CN116640095A - Diaryl amine derivative containing aliphatic carboxyl and preparation method and application thereof - Google Patents

Abstract

The invention relates to a diaryl amine derivative containing aliphatic carboxyl, a preparation method and application thereof. The compound isHas a structure shown in a formula I. The invention also relates to a preparation method of the compound containing the structure shown in the formula I and a pharmaceutical composition. The invention also provides application of the compound in preparing uric acid reducing medicines.

Description

A diarylamine derivative containing a fatty carboxyl group and its preparation method and application

Technical Field

The present invention relates to the field of drugs for treating hyperuricemia and gout, and in particular to a diarylamine compound containing a fatty carboxyl group having uric acid-lowering activity, a preparation method thereof, or a drug combination containing the same, and a use thereof in medicine.

Background Art

Gout is a metabolic disease caused by uric acid metabolism disorder in the body. Its clinical manifestations are mainly arthritis, tophi and kidney damage. Uric acid is the end product of purine metabolism. Under normal circumstances, it is excreted from the body through the kidneys. However, gout patients cannot effectively excrete uric acid from the body, resulting in excessive accumulation in the body. This accumulation will eventually lead to uric acid crystallization in joints and soft tissues, causing the onset of acute symptoms of gout. Gout is more common in men, especially middle-aged and elderly men. High-calorie, high-purine diet and alcoholism are the main risk factors for gout attacks. In addition, diseases such as obesity, hypertension, diabetes and kidney disease also increase the risk of gout. Currently, drugs for the treatment of gout are mainly divided into two categories: one is xanthine oxidoreductase inhibitors (XOI) that inhibit uric acid production, and the other is uric acid transporter 1 (URAT1) inhibitors that promote uric acid excretion. URAT1 is located on the brush border of human renal proximal tubular epithelial cells and mainly mediates the reabsorption of uric acid in the kidney. Increased URAT1 activity or gene expression caused by its gene mutation is one of the important pathogenesis of hyperuricemia. Lesinurad is a URAT1 inhibitor used to treat hyperuricemia and gout. It has been listed as a black box warning drug by the FDA due to its large therapeutic dose and serious toxic side effects. It was withdrawn from the US market in 2019 and has not been listed in China so far. Therefore, it is of great significance to discover new anti-gout drugs that are highly effective, low-toxic and have independent intellectual property rights.

Summary of the invention

In view of the deficiencies of the prior art, the present invention provides a diarylamine derivative containing a fatty carboxyl group and a preparation method thereof. The present invention also provides the activity screening results of the above-mentioned compounds as anti-gout drugs and their application.

The technical solution of the present invention is as follows:

1. Diarylamine derivatives containing fatty carboxyl groups

The diarylamine derivatives containing aliphatic carboxyl groups of the present invention or pharmaceutically acceptable salts thereof have a structure shown in the following general formula I:

Wherein, Y is a five-membered or six-membered fused ring pyrimidine; R is an alkane or a substituted alkane, and the substituent is a C1-C5 alkane.

According to the preferred embodiment of the present invention, Y is pyrimidine, quinazoline, 6,7-dimethoxyquinazoline, 7-fluoroquinazoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, 5,7-dihydrofurano[3,4-d]pyrimidine, 6,7-dihydrothieno[3,2-d]pyrimidine, 6,7-dihydro-5H-cyclopentylpyrimidine; R is

According to the present invention, the diarylamine derivative containing aliphatic carboxyl groups is preferably one of the following:

Table 1 Structures of compounds in YJ series 1 to 54

2. Preparation method of diarylamine derivatives containing fatty carboxyl groups The preparation method of diarylamine derivatives containing fatty carboxyl groups YJ-1 to 54 of the present invention comprises the following steps:

The starting materials 2,4-dichloropyrimidine, 2,4-dichloroquinazoline, 2,4-dichloro-6,7-dimethoxyquinazoline, 2,4-dichloro-7-fluoroquinazoline, 2,4-dichlorothieno[3,2-d]pyrimidine, 2,4-dichlorothieno[2,3-d]pyrimidine, 2,4-dichloro-5,7-dihydrofuranopyrimidine, 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine, 2,4-dihydro-6,7-dihydro-5H-cyclopentyl[d]pyrimidine were reacted with 4-cyano -1-aniline is placed in a hydrochloric acid aqueous solution, and intermediates 2a~2i are obtained by nucleophilic substitution reaction at 50°C; then 2a~2i are reacted with thiourea in an acetonitrile solution at 80°C to generate intermediates 3a~3i; then, intermediates 3a~3i are reacted with different halogenated esters in a potassium carbonate N,N-dimethylformamide (DMF) solution to undergo nucleophilic substitution reaction to obtain ester intermediates; finally, the ester intermediates are hydrolyzed with lithium hydroxide to obtain target compounds YJ-1~54;

The synthetic route is as follows:

Reaction reagents and conditions: (i) 4-cyano-1-aniline, concentrated hydrochloric acid, water, 50°C; (ii) thiourea, acetonitrile, 80°C; (iii) methyl 2-bromoacetate or other different halogenated esters, potassium carbonate, N,N-dimethylformamide, room temperature; (iv) lithium hydroxide, tetrahydrofuran, methanol, room temperature.

The different halogenated esters are selected from: methyl 2-bromoacetate, methyl 2-bromopropionate, methyl 2-bromo-2-methylpropionate, methyl 3-bromopropionate, methyl 4-bromobutyrate or ethyl 1-bromocyclobutane-1-carboxylate.

The room temperature described in the present invention refers to 20-30°C.

3. Application of diarylamine derivatives containing fatty carboxyl groups

The present invention discloses the results of screening the blood uric acid lowering activity of diarylamine derivatives containing aliphatic carboxyl groups and the first application thereof in preparing a uric acid lowering drug. Experiments prove that the diarylamine derivatives containing aliphatic carboxyl groups of the present invention can be used as a blood uric acid lowering drug. Specifically, they can be used as blood uric acid lowering compounds for preparing a uric acid lowering drug. The present invention also provides the application of the above compounds in preparing a uric acid lowering drug.

Uric acid-lowering activity of target compounds in mice:

The 54 target compounds (structural formulas shown in Table 1) synthesized according to the above method were tested for their uric acid-lowering activity in mice. The results are shown in Table 2.

It can be seen from Tables 2-5 that 40 compounds have better uric acid-lowering activity in mice than Lecithin (36.5%), among which compounds YJ-20 (74.2%), YJ-21 (71.9%), YJ-26 (75.4%), YJ-49 (89.9%) and YJ-50 (78.3%) have blood uric acid reduction rates of more than 70%, showing excellent uric acid-lowering activity and can be used as candidate uric acid-lowering drugs.

Therefore, the fatty carboxyl-containing diarylamine derivatives of the present invention are a series of novel compounds with blood uric acid lowering activity, which can be used as candidate anti-gout drugs and used for preparing uric acid lowering drugs.

A uric acid-lowering pharmaceutical composition comprises the fatty carboxyl-containing diarylamine derivative of the present invention and one or more pharmaceutically acceptable carriers or excipients.

DETAILED DESCRIPTION

The following examples are helpful for understanding the present invention, but they cannot limit the content of the present invention. In the following examples, the numbers of all target compounds are the same as those in Table 1.

Scheme 1. Reagents and conditions: (i) 4-cyano-1-aniline, concentrated hydrochloric acid, water, 50°C; (ii) thiourea, acetonitrile, 80°C; (iii) methyl 2-bromoacetate or other different halogenated esters, potassium carbonate, N,N-dimethylformamide, room temperature; (iv) lithium hydroxide, tetrahydrofuran, methanol, room temperature.

As shown in Scheme 1, the starting materials 2,4-dichloropyrimidine, 2,4-dichloroquinazoline, 2,4-dichloro-6,7-dimethoxyquinazoline, 2,4-dichloro-7-fluoroquinazoline, 2,4-dichlorothieno[3,2-d]pyrimidine, 2,4-dichlorothieno[2,3-d]pyrimidine, 2,4-dichloro-5,7-dihydrofuranopyrimidine, 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine, and 2,4-dihydro-6,7-dihydro-5H-cyclopentyl[d]pyrimidine are placed in a hydrochloric acid aqueous solution with 4-cyano-1-aniline, and the intermediates 2a to 2i are obtained by nucleophilic substitution reaction at 50°C. Subsequently, 2a to 2i are reacted with thiourea in an acetonitrile solution at 80°C to generate intermediates 3a to 3i. Next, intermediates 3a-3i are reacted with different halogenated esters in a DMF solution of potassium carbonate to undergo nucleophilic substitution reaction to obtain ester intermediates. Finally, the ester intermediates are hydrolyzed with lithium hydroxide to obtain target compounds YJ-1-54.

The different halogenated esters are selected from: methyl 2-bromoacetate, methyl 2-bromopropionate, methyl 2-bromo-2-methylpropionate, methyl 3-bromopropionate, methyl 4-bromobutyrate, or ethyl 1-bromocyclobutane-1-carboxylate. The room temperature of the present invention refers to 20-30°C. Synthesis steps of YJ series target compounds (Scheme 1)

General method for preparing compounds 2a to 2i

4-Cyano-1-aniline (1.08 eq), concentrated HCl (0.5 mL) and different starting materials 1a-1i (1.0 eq) were mixed in 40 mL _{H 2} O and stirred at 50° C. for 12 h. After the reaction was completed (TLC monitoring), the precipitate was filtered from the solution and washed with 20 mL petroleum ether. The precipitate was collected and dried in a drying oven to obtain 2a-2i.

4-((2-Chloropyrimidin-4-yl)amino)benzonitrile (2a)

White solid. Yield: 77.4%. Melting point: 104-106°C. ESI-MS: m/z 231.05 [M+H] ⁺ .C ₁₁ H ₇ ClN ₄ (Exact Mass: 230.04).

4-((2-Chloroquinazolin-4-yl)amino)benzonitrile (2b)

Yellow solid. Yield: 78.0%. Melting point: 93-96°C. ESI-MS: m/z 281.07 [M+H] ⁺ .C ₁₅ H ₉ ClN ₄ (Exact Mass: 280.05).

4-((2-Chloro-6,7-dimethoxyquinazolin-4-yl)amino)benzonitrile (2c)

Yellow solid. Yield: 80.0%. Melting point: 204-206°C. ESI-MS: m/z 341.10 [M+H] ⁺ .C ₁₇ H ₁₃ ClN ₄ O ₂ (Exact Mass: 340.07).

4-((2-Chloro-7-fluoroquinazolin-4-yl)amino)benzonitrile (2d)

Purple solid. Yield: 80.0%. Melting point: 153-156°C. ESI-MS: m/z 299.22 [M+H] ⁺ .C ₁₅ H ₈ ClFN ₄ (Exact Mass: 298.04).

4-((2-Chlorothieno[3,2-d]pyrimidin-4-yl)amino)benzonitrile (2e)

White solid. Yield: 77.0%. Melting point: 114-116°C. ESI-MS: m/z 287.06 [M+H] ⁺ .C ₁₃ H ₇ ClN ₄ S (Exact Mass: 286.01).

4-((2-Chlorothieno[2,3-d]pyrimidin-4-yl)amino)benzonitrile (2f)

White solid. Yield: 79.0%. Melting point: 133-136°C. ESI-MS: m/z 287.10 [M+H] ⁺ .C ₁₃ H ₇ ClN ₄ S (Exact Mass: 286.01).

