阅读说明：本技术 一类4-磺酰亚胺-1H-吡咯类Mcl-1抑制剂及其抗肿瘤医药用途 (4-sulfimide-1H-pyrrole Mcl-1 inhibitor and anti-tumor medical application thereof ) 是由 尤启冬 姜正羽 于泽洲 朱鹏举 仝媛媛 金雨辉 郭小可 徐晓莉 王磊 于 2021-10-11 设计创作，主要内容包括：本发明公开了一类4-磺酰亚胺-1H-吡咯类Mcl-1抑制剂及其抗肿瘤医药用途。本发明提供了一种4-磺酰亚胺-1H-吡咯类化合物,该化合物具有良好的Mcl-1抑制活性,部分化合物对Mcl-1的抑制活性达到纳摩尔级,且对Bcl-2蛋白有较好的选择性,具有开发成抗肿瘤药物的前景。(The invention discloses a 4-sulfimide-1H-pyrrole Mcl-1 inhibitor and an anti-tumor medical application thereof. The invention provides a 4-sulfimide-1H-pyrrole compound, which has good Mcl-1 inhibitory activity, part of the compound has nanomolar inhibitory activity to Mcl-1, has good selectivity to Bcl-2 protein, and has a prospect of being developed into antitumor drugs.)

1. A4-sulfimide-1H-pyrrole compound is characterized in that the chemical structure is shown as the following general formula:

wherein R represents H, methyl, ethyl, isopropyl, cyclopropyl, N-propyl, acetyl, formylphenyl, phenyl, 3-thienyl, 2-pyridyl, 2-pyrimidinyl, 2-thiazinyl, 5-pyrimidinyl, 1-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3, 4-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-piperazinylphenyl, N-4-methylpiperazinylphenyl, Boc-4-piperazinylphenyl, 3-ethylphenyl, N-propyl, acetyl, formylphenyl, 2-pyrimidinyl, 2-thienyl, 2-pyrimidinyl, 3-pyrimidinyl, 4-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-piperazinylphenyl, N-4-methylpiperazinylphenyl, Boc-4-piperazinylphenyl, 3-ethylphenyl, N-methyl, N-propylphenyl, N-methyl-4-p-piperazinylphenyl, 3-isopropylphenyl, 3-tert-butylphenyl, 3-ethoxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 3-acetamidophenyl, benzyl, 3-methylbenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methoxybenzyl, 4-tert-butylbenzyl, 4-phenylbenzyl, 4-ethynylbenzyl, 3-chloro-4 phenylbenzyl or 3-chloro-4 ethynylbenzyl.

2. A process for the preparation of a 4-sulfonimide-1H-pyrrole compound of claim 1 wherein R is H, comprising the steps of: p-toluene thiophenol forms an active intermediate under the action of triethylamine and sulfonyl chloride, and reacts with the raw material I-1 to generate different thioether intermediates I-2; performing nucleophilic substitution reaction on the raw material I-3 and 1, 3-dibromopropane in acetonitrile by taking potassium carbonate as an acid-binding agent to obtain an intermediate I-4; taking cesium carbonate as alkali, carrying out nucleophilic substitution reaction on I-2 and I-4 to obtain an intermediate I-5, oxidizing the I-5 by PIDA and ammonium carbamate to generate I-6, and hydrolyzing the I-6 under the action of NaOH to generate a target product; the synthetic route is as follows:

3. a process for the preparation of 4-sulfonimide-1H-pyrrole compounds according to claim 1, wherein R is methyl, ethyl, isopropyl, cyclopropyl, n-propyl, benzyl, 3-methylbenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methoxybenzyl, 4-tert-butylbenzyl, 4-phenylbenzyl, 4-ethynylbenzyl, 3-chloro-4 phenylbenzyl or 3-chloro-4 ethynylbenzyl, which comprises the following steps: under the action of NaH, reacting an initial raw material II-1 with corresponding iodoalkane or corresponding bromobenzyl to obtain an intermediate II-2, and hydrolyzing the intermediate II-2 with NaOH to obtain a target product; the synthetic route is as follows:

4. a process for the preparation of a 4-sulfonimide-1H-pyrrole compound of claim 1 wherein R is acetyl or formylphenyl, comprising the steps of: under the action of triethylamine, III-1 reacts with acetyl chloride or benzoyl chloride to obtain an intermediate III-2, and III-2 is hydrolyzed by NaOH to obtain a target product; the synthetic route is as follows:

5. a process for preparing a 4-sulfonimide-1H-pyrrole compound according to claim 1, wherein R is phenyl, 3-thienyl, 2-pyridyl, 2-pyrimidinyl, 2-thiazinyl, 5-pyrimidinyl, 1-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3, 4-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-piperazinylphenyl, N-4-methylpiperazinylphenyl, Boc-4-piperazinylphenyl, 3-ethylphenyl, 3-isoPropyl phenyl, 3-tert-butylphenyl, 3-ethoxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl or 3-acetamidophenyl, characterized by comprising the following steps: by Cs₂CO₃Being a base, in Pd (OAc)₂Under the catalysis of Ruphos, carrying out Buchward reaction on the IV-1 and different bromobelt aromatic hydrocarbons to obtain an intermediate IV-2, and hydrolyzing the intermediate IV-2 by NaOH to obtain a target product; the synthetic route is as follows:

6. use of a 4-sulfonimide-1H-pyrrole compound as claimed in claim 1 for the preparation of Mcl-1 inhibitor drugs.

7. The use of 4-sulfonimide-1H-pyrrole compounds as claimed in claim 1 for preparing antitumor drugs.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a 4-sulfimide-1H-pyrrole Mcl-1 inhibitor and an anti-tumor medical application thereof.

Background

Apoptosis, also known as programmed cell death, plays an important role in the clearance of harmful and potentially dangerous cells and in the maintenance of the intracellular environment. Mcl-1 is commonly overexpressed in tumor cells as an anti-apoptotic protein and is closely associated with the development of cancer and the development of drug resistance, and thus is intensively studied as a potential target for tumor therapy.

An important process in the endogenous apoptosis pathway is that the pro-apoptotic proteins Bax/Bak are combined with each other to form a dimer, so that the outer membrane of mitochondria is depolarized, apoptosis factors such as cytochrome c flow out, and the like, and downstream apoptosis signal pathway transduction is induced. Mcl-1 can bind to Bax/Bak through its hydrophobic groove to inhibit the formation of its dimer, thereby inhibiting apoptosis.

The strategy that a small-molecule BH3 mimic can mimic the binding of a BH3 domain and an Mcl-1 protein so as to inhibit the interaction of Mcl-1 and a pro-apoptotic protein is widely applied to the design of an Mcl-1 small-molecule inhibitor. In recent years, more and more small molecule inhibitors are reported, and some Mcl-1 with high activity and good drug forming property is undergoing clinical research and is expected to become a new cancer treatment drug.

Disclosure of Invention

The invention aims to provide a 4-sulfimide-1H-pyrrole Mcl-1 inhibitor and an anti-tumor medical application thereof.

The above purpose of the invention is realized by the following technical scheme:

A4-sulfimide-1H-pyrrole compound has a chemical structure shown as the following general formula:

wherein R represents H, methyl, ethyl, isopropyl, cyclopropyl, acetyl, formylphenyl, phenyl, 3-thienyl, 2-pyridyl, 2-pyrimidinyl, 2-thiazinyl, 5-pyrimidinyl, 1-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3, 4-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-piperazinylphenyl, N-4-methylpiperazinylphenyl, Boc-4-piperazinylphenyl, 3-ethylphenyl, cyclopropyl, acetyl, formylphenyl, phenyl, 3-thienyl, 2-pyrimidinyl, 2-thienyl, 4-methoxyphenyl, 4-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-piperazinylphenyl, N-4-methylpiperazinylphenyl, Boc-4-piperazinylphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-tert-butylphenyl, 3-ethoxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 3-acetamidophenyl, benzyl, 3-methylbenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methoxybenzyl, 4-tert-butylbenzyl, 4-phenylbenzyl, 4-ethynylbenzyl, 3-chloro-4 phenylbenzyl or 3-chloro-4 ethynylbenzyl.

