WO2019085441A1 - Immune cell migration inhibitor - Google Patents

Abstract

An immune cell migration inhibitor provided by the present invention has a structure represented by the following equation: the inhibitor has balanced hydrophilic and lipophilic properties, and can be easily developed into eye drops and externally applied ointments. The inhibitor has strong inhibition to immune cell migration, can relieve most of dry eye symptoms, and can alleviate eczematous dermatitis and psoriasis.

Description

Immune cell migration inhibitor Technical field

The present invention relates to the field of pharmacy, and in particular to an immune cell migration inhibitor.

Background technique

Many local diseases are related to inflammation, such as irritant contact dermatitis, eczema dermatitis, seborrheic dermatitis, scar formation, atopic dermatitis, psoriasis, etc. in hair care diseases; detachment associated with hair loss; ophthalmologic inflammation or Immune diseases such as intraocular inflammation, periocular inflammation, ocular surface inflammation, keratoconjunctivitis, keratoconjunctivitis sicca (KCS, also known as dry eye), KCS in patients with Sjogren syndrome, allergic conjunctivitis, ocular pigmentation Inflammation, inflammation of the eye caused by wearing a contact lens, corneal inflammation caused by wearing a contact lens, inflammation of the periocular tissue caused by wearing a contact lens, inflammation of the eye after surgery, inflammation of the eye, retinitis, edema, retinopathy, corneal inflammation Graves disease (Basedow disease) or Graves eye disease; in addition, graft-versus-host disease (GVHD) and the like.

Psoriasis and eczema are associated with systemic immune system disorders. Therefore, when the symptoms are severe, systemic medications, such as TNF-alpha antibody inhibitors (such as adalimumab (Humira), infliximab, certolizumab, and golimumab), interleukin IL-12 antibody inhibitor infliximab, interleukin IL-4 antibody inhibition Agent Dupilumab, T cell inhibitory antibody efalizumab and the like. These systemic medications have obvious effects, but at the same time, they systematically inhibit the immune system, causing side effects. For example, patients who are taking drugs are susceptible to viruses and bacterial diseases, allergic reactions, a few serious cancers, or high fatality. The viral infection is "progressive multifocal leukoencephalopathy (PML)".

For the above reasons, topical dry eye disease, mild-to-moderate psoriasis and eczema, topical medication is preferred. There are only a limited number of patients with dry eye syndrome in the world (cyclosporine, Lifitegrast, etc.) but there are no topical drugs approved for the treatment of dry eye in China, and the external use of psoriasis and eczema is mainly hormones and cyclosporine. Wait, there are strong side effects on the skin. Therefore, it is very necessary to invent and test a drug for treating local inflammatory diseases with high efficiency and low side effects, which can benefit a large part of patients.

Summary of the invention

The present invention aims to overcome the above drawbacks and to provide a novel immune cell migration inhibitor.

The present invention provides an immune cell migration inhibitor characterized by the structure shown by the following equation:

or

R _{1 is} selected from the group consisting of aryl, heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl;

R ₂ is any optionally substituted halogen, alkyl, cyano, alkoxy, nitro;

R _{3 is} selected from the group consisting of aryl, heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl;

X is selected from CR ₄ R ₅ , NR ₆ , O, CO (ie,

), SO _n ;

Y is selected from CR ₇ and N;

Z is selected from CR ₈ R ₉ , (CR ₈ R ₉ ) ₂ , CO (ie,

);

U is selected from C and N;

W is selected from the group consisting of CR ₁₀ , N, NR ₁₁ , O;

V is selected from the group consisting of CR ₁₂ , N, NR ₁₃ , O;

I is selected from CR ₁₄ R ₁₅ , CO (ie,

);

Wherein n is selected from 0, 1, 2;

m is selected from 0 and an integer (eg: 1, 2, 3...);

R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₄ , R _{15 are} selected from hydrogen, alkyl, substituted alkyl;

R ₁₀ , R _{12 is} selected from the group consisting of hydrogen, alkyl, halogen, cyano, alkoxy;

R ₁₁ , R _{13 is} selected from the group consisting of hydrogen and alkyl;

X-Y, Z-U, U-W, W-V are connected by single or double bonds;

Y-Z is connected by a single bond or a double bond, or there is no chemical bond between Y-Z (ie, an acyclic structure).

The alkyl group may be a linear alkyl group, a branched alkyl group, a cycloalkyl group, a heterocycloalkyl group or the like, and the above alkyl group is preferably an alkyl group having a carbon number of not more than 6, such as a methyl group, an ethyl group, or a propyl group. , isopropyl, n-butyl, isobutyl, cyclopentyl, N-heterocyclopentyl (

), cyclohexyl, N-heterocyclohexyl (

);

The alkenyl group may be a linear alkenyl group, a branched alkenyl group, a cycloalkenyl group, a heterocycloalkenyl group or the like, and the above alkenyl group is preferably an alkenyl group having a carbon number of not more than 6, such as a vinyl group, a propenyl group or an allylic group. Base, butenyl, cis-butadienyl, cyclohexenyl, N-heterocyclohexenyl (

);

The above substituted alkyl group preferably has one or more hydrogen atoms on the alkane chain having a carbon chain length of not more than 6 being an aryl group, a heteroaryl group, a cyano group or a hydroxy group; for example, a benzyl group, a 4-hydroxy-benzyl group, 2-phenyl-ethyl, ethanoyl, hydroxymethyl, etc.;

The above substituted alkenyl group preferably has one or more hydrogen atoms on the olefin chain having a carbon chain length of not more than 6 being an aryl group, a heteroaryl group, a cyano group or a hydroxy group; for example, 2-phenyl-vinyl group, 2- (4-hydroxy-phenyl)-vinyl, etc.;

The above alkoxy group may be a linear alkoxy group, a branched alkoxy group or the like, such as a methoxy group, an ethoxy group or a propoxy group;

The above aryl group is selected from an aromatic system consisting of one or more five-, six-, seven-membered aromatic rings, and one or more hydrogens on the aromatic ring may be an alkyl group, an aryl group, a cyano group, a nitro group, an amino group, or a hydroxyl group. Substituted with a halogen or the like, which is preferably selected from the group consisting of phenyl, naphthyl, anthracenyl, 2-hydroxyphenyl, 6-methyl-naphthyl and the like;

The above heteroaryl group is selected from an aromatic system consisting of one or more five-, six-, seven-membered aromatic rings, wherein one or more carbon atoms on the aromatic ring are replaced by nitrogen, oxygen, sulfur, and one on the aromatic ring. The plurality of hydrogens may be substituted with a group such as an alkyl group, an aryl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a halogen or the like, which is preferably selected from the group consisting of N-pyridyl, quinolyl, p-hydroxypyridyl, 2-methyl- Quinoline and the like.

Further, the present invention provides an immune cell migration inhibitor, which further has the following characteristics: that is, a compound preferably selected from G1, G2, G3, G4, G5;

Wherein, the above G1 compound is a structure represented by the following equation:

The above G2 compound is a structure shown by the following equation:

The above G3 compound is a structure shown by the following equation:

The above G4 compound is a structure shown by the following equation:

The above G5 compound is a structure shown by the following equation:

Further, the present invention provides an immune cell migration inhibitor having the following characteristics: (S)-2-(8-chloro-2-(benzofuran-6-carbonyl)-2,3- Dihydro-1H-pyrrole[3,2,1-ij]quinazolin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(pyrazole[1,5-a]pyridine-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(1H-indol-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(1H-indol-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(1H-indole-4-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(3-hydroxyphenyl-1-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7 -carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(3-methyl-1H-indole-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]isoquinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S,E)-2-(8-chloro-2-(3-(2-hydroxyphenyl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S,E)-2-(8-chloro-2-(3-(furan-3-yl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S,E)-2-(8-chloro-2-(3-(furan-2-yl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S,E)-2-(8-chloro-2-(3-(thiophen-2-yl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(naphthalene-2-formyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]isoquinazoline-7-carboxamide Benzyl-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(benzofuran-2-yl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(5-chloro-7-((3-hydroxybenzyl)carbamoyl)-1H-indole-4-carboxamido)-3-(3-(methylsulfonyl)phenyl Propionic acid

(S)-2-(8-chloro-2-(benzofuran-6-carbonyl)-2,3,5,6-tetrahydro-1H-pyrrole[3,2,1-ij]-quinazoline -7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(1H-indol-6-carbonyl)-2,3,5,6-tetrahydro-1H-pyrrole[3,2,1-ij]isoquinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(3-hydroxybenzyl)-1-oxo-2,3,5,6-tetrahydro 1H-pyrrole[3,2,1-ij]-quinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

(S)-2-(8-chloro-2-(3-hydroxybenzyl)-3-oxo-2,3-dihydro 1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid.

