A 4-amino-1H-pyrrole compound, preparation method and use

Abstract

The present invention discloses a 4-amino-1H-pyrrole compound, a preparation method and uses thereof. The present invention provides a series of 4-amino-1H-pyrrole compounds. Activity tests show that they have Mcl-1 inhibitory effects, and most of the compounds have nanomolar Mcl-1 inhibitory activities. They have good selectivity for other subtypes of the Bcl-2 anti-apoptotic protein family, namely Bcl-2, Bcl-xL, Bcl-w and Bfl-1. They also exhibit good activities in the evaluation of in vitro anti-tumor proliferation activities. Among them, the compound 52 with the best activity has good drug-like properties and shows good anti-tumor activities in the Mv4-11 xenograft nude mouse model. Therefore, the 4-amino-1H-pyrrole compounds provided by the present invention have the prospect of being developed into Mcl-1 inhibitor drugs and are expected to be developed into anti-tumor drugs.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a 4-amino-1H-pyrrole compound, a preparation method and uses thereof. Background Art

[0002] Apoptosis, also known as programmed cell death, plays an important role in removing harmful and potentially dangerous cells and maintaining the intracellular environment. Mcl-1, as an anti-apoptotic protein, is usually overexpressed in tumor cells and is closely related to the occurrence and drug resistance of cancer, and thus has been intensively studied as a potential target for tumor treatment.

[0003] An important process in the endogenous apoptotic pathway is that the pro-apoptotic proteins Bax / Bak bind to each other to form dimers, depolarize the outer mitochondrial membrane, and the apoptosis factors such as cytochrome c flow out to induce the transduction of downstream signaling pathways. Mcl-1 can bind to Bax / Bak through its hydrophobic groove to inhibit the formation of their dimers, thereby inhibiting apoptosis.

[0004] Small molecule BH3 mimetics can mimic the binding of the BH3 domain to the Mcl-1 protein to inhibit the interaction between Mcl-1 and pro-apoptotic proteins, and this strategy has been widely applied to the design of small molecule inhibitors of Mcl-1. In recent years, more and more small molecule inhibitors have been reported, and some Mcl-1 with high activity and good drugability are undergoing clinical studies and are expected to become new cancer treatment drugs (Tron AE et al., Nat Commun. 9(2018):5341). Summary of the Invention

[0005] The purpose of the present invention is to provide a 4-amino-1H-pyrrole compound, a preparation method and uses thereof.

[0006] The above purpose of the present invention is achieved by the following technical solutions:

[0007] A 4-amino-1H-pyrrole compound, the general structural formula is as follows:

[0008]

[0009] R1 and R2 are selected from alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, mercapto, alkoxy and alkylthio; R3 and R4 are each independently selected from a hydrogen atom, a substituted or unsubstituted C1-C5 alkyl group.

[0010] Preferably, the alkyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl are alkyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl substituted by one or more substituents selected from alkyl, halogen, hydroxyl, mercapto, amino, oxo, carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclic group, aryl, and heteroaryl.

[0011] More preferably, R1 is selected from phenyl, 2-pyridyl, 1-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-cyclopropylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-tert-butylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-acetylphenyl, 3-nitrophenyl, 3-cyanophenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-(1-hydroxyethyl)phenyl, 3,4-dimethylphenyl, and 3-methyl-4-chlorophenyl.

[0012] More preferably, R2 is selected from 3-thienyl, 1-naphthyl, 2-naphthyl, phenyl, 2-chlorophenyl, 2-methylphenyl, 3-chloromethyl, 3-methylphenyl, 4-chlorophenyl, 4-methylphenyl, 3-bromophenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-aldehydephenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-biphenyl, 1-phenyl-1H-1,2,3-triazol-4-yl, 4-ethynylphenyl, 4-propynylphenyl, 3,4-dimethylphenyl, 3-bromo-4-methylphenyl, 3,4-dichlorophenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3-chloro-4-phenylphenyl, and 3-chloro-4-ethynylphenyl.

[0013] A method for preparing the above 4-amino-1H-pyrrole compound, where R1 is as defined above, R2 = 3-chlorophenyl, and R3, R4 are hydrogen atoms, includes the following synthetic route and steps:

[0014]

[0015] Starting material I-2 and 1,3-dibromopropane undergo a nucleophilic substitution reaction in acetonitrile with potassium carbonate as the acid-binding agent to obtain intermediate I-3. Intermediate I-1 and I-3 react under the action of cesium carbonate to obtain an intermediate, which undergoes a nucleophilic substitution reaction in DMF to obtain intermediate I-4. I-4 is reduced by stannous chloride to obtain I-5. I-5 reacts with different bromoaromatics under the catalysis of Pd2(dba)3 and BINAP, using Cs2CO3 as the base, through the Buchward-Hartwig reaction to obtain intermediate I-6. I-6 reacts with 3-chlorobenzyl bromide, using NaH as the acid-binding agent, through a nucleophilic substitution reaction to obtain intermediate I-7. Subsequently, I-7 undergoes hydrolysis to obtain the target product and intermediate I-8. I-8 undergoes debenzylation with H2 and Pt / C to obtain target product a. The target product substituted by 3-acetylphenyl for R1 is reduced by sodium borohydride to obtain target product b.

[0016] A method for preparing the above 4-amino-1H-pyrrole compound, where R1 = 3-methylphenyl, R2 is defined as follows, and R3 and R4 are hydrogen atoms, including the following synthetic route and steps:

[0017] R2 = 3-thienyl, 1-naphthyl, 2-naphthyl, phenyl, 2-chlorophenyl, 2-methylphenyl, 3-chloromethyl, 3-methylphenyl, 4-chlorophenyl, 4-methylphenyl, 3-bromophenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-aldehydephenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-biphenyl, 1-phenyl-1H-1,2,3-triazol-4-yl, 4-ethynylphenyl, 4-propynylphenyl, 3,4-dimethylphenyl, 3-bromo-4-methylphenyl, 3,4-dichlorophenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl or 2,6-dichlorophenyl;

[0018]

[0019] Using NaH as the acid-binding agent, intermediate I-9 undergoes a nucleophilic substitution reaction with differently substituted benzyl bromides to obtain intermediate II-1. II-2 undergoes hydrolysis with NaOH to obtain target product a. One of the II-2 reacts with azidobenzene under the action of DIPEA and CuI through a click reaction to obtain intermediate II-3. II-3 undergoes hydrolysis with NaOH to obtain target product b.

[0020] A method for preparing the above 4-amino-1H-pyrrole compound, where R1 = 3-methylphenyl, 3-chloromethyl, 3-fluoromethylphenyl, 3-methoxyphenyl, 3,4-dimethylphenyl, 3-chloro-4-methylphenyl, R2 = 3-chloro-4-phenylphenyl, 3-chloro-4-ethynylphenyl, and R3 and R4 are hydrogen atoms or methyl groups, including the following synthetic route and steps:

[0021]

[0022] The starting material III-1 and phenylboronic acid react under the catalysis of Pd(PPh3)4 through the Suzuki reaction to obtain the intermediate III-2. III-2 is reduced by borane to obtain benzyl alcohol III-3. III-3 reacts with phosphorus tribromide to obtain benzyl bromide III-4. III-1 is reduced by borane to obtain benzyl alcohol III-5. III-5 and trimethylsilylacetylene react under the catalysis of PdCl2(PPh3)2 and copper iodide through the Sonogashira coupling to introduce an alkynyl group to obtain the intermediate III-6. III-6 is deprotected by TBAF to obtain III-7. III-7 reacts with PBr3 again to obtain benzyl bromide III-8. Under the action of NaH, the intermediate III-9 reacts with III-4 and III-8 through a nucleophilic substitution reaction to obtain the intermediate III-10. III-10 is hydrolyzed by NaOH to obtain the target product.

[0023] Use of the above-mentioned 4-amino-1H-pyrrole compound for preparing an Mcl-1 inhibitor drug.

[0024] Use of the above-mentioned 4-amino-1H-pyrrole compound for preparing an anti-tumor drug.

[0025] Beneficial effects:

[0026] The present invention provides a series of 4-amino-1H-pyrrole compounds. Activity tests show that they have Mcl-1 inhibitory effects, and most of the compounds have nanomolar Mcl-1 inhibitory activities. They have good selectivity for other subtypes of the Bcl-2 anti-apoptotic protein family, namely Bcl-2, Bcl-xL, Bcl-w, and Bfl-1. They also show good activities in the evaluation of in vitro anti-tumor proliferation activities. Among them, the compound 52 with the best activity has good drug-like properties and shows good anti-tumor activities in the Mv4-11 xenograft nude mouse model. Therefore, the 4-amino-1H-pyrrole compounds provided by the present invention have the prospect of being developed into Mcl-1 inhibitor drugs and are expected to be developed into anti-tumor drugs. Description of the drawings

[0027] Figure 1 It is a diagram for evaluating the affinity of compound 52 for Bcl-2 subtypes;

[0028] Figure 2 It is the research result of the in vivo anti-tumor activity of compound 52; wherein: A is the change in tumor volume during the administration period; during the administration period, the long diameter a and short diameter b of the tumor are measured, and the tumor volume is calculated according to the formula V = a × b 2Calculated using / 2, ***p < 0.01, ****p < 0.0001 (n = 6), one-way ANOVA with Tukey-Kramer posttest; B shows the trend of body weight changes in nude mice during drug administration; C shows the weights of the heart, liver, and kidney in each group after drug administration; D shows the tumor tissues isolated after the end of drug administration. Detailed implementation mode

[0029] The following specifically introduces the substantial content of the present invention in combination with embodiments, but does not limit the protection scope of the present invention thereto.

[0030] Example 1:

[0031] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(phenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 1)

[0032]

[0033] (1) Preparation of 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene

[0034] Dissolve 4-chloro-3,5-dimethylphenol (25.6 mmol, 4 g, 1 eq) in 40 ml of acetonitrile, add potassium carbonate (3 eq), 1,3-dibromopropane (3 eq), and reflux for 3 h. After the reaction is complete, cool to room temperature, add 150 ml of water, extract with EA 3 times, combine the organic phases, wash with saturated brine, dry with sodium sulfate, evaporate the organic phase to dryness, pulverize, and perform column chromatography (PE) to obtain 6 g of a colorless liquid with a yield of 85.2%.

[0035] (2) Preparation of ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-nitro-1H-pyrrole-2-carboxylate

[0036] Dissolve the above-mentioned ethyl 4-nitro-1H-pyrrole-2-carboxylate (1 mmol, 0.289 g, 1 eq) in 20 ml of DMF, add cesium carbonate (2 eq), stir at 50 °C for 5 min, then add the above-mentioned 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene (2 eq). After the reaction is complete, cool to room temperature, add 60 ml of water, extract with EA 3 times, combine the organic phases, wash with saturated brine, dry with sodium sulfate, evaporate the organic phase to dryness, pulverize, and perform column chromatography (EA:PE = 20:1) to obtain 0.35 g of a colorless liquid with a yield of 76.4%.

