KR20210017860A - A pharmaceutical composition comprising novel pyrimidine sulfonamide derivatives for preventing or treating cancer - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising a pyrimidine sulfonamide derivative, in which a trifluoroethoxy group is disubstituted at a specific position, as an active component. The present invention can provide a compound with increased usefulness of a drug as an anticancer drug since the trifluoroethoxy group is introduced into pyrimidine sulfonamide to improve CD73 inhibitory activity, metabolic stability, and drug efficacy.

Description

A pharmaceutical composition comprising novel pyrimidine sulfonamide derivatives for preventing or treating cancer, comprising a novel pyrimidine sulfonamide derivative as an active ingredient.

The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising a novel pyrimidine sulfonamide derivative as an active ingredient.

ATP (adenosine triphosphate) is present in all living cells and plays a very important role in energy metabolism. One ATP molecule releases a large amount of energy through hydrolysis so that it can be used for biological activities. In a normal physiological state, the intracellular ATP concentration is maintained at an mM concentration, while the extracellular concentration is thoroughly controlled in the nM concentration range. However, under certain conditions, such as tissue damage, inflammation, ischemia, or 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 the purinergic 2 receptor (P2R), one of the purinergic receptors, and are involved in several physiological and pathological processes.

The current paradigm of purinergic signaling for the immune response can be explained by the balance between pro-inflammatory and anti-inflammatory signaling from individual extracellular ATP and adenosine. The secretion of ATP from stressed cells, apoptotic and necrotic cells during a physiological acute inflammatory reaction can serve as a'risk signal', which is essential for the elimination of bacteria, parasites and viruses in cells. In addition, ATP can induce immunogenic cell death in cancer cells that promote immune surveillance in the tumor microenvironment.

In contrast, 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 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 in 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.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 denosine receptor 2B).

CD73 (5'-nucleotidase, ecto-5'-nucelotidase) is an external nucleotide hydrolase (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 contributes to antitumor immunity suppression by interacting with specific receptors of T cells. This role of CD73 in inflammation and tumor formation is supported by the fact that CD73-deficient mice are vulnerable to inflammation/autoimmunity and exhibit resistance to tumor growth following adenosine-mediated immune suppression relief. In addition, CD73 was found to be a biomarker in patients with several tumor types, and most studies showed that high expression of CD73 was found 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 low treatment response.

Accordingly, a number of studies have recently been 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 a composition for preventing or treating cancer containing a pyrimidine sulfonamide derivative, International Publication No. 2011-072243 discloses a pyrimidine sulfonamide derivative having histone acetyl transferase (HAT) activity and its use. In addition, International Publication No. 2002-090348 discloses a sulfonamide derivative and its use as an antagonist of eurotensin II, and the preceding paper [Elderfield, RC et al., The Journal of Organic Chemistry, 26(10), 1961] Has disclosed 6-methyluracil 5-sulfonic acid, derivatives and anticancer uses thereof. However, there is no previous report mentioning the anticancer activity and the usefulness of drugs according to the introduction of a compound in which a trifluoroethoxy group is disubstituted at a specific position of a pyrimidine sulfonamide compound as in the present invention, and the substituent.

Accordingly, in the course of researching pyrimidine sulfonamide derivatives, the present inventors studied pyrimidine sulfonamide (4,6-bis (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) , A 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 A trifluoroethoxy group was introduced, but a benzene sulfonamide compound containing a benzene ring instead of pyrimidine (4,6-bis(2,2,2-trifluoroethoxy)- N -(3,4,5-trifluorophenyl)benzene- The present invention was completed by confirming that the bioavailability of the drug such as metabolic stability and persistence of drug efficacy, including CD73 inhibitory activity, was improved superiorly compared to 5-sulfonamide).

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

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 pharmaceutical composition for preventing or treating cancer comprising a novel pyrimidine sulfonamide derivative with improved CD73 inhibitory activity, metabolic stability, and drug persistence as an active ingredient.

The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[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,

At this time, 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 -C ₆ alkynyl, C ₁ -C ₆ alkylphenyl, C ₁ -C ₁₀ alkoxy, C ₄ -C ₁₀ aryl or C ₄ -C ₁₀ heterocycloalkyl is substituted with one or more substituents selected from the group consisting of.

More preferably in the 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,

At this time, 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 its It relates to a pharmaceutical composition for preventing or treating cancer comprising a pharmaceutically acceptable salt as an active ingredient.

To illustrate the compound of Formula 1 in more detail of the present invention,

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); It is selected from the group consisting of.

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

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

The term “alkyl” refers to a single bonded linear 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 bonded linear 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 of a single ring-shaped bond. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like can be mentioned.