Further, the present invention provides an immune cell migration inhibitor, which is further characterized in that the preparation method of the above G1 compound is:

Dimethyl 2-aminoterephthalate is halogenated to obtain an intermediate product 1;

The intermediate product is obtained by bromination or iodo, alkynylation to obtain intermediate product 2;

The intermediate product 2 forms an intermediate product three by a cyclization reaction;

The intermediate product 3 is sequentially subjected to hydrolysis, reduction, and amination reaction to obtain an intermediate product IV;

The intermediate product is subjected to a ring formation reaction to obtain an intermediate product five;

The intermediate product five is hydrolyzed and amidated to obtain an intermediate product six;

The intermediate product is deprotected, amidated, and hydrolyzed to obtain the target product G1;

Wherein, the above intermediate product is a 5- and/or 6-halogenated dimethylamino-terephthalate, and the structure thereof is as follows:

Alkyl is an alkyl group, preferably a methyl group;

The above intermediate product 2 is a compound represented by the following structure:

LG ₁ is a leaving group, preferably a macromolecule such as TMS;

The above intermediate product three is a five-membered benzene nitrogen-containing heterocyclic ring, and its structure is as follows:

The above intermediate product 4 is a compound represented by the following structure:

The above intermediate product 5 is a compound represented by the following structure:

Pro is an amino protecting group;

The above intermediate product six is a compound represented by the following structure:

LG ₂ is a leaving group, preferably a macromolecule such as Bn; the specific equation of the above steps is as follows:

Further, the present invention provides an immune cell migration inhibitor, which has the following characteristics: that is, the preparation method of the above G2 compound is as follows:

Compound A is subjected to reduction, deprotection, amidation, and hydrolysis to obtain a target product;

Wherein the above compound A is a compound represented by the following structure:

Pro is an amino protecting group and LG ₂ is a leaving group.

The specific equation for the above steps is as follows:

Further, the present invention provides an immune cell migration inhibitor, which has the following characteristics: that is, the preparation method of the above G3 compound is as follows:

Compound B-1 is subjected to amidation, hydrolysis, amidation, and hydrolysis to obtain a target product;

Wherein the compound B-1 is a compound represented by the following structure:

The alkyl group is an alkyl group, preferably a methyl group.

The specific equation for the above steps is as follows:

Further, the present invention provides an immune cell migration inhibitor, which has the following characteristics: that is, the preparation method of the above G4 compound is as follows:

Compound B-2 is subjected to amidation, hydrolysis, amidation, and hydrolysis to obtain a target product;

The preparation method of the above G5 compound is as follows:

Compound B-2 is subjected to amidation, reduction, ring formation, hydrolysis, amidation, hydrolysis to obtain a target product;

Wherein the compound B-2 is a compound represented by the following structure:

The alkyl group is an alkyl group, preferably a methyl group.

The specific equation of the above G4 step is as follows:

The specific equation of the above G5 step is as follows:

In the preparation of the above G1-G5 compound, the starting materials are all dialkyl ester compounds, preferably dimethyl ester compounds.

Further, the present invention provides an immune cell migration inhibitor, which is characterized in that the above-mentioned immune cell migration inhibitor is used for alleviating and treating dry eye disease, eczema dermatitis and psoriasis.

Further, the present invention provides a preparation for the production of an immune cell migration inhibitor, which is characterized by the following steps:

Step 1: mixing the above-mentioned immune cell migration inhibitor, sterile physiological saline and alkali;

Step 2, adding a buffer solution to the pH of the system is 6.75-7.25;

Step 3, continue to add sterile physiological saline, and bubbling nitrogen to the system for 0.5-3 hours after packaging;

Wherein, in step 1, the mass ratio of the above immune cell migration inhibitor, sterile physiological saline, and alkali is 1:10-25:0.01-0.5;

The mass ratio of the sterile physiological saline in the above steps 1 and 3 is 1:0.01-0.5.

Further, the present invention provides a preparation of another immune cell migration inhibitor, which is produced by mixing the following parts by mass:

The effects and effects of the present invention:

The immune cell migration inhibitor provided by the invention has balanced hydrophilicity and lipophilicity, and is easy to be developed into an eyedrop and a topical ointment. It has a strong inhibitory effect on immune cell migration, can alleviate most dry eye diseases, relieve eczema dermatitis and psoriasis. The mechanism is to locally inhibit the migration of T immune cells to the site of inflammation, and the activation of T immune cells, which will have far fewer side effects than corticosteroids and highly toxic cycloheximides.

Detailed ways

Embodiment 1.

(S)-2-(8-chloro-2-(benzofuran-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]quinazoline-7-carboxamide 3-(3-(methylsulfonyl)phenyl)propanoic acid

The specific reaction equation is as follows:

Step A: 2-Amino-5-chloroterephthalic acid dimethyl ester (Compound 1-1)

To a vigorously stirred solution of dimethyl 2-aminoterephthalate (10 g, 48 mmol) in isopropanol (1.5 L) was added NCS (7.34 g, 55 mmol). After the addition was completed, the reaction mixture was heated to reflux and reacted for 48 hours. After cooling to rt, EtOAc (EtOAc m. LCMS ESI (+) m/z: 244 (M+1). ^{1 H NMR (600MHz, CDCl3)} δ7.92 (s, 1H), 7.10 (s, 1H), 5.71 (brs, 2H), 3.92 (s, 3H), 3.90 (s, 3H).

Step B: 2-Amino-3-bromo-5-chloroterephthalic acid dimethyl ester (Compound 1-2)

NBS (5.09 g, 28.6 mmol) was added to a vigorously stirred solution of dimethyl 2-amino-5-chloroterephthalate (6.4 g, 26 mmol) in methanol (85 mL) . After the addition was completed, the reaction mixture was heated to 40 ° C for 3 hours. After cooling to rt, EtOAc (EtOAc m. LCMS ESI (+) m. ^{1 H NMR (600MHz, CDCl3)} δ7.92 (s, 1H), 6.48 (brs, 2H), 3.99 (s, 3H), 3.91 (s, 3H).

Step C: 2-Amino-3-(trimethylsilylethynyl)-5-chloroterephthalic acid dimethyl ester (Compound 1-3)

Pd(PPh ₃ ) ₂ Cl ₂ (1.75 g, 2.5 mmol), CuI (950 mg, 5 mmol) and trimethylsilylacetylene (10.6 mL, 75 mmol) were added to the vigorously stirred 2-amino group under a nitrogen atmosphere. A solution of dimethyl 3-bromo-5-chloroterephthalate (8.1 g, 25 mmol) in EtOAc (EtOAc)EtOAc. After cooling to room temperature. Filtration through celite, EtOAc (EtOAc) eluting elut elut elut elut elut elut elut 93%). LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ7.80 (s, 1H), 6.88 (brs, 2H), 3.87 (s, 3H), 3.84 (s, 4H), 0.24 (s, 9H). 13 C NMR (151MHz , DMSO) δ 166.00, 165.36, 149.66, 140.57, 131.70, 113.44, 111.11, 107.42, 106.28, 96.57, 52.91, 52.34, -0.35.

Step D: 5-Chloro-1H-indole-4,7-dicarboxylic acid methyl ester (Compound 1-4)

CuI (5.24 g, 27.6 mmol) was added to vigorously stirred 2-amino-3-(trimethylsilylethynyl)-5-chloroterephthalate (7.9 g) under nitrogen. , 23 mmol) of a solution of DMF (60 mL), and the reaction mixture was heated to 100 ° C for 5 hours. After cooling to room temperature. The mixture was filtered through EtOAc (EtOAc) (EtOAc)EtOAc. The filtrate was concentrated and the residue was purified EtOAcjjjjjjjj LCMS ESI (+) m/z: ^{1 H NMR (600MHz, DMSO)} δ11.64 (s, 1H), 7.76 (s, 1H), 7.61 (s, 1H), 6.62 (s, 1H), 3.97 (s, 6H).

Step E. 5-Chloro-4-(methoxycarbonyl)-1H-indole-7-carboxylic acid (Compound 1-5)

A solution of a solution of 5-chloro-1H-indole-4,7-dicarboxylate (3.93 g, 14.7 mmol) in THF (73 mL) The reaction mixture was acidified with EtOAc (EtOAc) (EtOAc)EtOAc. After filtration, the filtrate was evaporated to give crystals crystals crystals crystals LCMS ESI (+) m/z: 254 (M-1). ^{1 H NMR (400MHz, DMSO)} δ13.77 (brs, 1H), 11.53 (s, 1H), 7.74 (s, 1H), 7.54 (t, J = 2.8Hz, 1H), 6.59 (dd, J = 2.9 , 1.9 Hz, 1H), 3.96 (s, 3H).