[0037] (3) Ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-(phenylamino)-1H-pyrrole-2-carboxylate

[0038] Dissolve ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-nitro-1H-pyrrole-2-carboxylate (1.5 g, 4.1 mmol) in EtOH (50 ml), then add SnCl2·2H2O (4.6 g, 20 mmol). Under nitrogen protection, heat at 60 °C for 4 hours. After the raw material has reacted completely, cool to room temperature and add NaOH (2 M) until pH = 9. Add DCM (70 ml) and stir for 15 minutes. Separate the organic layer, extract the aqueous layer twice, combine the organic phases, dry over Na2SO4, and evaporate the organic phase to obtain a dark brown oil. Dissolve 1.0 g of the above crude product in 30 ml of toluene, add Pd2(dba)3 (0.1 eq), BINAP (0.1 eq), and cesium carbonate (2 eq) to the solution, and heat at 90 °C under N2 protection overnight. After the reaction is complete, cool to room temperature, triturate, and purify by column chromatography (PE / EA = 100:1 to 80:1 v / v) to obtain a yellow liquid with a yield of 35%.

[0039] (4) Preparation of ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(phenyl)amino)-1H-pyrrole-2-carboxylate

[0040] Under ice bath conditions, add NaH (2 eq) to a DMF (10 ml) solution of the above ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-nitro-1H-pyrrole-2-carboxylate. After stirring for 10 minutes, add 3-chlorobenzyl bromide (2 eq) and stir at room temperature. After the reaction is complete, slowly add 30 ml of H2O, extract with ethyl acetate 3 times, combine the organic phases, dry the organic phase over Na2SO4, and obtain an oil by column chromatography (PE / EA = 100:1 to 80:1 v / v) with a yield of 54%.

[0041] (5) Preparation of the title compound

[0042] Dissolve the above-mentioned oily substance (0.3 g, 0.58 mmol, 1 eq) in an ethanol / tetrahydrofuran mixed solution (7 ml / 7 ml), add NaOH (2 M, 10 eq), heat and stir at 50 °C overnight. After the reaction is complete, cool to room temperature, add 1 M HCl to pH = 1, filter, wash the filter cake with water, and dry to obtain 0.252 g of a pale yellow solid, with a yield of 95%. mp: 208 - 209 °C. 1H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 7.37–7.19 (m, 4H), 7.12–7.02 (m, 3H), 6.82–6.62 (m, 6H), 4.77 (s, 2H), 4.43 (t, J = 5.6 Hz, 2H), 3.83 (t, J = 5.1 Hz, 2H), 2.27 (s, 6H), 2.21–2.07 (m, 2H). HRMS (ESI): calcd for C 29 H 28 Cl2N2O3 [M+H]+ 523.1555, found 523.1546. HPLC (80:20 methanol:water with 1‰ TFA): tR = 9.78 min, 96.6%.

[0043] Example 2:

[0044] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(pyridin-2-yl)amino)-1H-pyrrole-2-carboxylic acid (Compound 2)

[0045]

[0046] This product is prepared from 2-bromopyridine, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1, a brown solid, with a yield of 76%, melting point: 139 - 140 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 8.02 (d, J = 5.3 Hz, 1H), 7.73 (s, 1H), 7.28 (d, J = 5.2 Hz, 3H), 7.18 (s, 2H), 7.03–6.84 (m, 2H), 6.80 (s, 1H), 6.72 (s, 2H), 5.04 (s, 2H), 4.41 (t, J = 6.1 Hz, 2H), 3.82 (t, J = 5.7 Hz, 2H), 2.25 (s, 6H), 2.10 (q, J = 6.1 Hz, 2H). HRMS (ESI): calcd for C 28 H 27 Cl2N3O3 [M+H] +524.1502, found 524.1508. HPLC (80:20 methanol:water with 1‰ TFA): t R = 5.95 min, 97.1%.

[0047] Example 3:

[0048] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(naphthalen-1-yl)amino)-1H-pyrrole-2-carboxylic acid (Compound 3)

[0049]

[0050] This product was prepared from 1-bromonaphthalene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a white solid with a yield of 65% and a melting point of 118 - 120 °C. 1 H NMR (300 MHz, d6-DMSO) δ 7.99 (d, J = 8.1 Hz, 1H), 7.91–7.87 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.49–7.37 (m, 4H), 7.32 (d, J = 7.4 Hz, 2H), 7.29–7.17 (m, 2H), 6.68 (s, 2H), 6.34 (d, J = 2.1 Hz, 1H), 6.08 (d, J = 2.0 Hz, 1H), 4.73 (s, 2H), 4.25 (t, J = 6.5 Hz, 2H), 3.72 (t, J = 5.9 Hz, 2H), 2.28 (s, 6H), 2.00 (p, J = 6.6 Hz, 2H). HRMS (ESI): calcd for C 33 H 30 Cl2N2O3 [M+H] + 573.1712, found 573.1712. HPLC (80:20 methanol:water with 1‰ TFA): t R = 13.9 min, 96.9%.

[0051] Example 4:

[0052] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(o-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 4)

[0053]

[0054] This product is prepared from 2-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a brown solid with a yield of 72% and a melting point of 109 - 110 °C. 1 H NMR(300MHz,Chloroform-d)δ7.23–7.05(m,8H),6.80(d,J=2.1Hz,1H),6.73–6.62(m,3H),4.75(s,2H),4.45(t,J=6.4Hz,2H),3.91–3.81(m,2H),2.32–2.27(m,9H),2.20–2.11(m,2H).HRMS(ESI):calcd for C 30 H 30 Cl2N2O3[M+H] + 537.1712,found 537.1720.HPLC(80:20methanol:water with 1‰TFA):t R =10.2min,97.2%.

[0055] Example 5:

[0056] 5-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-((3-chlorobenzyl)(m-tolyl)amino)cyclopent-1,3-diene-1-carboxylic acid (Compound 5)

[0057]

[0058] This product is prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a white solid with a yield of 76% and a melting point of 111 - 112 °C. 1 H NMR(300MHz,d6-DMSO)δ12.30(s,1H),7.24(dq,J=15.2,7.3,6.8Hz,4H),6.95(dd,J=15.5,7.8Hz,2H),6.72(s,2H),6.68(s,1H),6.63–6.44(m,3H),4.72(s,2H),4.40(t,J=5.6Hz,2H),3.80(t,J=5.5Hz,2H),2.24(s,6H),2.12(s,5H). 1313C NMR(75MHz, d6-DMSO) δ 162.06, 154.41, 148.60, 142.44, 138.47, 134.51, 133.57, 130.79, 130.68, 129.23, 127.88, 127.04, 126.91, 126.77, 126.63, 125.71, 125.57, 125.40, 124.27, 122.15, 120.89, 120.41, 119.29, 113.64, 112.16, 105.29, 65.23, 46.11, 31.00, 21.85. HRMS(ESI): calcd for C 30 H 30 Cl2N2O3 [M+H] + 537.1668, found 537.1682. HPLC(80:20 methanol:water with 1‰ TFA): t R =8.32 min, 97.6%.

[0059] Example 6:

[0060] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(p-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 6)

[0061]

[0062] This product was prepared from 4-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a light yellow solid with a yield of 74% and a melting point of 117 - 118 °C. 1 1H NMR(300MHz, d6-DMSO) δ 12.31(s, 1H), 7.37–7.17(m, 4H), 6.96(s, 1H), 6.86(d, J=8.3Hz, 2H), 6.78–6.65(m, 5H), 4.74(s, 2H), 4.41(t, J=6.1Hz, 2H), 3.81(t, J=5.3Hz, 2H), 2.28(s, 6H), 2.15(d, J=7.8Hz, 5H). HRMS(ESI): calcd for C 30 H 30 Cl2N2O3 [M+H] + 537.1704, found 537.1712. HPLC(80:20 methanol:water with 1‰ TFA): t R= 12.4 min, 98.1%.

[0063] Example 7:

[0064] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(4-ethylphenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 7)

[0065]

[0066] This product was prepared from 4-ethylbromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 82% and a melting point of 121 - 122 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.23 (s, 1H), 7.23 (dt, J = 21.8, 7.5 Hz, 4H), 6.94 (d, J = 1.9 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.75–6.60 (m, 5H), 4.72 (s, 2H), 4.38 (t, J = 6.3 Hz, 2H), 3.79 (t, J = 5.9 Hz, 2H), 2.44 (q, J = 7.7 Hz, 2H), 2.26 (s, 6H), 2.11 (p, J = 5.7, 5.0 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H). HRMS (ESI): calcd for C 31 H 32 Cl2N2O3 [M+H] + 551.1862, found 551.1868. HPLC (80:20 methanol:water with 1‰ TFA): t R = 15.1 min, 96.5%.

[0067] Example 8:

[0068] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(4-isopropylphenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 8)

[0069]

[0070] This product was prepared from 4-isopropylbromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 64% and a melting point of 124 - 125 °C. 11H NMR (300 MHz, d6-DMSO) δ 12.28 (s, 1H), 7.35–7.20 (m, 4H), 6.98 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.81–6.68 (m, 5H), 4.75 (s, 2H), 4.41 (t, J = 6.2 Hz, 2H), 3.81 (t, J = 5.7 Hz, 2H), 2.73 (p, J = 6.7 Hz, 1H), 2.28 (s, 6H), 2.15 (q, J = 6.1 Hz, 2H), 1.13 (d, J = 6.9 Hz, 6H). HRMS (ESI): calcd for C 32 H 34 Cl2N2O3 [M+H] + 565.2011, found 565.2025. HPLC (80:20 methanol:water with 1‰ TFA): t R = 17.5 min, 98.3%.

[0071] Example 9:

[0072] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(4-cyclopropylphenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 9)

[0073]

[0074] This product was prepared from 4-cyclopropylbromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 75% and a melting point of 152 - 153 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.31 (s, 1H), 7.39–7.17 (m, 4H), 7.15–7.03 (m, 2H), 6.82–6.64 (m, 7H), 4.77 (s, 2H), 4.43 (t, J = 6.7 Hz, 2H), 3.83 (t, J = 6.0 Hz, 4H), 2.28 (d, J = 4.3 Hz, 8H), 2.14 (q, J = 6.4 Hz, 2H). HRMS (ESI): calcd for C 32 H 32 Cl2N2O3 [M+H] + 563.1862, found 563.1868. HPLC (80:20 methanol:water with 1‰ TFA): t R = 16.6 min, 96.3%.