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

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

The term "heterocycloalkyl" refers to a saturated hydrocarbon group of a single ring-shaped bond containing one or more heteroatoms such as N, O, or S, and the number and type of heteroatoms included in the ring, and the number of carbon atoms Lidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

The term “heteroaryl” refers to an aromatic cyclic compound containing one or more heteroatoms such as N, O, or S, and pyrrolyl, furanyl, pyridine depending on the number and type of heteroatoms contained in the ring, and the number of carbon atoms. Il, pyrimidinyl, and pyranyl.

In the present invention, the pharmaceutically acceptable salt refers to a salt or complex of Formula 1 having a desirable biological activity. Examples of such salts are not limited thereto, but inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid), phosphoric acid, nitric acid, etc. ], and acetic acid, oxalic acid, tartaric 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 And salts formed of organic acids such as naphthalene disulfonic acid and poly-galacturonic acid. The compounds can 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 carboxylate. Boxylate (e.g. benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate 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 May be prepared by filtration and drying, or may be prepared by distilling a solvent and an excess of acid under reduced pressure and drying to crystallize under an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be made 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. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is 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 the present invention.

In addition, the cancer is lung cancer, liver cancer, stomach cancer, colon cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, thyroid cancer, melanoma, blood cancer, colon cancer, non-small cell lung cancer, pancreatic cancer, skin cancer, head and neck cancer, small intestine Cancer, rectal cancer, endometrial cancer, vaginal cancer, testicular cancer, esophageal cancer, biliary cancer, lymph adenocarcinoma, gallbladder cancer, endocrine adenocarcinoma, adrenal cancer, lymphoma, multiple myeloma, thymoma, mesothelioma, kidney cancer, brain cancer, central nervous system tumor, brainstem glioma It may be selected from the group consisting of pituitary adenoma, but is not particularly limited thereto.

The pharmaceutical composition according to the present invention may be formulated in a suitable form together with a generally used pharmaceutically acceptable carrier. "Pharmacologically acceptable" refers to a composition that is physiologically acceptable and, when administered to humans, does not usually cause allergic reactions or similar reactions such as gastrointestinal disorders and dizziness. In addition, the compositions may be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injectable solutions according to a conventional method.

Carriers, excipients, and diluents that can be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil may be included, but are not limited thereto. In the case of formulation, it is prepared using diluents or excipients such as commonly used fillers, stabilizers, binders, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient, such as starch, microcrystalline cellulose, sucrose or lactose, in the compound of the present invention, It is prepared by mixing low-substituted hydroxypropyl cellulose and hypromellose. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, and preservatives may be included. . Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used as the non-aqueous solvent and the suspension. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like may be used. To formulate a formulation for parenteral administration, the pyrimidine sulfonamide derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized and/or a preservative, a stabilizer, a hydrating agent or an emulsification accelerator, a salt for controlling osmotic pressure, and/or Auxiliary agents such as buffers, and other therapeutically useful substances are mixed in water to prepare a solution or suspension, which can be prepared in ampoules or vials unit dosage form.

The pharmaceutical composition provides a pharmaceutical composition comprising the pyrimidine sulfonamide derivative compound of Formula 1 and an excipient. The compound may be added in an amount of preferably 0.001% to 50% by weight, more preferably 0.001% to 40% by weight, and most preferably 0.001% to 30% by weight based on the total weight of the total composition.

The pharmaceutical composition comprising the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals such as mice, livestock, and humans by various routes. All modes of administration can be expected and can be administered, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injection. The dosage is the age, sex, weight of the subject to be treated, the specific disease or pathology to be treated, the severity of the disease or pathology, the time of administration, the route of administration, the absorption, distribution and excretion rate of the drug, the types of other drugs used, and the prescriber's It will depend on your judgment, etc. Dosage determination based on these factors is within the level of one of ordinary skill in the art, and dosages generally range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is from 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be divided several times. The above dosage does not in any way limit the scope of the present invention.

The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising a pyrimidine sulfonamide derivative having a disubstituted trifluoroethoxy group at a specific position as an active ingredient, and introducing a trifluoroethoxy group to the pyrimidine sulfonamide By doing so, it is possible to provide a compound in which CD73 inhibitory activity, metabolic stability, and drug persistence are excellently improved, and thus the usefulness of the drug is increased as an anticancer drug.

Hereinafter, a preferred embodiment 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, the content introduced herein becomes thorough and complete, and is provided to sufficiently convey the spirit of the present invention to those skilled in the art.

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

Compounds 1 to 38 of the present invention synthesized pyrimidine sulfonamide derivatives containing various substituents R ₁ with reference to the following [Scheme], and the physicochemical properties thereof are as follows.