A method for preparing the 4-sulfimide-1H-pyrrole compound, wherein R is H, comprises the following steps: p-toluene thiophenol forms an active intermediate under the action of triethylamine sulfonyl chloride, and reacts with the raw material I-1 to generate different thioether intermediates I-2; performing nucleophilic substitution reaction on the raw material I-3 and 1, 3-dibromopropane in acetonitrile by taking potassium carbonate as an acid-binding agent to obtain an intermediate I-4; taking cesium carbonate as alkali, carrying out nucleophilic substitution reaction on I-2 and I-4 to obtain an intermediate I-5, oxidizing the I-5 by PIDA and ammonium carbamate to generate I-6, and hydrolyzing the I-6 under the action of NaOH to generate a target product; the synthetic route is as follows:

a process for preparing the above-mentioned 4-sulfonimide-1H-pyrrole compounds, wherein R is methyl, ethyl, isopropyl, cyclopropyl, n-propyl, benzyl, 3-methylbenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methoxybenzyl, 4-tert-butylbenzyl, 4-phenylbenzyl, 4-ethynylbenzyl, 3-chloro-4 phenylbenzyl, or 3-chloro-4 ethynylbenzyl, comprising the steps of: under the action of NaH, reacting an initial raw material II-1 with corresponding iodoalkane or corresponding bromobenzyl to obtain an intermediate II-2, and hydrolyzing the intermediate II-2 with NaOH to obtain a target product; the synthetic route is as follows:

a method for preparing the 4-sulfimide-1H-pyrrole compound, wherein R is acetyl or formylphenyl, comprises the following steps: under the action of triethylamine, III-1 reacts with acetyl chloride or benzoyl chloride to obtain an intermediate III-2, and III-2 is hydrolyzed by NaOH to obtain a target product; the synthetic route is as follows:

a process for producing the above-mentioned 4-sulfonimide-1H-pyrrole compound, wherein R is phenyl, 3-thienyl, 2-pyridyl, 2-pyrimidinyl, 2-thiazinyl, 5-pyrimidinyl, 1-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3, 4-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-piperazinylphenyl, N-4-methylpiperazinylphenyl, Boc-4-piperazinylphenyl, 3-ethylphenylphenyl, 4-methylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-piperazinylphenyl, Boc-4-ethylpiperazinylphenyl, 3-isopropylphenyl, 3-tert-butylphenyl, 3-ethoxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl or 3-acetamidophenyl, comprising the following steps: by Cs₂CO₃Being a base, in Pd (OAc)₂Under the catalysis of Ruphos, carrying out Buchward reaction on the IV-1 and different bromobelt aromatic hydrocarbons to obtain an intermediate IV-2, and hydrolyzing the intermediate IV-2 by NaOH to obtain a target product; the synthetic route is as follows:

the 4-sulfimide-1H-pyrrole compound is used for preparing Mcl-1 inhibitor drugs.

The 4-sulfimide-1H-pyrrole compound is used for preparing antitumor drugs.

Has the advantages that:

the invention provides a 4-sulfimide-1H-pyrrole compound, which has good Mcl-1 inhibitory activity, part of the compound has nanomolar inhibitory activity to Mcl-1, has good selectivity to Bcl-2 protein, and has a prospect of being developed into antitumor drugs.

Drawings

FIG. 1 is a graph showing the gastrointestinal fluid stability of compound DDO-8298;

FIG. 2 is a graph showing the gastrointestinal fluid stability of compound DDO-8299.

Detailed Description

The following examples are given to illustrate the essence of the present invention, but not to limit the scope of the present invention.

Example 1: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methylphenylsulfonylimido) -1H-pyrrole-2-carboxylic acid (DDO-8248)

(1) Preparation of ethyl 3, 5-dimethyl-4- (p-toluenesulfonyl) -1H-pyrrole-2-carboxylate

4-methylthiophenol (2,5g,20mmol, 2eq) and triethylamine (cat.) were dissolved in 30ml of DCM, SO2Cl2(2eq) was slowly added dropwise under ice-bath conditions, the ice-bath was removed, the mixture was stirred at room temperature for 1 hour, and then the solution was added to a solution of ethyl 3, 5-dimethyl-1H-pyrrole-2-carboxylate (1eq) in DCM (30ml) and reacted at room temperature for 0.5 hour. After completion of the reaction, saturated sodium bicarbonate solution was slowly added until air bubbles disappeared completely, extracted with DCM (3 times), the organic phases were combined, washed with saturated brine, dried over sodium sulfate, the solvent was suspended dry, and the crude product was recrystallized with DCM to give 1.5g of white solid with a yield of 51.9%.

(2) Preparation of 5- (3-bromopropoxy) -2-chloro-1, 3-dimethylbenzene

4-chloro-3, 5-dimethylphenol (25.6mmol, 4g, 1eq) was dissolved in 40ml of acetonitrile, and potassium carbonate (3eq) and 1, 3-dibromopropane (3eq) were added to the solution and refluxed for 3 hours. After complete reaction, cooling to room temperature, adding 150ml of water, EA extracting for 3 times, combining organic phases, washing with saturated salt water, drying with sodium sulfate, suspending the organic phases, preparing sand, and performing column chromatography (PE) to obtain 6g of colorless liquid, wherein the yield is 85.2%.

(3) Preparation of ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (p-tolylmethylthio) -1H-pyrrole-2-carboxylate

Dissolving the 3, 5-dimethyl-4- (p-toluenesulfonyl) -1H-pyrrole-2-carboxylic acid ethyl ester (1mmol, 0.289g, 1eq) in 20ml DMF, adding cesium carbonate (2eq), stirring at 50 ℃ for 5min, adding the 5- (3-bromopropoxy) -2-chloro-1, 3-dimethylbenzene (2eq), cooling to room temperature after the reaction is completed, adding 60ml water, extracting with EA for 3 times, combining organic phases, washing with saturated salt water, drying with sodium sulfate, suspending the organic phases, making sand, and performing column chromatography (EA: PE 20:1) to obtain 0.35 g of colorless liquid with a yield of 76.4%.

(4) Preparation of 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methylphenylsulfonylimido) -1H-pyrrole-2-carboxylic acid ethyl ester

The above ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (p-tolylmethylthio) -1H-pyrrole-2-carboxylate was dissolved in DCM/MeOH (1:5), and ammonium carbamate (1.5eq) was added. After stirring at room temperature for 10 minutes, PIDA (2eq) was added; after the reaction was complete, sand was prepared and column chromatography (DCM/MeOH ═ 100: 1to 30:1v/v) gave a dark yellow solid in 76% yield.

(5) Preparation of the title Compound

Dissolving the above ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methylphenylsulfonylimido) -1H-pyrrole-2-carboxylate (0.3g, 0.58mmol, 1eq) in an ethanol/tetrahydrofuran mixed solution (7ml/7ml), adding NaOH (2M, 10eq), heating and stirring overnight at 50 ℃, cooling to room temperature after completion of the reaction, adding 1M HCl to pH 1, filtering, washing the filter cake with water, and drying to obtain 0.252g of a pale yellow solid, yield 95%, melting point: 204 ℃. 205 ℃.1H NMR (300MHz, d 6-DMSO). delta.7.72 (d, J ═ 8.2Hz,2H),7.29(d, J ═ 8.0Hz,2H),6.75(s,2H),4.39(t, J ═ 7.1Hz,2H), 3.86(t, J ═ 5.7Hz,2H),2.56(s,3H),2.37(s,3H),2.33(s,3H),2.29(s,6H), 2.03-1.96 (m,2H). HRMS (ESI). calcd for C25H29ClN2O4S [, ]M+H]+489.1615,found 485.1609.HPLC (80:20 methanol:water with 1‰TFA):t_R＝8.43min,95.6％.

Example 2: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N-methyl-4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8249)

(1) Preparation of ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate

The above ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methylphenylsulfonylimido) -1H-pyrrole-2-carboxylate (0.5g) was dissolved in DMF (10ml), and NaH (2eq) was added under ice-bath conditions. After stirring for 10 minutes, CH was added₃I (2 eq). After the reaction was complete, the ice bath was removed and 30ml of H was slowly added₂Extracting with EA for three times, mixing organic phases, washing with saturated salt water, and drying with sodium sulfate. Preparing sand, and performing column chromatography to obtain colorless oily substance.

(2) Preparation of the title Compound

Dissolving the ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methylphenylsulfonylimido) -1H-pyrrole-2-carboxylate (0.3g, 0.58mmol, 1eq) in an ethanol/tetrahydrofuran mixed solution (7ml/7ml), adding NaOH (2M, 10eq), heating and stirring at 50 ℃ overnight, cooling to room temperature after complete reaction, adding 1M HCl to pH 1, filtering, washing a filter cake with water, and drying to obtain a brown solid with a melting point of 78% and a melting point of 178-179 ℃.¹H NMR(300MHz,CDCl₃) δ7.91(d,J＝6.3Hz,2H),7.42(d,J＝6.1Hz,2H),6.63(s,2H),4.53(s,2H),3.89(s,2H),2.90(s, 3H),2.60(s,3H),2.44(s,3H),2.36(s,6H),2.19(s,2H).HRMS(ESI):calcd for C₂₆H₃₁ClN₂O₄S [M+H]⁺503.1767,found 503.1771.HPLC(80:20 methanol:water with 1‰TFA):t_R＝7.53min, 96.9％.

Example 3: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N-ethyl-4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8250)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate and iodoethane as in example 2. Yellow solid, yield: 76%, melting point: 211 ℃ and 212 ℃.¹H NMR(300MHz,d₆-DMSO)δ7.86–7.76(m,2H),7.43(d,J＝8.0Hz,2H),6.75(s, 2H),4.45(q,J＝7.3,6.7Hz,2H),3.86(s,2H),3.03(dt,J＝16.5,7.2Hz,2H),2.54(s,3H),2.40(s, 3H),2.37(s,3H),2.30(s,6H),2.14–1.99(m,2H),1.17(t,J＝7.1Hz,3H).HRMS(ESI):calcd for C₂₇H₃₃ClN₂O₄S[M+H]⁺517.1928,found 517.1928.HPLC(80:20 methanol:water with 1‰TFA): t_R＝7.82min,97.8％.