[0075] Example 10:

[0076] 4-((4-(tert-Butyl)phenyl)(3-chlorobenzyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid (Compound 10)

[0077]

[0078] This product was prepared from 4-tert-butylbromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 67% and a melting point of 179 - 180 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.23 (s, 1H), 7.23 (d, J = 17.6 Hz, 4H), 7.12–6.91 (m, 3H), 6.84–6.55 (m, 5H), 4.73 (s, 2H), 4.38 (s, 2H), 3.79 (s, 2H), 2.26 (s, 6H), 2.11 (s, 2H), 1.18 (s, 9H). HRMS (ESI): calcd for C 33 H 36 Cl2N2O3 [M+H] + 579.2176, found 579.2181. HPLC (80:20 methanol:water with 1‰ TFA): t R = 21.6 min, 95.9%.

[0079] Example 11:

[0080] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(3-ethylphenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 11)

[0081]

[0082] This product was prepared from 3-ethylbromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 76% and a melting point of 106 - 107 °C. 11H NMR (300 MHz, d6-DMSO) δ 12.24 (s, 1H), 7.26 (dd, J = 26.7, 6.2 Hz, 4H), 7.02–6.91 (m, 2H), 6.72 (s, 2H), 6.68 (d, J = 2.0 Hz, 1H), 6.63 (s, 1H), 6.55 (dd, J = 13.2, 7.9 Hz, 2H), 4.73 (s, 2H), 4.40 (t, J = 6.4 Hz, 2H), 3.81 (t, J = 5.9 Hz, 2H), 2.47–2.34 (m, 2H), 2.24 (s, 6H), 2.11 (p, J = 6.1 Hz, 2H), 1.05 (t, J = 7.6 Hz, 3H). HRMS (ESI): calcd for C 31 H 32 Cl2N2O3 [M+H] + 551.1866, found 551.1868. HPLC (80:20 methanol:water with 1‰ TFA): t R = 14.7 min, 96.7%.

[0083] Example 12:

[0084] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(3-isopropylphenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 12)

[0085]

[0086] This product was prepared from 4-isopropylbromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 77% and a melting point of 121-122 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.25 (s, 1H), 7.47–7.15 (m, 4H), 7.11–6.93 (m, 2H), 6.71 (q, J = 10.3, 7.1 Hz, 3H), 6.57 (d, J = 7.1 Hz, 2H), 4.74 (s, 2H), 4.40 (s, 2H), 3.82 (s, 2H), 2.77–2.59 (m, 1H), 2.25 (s, 5H), 2.12 (s, 2H), 1.07 (d, J = 6.6 Hz, 6H). HRMS (ESI): calcd for C 32 H 32 Cl2N2O3 [M+H] +565.2018, found 565.2025. HPLC (80:20 methanol:water with 1‰ TFA): t R = 14.8 min, 97.2%.

[0087] Example 13:

[0088] 4-((3-(tert-Butyl)phenyl)(3-chlorobenzyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid (Compound 13)

[0089]

[0090] This product was prepared from 3-tert-butylbromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 68% and a melting point of 107 - 109 °C. 1 H NMR (300 MHz, CDCl3) δ 7.31 (s, 2H), 7.24–7.18 (m, 2H), 7.10 (t, J = 7.9 Hz, 1H), 7.01 (s, 1H), 6.95 (s, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.77 (s, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.63 (s, 2H), 4.73 (s, 2H), 4.49 (d, J = 5.7 Hz, 2H), 3.85 (t, J = 4.5 Hz, 2H), 2.35 (s, 6H), 2.27 (s, 2H), 1.27 (s, 9H). HRMS (ESI): calcd for C 33 H 36 Cl2N2O3 [M+H] + 579.2174, found 579.2181. HPLC (80:20 methanol:water with 1‰ TFA): t R = 17.4 min, 98.1%.

[0091] Example 14:

[0092] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(3-chlorophenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 14)

[0093]

[0094] This product is prepared according to Example 1 from 3-chlorobromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate. It is a white solid with a yield of 71% and a melting point of 132 - 133 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.38 (s, 1H), 7.38–7.14 (m, 4H), 7.05 (s, 3H), 6.80–6.62 (m, 5H), 4.73 (s, 2H), 4.43 (s, 2H), 3.78 (s, 2H), 2.27 (s, 6H), 2.19–2.06 (m, 2H). HRMS (ESI): calcd for C 29 H 27 Cl3N2O3 [M + H] + 559.1127, found 559.1136. HPLC (80:20 methanol:water with 1‰ TFA): t R = 11.5 min, 97.6%.

[0095] Example 15:

[0096] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(3-fluorophenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 15)

[0097]

[0098] This product is prepared according to Example 1 from 3-fluorobromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate. It is a yellow solid with a yield of 68% and a melting point of 122 - 123 °C. 1 H NMR (300 MHz, d6-DMSO) δ 7.28 (d, J = 10.4 Hz, 3H), 7.18 (d, J = 7.0 Hz, 1H), 7.11–7.01 (m, 2H), 6.73 (d, J = 2.1 Hz, 1H), 6.71 (s, 2H), 6.56–6.38 (m, 3H), 4.75 (s, 2H), 4.42 (t, J = 6.4 Hz, 2H), 3.81 (t, J = 5.9 Hz, 2H), 2.23 (s, 6H), 2.12 (p, J = 5.9 Hz, 2H). HRMS (ESI): calcd for C 29 H 27 Cl2FN2O3 [M + H] +541.1469, found 541.1461. HPLC (80:20 methanol:water with 1‰ TFA): t R = 9.93 min, 95.7%.

[0099] Example 16:

[0100] 4-((3-Acetylphenyl)(3-chlorobenzyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid (Compound 16)

[0101]

[0102] This product was prepared from 3-bromoacetophenone, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 43% and a melting point of 125 - 126 °C. 1 H NMR (300 MHz, Chloroform-d) δ 7.41 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.18 (t, J = 12.8 Hz, 6H), 6.96 (s, 1H), 6.70 (s, 1H), 6.56 (s, 2H), 4.70 (s, 2H), 4.46 (s, 2H), 3.76 (s, 2H), 2.49 (s, 3H), 2.29 (s, 6H), 2.20 (s, 1H). HRMS (ESI): calcd for C 31 H 30 Cl2N2O4 [M+H] + 565.1661, found 565.1652. HPLC (80:20 methanol:water with 1‰ TFA): t R = 7.05 min, 96.3%.

[0103] Example 17:

[0104] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(3-nitrophenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 17)

[0105]

[0106] This product was prepared from 3-nitro-bromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a red solid with a yield of 75% and a melting point of 162 - 163 °C. 11H NMR (300 MHz, CDCl3) δ 7.59 (dd, J = 4.2, 1.8 Hz, 2H), 7.25 (t, J = 3.7 Hz, 4H), 7.13 (dd, J = 6.5, 3.0 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.04–6.98 (m, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.62 (s, 2H), 4.76 (s, 2H), 4.57 (t, J = 6.3 Hz, 2H), 3.85 (t, J = 5.4 Hz, 2H), 2.32 (s, 8H). HRMS (ESI): calcd for C 29 H 27 Cl2N3O5[M + H] + 568.1396, found 568.1406. HPLC (80:20 methanol:water with 1‰ TFA): t R = 8.4 min, 95.1%.

[0107] Example 18:

[0108] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(3-cyanophenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 18)

[0109]

[0110] This product was prepared from 3-cyanobromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 67% and a melting point of 136 - 137 °C. 1 1H NMR (300 MHz, CDCl3) δ 7.28–7.14 (m, 4H), 7.09–6.92 (m, 5H), 6.83 (s, 1H), 6.62 (s, 2H), 4.70 (s, 2H), 4.56 (s, 2H), 3.84 (s, 2H), 2.34 (s, 6H), 2.30 (s, 2H). HRMS (ESI): calcd for C 30 H 27 Cl2N3O3[M + H] + 548.1495, found 548.1508. HPLC (80:20 methanol:water with 1‰ TFA): t R = 6.8 min, 95.4%.

[0111] Example 19:

[0112] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(3-methoxyphenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 19)

[0113]

[0114] This product was prepared from 3-methoxybromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a yellow solid with a yield of 78% and a melting point of 121 - 122 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.37 (s, 1H), 7.27 (h, J = 7.4, 6.8 Hz, 4H), 7.07 (s, 1H), 6.98 (t, J = 8.3 Hz, 1H), 6.74 (s, 3H), 6.36 (d, J = 8.7 Hz, 1H), 6.28 (s, 2H), 4.74 (s, 2H), 4.50–4.36 (m, 2H), 3.82 (t, J = 5.0 Hz, 2H), 3.62 (s, 3H), 2.26 (s, 6H), 2.13 (t, J = 6.6 Hz, 2H). 13 C NMR (75 MHz, d6-DMSO) δ 161.97, 160.57, 156.88, 149.76, 142.36, 136.94, 133.61, 130.67, 130.55, 130.09, 127.06, 126.72, 125.56, 125.52, 124.80, 120.96, 115.04, 114.03, 107.55, 103.10, 100.97, 55.80, 55.12, 45.79, 30.61, 20.87. HRMS (ESI): calcd for C 30 H 30 Cl2N2O4 [M+H] + 553.1656, found 553.1661. HPLC (80:20 methanol:water with 1‰ TFA): t R = 10.4 min, 97.8%.

[0115] Example 20:

[0116] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(3-hydroxyphenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 20)

[0117]

[0118] (1) Preparation of 4-((3-(Benzyloxy)phenyl)(3-chlorobenzyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid

[0119] This product was prepared from 3-benzyloxybromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, and ethyl 4-nitro-1H-pyrrole-2-carboxylate according to Example 1. It is a brown oil with a yield of 64%. 1 H NMR(300MHz,Chloroform-d)δ7.42(ddq,J=7.0,1.8,1.0Hz,2H),7.38–7.29(m,8H),7.27–7.20(m,2H),6.99(dt,J=7.5,1.5Hz,1H),6.72(dt,J=7.5,1.5Hz,1H),6.69(s,2H),6.63(t,J=1.5Hz,1H),5.05(t,J=0.9Hz,2H),5.01(t,J=1.0Hz,2H),4.03(dt,J=16.9,7.0Hz,4H),2.29(s,6H),2.08(p,J=7.1Hz,2H).ESI-MS m / z:627.2[M+H] + .

