×2), and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Thereafter, it was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a transparent solid product with a yield of 89% (47.2 mg), and the NMR results thereof are as follows.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.41 (s, 1H), 7.54 (s, 1H), 7.39 (d, J = 2.1 Hz, 1H), 6.81 (dt, J = 8.2, 1.4 Hz, 1H) ), 6.68 (d, J = 8.3 Hz, 1H), 4.89 (q, J = 8.1 Hz, 4H), 3.74 (s, 3H).

<Experimental Example 2. Confirmation of anticancer activity>

The anticancer activity of the compound of the present invention was confirmed by measuring the CD73 inhibitory activity.

First, Malachite Green Phosphate Detection kit (R&D, cat. DY996), rhCD73 (Recombinant Human 5'Nucleotidase/CD73), AMP (Adenosine monophosphate) and Assay buffer (UltraPure DNase/RNase-Free Distilled Water) were added to 25mM Tris- HCl and 5 mM magnesium chloride) were prepared.

Next, the compound of the present invention is prepared by diluting with the assay buffer, rhCD73 is diluted with the assay buffer to 0.25 μg/ml, the diluted CD73 enzyme is added to the wells except for the control, and mixed and reacted at 37°C for 10 minutes did.

After 10 minutes, AMP was made to 100 μM using the assay buffer, and then put into all wells, mixed and reacted at 37 °C for 20 minutes. After 20 minutes, 20 μl of Malachite Green Reagent A was added per well and mixed at room temperature for 10 minutes. After 10 minutes, 20 μl of Malachite Green Reagent B was added per well, mixed at room temperature for 20 minutes, and absorbance was measured at 620 nm to calculate CD73 inhibitory activity.

compound number CD73 inhibitory activity (IC ₅₀ , μM) compound 2 80.71 compound 4 80.21 compound 5 50.1 compound 6 91.81 compound 7 110.67 compound 8 60.1 compound 9 80.71 compound 10 48.8 compound 11 92.1 compound 12 119 compound 13 140 compound 14 80.28 compound 15 101.38 compound 16 120.21 compound 17 91.81 compound 18 91.81 compound 21 128.28 compound 23 148.28

Referring to Table 1, it can be seen that the compound of the present invention (a pyrimidine sulfonamide derivative in which a trifluoroethoxy group is disubstituted) exhibits CD73 enzyme inhibitory activity and can be used as a candidate for a cancer treatment.

In particular, Table 1 contains the compound of the present invention with a Talk time instead trifluoromethoxy Messenger time disubstituted trifluoroethoxy pyrimidin-sulfonamide compound (4,6-bis (2,2,2-trifluoromethoxy did not show) - N - ( 3,4,5-trifluorophenyl)pyrimidine-5-sulfonamide), a pyrimidine sulfonamide compound in which a trifluoroethoxy group is not disubstituted and only one trifluoroethoxy group is substituted (4-(2,2,2) -trifluoromethoxy)- N -(3,4,5-trifluorophenyl)pyrimidine-5-sulfonamide), a pyrimidine sulfonamide compound in which an ethoxy group is disubstituted instead of a trifluoroethoxy group (4,6-diethoxy- N -(3) ,4,5-trifluorophenyl)pyrimidine-5-sulfonamide) and trifluoroethoxy groups were introduced, but a benzene sulfonamide compound containing a benzene ring instead of pyrimidine (4,6-bis(2,2,2-trifluoroethoxy) - it was found that (3,4,5-trifluorophenyl) benzene-5 -sulfonamide) is improved to excellent metabolic stability and efficacy, including persistent CD73 inhibitory activity compared to the increase in the availability of the drug compound-N.

<Formulation Example 1. Preparation of powder>

Compound 5 of the present invention (4,6-bis (2,2,2-trifluoroethoxy) -N - (3,4,5-trifluorophenyl) pyrimidine-5-sulfonamide) 2 g, lactose 1 g was mixed and filled in an airtight cloth to prepare a powder.

<Formulation Example 2. Preparation of tablets>

The compound of the present invention 5 (the 4,6-bis (2,2,2-trifluoroethoxy) - N - (3,4,5-trifluorophenyl) pyrimidin-5-sulfonamide) 100㎎, microcrystalline 100 mg of cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed, and then tableted according to a conventional tablet manufacturing method to prepare tablets.