4-((2-Chloro-5,7-dihydrofuran[3,4-d]pyrimidin-4-yl)amino)benzonitrile (2 g)

White solid. Yield: 79.0%. Melting point: 134-136°C. ESI-MS: m/z 273.08 [M+H] ⁺ .C ₁₃ H ₉ ClN ₄ O (Exact Mass: 272.05).

4-((2-Chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)benzonitrile (2h)

Yellow solid. Yield: 79.0%. Melting point: 213-216°C. ESI-MS: m/z 289.03 [M+H] ⁺ .C ₁₃ H ₉ ClN ₄ S (Exact Mass: 288.02).

4-((2-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)benzonitrile (2i)

Blue solid. Yield: 78.0%. Melting point: 143-146°C. ESI-MS: m/z 271.10 [M+H] ⁺ .C ₁₄ H ₁₁ ClN ₄ (Exact Mass: 270.07).

General method for preparing compounds 3a to 3i

Thiourea (3.0 eq) and different raw materials 2a-2i (1.0 eq) were added to 50 mL of acetonitrile, respectively, and stirred at 80°C for 6 h. After the reaction was completed (monitored by TLC), it was cooled to room temperature and the solvent was filtered. The residue was washed with water and dried, and recrystallized from ethyl acetate to obtain 3a-3i.

4-((2-Mercaptopyrimidin-4-yl)amino)benzonitrile (3a)

White solid. Yield: 67.3%. Melting point: 109-112°C. ESI-MS: m/z 227.05 [MH] ^- .C ₁₁ H ₈ N ₄ S (Exact Mass: 228.05).

4-((2-Mercaptoquinazolin-4-yl)amino)benzonitrile (3b)

Yellow solid. Yield: 70.0%. Melting point: 103-106°C. ESI-MS: m/z 277.03 [MH] ^- .C ₁₅ H ₁₀ N ₄ S (Exact Mass: 278.06).

4-((2-Mercapto-6,7-dimethoxyquinazolin-4-yl)amino)benzonitrile (3c)

Yellow solid. Yield: 70.0%. Melting point: 211-213°C. ESI-MS: m/z 337.06 [MH] ^- .C ₁₇ H ₁₄ N ₄ O ₂ S (Exact Mass: 338.08).

4-((7-Fluoro-2-mercaptoquinazolin-4-yl)amino)benzonitrile (3d)

Purple solid. Yield: 70.0%. Melting point: 173-176°C. ESI-MS: m/z 295.03 [MH] ^- .C ₁₅ H ₉ FN ₄ S (Exact Mass: 296.05).

4-((2-Mercaptothieno[3,2-d]pyrimidin-4-yl)amino)benzonitrile (3e)

White solid. Yield: 70.0%. Melting point: 117-120°C. ESI-MS: m/z 283.02 [MH] ^- .C ₁₃ H ₈ N ₄ S ₂ (Exact Mass: 284.02).

4-((2-Mercaptothieno[2,3-d]pyrimidin-4-yl)amino)benzonitrile (3f)

White solid. Yield: 69.0%. Melting point: 133-136°C. ESI-MS: m/z 283.03 [MH] ^- .C ₁₃ H ₈ N ₄ S ₂ (Exact Mass: 284.02).

4-((2-Mercapto-5,7-dihydrofuran[3,4-d]pyrimidin-4-yl)amino)benzonitrile (3 g)

White solid. Yield: 79.0%. Melting point: 143-146°C. ESI-MS: m/z 269.08 [MH] ^- .C ₁₃ H ₁₀ N ₄ OS (Exact Mass: 270.06).

4-((2-Mercapto-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)benzonitrile (3h)

Yellow solid. Yield: 70.0%. Melting point: 221-223°C. ESI-MS: m/z 285.03 [MH] ^- .C ₁₃ H ₁₀ N ₄ S ₂ (Exact Mass: 286.03).

4-((2-Mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)benzonitrile (3i)

Blue solid. Yield: 60.0%. Melting point: 153-156°C. ESI-MS: m/z 267.07 [MH] ^- .C ₁₄ H ₁₂ N ₄ S (Exact Mass: 268.08).

General method for preparing compounds 4X1 to 4X6 (X = a to i)

Different intermediates 3a-3i (1.0 eq) were dissolved in N,N-dimethylformamide (10 mL) in the presence of potassium carbonate (1.2 eq), and then methyl 2-bromoacetate or methyl 2-bromopropionate or methyl 2-bromo-2-methylpropionate or methyl 3-bromopropionate or methyl 4-bromobutyrate or ethyl 1-bromocyclobutane-1-carboxylate (1.5 eq) were added, and the mixture was stirred at room temperature for 4 h (TLC monitoring). Subsequently, it was dissolved in ethyl acetate (30 mL), washed with saturated sodium chloride aqueous solution (3×10 mL), dried over anhydrous Na ₂ SO ₄ , and filtered. Column chromatography purification gave compounds 4X1-4X6 (X=a-i).

Methyl 2-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)acetate (4a-1)

White solid. Yield: 79.0%. Melting point: 98-101°C. ESI-MS: m/z 301.06 [M+H] ⁺ .C ₁₄ H ₁₂ N ₄ O ₂ S (Exact Mass: 300.07).

Methyl 2-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)propanoate (4a-2)

White solid. Yield: 79.0%. Melting point: 102-104°C. ESI-MS: m/z 315.18 [M+H] ⁺ .C ₁₅ H ₁₄ N ₄ O ₂ S (Exact Mass: 314.08).

Methyl 2-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)-2-methylpropanoate (4a-3)

White solid. Yield: 79.0%. Melting point: 110-112°C. ESI-MS: m/z 329.20 [M+H] ⁺ .C ₁₆ H ₁₆ N ₄ O ₂ S (Exact Mass: 328.10).

Methyl 3-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)propanoate (4a-4)

White solid. Yield: 72.6%. Melting point: 111-113°C. ESI-MS: m/z 315.08 [M+H] ⁺ .C ₁₅ H ₁₄ N ₄ O ₂ S (Exact Mass: 314.08).

Methyl 4-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)butanoate (4a-5)

White solid. Yield: 66.4%. Melting point: 154-157°C. ESI-MS: m/z 329.17 [M+H] ⁺ .C ₁₆ H ₁₆ N ₄ O ₂ S (Exact Mass: 328.10).

Ethyl 1-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)cyclobutane-1-carboxylate (4a-6)

White solid. Yield: 42.0%. Melting point: 104-107°C. ESI-MS: m/z 355.19 [M+H] ⁺ .C ₁₈ H ₁₈ N ₄ O ₂ S (Exact Mass: 354.12).

Methyl 2-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)acetate (4b-1)

Yellow solid. Yield: 80.0%. Melting point: 155-157°C. ESI-MS: m/z 351.12 [M+H] ⁺ .C ₁₈ H ₁₄ N ₄ O ₂ S (Exact Mass: 350.08).

Methyl 2-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)propanoate (4b-2)

White solid. Yield: 79.8%. Melting point: 133-136°C. ESI-MS: m/z 365.17 [M+H] ⁺ .C ₁₉ H ₁₆ N ₄ O ₂ S (Exact Mass: 364.10).

Methyl 2-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)-2-methylpropanoate (4b-3)

White solid. Yield: 70.0%. Melting point: 108-111°C. ESI-MS: m/z 379.13 [M+H] ⁺ .C ₂₀ H ₁₈ N ₄ O ₂ S (Exact Mass: 378.12).

Methyl 3-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)propanoate (4b-4)

Yellow solid. Yield: 60.0%. Melting point: 157-160°C. ESI-MS: m/z 365.10 [M+H] ⁺ .C ₁₉ H ₁₆ N ₄ O ₂ S (Exact Mass: 364.10).

Methyl 4-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)butanoate (4b-5)

White solid. Yield: 60.0%. Melting point: 111-114°C. ESI-MS: m/z 379.10 [M+H] ⁺ .C ₂₀ H ₁₈ N ₄ O ₂ S (Exact Mass: 378.12).

Ethyl 1-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)cyclobutane-1-carboxylate (4b-6)

White solid. Yield: 54.0%. Melting point: 165-168°C. ESI-MS: m/z 405.15 [M+H] ⁺ .C ₂₂ H ₂₀ N ₄ O ₂ S (Exact Mass: 404.13).

Methyl 2-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)acetate (4c-1)

Yellow solid. Yield: 79.0%. Melting point: 150-153°C. ESI-MS: m/z 411.11 [M+H] ⁺ .C ₂₀ H ₁₈ N ₄ O ₄ S (Exact Mass: 410.10).

Methyl 2-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)propanoate (4c-2)

Yellow solid. Yield: 80.0%. Melting point: 176-178°C. ESI-MS: m/z 425.11 [M+H] ⁺ .C ₂₁ H ₂₀ N ₄ O ₄ S (Exact Mass: 424.12).

Methyl 2-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)-2-methylpropanoate (4c-3)

Yellow solid. Yield: 66.0%. Melting point: 154-157°C. ESI-MS: m/z 439.17 [M+H] ⁺ .C ₂₂ H ₂₂ N ₄ O ₄ S (Exact Mass: 438.14).

Methyl 3-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)propanoate (4c-4)

Yellow solid. Yield: 45.0%. Melting point: 180-183°C. ESI-MS: m/z 425.13 [M+H] ⁺ .C ₂₁ H ₂₀ N ₄ O ₄ S (Exact Mass: 424.12).

Methyl 4-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)butanoate (4c-5)

White solid. Yield: 60.1%. Melting point: 175-179°C. ESI-MS: m/z 439.15 [M+H] ⁺ .C ₂₂ H ₂₂ N ₄ O ₄ S (Exact Mass: 438.14).

Ethyl 1-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)cyclobutane-1-carboxylate (4c-6)

Yellow solid. Yield: 40.0%. Melting point: 207-210°C. ESI-MS: m/z 465.17 [M+H] ⁺ .C ₂₄ H ₂₄ N ₄ O ₄ S (Exact Mass: 464.15).

Methyl 2-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)acetate (4d-1)

White solid. Yield: 78.0%. Melting point: 107-109°C. ESI-MS: m/z 369.11 [M+H] ⁺ .C ₁₈ H ₁₃ FN ₄ O ₂ S (Exact Mass: 368.07).

Methyl 2-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)propanoate (4d-2)

Red solid. Yield: 72.0%. Melting point: 107-110°C. ESI-MS: m/z 383.11 [M+H] ⁺ .C ₁₉ H ₁₅ FN ₄ O ₂ S (Exact Mass: 382.09).

Methyl 2-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)-2-methylpropanoate (4d-3)

White solid. Yield: 79.0%. Melting point: 130-135°C. ESI-MS: m/z 397.13 [M+H] ⁺ .C ₂₀ H ₁₇ FN ₄ O ₂ S (Exact Mass: 396.11).

Methyl 3-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)propanoate (4d-4)

White solid. Yield: 69.0%. Melting point: 170-175°C. ESI-MS: m/z 383.10 [M+H] ⁺ .C ₁₉ H ₁₅ FN ₄ O ₂ S (Exact Mass: 382.09).