[0120] (2) Preparation of the title compound

[0121] Dissolve the above 4-((3-(benzyloxy)phenyl)(3-chlorobenzyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid in ethanol, add palladium / carbon (0.05eq), replace with hydrogen three times, heat at 60 °C for 3 hours, filter after cooling to room temperature, and dry the filtrate to obtain the target product, which is a gray solid with a yield of 64% and a melting point of 121 - 122 °C. 1 H NMR(300MHz,CDCl3)δ7.27–7.11(m,4H),7.05–6.94(m,2H),6.78(s,1H),6.62(s,2H),6.42–6.24(m,3H),4.69(s,2H),4.49(t,J=5.6Hz,2H),3.81(t,J=5.0Hz,2H),2.34(s,6H),2.29–2.19(m,2H).HRMS(ESI):calcd for C 29 H 28 Cl2N2O4[M+H] + 539.1504,found539.1500.HPLC(80:20methanol:water with 1‰TFA):t R= 7.26 min, 96.4%.

[0122] Example 21:

[0123] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(3-(1-hydroxyethyl)phenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 21)

[0124]

[0125] Dissolve the above Example 16 (0.2 g) in THF / DCM (1:1, 10 ml), and add NaBH4 (2 eq). After the reaction is completed, add HCl (2 M) under ice bath conditions. Extract with DCM three times, combine the organic phases, wash the organic layer with saturated brine and dry over sodium sulfate, and evaporate to dryness to obtain a brown solid, with a yield of 56%, melting point: 131 - 132 °C. 1 H NMR (300 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.33–7.19 (m, 4H), 7.06–6.98 (m, 2H), 6.85 (s, 1H), 6.75 (s, 2H), 6.72–6.60 (m, 3H), 4.76 (s, 2H), 4.62–4.51 (m, 1H), 4.42 (t, J = 6.4 Hz, 2H), 3.83 (t, J = 5.9 Hz, 2H), 2.27 (s, 6H), 2.19–2.07 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H). HRMS (ESI): calcd for C 31 H 32 Cl2N2O4 [M+H] + 567.1817, found 567.1820. HPLC (80:20 methanol:water with 1‰ TFA): t R = 6.04 min, 97.1%.

[0126] Example 22:

[0127] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((thiophen-3-ylmethyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 22)

[0128]

[0129] This product is prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-bromomethylthiophene according to Example 1, yellow solid, yield 56%, melting point: 137 - 138 °C.1 1H NMR (300 MHz, d6-DMSO) δ 12.20 (s, 1H), 7.41 (dd, J = 4.8, 3.0 Hz, 1H), 7.18 (s, 1H), 7.02–6.90 (m, 3H), 6.74 (d, J = 3.7 Hz, 2H), 6.72–6.54 (m, 3H), 6.45 (dd, J = 13.3, 7.1 Hz, 1H), 4.68 (s, 2H), 4.40 (t, J = 6.2 Hz, 2H), 3.83 (t, J = 5.9 Hz, 2H), 2.26 (s, 6H), 2.13 (d, J = 4.1 Hz, 5H). HRMS (ESI): calcd for C 28 H 29 ClN2O3 [M+H] + 509.1657, found 509.1666. HPLC (80:20 methanol:water with 1‰ TFA): t R =9.22 min, 97.6%.

[0130] Example 23:

[0131] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((naphthalen-1-ylmethyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 23)

[0132]

[0133] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 1-(bromomethyl)naphthalene according to Example 1, with a yield of 67%, melting point: 91.0 - 92.4 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.20 (s, 1H), 8.10–7.69 (m, 3H), 7.44 (dd, J = 58.0, 4.8 Hz, 4H), 7.08–6.84 (m, 2H), 6.82–6.19 (m, 6H), 5.22 (s, 2H), 4.37 (s, 2H), 3.80 (s, 2H), 2.17 (d, J = 37.3 Hz, 11H). HRMS (ESI): calcd for C 34 H 33 ClN2O3 [M+H] + 553.2246, found 553.2258. HPLC (80:20 methanol:water with 1‰ TFA): t R= 15.2 min, 96.5%.

[0134] Example 24:

[0135] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((naphthalen-2-ylmethyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 24)

[0136]

[0137] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 2-bromomethylnaphthalene according to Example 1. It is a white solid with a yield of 72% and a melting point of 101 - 102 °C. 1 H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.92–7.69 (m, 4H), 7.52–7.36 (m, 3H), 7.05 (s, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.85–6.52 (m, 5H), 6.48 (d, J = 6.8 Hz, 1H), 4.89 (s, 2H), 4.40 (t, J = 6.2 Hz, 2H), 3.81 (t, J = 5.9 Hz, 2H), 2.23 (s, 6H), 2.12 (s, 5H). HRMS (ESI): calcd for C 34 H 33 ClN2O3 [M + H] + 553.2246, found 553.2248. HPLC (80:20 methanol:water with 1‰ TFA): t R = 15.4 min, 97.2%.

[0138] Example 25:

[0139] 4-(Benzyl(m-tolyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid (Compound 25)

[0140]

[0141] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and benzyl bromide according to Example 1. It is a white solid with a yield of 67% and a melting point of 149 - 150 °C. 11H NMR (300 MHz, d6-DMSO) δ 12.23 (s, 1H), 7.25 (d, J = 6.2 Hz, 5H), 6.94 (dd, J = 14.9, 7.3 Hz, 2H), 6.70 (d, J = 13.2 Hz, 3H), 6.67–6.54 (m, 2H), 6.47 (d, J = 7.2 Hz, 1H), 4.73 (s, 2H), 4.39 (t, J = 5.8 Hz, 2H), 3.81 (t, J = 5.6 Hz, 2H), 2.25 (s, 6H), 2.12 (s, 5H). HRMS (ESI): calcd for C 30 H 31 ClN2O3 [M+H] + 503.2095, found 503.2101. HPLC (80:20 methanol:water with 1‰ TFA): t R = 10.9 min, 96.7%.

[0142] Example 26:

[0143] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((2-chlorobenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 26)

[0144]

[0145] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-chlorobenzyl bromide according to Example 1. It is a yellow solid with a yield of 65% and a melting point of 134 - 135 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.22 (s, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.21–7.07 (m, 3H), 6.95 (d, J = 2.1 Hz, 1H), 6.85 (t, J = 7.8 Hz, 1H), 6.62 (d, J = 2.9 Hz, 3H), 6.45–6.33 (m, 3H), 4.65 (s, 2H), 4.29 (t, J = 6.7 Hz, 2H), 3.70 (t, J = 6.0 Hz, 2H), 2.14 (s, 6H), 2.02 (s, 5H). HRMS (ESI): calcd for C 30 H 30 Cl2N2O3 [M+H] + 537.1705, found 537.1702. HPLC (80:20 methanol:water with 1‰ TFA): tR = 14.1 min, 98.1%.

[0146] Example 27:

[0147] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((2-methylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 27)

[0148]

[0149] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 2-methylbenzyl bromide according to Example 1. It is a white solid with a yield of 56% and a melting point of 121 - 122 °C. 1 H NMR (300 MHz, Chloroform-d) δ 7.28 (d, J = 7.5 Hz, 1H), 7.20–7.16 (m, 2H), 7.12–7.00 (m, 3H), 6.78 (d, J = 1.8 Hz, 1H), 6.71–6.59 (m, 5H), 4.72 (s, 2H), 4.48 (t, J = 6.3 Hz, 2H), 3.84 (t, J = 5.4 Hz, 2H), 2.36 (s, 6H), 2.30 (s, 3H), 2.27 (s, 3H), 2.24 (d, J = 5.8 Hz, 2H). HRMS (ESI): calcd for C 31 H 33 ClN2O3 [M+H] + 537.1705, found 537.1702. HPLC (80:20 methanol:water with 1‰ TFA): t R = 13.0 min, 97.6%.

[0150] Example 28:

[0151] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-methylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 28)

[0152]

[0153] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-methylbenzyl bromide according to Example 1. It is a yellow solid with a yield of 72% and a melting point of 139 - 140 °C. 11H NMR (300 MHz, d6-DMSO) δ 12.32 (s, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.12–6.92 (m, 5H), 6.77 (s, 2H), 6.72 (d, J = 2.1 Hz, 1H), 6.66–6.55 (m, 2H), 6.51 (d, J = 7.4 Hz, 1H), 4.72 (s, 2H), 4.43 (t, J = 6.4 Hz, 2H), 3.85 (t, J = 6.0 Hz, 2H), 2.28 (s, 9H), 2.16 (s, 5H). HRMS (ESI): calcd for C 31 H 33 ClN2O3 [M+H] + 517.2248, found 517.2258. HPLC (80:20 methanol:water with 1‰ TFA): t R = 9.84 min, 98.5%.

[0154] Example 29:

[0155] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((4-chlorobenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 29)

[0156]

[0157] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-chlorobenzyl bromide according to Example 1. It is a yellow solid with a yield of 57% and a melting point of 141 - 142 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.33 (s, 1H), 7.33 (d, J = 7.4 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.04–6.93 (m, 2H), 6.76 (s, 2H), 6.72 (s, 1H), 6.65–6.48 (m, 3H), 4.74 (s, 2H), 4.48–4.38 (m, 2H), 3.88–3.78 (m, 2H), 2.28 (s, 6H), 2.15 (s, 5H). HRMS (ESI): calcd for C 30 H 30 Cl2N2O3 [M+H] + 537.1706, found 537.1702. HPLC (80:20 methanol:water with 1‰ TFA): t R= 12.4 min, 97.6%.

[0158] Example 30:

[0159] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((4-methylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 30)

[0160]

[0161] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-methylbenzyl bromide according to Example 1. It is a white solid with a yield of 66% and a melting point of 128 - 129 °C. 1 H NMR (300 MHz, d6-DMSO) δ 7.10 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 7.9 Hz, 2H), 6.98–6.89 (m, 2H), 6.73 (s, 2H), 6.67 (d, J = 2.1 Hz, 1H), 6.62–6.53 (m, 2H), 6.46 (d, J = 7.4 Hz, 1H), 4.67 (s, 2H), 4.39 (t, J = 6.5 Hz, 2H), 3.81 (t, J = 6.1 Hz, 2H), 2.25 (s, 6H), 2.23 (s, 3H), 2.10 (d, J = 8.0 Hz, 5H). HRMS (ESI): calcd for C 31 H 33 ClN2O3 [M+H] + 517.2253, found 517.2258. HPLC (80:20 methanol:water with 1‰ TFA): t R = 12.8 min, 98.1%.

[0162] Example 31:

[0163] 4-((3-bromobenzyl)(m-tolyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid (Compound 31)

[0164]

[0165] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-bromobenzyl bromide according to Example 1. It is a yellow solid with a yield of 63% and a melting point of 141 - 142 °C. 11H NMR (300 MHz, d6-DMSO) δ 7.42 (d, J = 10.8 Hz, 2H), 7.25 (s, 2H), 6.99 (d, J = 14.0 Hz, 2H), 6.72 (d, J = 15.3 Hz, 3H), 6.67–6.48 (m, 3H), 4.75 (s, 2H), 4.43 (s, 2H), 3.83 (s, 2H), 2.27 (s, 6H), 2.15 (s, 5H). HRMS (ESI): calcd for C 30 H 30 BrClN2O3 [M + H] + 583.1180, found 583.1186. HPLC (80:20 methanol:water with 1‰ TFA): t R = 13.5 min, 97.8%.