Example 4: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N-cyclopropyl-4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8251)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, iodocyclopropane as in example 2. 83%, melting point 204-.¹H NMR(300MHz,CDCl₃)δ7.93(d,J＝5.9Hz,2H),7.37(s,2H),6.69(s,2H),4.59 (s,2H),3.95(s,2H),2.75(s,3H),2.63(s,3H),2.50(s,3H),2.43(s,6H),2.24(s,2H),1.06–0.51 (m,5H).HRMS(ESI):calcd for C₂₈H₂₃ClN₂O₄S[M+H]⁺529.1928,found 529.1925.HPLC (80:20 methanol:water with 1‰TFA):t_R＝9.72min,98.5％.

Example 5: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N-isopropyl-4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8252)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, iodoisopropane as in example 2, as a white solid in yield: 77%, melting point: 224 ℃ and 226 ℃.¹H NMR(300MHz,CDCl₃)δ7.86(d,J＝8.0Hz,2H),6.63(s,2H),4.50(t,J＝7.1Hz, 2H),3.88(t,J＝5.0Hz,2H),3.53–3.35(m,1H),2.66(s,3H),2.52(s,3H),2.44(s,3H),2.36(s, 6H),2.22–2.12(m,2H),1.32(d,J＝5.9Hz,6H).HRMS(ESI):calcd for C₂₈H₃₅ClN₂O₄S[M+ H]⁺531.2084,found 531.2080.HPLC(80:20 methanol:water with 1‰TFA):t_R＝8.54min, 98.3％.

Example 6: 4- (N-acetyl-4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8253)

(1) Preparation of ethyl 4- (N-acetyl-4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylate

The above ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.5g) was dissolved in anhydrous triethylamine (10ml), and acetyl chloride (2eq) was added to give a yellow liquid,¹H NMR(300MHz,Chloroform-d)δ7.83(d,J＝7.6Hz,2H),7.25(d,J＝7.5Hz,2H),6.69(s, 2H),4.35(q,J＝8.0Hz,2H),4.15(t,J＝7.1Hz,2H),4.06(t,J＝7.1Hz,2H),2.56(s,3H),2.43(s, 3H),2.38(s,3H),2.35(s,3H),2.32(s,6H),2.10(q,J＝7.1Hz,2H),1.35(t,J＝8.0Hz,3H). ESI-MS m/z:559.2[M+H]⁺.

(2) preparation of the title Compound

This was prepared from the above ethyl 4- (N-acetyl-4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylate as described in example 2 as a white solid with a yield of 87% and a melting point of 209-.¹H NMR(300MHz,DMSO-d₆)δ7.94(d,J＝8.2Hz,2H),7.53(d,J＝8.1Hz,2H), 6.78(s,2H),4.48(t,J＝6.5Hz,2H),3.93(t,J＝5.3Hz,2H),2.60(s,3H),2.53(s,3H),2.44(s, 3H),2.42(s,3H),2.30(s,6H).HRMS(ESI):calcd for C₂₇H₃₁ClN₂O₅S[M+H]⁺531.1720,found 531.1725.HPLC(80:20 methanol:water with 1‰TFA):t_R＝8.76min,97.4％.

Example 7: 4- (N-benzoyl-4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8254)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, benzoyl chloride as in example 6, as a yellow solid in 72% yield, m.p.: 213-214 ℃.¹H NMR(300MHz,CDCl₃)δ8.24(d,J＝7.4Hz,2H),7.99(d,J＝8.0Hz,2H),7.56 (t,J＝7.4Hz,1H),7.46(t,J＝7.4Hz,2H),7.37(d,J＝7.9Hz,2H),6.63(s,2H),4.53(s,2H),3.89 (s,2H),2.74(s,3H),2.48(s,3H),2.43(s,3H),2.35(s,6H).HRMS(ESI):calcd for C₃₂H₃₃ClN₂O₅S[M+H]⁺593.1877,found 593.1873.HPLC(80:20 methanol:water with 1‰TFA): t_R＝6.57min,98.6％.

Example 8: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N-phenylsulfonylimido) -1H-pyrrole-2-carboxylic acid (DDO-8255)

(1) Preparation of ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N-phenylsulfonylimido) -1H-pyrrole-2-carboxylate.

The above ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.5g), bromobenzene (1.5eq), palladium acetate (0.1eq), Ruphos (0.1eq) and cesium carbonate (2eq) were added to a sealed tube, and toluene (6ml) was added. Heating at 90 deg.C overnight under nitrogen protection, making sand, purifying by column chromatography (PE/EA is 40:1to 15:1v/v) to obtain yellow oil,¹H NMR(300MHz,Chloroform-d)δ7.81(d,J ＝7.5Hz,2H),7.45(t,J＝7.5Hz,2H),7.28(dd,J＝7.6,1.5Hz,2H),7.23(d,J＝7.5Hz,3H),6.69 (s,2H),4.35(q,J＝8.0Hz,2H),4.15(t,J＝7.1Hz,2H),4.06(t,J＝7.1Hz,2H),2.58(s,3H),2.38 (s,3H),2.32(s,6H),2.30(s,3H),2.09(p,J＝7.1Hz,2H),1.35(t,J＝8.0Hz,3H).ESI-MS m/z: 593.2[M+H]⁺.

(2) preparation of the title Compound

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N-phenylphenylsulfonylimino) -1H-pyrrole-2-carboxylate as described above according to example 2 as a white solid in yield: 67%, melting point: 203-.¹H NMR(300MHz,CDCl₃)δ7.95(d,J＝7.9Hz,2H),7.30(s,4H),7.18(s,2H),6.92(t,J＝6.3 Hz,1H),6.59(s,2H),4.46(s,2H),3.80(s,2H),2.65(s,3H),2.53(s,3H),2.43(s,3H),2.35(s, 6H),2.11(s,2H).HRMS(ESI):calcd for C₃₂H₃₃ClN₂O₅S[M+H]⁺565.1928,found 565.1923. HPLC(80:20 methanol:water with 1‰TFA):t_R＝10.2min,97.1％.

Example 9: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (thiophen-2-yl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8256)

This was prepared from the above ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 2-bromothiophene according to example 8, yield 64%, red solid, melting point: 195 ℃ and 196 ℃.¹H NMR(300MHz,DMSO-d₆)δ12.82(s,1H),7.86(d,J＝7.9Hz,2H),7.39(d,J＝ 7.8Hz,2H),7.31(s,1H),6.83(d,J＝4.5Hz,1H),6.74(s,2H),6.49(s,1H),4.42(s,2H),3.81(s, 2H),2.58(s,3H),2.38(s,3H),2.34(s,3H),2.31(s,6H),2.02(s,2H).HRMS(ESI):calcd for C₂₉H₃₁ClN₂O₄S₂[M+H]⁺571.1488,found 571.1470.HPLC(80:20 methanol:water with 1‰TFA): t_R＝9.58min,98.3％.

Example 10: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (pyrimidin-2-yl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8257)

This was prepared from the above ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-bromopyridine according to example 8 in 73% yield, as a yellow solid, m.p.: 208 ℃ and 209 ℃.¹H NMR(300MHz,CDCl₃)δ8.45(s,1H),8.25(s,1H),7.89(s,3H),7.41(d,J＝37.6 Hz,3H),6.60(s,2H),4.52(s,2H),3.85(s,2H),2.67(s,3H),2.46(s,6H),2.35(s,6H),2.17(s, 2H).HRMS(ESI):calcd for C₃₀H₃₂ClN₃O₄S[M+H]⁺566.1880,found 566.1875.HPLC(80:20 methanol:water with 1‰TFA):t_R＝8.64min,97.6％.

Example 11: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (pyrimidin-2-yl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8258)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 2-bromopyrimidine as in example 8 as a purple solid in 69% yield, m.p.: 213-214 ℃.¹H NMR(300MHz,DMSO-d₆)δ8.60(d,J＝4.4Hz,2H),7.93(d,J＝7.8Hz,2H), 7.46(d,J＝7.7Hz,2H),7.10(t,J＝4.4Hz,1H),6.74(s,2H),4.45(s,2H),3.85(s,2H),2.59(s, 3H),2.41(s,3H),2.30(s,6H),2.25(s,3H).HRMS(ESI):calcd for C₂₉H₃₁ClN₄O₄S[M+H]⁺ 567.1840,found 567.1833.HPLC(80:20 methanol:water with 1‰TFA):t_R＝7.85min,96.1％.