Methyl 4-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)butanoate (4d-5)

White solid. Yield: 60.0%. Melting point: 90-93°C. ESI-MS: m/z 397.13 [M+H] ⁺ .C ₂₆ H ₂₄ FN ₃ O ₂ S (Exact Mass: 396.11).

Ethyl 1-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)cyclobutane-1-carboxylate (4d-6)

Yellow solid. Yield: 40.0%. Melting point: 143-147°C. ESI-MS: m/z 423.15 [M+H] ⁺ .C ₂₂ H ₁₉ FN ₄ O ₂ S (Exact Mass: 422.12).

Methyl 2-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)acetate (4e-1)

Yellow solid. Yield: 78.0%. Melting point: 180-183°C. ESI-MS: m/z 357.08 [M+H] ⁺ .C ₁₆ H1 ₂ N ₄ O ₂ S ₂ (Exact Mass: 356.04).

Methyl 2-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)propanoate (4e-2)

Yellow solid. Yield: 81.2%. Melting point: 132-135°C. ESI-MS: m/z 371.06 [M+H] ⁺ .C ₁₇ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 370.06).

Methyl 2-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)-2-methylpropanoate (4e-3)

Yellow solid. Yield: 70.0%. Melting point: 131-133°C. ESI-MS: m/z 385.17 [M+H] ⁺ .C ₁₈ H ₁₆ N ₄ O ₂ S ₂ (Exact Mass: 384.07).

Methyl 3-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)propanoate (4e-4)

White solid. Yield: 50.0%. Melting point: 111-114°C. ESI-MS: m/z 371.08 [M+H] ⁺ .C ₁₇ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 370.06).

Methyl 4-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)butanoate (4e-5)

White solid. Yield: 40%. Melting point: 132-134°C. ESI-MS: m/z 385.07 [M+H] ⁺ .C ₁₈ H ₁₆ N ₄ O ₂ S ₂ (Exact Mass: 384.07).

Ethyl 1-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)cyclobutane-1-carboxylate (4e-6)

White solid. Yield: 35.0%. Melting point: 176-180°C. ESI-MS: m/z 411.11 [M+H] ⁺ .C ₂₀ H ₁₈ N ₄ O ₂ S ₂ (Exact Mass: 410.09).

Methyl 2-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)acetate (4f-1)

Yellow solid. Yield: 80.0%. Melting point: 180-183°C. ESI-MS: m/z 357.08 [M+H] ⁺ .C ₁₆ H ₁₂ N ₄ O ₂ S ₂ (Exact Mass: 356.04).

Methyl 2-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)propanoate (4f-2)

Yellow solid. Yield: 80.0%. Melting point: 132-135°C. ESI-MS: m/z 371.06 [M+H] ⁺ .C ₁₇ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 370.06).

Methyl 2-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)-2-methylpropanoate (4f-3)

White solid. Yield: 79.0%. Melting point: 123-125°C. ESI-MS: m/z 385.17 [M+H] ⁺ .C ₁₈ H ₁₆ N ₄ O ₂ S ₂ (Exact Mass: 384.07).

Methyl 3-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)propanoate (4f-4)

Yellow solid. Yield: 55.0%. Melting point: 110-114°C. ESI-MS: m/z 371.08 [M+H] ⁺ .C ₁₇ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 370.06).

Methyl 4-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)butanoate (4f-5)

Yellow solid. Yield: 35%. Melting point: 152-155°C. ESI-MS: m/z 385.07 [M+H] ⁺ .C ₁₈ H ₁₆ N ₄ O ₂ S ₂ (Exact Mass: 384.07).

Ethyl 1-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)cyclobutane-1-carboxylate (4f-6)

White solid. Yield: 35.0%. Melting point: 177-180°C. ESI-MS: m/z 411.11 [M+H] ⁺ .C ₂₀ H ₁₈ N ₄ O ₂ S ₂ (Exact Mass: 410.09).

Methyl 2-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)acetate (4g-1)

Yellow solid. Yield: 72.5%. Melting point: 143-146°C. ESI-MS: m/z 343.12 [M+H] ⁺ .C ₁₆ H ₁₄ N ₄ O ₃ S (Exact Mass: 342.08).

Methyl 2-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)propanoate (4g-2)

White solid. Yield: 77.0%. Melting point: 120-123°C. ESI-MS: m/z 357.10 [M+H] ⁺ .C ₁₇ H ₁₆ N ₄ O ₃ S (Exact Mass: 356.09).

Methyl 2-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)-2-methylpropanoate (4g-3)

White solid. Yield: 72.0%. Melting point: 130-134°C. ESI-MS: m/z 370.12 [M+H] ⁺ .C ₁₈ H ₁₈ N ₄ O ₃ S (Exact Mass: 370.11).

Methyl 3-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)propanoate (4g-4)

Yellow solid. Yield: 70.0%. Melting point: 160-165°C. ESI-MS: m/z 357.09 [M+H] ⁺ .C ₁₇ H ₁₆ N ₄ O ₃ S (Exact Mass: 356.09).

Methyl 4-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)butanoate (4g-5)

White solid. Yield: 70.0%. Melting point: 143-146°C. ESI-MS: m/z 370.11 [M+H] ⁺ .C ₁₈ H ₁₈ N ₄ O ₃ S (Exact Mass: 370.11).

1-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)cyclobutane-1-carboxylic acid ethyl ester (4g-6)

White solid. Yield: 55.0%. Melting point: 153-157°C. ESI-MS: m/z 397.15 [M+H] ⁺ .C ₂₀ H ₂₀ N ₄ O ₃ S (Exact Mass: 396.13).

Methyl 2-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)acetate (4h-1)

Yellow solid. Yield: 68.0%. Melting point: 114-117°C. ESI-MS: m/z 359.15 [M+H] ⁺ .C ₁₆ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 358.06).

Methyl 2-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)propanoate (4h-2)

White solid. Yield: 62.0%. Melting point: 131-132°C. ESI-MS: m/z 373.17 [M+H] ⁺ .C ₁₇ H ₁₆ N ₄ O ₂ S ₂ (Exact Mass: 372.07).

Methyl 2-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)-2-methylpropanoate (4h-3)

White solid. Yield: 69.0%. Melting point: 170-174°C. ESI-MS: m/z 387.10 [M+H] ⁺ .C ₁₈ H ₁₈ N ₄ O ₂ S ₂ (Exact Mass: 386.09).

Methyl 3-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)propanoate (4h-4)

Yellow solid. Yield: 65.0%. Melting point: 111-114°C. ESI-MS: m/z 373.15 [M+H] ⁺ .C ₁₇ H ₁₆ N ₄ O ₂ S ₂ (Exact Mass: 372.07).

Methyl 4-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)butanoate (4h-5)

White solid. Yield: 61.0%. Melting point: 116-118°C. ESI-MS: m/z 387.15 [M+H] ⁺ .C ₁₈ H ₁₈ N ₄ O ₂ S ₂ (Exact Mass: 386.09).

Ethyl 1-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)cyclobutane-1-carboxylate (4h-6)

White solid. Yield: 35.0%. Melting point: 190-193°C. ESI-MS: m/z 413.15 [M+H] ⁺ .C ₂₀ H ₂₀ N ₄ O ₂ S ₂ (Exact Mass: 412.10).

Methyl 2-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)thio)acetate (4i-1)

White solid. Yield: 79.0%. Melting point: 133-136°C. ESI-MS: m/z 341.11 [M+H] ⁺ .C ₁₇ H ₁₆ N ₄ O ₂ S (Exact Mass: 340.10).

Methyl 2-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)thio)propanoate (4i-2)

White solid. Yield: 83.0%. Melting point: 121-125°C. ESI-MS: m/z 355.13 [M+H] ⁺ .C ₁₈ H ₁₈ N ₄ O ₂ S (Exact Mass: 354.12).

2-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)thio)-2-methylpropanoic acid methyl ester (4i-3)

White solid. Yield: 79.0%. Melting point: 125-129°C. ESI-MS: m/z 369.09 [M+H] ⁺ .C ₁₉ H ₂₀ N ₄ O ₂ S (Exact Mass: 368.13).

Methyl 3-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-yl)thio)propanoate (4i-4)

White solid. Yield: 80.0%. Melting point: 135-138°C. ESI-MS: m/z 355.12 [M+H] ⁺ .C ₁₈ H ₁₈ N ₄ O ₂ S (Exact Mass: 354.12).

2-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)thio)-2-methylpropanoic acid methyl ester (4i-5)

White solid. Yield: 60.0%. Melting point: 156-159°C. ESI-MS: m/z 369.15 [M+H] ⁺ .C ₁₉ H ₂₀ N ₄ O ₂ S (Exact Mass: 368.13).

Methyl 3-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)thio)propanoate (4i-6)

White solid. Yield: 40.0%. Melting point: 150-155°C. ESI-MS: m/z 395.17 [M+H] ⁺ .C ₂₁ H ₂₂ N ₄ O ₂ S (Exact Mass: 394.15).

General method for preparing compounds YJ-1 to 54

Compound 4X1-4X6 (X = a-i) (1.0 eq) was dissolved in a mixture of 5 mL of tetrahydrofuran and 5 mL of ethanol. Lithium hydroxide (10.0 eq) was dissolved in water (3 mL) and added dropwise to the above solution, and then the mixture was stirred at room temperature for 2 h. After the reaction was completed, the organic solvent was removed by rotary evaporation under reduced pressure. 10 mL of water was added to the residue, and 1 M HCl solution was added dropwise to adjust the pH to 3-4. The product was collected by filtration and recrystallized from ethyl acetate to obtain the target compound.

Example 1. Preparation of compound 2-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)acetic acid (YJ-1)

White solid, yield 79.0%, melting point: 100-103°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H, Pyrimidine-H), 8.21 (d, J = 5.9 Hz, 1H, Benzene-H), 7.87 (s, 1H, Benzene-H), 7.84 (s, 1H, Benzene-H), 7.77 (s, 1H, Benzene-H), 7.74 (s, 1H, NH), 6.62 (d, J = 5.9 Hz, 1H, Pyrimidine-H), 3.94 (s, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ170.67,169.74,159.75,157.25,156.45,144.26,133.62,133.33,119.83,119.42,104.85,104.11,33.41.HR-MS:m/z285.0449[MH] ^- .C ₁₃ H ₁₀ N ₄ O ₂ S (Exact Mass: 286.05).

Example 2. Preparation of compound 2-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)propanoic acid (YJ-2)

White solid, yield 79.1%, melting point: 142-145°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H, Pyrimidine-H), 8.22 (d, J = 5.9 Hz, 1H, Benzene-H), 7.86 (s, 1H, Benzene-H), 7.84 (s, 1H, Benzene-H), 7.78 (s, 1H, Benzene-H), 7.76 (s, 1H, NH), 6.62 (d, J = 5.9 Hz, 1H, Pyrimidine-H), 4.42 (q, J = 7.3 Hz, 1H, CH), 1.54 (d, J = 7.3 Hz, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.70,169.54,159.75,156.55,144.23,133.66,133.33,119.84,119.41,106.79,104.93,104.19,42.45,18.27.HR-MS:m/z 299.0604[MH] ^- .C _{1 4} H ₁₂ N ₄ O ₂ S (ExactMass: 300.07).