[0166] Example 32:

[0167] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-methoxybenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 32)

[0168]

[0169] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-methoxybenzyl bromide according to Example 1. It is a yellow solid with a yield of 79% and a melting point of 145 - 146 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.22 (s, 1H), 7.10 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.99–6.94 (m, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.73 (s, 2H), 6.67 (d, J = 2.1 Hz, 1H), 6.63–6.53 (m, 2H), 6.46 (d, J = 7.4 Hz, 1H), 4.67 (s, 2H), 4.39 (t, J = 6.5 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H), 2.25 (s, 6H), 2.23 (s, 3H), 2.11 (s, 5H). HRMS (ESI): calcd for C 31 H 33 ClN2O4 [M + H] +533.2207, found 533.2203. HPLC (80:20 methanol:water with 1‰ TFA): t R = 12.5 min, 96.2%.

[0170] Example 33:

[0171] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-fluorobenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 33)

[0172]

[0173] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-fluorobenzyl bromide according to Example 1. It is a yellow solid with a yield of 83% and a melting point of 146 - 147 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.23 (s, 1H), 7.37–7.25 (m, 1H), 7.13–6.89 (m, 5H), 6.72 (s, 2H), 6.68 (d, J = 2.1 Hz, 1H), 6.65–6.42 (m, 3H), 4.74 (s, 2H), 4.40 (t, J = 6.3 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H), 2.25 (s, 6H), 2.11 (d, J = 9.6 Hz, 5H). 13 C NMR (75 MHz, d6-DMSO) δ 161.96, 156.90, 148.63, 142.93, 138.42, 136.95, 130.80, 130.76, 129.19, 125.54, 124.59, 122.90, 120.84, 119.16, 115.29, 115.06, 113.95, 113.82, 113.71, 113.43, 112.04, 64.91, 55.77, 45.74, 30.57, 21.82, 20.87. HRMS (ESI): calcd for C 30 H 30 ClFN2O3 [M+H] + 521.1998, found 521.2007. HPLC (80:20 methanol:water with 1‰ TFA): t R = 9.39 min, 96.2%.

[0174] Example 34:

[0175] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-(m-tolyl(3-(trifluoromethyl)benzyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 34)

[0176]

[0177] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-(trifluoromethyl)benzyl bromide according to Example 1. It is an orange solid with a yield of 67% and a melting point of 121 - 122 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.20 (s, 1H), 7.43 (q, J = 9.4, 7.8 Hz, 4H), 6.95–6.80 (m, 3H), 6.60 (d, J = 11.0 Hz, 2H), 6.54–6.34 (m, 3H), 4.72 (s, 2H), 4.29 (s, 2H), 3.69 (s, 2H), 2.13 (s, 6H), 2.02 (s, 5H). HRMS (ESI): calcd for C 31 H 30 ClF3N2O3 [M+H] + 571.1972, found 571.1975. HPLC (80:20 methanol:water with 1‰ TFA): t R = 12.6 min, 97.4%.

[0178] Example 35:

[0179] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-(m-tolyl(3-(trifluoromethoxy)benzyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 35)

[0180]

[0181] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-(trifluoromethoxy)benzyl bromide according to Example 1. It is a red solid with a yield of 59% and a melting point of 104 - 105 °C. 11H NMR (300 MHz, d6-DMSO) δ 12.30 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.02–6.91 (m, 2H), 6.72 (s, 2H), 6.67 (d, J = 2.1 Hz, 1H), 6.63–6.45 (m, 3H), 4.77 (s, 2H), 4.39 (t, J = 6.3 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 2.24 (s, 6H), 2.12 (s, 5H). HRMS (ESI): calcd for C 31 H 30 ClF3N2O4 [M+H] + 587.1917, found 587.1924. HPLC (80:20 methanol:water with 1‰ TFA): t R = 10.8 min, 96.5%.

[0182] Example 36:

[0183] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-formylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 36)

[0184]

[0185] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-formylbromobenzene according to Example 1. It is a white solid with a yield of 69% and a melting point of 106-107 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.19 (s, 1H), 9.95 (s, 1H), 7.82–7.69 (m, 2H), 7.52 (dt, J = 15.0, 7.4 Hz, 2H), 6.96 (dd, J = 16.7, 9.0 Hz, 2H), 6.70 (s, 3H), 6.63–6.54 (m, 2H), 6.49 (d, J = 7.1 Hz, 1H), 4.82 (s, 2H), 4.39 (t, J = 5.8 Hz, 2H), 3.79 (t, J = 5.3 Hz, 2H), 2.23 (s, 6H), 2.10 (d, J = 11.7 Hz, 5H). HRMS (ESI): calcd for C 31 H 31 ClN2O4 [M+H] +531.2043, found 531.2051. HPLC (80:20 methanol:water with 1‰ TFA): t R = 6.99 min, 97.8%.

[0186] Example 37:

[0187] -(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((4-isopropylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 37)

[0188]

[0189] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-isopropylbromobenzyl according to Example 1. It is a white solid with a yield of 67% and a melting point of 118 - 119 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.30 (s, 1H), 7.14 (s, 4H), 7.08–6.89 (m, 2H), 6.76 (s, 2H), 6.70 (d, J = 2.0 Hz, 1H), 6.63 (s, 1H), 6.58 (d, J = 8.3 Hz, 1H), 6.48 (d, J = 7.4 Hz, 1H), 4.70 (s, 2H), 4.41 (t, J = 6.6 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 2.81 (dq, J = 13.9, 6.9 Hz, 1H), 2.26 (s, 6H), 2.14 (s, 5H), 1.18 (s, 3H), 1.16 (s, 3H). HRMS (ESI): calcd for C 33 H 37 ClN2O3 [M+H] + 545.2565, found 545.2571. HPLC (80:20 methanol:water with 1‰ TFA): t R = 18.3 min, 98.2%.

[0190] Example 38:

[0191] 4-((4-(tert-Butyl)benzyl)(m-tolyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid (Compound 38)

[0192]

[0193] This product is prepared according to Example 1 from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-tert-butylbenzyl bromide. It is a yellow solid with a yield of 67% and a melting point of 123 - 124 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.31 (s, 1H), 7.29 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 2.1 Hz, 1H), 6.95 (t, J = 7.8 Hz, 1H), 6.76 (s, 2H), 6.71 (d, J = 2.0 Hz, 1H), 6.64 (s, 1H), 6.58 (d, J = 8.5 Hz, 1H), 6.48 (d, J = 7.4 Hz, 1H), 4.71 (s, 2H), 4.48–4.36 (m, 2H), 3.83 (t, J = 6.1 Hz, 2H), 2.26 (s, 6H), 2.14 (s, 5H), 1.25 (s, 9H). HRMS (ESI): calcd for C 34 H 39 ClN2O3 [M+H] + 559.2724, found 559.2727. HPLC (80:20 methanol:water with 1‰ TFA): t R = 21.1 min, 97.3%.

[0194] Example 39:

[0195] 4-(((1,1'-Biphenyl)-4-ylmethyl)(m-tolyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid (Compound 39)

[0196]

[0197] This product is prepared according to Example 1 from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-tert-butylbenzyl bromide. It is a light yellow solid with a yield of 65% and a melting point of 104 - 105 °C. 11H NMR (300 MHz, d6-DMSO) δ 12.23 (s, 1H), 7.57 (dd, J = 16.0, 7.8 Hz, 4H), 7.43 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 8.5 Hz, 3H), 7.01 (d, J = 2.1 Hz, 1H), 6.95 (t, J = 7.8 Hz, 1H), 6.72 (d, J = 2.7 Hz, 3H), 6.67–6.56 (m, 2H), 6.48 (d, J = 7.5 Hz, 1H), 4.78 (s, 2H), 4.40 (t, J = 6.5 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H), 2.23 (s, 6H), 2.13 (s, 5H). HRMS (ESI): calcd for C 36 H 35 ClN2O3 [M+H] + 579.2404, found 579.2414. HPLC (80:20 methanol:water with 1‰ TFA): t R = 16.8 min, 96.8%.

[0198] Example 40:

[0199] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((4-ethynylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 40)

[0200]

[0201] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-ethynylbenzyl bromide according to Example 1. It is a white solid with a yield of 64% and a melting point of 142 - 143 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.35 (s, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.08–6.95 (m, 2H), 6.79 (s, 2H), 6.75 (d, J = 2.1 Hz, 1H), 6.69–6.51 (m, 3H), 4.79 (s, 2H), 4.46 (s, 2H), 4.18 (s, 1H), 3.86 (s, 2H), 2.31 (s, 6H), 2.18 (s, 5H). 1313C NMR (75 MHz, d6-DMSO) δ 161.96, 156.91, 148.63, 140.86, 138.41, 136.97, 132.21, 130.76, 129.19, 127.24, 125.54, 124.63, 120.79, 120.38, 119.05, 115.20, 115.07, 113.90, 111.98, 83.92, 80.85, 64.88, 55.94, 45.73, 30.55, 21.85, 20.90. HRMS (ESI): calcd for C 32 H 31 ClN2O3 [M+H] + 527.2094, found 527.2101. HPLC (80:20 methanol:water with 1‰ TFA): t R = 9.34 min, 97.1%.

[0202] Example 41:

[0203] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((4-(prop-1-yn-1-yl)benzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 41)

[0204]

[0205] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-propynylbromobenzyl according to Example 1. It is a white solid with a yield of 64% and a melting point of 136 - 137 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.32 (s, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.04–6.91 (m, 2H), 6.75 (s, 2H), 6.71 (s, 1H), 6.64–6.53 (m, 2H), 6.49 (d, J = 7.3 Hz, 1H), 4.73 (s, 2H), 4.42 (t, J = 6.4 Hz, 2H), 3.82 (t, J = 6.0 Hz, 2H), 2.27 (s, 6H), 2.14 (s, 5H), 2.04 (s, 3H). HRMS (ESI): calcd for C 33 H 33 ClN2O3 [M+H] +541.2258, found 541.2258. HPLC (80:20 methanol:water with 1‰ TFA): t R = 12.7 min, 98.5%.