Step F: 5-Chloro-7-(hydroxymethyl)-1hydro-indole-4-carboxylic acid methyl ester (Compound 1-6)

BH ₃ (1 M in THF, 28 mL) was added dropwise to THF stirred vigorously 5-chloro-4-(methoxycarbonyl)-1H-indole-7-carboxylic acid (3.54 g, 14 mmol) (70 mL) 0 ° C solution, after completion of dropwise addition, the reaction mixture was warmed to room temperature for 2 hours. It was quenched by the addition of methanol (20 mL). The solvent was concentrated, and the residue was crystalljjjjjjjjjjjjjjjjjjjjj The title product (2.68 g, 11.2 mmol, 80%) was obtained as a white solid. LCMS ESI (+) m/z: ^{1 H NMR (600MHz, DMSO)} δ11.46 (s, 1H), 7.50 (t, J = 2.7Hz, 1H), 7.20 (s, 1H), 6.60-6.50 (m, 1H), 5.45 (t, J =5.7 Hz, 1H), 4.81 (d, J = 5.7 Hz, 2H), 3.92 (s, 3H).

Step G: 5-Chloro-7-(azidomethyl)-1hydro-indole-4-carboxylic acid methyl ester (Compound 1-7)

DPPA (4g, 14.56mmol), DBU (3.4g, 22.4mmol) was added dropwise to the vigorously stirred 5-chloro-7-(hydroxymethyl)-1hydro-indole-4-carboxylic acid A under nitrogen. A solution of the lipid (2.68 g, 11.2 mmol) in THF (56 mL). Ethyl acetate (200 mL) was added, and the mixture was washed with EtOAc EtOAc. The mystery of 30% ethyl acetate eluted to give the desired product as a white solid (2.37 g, 9 mmol, 80%). LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ11.82 (s, 1H), 7.60 (t, J = 2.6Hz, 1H), 7.28 (s, 1H), 6.60 (s, 1H), 4.79 (s, 2H), 3.93 (s, 3H).

Step H: 5-Chloro-7-(aminomethyl)-1hydro-indole-4-carboxylic acid methyl ester (Compound 1-8)

PPh3 (2.59 g, 9.9 mmol) in THF (24 mL) was added dropwise to a vigorously stirred 5-chloro-7-(azidomethyl)-1 hydrogen-indole-4-carboxylic acid methyl ester under a nitrogen atmosphere. (2.37g, 9mmol) in THF (24mL) solution, the reaction mixture was reacted at room temperature for 16 h addition of H ₂ O (1.6mL), the mixture was further stirred at room temperature for 2 hours, added ethyl acetate (200 mL), the organic phase Drying over anhydrous sodium sulfate, EtOAc (EtOAc m. The desired product (1.82 g, 7.65 mmol 85%). LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ7.50 (d, J = 3.0Hz, 1H), 7.25 (s, 1H), 6.57 (d, J = 3.0Hz, 1H), 4.03 (s, 2H), 3.91 ( s, 3H)

Step I: 2-tert-Butyl 7-methyl 8-chloro-1H-pyrrole [3,2,1-ij]quinazoline-2,7(3H)-dicarboxylate (Compound 1-9)

K2CO3 (2.11 g, 15.3 mmol) and paraformaldehyde (252 mg, 8.42 mmol) were added to vigorously stirred 5-chloro-7-(aminomethyl)-1hydro-indole-4-carboxylic acid methyl ester (1.82 g). , 7.65 mmol) in methanol (76 mL). The reaction mixture was reacted at 40 ° C for 48 hours, then di-tert-butyl dicarbonate (5 g, 22.9 mmol) and triethylamine (1.53 g, 15.3 mmol). After stirring for 16 hours, the reaction mixture was evaporated. EtOAcjjjjjjjjjjjjjj The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut LCMS ESI (+) m. 1H NMR (600MHz, CDCl3) δ 7.23 (s, 1H), 7.03 (s, 1H), 6.69 (d, J = 2.6 Hz, 1H), 5.65 (s, 2H), 4.86 (s, 2H), 4.00 (s, 3H), 1.46 (s, 9H).

Step J: 2-tert-Butoxycarbonyl 8-chloro-2,3-dihydro 1H-pyrrole [3,2,1-ij]-quinazoline-7-carboxylic acid (Compound 1-10)

An aqueous solution of NaOH (2M, 5.36 mL, 10.72 mmol) was added to vigorously stirred 2-tert-butyl 7-methyl 8-chloro-1H-pyrrole [3,2,1-ij]quinazoline-2,7 ( 3H)-Dicarboxylic acid ester (1.87 g, 5.36 mmol) in methanol (53 mL), the reaction mixture was reacted at 80 ° C for 3 hours, and after cooling to room temperature, the reaction mixture was diluted with dichloromethane (200 mL). The aqueous solution of citric acid was adjusted to pH 3, the aqueous phase was extracted with methylene chloride, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. 1.71 g, 5.09 mmol 95%). LCMS ESI (+) m/z: ^{1 H NMR (600MHz, MeOD)} δ7.44 (d, J = 3.0Hz, 1H), 7.08 (s, 1H), 6.67 (d, J = 3.0Hz, 1H), 5.72 (s, 2H), 4.90 ( s, 2H), 1.48 (s, 9H).

Step K: (S)-2-(8-chloro-2-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7-A Amido)-3-(3-(methylsulfonyl)phenyl)propanoic acid benzyl ester (Compound 1-11)

Under a nitrogen atmosphere, HATU (1.15 g, 3 mmol) and DIPEA (1.12 g, 8.63 mmol) were added to vigorously stirred 2-tert-butoxycarbonyl 8-chloro-2,3-dihydro 1H-pyrrole [3,2 , 1-ij] quinazoline-7-carboxylic acid (968mg, 2.875mmol) in DMF (14mL), the reaction mixture was reacted at room temperature for 1 hour, then added (S) 2-amino-3-(3-(methylsulfonate) A solution of benzyl)phenyl)propanoic acid benzyl ester hydrochloride (1.17 g, 3.16 mmol) in EtOAc (EtOAc) The mixture was washed with EtOAc (EtOAc) 1.69 g, 2.59 mmol 90%). LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ8.92 (d, J = 8.0Hz, 1H), 7.95 (s, 1H), 7.90 (s, 1H), 7.80 (d, J = 7.8Hz, 1H), 7.69 ( d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 3.0 Hz, 1H), 7.42 - 7.32 (m, 5H), 7.00 (s, 1H), 5.94 (d, J = 2.9 Hz, 1H), 5.65 (q, J = 12.0 Hz, 2H), 5.21 (s, 2H), 4.96 (ddd, J = 10.7, 8.1, 4.9 Hz, 1H), 4.81 (s) , 2H), 3.35 (dd, J = 14.2, 4.9 Hz, 1H), 3.12 (dd, J = 10.7, 14.2 Hz, 1H), 3.10 (s, 3H), 1.38 (s, 9H).

Step L: (S)-2-(8-chloro-2,3-dihydro-1H-pyrrole[3,2,1-ij]isoquinazolin-7-carbonylamino)-3-(3-( Methanesulfonyl)phenyl)propanoic acid benzyl ester (Compound 1-12)

Add TFA (2 mL) to vigorously stirred (S)-2-(8-chloro-2-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole [3,2,1-ij] and A solution of quinazolin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid benzyl ester (1.3 g, 2 mmol) in dichloromethane (10 mL). The reaction mixture was concentrated to give the desired product (l.l, g. The product was used directly in the subsequent reaction without purification. LCMS ESI (+) m.