Example 3. Preparation of compound 2-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)-2-methylpropanoic acid (YJ-3)

White solid, yield 78.5%, melting point: 120-123°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.18 (s, 1H, Pyrimidine-H), 8.18 (d, J = 5.9 Hz, 1H, Benzene-H), 7.85 (s, 1H, Benzene-H), 7.82 (s, 1H, Benzene-H), 7.77 (s, 1H, Benzene-H), 7.75 (s, 1H, NH), 6.60 (d, J = 5.9 Hz, 1H, Pyrimidine-H), 1.64 (s, 6H, CH ₃ × 2). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ175.31,169.89,159.64,155.96,144.23,133.65,133.36,119.79,119.49,106.82,104.91,104.11,50.90,50.86,26.62.HR-MS:m/z 313.0762[MH] ^- .C ₁₅ H ₁₄ N ₄ O ₂ S (Exact Mass: 314.08).

Example 4. Preparation of compound 3-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)propanoic acid (YJ-4)

White solid, yield 78.9%, melting point: 183-186°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H, Pyrimidine-H), 8.22 (d, J = 5.7 Hz, 1H, Benzene-H), 7.88 (s, 1H, Benzene-H), 7.85 (s, 1H, Benzene-H), 7.77 (s, 1H, Benzene-H), 7.75 (s, 1H, NH), 6.61 (d, J = 5.9 Hz, 1H, Pyrimidine-H), 3.26 (t, J = 7.2 Hz, 2H, CH ₂ ), 2.71 (t, J = 7.2 Hz, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.48,170.26,159.82,156.55,144.37,144.15,133.67,133.34,119.72,119.42,104.68,104.08,34.62,25.91.HR-MS:m/z 299.0606[MH] ^- .C _{1 4} H ₁₂ N ₄ O ₂ S (ExactMass: 300.07).

Example 5. Preparation of compound 4-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)butyric acid (YJ-5)

White solid, yield 79.3%, melting point: 177-180℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.19 (s, 1H, Pyrimidine-H), 8.21 (d, J = 5.9Hz, 1H, Benzene-H), 7.88 (s, 1H, Benzene-H), 7.86 (s, 1H, Benzene-H), 7.80 (s, 1H, Benzene-H), 7.77 (s ,1H,Pyrimidine-H),6.61(d,J＝5.7Hz,1H,NH),3.12(t,J＝7.3Hz,2H,CH ₂ ),2.37(t,J＝7.3Hz,2H,CH ₂ ),1.96–1.86(m,2H,CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ174.49,170.55,159.76,156.56,144.43,133.67,133.33,119.68,119.42,106.79,104.62,104.03,33.31,29.95,25.10.HR-MS:m/z 349.0764[M+ Cl] ⁺ .C ₁₅ H ₁₄ N ₄ O ₂ S (Exact Mass: 314.08).

Example 6. Preparation of compound 1-((4-((4-cyanophenyl)amino)pyrimidin-2-yl)thio)cyclobutane-1-carboxylic acid (YJ-6)

White solid, yield 50.0%, melting point: 118-121°C. Spectral data: ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.18 (s, 1H, Pyrimidine-H), 8.17 (d, J＝5.9 Hz, 1H, Benzene-H), 7.85 (s, 1H, Benzene-H), 7.83 (s, 1H, Benzene-H), 7.76 (s, 1H, Benzene-H), 7.74 (s, 1H, Pyrimidine-H), 6.61 (d, J＝5.9 Hz, 1H, NH), 2.88-2.83 (m, 2H, CH ₂ ), 2.22 (t, J＝5.1 Hz, 2H, CH ₂ ), 2.20 (q, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.29,169.91,159.83,156.20,144.21,133.53,120.70,119.88,119.75,104.98,104.09,99.35,52.09,32.24,18.54,17.11.HR-MS: m/z 325.07 62[MH] ^- .C ₁₆ H ₁₄ N ₄ O ₂ S (Exact Mass: 326.08).

Example 7. Preparation of compound 2-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)acetic acid (YJ-7)

Yellow solid, yield 78.6%, melting point: 94-97°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.24 (s, 1H, Quinazoline-H), 8.54 (d, J=7.2 Hz, 1H, Quinazoline-H), 8.12 (s, 1H, Quinazoline-H), 8.10 (s, 1H, Quinazoline-H), 7.85 (s, 1H, NH), 7.83 (s, 1H, Benzene-H), 7.82 (s, 1H, Benzene-H), 7.64 (d, J=7.3 Hz, 1H, Benzene-H), 7.55 (t, J=7.6 Hz, 1H, Benzene-H), 3.98 (s, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ170.92,165.81,157.27,150.80,143.88,134.36,133.30,132.64,126.94,125.78,123.97,122.11,121.58,119.64,113.64,105.50,34.04.HR- MS: m/z 335.0607 [MH] ^- .C ₁₇ H ₁₂ N ₄ O ₂ S (Exact Mass: 336.07).

Example 8. Preparation of compound 2-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)propanoic acid (YJ-8)

White solid, yield 78.9%, melting point: 133～136℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.25 (s, 1H, Quinazoline-H), 8.52 (d, J = 7.6Hz, 1H, Quinazoline-H), 8.11 (s, 1H, Quinazoline-H), 8.09 (s, 1H, Quinazoline-H), 7.86 (s, 1H, NH), 7.84 (s ,1H,Benzene-H),7.82(s,1H,Benzene-H),7.65(d,J＝7.3Hz,1H,Benzene-H),7.56(t,J＝7.6Hz,1H,Benzene-H),4.49(q,J＝7.2Hz,1H,CH),1.56(d,J＝7.3Hz,3H,CH ₃ ). ¹³ C NMR (10 0MHz, DMSO-d ₆ )δ174.10,165.85,157.29,150.79,143.85,134.40,133.28,132.61,126.90,125.85,123.87,122.65,122.16,119.64,113.63,105.54,43.45,18 .89.HR-MS: m/z 349.0762 [MH] ^- .C ₁₈ H ₁₄ N ₄ O ₂ S (Exact Mass: 350.08).

Example 9. Preparation of Compound 2-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)-2-methylpropanoic acid (YJ-9)

White solid, yield 79.0%, melting point: 151-154°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.55 (d, J=8.3 Hz, 1H, Quinazoline-H), 8.14 (s, 1H, Quinazoline-H), 8.12 (s, 1H, Quinazoline-H), 7.84 (s, 1H, Quinazoline-H), 7.82 (s, 1H, Benzene-H), 7.80 (s, 1H, Benzene-H), 7.58 (d, J=8.4 Hz, 1H, Benzene-H), 7.54 (t, J=7.6 Hz, 1H, Benzene-H), 1.71 (s, 6H, CH ₃ ×2). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ175.74,166.46,165.13,157.01,150.48,144.28,134.11,133.29,132.61,126.72,125.67,124.03,121.97,119.72,113.74,105.24,52.70,29 .71, 26.77. HR-MS: m/z 363.0921 [MH] ^- .C ₁₉ H ₁₆ N ₄ O ₂ S (Exact Mass: 364.10).

Example 10. Preparation of compound 3-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)propanoic acid (YJ-10)

Yellow solid, yield 78.7%, melting point: 238～241℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.27(s,1H,Quinazoline-H),8.54(d,J＝7.5Hz,1H,Quinazoline-H),8.14(s,1H,Quinazoline-H),8.11(s,1H,Quinazoline-H),7.85(s,1H,NH),7.84 (s,1H,Benzene-H),7.82(d,J＝2.6Hz,1H,Benzene-H),7.66(d,J＝7.3Hz,1H,Benzene-H),7.55(t,J＝7.6Hz,1H,Benzene-H),3.31(t,J＝7.1Hz,2H,CH ₂ ),2.68(t,J＝7.2Hz,2H,CH ₂ ) ^.13C NMR (100MHz, DMSO-d ₆ ) δ174.01,166.33,165.77,157.30,150.95,143.95,134.34,133.28,126.93,125.71,123.92,123.01,122.08,119.66,113.60, 105.44, 35.47, 26.36. HR-MS: m/z349.0767[MH] ^- .C ₁₈ H ₁₄ N ₄ O ₂ S (Exact Mass: 350.08).

Example 11. Preparation of compound 4-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)butyric acid (YJ-11)

White solid, yield 78.7%, melting point: 208～211℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ12.16 (s, 1H, COOH), 10.13 (s, 1H, Quinazoline-H), 8.50 (d, J = 8.4Hz, 1H, Quinazoline-H), 8.12 (s, 1H, Quinazoline-H), 7.88 (s,1H,NH),7.86(s,1H,Benzene-H),7.83(d,J＝7.1Hz,1H,Benzene-H),7.67(d,J＝8.4Hz,1H,Benzene-H),7.56(t,J＝7.6Hz,1H,Benzene-H),3.19(t,J＝7.2Hz,2H,CH ₂ ¹³ C NMR .70,124.06,123.85,122.55,122.08,119.64,113.63,105.53,33.14,29.95,25.13.HR-MS: m/z363.0921[MH] ^- .C _{19 H 16} N ₄ O _{2 S} (Exact _Mass : 364.10).

Example 12. Preparation of Compound 1-((4-((4-cyanophenyl)amino)quinazolin-2-yl)thio)cyclobutane-1-carboxylic acid (YJ-12)

White solid, yield 40.0%, melting point: 98～100℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ12.68(s,1H,COOH),10.12(t,1H,Quinazoline-H),8.56(d,J＝8.8Hz,1H,Quinazoline-H),8.10(d,J＝8.6Hz,1H,Quinazoline-H),7.99(s,1H,Quinazoline line-H),7.93(s,1H,NH),7.86(s,1H,Benzene-H),7.83(d,J＝10.5Hz,1H,Benzene-H),7.58(s,1H,Benzene-H),7.56(s,1H,Benzene-H),3.35(s,2H,CH ₂ ),2.87(d,J＝6.0Hz,2H,CH ₂ ),2.25(d,J＝13.6Hz,2H,CH ₂ ). ¹³ CNMR(100MHz,DMSO-d ₆ )δ174.54,157.46,150.55,143.82,134.35,133.31,130.45,128.50,126.78,125.89,124.02 ,122.18,121.66,119.67,113.67,105.54,52.30,45.93,32.27,17.19.HR-MS: m/z 375.0919[MH] ^- .C ₂₀ H ₁₆ N ₄ O ₂ S (Exact Mass: 376.10).

Example 13. Preparation of compound 2-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)acetic acid (YJ-13)

White solid, yield 80.0%, melting point: 204-207°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.86 (s, 1H, Quinazoline-H), 8.02 (s, 1H, NH), 8.00 (s, 1H, Benzene-H), 7.85 (s, 1H, Benzene-H), 7.83 (s, 1H, Quinazoline-H), 7.79 (s, 1H, Benzene-H), 7.06 (s, 1H, Benzene-H), 3.98 (s, 2H, CH ₂ ), 3.95 (s, 3H, CH ₃ ), 3.93 (s, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ171.03,163.20,156.00,155.96,155.49,148.74,148.43,144.19,144.16,133.29,121.95,119.70,107.14,106.64,105.09,102.76,56.71,56 .38,33.35.HR-MS: m/z 395.0815[MH] ^- .C ₁₉ H ₁₆ N ₄ O ₄ S (Exact Mass: 396.09).