<Formulation Example 3. Preparation of capsules>

The compound of the present invention 5 (the 4,6-bis (2,2,2-trifluoroethoxy) - N - (3,4,5-trifluorophenyl) pyrimidin-5-sulfonamide) 100㎎, microcrystalline After mixing 100 mg of cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose and 2 mg of magnesium stearate, the above ingredients are mixed according to a conventional capsule preparation method and filled in a gelatin capsule to prepare a capsule. prepared.

<Formulation Example 4. Preparation of Pills>

The compound of the present invention 5 (the 4,6-bis (2,2,2-trifluoroethoxy) - N - (3,4,5- trifluorophenyl) pyrimidin-5-sulfonamide) 90㎎, glutinous After mixing 5 mg of starch and 5 mg of purified water and a small amount of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as an additive for inhibiting hygroscopicity, 100 mg of pills were prepared according to a conventional method.

<Formulation Example 5. Preparation of injection>

The compound of the present invention 5 (the 4,6-bis (2,2,2-trifluoroethoxy) - N - (3,4,5-trifluorophenyl) pyrimidin-5-sulfonamide) 10㎎, week After mixing an appropriate amount of used sterile distilled water and an appropriate amount of a pH adjusting agent, the content of the above components per 1 ampoule (2 ml) was prepared according to a conventional method for preparing injections.

Claims (3)

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ₁ is substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₁₀ heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl or substituted or unsubstituted C ₆ - substituted with one or more substituents selected from the group consisting of C _{10 heteroaryl,}
In this case, the substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl is hydrogen, halogen, hydroxy, phenoxy, CF ₃ , NO ₂ , -S-(C ₁ -C ₆ alkyl), C ₁ -C ₆ at least one selected from the group consisting of alkyl, C ₂ -C ₆ alkynyl, -C ₁ -C ₆ alkylphenyl, C ₁ -C ₁₀ alkoxy, C ₆ -C ₁₀ aryl or C ₄ -C _{10 heterocycloalkyl} substituted with a substituent. According to claim 1,
In Formula 1,
R ₁ is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C ₆ -C ₁₀ aryl or substituted or unsubstituted C ₆ -C _{10 heteroaryl,}
In this case, the substituted aryl or heteroaryl is hydrogen, halogen, hydroxy, phenoxy, CF ₃ , NO ₂ , -S-(C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ A compound substituted with one or more substituents selected from the group consisting of alkynyl, -C ₁ -C ₆ alkylphenyl, C ₁ -C ₁₀ alkoxy, C ₆ -C ₁₀ aryl, or C ₄ -C _{10 heterocycloalkyl, or a compound thereof} Pharmaceutically acceptable salts. 3. The method of claim 1 or 2,
The compound of Formula 1 is
N- (3-phenoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 1);
N- (3-(methylthio)phenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 2);
N- (3,5-di-tert-butylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 3);
N- (benzo[ d ][1,3]dioxol-5-yl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 4);
4,6-bis (2,2,2-trifluoroethoxy-ethoxy) - N - (3,4,5- trifluorophenyl) pyrimidin-5-sulfonamide (compound 5);
4,6-bis (2,2,2-trifluoroethoxy) - N - (3,4,5- trimethoxyphenyl) pyrimidine-5-sulfonamide (compound 6);
N- (3,4-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 7);
N- (3-Chloro-4-iodophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 8);
N- (4-fluoro-3-(trifluoromethyl)phenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 9);
N- (3,5-dinitrophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 10);
N- (3-isopropylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 11);
N- (3-fluorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 12);
N- (3-Chloro-4-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 13);
N- (4-ethynylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 14);
N- (2-Chloro-5-methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 15);
N- (2-Fluoro-4-morpholinophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 16);
N- (3-Methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 17);
N- (1-Benzyl-1 H -pyrazol-4-yl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 18);
N- (2,6-dimethoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 19);
N- (2-Methoxyphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 20);
N- (4-iodo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 21);
N- ( o -Tolyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 22);
N- ( p -Tolyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 23);
N- (2,3-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 24);
N- (4-Methoxy-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 25);
N- (3-Chloro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 26);
N- (4-Chloro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 27);
N- (3-Bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 28);
N- (4-Bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 29);
N- (5-Bromo-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 30);
N- (2,4-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 31);
N- (4-Chloro-2,6-dimethylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 32);
N- (2,4,5-trichlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 33);
N- (3-Fluoro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 34);
N- (4-Fluoro-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 35);
N- (3-Chlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 36);
N- (4-Chlorophenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 37); and
N- (5-Methoxy-2-methylphenyl)-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonamide (Compound 38);
A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.