Step M: (S)-2-(8-Chloro-2-(benzofuran-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]quinazolin-7 -carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid benzyl ester (Compound 1-13)

Add HATU (418 mg, 1.1 mmol) and DIPEA (390 mg, 3 mmol) to a vigorously stirred solution of benzofuran-6-carboxylic acid (178 mg, 1.1 mmol) in DMF (5 mL). After 1 hour, (S)-2-(8-chloro-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7-carbonylamino)-3-(3- (Methanesulfonyl)phenyl)propanoic acid benzyl ester trifluoroacetate (649 mg, 1 mmol), the mixture was stirred and stirred at room temperature for 2 hr, ethyl acetate (100 mL) was added, then water (20 mL) After washing with water (20 mL), EtOAc EtOAc m. 0.95 mmol 95%). LCMS ESI (+) m/z: ^{1 H NMR (600MHz, DMSO)} δ8.95 (d, J = 8.0Hz, 1H), 8.16 (d, J = 2.0Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 7.8Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.69 (s, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.43 - 7.32 ( m, 5H), 7.28 (d, J = 7.6 Hz, 1H), 7.08 (s, 1H), 7.05 - 6.82 (m, 1H), 5.95 (s, 1H), 5.98 - 5.68 (m, 2H), 5.21. (s, 2H), 5.14 - 4.96 (m, 2H), 4.98 - 4.92 (m, 1H), 3.35 (dd, J = 14.6, 5.3 Hz, 1H), 3.13 (dd, J = 12.5, 9.5 Hz, 1H) ), 3.11 (s, 3H).

Step N: (S)-2-(8-Chloro-2-(benzofuran-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline- 7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propionic acid (compounds 1-14)

LiOH (0.8 mL, 0.5 M in water) was added to vigorously stirred (S)-2-(8-chloro-2-(benzofuran-6-carbonyl)-2,3-dihydro-1H-pyrrole [ a solution of 3,2,1-ij]quinazolin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid benzyl ester (250 mg, 0.359 mmol) in THF (3.6 mL) After the reaction mixture was allowed to react at room temperature for 1 hr, EtOAc (EtOAc m. LCMS ESI (+) m/z: ^{1 H NMR (600MHz, DMSO)} δ13.15 (brs, 1H), 8.84 (d, J = 8.3Hz, 1H), 8.21 (d, J = 2.1Hz, 1H), 7.94 (s, 1H), 7.84 ( t, J = 8.9 Hz, 2H), 7.76 (d, J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.60 - 7.40 (m, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 1.2 Hz, 1H), 7.10 - 6.90 (m, 1H), 6.18 (s, 1H), 5.92 (brs, 2H), 5.08 (brs , 2H), 4.93 - 4.76 (m, 1H), 3.39 (dd, J = 14.2, 4.2 Hz, 1H), 3.18 (s, 3H), 3.13 (dd, J = 13.9, 11.2 Hz, 1H).

Example 2

(S)-2-(8-chloro-2-(1H-indol-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of EtOAc m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.89 (brs, 1H), 11.39 (s, 1H), 8.78 (d, J = 8.2Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.53 – 7.46 (m, 1H), 7.46 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 7.03 - 6.93 (m, 1H), 6.52 (s, 1H), 6.13 (s, 1H), 5.99 – 5.78 (m, 2H), 5.14–4.95 (m, 2H), 4.85–4.69 (m, 1H), 3.30–3.26 (m, 1H), 3.12 (s, 3H), 3.10–3.03 (m, 1H) .

Example 3

(S)-2-(8-chloro-2-(pyrazole[1,5-a]pyridine-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was obtained according to the procedure of m. m. LCMS ESI (+) m/z: ^{1 H NMR (600MHz, DMSO)} δ12.89 (brs, 1H), 8.76 (d, J = 8.0Hz, 1H), 8.75 (d, J = 6.5Hz, 1H), 7.88 (s, 1H), 7.79 ( d, J = 8.3 Hz, 1H), 7.77 (d, J = 10.1 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.63 - 7.40 ( m, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.10 - 7.01 (m, 1H), 7.15 - 6.92 (m, 1H), 6.90 (s, 1H), 6.30 - 6.18 (m, 1H) , 6.17–6.06(m,1H),,6.06–5.93(m,1H),5.44–5.31(m,1H), 5.23–5.08(m,1H),4.82–4.74(m,1H),3.32(dd , J = 14.3, 4.3 Hz, 1H), 3.11 (s, 3H), 3.05 (dd, J = 13.5, 11.4 Hz, 1H).

Example 4

(S)-2-(8-chloro-2-(1H-indol-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of m. m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.88 (brs, 1H), 11.70 (s, 1H), 8.76 (d, J = 8.3Hz, 1H), 7.88 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.73–7.65 (m, 2H), 7.63–7.52 (m, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.12–7.06 (m, 2H), 6.95 (s, 1H), 6.13 (d, J = 2.4 Hz, 1H), 6.16 - 5.99 (m, 2H), 5.40 - 5.08 (m, 2H), 4.84 - 4.70 (m, 1H) ), 3.31–3.28 (m, 1H), 3.11 (s, 3H), 3.08–3.02 (m, 1H).

Example 5

(S)-2-(8-chloro-2-(1H-indole-4-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of m. m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.92 (brs, 1H), 11.42 (s, 1H), 8.78 (d, J = 8.2Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.45 (t, J = 2.6 Hz, 1H), 7.39 - 7.19 (m, 1H), 7.16 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.94 - 6.66 (m, 1H), 6.24 (s, 1H) ), 6.11(s, 1H), 6.06–5.50 (m, 2H), 5.34–4.83 (m, 2H), 4.83–4.75 (m, 1H), 3.33 (dd, J=14.0, 4.2 Hz, 1H), 3.12 (s, 3H), 3.07 (dd, J = 13.9, 11.2 Hz, 1H).

Example 6

(S)-2-(8-chloro-2-(3-hydroxyphenyl-1-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7 -carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.92 (brs, 1H), 9.81 (s, 1H), 8.77 (s, 1H), 7.88 (s, 1H), 7.79 (d, J = 7.9Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.52 - 7.36 (m, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.17 - 6.95 (m) , 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.78 - 6.74 (m, 1H), 6.71 (s, 1H), 6.12 (s, 1H), 6.04 - 5.57 (m, 2H), 5.20 - 4.82 (m, 2H), 4.82 - 4.72 (m, 1H), 3.47 - 3.42 (m, 1H), 3.12 (s, 3H), 3.07 (dd, J = 13.5, 11.5 Hz, 1H).

Example 7

(S)-2-(8-chloro-2-(3-methyl-1H-indole-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]isoquinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of m. m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.89 (brs, 1H), 8.78 (d, J = 8.3Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 7.8Hz, 1H), 7.70 ( d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.55 - 7.43 (m, 3H), 7.38 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.4) Hz, 1H), 7.15–6.95 (m, 1H), 6.13 (brs, 1H), 6.04–5.75 (m, 2H), 5.18–4.90 (m, 2H), 4.86–4.74 (m, 1H), 3.56 ( s, 2H), 3.33 (dd, J = 14.1, 4.2 Hz, 1H), 3.12 (s, 3H), 3.08 (dd, J = 13.9, 11.2 Hz, 1H), 2.05 (s, 3H).

Example 8

(S,E)-2-(8-chloro-2-(3-(2-hydroxyphenyl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of EtOAc m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.88 (brs, 1H), 10.08 (s, 1H), 8.73 (d, J = 8.2Hz, 1H), 7.87 (s, 1H), 7.83 (d, J = 15.5 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.56–7.43 (m, 1H), 7.32 (d, J = 14.6 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.03 (brs, 1H), 6.89 (d, J = 8.1) Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.11 (s, 1H), 6.07 - 5.79 (m, 2H), 5.31 - 4.94 (m, 2H), 4.82 - 4.73 (m, 1H) , 3.32 (dd, J = 14.1, 4.2 Hz, 1H), 3.11 (s, 3H), 3.05 (dd, J = 13.9, 11.1 Hz, 1H).

Example 9

(S,E)-2-(8-chloro-2-(3-(furan-3-yl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of EtOAc m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.91 (brs, 1H), 8.73 (s, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 7.79 (d, J = 7.8Hz, 1H), 7.76(s,1H), 7.69(d,J=7.7Hz,1H), 7.58(t,J=7.7Hz,1H),7.59–7.45(m,1H),7.49(t,J=14.8Hz,1H ), 7.21–6.96 (m, 2H), 7.03 (s, 1H), 6.11 (s, 1H), 6.09–5.80 (m, 2H), 5.27–4.93 (m, 2H), 4.81–4.71 (m, 1H) ), 3.32–3.27 (m, 1H), 3.11 (s, 3H), 3.05 (dd, J = 13.8, 11.1 Hz, 1H).

Example 10

(S,E)-2-(8-chloro-2-(3-(furan-2-yl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of EtOAc m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.91 (brs, 1H), 8.75 (d, J = 8.3Hz, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.40 (d, J = 15.1 Hz, 1H), 7.16–7.06(m,1H),7.06(s,1H),6.91(d,J=3.0Hz,1H),6.67–6.60(m,1H),6.10(s,1H),6.08–5.80(m, 2H), 5.25–4.93 (m, 2H), 4.84–4.71 (m, 1H), 3.32 (dd, J=14.0, 4.3 Hz, 1H), 3.11 (s, 3H), 3.04 (dd, J=14.0, 11.2Hz, 1H).