Example 14. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)propanoic acid (YJ-14)

White solid, yield 80.0%, melting point: 184-187°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H, Quinazoline-H), 8.11 (s, 1H, NH), 7.96 (s, 1H, Benzene-H), 7.94 (s, 1H, Benzene-H), 7.88 (s, 1H, Quinazoline-H), 7.86 (s, 1H, Benzene-H), 7.09 (s, 1H, Benzene-H), 3.98 (s, 3H, CH ₃ ), 3.94 (s, 3H, CH ₃ ), 3.91 (s, 1H, CH), 1.63 (s, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.79,166.48,162.56,156.51,156.11,149.27,143.03,133.37,132.75,123.76,121.96,119.57,106.63,103.98,103.23,101.80,57.11,56 .60, 52.31, 26.72. HR-MS: m/z 409.0978 [MH] ^- .C ₂₀ H ₁₈ N ₄ O ₄ S (Exact Mass: 410.10).

Example 15. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)-2-methylpropanoic acid (YJ-15)

White solid, yield 79.0%, melting point: 226-229°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.18 (s, 1H, Quinazoline-H), 8.23 (s, 1H, NH), 8.02 (s, 1H, Benzene-H), 8.00 (s, 1H, Benzene-H), 7.90 (s, 1H, Quinazoline-H), 7.88 (s, 1H, Benzene-H), 7.19 (s, 1H, Benzene-H), 3.97 (d, J = 15.3 Hz, 6H, CH ₃ × 2), 2.51 (s, 3H, CH ₃ ), 1.54 (d, J = 7.3 Hz, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ172.94,161.74,156.52,156.41,149.74,149.41,142.66,133.26,133.21,124.12,122.36,119.46,107.10,106.45,104.46,102.19,57.31,56 .70, 56.55, 43.14, 18.47. HR-MS: m/z 423.1133 [MH] ^- .C ₂₁ H ₂₀ N ₄ O ₄ S (Exact Mass: 424.12).

Example 16. Preparation of compound 3-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)propane acid (YJ-16)

Yellow solid, yield 79.0%, melting point: 240-243°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H, Quinazoline-H), 8.20 (s, 1H, NH), 8.03 (s, 1H, Benzene-H), 8.00 (s, 1H, Benzene-H), 7.88 (s, 1H, Quinazoline-H), 7.86 (s, 1H, Benzene-H), 7.15 (s, 1H, Benzene-H), 3.98 (s, 3H, CH ₃ ), 3.94 (s, 3H, CH ₃ ), 3.31 (t, J＝7.0 Hz, 2H, CH ₂ ), 2.70 (t, J＝7.1 Hz, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.35,156.42,156.13,155.84,149.22,133.25,133.04,132.83,123.62,122.66,121.69,119.48,106.43,105.15,103.87,57.09,56.89,56. 66, 34.51, 26.11. HR-MS: m/z 409.0974 [MH] ^- .C ₂₀ H ₁₈ N ₄ O ₄ S (Exact Mass: 410.10).

Example 17. Preparation of Compound 4-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)butyric Acid (YJ-17)

White solid, yield 80.0%, melting point: 243～246℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ11.48(s,1H,Quinazoline-H),8.30(s,1H,NH),8.02(s,1H,Benzene-H),8.00(s,1H,Benzene-H),7.93(s,1H,Quinazoline-H),7.91(s,1H,Benzene-H), 7.20(s,1H,Benzene-H),3.99(s,3H,CH ₃ ),3.95(s,3H,CH ₃ ),3.16(t,J＝7.3Hz,2H,CH ₂ ),2.27(t,J＝7.3Hz,2H,CH ₂ ),1.89–1.80(m,2H,CH ₂ ). ¹³ C NMR (100MHz, DMSO -d ₆ )δ174.18,162.64,156.61,149.42,142.36,133.25,133.16,124.69,122.33,119.33,107.65,106.06,105.62,104.68,100.96,57.36,56.75,32. 92, 30.28, 30.15, 24.84. HR-MS: m/z 423.1132[MH] ^- .C ₂₁ H ₂₀ N ₄ O ₄ S (ExactMass: 424.12).

Example 18. Preparation of Compound 1-((4-((4-cyanophenyl)amino)-6,7-dimethoxyquinazolin-2-yl)thio)cyclobutane-1-carboxylic acid (YJ-18)

Yellow solid, yield 80.0%, melting point: 204～207℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.33(d,1H,Quinazoline-H),8.09(d,J＝8.9Hz,1H,NH),8.02(s,1H,Benzene-H),7.98(s,1H,Benzene-H),7.96(s,1H,Quinazoline-H),7.88(d,J ＝8.8Hz,1H,Benzene-H),7.85(d,J＝8.7Hz,1H,Benzene-H),3.99(s,2H,CH ₂ ),3.97(s,3H,CH ₃ ),3.94(d,J＝4.6Hz,3H,CH ₃ ),2.88–2.74(m,2H,CH ₂ ),2.24(q,2H,CH ₂ ) ^.13C NMR (100MHz, DMSO-d ₆ ) δ173.53,161.72,156.76,156.26,155.91,149.31,143.82,133.15,132.61,124.25,122.17,119.43,107.50,105.58,105.00, 104.08, 57.54, 57.35, 56.64, 52.81, 32.33, 17.18. HR-MS: m/z 435.1132[MH] ^- .C ₂₂ H ₂₀ N ₄ O ₄ S (Exact Mass: 436.12).

Example 19. Preparation of compound 2-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)acetic acid (YJ-19)

White solid, yield 80.0%, melting point: 156-159°C. Spectral data: ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.27 (s, 1H, Quinazoline-H), 8.63 (q, J＝6.0 Hz, 1H, Quinazoline-H), 8.06 (s, 1H, Quinazoline-H), 8.05 (s, 1H, NH), 7.85 (s, 1H, Benzene-H), 7.83 (s, 1H, Benzene-H), 7.51-7.47 (m, 1H, Benzene-H), 7.37 (q, J＝2.7 Hz, 1H, Benzene-H), 3.99 (s, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ170.69,167.20,166.50,164.83,157.10,152.76,152.67,143.59,133.30,127.38,122.39,119.54,115.25,115.08,110.82,105.88,33.50.HR- MS: m/z353.0511[MH] ^- .C ₁₇ H ₁₁ FN ₄ O ₂ S (Exact Mass: 354.06).

Example 20. Preparation of compound 2-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)propanoic acid (YJ-20)

Purple solid, yield 79.0%, melting point: 142～145℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.39 (s, 1H, Quinazoline-H), 8.70 (q, J = 5.9Hz, 1H, Quinazoline-H), 8.10 (s, 1H, Quinazoline-H), 8.08 (s, 1H, NH), 7.87 (s, 1H, Benzene-H), 7.85 (s, 1H, Benzene-H), 7.53–7.46 (m, 1H, Benzene-H), 7.39 (q, J＝2.7Hz, 1H, Benzene-H), 4.52 (q, J＝7.3Hz, 1H, CH), 1.56 (d, J＝7.3Hz, 3H, CH ₃ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ173.74,166.90,164.40,157.16,152.82,143.63,133.29,127.56,127.46,122.42,119.57,115.33,115.10,111.10,110.90,105.84,42.49,18 .40. HR-MS: m/z 367.0664 [MH] ^- .C ₁₈ H ₁₃ FN ₄ O ₂ S (Exact Mass: 368.07).

Example 21. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)-2-methylpropanoic acid (YJ-21)

White solid, yield 78.0%, melting point: 162-165°C. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ )δ10.20(d, J＝7.6Hz,1H,Quinazoline-H),8.58(q, J＝6.0Hz,1H,Quinazoline-H),8.05(s,1H,Quinazoline-H),8.03(s,1H,NH),7.86(s,1H,Benzene-H),7.84(d, J＝2.2Hz,1H,Benzene-H),7.51-7.46(m,1H,Benzene-H),7.25(q, J＝2.8Hz,1H,Benzene-H),1.68(s,6H,CH ₃ ×2). ¹³ CNMR (100MHz,DMSO-d ₆ )δ175.52,174.59,167.34,166.76,164.26,156.97,152.49,152.35,143.63,133.33,127.28,127.16,122.20,119.61,115.04,110.77,105.70,5 1.25,26.56. HR-MS: m/z381.0830[MH] ^- .C ₁₉ H ₁₅ FN ₄ O ₂ S (Exact Mass: 382.09).

Example 22. Preparation of compound 3-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)propanoic acid (YJ-22)

White solid, yield 79.0%, melting point: 240～243℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.39 (s, 1H, Quinazoline-H), 8.68 (q, J＝6.0Hz, 1H, Quinazoline-H), 8.10 (s, 1H, Quinazoline-H), 8.07 (s, 1H, NH), 7.86 (s, 1H, Benzene-H), 7.83 (s, 1H, Benzene-H), 7.52–7.46 (m, 1H, Benzene-H), 7.41 (q, J＝2.6Hz, 1H, Benzene-H), 3.31 (t, J＝7.1Hz, 2H, CH ₂ ), 2.73 (t, J＝7.1Hz, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ173.48,167.70,166.91,164.41,157.12,143.59,133.71,133.28,127.42,122.44,119.57,115.23,114.98,110.73,110.57,105.91,34.62,26 .00.HR-MS: m/z 367.0665 [MH] ^- .C ₁₈ H ₁₃ FN ₄ O ₂ S (Exact Mass: 368.07).

Example 23. Preparation of Compound 4-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)butyric Acid (YJ-23)

White solid, yield 76.0%, melting point: 241-244℃. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.15(s,1H,Quinazoline-H),8.88(q,1H,Quinazoline-H),8.06(s,1H,Quinazoline-H),8.04(s,1H,NH),7.92 ₍ s,1H,Benzene-H),7.90(s,1H, _Benzene ¹³ C NMR DMSO _- d ₆ )δ174.26,167.35,167.16,164.64,157.33,142.80,133.28,128.42,128.32,123.70,119.39,115.78,115.55,110.32,108.53,107.08,32.98,30 .17,24.96.HR-MS: m/z 381.0825[MH] ^- .C ₁₉ H ₁₅ FN ₄ O ₂ S (ExactMass: 382.09).

Example 24. Preparation of Compound 1-((4-((4-cyanophenyl)amino)-7-fluoroquinazolin-2-yl)thio)cyclobutane-1-carboxylic acid (YJ-24)

White solid, yield 79.0%, melting point: 142～145℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.31(s,1H,Quinazoline-H),8.64(q,1H,Quinazoline-H),8.08(s,1H,Quinazoline-H),8.06 ₍ s,1H,NH),7.88 ₍ s,1H,Benzene-H), _7.86 (s,1H,Benzene ¹³ C NMR ₆ )δ175.81,168.27,164.41,156.94,143.67,133.71,133.30,132.78,127.42,122.98,122.48,119.57,115.10,110.73,105.85,101.97,34.03,24 .54,24.29,15.81.HR-MS: m/z 393.0830[MH] ^- .C ₂₀ H ₁₅ FN ₄ O ₂ S (ExactMass: 394.09).