[Reaction Scheme]

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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-phenoxyaniline (25 mg, 1.0 eq. , 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45 wt%) (0.02 ml, 1.6 eq, 0.213 mmol) 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 36% (25.4 mg), and the NMR result thereof is 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 (50mg, 0.133mmol) and 3-(methylthio)aniline (0.02ml, 1.0) in a 7ml vial. eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45 wt%) (0.02 ml, 1.6 eq, 0.213 mmol) 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 51% (32.3 mg), and the NMR result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3,5-di-tert-butylaniline (27 Mg, 1.0eq., 0.133mmol) was added. Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a white solid product in a yield of 47% (34 mg), and the NMR result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3,4-methylenedioxyaniline (18 mg, 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 27% (17.1 mg), and the NMR result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3,4,5-trifluoroaniline (20 Mg, 1.0eq., 0.133mmol) was added. Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, silica gel column chromatography (EA: Hex = 1:1) was used to obtain a transparent solid product with a yield of 17% (10.8 mg), and the NMR results 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3,4,5-trimethoxyaniline (24 Mg, 1.0eq., 0.133mmol) was added. Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 39% (27.3 mg), and the NMR result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3,4-dimethylaniline (16 mg, 1.0 eq. ., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 46% (28.3 mg), and the NMR result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-chloro-4-iodoaniline (34 mg) , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 result thereof is 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 (50mg, 0.133mmol) and 4-fluoro-3-(trifluoromethyl) in a 7ml vial. ) Add aniline (0.02ml, 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 its NMR results 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3,5-dinitroaniline (20 mg, 1.0 eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a yellow solid product in a yield of 12% (8.3 mg), and the NMR result thereof is 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)

In a 7ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3-isopropylaniline (18mg, 1.0eq. , 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, silica gel column chromatography (EA: Hex = 1:1) was used to obtain a transparent solid product with a yield of 44% (27.6 mg), and the NMR results 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-fluoroaniline (0.013 ml, 1.0 eq. , 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, silica gel column chromatography (EA: Hex = 1:1) was used to obtain a transparent solid product with a yield of 16% (9.8 mg), and the NMR results 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 (50mg, 0.133mmol) and 3-chloro-4-methoxyaniline (17.5mg) in a 7ml vial. , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-ethynylaniline (13 mg, 1.0 eq. , 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 its NMR result is 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, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 12% (7.6 mg), and its NMR result is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 2-fluoro-4-morpholinoaniline ( 22mg, 1.0eq., 0.133mmol) was added. Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-methoxyaniline (14 mg, 1.0 eq. , 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 33% (20.4 mg), and the NMR result thereof is 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 (50 mg, 0.133 mmol) and 1-benzyl-1H-pyrazol-4-amine in a 7 ml vial (14mg, 1.0eq., 0.133mmol) is added. Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, silica gel column chromatography (EA: Hex = 1:1) was used to obtain a white solid product in a yield of 37% (25.5 mg), and the NMR results 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 2,6-dimethoxyaniline (17 mg, 1.0 eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 result thereof is 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 (50 mg, 0.133 mmol) and o-anisidine (14 mg, 1.0 eq., in a 7 ml vial) 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45 wt%) (0.02 ml, 1.6 eq, 0.213 mmol) 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 20% (12.3 mg), and the NMR result thereof is 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 (50mg, 0.133mmol) and 4-iodo-2-methylaniline (26mg) in a 7ml vial. , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 result thereof is 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). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 19% (9.6 mg), and the NMR result thereof is 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). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, silica gel column chromatography (EA: Hex = 1:1) was used to obtain a transparent solid product with a yield of 17% (8.6 mg), and the NMR results 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)

In a 7ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 2,3-dimethylaniline (14mg, 1.0eq. ., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-methoxy-2-methylaniline (15 mg) , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, silica gel column chromatography (EA: Hex = 1:1) was used to obtain a transparent solid product with a yield of 13% (6.8 mg), and the NMR results 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)

In a 7ml vial, 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, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 18% (9.5 mg), and the NMR result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-chloro-2-methylaniline (16 mg, 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 18% (9.7 mg), and the NMR result thereof is 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)

In a 7ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50mg, 0.133mmol) and 3-bromo-2-methylaniline (21mg) , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 23% (13.2 mg), and its NMR results 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, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, silica gel column chromatography (EA: Hex = 1:1) was used to obtain a transparent solid product with a yield of 11% (6 mg), and the NMR results 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 5-bromo-2-methylaniline (21 mg) , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 result thereof is 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 ., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 22% (11.1 mg), and the NMR result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 4-chloro-2,6-dimethylaniline (17 Mg, 1.0eq., 0.133mmol) was added. Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 18% (9.6 mg), and its NMR result is 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 (50mg, 0.133mmol) and 2,4,5-trichloroaniline (22mg) in a 7ml vial. , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in a yield of 20% (12.1 mg), and its NMR results 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 3-fluoro-2-methylaniline (14 mg) , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 result thereof is 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, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 result thereof is 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., in a 7ml vial) 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product 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 its NMR results 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 (50 mg, 0.133 mmol) and 4-chloroaniline (14 mg, 1.0 eq., in a 7 ml vial) 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid with a yield of 41% (21.3 mg), and the NMR result thereof is 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)