[0206] Example 42:

[0207] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3,4-dimethylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 42)

[0208]

[0209] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3,4-dimethylbenzyl bromide according to Example 1. It is a white solid with a yield of 75% and a melting point of 136 - 137 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.14 (s, 1H), 7.02–6.89 (m, 5H), 6.72 (s, 2H), 6.67 (d, J = 2.1 Hz, 1H), 6.60 (s, 1H), 6.55 (dd, J = 7.9, 2.4 Hz, 1H), 6.46 (d, J = 7.4 Hz, 1H), 4.64 (s, 2H), 4.39 (t, J = 6.5 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H), 2.14 (s, 6H), 2.11 (s, 5H). HRMS (ESI): calcd for C 32 H 35 ClN2O3 [M + H] + 531.2404, found 531.2414. HPLC (80:20 methanol:water with 1‰ TFA): t R = 9.78 min, 97.3%.

[0210] Example 43:

[0211] 4-((3-Bromo-4-methylbenzyl)(m-tolyl)amino)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-pyrrole-2-carboxylic acid (Compound 43)

[0212]

[0213] This product is prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-bromo-4-methylbenzyl bromide according to Example 1. It is a yellow solid with a yield of 77% and a melting point of 147-148 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.28 (s, 1H), 7.42 (s, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.71 (s, 2H), 6.68–6.38 (m, 4H), 4.69 (s, 2H), 4.40 (t, J = 6.5 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H), 2.26 (d, J = 8.3 Hz, 9H), 2.12 (s, 5H). HRMS (ESI): calcd for C 31 H 32 BrClN2O3 [M+H] + 597.1335, found 597.1343. HPLC (80:20 methanol:water with 1‰ TFA): t R = 16.2 min, 98.1%.

[0214] Example 44:

[0215] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((3,4-dichlorobenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 44)

[0216]

[0217] This product is prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3,4-dichlorobenzyl bromide according to Example 1. It is a yellow solid with a yield of 57% and a melting point of 143-144 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.24 (s, 1H), 7.55–7.40 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 7.05–6.90 (m, 2H), 6.70 (d, J = 6.7 Hz, 3H), 6.62–6.43 (m, 3H), 4.72 (s, 2H), 4.40 (t, J = 6.2 Hz, 2H), 3.80 (t, J = 5.8 Hz, 2H), 2.24 (s, 6H), 2.13 (s, 5H). HRMS (ESI): calcd for C30 H 29 Cl3N2O3[M+H] + 573.1293, found 573.1293. HPLC (80:20 methanol:water with 1‰ TFA): t R =15.1 min, 97.7%.

[0218] Example 45:

[0219] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3,5-dimethylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 45)

[0220]

[0221] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3,5-dimethylbenzyl bromide according to Example 1. It is a yellow solid with a yield of 53% and a melting point of 161 - 162 °C. 1 H NMR (300 MHz, CDCl3) δ 7.08 (tt, J=14.0, 7.4 Hz, 5H), 6.81 (s, 1H), 6.67 (d, J=16.7 Hz, 4H), 4.76 (s, 2H), 4.48 (t, J=6.4 Hz, 2H), 3.86 (t, J=5.8 Hz, 2H), 2.36 (s, 9H), 2.27 (s, 3H), 2.20 (s, 5H). HRMS (ESI): calcd for C 32 H 35 ClN2O3[M+H] + 531.2409, found 531.2414. HPLC (80:20 methanol:water with 1‰ TFA): t R =15.0 min, 98.5%.

[0222] Example 46:

[0223] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((2,3-dimethylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 46)

[0224]

[0225] This product is prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 2,3-dimethylbromobenzyl according to Example 1, with a yield of 75% and a melting point of 161 - 162 °C. 1 H NMR (300 MHz, Chloroform-d) δ 7.14 (d, J = 7.2 Hz, 1H), 7.10–6.95 (m, 4H), 6.79 (d, J = 1.9 Hz, 1H), 6.68 (d, J = 4.7 Hz, 1H), 6.62 (d, J = 4.7 Hz, 3H), 4.75 (s, 2H), 4.53–4.42 (m, 2H), 3.85 (t, J = 5.6 Hz, 2H), 2.36 (s, 9H), 2.26 (s, 3H), 2.23 (d, J = 6.1 Hz, 2H), 2.20 (s, 3H). HRMS (ESI): calcd for C 32 H 35 ClN2O3 [M + H] + 531.2414, found 531.2399. HPLC (80:20 methanol:water with 1‰ TFA): t R = 14.5 min, 97.4%.

[0226] Example 47:

[0227] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((2,3-difluorobenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 47)

[0228]

[0229] This product is prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 2,3-difluorobromobenzyl according to Example 1, as a yellow solid, with a yield of 96% and a melting point of 148.0 - 151.3 °C. 1 H NMR (300 MHz, CDCl3) δ 7.14–6.94 (m, 5H), 6.76 (d, J = 2.0 Hz, 1H), 6.67 (d, J = 7.5 Hz, 3H), 6.63 (s, 2H), 4.68 (s, 2H), 4.51 (t, J = 6.4 Hz, 2H), 3.88–3.79 (m, 2H), 2.35 (s, 6H), 2.27 (s, 5H). HRMS (ESI): calcd for C 30 H 29 ClF2N2O3 [M + H] +539.1903, found 539.1913. HPLC (80:20 methanol:water with 1‰ TFA): t R = 9.34 min, 98.2%.

[0230] Example 48:

[0231] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((2,4-dichlorobenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 48)

[0232]

[0233] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 2,4-dichlorobenzyl bromide according to Example 1. It is a yellow solid with a yield of 58% and a melting point of 137 - 138 °C. 1 H NMR (300 MHz, CDCl3) δ 7.40 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.15–7.00 (m, 3H), 6.81 (d, J = 2.3 Hz, 1H), 6.63 (d, J = 6.3 Hz, 5H), 4.79 (s, 2H), 4.51 (t, J = 6.5 Hz, 2H), 3.84 (t, J = 5.6 Hz, 2H), 2.35 (s, 6H), 2.27 (s, 5H). HRMS (ESI): calcd for C 30 H 29 Cl3N2O3 [M+H] + 573.1289, found 573.1293. HPLC (80:20 methanol:water with 1‰ TFA): t R = 23.67 min, 97.0%.

[0234] Example 49:

[0235] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((2,6-dichlorobenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 49)

[0236]

[0237] This product is prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 2,6-dichlorobenzyl bromide according to Example 1. It is a yellow solid with a yield of 71% and a melting point of 148 - 149 °C. 1 H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 2.4 Hz, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 7.17 (dd, J = 8.5, 2.5 Hz, 1H), 7.10–7.00 (m, 2H), 6.82 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 12.2 Hz, 5H), 4.79 (s, 2H), 4.52 (t, J = 6.5 Hz, 2H), 3.85 (t, J = 5.7 Hz, 2H), 2.35 (s, 6H), 2.29 (d, J = 4.5 Hz, 5H). HRMS (ESI): calcd for C 30 H 29 Cl3N2O3 [M+H] + 573.1325, found 573.1322. HPLC (80:20 methanol:water with 1‰ TFA): t R = 16.8 min, 98.7%.

[0238] Example 50:

[0239] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 50)

[0240]

[0241] (1) Preparation of ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-(prop-2-yn-1-yl(m-tolyl)amino)-1H-pyrrole-2-carboxylate

[0242] This product is prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 3-bromoprop-1-yne according to the preparation method of ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((3-chlorobenzyl)(phenyl)amino)-1H-pyrrole-2-carboxylate described above. It is a yellow oil with a yield of 56%. 11H NMR (300 MHz, Chloroform-d) δ 7.28–7.22 (m, 2H), 7.13 (dt, J = 7.5, 1.6 Hz, 1H), 6.93 (t, J = 1.5 Hz, 1H), 6.88 (ddq, J = 7.3, 1.5, 0.7 Hz, 1H), 6.69 (s, 2H), 6.61 (d, J = 1.5 Hz, 1H), 4.78 (d, J = 3.1 Hz, 2H), 4.29 (q, J = 8.0 Hz, 2H), 4.04 (dt, J = 8.8, 7.1 Hz, 4H), 2.71 (t, J = 2.9 Hz, 1H), 2.37 (d, J = 0.7 Hz, 3H), 2.33 (s, 6H), 2.10 (p, J = 7.1 Hz, 2H), 1.35 (t, J = 8.0 Hz, 3H). ESI-MS m / z: 479.2 [M+H] + .

[0243] (2) Preparation of ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylate

[0244] The above-mentioned ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-(prop-2-yn-1-yl(m-tolyl)amino)-1H-pyrrole-2-carboxylate (0.3 g), DIPEA (2 eq), CuI (0.1 eq), and azidobenzene (2 eq) were dissolved in methanol. Under nitrogen protection, it was heated at 50 °C for 2 hours. After the reaction was completed, it was cooled to room temperature, triturated, and separated by column chromatography (PE / EA = 20:1 to 10:1 v / v) to obtain a brown oil, with a yield of 73%. 1 1H NMR (300 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.75–7.65 (m, 2H), 7.52–7.46 (m, 2H), 7.31–7.13 (m, 4H), 6.93 (q, J = 1.1 Hz, 1H), 6.85 (dtd, J = 7.3, 1.5, 0.8 Hz, 1H), 6.69 (s, 2H), 6.58 (d, J = 1.5 Hz, 1H), 5.24 (s, 2H), 4.28 (q, J = 8.0 Hz, 2H), 4.04 (td, J = 7.0, 5.5 Hz, 4H), 2.37 (t, J = 0.6 Hz, 3H), 2.29 (s, 6H), 2.08 (p, J = 7.1 Hz, 2H), 1.35 (t, J = 8.0 Hz, 3H). ESI-MS m / z: 598.2 [M+H] + .

[0245] (3) Preparation of the title compound

[0246] This product was prepared from the above-mentioned ethyl 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-(prop-2-yn-1-yl(m-tolyl)amino)-1H-pyrrole-2-carboxylate according to Example 1, a white solid, with a yield of 76%, melting point: 177 - 178 °C. 1 HNMR(300MHz, d6-DMSO) δ 12.32(s, 1H), 8.63(s, 1H), 7.94–7.80(m, 2H), 7.58(t, J = 7.5Hz, 2H), 7.48(t, J = 7.3Hz, 1H), 7.13(s, 1H), 6.98(t, J = 7.4Hz, 1H), 6.82(s, 1H), 6.72(d, J = 9.9Hz, 4H), 6.55–6.46(m, 1H), 4.83(s, 2H), 4.53–4.35(m, 2H), 3.95–3.76(m, 2H), 2.23(s, 6H), 2.17(s, 5H). 13 CNMR(75MHz, d6-DMSO) δ 162.07, 156.88, 148.59, 146.29, 138.33, 137.08, 136.90, 130.44, 130.23, 129.11, 128.90, 125.52, 121.51, 120.91, 120.33, 119.02, 115.49, 115.08, 114.86, 112.21, 65.01, 48.39, 45.82, 30.70, 21.85, 20.84. HRMS(ESI): calcd for C 32 H 32 ClN5O3 [M + H] + 570.2259, found 570.2272. HPLC(80:20 methanol:water with 1‰ TFA): t R = 7.92 min, 97.6%.