Example 25. Preparation of Compound 2-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)acetic acid (YJ-25)

Yellow solid, yield 77.0%, melting point: 112-115°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H, NH), 8.28 (d, J = 5.4 Hz, 1H, Benzene-H), 8.02 (s, 1H, Benzene-H), 8.00 (s, 1H, Benzene-H), 7.82 (s, 1H, Benzene-H), 7.80 (s, 1H, Thiophene-H), 7.38 (d, J = 5.4 Hz, 1H, Thiophene-H), 3.99 (s, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ170.85,165.51,161.84,154.48,143.94,137.73,136.36,133.37,124.03,123.87,121.48,119.67,113.60,105.10,33.57.HR-MS:m/z 341.0177[ MH]-.C ₁₅ H ₁₀ N ₄ O ₂ S ₂ (Exact Mass: 342.02).

Example 26. Preparation of Compound 2-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)propanoic acid (YJ-26)

Yellow solid, yield 70.0%, melting point: 95-98°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H, NH), 8.29 (d, J = 5.4 Hz, 1H, Benzene-H), 8.03 (d, J = 3.3 Hz, 1H, Benzene-H), 8.01 (s, 1H, Benzene-H), 7.83 (s, 1H, Benzene-H), 7.81 (s, 1H, Thiophene-H), 7.40 (d, J = 5.5 Hz, 1H, Thiophene-H), 4.50 (t, J = 7.3 Hz, 1H, CH), 1.56 (d, J = 7.3 Hz, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.84,165.21,161.80,154.53,143.93,136.37,133.37,132.93,124.05,121.52,121.15,119.65,113.66,105.17,42.49,18.46.HR-MS: m/z 355 .0329[MH]-.C ₁₆ H ₁₂ N ₄ O ₂ S ₂ (Exact Mass: 356.04).

Example 27. Preparation of Compound 2-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)-2-methylpropanoic acid (YJ-27)

White solid, yield 70.0%, melting point: 89-92°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.53 (s, 1H, COOH), 10.12 (s, 1H, NH), 8.26 (d, J = 5.4 Hz, 1H, Benzene-H), 8.02 (s, 1H, Benzene-H), 7.99 (s, 1H, Benzene-H), 7.82 (s, 1H, Benzene-H), 7.79 (s, 1H, Thiophene-H), 7.30 (d, J = 5.4 Hz, 1H, Thiophene-H), 1.67 (s, 6H, CH ₃ × 2). ¹³ C NMR (100 MHz, DMSO-d ₆ : m/z 369.0483[MH] ^- .C ₁₇ H ₁₄ N ₄ O ₂ S ₂ (ExactMass:370.06).

Example 28. Preparation of Compound 3-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)propanoic acid (YJ-28)

Yellow solid, yield 77.0%, melting point: 127-130°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.45 (s, 1H, COOH), 8.34 (d, J = 5.5 Hz, 1H, Benzene-H), 8.27 (s, 1H, Benzene-H), 8.26 (s, 1H, Benzene-H), 7.49 (d, J = 5.4 Hz, 1H, Benzene-H), 7.39 (s, 1H, Thiophene-H), 7.38 (s, 1H, Thiophene-H), 3.53 (t, J = 6.7 Hz, 2H, CH ₂ ), 2.74 (s, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ206.31,178.64,173.31,166.29,159.85,152.52,139.57,137.49,125.05,124.01,34.47,34.22,33.94,26.32,25.86,24.81.HR-MS: m/z 355.032 6[MH]-.C ₁₆ H ₁₂ N ₄ O ₂ S ₂ (Exact Mass: 356.04).

Example 29. Preparation of Compound 4-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)butenoic acid (YJ-29)

White solid, yield 77.8%, melting point: 158～161℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.14(s,1H,NH),8.09(s,1H,Benzene-H),8.07(s,1H,Benzene-H),7.89(d,J＝6.1Hz,1H,Benzene-H),7.85(s,1H,Benzene-H),7.83(s,1H,Thi ophene-H), 7.61 (d, J＝6.0Hz, 1H, Thiophene-H), 3.17 (t, J＝7.2Hz, 2H, CH ₂ ), 2.38 (t, J＝7.3Hz, 2H, CH ₂ ), 1.97–1.88 (m, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ : m/z369.0483[MH] ^- .C ₁₇ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 370.06).

Example 30. Preparation of Compound 1-((4-((4-cyanophenyl)amino)thieno[3,2-d]pyrimidin-2-yl)thio)cyclobutane-1-carboxylic acid (YJ-30)

White solid, yield 45.0%, melting point: 216～219℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ12.60(s,1H,COOH),10.13(s,1H,NH),8.26(d,J＝5.4Hz,1H,Benzene-H),8.01(s,1H,Benzene-H),7.98(s,1H,Benzene-H),7.82(s,1H,Benzene- H), 7.80 (s, 1H, Thiophene-H), 7.31 (d, J = 5.4Hz, 1H, Thiophene-H), 2.86 (t, J = 7.6Hz, 2H, CH ₂ ), 2.25 (t, 2H, CH ₂ ), 2.22 (t, J = 4.2Hz, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ174.50,165.70,161.59,154.62,143.91,136.20,133.35,128.58,123.98,121.47,121.04,119.72,113.67,105.03,52.18,52.14,32.30,17.1 7. HR-MS: m/z 381.0490 [MH] ^- .C ₁₈ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 382.06).

Example 31. Preparation of Compound 2-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)acetic acid (YJ-31)

Yellow solid, yield 77.8%, melting point: 130-133°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H, NH), 8.04 (s, 1H, Benzene-H), 8.02 (s, 1H, Benzene-H), 7.84 (d, J = 6.1 Hz, 1H, Benzene-H), 7.83 (s, 1H, Benzene-H), 7.81 (s, 1H, Thiophene-H), 7.63 (d, J = 6.0 Hz, 1H, Thiophene-H), 3.98 (s, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ170.71,168.25,164.83,154.04,143.89,133.56,133.43,123.14,121.52,121.26,119.86,119.66,115.15,105.08,33.70.HR-MS:m/z 341.0171[ MH] ^- .C ₁₅ H ₁₀ N ₄ O ₂ S ₂ (Exact Mass: 342.02).

Example 32. Preparation of Compound 2-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)propanoic acid (YJ-32)

White solid, yield 78.9%, melting point: 103-107°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 (s, 1H, NH), 8.06 (s, 1H, Benzene-H), 8.03 (s, 1H, Benzene-H), 7.86 (d, J = 6.0 Hz, 1H, Benzene-H), 7.84 (s, 1H, Benzene-H), 7.82 (s, 1H, Thiophene-H), 7.63 (d, J = 6.0 Hz, 1H, Thiophene-H), 4.47 (q, J = 7.3 Hz, 1H, CH), 1.56 (d, J = 7.3 Hz, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.77,168.21,164.63,154.08,143.92,133.41,125.73,123.14,121.52,121.27,119.92,119.65,115.21,105.10,42.95,18.50.HR-MS: m/z 355 .0329[MH] ^- .C ₁₆ H ₁₂ N ₄ O ₂ S ₂ (Exact Mass: 356.04).

Example 33. Preparation of Compound 2-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)-2-methylpropanoic acid (YJ-33)

White solid, yield 78.8%, melting point: 110-113°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.61 (s, 1H, COOH), 10.06 (d, 1H, NH), 8.06 (s, 1H, Benzene-H), 8.04 (s, 1H, Benzene-H), 7.86 (d, J = 6.1 Hz, 1H, Benzene-H), 7.83 (s, 1H, Benzene-H), 7.81 (s, 1H, Thiophene-H), 7.62 (d, J = 6.0 Hz, 1H, Thiophene-H), 1.67 (s, 6H, CH ₃ CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ175.45,167.81,164.95,154.04,144.03,133.43,128.64,122.97,121.56,121.12,120.58,119.92,119.69,115.10,104.97,51.33,26.70.HR-MS :m/z 369.0480[MH] ^- .C ₁₇ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 370.06).

Example 34. Preparation of Compound 3-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)propanoic acid (YJ-34)

Yellow solid, yield 79.4%, melting point: 224-227°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H, NH), 8.08 (s, 1H, Benzene-H), 8.06 (s, 1H, Benzene-H), 7.88 (d, J = 6.1 Hz, 1H, Benzene-H), 7.83 (s, 1H, Benzene-H), 7.80 (s, 1H, Thiophene-H), 7.62 (d, J = 6.0 Hz, 1H, Thiophene-H), 3.31 (t, J = 7.2 Hz, 2H, CH ₂ ), 2.73 (t, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.54,168.41,165.34,154.14,144.02,133.40,133.00,122.95,121.18,120.97,119.95,119.68,115.07,105.02,34.71,26.19.HR-MS: m/z 355 .0331[MH] ^- .C ₁₆ H ₁₂ N ₄ O ₂ S ₂ (ExactMass:356.04).

Example 35. Preparation of Compound 4-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)butenoic acid (YJ-35)

White solid, yield 79.0%, melting point: 196～199℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.14(s,1H,NH),8.09(s,1H,Benzene-H),8.07(s,1H,Benzene-H),7.89(d,J＝6.1Hz,1H,Benzene-H),7.85(s,1H,Benzene-H),7.83(s,1H,Thi ophene-H), 7.61 (d, J＝6.0Hz, 1H, Thiophene-H), 3.17 (t, J＝7.2Hz, 2H, CH ₂ ), 2.38 (t, J＝7.3Hz, 2H, CH ₂ ), 1.92 (t, J＝7.2Hz, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ : m/z369.0480[MH] ^- .C ₁₇ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 370.06).

Example 36. Preparation of Compound 1-((4-((4-cyanophenyl)amino)thieno[2,3-d]pyrimidin-2-yl)thio)cyclobutane-1-carboxylic acid (YJ-36)

White solid, yield 50.0%, melting point: 99-102°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.59 (s, 1H, COOH), 10.06 (s, 1H, NH), 8.04 (s, 1H, Benzene-H), 8.02 (s, 1H, Benzene-H), 7.87 (d, J＝6.0 Hz, 1H, Benzene-H), 7.83 (s, 1H, Benzene-H), 7.80 (s, 1H, Thiophene-H), 7.60 (d, J＝6.0 Hz, 1H, Thiophene-H), 2.86 (q, 2H, CH ₂ ), 2.30–2.17 (m, 4H, CH ₂ ×2). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.45,168.05,164.96,154.21,143.92,133.53,133.38,128.63,122.94,121.56,121.23,119.96,119.70,115.18,104.98,52.38,32.32,17. 19. HR-MS: m/z381.0484[MH] ^- .C ₁₈ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 382.06).

Example 37. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)acetic acid (YJ-37)

White solid, yield 78.8%, melting point: 134-137°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.60 (s, 1H, NH), 7.89 (s, 1H, Benzene-H), 7.87 (s, 1H, Benzene-H), 7.76 (s, 1H, Benzene-H), 7.74 (s, 1H, Benzene-H), 5.02 (s, 2H, CH ₂ ), 4.82 (s, 2H, CH ₂ ), 3.93 (s, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ170.61,169.49,169.29,154.04,143.97,137.00,133.40,128.40,120.81,119.68,111.11,104.68,72.35,70.64,33.58.HR-MS:m/z 327.0557[MH] ^- .C ₁₅ H ₁₂ N ₄ O ₃ S (Exact Mass: 328.06).