Example 12: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (pyrazin-2-yl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8259)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 2-bromothiazine as in example 8 as a white solid in 82% yield, m.p.: 197 ℃ and 198 ℃.¹H NMR(300MHz,d6-DMSO)δ12.79(s,1H),7.86(d,J＝8.2Hz,2H),7.37(d,J＝ 8.2Hz,2H),6.92(d,J＝8.8Hz,2H),6.70(s,2H),4.40(t,J＝6.4Hz,2H),3.81(t,J＝5.0Hz,2H), 3.64(s,3H),2.59(s,3H),2.38(s,3H),2.32(s,3H),2.30(s,6H).HRMS(ESI):calcd for C₂₉H₃₁ClN₄O₄S[M+H]⁺567.1863,found 567.1861.HPLC(80:20 methanol:water with 1‰TFA): t_R＝9.76min,96.8％.

Example 13: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (pyrimidin-5-yl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8260)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 5-bromopyrimidine as in example 8 as a white solid in yield: 74%, melting point: 189 deg.C and 190 deg.C.¹H NMR(300MHz,CDCl₃)δ9.02(s,1H),8.83(s,2H),8.17(d,J＝6.6Hz,2H),7.57 (d,J＝3.3Hz,2H),6.84(s,2H),4.73(s,2H),4.07(s,2H),2.90(s,3H),2.69(s,6H),2.59(s,6H), 2.38(s,2H).¹³C NMR(75MHz,DMSO-d₆)δ162.52,156.68,155.80,143.67,142.24,140.10, 136.96,136.33,130.27,127.95,126.99,125.59,121.14,115.93,115.05,92.50,64.88,56.47,42.66, 30.25,21.38,20.88,12.04,11.37.HRMS(ESI):calcd for C₂₉H₃₁ClN₄O₄S[M+H]⁺567.1826, found 567.1833.HPLC(80:20 methanol:water with 1‰TFA):t_R＝9.26min,98.5％.

Example 14: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (naphthalen-1-yl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8261)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 1 bromonaphthalene as in example 8 as a green solid in 77% yield, m.p.: 190 ℃ and 191 ℃.¹H NMR(300MHz,d₆-DMSO)δ12.83(s,1H),8.60(d,J＝9.1Hz,1H),8.06(d,J＝ 8.3Hz,2H),7.86–7.78(m,1H),7.52(dd,J＝6.5,2.9Hz,2H),7.47(d,J＝8.3Hz,2H),7.39(d,J ＝8.2Hz,1H),7.19(t,J＝7.8Hz,1H),7.03(d,J＝7.3Hz,1H),6.70(s,2H),4.41(t,J＝6.8Hz, 2H),3.79(t,J＝5.4Hz,2H),2.58(s,3H),2.42(s,3H),2.29(s,6H),2.24(s,3H),1.98(dd,J＝12.8, 7.1Hz,2H).HRMS(ESI):calcd for C35H35ClN2O4S[M+H]+615.2076,found 615.2084.HPLC (80:20 methanol:water with 1‰TFA):t_R＝5.49min,98.5％.

Example 15: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (naphthalen-2-yl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8262)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate and 2-bromonaphthalene as in example 8 as a brown solid with a yield of 59% and a melting point of 196-.¹H NMR(300MHz,d6-DMSO)δ7.94(d,J＝8.3Hz,2H),7.73(t,J＝7.8Hz,2H), 7.64(d,J＝8.1Hz,1H),7.44–7.25(m,6H),6.71(s,2H),4.50–4.32(m,2H),3.80(t,J＝5.6Hz, 2H),2.67(s,3H),2.39(s,3H),2.35(s,3H),2.29(s,6H),2.06–1.94(m,2H).HRMS(ESI):calcd for C35H35ClN2O4S[M+H]+615.2073,found 615.2084.HPLC(80:20 methanol:water with 1‰ TFA):t_R＝9.72min,96.7％.

Example 16: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (o-tolyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8263)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 2-bromotoluene as in example 8 as a yellow solid in 64% yield, m.p.: 203 ℃ and 204 ℃.¹H NMR(300MHz,CDCl₃)δ7.99(d,J＝8.3Hz,2H),7.31(d,J＝8.1Hz,2H),7.16 (d,J＝6.9Hz,1H),7.06(d,J＝7.5Hz,1H),6.93(t,J＝7.5Hz,1H),6.84(t,J＝6.9Hz,1H),6.59 (s,2H),4.48(t,J＝6.7Hz,2H),3.80(s,2H),2.66(s,3H),2.47(s,3H),2.47(s,3H),2.45(s,3H), 2.19–2.04(m,2H).HRMS(ESI):calcd for C35H35ClN2O4S[M+H]+579.2084,found 579.2075.HPLC(80:20 methanol:water with 1‰TFA):t_R＝8.54min,98.2％.

Example 17: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (m-tolyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8264)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-bromotoluene as in example 8, yellow, solid, 73% yield, melting point: 211 ℃ and 212 ℃.¹H NMR(300MHz,CDCl₃)δ8.00–7.88(m,2H),7.31(s,2H),7.12–6.91(m,3H), 6.75(d,J＝7.2Hz,1H),6.60(s,2H),4.48(s,2H),3.83(s,2H),2.68(s,3H),2.54(s,3H),2.44(s, 3H),2.36(s,6H),2.28(s,3H).HRMS(ESI):calcd for C₃₂H₃₅ClN₂O₄S[M+H]⁺579.2080,found 579.2084.HPLC(80:20 methanol:water with 1‰TFA):t_R＝9.58min,97.9％.

Example 18: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (p-tolyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8265)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-bromotoluene as in example 8 as a white solid in 87% yield, m.p.: 183 ℃ and 184 ℃.¹H NMR(300MHz,CDCl₃)δ7.95(d,J＝7.9Hz,2H),7.30(d,J＝6.6Hz,2H),7.07 (d,J＝8.1Hz,2H),6.99(d,J＝8.0Hz,2H),6.60(s,2H),4.47(t,J＝6.3Hz,2H),3.82(t,J＝4.3 Hz,2H),2.67(s,3H),2.53(s,3H),2.44(s,3H),2.36(s,6H),2.27(s,3H),2.12(s,2H).¹³C NMR (75MHz,d₆-DMSO)δ162.59,156.69,143.14,140.33,140.17,136.94,130.07,129.84,128.59, 127.18,125.57,122.75,121.00,116.61,115.05,30.25,21.33,20.88,20.68,12.06,11.31.HPLC (80:20 methanol:water with 1‰TFA):t_R＝10.03min,97.2％.

Example 19: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (2-methoxyphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8266)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 2-methoxybromobenzene as in example 8 as a yellow solid in 75% yield, m.p. 187 at 188 ℃.¹H NMR(300MHz,CDCl₃)δ7.95(d,J＝8.2Hz,2H),7.30(d,J＝6.5Hz,2H),7.07 (t,J＝8.4Hz,1H),6.75(d,J＝7.3Hz,2H),6.60(s,2H),6.54–6.47(m,1H),4.48(t,J＝6.7Hz, 2H),3.83(t,J＝5.9Hz,2H),3.77(s,3H),2.67(s,3H),2.55(s,3H),2.44(s,3H),2.36(s,6H),2.12 (dt,J＝12.7,7.1Hz,2H).HRMS(ESI):calcd for C₃₂H₃₅ClN₂O₅S[M+H]⁺595.2028,found 595.2033.HPLC(80:20 methanol:water with 1‰TFA):t_R＝9.76min,96.8％.

Example 20: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-methoxyphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8267)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-methoxybromobenzene as in example 8 as a yellow solid with a melting point of 85%, a melting point of 178-.¹H NMR(300MHz,CDCl₃)δ7.95(d,J＝8.2Hz,2H),7.30(d,J＝6.5Hz,2H),7.07 (t,J＝8.4Hz,1H),6.75(d,J＝7.3Hz,2H),6.60(s,2H),6.54–6.47(m,1H),4.48(t,J＝6.7Hz, 2H),3.83(t,J＝5.9Hz,2H),3.77(s,3H),2.67(s,3H),2.55(s,3H),2.44(s,3H),2.36(s,6H),2.12 (dt,J＝12.7,7.1Hz,2H).HRMS(ESI):calcd for C₃₂H₃₅ClN₂O₅S[M+H]⁺595.2026,found 595.2033.HPLC(80:20 methanol:water with 1‰TFA):t_R＝9.89min,98.4％.

Example 21: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (4-methoxyphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8268)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 4-methoxybromobenzene as in example 8 as a yellow solid in 85% yield, m.p.: 189 deg.C and 190 deg.C.¹H NMR(300MHz,DMSO-d₆)δ12.79(s,-1H),7.86(d,J＝8.2Hz,2H),7.37(d,J＝ 8.2Hz,2H),6.92(d,J＝8.8Hz,2H),6.70(s,2H),4.40(t,J＝6.4Hz,2H),3.81(t,J＝5.0Hz,2H), 3.64(s,3H),2.59(s,3H),2.38(s,3H),2.32(s,3H),2.30(s,6H),2.03–1.96(m,2H).HRMS(ESI): calcd for C₂₉H₃₁ClN₄O₄S[M+H]⁺595.2029,found 595.2033.HPLC(80:20 methanol:water with 1‰TFA):t_R＝8.87min,97.4％.