Example 11

(S,E)-2-(8-chloro-2-(3-(thiophen-2-yl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of EtOAc (m. LCMS ESI (+) m/z: 598 (M+l). ^{1 H NMR (600MHz, DMSO)} δ12.89 (brs, 1H), 8.74 (d, J = 8.2Hz, 1H), 7.88 (s, 1H), 7.79 (d, J = 7.7Hz, 1H), 7.74- 7.66 (m, 3H), 7.58 (t, J = 7.7 Hz, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.56 - 7.46 (m, 1H), 7.14 (dd, J = 4.9, 3.8 Hz) , 1H), 7.13 - 7.00 (m, 2H), 6.11 (s, 1H), 6.09 - 5.79 (m, 2H), 5.12 (d, J = 76.7 Hz, 2H), 4.83 - 4.70 (m, 1H), 3.32 (dd, J = 14.2, 4.3 Hz, 1H), 3.11 (s, 3H), 3.05 (dd, J = 13.9, 11.2 Hz, 1H).

Example 12

(S)-2-(8-chloro-2-(naphthalene-2-formyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]isoquinazoline-7-carboxamide 3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.90 (s, 1H), 8.79 (d, J = 8.3Hz, 1H), 8.07-7.98 (m, 4H), 7.89 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.67 - 7.56 (m, 3H), 7.48 (d, J = 8.1 Hz, 1H), 7.51 - 7.27 (m, 1H), 7.23 –6.77(m,1H), 6.12(s,1H), 6.05–5.69(m,2H),5.31–4.85(m,2H),4.84–4.71(m,1H),3.33(dd,J=14.0, 4.1 Hz, 1H), 3.12 (s, 3H), 3.07 (dd, J = 13.8, 11.2 Hz, 1H).

Example 13

(S)-2-(8-chloro-2-(benzofuran-2-yl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of mp. LCMS ESI (+) m/z:

^{1 H NMR (600MHz, DMSO)} δ12.90 (brs, 1H), 8.77 (d, J = 8.3Hz, 1H), 7.88 (s, 1H), 7.79 (d, J = 7.8Hz, 2H), 7.71 ( d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.56 (brs, 1H), 7.54 (s, 1H), 7.51 ( t, J = 7.8 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.09 (s, 1H), 6.13 (s, 1H), 6.11 - 5.94 (m, 2H), 5.34 - 5.03 (m , 2H), 4.84 - 4.74 (m, 1H), 3.30 (dd, J = 14.0, 4.0 Hz, 1H), 3.12 (s, 3H), 3.05 (dd, J = 13.9, 11.1 Hz, 1H).

Example 14

(S)-2-(5-chloro-7-((3-hydroxybenzyl)carbamoyl)-1H-indole-4-carboxamido)-3-(3-(methylsulfonyl)phenyl Propionic acid

The synthesis method is as follows:

Step O: 5-Chloro-7-((3-methoxybenzyl)carbamoyl)-1H-indole-4-carboxylic acid methyl ester (Compound 2-1)

HATU (418 mg, 1.1 mmol) and DIPEA (390 mg, 3 mmol) were added to a vigorously stirred solution of compound 1-5 (279 mg, 1.1 mmol) in DMF (5 mL). m-Methoxybenzylammonium (137 mg, 1 mmol) was added, and the mixture was stirred at room temperature for 2 hr, ethyl acetate (100 mL) was added, and then washed with water (20 mL), brine (20 mL) After drying, the residue was purified by EtOAc EtOAcjjjjjjj LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ11.60 (s, 1H), 9.36 (t, J = 5.7Hz, 1H), 7.86 (s, 1H), 7.50 (s, 1H), 7.26 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.94 (s, 1H), 6.83 (dd, J = 2.1, 7.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 4.52 (d, J = 5.8 Hz, 2H), 3.96 (s, 3H), 3.74 (s, 3H).

Compound 2-3 was prepared according to the procedure of Steps J and K of Example 1 using Compound 2-1 instead of Compound 1-9 to afford a pale yellow solid. LCMS ESI (+) m/z: 674 (M+1).

Step P: (S)-2-(5-chloro-7-((3-hydroxybenzyl)carbamoyl)-1H-indole-4-carboxamido)-3-(3-(methylsulfonyl) Phenyl) propionic acid (compounds 2-4)

BBr ₃ (1M solution in dichloromethane, 0.3 mL, 0.3 mmol) was added dropwise EtOAc (EtOAc m. After 2 hours, the reaction mixture was diluted with EtOAc EtOAc. (20 mg, 0.35 mmol, 35%). LCMS ESI (+) m/z: 570 (M+). ^{1 H NMR (600MHz, MeOD)} δ7.96 (s, 1H), 7.88 (d, J = 7.8Hz, 1H), 7.75 (d, J = 7.6Hz, 1H), 7.67 (s, 1H), 7.62 ( t, J = 7.7 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.82 (s, 1H), 6.69 (dd, J = 7.9, 1.2 Hz, 1H), 6.34 (d, J = 3.1 Hz, 1H), 5.15 (dd, J = 10.6, 4.6 Hz, 1H), 3.56 (dd, J = 14.2) , 4.6 Hz, 1H), 3.19 (dd, J = 14.2, 10.6 Hz, 1H), 3.07 (s, 3H).

Example 15

(S)-2-(5-chloro-7-((benzofuran-6-carboxamido)methyl)-1H-indole-4-carboxamido)-3-(3-(methylsulfonyl) Phenyl) propionic acid

The synthesis method is as follows:

Compound 3-4 was prepared according to the procedure of Step M, J, K and N of Example 1 to afford a pale yellow solid. LCMS ESI (+) m/z: 594 (M+1). ^{1 H NMR (600MHz, MeOD)} δ8.06 (s, 1H), 7.94 (s, 1H), 7.93 (d, J = 1.9Hz, 1H), 7.86 (d, J = 7.9Hz, 1H), 7.79 ( d, J = 8.2 Hz, 1H), 7.75 - 7.70 (m, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 3.1 Hz, 1H), 7.10 (s, 1H), 6.94 (d, J = 0.9 Hz, 1H), 6.32 (d, J = 3.1 Hz, 1H), 5.12 (dd, J = 10.4, 4.7 Hz, 1H), 4.83 (s, 2H), 3.54 (dd, J =14.2, 4.6 Hz, 1H), 3.19 (dd, J = 14.1, 10.5 Hz, 1H).

Example 16

(S)-2-(8-chloro-2-(benzofuran-6-carbonyl)-2,3,5,6-tetrahydro-1H-pyrrole[3,2,1-ij]-quinazoline -7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

The synthesis method is as follows:

Step Q: (S)-2-(8-chloro-2-(tert-butoxycarbonyl)-2,3,5,6-tetrahydro-1H-pyrrole[3,2,1-ij]-quinazoline -7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid benzyl ester (4-1)

Sodium cyanoborohydride (126 mg, 2 mmol) was added dropwise to a vigorously stirred solution of compound 1-11 (326 mg, 0.5 mmol) in acetic acid (5 mL). The reaction mixture was reacted at room temperature for 16 hours and then diluted with DCM (50 mL). The system was quenched with EtOAc (EtOAc)EtOAc. 262 mg, 0.4 mmol 80%). LCMS ESI (+) m/z: 654 (M+1).

The title compound was prepared according to the procedure of m. LCMS ESI (+) m. ^{1 H NMR (600MHz, MeOD)} δ7.93 (s, 1H), 7.92 (d, J = 2.1Hz, 1H), 7.85 (d, J = 7.6Hz, 1H), 7.79-7.67 (m, 3H), 7.60 (t, J = 7.7 Hz, 1H), 7.52 - 7.38 (m, 1H), 7.10 - 6.99 (m, 1H), 6.96 (d, J = 1.4 Hz, 1H), 5.02 (dd, J = 10.3, 4.5 Hz, 1H), 4.49 - 4.34 (m, 1H), 3.51 (dd, J = 14.2, 4.5 Hz, 1H), 3.16 (dd, J = 14.0, 10.5 Hz, 2H), 3.11 (s, 3H), 2.94–2.85 (m, 1H), 2.81-2.73 (m, 1H).