Example 38. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyridin-2-yl)thio)propanoic acid (YJ-38)

White solid, yield 78.9%, melting point: 196-199°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.63 (s, 1H, NH), 7.90 (s, 1H, Benzene-H), 7.88 (s, 1H, Benzene-H), 7.78 (s, 1H, Benzene-H), 7.76 (s, 1H, Benzene-H), 5.02 (s, 2H, CH ₂ ), 4.83 (s, 2H, CH ₂ ), 4.42 (q, J＝7.3 Hz, 1H, CH), 1.53 (d, J＝7.2 Hz, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.68,169.27,169.24,154.08,143.94,133.54,133.41,121.03,120.85,119.67,111.17,104.75,72.37,70.64,42.71,18.44.HR-MS: m/z341.0 718[MH] ^- .C ₁₆ H ₁₄ N ₄ O ₃ S (Exact Mass: 342.08).

Example 39. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)-2-methylpropanoic acid (YJ-39)

White solid, yield 79.0%. Melting point: 119-122°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.58 (s, 1H, NH), 7.90 (s, 1H, Benzene-H), 7.88 (s, 1H, Benzene-H), 7.77 (s, 1H, Benzene-H), 7.75 (s, 1H, Benzene-H), 5.02 (s, 2H, CH ₂ ), 4.79 (s, 2H, CH ₂ ), 1.63 (s, 6H, CH ₃ ×2). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ175.31,174.35,169.61,168.73,154.17,143.96,133.44,120.81,119.68,111.12,104.63,72.47,72.42,70.71,52.87,50.85,26.66.HR-MS:m/z 355.0869[MH] ^- .C ₁₇ H ₁₆ N ₄ O ₃ S (Exact Mass: 356.09).

Example 40. Preparation of Compound 3-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)propanoic acid (YJ-40)

White solid, yield 78.8%. Melting point: 168-171°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.69 (s, 1H, NH), 7.95 (s, 1H, Benzene-H), 7.93 (s, 1H, Benzene-H), 7.77 (s, 1H, Benzene-H), 7.75 (s, 1H, Benzene-H), 5.04 (s, 2H, CH ₂ ), 4.83 (s, 2H, CH ₂ ), 3.26 (t, J＝7.2 Hz, 2H, CH ₂ ), 2.69 (t, J＝7.2 Hz, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.45,169.94,169.38,167.87,154.14,144.16,133.40,133.12,120.70,119.70,110.95,104.61,72.37,70.75,34.56,26.02.HR-MS: m/z341.0 717[MH] ^- .C ₁₆ H ₁₄ N ₄ O ₃ S (Exact Mass: 342.08).

Example 41. Preparation of Compound 4-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)butanoic acid (YJ-41)

White solid, yield 79.1%, melting point: 216-219°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.56 (s, 1H, NH), 7.93 (s, 1H, Benzene-H), 7.91 (s, 1H, Benzene-H), 7.80 (s, 1H, Benzene-H), 7.78 (s, 1H, Benzene-H), 5.02 (s, 2H, CH ₂ ), 4.83 (s, 2H, CH ₂ ), 3.11 (t, J＝7.2 Hz, 2H, CH ₂ ), 2.35 (t, J＝7.3 Hz, 2H, CH ₂ ), 1.92–1.85 (m, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.45,170.21,169.33,169.29,154.07,144.14,133.43,121.00,120.70,119.68,110.84,104.64,72.38,70.66,33.18,30.05,24.95.HR-MS: m/z 355.0873[MH] ^- .C ₁₇ H ₁₆ N ₄ O ₃ S (Exact Mass: 356.09).

Example 42. Preparation of Compound 1-((4-((4-cyanophenyl)amino)-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)thio)cyclobutane-1-carboxylic acid (YJ-42)

White solid, yield 40.0%, melting point: 111-114°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.67 (s, 1H, NH), 7.92 (s, 1H, Benzene-H), 7.90 (s, 1H, Benzene-H), 7.75 (s, 1H, Benzene-H), 7.73 (s, 1H, Benzene-H), 5.03 (s, 2H, CH ₂ ), 4.77 (s, 2H, CH ₂ ), 2.83 (d, J＝4.2 Hz, 2H, CH ₂ ), 2.21 (d, J＝11.1 Hz, 2H, CH ₂ ), 2.19 (d, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.41,169.71,168.91,168.26,154.18,144.00,133.30,130.55,128.62,120.83,119.78,111.14,104.45,72.35,70.82,52.46,32.32,17.17 .HR-MS: m/z 367.0865 [MH] ^- .C ₁₈ H ₁₆ N ₄ O ₃ S (Exact Mass: 368.09).

Example 43. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)acetic acid (YJ-43)

Yellow solid, yield 75.0%, melting point: 184-187°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.27 (s, 1H, NH), 7.84 (s, 1H, Benzene-H), 7.82 (s, 1H, Benzene-H), 7.73 (s, 1H, Benzene-H), 7.70 (s, 1H, Benzene-H), 3.86 (s, 2H, CH ₂ ), 3.38 (t, J＝8.2 Hz, 2H, CH ₂ ), 3.21 (t, J＝8.1 Hz, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ170.70,170.21,170.17,165.36,153.55,144.16,133.20,125.38,121.02,119.79,113.84,104.38,36.94,34.08,29.98.HR-MS:m/z343.0328[MH] ^- .C ₁₅ H ₁₂ N ₄ O ₂ S ₂ (Exact Mass: 344.04).

Example 44. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)sulfur)propane acid (YJ-44)

White solid, yield 77.0%, melting point: 180-183°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.30 (s, 1H, NH), 7.85 (s, 1H, Benzene-H), 7.82 (s, 1H, Benzene-H), 7.75 (s, 1H, Benzene-H), 7.73 (s, 1H, Benzene-H), 4.36 (q, J = 7.2 Hz, 1H, CH), 3.39 (t, J = 8.4 Hz, 2H, CH ₂ ), 3.23 (t, J = 7.6 Hz, 2H, CH ₂ ), 1.50 (d, J = 7.3 Hz, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.70,170.21,164.79,153.63,144.11,133.37,133.21,121.52,121.13,119.74,114.08,104.56,42.64,36.95,29.98,18.48.HR-MS: m/z 357.0 490[MH] ^- .C ₁₆ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 358.06).

Example 45. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)-2-methylpropanoic acid (YJ-45)

White solid, yield 71.0%, melting point: 186-189°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.26 (s, 1H, NH), 7.87 (s, 1H, Benzene-H), 7.85 (s, 1H, Benzene-H), 7.77 (s, 1H, Benzene-H), 7.74 (s, 1H, Benzene-H), 3.39 (s, 2H, CH ₂ ), 3.06 (t, J＝7.2 Hz, 2H, CH ₂ ), 2.33 (t, J＝7.3 Hz, 3H, CH ₃ ), 1.87 (q, J＝7.3 Hz, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.47,170.27,168.95,166.15,165.78,153.65,144.25,133.19,121.06,119.76,113.63,104.47,36.95,33.17,30.09,29.94,25.01.HR-MS: m/z 371.0644[MH] ^- .C ₁₇ H ₁₆ N ₄ O ₂ S ₂ (Exact Mass: 372.07).

Example 46. Preparation of Compound 3-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)propanoic acid (YJ-46)

Yellow solid, yield 72.0%, melting point: 116-119°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.26 (s, 1H, NH), 7.88 (s, 1H, Benzene-H), 7.86 (s, 1H, Benzene-H), 7.74 (s, 1H, Benzene-H), 7.71 (s, 1H, Benzene-H), 3.39 (s, 2H, CH ₂ ), 3.24 (d, J＝7.7 Hz, 2H, CH ₂ ), 3.20 (d, J＝7.1 Hz, 2H, CH ₂ ), 2.66 (t, J＝7.2 Hz, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.48,170.32,165.55,153.70,144.24,133.19,132.82,121.02,120.87,119.76,113.69,104.46,36.97,34.63,29.96,26.06.HR-MS: m/z 357.0 480[MH] ^- .C ₁₆ H ₁₄ N ₄ O ₂ S ₂ (Exact Mass: 358.06).

Example 47. Preparation of Compound 4-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)butanoic acid (YJ-47)

White solid, yield 73.0%, melting point: 214-217°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.56 (s, 1H, COOH), 9.19 (s, 1H, NH), 7.82 (s, 1H, Benzene-H), 7.80 (s, 1H, Benzene-H), 7.74 (s, 1H, Benzene-H), 7.72 (s, 1H, Benzene-H), 3.38 (t, J = 8.3 Hz, 2H, CH ₂ ), 3.18 (t, J = 8.3 Hz, 2H, CH ₂ ), 1.61 (s, 6H, CH ₂ × 3). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ175.30,169.63,165.19,153.63,144.11,133.23,132.82,121.01,119.78,114.10,104.44,67.48,51.03,36.94,29.93,26.72,25.60.HR-MS:m/z 371.0643[MH] ^- .C ₁₇ H ₁₆ N ₄ O ₂ S ₂ (Exact Mass: 372.07).

Example 48. Preparation of Compound 1-((4-((4-cyanophenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)thio)cyclobutane-1-carboxylic acid (YJ-48)

White solid, yield 56.0%, melting point: 130-133°C. Spectral data: ¹ H NMR (600 MHz, DMSO-d ₆ ) δ9.14 (s, 1H, NH), 7.81 (s, 1H, Benzene-H), 7.80 (s, 1H, Benzene-H), 7.72 (s, 1H, Benzene-H), 7.71 (s, 1H, Benzene-H), 3.37 (t, J＝8.3 Hz, 2H, CH ₂ ), 3.18 (t, J＝8.3 Hz, 2H, CH ₂ ), 2.82-2.77 (m, 2H, CH ₂ ), 2.21-2.18 (m, 2H, CH ₂ ), 2.18-2.15 (m, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.29,169.85,165.23,153.78,144.07,138.61,133.15,122.75,121.11,119.80,114.18,104.43,52.14,36.95,32.32,31.12,29.92,17.11. HR-MS: m/z 383.0644[MH] ^- .C ₁₈ H ₁₆ N ₄ O ₂ S ₂ (Exact Mass: 384.07).

Example 49. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopentadienyl[d]pyrimidin-2-yl)thio)acetic acid (YJ-49)

White solid, yield 77.0%, melting point: 146-149°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.22 (s, 1H, NH), 7.94 (s, 1H, Benzene-H), 7.92 (s, 1H, Benzene-H), 7.73 (s, 1H, Benzene-H), 7.70 (s, 1H, Benzene-H), 3.87 (s, 2H, CH ₂ ), 2.83 (d, J＝7.1 Hz, 2H, CH ₂ ), 2.79 (t, 2H, CH ₂ ), 2.05–1.99 (m, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.40,173.81,170.85,167.81,156.07,144.59,133.23,132.84,120.54,120.18,115.17,103.93,34.15,27.72,27.47,21.72.HR-MS: m/z 325.0 767[MH] ^- .C ₁₆ H ₁₄ N ₄ O ₂ S (Exact Mass: 326.08).