[0247] Example 51:

[0248] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((((2-chloro-[1,1'-biphenyl]-4-yl)methyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 51)

[0249]

[0250] (1) Preparation of 2-chloro-[1,1'-biphenyl]-4-carboxylic acid

[0251] In a toluene (30 mL) solution of 4-bromo-3-chlorobenzoic acid (3 g), phenylboronic acid (2 eq), and Pd(PPh3)4 (0.1 eq), Cs2CO3 (2 eq) was added. The mixture was heated under reflux overnight under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, the filtrate was triturated, and column chromatography (PE / EA = 80:1 to 50:1 v / v) was performed to obtain a white solid. The yield was 87%. 1 1H NMR (300 MHz, Chloroform-d) δ 8.03 (d, J = 1.5 Hz, 1H), 7.91 (dd, J = 7.5, 1.5 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 4.6 Hz, 4H), 7.38–7.33 (m, 1H). ESI-MS m / z: 231.0 [M-H] - .

[0252] (2) Preparation of 4-(bromomethyl)-2-chloro-1,1'-biphenyl

[0253] After the above-prepared 2-chloro-[1,1'-biphenyl]-4-carboxylic acid (2 g) was dissolved in THF (50 mL), BH3-THF (1 M) was slowly added under an ice bath condition, and then the mixture was heated at 40 °C overnight. After the reaction was complete, methanol was added to quench the reaction, and then the solvent was evaporated to dryness to obtain a white solid. The above white solid (1.5 g) was dissolved in THF (30 mL), and BBr3 (2 eq) was slowly added under an ice bath condition. The reaction solution was slowly warmed to room temperature, and after the reaction was complete, column chromatography separation (PE / EA = 80:1 to 50:1 v / v) was performed to obtain a colorless liquid. The yield was 57%. 1 1H NMR (300 MHz, Chloroform-d) δ 7.52 (q, J = 1.1 Hz, 1H), 7.51–7.42 (m, 5H), 7.39–7.34 (m, 1H), 7.21 (dq, J = 7.5, 1.1 Hz, 1H), 4.44 (s, 2H). ESI-MS m / z: 281.1 [M+H] + .

[0254] (3) Preparation of the title compound

[0255] This product was prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-(bromomethyl)-2-chloro-1,1'-biphenyl according to Example 1. It was a white solid with a yield of 37% and a melting point of 157-158 °C. 11H NMR (300 MHz, d6-DMSO) δ 7.35 (d, J = 34.8 Hz, 9H), 7.11–6.92 (m, 2H), 6.85–6.46 (m, 6H), 4.80 (s, 2H), 4.43 (s, 2H), 3.83 (s, 2H), 2.24 (s, 6H), 2.16 (s, 5H). 13 13C NMR (75 MHz, DMSO) δ 161.97, 156.88, 148.56, 141.32, 138.98, 138.50, 138.42, 136.95, 131.93, 131.67, 130.71, 129.66, 128.64, 128.17, 126.00, 125.51, 124.51, 120.88, 119.26, 115.35, 115.07, 113.67, 112.07, 64.92, 55.32, 45.77, 30.54, 21.86, 20.87. HRMS (ESI): calcd for C 36 H 34 Cl2N2O3 [M + H] + 613.2032, found 613.2025. HPLC (80:20 methanol:water with 1‰ TFA): t R = 10.2 min, 98.5%.

[0256] Example 52:

[0257] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chloro-4-ethynylbenzyl)(m-tolyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 52)

[0258]

[0259] (1) Preparation of (3-chloro-4-((trimethylsilyl)ethynyl)phenyl)methanol

[0260] Dissolve 4-bromo-3-chlorobenzoic acid (4 g) in THF (50 ml), slowly add BH3-THF under ice bath conditions, and then heat at 40 °C overnight. After the reaction is complete, quench the reaction with methanol and then evaporate to dryness to obtain a white solid. Dissolve the above white solid (3.5 g) in triethylamine, and then add Pd(OAc)2 (0.1 eq), CuI (0.1 eq) and trimethylsilylacetylene (2 eq). Under nitrogen protection, heat at 70 °C for 30 hours. After the reaction is complete, cool to room temperature, triturate, and column chromatography (PE / EA = 50:1 to 20:1 v / v) to obtain a yellow oil, with a yield of 65%. 11H NMR (300 MHz, Chloroform-d) δ 7.48 (d, J = 7.5 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 4.74 (s, 2H), 0.25 (s, 9H). ESI-MS m / z: 237.1 [M-H] - .

[0261] (2) Preparation of 4-(bromomethyl)-2-chloro-1-ethynylbenzene

[0262] Dissolve the above-mentioned (3-chloro-4-((trimethylsilyl)ethynyl)phenyl)methanol (1.5 g) in THF (30 ml), add TBAF-THF (1 M), stir the reaction solution at room temperature for 30 minutes. After the reaction is complete, add 100 ml of H2O, extract with EtOAc (3 times), combine the organic phases, wash the organic phase with saturated brine, dry over sodium sulfate, and evaporate to dryness to obtain a brown oil. Dissolve the above brown oil in THF and then add BBr3 (2 eq), stir at room temperature for 30 minutes, triturate, and perform column chromatography to obtain a colorless liquid with a yield of 46%. 1 1H NMR (300 MHz, Chloroform-d) δ 7.54–7.41 (m, 2H), 7.24 (dt, J = 7.5, 1.3 Hz, 1H), 4.40 (s, 2H), 3.31 (s, 1H). ESI-MS m / z: 229.0 [M+H] + .

[0263] (3) Preparation of the title compound

[0264] This product is prepared from 3-bromotoluene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-(bromomethyl)-2-chloro-1-ethynylbenzene according to Example 1. It is a white solid with a yield of 67% and a melting point of 147-148 °C. 1 1H NMR (300 MHz, d6-DMSO) δ 12.32 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.97 (t, J = 7.7 Hz, 1H), 6.74 (s, 2H), 6.71 (s, 1H), 6.64–6.49 (m, 3H), 4.76 (s, 2H), 4.54 (s, 1H), 4.48–4.39 (m, 2H), 3.82 (t, J = 6.0 Hz, 2H), 2.26 (s, 6H), 2.15 (s, 5H). 1313C NMR(75MHz,d6-DMSO)δ161.02,151.69,143.53,137.31,134.27,132.51,131.76,129.43,126.97,124.29,122.52,121.75,120.45,119.94,115.35,114.60,111.23,110.86,109.60,107.80,77.42,75.52,72.78,72.36,71.94,59.39,51.53,41.47,25.80,17.03,16.26.HRMS(ESI):calcd for C 32 H 30 Cl2N2O3[M+H] + 561.1700,found 561.1712.HPLC(80:20methanol:water with 1‰TFA):t R =15.9min,98.7%.

[0265] Example 53:

[0266] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chloro-4-ethynylbenzyl)(3,4-dimethylphenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 53)

[0267]

[0268] This product was prepared from 3,4-dimethylbromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-(bromomethyl)-2-chloro-1-ethynylbenzene according to Example 1. It is a yellow solid with a yield of 47% and a melting point of 156 - 157 °C. 1 1H NMR(300MHz,CDCl3)δ7.44(d,J=7.9Hz,1H),7.34(s,1H),7.13(d,J=8.0Hz,1H),6.94–6.85(m,2H),6.69(s,2H),6.63(s,3H),4.68(s,2H),4.48(t,J=6.3Hz,2H),3.83(t,J=5.4Hz,2H),3.38(s,1H),2.35(s,6H),2.26(d,J=6.1Hz,2H),2.19(s,3H),2.18(s,3H).HRMS(ESI):calcd for C 33 H 32 Cl2N2O3[M+Na] +597.1683, found 597.1688. HPLC (80:20 methanol:water with 1‰ TFA): t R = 14.6 min, 97.2%.

[0269] Example 54:

[0270] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chloro-4-ethynylbenzyl)(3-chlorophenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 54)

[0271]

[0272] This product was prepared from 3-chlorobromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-(bromomethyl)-2-chloro-1-ethynylbenzene according to Example 1. It is a green solid with a yield of 63% and a melting point of 156 - 157 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.41 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.21 (dd, J = 8.1, 1.7 Hz, 1H), 7.15–7.05 (m, 2H), 6.77 (d, J = 2.1 Hz, 1H), 6.73 (s, 2H), 6.72–6.64 (m, 3H), 4.78 (s, 2H), 4.54 (s, 1H), 4.45 (t, J = 6.5 Hz, 2H), 3.82 (t, J = 5.9 Hz, 2H), 2.26 (s, 6H), 2.15 (p, J = 6.3 Hz, 2H). 13 C NMR (75 MHz, d6-DMSO) δ 161.89, 156.87, 149.95, 142.31, 136.93, 135.51, 134.43, 134.18, 130.88, 129.46, 127.71, 125.70, 125.58, 121.37, 120.29, 117.52, 115.01, 114.49, 113.43, 112.64, 86.25, 80.39, 64.91, 55.61, 45.93, 30.52, 20.87, 14.41. HRMS (ESI): calcd for C 31 H 27 Cl3N2O3 [M + H] + 583.1131, found 583.1136. HPLC (80:20 methanol:water with 1‰ TFA): tR = 15.7 min, 96.8%.

[0273] Example 55:

[0274] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chloro-4-ethynylbenzyl)(3-fluorophenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 55)

[0275]

[0276] This product was prepared from 3-fluorobromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-(bromomethyl)-2-chloro-1-ethynylbenzene according to Example 1. It is a pink solid with a yield of 65% and a melting point of 144 - 145 °C. 1 H NMR (300 MHz, d6-DMSO) δ 12.40 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.21 (dd, J = 8.1, 1.7 Hz, 1H), 7.15–7.04 (m, 2H), 6.77 (d, J = 2.2 Hz, 1H), 6.74 (s, 2H), 6.59–6.42 (m, 3H), 4.78 (s, 2H), 4.54 (s, 1H), 4.45 (t, J = 6.5 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 2.26 (s, 6H), 2.16 (q, J = 6.3 Hz, 2H). HRMS (ESI): calcd for C 31 H 27 Cl2FN2O3 [M + H] + 565.1454, found 565.1461. HPLC (80:20 methanol:water with 1‰ TFA): t R = 10.6 min, 97.2%.