Example 22: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (2-nitrophenyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8269)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 2-nitrobromobenzene as in example 8 as an orange solid with a melting point of 77%, melting point: 186 ℃ and 187 ℃.¹H NMR(300MHz,d6-DMSO)δ12.95(s,1H),7.90(d,J＝8.3Hz,2H),7.73(d,J＝ 7.1Hz,1H),7.45(d,J＝8.2Hz,2H),7.32(t,J＝7.7Hz,1H),7.13(d,J＝8.0Hz,1H),6.98(t,J＝ 7.5Hz,1H),6.71(s,2H),4.43(t,J＝6.5Hz,2H),3.80(s,2H),2.57(s,3H),2.40(s,3H),2.30(s, 6H),2.27(s,3H),2.09–1.91(m,2H).HRMS(ESI):calcd for C₃₁H₃₂ClN₃O₆S[M+H]⁺610.1764, found 610.1779.HPLC(80:20 methanol:water with 1‰TFA):t_R＝6.58min,97.9％.

Example 23: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (3-nitrophenyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8270)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-nitrobromobenzene as in example 8 as a yellow solid with a melting point of 73%, a melting point of 198-.¹H NMR(300MHz,Chloroform-d)δ8.34(t,J＝1.5Hz,1H),8.26(dt,J＝7.5,1.5Hz, 1H),7.81(d,J＝7.5Hz,2H),7.65(t,J＝7.5Hz,1H),7.59(dt,J＝7.5,1.5Hz,1H),7.23(d,J＝7.6 Hz,2H),6.69(s,2H),4.13(t,J＝7.1Hz,2H),4.06(t,J＝7.1Hz,2H),2.58(s,3H),2.42(s,3H), 2.37(d,J＝0.9Hz,3H),2.31(s,6H),2.08(p,J＝7.1Hz,2H).HRMS(ESI):calcd for C₃₁H₃₂ClN₃O₆S[M-H]^-608.1621,found 608.1628.HPLC(80:20 methanol:water with 1‰TFA): t_R＝6.93min,98.2％.

Example 24: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (4-nitrophenyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8271)

The product is prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimideYl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-nitrobromobenzene are prepared as in example 8 in the form of a yellow solid with a yield of 68% and a melting point of 207-.¹H NMR(300MHz,d₆-DMSO)δ12.97(s,1H),8.06(d,J＝9.1Hz,2H),7.94(d,J＝ 8.3Hz,2H),7.45(d,J＝8.2Hz,2H),7.13(d,J＝9.1Hz,2H),6.71(s,2H),4.44(t,J＝6.7Hz,2H), 3.82(t,J＝5.6Hz,2H),2.61(s,3H),2.41(s,3H),2.32(s,3H),2.29(s,6H),2.03(q,J＝6.0Hz, 2H).HRMS(ESI):calcd for C₃₁H₃₂ClN₃O₆S[M+H]⁺610.1779,found 610.1763.HPLC(80:20 methanol:water with 1‰TFA):t_R＝7.24min,97.5％.

Example 25: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3, 4-dimethylphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO8272)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3, 4-dimethylbromobenzene as in example 8 as a yellow solid in 57% yield, m.p.: 203 ℃ and 204 ℃.¹H NMR(300MHz,Chloroform-d)δ9.40(s,1H),7.59(d,J＝7.5Hz,2H),7.16(d, J＝6.8Hz,2H),7.11(d,J＝7.7Hz,2H),7.06(dd,J＝7.5,1.8Hz,1H),6.66(s,2H),4.34(t,J＝ 7.0Hz,2H),4.22(t,J＝7.1Hz,2H),2.42(s,3H),2.23(s,12H),2.16(s,3H),2.08(s,3H),1.98(p, J＝7.1Hz,2H).HRMS(ESI):calcd for C₃₁H₃₂ClN₃O₆S[M+H]⁺593.2163,found 593.2169. HPLC(80:20 methanol:water with 1‰TFA):t_R＝8.35min,98.4％.

Example 26: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (4-ethylphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8273)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-ethylbromobenzene as for example 8 as a white solid in 65% yield, m.p.: 215 ℃ and 216 ℃.¹H NMR(300MHz,CDCl₃)δ7.94(d,J＝8.2Hz,2H),7.27(s,2H),7.03(q,J＝8.4 Hz,4H),6.60(s,2H),4.46(t,J＝6.8Hz,2H),3.82(t,J＝5.3Hz,2H),2.67(s,3H),2.63–2.53(m, 5H),2.43(s,3H),2.35(s,6H),2.11(q,J＝6.6,6.1Hz,2H),1.20(t,J＝7.6Hz,3H).HRMS(ESI): calcd for C₃₃H₃₇ClN₂O₄S[M+H]⁺593.2241,found 593.2235.HPLC(80:20 methanol:water with 1‰TFA):t_R＝9.54min,98.2％.

Example 27: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (4-isopropylphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8274)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 4-isopropylbromobenzene as in example 8 as a pale yellow solid with a yield of 72%, m.p. 211-212 ℃.¹H NMR(300MHz,d6-DMSO)δ7.87(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H), 7.00(d,J＝8.5Hz,2H),6.91(d,J＝8.3Hz,2H),6.73(s,2H),4.55–4.25(m,2H),3.95–3.66(m, 2H),2.74(p,J＝6.9Hz,1H),2.60(s,3H),2.38(s,4H),2.33(s,3H),2.30(s,6H),2.04–1.95(m, 2H),1.13(d,J＝6.8Hz,6H).¹³C NMR(75MHz,d6-DMSO)δ162.65,156.68,143.34,143.12, 141.13,140.44,140.01,136.93,130.10,127.12,125.57,122.68,121.12,116.78,115.06,33.04, 24.35,21.33,20.88,12.06,11.33.HRMS(ESI):calcd for C₃₄H₃₉ClN₂O₄S[M+H]⁺607.2397, found 607.2389.HPLC(80:20 methanol:water with 1‰TFA):t_R＝12.1min,97.4％.

Example 28: 4- (N- (4- (tert-butyl) phenyl) -4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8275)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-tert-butylbromobenzene as for example 8 as a white solid in yield: 67%, melting point: 219 — 220 ℃.¹H NMR(300MHz,CDCl₃)δ7.94(d,J＝8.2Hz,2H),7.27(s,2H),7.19(d,J＝8.6 Hz,2H),7.06(d,J＝8.5Hz,2H),6.60(s,2H),4.47(t,J＝6.9Hz,2H),3.83(t,J＝5.4Hz,2H), 2.67(s,3H),2.55(s,3H),2.43(s,3H),2.35(s,6H),2.12(q,J＝5.9Hz,2H),1.28(s,9H).¹³C NMR(75MHz,d6-DMSO)δ162.59,156.69,143.43,143.13,142.98,140.49,140.06,136.94, 130.11,128.58,127.12,126.01,125.58,122.38,121.04,116.91,115.08,34.14,31.65,21.35,20.89, 12.08,11.35.HRMS(ESI):calcd for C₃₅H₄₁ClN₂O₄S[M+H]⁺621.2554,found 621.2547.

Example 29: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (4- (piperazin-1-yl) phenyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8276)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-piperazinylbenzene as in example 8 as a white solid in 64% yield, m.p.: 221-222 ℃.¹H NMR(300MHz,Chloroform-d)δ7.81(d,J＝7.5Hz,2H),7.24(d,J＝7.5Hz,4H), 6.73(d,J＝7.5Hz,2H),6.69(s,2H),4.13(t,J＝7.1Hz,2H),4.07(t,J＝7.1Hz,2H),3.38(t,J＝ 7.0Hz,4H),3.09(td,J＝7.1,5.0Hz,4H),2.58(s,3H),2.45–2.42(m,3H),2.37(s,3H),2.27(s, 6H),2.08(p,J＝7.1Hz,2H),1.93(p,J＝5.1Hz,1H).HRMS(ESI):calcd for C₃₅H₄₁ClN₄O₄S[M- H]^-647.2459,found 647.2460.HPLC(80:20 methanol:water with 1‰TFA):t_R＝7.65min,96.9％.

Example 30: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (4- (4-methylpiperazin-1-yl) phenyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8277)

This product was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-methylpiperazinylbenzene as in example 8 as a white solid in 57% yield, m.p.: 217 ℃ and 218 ℃.¹H NMR(300MHz,CDCl₃)δ8.00–7.91(m,2H),7.29(d,J＝9.4Hz,2H),7.03 (d,J＝8.7Hz,2H),6.60(d,J＝5.6Hz,4H),4.43(t,J＝6.7Hz,2H),3.81(s,2H),3.30(s,8H),2.84 (s,3H),2.69(s,3H),2.43(s,6H),2.34(s,6H),2.09(s,2H).HRMS(ESI):calcd for C₃₆H₄₃ClN₄O₄S[M+H]⁺663.2772,found 663.2776.HPLC(80:20 methanol:water with 1‰TFA): t_R＝8.47min,98.2％.