In a 7 ml vial, 4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-sulfonyl chloride (50 mg, 0.133 mmol) and 2-methoxy-5-methylaniline (15 mg) , 1.0eq., 0.133mmol). Then, acetonitrile (0.53M, 0.25ml) was added at 0℃. After that, potassium hydroxide (45wt%) (0.02ml, 1.6eq, 0.213mmol) was added and reacted at 0℃ 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 concentrated under reduced pressure. Thereafter, the product was separated by silica gel column chromatography (EA: Hex = 1:1) to obtain a product as a transparent solid in 89% (47.2 mg) yield, and its NMR result is 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. Anticancer activity confirmation>

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

First, 25mM Tris- HCl and 5 mM magnesium chloride were mixed) to prepare.

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

After 10 minutes, AMP was made to be 100 μM using the assay buffer, and then put into all wells and mixed and reacted at 37 °C for 20 minutes. After 20 minutes, 20 µl of Malachite Green Reagent A was added per well, followed by mixing 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

Looking at Table 1, it was found that the compounds of the present invention (pyrimidine sulfonamide derivatives having a disubstituted trifluoroethoxy group) exhibited CD73 enzyme inhibitory activity and thus could be used as a candidate material for cancer treatment.

In particular, although not shown in Table 1 above, the compound of the present invention is a pyrimidine sulfonamide compound in which a trifluoromethoxy group is disubstituted instead of a trifluoroethoxy group (4,6-bis(2,2,2-trifluoromethoxy) -N -( 3,4,5-trifluorophenyl)pyrimidine-5-sulfonamide), a pyrimidine sulfonamide compound in which only one trifluoroethoxy group is substituted without a trifluoroethoxy group disubstituted (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 benzene sulfonamide compounds containing benzene ring instead of pyrimidine (4,6-bis(2,2,2-trifluoroethoxy) -Compared to N- (3,4,5-trifluorophenyl)benzene-5-sulfonamide), metabolic stability and persistence of drug efficacy including CD73 inhibitory activity were excellently improved, indicating that it was a compound with increased drug usefulness.

<Formulation Example 1. Preparation of powder>

The compound of the present invention 5 (the 4,6-bis (2,2,2-trifluoroethoxy) - N - (3,4,5- trifluorophenyl) pyrimidin-5-sulfonamide), 2g, 1g Lactose 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 After mixing 100 mg of cellulose, 60 mg of lactose, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, tablets were prepared by tableting according to a conventional tablet preparation method.

<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, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, the above ingredients were mixed according to a conventional capsule preparation method, and then filled into a gelatin capsule to prepare a capsule. Was 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 5 mg of starch and 5 mg of purified water and a small amount of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives to inhibit hygroscopicity were mixed, and then 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 sterilized distilled water and an appropriate amount of a pH adjuster, it was prepared in the amount of the above components per ampoule (2 ml) according to a conventional method for preparing an injection.

Claims (4)

A pharmaceutical composition for preventing or treating cancer comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[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,
At this time, 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 -C ₆ alkynyl, C ₁ -C ₆ alkylphenyl, C ₁ -C ₁₀ alkoxy, C ₄ -C ₁₀ aryl or C ₄ -C ₁₀ heterocycloalkyl is substituted with one or more substituents selected from the group consisting of. The method of claim 1,
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,
At this time, 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 heterocycloalkyl. Cancer prevention or treatment, characterized in that substituted with one or more substituents selected from the group consisting of Pharmaceutical composition for use. The method according to 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);
Cancer prevention or treatment pharmaceutical composition, characterized in that selected from the group consisting of. The method according to claim 1 or 2,
The cancer is lung cancer, liver cancer, stomach cancer, colon cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, thyroid cancer, melanoma, blood cancer, colon cancer, non-small cell lung cancer, pancreatic cancer, skin cancer, head and neck cancer, small intestine cancer, Rectal cancer, endometrial cancer, vaginal cancer, testicular cancer, esophageal cancer, biliary tract cancer, lymph adenocarcinoma, gallbladder cancer, endocrine adenocarcinoma, adrenal cancer, lymphoma, multiple myeloma, thymoma, mesothelioma, kidney cancer, brain cancer, central nervous system tumor, brainstem glioma and pituitary adenoma Cancer prevention or treatment pharmaceutical composition, characterized in that selected from the group consisting of.