[0277] Example 56:

[0278] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chloro-4-ethynylbenzyl)(3-methoxyphenyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 56)

[0279]

[0280] This product was prepared according to Example 1 from 3-methoxybromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-(bromomethyl)-2-chloro-1-ethynylbenzene. It is a white solid with a yield of 49% and a melting point of 119 - 120 °C. 1 H NMR(300MHz,d6-DMSO)δ12.34(s,1H),7.51(d,J=8.0Hz,1H),7.40(d,J=1.6Hz,1H),7.21(dd,J=8.1,1.7Hz,1H),7.07(d,J=2.2Hz,1H),6.99(t,J=8.1Hz,1H),6.78–6.70(m,3H),6.40–6.25(m,3H),4.76(s,2H),4.53(s,1H),4.43(t,J=6.4Hz,2H),3.83(t,J=6.0Hz,2H),3.63(s,3H),2.26(s,6H),2.14(t,J=6.2Hz,2H).HRMS(ESI):calcdfor C 32 H 30 Cl2N2O4[M+H] + 577.1628,found 577.1661.HPLC(80:20methanol:water with 1‰TFA):t R =11.6min,96.7%.

[0281] Example 57:

[0282] 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-((4-chloro-3-methylphenyl)(3-chloro-4-ethynylbenzyl)amino)-1H-pyrrole-2-carboxylic acid (Compound 57)

[0283]

[0284] This product was prepared according to Example 1 from 3-methyl-4-chlorobromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-2-carboxylate, and 4-(bromomethyl)-2-chloro-1-ethynylbenzene. It is a yellow solid with a yield of 54% and a melting point of 152 - 153 °C. 11H NMR (300 MHz, CDCl3) δ 7.46 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.00–6.90 (m, 2H), 6.78 (dd, J = 17.2, 2.3 Hz, 2H), 6.67–6.55 (m, 3H), 4.66 (s, 2H), 4.51 (t, J = 6.4 Hz, 2H), 3.83 (t, J = 4.9 Hz, 2H), 3.39 (s, 1H), 2.35 (s, 6H), 2.28 (s, 5H). HRMS (ESI): calcd for C 32 H 29 Cl3N2O3 [M+Na] + 617.1141, found 617.1165. HPLC (80:20 methanol:water with 1‰ TFA): t R = 12.5 min, 98.1%.

[0285] Example 58:

[0286] 1-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-4-((3-chloro-4-ethynylbenzyl)(m-tolyl)amino)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (Compound 58)

[0287]

[0288] This product was prepared from 3-methyl-4-chlorobromobenzene, 4-chloro-3,5-dimethylphenol, 1,3-dibromopropane, ethyl 4-nitro-1H-pyrrole-3,5-dimethyl-2-carboxylate, and 4-(bromomethyl)-2-chloro-1-ethynylbenzene according to Example 1. It is a yellow solid with a yield of 37% and a melting point of 168 - 169 °C. 1 1H NMR (300 MHz, Chloroform-d) δ 7.27–7.19 (m, 3H), 7.12 (d, J = 3.3 Hz, 1H), 7.02–6.90 (m, 2H), 6.76 (s, 1H), 6.63 (s, 2H), 4.68 (s, 2H), 4.51 (t, J = 6.2 Hz, 2H), 3.83 (t, J = 5.3 Hz, 2H), 2.35 (s, 6H), 2.28 (s, 6H), 1.32 (s, 3H), 0.98–0.86 (m, 2H). HRMS (ESI): calcd for C 34 H 34 Cl2N2O3 [M+Na] +611.1844, found 611.1850. HPLC (80:20 methanol:water with 1‰ TFA): t R = 13.7 min, 98.5%.

[0289] Example of activity test:

[0290] 1. Use fluorescence polarization method (FP experiment) to test the inhibitory activities of the compound against Mcl-1, Bcl-2 and Bfl-1

[0291] Use the FP method to test the inhibitory activities of the target compound against Mcl-1, Bcl-2 and Bfl-1. For Mcl-1 protein, the final protein concentration is 20 nM, and the selected probe is FITC-Bak-BH3 with a probe concentration of 10 nM; for Bcl-2 protein, the final protein concentration is 20 nM, the probe is Fam-Bid, and the final probe concentration is 0.66 nM; for Bfl-1 protein, the final protein concentration is 13.3 nM, the probe is Fam-Bid, and the final probe concentration is 0.33 nM. The test uses a 384-well black plate (model Corning 3676), and the final test volume is selected as 40 μL. The tested compound and the FITC-9merNrf2 polypeptide fluorescent probe are dissolved in DMSO (10 mmol stock solution) for standby. The compound is serially diluted 11 concentration gradients with HEPES buffer. Add 20 μL of the diluted compound to each well plate, and then sequentially add 10 μL of the 10 nM probe diluted with buffer and 10 μL of 12 nM protein. Set two replicates for each compound concentration. The experiment sets a blank control (10 μL probe + 40 μL buffer, denoted as Pmin) and a negative control (10 μL probe + 10 μL protein + 20 μL buffer, denoted as Pmax). Then incubate on a shaker at room temperature for 30 min, and scan the plate with a SpectraMax Multi-Mode Microplate Reader (Molecular Devices). Set the excitation wavelength to 485 nm and the emission wavelength to 535 nm. The reading of the test well is denoted as Pobs. The inhibition rate calculation formula is: Inhibition rate (%) = [1 - (Pobs - Pmin) / (Pmax - Pmin)] × 100%. Use Graphpad Prism 6.0 software to calculate IC 50 . Ki is calculated according to the following formula:

[0292] K i = [I] 50 / ([L] 50 / K d + [P]0 / K d + 1)

[0293] Among them, [I]50 represents the half inhibitory concentration of the compound, [L]50 represents the probe concentration, [P]0 represents the protein concentration, and Kd represents the dissociation constant of the protein and the probe.

[0294] The test results show that most compounds have nanomolar inhibitory activity against Mcl-1. The results are shown in Table 1.

[0295] Table 1

[0296]

[0297] 2. Selectivity of Bcl-2 family subtypes of representative compounds

[0298] The inhibition rate results of the compounds against Bcl-2, Bfl-1, and Bcl-xL at a concentration of 10 μM show that the active compounds Compound 41, Compound 51, and Compound 52 have good subtype selectivity. The results are shown in Table 2.

[0299] Table 2 Evaluation of Bcl-2 subtype selectivity of representative compounds

[0300]

[0301] The results show that none of our compounds have obvious inhibitory activity against the three Bcl-2 subtypes Bcl-2, Bcl-xL, and Bfl-1 at a concentration of 10 μM. Subsequently, we selected Compound 52 and used the Bcl-2scan technology of DiscoveryX company to evaluate the affinity selectivity of the compound for Bcl-2 family proteins. The results are as Figure 1 shown. Figure 1 The results show that the affinity of Compound 52 for Mcl-1 reaches a high affinity at the low nanomolar level (K d = 0.063 nM), and the selectivity for other Bcl-2 subtypes Bcl-2, Bcl-xL, Bcl-w, and Bcl-2A1 exceeds 10 6 times (K d ≥ 10000 nM).

[0302] 3. Evaluation of in vitro anti-tumor activity of representative compounds

[0303] After confirming the target activity and subtype selectivity of the representative compounds, we then evaluated the in vitro anti-tumor activities of Compounds 41, 51, and 52. Using the Mc-1 inhibitor A1210477 reported by AbbVie as a positive control, the in vitro anti-tumor activities of the compounds against Mcl-1 sensitive cell lines, namely human myeloma cell line H929, human leukemia cell line MV4-11, human breast cancer cell line SX-BR3, and human non-small cell lung cancer cell line NCI-H23, were evaluated using the Methylthiazolyldiphenyl-tetrazolium bromide (MTT) method. At the same time, the anti-proliferative activities of the compounds against the Mcl-1 insensitive cell line, human leukemia cell line K562, were evaluated using the MTT method. The results are shown in Table 3.

[0304] Table 3 Evaluation of the in vitro anti-tumor activities of representative compounds

[0305]

[0306] The MTT assay results showed that all compounds had good anti-proliferative activities against the H929 cell line, and Compound 52 showed better anti-proliferative activity than the positive drug A1210477. For the MV4-11 cells, the activities of all compounds decreased, but Compound 52 still maintained low micromolar activity. The anti-proliferative activities of all compounds against SX-BR3 and NCI-H23 decreased significantly, which was consistent with the previously reported decrease in anti-proliferative activity of Mcl-1 inhibitors against solid tumors. All compounds had poor activities against the Mcl-1 insensitive strain K562, indicating that the compounds had good cell selectivity.

[0307] 4. Evaluation of the anti-tumor activity of Compound 52 in the MV4-11 nude mouse xenograft model

[0308] We constructed an MV4-11 balb / c nude mouse model to evaluate the in vivo anti-tumor activity of Compound 52. Selecting the clinically candidate compound AZD5991 targeting Mcl-1 reported by AstraZeneca as a positive control, Compound 52 was administered by gavage and intraperitoneal injection, and AZD5991 was administered intraperitoneally once every two days for 14 days. The results are as Figure 2 , Compound 52 could significantly inhibit tumor growth in nude mice. The T / C of the oral administration group (80 mg / kg) reached 8.2%; the T / C of the intraperitoneal administration group of Compound 52 (20 mg / kg) reached 1.0%, which was better than the activity of the intraperitoneal administration group of AZD5991 (20 mg / kg) (T / C = 3.3%). During the administration process, Compound 52 did not cause obvious changes in the body weight of nude mice and the weights of the heart, liver, and kidneys.

Claims

1. A 4-amino-1H-pyrrole compound, with the general structural formula as follows: R1 is selected from phenyl, 2-pyridyl, 1-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-cyclopropylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-tert-butylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-acetylphenyl, 3-nitrophenyl, 3-cyanophenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-(1-hydroxyethyl)phenyl, 3,4-dimethylphenyl, and 3-methyl-4-chlorophenyl; R2 is selected from 3-thienyl, 1-naphthyl, 2-naphthyl, phenyl, 2-chlorophenyl, 2-methylphenyl, 3-chloromethyl, 3-methylphenyl, 4-chlorophenyl, 4-methylphenyl, 3-bromophenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-aldehydephenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-biphenyl, 1-phenyl-1H-1,2,3-triazol-4-yl, 4-ethynylphenyl, 4-propynylphenyl, 3,4-dimethylphenyl, 3-bromo-4-methylphenyl, 3,4-dichlorophenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3-chloro-4-phenylphenyl, and 3-chloro-4-ethynylphenyl; R3 and R4 are each independently selected from a hydrogen atom or an unsubstituted C1-C5 alkyl group.

2. Use of the 4-amino-1H-pyrrole compound according to claim 1 for the preparation of an Mcl-1 inhibitor drug.

3. Use of the 4-amino-1H-pyrrole compound according to claim 1 for the preparation of an anti-tumor drug.

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