Example 31: 4- (N- (4- (4- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenyl) -4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8278)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-Boc piperazinylbenzene as in example 8 as a yellow solid in 62% yield, mp: 207-208 ℃.¹H NMR(300MHz,CDCl₃)δ7.92(d,J＝8.2Hz,2H),7.28(d,J＝8.2Hz,2H), 7.07(d,J＝8.7Hz,2H),6.80(d,J＝8.5Hz,2H),6.59(s,2H),4.46(t,J＝5.9Hz,2H),3.82(t,J＝ 4.7Hz,2H),3.58(s,4H),3.02(s,4H),2.66(s,3H),2.52(s,3H),2.43(s,3H),2.35(s,6H),2.10(s, 2H),1.51(s,9H).HRMS(ESI):calcd for C₄₀H₄₉ClN₄O₆S[M+H]⁺749.3140,found 749.3136. HPLC(80:20 methanol:water with 1‰TFA):t_R＝9.89min,98.3％.

Example 32: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-ethylphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8279)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 3-ethylbromobenzene as for example 8 as a yellow solid in 53% yield, melting point: 178 ℃ and 179 ℃.¹H NMR(300MHz,CDCl₃)δ7.95(d,J＝8.2Hz,2H),7.28(s,2H),7.13–6.91(m, 3H),6.77(d,J＝7.5Hz,1H),6.60(s,2H),4.47(t,J＝6.5Hz,2H),3.82(t,J＝5.1Hz,2H),2.67(s, 3H),2.63–2.51(m,5H),2.44(s,3H),2.36(s,6H),2.12(dd,J＝9.9,5.6Hz,2H),1.19(t,J＝7.6 Hz,3H).HRMS(ESI):calcd for C₃₃H₃₇ClN₂O₄S[M+H]⁺593.2220,found 593.2228.HPLC(80:20 methanol:water with 1‰TFA):t_R＝12.3min,98.7％.

Example 33: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-isopropylphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8280)

The product is prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 3-isopropylbromobenzene was prepared as in example 8 as a yellow solid in 71% yield, melting point: 183 ℃ and 184 ℃.¹H NMR(300MHz,CDCl₃)δ8.03(d,J＝9.0Hz,2H),7.39(d,J＝5.3Hz,2H),7.20– 7.11(m,2H),7.06(d,J＝5.4Hz,1H),6.89(d,J＝8.5Hz,1H),6.67(s,2H),4.54(s,2H),3.90(s, 2H),2.98–2.83(m,1H),2.72(s,3H),2.59(s,3H),2.51(s,3H),2.43(s,6H),2.17(s,2H),1.29(s, 3H),1.26(s,3H).HRMS(ESI):calcd for C₃₄H₃₉ClN₂O₄S[M+H]⁺607.2397,found 607.2389. HPLC(80:20 methanol:water with 1‰TFA):t_R＝12.8min,96.6％.

Example 34: 4- (N- (3- (tert-butyl) phenyl) -4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8281)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-tert-butylbromobenzene as in example 8 as a yellow solid in 64% yield, melting point: 187-188 ℃.¹H NMR(300MHz,CDCl₃)δ8.03(d,J＝8.2Hz,2H),7.36(d,J＝5.9Hz,3H),7.16 (t,J＝7.6Hz,1H),7.02(d,J＝9.1Hz,2H),6.66(s,2H),4.63–4.45(m,2H),3.95–3.82(m,2H), 2.72(s,3H),2.58(s,3H),2.50(s,3H),2.42(s,6H),2.20–2.10(m,2H),1.34(s,9H).HRMS(ESI): calcd for C₃₅H₄₁ClN₂O₄S[M+H]⁺621.2554,found 621,2549.HPLC(80:20 methanol:water with 1‰TFA):t_R＝13.1min,96.8％.

Example 35: 4- (N- ([ [1,1' -biphenyl ] -3-yl) -4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8282)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 3-bromobiphenyl as for example 8 as a white solid in 67% yield, melting point: 193 ℃ and 194 ℃.¹H NMR(300MHz,CDCl₃)δ8.13(s,2H),7.80(s,1H),7.57(s,10H),6.70(s,2H), 4.59(s,2H),3.95(s,2H),2.40(s,12H).¹³C NMR(75MHz,d6-DMSO)δ162.59,156.71,146.42, 143.44,141.41,140.85,140.19,136.98,130.25,129.94,129.36,128.59,127.84,127.31,127.00, 125.61,121.29,120.00,116.38,115.11,64.98,42.73,30.32,21.44,20.95,12.17,11.45.HRMS (ESI):calcd for C₃₇H₃₇ClN₂O₄S[M+H]⁺641.2230,found 641.2235.HPLC(80:20 methanol:water with 1‰TFA):t_R＝15.7min,96.3％.

Example 36: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-ethoxyphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8283)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-ethoxybromobenzene as in example 8 as a yellow solid in 72% yield, m.p. 203-.¹H NMR(300MHz,CDCl₃)δ8.08(s,2H),7.44(s,2H),7.24–7.04(m,3H),6.72(d, J＝13.5Hz,3H),4.59(s,2H),4.12–4.00(m,2H),3.96(s,2H),2.51(s,3H),2.46(s,3H),2.40(s, 9H),2.26(s,2H),1.42(t,J＝6.3Hz,3H).HRMS(ESI):calcd for C₃₃H₃₇ClN₂O₅S[M+H]⁺ 609.2190,found 609.2182.HPLC(80:20 methanol:water with 1‰TFA):t_R＝9.72min,97.8％.

Example 37: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-cyanophenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8284)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-cyanobenzene as in example 8 as a yellow solid in 62% yield, mp 210-.¹H NMR(300MHz,d6-DMSO)δ12.93(s,-1H),7.91(d,J＝8.1Hz,2H),7.42(d,J＝ 8.1Hz,2H),7.36–7.19(m,4H),6.71(s,2H),4.42(t,J＝6.1Hz,2H),3.81(s,2H),2.58(s,3H), 2.39(s,3H),2.33(s,3H),2.30(s,6H).¹³C NMR(75MHz,DMSO-d₆)δ167.77,162.48,156.64, 146.06,143.45,140.26,139.90,136.89,131.87,130.18,129.45,128.36,127.16,125.52,121.21, 115.95,114.99,64.85,42.64,30.17,21.33,20.85,12.02,11.32.HRMS(ESI):calcd for C₃₇H₃₇ClN₂O₄S[M+Na]⁺612.1694,found 612.1691.HPLC(80:20 methanol:water with 1‰TFA): t_R＝5.58min,96.8％.

Example 38: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-fluorophenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8285)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-fluorobromobenzene as in example 8 as a yellow solid in 67% yield, m.p.: 215 ℃ and 216 ℃.¹H NMR(300MHz,CDCl₃)δ7.93(d,J＝8.2Hz,2H),7.32(d,J＝5.1Hz,2H),7.11 (q,J＝7.8Hz,1H),6.88(dd,J＝18.0,9.5Hz,2H),6.63(dd,J＝8.5,2.2Hz,1H),6.60(s,2H),4.49 (t,J＝6.5Hz,2H),3.82(t,J＝5.0Hz,2H),2.67(s,3H),2.52(s,3H),2.45(s,3H),2.36(s,6H). HRMS(ESI):calcd for C₃₁H₃₂ClFN₂O₄S[M+H]⁺583.1829,found 583.1834.HPLC(80:20 methanol:water with 1‰TFA):t_R＝7.04min,97.5％.

Example 39: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-chlorophenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8286)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-chlorobromobenzene as in example 8 as a yellow solid in 58% yield, m.p.: 189 deg.C and 190 deg.C.¹H NMR(300MHz,d6-DMSO)δ7.89(d,J＝8.3Hz,2H),7.40(d,J＝8.3Hz,2H), 7.15(t,J＝8.0Hz,1H),7.01(t,J＝1.9Hz,1H),6.97–6.86(m,2H),6.72(s,2H),4.43(t,J＝6.6 Hz,2H),3.82(t,J＝5.9Hz,2H),2.59(s,3H),2.39(s,3H),2.33(s,3H),2.30(s,8H).¹³C NMR(75 MHz,d6-DMSO)δ162.53,156.68,147.57,143.62,140.26,139.84,136.95,133.54,130.80,130.27, 128.46,127.14,125.60,122.37,121.38,115.85,115.06,21.37,20.90,12.08,11.36.HRMS(ESI): calcd for C₃₁H₃₂Cl₂N₂O₄S[M+H]⁺599.1525,found 599.1532.HPLC(80:20 methanol:water with 1‰TFA):t_R＝12.3min,97.7％.