Example 50. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopentadienyl[d]pyrimidin-2-yl)thio)propanoic acid (YJ-50)

White solid, yield 75.0%, melting point: 131-134°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.24 (s, 1H, NH), 7.94 (s, 1H, Benzene-H), 7.92 (s, 1H, Benzene-H), 7.75 (s, 1H, Benzene-H), 7.73 (s, 1H, Benzene-H), 4.40 (q, J = 7.2 Hz, 1H, CH), 2.84 (d, J = 7.6 Hz, 2H, CH ₂ ), 2.80 (d, J = 7.9 Hz, 2H, CH ₂ ), 2.04 (t, 2H, CH ₂ ), 1.51 (d, J = 7.3 Hz, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ173.88,167.39,156.16,144.53,133.26,132.84,120.62,120.18,119.81,117.32,115.39,104.09,42.71,34.19,27.49,21.70,18.64.HR-MS: m/z 339.0925[MH] ^- .C ₁₇ H ₁₆ N ₄ O ₂ S (ExactMass:340.10).

Example 51. Preparation of Compound 2-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopentadienyl[d]pyrimidin-2-yl)thio)-2-methylpropanoic acid (YJ-51)

White solid, yield 79.0%, melting point: 202-205°C. Spectral data: ¹ H NMR (600 MHz, DMSO-d ₆ )δ9.10 (s, 1H, NH), 7.92 (s, 1H, Benzene-H), 7.90 (s, 1H, Benzene-H), 7.74 (s, 1H, Benzene-H), 7.72 (s, 1H, Benzene-H), 2.83 (t, J＝7.4 Hz, 2H, CH ₂ ), 2.76 (t, J＝7.8 Hz, 2H, CH ₂ ), 2.06-2.01 (m, 2H, CH ₂ ), 1.62 (s, 6H, CH ₃ ×2). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ175.37,173.26,167.71,156.20,144.54,133.27,120.63,120.56,119.82,115.40,104.06,50.90,40.61,34.19,27.55,26.74,21.72,21.67.HR - MS: m/z 353.1077 [MH] ^- .C ₁₈ H ₁₈ N ₄ O ₂ S (Exact Mass: 354.12).

Example 52. Preparation of Compound 3-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopentadienyl[d]pyrimidin-2-yl)thio)propanoic acid (YJ-52)

White solid, yield 75.0%, melting point: 152-153°C. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ9.26 (s, 1H, NH), 7.99 (s, 1H, Benzene-H), 7.97 (s, 1H, Benzene-H), 7.74 (s, 1H, Benzene-H), 7.72 (s, 1H, Benzene-H), 3.22 (t, J＝7.2Hz, 2H, CH ₂ ), 2.83 (d, J＝7.6Hz, 2H, CH ₂ ), 2.78 (d, J＝8.1Hz, 2H, CH ₂ ), 2.63 (t, J＝7.2Hz, 2H, CH ₂ ), 2.04 (t, J＝7.4Hz, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ173.97,173.85,168.16,156.22,144.72,133.28,132.84,121.67,120.45,119.85,115.08,103.93,35.35,34.19,27.52,26.27,21.71.HR-MS: m/z 339.0918[MH] ^- .C ₁₇ H ₁₆ N ₄ O ₂ S (Exact Mass: 340.10).

Example 53. Preparation of Compound 4-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopentadienyl[d]pyrimidin-2-yl)thio)butanoic acid (YJ-53)

White solid, yield 70.0%, melting point: 192～195℃. Spectral data: ¹ HNMR (400MHz, DMSO-d ₆ ) δ9.21 (s, 1H, NH), 7.97 (s, 1H, Benzene-H), 7.95 (s, 1H, Benzene- _H ), 7.77 (s, 1H, Benzene-H), 7.75 ₍ s _, 1H, Benzene-H), 3.08 (t, J＝ _{7.3Hz, 2H, CH 2 ) ,} ¹³ C NMR -d _6. 71. HR-MS: m/z353.1081[MH] ^- .C ₁₈ H ₁₈ N ₄ O ₂ S (Exact Mass: 354.12).

Example 54. Preparation of Compound 1-((4-((4-cyanophenyl)amino)-6,7-dihydro-5H-cyclopentadienyl[d]pyrimidin-2-yl)thio)cyclobutane-1-carboxylic acid (YJ-54)

White solid, yield 55.0%, melting point: 182～185℃. Spectral data of compound YJ-54: ¹ H NMR (600 MHz, DMSO-d ₆ ) δ9.09 (s, 1H, NH), 7.91 (s, 1H, Benzene-H), 7.89 (s, 1H, Benzene-H), 7.73 (s, 1H, Benzene-H), 7.72 (s, 1H, Benzene-H), 2.84 (s, 2H, CH ₂ ), 2.82 (d, J＝7.2 Hz, 2H, CH ₂ ), 2.76 (t, J＝7.8 Hz, 2H, CH ₂ ), 2.20–2.18 (m, 2H, CH ₂ ), 2.04 (t, J＝7.7 Hz, 2H, CH ₂ ), 2.02–1.97 (m, 2H, CH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.39,173.44,167.64,156.34,144.42,133.21,128.52,120.67,120.26,119.84,115.49,104.07,51.98,34.14,34.10,32.31,27.54,21.67, 17.09. HR-MS: m/z 365.1080 [MH] ^- .C ₁₉ H ₁₈ N ₄ O ₂ S (Exact Mass: 366.12).

Example 55. In vivo uric acid-lowering activity test of target compounds

Test Materials and Methods:

(1) Experimental animals: Male Kunming mice, provided by Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

(2) Sample treatment: Before use, the test compound was prepared with DMSO and CMC-Na to an appropriate concentration.

(3) Modeling compounds: hypoxanthine and potassium oxalate.

(4) Positive drug: Resinade.

(5) Test method: Each group was gavaged with 0.2 mL of hypoxanthine and subcutaneously injected with 0.2 mL of potassium oxonate. After gavage with 0.2 mL of drug, the timing was started. The eyeballs were removed and blood was collected 4 hours after administration. After 30 minutes of coagulation, the blood was centrifuged and the supernatant serum was collected. The uric acid concentration in the serum was tested with a uric acid meter.

Table 2 Uric acid lowering activity of compounds YJ1-YJ12 in mice

The in vivo uric acid lowering activity of compounds YJ1 to YJ12 containing pyrimidine and quinazoline structures in mice is shown in Table 2: 7 compounds have better activity than Lesinade. Among them, YJ-2 has the best activity, reducing the model's high blood uric acid value (SUA = 1166.00 μmol/L) to a moderate blood uric acid level (SUA = 524.50 μmol/L) within 4 hours, with a blood uric acid reduction rate of 60.7%, and the in vivo activity is more than twice that of Lesinade.

Table 3 Uric acid lowering activity of compounds YJ13-YJ24 in mice

The results of the uric acid-lowering activity of compounds YJ13 to YJ24 in mice are shown in Table 3: After using quinazoline modified with dimethoxy or fluorine atoms as the parent ring, the compounds showed better uric acid-lowering activity in mice, such as YJ-20 (SUA = 334.0 μmol/L, DR = 74.2%) and YJ-21 (SUA = 354.2 μmol/L, DR = 71.9%), with more prominent activities, and the in vivo SUA reduction rates were greater than 70%.

Table 4 Uric acid lowering activity of compounds YJ25-YJ36 in mice

The results of the uric acid-lowering activity of compounds YJ25 to YJ36 in mice are shown in Table 4: using thienopyrimidine rings with different sulfur atom positions as the parent ring, YJ-26 (SUA = 347.2 μmol/L, DR = 75.4%) had the best activity, which was more than twice the in vivo activity of Resinade.

Table 5 Uric acid lowering activity of compounds YJ37-YJ54 in mice

The in vivo uric acid lowering activity of compounds YJ37 to YJ54 in mice is shown in Table 5: When dihydrocyclopentylpyrimidine was used as the parent ring, YJ-49 (SUA = 217.2 μmol/L, DR = 89.9%) and YJ-50 (SUA = 330.4 μmol/L, DR = 78.3%) had the best activity, which was more than twice that of Resinade.

Conclusion: From Tables 2 to 5, it can be seen that 40 compounds have better uric acid-lowering activity in mice than Lecithin (36.5%). Among them, the uric acid-lowering rates of YJ-20 (74.2%), YJ-21 (71.9%), YJ-26 (75.4%), YJ-49 (89.9%) and YJ-50 (78.3%) were all over 70%, showing excellent uric acid-lowering activity and worthy of further development.

Claims (6)

1. A diarylamine derivative containing an aliphatic carboxyl group or a pharmaceutically acceptable salt thereof, having a structure as shown in the following general formula I: Wherein, Y is a five-membered or six-membered condensed pyrimidine; R is an alkane or a substituted alkane, and the substituent is a C1-C5 alkane. 2. the diarylamine derivatives containing aliphatic carboxyl as claimed in claim 1, is characterized in that Y is pyrimidine, quinazoline, 6,7-dimethoxyquinazoline, 7-fluoroquinazoline , Thieno[3,2-d]pyrimidine, Thieno[2,3-d]pyrimidine, 5,7-dihydrofuro[3,4-d]pyrimidine, 6,7-dihydrothieno[3 ,2-d]pyrimidine, 6,7-dihydro-5H-cyclopentylpyrimidine; R is 3. The diarylamine derivative containing aliphatic carboxyl group as claimed in claim 1 or 2, is characterized in that, it is one of the following compounds: 4. the preparation method of the diarylamine derivatives containing aliphatic carboxyl as claimed in claim 3, is characterized in that, step is as follows: Starting materials 2,4-dichloropyrimidine, 2,4-dichloroquinazoline, 2,4-dichloro-6,7-dimethoxyquinazoline, 2,4-dichloro-7-fluoroquinazole 2,4-dichlorothieno[3,2-d]pyrimidine, 2,4-dichlorothieno[2,3-d]pyrimidine, 2,4-dichloro-5,7-dihydrofuran pyrimidine, 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine, 2,4-dihydro-6,7-dihydro-5H-cyclopentyl[d] Pyrimidine and 4-cyano-1-aniline were co-placed in hydrochloric acid aqueous solution, and intermediates 2a~2i were respectively obtained through nucleophilic substitution reactions at 50°C; then 2a~2i were respectively mixed with thiourea in acetonitrile solution, 80 Reaction at ℃ to generate intermediates 3a~3i; then, intermediates 3a~3i undergo nucleophilic substitution reactions with different halogenated esters in N,N-dimethylformamide (DMF) solution of potassium carbonate to obtain esters class intermediates; finally the ester intermediates are hydrolyzed with lithium hydroxide to obtain the target compound YJ-1-54; The synthetic route is as follows: Reagents and conditions: (i) 4-cyano-1-aniline, concentrated hydrochloric acid, water, 50°C; (ii) thiourea, acetonitrile, 80°C; (iii) methyl 2-bromoacetate or other different halogens Substituted ester, potassium carbonate, N,N-dimethylformamide, room temperature; (iv) lithium hydroxide, tetrahydrofuran, methanol, room temperature; The different halogenated esters are selected from: methyl 2-bromoacetate, methyl 2-bromopropionate, methyl 2-bromo-2-methylpropionate, methyl 3-bromopropionate, 4-bromopropionate Methyl butyrate or ethyl 1-bromocyclobutane-1-carboxylate. 5. The application of the fatty carboxyl-containing diarylamine derivatives according to any one of claims 1 to 3 in the preparation of uric acid-lowering drugs. 6. A pharmaceutical composition for lowering uric acid, comprising the fatty carboxyl group-containing diarylamine derivative according to any one of claims 1-3 and one or more pharmaceutically acceptable carriers or excipients.