Example 17

(S)-2-(8-chloro-2-(1H-indol-6-carbonyl)-2,3,5,6-tetrahydro-1H-pyrrole[3,2,1-ij]isoquinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was obtained according to the title compound m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.85 (brs, 1H), 11.37 (s, 1H), 8.75 (d, J = 8.1Hz, 1H), 7.87 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.61 - 7.47 (m, 3H), 7.13 (d, J = 5.9 Hz, 1H), 7.09–6.91 (m, 1H), 6.51 (s, 1H), 4.77–4.34 (m, 4H), 3.31 (dd, J=14.1, 4.1 Hz, 2H), 3.16 (s, 3H), 3.15–3.08 ( m, 2H), 3.03 (dd, J = 13.9, 11.3 Hz, 1H), 2.72 - 2.56 (m, 2H).

Example 18

(S)-2-(8-chloro-2-(3-hydroxybenzyl)-1-oxo-2,3,5,6-tetrahydro 1H-pyrrole[3,2,1-ij]-quinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The synthesis method is as follows:

Compound 5-1 was prepared according to the procedure of Step 16 of Example 16 using Compound 3-1 instead of Compound 1-11 to give a white solid. LCMS ESI (+) m.

Step R: 8-Chloro-2-(3-hydroxybenzyl)-1-oxo-2,3,5,6-tetrahydro 1H-pyrrole [3,2,1-ij]-quinazoline-7- Methyl formate (5-2)

Add paraformaldehyde (4 mg, 0.128 mmol) and BEMP (0.4 mL, 1 M in THF) to a vigorously stirred solution of compound 5-1 (24 mg, 0.064 mmol) in DMA (1 mL). After the addition of TosCl (37 mg, 0.194 mmol), the reaction mixture was stirred at room temperature for 2 hours, then the reaction was quenched with water (5 mL). The residue was purified eluting with EtOAc EtOAc (EtOAc:EtOAc LCMS ESI (+) m/z: 387 (M-1).

Compound 5-4 was prepared according to the procedure of Steps J and K of Example 1 using Compound 5-2 instead of Compound 1-9 to afford a pale yellow solid. LCMS ESI (+) m.

The title compound was prepared according to the procedure of EtOAc (m. LCMS ESI (+) m. ^{1 H NMR (600MHz, MeOD)} δ7.93 (s, 1H), 7.86 (d, J = 8.0Hz, 1H), 7.72 (d, J = 7.6Hz, 1H), 7.61 (t, J = 7.8Hz, 1H), 7.46 (s, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.78 (s, 1H), 6.73 (dd, J = 8.1, 2.1 Hz, 1H), 5.03 (dd, J = 10.6, 4.6 Hz, 1H), 4.66 (s, 2H), 4.42 (q, J = 8.1 Hz, 2H), 3.65 - 3.60 (m, 1H), 3.52 (dd , J = 14.3, 4.4 Hz, 1H), 3.17 - 3.12 (m, 2H), 3.12 (s, 3H), 3.00 - 2.93 (m, 1H), 2.87 - 2.79 (m, 1H).

Example 19

(S)-2-(8-chloro-2-(3-hydroxybenzyl)-3-oxo-2,3-dihydro 1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

Step S: 5-Chloro-7-(((3-methoxybenzyl)amino)methyl)-1H-indole-4-carboxylic acid methyl ester (6-1)

Under a nitrogen atmosphere, a solution of PPh3 (26 mg, 0.99 mmol) in THF (0.5 mL) was added dropwise to vigorously stirred 5-chloro-7-(azidomethyl)-1hydro-indole-4-carboxylic acid methyl ester. (24 mg, 0.09 mmol) in THF (0.5 mL), EtOAc (EtOAc:EtOAc. Methanol (1 mL) was added, and the reaction mixture was added with sodium cyanoborohydride (23 mg, 0.36 mmol), and the mixture was stirred for 1 hr. After filtration, the filtrate was concentrated, EtOAcjjjjjjjjj LCMS ESI (+) m.

Step T: 8-Chloro-2-(3-hydroxybenzyl)-3-oxo-2,3-dihydro 1H-pyrrole [3,2,1-ij]-quinazoline-7-carboxylic acid methyl ester ( 6-2)

Triphosgene (30 mg, 0.1 mmol) and DBU (30 mg, 0.2 mmol) were sequentially added to vigorously stirred 5-chloro-7-(((3-methoxybenzyl)amino)methyl)-under a nitrogen atmosphere. A solution of 1H-indole-4-carboxylic acid methyl ester (30 mg, 0.0819 mmol) in dichloromethane (5 mL). After the reaction was carried out for 3 hours at room temperature, the reaction was quenched with EtOAc EtOAc (EtOAc) Elution with 30% ethyl acetate in EtOAc EtOAc (EtOAc) LCMS ESI (+) m/z: 385 (M-1).

Compound 6-4 was prepared according to the procedure of Steps J and K of Example 1 using Compound 6-2 instead of Compound 1-9 to afford a pale yellow solid. LCMS ESI (+) m.

The title compound was prepared according to the procedure of mp. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ9.45 (s, 1H), 7.88 (s, 1H), 7.82-7.78 (m, 2H), 7.69 (d, J = 7.8Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.8 Hz, 2H), 6.76 (d, J = 7.4 Hz, 1H), 6.73 (s, 1H), 6.68 (dd, J = 7.8, 2.6 Hz, 1H) ), 6.54 (s, 1H), 6.34 (s, 1H), 4.80 (s, 2H), 4.79 - 4.74 (m, 1H), 4.64 (s, 2H), 3.19 - 3.16 (m, 1H), 3.13 ( s, 3H), 3.10–3.05 (m, 1H).

Example 20

(S)-2-(9-chloro-2-(1H-indol-6-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepine [6,7,1 -hi]吲哚-8-carboxamido)-3-(3-(methylsulfonyl)phenyl)propionic acid

Step U: 9-chloro-1,2,3,4-tetrahydro-[1,4]diazepine [6,7,1-hi]indole-8-carboxylic acid methyl ester (7-1) A solution of compound 1-8 (80 mg, 0.336 mmol) in DMF (1.sub.5 mL) was added dropwise to a vigorously stirred suspension of NaH (27 mg, 0.675 mmol) of DCM (1. After the reaction mixture was stirred for 10 minutes at 0 °, a solution of 2-bromoethyl)diphenylphosphonium trifluoromethanesulfonate (200 mg, 0.451 mmol) in DCM (1.5 mL) After stirring for 4 hours, it was quenched with EtOAc EtOAc (EtOAc m. The desired product (78 mg, 0.295 mmol, 88%) LCMS ESI (+) m.

The compound 7 was prepared according to the procedure of Example 1 using the steps M, J, K and N in sequence instead of the compound 1-12, 1H-indole-6-carboxylic acid in place of the compound benzofuran-6-carboxylic acid. -5, a white solid was obtained. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.83 (brs, 1H), 11.28 (s, 1H), 8.81 (d, J = 8.2Hz, 1H), 7.90 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 2.5 Hz, 1H), 7.43–7.38 (m, 1H), 7.36 (s, 1H), 6.88 (brs, 1H), 6.78–6.58 (m, 1H), 6.49 (s, 1H), 6.22 (brs, 1H), 4.90 (brs, 2H), 4.84 - 4.75 (m, 1H), 4.41 (brs, 2H), 4.13 (brs, 2H), 3.34 (dd, J = 14.1, 4.1 Hz, 1H), 3.13 (s, 3H), 3.07 (dd, J = 13.9, 11.2 Hz, 1H).

Example 21

(S)-2-(9-chloro-2-(3-hydroxybenzyl)-1-oxo-1,2,3,4-tetrahydro-[1,4]diazepine [6,7, 1-hi]吲哚-8-carboxamido)-3-(3-(methylsulfonyl)phenyl)propionic acid (8-7)

Step V: 1-(2-((tert-Butoxycarbonyl)amino)ethyl)-5-chloro-1H-indole-4,7-dicarboxylic acid methyl ester (8-1)

Cs ₂ CO ₃ (1.95 g, 6 mmol) and compound 2-(tert-butoxycarbonylamino)ethyl bromide (896 mg, 4 mmol) were added to compound 1-4 (534 mg, 2 mmol) EtOAc (10 mL) After the reaction mixture was stirred at 80 ° C for 16 hours, it was filtered, and the filtered cake was washed with ethyl acetate. The filtrate was evaporated. The desired product (421 mg, 1.02 mmol 51%). LCMS ESI (+) m. ^{1 H NMR (400MHz, CDCl3)} δ7.71 (s, 1H), 7.20 (d, J = 2.9Hz, 1H), 6.69 (d, J = 3.1Hz, 1H), 4.48 (t, J = 6.0Hz, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.41 (q, J = 6.0 Hz, 2H), 2.05 (s, 1H), 1.40 (s, 9H).