Example 40: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (3- (trifluoromethyl) phenyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8287)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-trifluoromethylbromobenzene as in example 8 as a yellow solid in 67% yield, m.p.: 173 ℃ and 174 ℃.¹H NMR(300MHz,CDCl₃)δ7.99(d,J＝7.6Hz,2H),7.40(d,J＝16.1Hz,3H), 7.35–7.25(m,2H),7.19(d,J＝6.8Hz,1H),6.63(s,2H),4.54(s,2H),3.85(s,2H),2.73(s,3H), 2.52(s,3H),2.49(s,3H),2.39(s,6H),2.15(s,2H).HRMS(ESI):calcd for C₃₂H₃₂ClF₃N₂O₄S[M+ H]⁺633.1787,found 633.1796.HPLC(80:20 methanol:water with 1‰TFA):t_R＝7.81min, 96.8％.

Example 41: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-formylphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8288)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 3-formylbromobenzene as in example 8 as a white solid in 87% yield, m.p.: 168 ℃ and 169 ℃.¹H NMR (300MHz, Chloroform-d) δ 9.87(s,1H),9.40(s,1H),8.09(s,1H),7.75(d, J ═ 7.3Hz,1H),7.59(d, J ═ 7.5Hz,2H),7.53(t, J ═ 7.4Hz,1H),7.49(dt, J ═ 7.3,1.9Hz,1H),7.16 (d, J ═ 6.8Hz,2H),6.66(s,2H),4.34(t, J ═ 7.0Hz,2H),4.22(t, J ═ 7.1Hz,2H),2.42(s,3H),2.23 (s,6H),2.16(s,3H),2.08(s,3H),1.98 (J ℃, (H), 2.179H), 2.178C ℃, (C), (hrc), (C), (H₃₂H₃₃ClN₂O₅S[M+Na]⁺615.1692,found 615.1696.HPLC(80:20 methanol:water with 1‰ TFA):t_R＝8.26min,98.3％.

Example 42: 4- (N- (3-Acylaminophenyl) -4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8289)

The product is prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acidEthyl ester, 3-formylbromobenzene was prepared as in example 8 as a brown solid in 76% yield, m.p.: 189 deg.C and 190 deg.C.¹H NMR(300MHz,CDCl₃)δ7.93(d,J＝8.0Hz,2H),7.30–7.05(m,5H),6.89(d,J ＝8.0Hz,1H),6.59(s,2H),4.45(t,J＝7.3Hz,2H),3.80(t,J＝5.6Hz,2H),2.66(s,3H),2.52(s, 3H),2.43(s,3H),2.34(s,6H),2.12(d,J＝13.8Hz,5H).HRMS(ESI):calcd for C₃₃H₃₆ClN₃O₅S [M+Na]⁺644.1954,found 644.1962.HPLC(80:20 methanol:water with 1‰TFA):t_R＝6.53min, 98.5％.

Example 43: 4- (N-benzyl-4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8290)

This product was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, benzyl bromide as in example 2 as a white solid in 75% yield, m.p.: 187-188 ℃.¹H NMR(300MHz,Chloroform-d)δ7.93(s,2H),7.47–7.31(m,5H),7.28(s,2H), 6.64(s,2H),4.46(d,J＝25.3Hz,4H),3.88(s,2H),2.53(s,3H),2.48(s,3H),2.40(s,3H),2.36(s, 6H),2.24–2.11(m,2H).HRMS(ESI):calcd for C₃₂H₃₅ClN₂O₄S[M+H]⁺579.2084,found 579.2079.HPLC(80:20 methanol:water with 1‰TFA):t_R＝10.4min,97.8％.

Example 44: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (3-methylbenzyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8291)

The product is prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyridineEthyl pyrrole-2-carboxylate, 3-methylbenzyl bromide, was prepared as in example 2 as a yellow solid in 78% yield and 179. ang. 180 ℃.¹H NMR(300MHz,DMSO-d₆)δ7.84(d,J＝8.1Hz,2H),7.41(d,J＝8.1Hz,2H), 7.18(dd,J＝9.3,6.5Hz,3H),7.05(d,J＝6.7Hz,1H),6.76(s,2H),4.54–4.40(m,2H),4.04(d,J ＝14.9Hz,1H),2.40(s,3H),2.36(s,3H),2.07(dt,J＝11.7,7.0Hz,2H).HRMS(ESI):calcd for C₃₃H₃₇ClN₂O₄S[M+H]⁺593.2241,found 593.2235.HPLC(80:20 methanol:water with 1‰TFA): t_R＝11.3min,98.8％.

Example 45: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-chlorobenzyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8292)

This product was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 3-methylbenzobromobenzyl according to example 2 in 65% yield, melting point: 177 and 179 ℃.¹H NMR(300MHz,Chloroform-d)δ7.93(s,2H),7.39(s,2H),7.27–6.91(m,4H),6.64(s,2H),4.44 (d,J＝30.2Hz,4H),3.89(s,2H),2.49(s,3H),2.36(s,6H),2.22(d,J＝5.3Hz,6H),2.10(d,J＝ 3.1Hz,2H).HRMS(ESI):calcd for C₃₂H₃₄Cl₂N₂O₄S[M+H]⁺613.1695,found 613.1687.HPLC (80:20 methanol:water with 1‰TFA):t_R＝12.7min,97.8％.

Example 46: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-fluorobenzyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8293)

The product is prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimideYl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 3-fluorobenzyl bromide were prepared as in example 2 as a yellow solid in 84% yield, melting point: 190 ℃ and 191 ℃.¹H NMR(300MHz,DMSO-d₆)δ7.83(d,J＝8.0Hz,2H),7.37(t,J＝8.5Hz,3H), 7.21(d,J＝8.7Hz,2H),7.08–7.02(m,1H),6.77(d,J＝5.8Hz,2H),4.45(s,2H),4.21(s,1H), 4.04(d,J＝15.6Hz,1H),3.93–3.82(m,2H),2.46–2.24(m,15H),2.06(dd,J＝13.7,6.9Hz, 2H).HRMS(ESI):calcd for C₃₂H₃₄ClFN₂O₄S[M+H]⁺597.1990,found 597.1985.HPLC(80:20 methanol:water with 1‰TFA):t_R＝12.7min,97.8％.

Example 47: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (3-methoxybenzyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8294)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 3-methoxybenzyl bromide as in example 2 as a white solid in 65% yield, melting point: 195 ℃ and 196 ℃.¹H NMR(300MHz,DMSO-d₆)δ7.82(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H), 7.22(t,J＝7.8Hz,1H),7.02–6.90(m,2H),6.77(d,J＝6.2Hz,3H),4.44(s,2H),4.15(d,J＝15.2Hz,1H),4.02(d,J＝14.5Hz,1H),3.87(s,2H),3.75(s,3H),2.57(s,3H),2.38(d,J＝3.1Hz, 6H),2.29(s,6H),2.07(s,2H).HRMS(ESI):calcd for C₃₃H₃₇ClFN₂O₅S[M+H]⁺609.2183,found 609.2190.HPLC(80:20 methanol:water with 1‰TFA):t_R＝9.75min,98.2％.

Example 48: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-4- (4-methyl-N- (4-methylbenzyl) phenylsulfonylimino) -1H-pyrrole-2-carboxylic acid (DDO-8295)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-methylbenzobromobenzyl according to example 2 as a yellow solid in 73% yield, melting point: 170 ℃ and 171 ℃.¹H NMR(300MHz,Chloroform-d)δ7.91(d,J＝7.3Hz,2H),7.32(s,4H),7.10(d,J＝ 7.0Hz,2H),6.63(s,2H),4.49(s,2H),4.30(dd,J＝21.5,7.1Hz,2H),3.88(s,2H),2.57(s,3H), 2.45(s,6H),2.35(s,9H),2.16(s,2H).HRMS(ESI):calcd for C₃₃H₃₇ClN₂O₄S[M+H]⁺593.2241, found 593.2233.HPLC(80:20 methanol:water with 1‰TFA):t_R＝13.2min,98.1％.

Example 49: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (4-chlorobenzyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8296)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 4-chlorobenzyl bromide as in example 2 as a pale yellow solid in 67% yield, melting point: 175 ℃ and 176 ℃.¹H NMR(300MHz,DMSO-d₆)δ7.81(d,J＝8.3Hz,2H),7.38(d,J＝6.2Hz,6H), 6.76(s,2H),4.44(q,J＝6.2Hz,2H),4.15(d,J＝15.4Hz,1H),4.01(d,J＝15.3Hz,1H),3.91– 3.82(m,2H),2.37(d,J＝5.9Hz,6H),2.29(s,6H),2.12–2.03(m,2H).HRMS(ESI):calcd for C₃₂H₃₄Cl₂N₂O₄S[M+H]⁺613.1695,found 613.1689.HPLC(80:20 methanol:water with 1‰TFA): t_R＝13.5min,97.8％.

Example 50: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (4-fluorobenzyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8297)

This was prepared from ethyl 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylate, 4-fluorobenzyl bromide as in example 2, Red solid, melting point 72%, melting point 192-.¹H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.5Hz,2H),7.18–7.11(m,4H), 6.97(dd,J＝8.8,7.6Hz,2H),6.66(s,2H),4.34(t,J＝7.0Hz,2H),4.22(t,J＝7.1Hz,2H),2.60(s, 2H),2.42(s,3H),2.23(s,6H),2.16(s,3H),2.08(s,3H),1.98(p,J＝7.1Hz,2H).HRMS(ESI): calcd for C₃₂H₃₄ClFN₂O₄S[M+H]⁺597.1990,found 597.1982.HPLC(80:20 methanol:water with 1‰TFA):t_R＝12.9min,98.2％.

Example 51: 4- (N- (4- (tert-butyl) benzyl) -4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8298)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-tert-butylbenzyl bromide as in example 2 as a white solid in 75% yield, melting point: 201 ℃ and 202 ℃.¹H NMR(300MHz,Chloroform-d)δ7.91(s,2H),7.35(s,6H),6.63(s,2H),4.50(s, 2H),4.31(d,J＝29.9Hz,2H),3.88(s,2H),2.63(s,3H),2.51(s,3H),2.43(s,3H),2.35(s,6H), 2.16(s,2H),1.34(s,9H).HRMS(ESI):calcd for C₃₆H₄₃ClN₂O₄S[M+H]⁺635.2710,found 635.2706.HPLC(80:20 methanol:water with 1‰TFA):t_R＝13.2min,98.5％.

Example 52: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (4-methoxybenzyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8299)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-methoxybenzyl bromide as in example 2 as a white solid in 62% yield, melting point: 193 ℃ and 194 ℃.¹H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.5Hz,2H),7.19–7.14(m,4H), 6.78(d,J＝7.6Hz,2H),6.66(s,2H),4.34(t,J＝7.0Hz,2H),4.22(t,J＝7.1Hz,2H),3.80(s,3H), 2.60(s,2H),2.42(d,J＝1.2Hz,3H),2.23(s,6H),2.16(s,3H),2.08(s,3H),1.98(p,J＝7.1Hz, 2H).HRMS(ESI):calcd for C₃₃H₃₇ClFN₂O₅S[M+H]⁺609.2183,found 609.2186.HPLC(80:20 methanol:water with 1‰TFA):t_R＝9.82min,96.7％.

Example 53: 4- (N- ([ [1,1' -biphenyl ] -4-yl) -4-methylphenylsulfonylimido) -1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8300)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-biphenylbromobenzyl as example 2 as a white solid in 54% yield, melting point: 176-177 deg.c,¹H NMR(300MHz,DMSO-d₆)δ7.83(d,J＝8.1Hz,2H),7.67(d,J＝7.3Hz,2H), 7.60(d,J＝8.1Hz,2H),7.48(t,J＝7.7Hz,5H),7.38(d,J＝7.5Hz,2H),6.76(s,2H),4.45(q,J＝ 5.7Hz,2H),4.22(d,J＝15.1Hz,1H),4.07(d,J＝15.1Hz,1H),3.86(d,J＝5.2Hz,2H),2.58(s, 3H),2.39(d,J＝3.5Hz,6H),2.28(s,6H),2.12–2.01(m,2H).HRMS(ESI):calcd for C₃₇H₃₇ClN₂O₄S[M+H]⁺641.2241,found 641.2249.HPLC(80:20 methanol:water with 1‰TFA): t_R＝10.15min,97.4％.

example 54: 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N- (4-ethynylphenyl) -4-methylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid (DDO-8301)

This was prepared from 1- (3- (4-chloro-3, 5-dimethylphenoxy) propyl) -4- (N, 4-dimethylphenylsulfonylimido) -3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 4-ethynylbromobenzyl as example 2, as a yellow solid in 65% yield, melting point: 184-185 ℃ of the weight percentage,¹H NMR(300MHz,DMSO-d₆)δ7.83(d,J＝8.3Hz,2H),7.42(dt,J＝11.9,5.0Hz, 6H),6.76(s,2H),4.53–4.40(m,2H),4.20(d,J＝15.5Hz,1H),4.15(s,1H),4.07(d,J＝14.9Hz, 1H),3.86(dq,J＝9.8,5.5,4.9Hz,2H),2.55(s,3H),2.39(s,3H),2.36(s,3H),2.28(s,6H),2.06 (dd,J＝11.1,5.2Hz,2H).HRMS(ESI):calcd for C₃₃H₃₃ClN₂O₄S[M-H]^-587.1771,found 587.1767.HPLC(80:20 methanol:waterwith1‰TFA):t_R＝8.45min,98.2％.

example 55: effects of the embodiment

1. Testing the inhibitory Activity of test Compounds on Mcl-1 Using fluorescence-biased method (FP experiment)

The inhibition activity of the target compound on Mcl-1 is tested by adopting an FP method, the final concentration of protein is 20nM, the selected probe is FITC-Bak-BH3, and the concentration of the probe is 10 nM. The assay uses a 384-well blackboard (model Corning3676), 40. mu.L of final volume is selected for the assay, and the test compound and FITC-Bak-BH3 polypeptide fluorescent probe are dissolved in DMSO (10mmol stock solution) for use. The compounds were diluted 11 concentration gradients in HEPES buffer at fold ratio, and 20. mu.L of diluted compound was added to each well plate, followed by 10. mu.L of 10nM probe diluted in buffer and 10. mu.L of 12nM protein. Two duplicate wells were set for each compound concentration and the experiment set up for a blank (10. mu.L probe + 40. mu.L buffer, denoted Pmin) and a negative control (10. mu.L probe + 10. mu.L protein + 20. mu.L buffer, denoted Pmax). Then incubated on a shaker at room temperature for 30min with shaking, and the plates were scanned with a SpectraMax Multi-Mode microplate reader (Molecular Devices) to exciteThe wavelength was set at 485nm, the emission wavelength was set at 535nm, and the test well readings were recorded as Pobs. The inhibition rate calculation formula is as follows: inhibition (%) [1- (Pobs-Pmin)/(Pmax-Pmin)]X 100%, IC was calculated using Graphpad Prism 6.0 software₅₀。K_iThe calculation is performed according to the following formula:

K_i＝[I]₅₀/([L]₅₀/K_d+[P]₀/K_d+1)

wherein [ I]₅₀Represents the median inhibitory concentration of the compound, [ L]₅₀Represents the probe concentration, [ P ]]₀Represents the protein concentration, K_dRepresents the dissociation constant of the protein from the probe.

The test results show that most compounds have Mcl-1 low micromolar inhibitory activity, some compounds have nanomolar inhibitory activity, and all compounds have no obvious inhibitory activity on Bcl-2 protein at a concentration of 10 micromolar, and the results are shown in Table 1.

TABLE 1 Mcl-1 inhibitory Activity and Bcl-2 inhibitory Activity of all Compounds

2. Antiproliferative experiments on tumor cells (MTT experiments)

The antiproliferative activity of the compounds DDO-8300 and DDO-8301 of the invention on human multiple myeloma cell line H929 cell line, acute leukemia cell line Mv-4-11, breast cancer cell line SK-BR3, non-small cell lung cancer cell line NCI-H23 and chronic myelocytic leukemia cell line K562 (insensitive to Mcl-1 inhibitor) is tested. The method comprises the following steps: in the case of the H929 cell line, tumor cells were seeded in a 96-well plate (about 4000 cells per well), incubated at 37 ℃ for 24 hours under 5% CO2 conditions, compounds at various concentrations were added to the cells, and after further incubation for 72 hours, 20. mu.l of MTT in PBS (5 mg/ml) was added to each well, incubated at 37 ℃ for 4 hours, MTT and medium were removed, 150. mu.L of DMSO was added to each well, and the assay was performed at 490nm (using a Thermo Multiskan Spectrum reader), and the assay results were analyzed using Graphpad Prism 6.0.

The test result shows that DDO-8300 and DDO-8301 have better activity on H929 cells and Mv4-11 cells, and DDO-8301 has better selectivity on K562 cells, and the result is shown in Table 2.

TABLE 2 in vitro antitumor proliferative Activity of DDO-8300, DDO-8301

3. Evaluation of Membrane permeability

We used the PAMPA artificial membrane model to determine the membrane permeability (Pe) of representative compounds DDO-8300 and DDO-8301, and the results are shown in Table 4, which indicates that both compounds have acceptable membrane permeability.

TABLE 4 evaluation of antitumor Activity of representative Compounds in vitro

4. Evaluation of stability of DDO-8300 and DDO-8301 in Artificial gastrointestinal fluids

We measured the content of the compound after 0.25, 0.5, 1, 2, 4, 6, 12 hours of incubation in artificial gastrointestinal fluids using HPLC method and calculated the percentage content remaining in degradation. Compounds were selected at a concentration of 200 μ M and incubated in the gastrointestinal fluids at 37 ℃ for the indicated time respectively, and the measurements were performed according to the chromatographic conditions described above, and the peak areas were recorded and the residual percentages were calculated. The results show (figure 1, figure 2) that the compounds DDO-8300, DDO-8301 are more stable in a solution simulating the environment of the human gastrointestinal tract and are less affected by pepsin and trypsin.

The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.