The compound 8-2 was obtained according to the procedure of EtOAc (m.) LCMS ESI (+) m/z: 311 (M+1).

Step W: 9-Chloro-1-oxo-1,2,3,4-tetrahydro-[1,4]diazepine [6,7,1-hi]indole-8-carboxylic acid methyl ester (8 -3) A solution of the compound 8-2 (40 mg, 0.129 mmol) in acetic acid was stirred at 100 ° C for 16 hours, cooled to room temperature, the solution was concentrated, and the residue was purified by preparative thin layer chromatography, using 70% acetic acid of petroleum ether. Ethyl ester chromatography gave the desired product as a white solid (35 mg, 0.125 mmol, 95%). LCMS ESI (+) m.

Step X: 9-Chloro-2-(3-methoxybenzyl)-1-1-oxo-1,2,3,4-tetrahydro-[1,4]diazepine [6,7,1 -hi]吲哚-8-methyl formate (8-4)

A solution of compound 8-3 (35 mg, 0.125 mmol) in DMF (0.5 mL) wasEtOAc. After the reaction mixture was stirred for 10 minutes at 0, 3-methoxybenzyl bromide (59 mg, 0.336 mmol) was added dropwise to the reaction mixture, and the mixture was further stirred at room temperature for 2 hours, and quenched with saturated ammonium chloride solution. The mixture was extracted with EtOAc. EtOAc (EtOAc m. %). LCMS ESI (+) m/z: 399 (M-1).

The compound 8-6 was obtained according to the procedure of EtOAc (m.). LCMS ESI (+) m/z:

Compound 8-7 was prepared according to the procedure of Example 2, Step P, using Compound 8-6, Compound 2-3 to afford desired product 8-7 (10 mg, 0.0167 mmol). LCMS ESI (+) m/z: ^{1 H NMR (600MHz, DMSO)} δ9.41 (s, 1H), 8.84 (s, 1H), 7.89 (s, 1H), 7.80 (d, J = 7.9Hz, 1H), 7.78 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.46 (d, J = 3.1 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.77 ( d, J = 7.6 Hz, 1H), 6.75 (s, 1H), 6.68 (dd, J = 8.0, 1.7 Hz, 1H), 6.29 (d, J = 2.9 Hz, 1H), 4.84 - 4.63 (m, 3H) ), 4.30 (brs, 2H), 3.76 (brs, 2H), 3.35 (dd, J = 14.1, 4.1 Hz, 1H), 3.13 (s, 3H), 3.09 (dd, J = 14.0, 10.8 Hz, 1H) And a white solid by-product 8-8 (4 mg, 0.00594 mmol) LCMS ESI (+) m/z: ^{1 H NMR (600MHz, DMSO)} δ9.41 (s, 1H), 9.18-8.36 (m, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 7.77 (d, J = 7.7Hz, 1H ), 7.73–7.62 (m, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.75 (s) , 1H), 6.68 (dd, J = 8.0, 1.4 Hz, 1H), 4.75 (brs, 3H), 4.43 - 4.08 (m, 2H), 3.77 (brs, 2H), 3.32 - 3.00 (m, 5H).

Example 22

(S)-2-(8-chloro-6-fluoro-2-(1H-indol-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]isoquinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid

Step Y: 2-tert-Butyl 7-methyl 8-chloro-6-fluoro-1H-pyrrole [3,2,1-ij]quinazoline-2,7(3H)-dicarboxylate (Compound 9 -1)

1-Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (380 mg, 1.1 mmol) and acetic acid (120 mg, 2 mmol) under nitrogen. Add a solution of compound 9-1 (350 mg, 1 mmol) in EtOAc (2 mL). After the reaction mixture was stirred at room temperature for 1 hour, it was diluted with ethyl acetate. The mixture was washed with water and saturated aqueous sodium chloride, and the organic phase was dried over anhydrous sodium sulfate. The title product 9-1 (300 mg, 0.815 mmol, 82%). LCMS ESI (+) m.

Prepared according to Example 1 using the steps J, K, L, M and N in sequence, using compound 9-1 instead of compound 1-9, 1H-吲哚-6-carboxylic acid instead of compound benzofuran-6-carboxylic acid. Compound 9-6 gave a white solid. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.77 (brs, 1H), 11.40 (s, 1H), 8.92 (d, J = 8.1Hz, 1H), 7.87 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.54 - 7.44 (m, 3H), 7.11–6.95(m,2H), 6.53(s,1H), 5.79(s,2H), 5.20–4.96(m,2H),4.89–4.69(m,1H), 3.27(dd,J=14.1,4.9 Hz, 1H), 3.13 (s, 3H), 3.06 (dd, J = 14.0, 9.9 Hz, 1H).

Example 23

(S)-2-(8-chloro-2-(1H-indol-5-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid

The title compound was prepared according to the procedure of EtOAc m. LCMS ESI (+) m. ^{1 H NMR (600MHz, DMSO)} δ12.90 (s, 1H), 11.41 (s, 1H), 8.78 (d, J = 8.2Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.51 - 7.38 (m, 3H), 7.14 (d, J) = 8.2 Hz, 1H), 7.06–6.86 (m, 1H), 6.53 (s, 1H), 6.12 (s, 1H), 5.96–5.79 (m, 2H), 5.14–4.95 (m, 2H), 4.85– 4.74 (m, 1H), 3.34 (dd, J = 14.1, 4.1 Hz, 1H), 3.12 (s, 3H), 3.06 (dd, J = 13.8, 11.3 Hz, 1H).

Cell adhesion and inhibition experiments:

T-cell adhesion assay using human T lymphocyte strain Jurkat (ATCC TIB-152): goat anti-Human IgG (Fc specific) (Sigma I8885) was diluted to 10 μg/ml in PBS at 100 °L per well at 4 °C The cells were incubated for 12 hours in a /96 well plate. The liquid in the well plate was poured out, blocked with 200 uL of 1% BSA at 37 ° C for 90 minutes, and washed three times with PBS. 50 uL of 1 ug/mL ICAM-1 (containing 0.1% BSA, 0.01% Tween 20) was added to each well and incubated at 37 ° C for 3 hours. The plate was washed 3 times with assay buffer (20 mM HEPES pH 7.6, 140 mM NaCl, 1 mM MgCl ₂ , 1 mM MnCl ₂ , 0.2% glucose).

The Jurkat cytometer was centrifuged at 100-G, and the cells were resuspended in 37 ° C assay buffer (20 mM HEPES pH 7.6, 140 mM NaCl, 1 mM MgCl ₂ , 1 mM MnCl ₂ , 0.2% glucose) per mL of cell suspension. 2 μl of 1 mM of BCECF-AM was added. Incubate at 37 ° C for 30 minutes, and stir every 10 minutes during the incubation. After the incubation, the cells were washed with an assay buffer at 37 °C. The cells were suspended to a concentration of ⁶ x ^{10 6} /mL.

The inhibitor was diluted to a final concentration of 2X in assay buffer, and 50 uL of the compound solution and 60 uL of Jurkat cells were mixed at room temperature, and incubated at 37 ° C for 30 minutes. 100 μL/well of cells and inhibitor were added to the plate and incubated for 1 hour at room temperature. The total fluorescence was measured by a fluorometer: ex: 485; em: 530; cutoff: 530 to measure the total fluorescence. The plate was washed once with the assay buffer and the fluorescence was measured with a fluorometer: ex: 485; em: 530; cutoff:. Results obtained are plotted inhibition - concentration diagram, and the EC ₅₀ calculated by standard methods. Table 1 shows the partial EC ₅₀ values measured by this method.

Table 1: EC _{50 of} cell adhesion and inhibition

Application experiment example 1: eye drop preparation

The compound obtained in Example 2, 5.0 g (addition amount may also be 3.5 g, 4.5 g, 6 g, 8 g depending on the inhibitor) was added to 90 mL of sterile physiological saline, and 0.7 g (according to the inhibitor) Differently, the addition amount may also be 0.5 g, 1.0 g, 1.5 g) of NaOH, and the mixture is stirred to obtain a transparent solution; to the solution obtained above, a saturated aqueous solution of NaH ₂ PO ₄ is added until the pH of the solution is between 6.75 and 7.25. Sterile physiological saline was added to the obtained aqueous solution until the total volume reached 100.0 mL. The above solution was purged with nitrogen, and bubbled for 1 hour, and the resulting solution was sealed and stored at 5 ° C in the dark. Dispense into disposable eye drops bags, each containing 60 microL of formulation solution. The method and specific ratio of the formulation can also be adjusted as needed, depending on the nature of the particular compound and the requirements of the application.

Application Example 2: Ointment preparation

The following materials were mixed to prepare an ointment 1#: the compound obtained in Example 2, 1.0 g; PEG 400, 15 g; butylated hydroxytoluene: 0.02 g; Span 80 surfactant, 2 g; white wax, 10 g; white petrolatum 71.98g.

The following materials were mixed to prepare an ointment 2#: the compound obtained in Example 10, 1.5 g; PEG 900, 25 g; Span 80 surfactant, 0.9 g; white wax, 9.1 g; white petrolatum 78.3 g.

The following materials were mixed to prepare ointment 3#: compound obtained in Example 15, 1.0 g; PEG 200, 20 g; butylated hydroxytoluene: 0.01 g; Span 60 surfactant, 2 g; white wax, 7 g; white petrolatum 65g.

The following materials were mixed to prepare an ointment 4#: the compound obtained in Example 17, 1.2 g; PEG 400, 15 g; butylated hydroxytoluene: 0.01 g; Span 60 surfactant, 1 g; white wax, 10 g; white petrolatum 75g.

The following materials were mixed to prepare an ointment 5#: the compound obtained in Example 19, 2.0 g; PEG 100, 24 g; butylated hydroxytoluene: 0.02 g; Span 80 surfactant, 6 g; white wax, 15 g; white petrolatum 60g.

Claims (10)

1. An immune cell migration inhibitor characterized by the structure shown by the following equation:

   

   R _{1 is} selected from the group consisting of aryl, heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl;

   R ₂ is any optionally substituted halogen, alkyl, cyano, alkoxy, nitro;

   R _{3 is} selected from the group consisting of aryl, heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl;

   X is selected from the group consisting of CR ₄ R ₅ , NR ₆ , O, C0, SO _n ;

   Y is selected from CR ₇ and N;

   Z is selected from the group consisting of CR ₈ R ₉ , (CR ₈ R ₉ ) ₂ , C0;

   U is selected from N;

   W is selected from the group consisting of CR ₁₀ , N, NR ₁₁ , O;

   V is selected from the group consisting of CR ₁₂ , N, NR ₁₃ , O;

   I is selected from CR ₁₄ R ₁₅ , CO;

   Wherein n is selected from 0, 1, 2;

   R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₄ , R _{15 are} selected from hydrogen, alkyl, substituted alkyl;

   R ₁₀ , R _{12 is} selected from the group consisting of hydrogen, alkyl, alkoxy;

   R ₁₁ , R _{13 is} selected from the group consisting of hydrogen and alkyl;

   X-Y, Z-U, U-W, W-V are connected by single or double bonds;

   Y-Z is connected by a single button or a double button.
2. The immune cell migration inhibitor according to claim 1, which is a compound selected from the group consisting of G1, G2, G3, G4, and G5;

   Wherein, the G1 compound is a structure represented by the following equation:

   

   The G2 compound is a structure shown by the following equation:

   

   The G3 compound is a structure shown by the following equation:

   

   The G4 compound is a structure shown by the following equation:

   

   The G5 compound is a structure shown by the following equation:

   
3. An immune cell migration inhibitor according to claim 1 wherein:

   (S)-2-(8-chloro-2-(benzofuran-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]quinazoline-7-carboxamide Benzyl-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(pyrazole[1,5-a]pyridine-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(1H-indol-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(1H-indol-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(1H-indole-4-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(3-hydroxyphenyl-1-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7 -carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(3-methyl-1H-indole-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]isoquinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S,E)-2-(8-chloro-2-(3-(2-hydroxyphenyl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S,E)-2-(8-chloro-2-(3-(furan-3-yl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S,E)-2-(8-chloro-2-(3-(furan-2-yl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S,E)-2-(8-chloro-2-(3-(thiophen-2-yl)propanyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(naphthalene-2-formyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]isoquinazoline-7-carboxamide Benzyl-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(benzofuran-2-yl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(5-chloro-7-((benzofuran-6-carboxamido)methyl)-1H-indole-4-carboxamido)-3-(3-(methylsulfonyl) Phenyl) propionic acid;

   (S)-2-(8-chloro-2-(benzofuran-6-carbonyl)-2,3,5,6-tetrahydro-1H-pyrrole[3,2,1-ij]-quinazoline -7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(1H-indol-6-carbonyl)-2,3,5,6-tetrahydro-1H-pyrrole[3,2,1-ij]isoquinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(3-hydroxybenzyl)-1-oxo-2,3,5,6-tetrahydro 1H-pyrrole[3,2,1-ij]-quinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(3-hydroxybenzyl)-3-oxo-2,3-dihydro 1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(9-chloro-2-(1H-indol-6-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepine [6,7,1 -hi]吲哚-8-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(9-chloro-2-(3-hydroxybenzyl)-1-oxo-1,2,3,4-tetrahydro-[1,4]diazepine [6,7, 1-hi]吲哚-8-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-6-fluoro-2-(1H-indol-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]isoquinazoline Porphyrin-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;

   (S)-2-(8-chloro-2-(1H-indol-5-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]-quinazoline-7- Formamide)-3-(3-(methylsulfonyl)phenyl)propanoic acid.
4. An immune cell migration inhibitor according to claim 1, wherein the preparation method of the G1 compound is:

   The dialkyl 2-aminoterephthalate is halogenated to obtain an intermediate product 1;

   The intermediate product is obtained by bromination or iodo, alkynylation to obtain intermediate product 2;

   The intermediate product is bicyclically reacted to form an intermediate product three;

   The intermediate product 3 is sequentially subjected to hydrolysis, reduction, and amination reaction to obtain an intermediate product IV;

   The intermediate product is subjected to a ring formation reaction to obtain an intermediate product five;

   The intermediate product five is hydrolyzed and amidated to obtain an intermediate product six;

   The intermediate product is deprotected, amidated, and hydrolyzed to obtain the target product G1;

   Wherein, the intermediate product is a dialkyl 2-aminoterephthalate terephthalate at the 5-position and/or the 6-position, and the structure thereof is as follows:

   

   Alkyl is an alkyl group;

   The intermediate product 2 is a compound represented by the following structure:

   

   LG ₁ is a leaving group;

   The intermediate product three is a five-membered benzene nitrogen-containing heterocyclic ring, and its structure is as follows:

   

   The intermediate product four is a compound represented by the following structure:

   

   The intermediate product five is a compound shown by the following structure:

   

   Pro is an amino protecting group;

   The intermediate product six is a compound represented by the following structure:

   

   LG ₂ is a leaving group.
5. The immune cell migration inhibitor according to claim 1, wherein the preparation method of the G2 compound is as follows:

   Compound A is subjected to reduction, deprotection, amidation, and hydrolysis to obtain a target product;

   Wherein the compound A is a compound represented by the following structure:

   

   Pro is an amino protecting group and LG ₂ is a leaving group.
6. The immune cell migration inhibitor according to claim 1, wherein the preparation method of the G3 compound is as follows:

   Compound B-1 is subjected to amidation, hydrolysis, amidation, and hydrolysis to obtain a target product;

   Wherein the compound B-1 is a compound represented by the following structure:

   

   Alkyl is an alkyl group.
7. The immune cell migration inhibitor according to claim 1, wherein the preparation method of the G4 compound is as follows:

   Compound B-2 is subjected to amidation, hydrolysis, amidation, and hydrolysis to obtain a target product;

   The preparation method of the G5 compound is as follows:

   Compound B-2 is subjected to amidation, reduction, ring formation, hydrolysis, amidation, and hydrolysis to obtain the target product; wherein the compound B-2 is a compound represented by the following structure:

   

   Alkyl is an alkyl group.
8. An immune cell migration inhibitor according to any one of claims 1 to 7 wherein:

   The immune cell migration inhibitor is used to alleviate and treat dry eye disease, eczema dermatitis and psoriasis.
9. A preparation prepared by using an immune cell migration inhibitor according to any one of claims 1 to 7, which is produced by the following steps:

   Step 1. Mix the immune cell migration inhibitor, sterile physiological saline and alkali;

   Step 2, adding a buffer solution to the pH of the system is 6.75-7.25;

   Step 3, continue to add sterile physiological saline, and bubbling nitrogen to the system for 0.5-3 hours after packaging;

   Wherein, in step 1, the mass ratio of the immune cell migration inhibitor, sterile physiological saline, and alkali is 1:10-25:0.01-0.5;

   The mass ratio of the sterile physiological saline in the first step and the third step is 1:0.01-0.5.
10. A preparation prepared by using an immune cell migration inhibitor according to any one of claims 1 to 7, which is produced by mixing the following parts by mass: