WO2017129069A1 - Tetrahydroquinoline-related bicyclic compounds and use thereof - Google Patents

Abstract

The present invention falls within the field of chemical pharmaceutical techniques, and in particular provides the preparation of a tetrahydroquinoline-related bicyclic compound and use thereof, wherein the compound has the structure as shown in formula I. The compound and a pharmaceutically acceptable salt, an isomer, a racemate, a prodrug co-crystal complex, a hydrate and a solvate thereof can effectively regulate ROR receptors, and can be used to prepare drugs for treating related diseases regulated by ROR receptors, or can be used to prepare drugs for treating cancers, inflammatory diseases and autoimmune diseases.

Description

Tetrahydroquinoline-related bicyclic compounds and their applications Technical field

The invention relates to the technical field of chemical medicine, in particular to the preparation and application of a tetrahydroquinoline-related bicyclic compound.

Background technique

Retinoic acid receptor-related orphan receptor (ROR) is an important orphan receptor in the nuclear receptor family. The receptor family includes three subtypes, RORα, RORβ and RORγ. RORα is widely expressed in the liver, skeletal muscle, skin, lung, fat cell tissue, kidney, thymus, and brain. The expression of RORβ is very limited and is only expressed in the central nervous system. RORγ is expressed in liver, skeletal muscle, and adipocyte tissues, particularly in key cells in the immune system.

In the past few years, RORα and RORγ have attracted much attention due to their important role in the differentiation and development of helper T cell 17 (T _H 17). Found T _H 17 cells is a key regulator of immune pathology, thus regulating T _H 17 cells capable of modulating an immune system response. Interleukin-17 (IL-17) is a key pro-inflammatory cytokine in the development of inflammation and various autoimmune diseases, and is closely related to multiple sclerosis (MS) and rheumatoid arthritis (RA). Related. RORγ directly regulate IL-17 production and secretion of cytokines, it is a key factor in the development of T _H 17 cells. ROR family proteins inhibiting effective to inhibit T _H 17 cells, thereby regulating immune response, the drug multiple sclerosis, rheumatoid arthritis, psoriasis, clone disease, asthma, inflammatory bowel disease, lung disease and other diseases develop has great significance. It has been reported in the literature that ROR may be involved in the development and progression of inflammation and related tumors.

ROR is also able to regulate gene transcription in the absence of endogenous ligand ligation, and it has been found in the crystal structure test of the ligand binding domain of ROR that cholesterol and cholesterol sulfonate can enter the ligand pocket. Soon, a series of hydroxycholesterol derivatives were found to regulate the transcriptional activity of ROR. However, it is unclear whether these cholesterol derivatives are endogenous ligands for ROR. Subsequent studies have shown that a synthetic small molecule, T1317, binds to RORγ and RORα and regulates their activity, but this compound also interacts with at least four other nuclear receptors (LXRα/β, FXR, PXR). Thereby limiting its development as a drug for the treatment of immune diseases. A selective inverse agonist SR3335 of RORα, a reverse agonist SR1001 with dual effects on RORγ and RORα, and selective inverse agonists SR2211 and SR1555 of RORγ, which can inhibit interleukin-17 cells, are currently found. Differentiation. GlaxoSmithKline has published a series of patents that mention a class of aromatic amines that inhibit ROR receptors. It has also been reported that the natural products digoxin and ursolic acid can be used as selective regulators of RORγ and can inhibit the differentiation of interleukin-17 cells. However, further studies have shown that digoxin has strong side effects, and ursolic acid also has a role in the glucocorticoid receptor. These studies have shown that selective inhibitors of synthetic ROR have great potential as drugs for inhibiting the expression of interleukin-17.

Summary of the invention

One of the technical problems to be solved by the present invention is to provide a novel tetrahydroquinoline-related bicyclic compound having a novel structure.

The technical solution to solve the above technical problems is as follows:

A tetrahydroquinoline-related bicyclic compound having the structure shown in Formula I:

In formula I:

X is selected from: C, O or N;

Y is selected from: CO or SO ₂ ;

n is selected from: 0, 1 or 2;

R _{1 is} optionally selected from the group consisting of: C ₀ to C ₆ alkylene-R ₃ ;

R _{2 is} optionally selected from the group consisting of: C ₀ to C ₆ alkylene-R ₃ ;

R _{3 is} optionally selected from the group consisting of: H, cycloalkyl or heterocyclic;

The above cycloalkyl group is optionally selected from a saturated or unsaturated ring composed of 3 to 7 carbon atoms, and the cycloalkyl group is selected from 0, 1, 2 or 3, selected from halogen, C ₁ -C ₆ alkane. a group, a C ₁ -C ₆ haloalkyl group, a hydroxyl group, a cyano group, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ ～ C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ Alkyl-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ), or -N(R ₄ a SO ₂ -C ₁ -C ₆ alkyl group substituted; wherein R ₄ , R _{5 are each selected} from H or C ₁ -C ₆ alkyl; R _{6 is selected} from H or C ₁ -C ₆ alkyl;

The above heterocyclic group is optionally selected from 1 to 3 of a 5- or 6-membered heterocyclic ring selected from N, O or S heteroatoms, and the heterocyclic group is selected from 0, 1, 2 or 3 Halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )( R ₅ ), -C ₀ -C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ) -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ Or a -N(R ₄ )SO ₂ -C ₁ -C ₆ alkyl group; wherein R ₄ , R _{5 are each selected} from H or C ₁ -C ₆ alkyl; R _{6 is selected} from H or C ₁ ~C ₆ alkyl.

Preferably, the R ₁ and R _{2 are} independently selected from any one of the following groups:

1) methyl, ethyl, propyl, or butyl;

2) C ₀ - C ₆ alkylene-R ₃ ; said R _{3 is} independently selected from: H, cycloalkyl or heterocyclic; the cycloalkyl is selected from cyclobutane, cyclopentane , cyclohexane, cycloheptane, phenyl, naphthyl, benzyl, etc., wherein the cycloalkyl group is selected from the group consisting of fluorine, chlorine, bromine, iodine, and C ₁ -C ₆ alkane. a group, a C ₁ -C ₆ haloalkyl group, a hydroxyl group, a cyano group, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ ～ C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ Alkyl-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ) or -N(R ₄ ) Substituted with a SO ₂ -C ₁ -C ₆ alkyl group; wherein R ₄ and R _{5 are each selected} from H, methyl, ethyl, propyl or butyl; and R _{6 is selected} from H, methyl, ethyl, a propyl or butyl group; the heterocyclic group is selected from the group consisting of imidazolyl, triazolyl, pyrazolyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, iso Quinolinyl, porphyrin, 1H-carbazolyl, 1H-benzo[d]imidazolyl, 1H-indenyl, benzo[d][1,3]dioxole , Benzo [d] thiazolyl or H- pyrazol -3 (2H) - yl ketone and the like; said heterocyclyl is optionally selected from 2 or 3 fluoro, chloro, bromo, iodo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ -C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ) or -N (R ₄ )SO ₂ -C ₁ -C ₆ alkyl group substituted; wherein R ₄ , R _{5 are each selected} from H, methyl, ethyl, propyl, butyl; R _{6 is selected} from H, methyl , ethyl, propyl or butyl.

More preferably, the compound is selected from the group consisting of compounds of the formula IA or formula IB:

In the formula IA:

X is selected from: C, O or N;

Y is selected from: CO or SO ₂ ;

n is selected from: 0; 1 or 2;

R ₁ and R _{2 are} independently selected from the group consisting of methyl, ethyl, propyl, butyl or C ₀ -C ₆ alkylene-R ₃ ; said R _{3 is} independently selected from: H, cycloalkyl or a heterocyclic group; the cycloalkyl group is optionally selected from the group consisting of cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, naphthyl or benzyl; the cycloalkyl group is 0, 1, 2 or Three are selected from the group consisting of fluorine, chlorine, bromine, iodine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), —C ₀ —C ₆ alkylene-alkoxy, —C ₀ —C ₆ alkylene-COOR ₆ , —OC ₁ —C ₆ alkylene -N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , _{-SO 2 N (R 4) (} R 5) or _{-N (R 4) SO 2 -C} 1 ~ C 6 alkyl groups; wherein R _4, R ₅ optionally selected from H, methyl, ethyl, a propyl or butyl group; R _{6 is selected} from H, methyl, ethyl, propyl or butyl; the heterocyclic group is selected from the group consisting of imidazolyl, triazolyl, pyrazolyl, thienyl, oxazole , isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, porphyrinyl, 1H-carbazolyl, 1H-benzo[d] Azolyl, 1H-indenyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl or H-pyrazole-3(2H)-one; The heterocyclic group is selected from 0, 1, 2 or 3, and is selected from the group consisting of fluorine, chlorine, bromine, iodine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano and -N(R ₄ ). (R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ -C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ) or -N(R ₄ )SO ₂ -C ₁ -C ₆ alkyl group substituted; wherein R ₄ , R _{5 are} Selected from H, methyl, ethyl, propyl or butyl; R _{6 is selected} from H, methyl, ethyl, propyl or butyl;

In the formula IB:

X is selected from: C, O or N;

Y is selected from: CO or SO ₂ ;

n is selected from: 0; 1 or 2;

R ₁ and R _{2 are} independently selected from the group consisting of methyl, ethyl, propyl, butyl or C ₀ -C ₆ alkylene-R ₃ ; said R _{3 is} independently selected from: H, cycloalkyl or a heterocyclic group; the cycloalkyl group is optionally selected from the group consisting of cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, naphthyl or benzyl; the cycloalkyl group is 0, 1, 2 or Three are selected from the group consisting of fluorine, chlorine, bromine, iodine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), —C ₀ —C ₆ alkylene-alkoxy, —C ₀ —C ₆ alkylene-COOR ₆ , —OC ₁ —C ₆ alkylene -N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ) or -N(R ₄ )SO ₂ -C ₁ -C ₆ alkyl group substituted; wherein R ₄ and R _{5 are each selected} from H, methyl, ethyl, a propyl or butyl group; R _{6 is selected} from H, methyl, ethyl, propyl or butyl; the heterocyclic group is selected from the group consisting of imidazolyl, triazolyl, pyrazolyl, thienyl, oxazole , isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, porphyrinyl, 1H-carbazolyl, 1H-benzo[d] Azolyl, 1H-indenyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl or H-pyrazole-3(2H)-one; The heterocyclic group is selected from 0, 1, 2 or 3, and is selected from the group consisting of fluorine, chlorine, bromine, iodine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano and -N(R ₄ ). (R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ -C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ) or -N(R ₄ )SO ₂ -C ₁ -C ₆ alkyl group substituted; wherein R ₄ , R _{5 are} It is selected from H, methyl, ethyl, propyl or butyl; R _{6 is selected} from H, methyl, ethyl, propyl or butyl.

Most preferably, the compound is selected from any of the following compounds:

4-chloro-2-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

4-fluoro-N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzamide ,

2,6-Difluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

5-methyl-N-(1-(thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-sulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-7-yl)-5-methylthiophene-2-sulfonamide,

2-Chloro-4-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-sulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b][1,4 Dioxane-6-sulfonamide,

N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylthiophene- 2-sulfonamide,

N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzenesulfonamide,

N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)thiophene-2-sulfonamide,

N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-dihydro Benzo[b][1,4]dioxine-6-sulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-1-(4-(trifluoromethyl)phenyl) Sulfonamide,

N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(4-( Trifluoromethyl)phenyl)methanesulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzenesulfonamide,

N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-(trifluoromethyl) Phenylsulfonamide

N-(1-(2-(3,4-Dichlorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b ][1,4]dioxine-6-sulfonamide,

N-(1-(2-(2,4-dichlorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b ][1,4]dioxine-6-sulfonamide,

Methyl-4-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate,

Methyl-3-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate,

Methyl 2-(1-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(methylsulfonyl)benzenesulfonamide,

Methyl 4-((N-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoate,

Methyl 4-((N-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoate,

Methyl 3-((N-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfonyl)methyl)benzoate,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethoxy)benzenesulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-nitrobenzenesulfonamide,

2,4-Difluoro-N-(1-((3-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

2,4-Difluoro-N-(1-((4-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

Methyl 4-(((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)methyl)benzoate,

Methyl 3-(((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)methyl)benzoate,

Methyl 2-((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate,

Methyl 3-((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate,

Methyl 4-((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate,

2,4-Difluoro-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

N-(1-((4-(tert-butyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,4-difluorobenzene,

2,4-Difluoro-N-(1-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

2,4-Difluoro-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

2,4-Difluoro-N-(1-((4-methylbenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

2,4-Difluoro-N-(1-((4-(trifluoromethyl)benzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

2,4-Difluoro-N-(1-((2-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

2,4-Difluoro-N-(1-(2-(4-fluorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

4-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid,

3-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid,

2-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid,

4-((N-(1-(4-)4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoic acid,

3-((N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfonyl)methyl)benzoic acid,

3-(7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoic acid,

N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b][1,4] Oxecyclohexene-6-sulfonamide,

2,4-Difluoro-N-(1-(thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide,

Methyl 2-((7-(4-(trifluoromethoxy)phenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate,

Methyl 2-((7-((4-(methoxycarbonyl)phenyl)methylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate,

2-((7-(2,3-Dihydrobenzo[b][1,4]dioxine-6-sulfonyl)-3,4-dihydroquinolin-1(2H)- Methyl)sulfonyl)benzoate,

Methyl 2-((7-(3-chloro-2-fluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate,

2-((7-(2,6-Dichlorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoic acid,

Methyl 2-((7-((4-methoxyphenyl)sulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate,

Methyl 2-((7-((2,5-dimethoxyphenyl)sulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate,

2,4-Difluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonamide,

N-(1,2,3,4-tetrahydroquinolin-6-yl)-1-(p-tolyl)methanesulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b][1,4 Dioxane-6-sulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-sulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)cyclohexanesulfonamide,

N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)butane-1-sulfonamide,

2,4-Difluoro-N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonamide,

N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1-(p-tolyl)methanesulfonamide,

N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b][1,4] Oxecyclohexene-6-sulfonamide,

N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b][1,4] Oxecyclohexene-6-sulfonamide,

N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)butane-1-sulfonamide,

2-Fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide.

The present invention also provides a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate or solvate of the above compound.

Use of the above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal, complex, hydrate or solvate thereof for the preparation of a ROR receptor inhibitor.

Use of the above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate or solvate thereof for preparing a medicament for treating cancer, inflammatory disease or autoimmune disease .

Preferably, the cancer is selected from the group consisting of: acoustic neuroma, acral melanoma, acromegaly, acute eosinophilic leukemia, acute red leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute mononuclear cells. Leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumor, adrenocortical carcinoma, adrenal tumor, adult T cell leukemia/lymphoma, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma , ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid carcinoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical deformity rod-shaped tumor, B-cell chronic lymphocytic leukemia, B-cell Prolymphocytic leukemia, B cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone tumor, brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma in situ, chondroma, teeth Osteosarcoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, cranial Tumor, cutaneous t-cell lymphoma, cervical cancer, colon cancer, small round cell tumor, diffuse B-cell lymphoma, neuroepithelial tumor, dysgerminoma, embryonic cancer endocrine gland tumor, endoderm sinus tumor, esophagus Cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular astrocytoma, thyroid cancer, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone , glioma, glioblastoma multiforme, glioma, granulosa cell tumor, male cell tumor, gallbladder cancer, gastric cancer, hemangioblastoma, head and neck cancer, vascular epithelioma Malignant tumor, hepatocellular carcinoma, cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, fatal midline cancer, leukemia, testicular stroma Cell tumor, liposarcoma, lung cancer, lymphangioma, lymphoepithelial neoplasia, lymphoma, acute lymphangiosarcoma, lymphocytic leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer Non-small cell lung cancer, malt lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, marginal zone b-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, breast medullary carcinoma, medullary thyroid carcinoma, medullary canal Cell tumor, melanoma, meningioma, Merkel cell cancer, mesothelioma, metastatic cell carcinoma, mixed sputum tumor, mucinous tumor, multiple myeloma, muscle tissue tumor, sputum mucoid liposarcoma, mucus Tumor, mucinous sarcoma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, neuroma, ocular cancer, eosinophilic, optic nerve sheath meningioma, tumor, oral cancer, osteosarcoma, ovarian cancer, papillary thyroid carcinoma, tumor Paraganglioma, adult pineal cell tumor, pituitary cell tumor, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, peritoneal cancer, pancreatic cancer, pharyngeal carcinoma, renal cell carcinoma, renal pulp Carcinoid, retinoblastoma, rhabdomyosarcoma, rhabdomyosarcoma, rectal cancer, sarcoma, seminoma, trophoblastic tumor, skin cancer, small round cell tumor Small cell carcinoma, soft tissue sarcoma, somatostatin, spinal cord tumor, spleen marginal lymphoma, squamous cell carcinoma, synovial sarcoma, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer Transitional cell carcinoma, laryngeal cancer, urachal cancer, genitourinary cancer, prostate cancer, uterine cancer, verrucous cancer, visual pathway glioma, vulvar cancer or vaginal cancer.

Preferably, the inflammatory disease or autoimmune disease is selected from the group consisting of: inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, encephalomyelitis, myocarditis, nephritis, osteomyelitis, myositis , hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, asthma, allergic rhinitis, chronic Obstructive pulmonary disease, autoimmune disease, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenia, pulmonary hemorrhagic nephritis Syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, asthma, septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis , collagen-induced arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, allergic dermatitis, degenerative joint disease , Guillain - Barre syndrome, mycosis fungoides or acute inflammatory response.

The compounds of the present invention can be applied to various routes of administration when used, including but not limited to the following routes, oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, through lumbar puncture, menstrual Urethral, transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intra-abdominal, intrathecal, surgical implantation).

A pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate, solvate thereof, and optionally pharmaceutically acceptable Carrier or excipient.

Preferably, a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate, solvate thereof, together with one or more Other therapeutically active agents, and optionally pharmaceutically acceptable carriers or excipients.

Such other therapeutically active agents include, but are not limited to: (1) inhibitors of TNF-[alpha]; (2) non-selective COX-1 / COX-2 inhibitors; (3) COX-2 inhibitors; 4) Other inflammatory and autoimmune diseases for treatment, including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporin, tacrolimus, penicillium Amine, bucillamine, akitali, imidazoribine, clofibrate, ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclophosphamide , Lymphostat-B, BAFF/APRIL inhibitors, such as belimizumab; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist; (6) LTD4 receptor antagonist; (7) PDE4 inhibitor; (8) anti-histamine H1 receptor antagonist; (9) a1-adrenoceptor and a2-adrenoceptor agonist; (10) Anticholinergic; (11) adrenergic receptor agonist; (12) insulin-like growth factor type I (IGF-1) mimetic; (13) glucocorticoid; (14) kinase inhibitor, such as inhibitor Janus kinase (JAK 1 and / or JAK2 and / or JAK3 and / or TYK2) , p38 protein and IKK2; (15) B cell-targeted biological products, such as rituximab; (16) selective costimulatory modulators such as arbecept; (17) interleukin inhibitors, such as IL-1 inhibition Agent anazepacin, IL-6 inhibitor toci1izumab or sirukumab, IL-12/IL-23 inhibitor ustekinumab, IL-23 inhibitor guselkumab, and anti-IL-l7 antibody; (18) anti-GM-CSF Antibodies; (19) immunotherapy, such as antibodies against PD-1/anti-PD-L1, including pembrolizumab and nivolumab, and anti-CTLA4 antibodies, including ipilimum; (20) inhibitors of BET, such as GSK525762; 21) other neoplastic agents, such as fluorouracil, bevacizumab, irinotecan hydrochloride, capecitabine, cetuximab, ramucirumab, oxaliplatin, leucovorin, panitumumab, regorafenib, Ziv-aflibercept, trastuzumab, imatinib, sunitinib malate, sorafenib benzenesulfonate, paclitaxel, everolimus, erlotinib hydrochloride, gemcitabine hydrochloride, mitomycin C, dabrafenib, trametinib, lapatinib, ofatumumab, topotecan, doxorubicin hydrochloride, and ibrutinib.

The compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration employed. The compositions of the present invention can be administered by oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposome, and the like.

Oral compositions can be solid, gel or liquid. Examples of solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener, a flavoring agent and the like. Examples of binders include, but are not limited to, microcrystalline cellulose, dextrose solution, gum arabic, gelatin solution, sucrose, and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate And stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silica; examples of disintegrants include, but are not limited to, Sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar and carboxymethyl cellulose.

The compositions of the invention are administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection. The injection can be formulated into any conventional form, such as a liquid solution or suspension, a solid form or emulsion suitable for dissolution or suspension in a liquid prior to injection. Examples of pharmaceutically acceptable carriers which can be used in the injection of the present invention include, but are not limited to, aqueous carriers, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifiers, chelating agents And other pharmaceutically acceptable substances. Examples of the aqueous carrier include sodium chloride injection, lin format injection, isotonic glucose injection, sterile water injection, glucose and lactated Ringer's injection; examples of the non-aqueous carrier include fixed oil of plant origin, Cottonseed oil, corn oil, sesame oil and peanut oil; examples of the antimicrobial agent include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.; examples of isotonic agents include sodium chloride and glucose; buffers include phosphate And citrate.

The compositions of the invention may also be prepared as sterile lyophilized powders in which the compound is dissolved in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by standard solutions under standard conditions known to those skilled in the art. The bacteria are filtered, followed by lyophilization to give the desired preparation.

Advantageous Effects: (1) The present invention provides a novel structure of tetrahydroquinoline-related bicyclic compounds, which have a very good inhibitory effect on RORγ protein and can be used to develop new RORγ protein inhibitors; Such compounds are useful in the preparation of ROR gamma receptor inhibitors; or in the preparation of a medicament for the treatment of cancer, inflammatory diseases and autoimmune diseases.

DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the inhibitory activity of the compounds of Examples 1-68 on the RORγ protein.

Figure 2 is a graph showing the inhibitory activity of the compounds of Examples 1-68 on the level of RORγ cells.

detailed description

The invention is further explained in the following with reference to the specific examples, but the examples are not intended to limit the invention.

The chemical composition of the present invention, when any variable (e.g. R _1, R _2, etc.) appear in any component more than once defined, it is at each occurrence independently each occurrence of other definitions. Also, combinations of substituents and variables are allowed as long as such combinations stabilize the compound. A line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds which are chemically stable and which are readily synthesized from readily available starting materials by techniques in the art and the methods set forth below. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized. The phrase "optionally substituted with one or more substituents" is considered to be equivalent to the phrase "optionally substituted with at least one substituent" and in this case the preferred embodiment will have 0-3 substituents.

The terms "alkyl" and "alkylene" as used herein are meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C ₁ -C ₆ " in "C ₁ -C ₆ alkyl" includes a group having 1, 2, 3, 4, or 5 carbon atoms arranged in a straight chain or a branched chain. For example, "C ₁ -C ₆ alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.

The term "heteroaryl" as used herein denotes a stable monocyclic ring of up to 6 atoms in the ring or up to 6 atomic bicyclic carbocyclic rings in each ring, wherein at least one ring is an aromatic ring and contains from 1 to 4 Heteroatoms of O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, imidazolyl, triazolyl, pyrazolyl, indolyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl , pyrimidinyl, pyrrolyl. "Heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group for the definition of the following heteroaryl. In the case where the heteroaryl substituent is bicyclic and contains a ring which is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.

The term "heterocycle" or "heterocyclyl" as used herein, refers to a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups. group. "Heterocyclyl" thus includes the heteroaryl groups mentioned above, as well as the dihydrogenated and tetrahydrogenated analogs thereof. Further examples of "heterocyclyl" include, but are not limited to, imidazolyl, oxazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyridyl Azinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, l,4-dioxin Alkyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, Dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidine Alkyl, tetrahydrofuranyl and tetrahydrothiophenyl, and their N-oxides. The attachment of a heterocyclic substituent can be achieved by a carbon atom or by a hetero atom.

In one embodiment, the heterocyclic group is selected from the group consisting of imidazolyl, pyridyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidinone, 2-pyrrolidone, thienyl, oxazolyl, triazolyl, isomerism Azolyl.

As understood by those skilled in the art, "halogen" as used herein is meant to include chloro, fluoro, bromo and iodo.

Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents may be considered unsubstituted or substituted. For example, (C ₁ -C ₆ )alkyl may be substituted by one, two or three selected from OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like. Substituted.

The invention includes the free forms of the compounds of formula I, as well as the pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in a non-salt form. The pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. The free form of the particular salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate. Free form The solubility of the formula in certain physical properties, such as in polar solvents, is somewhat different from its respective salt form, but for the purposes of the present invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard. Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.

If the compound of the invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts. Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. A salt derived from a pharmaceutically acceptable organic non-toxic base, the base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as Arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxylamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine Azine, piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

Since the acidic moiety, such as a carboxyl group, which is deprotonated in a compound under physiological conditions, can be anionic, such charged charge can then be protonated or alkylated in the interior with a cationic moiety such as tetravalent The balance of nitrogen atoms is counteracted, so it should be noted that the compounds of the invention are potential internal salts or zwitterions.

In addition to the standard methods known in the literature or exemplified in the experimental procedures, the compounds of the invention can be prepared using the reactions as shown in the scheme below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituents are attached to a compound which allows multiple substituents under the definition of formula I above.

Preparation scheme of the compound of the invention

In the formula of the present invention, in the formula IA, Y is SO ₂ , and the definitions of R ₁ , R ₂ , n, and X are the same as defined above, and can be prepared by the following method (1):

In the formula of the present invention, in the formula IA, Y is CO, and the definitions of R1, R2, n, and X are the same as defined above, and can be prepared by the following method (2):

In the formula of the present invention, in the formula IB, Y is SO ₂ , and when the definitions of R1, R2, n, and X are the same as defined above, the method can be prepared by the following method (3):

In the formulas of the present invention, in the formula IB, Y is CO, and the definitions of R1, R2, n, and X are the same as defined above, and can be prepared by the following method (IV):

The invention is further described in the following examples, but this example is not intended to limit the scope of the invention.

Example 1 4-Chloro-2-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (4 -chloro-2-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 40 mg of the product was obtained. 1H NMR (400MHz, CDCl3) δ 7.84 (t, J = 8.2 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.26 - 7.24 (m, 2H) , 7.23 (s, 1H), 7.21 (s, 1H), 7.05 (m, 2H), 6.93 - 6.87 (m, 3H), 3.81 - 3.58 (m, 2H), 2.38 (t, J = 6.6 Hz, 2H ), 1.59–1.54 (m, 2H).

Step 1. Preparation of 7-nitro-1,2,3,4-tetrahydroquinoline

Take 1,2,3,4-tetrahydroquinoline (2g), dissolved in 20mL of DMF, placed in an ice bath, slowly added dropwise to the mixture by adding 10mL of H ₂ SO ₄ , reacted at 0 ° C for 1 hour, then added 5mL HNO ₃ , 0 ° C reaction for 5 hours, adding water, suction filtration, washing twice, to obtain a filter cake, EA / PE recrystallization, 1.9 g of product 7-nitro-1,2,3,4-tetrahydroquinoline .

Step 2. Preparation of 1-((4-fluorophenyl)sulfonyl)-7-nitro-1,2,3,4-tetrahydroquinoline

Taking 7-nitro-1,2,3,4-tetrahydroquinoline (500 mg), dissolved in 10 mL of pyridine, placed at 100 ° C, and added thiophene-2-sulfonyl chloride (762.6 mg) to the mixture, 100 The reaction mixture was stirred overnight with EtOAc EtOAc EtOAc.

Step 3. Preparation of 1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-amino group

Take 1-((4-fluorophenyl)sulfonyl)-7-nitro-1,2,3,4-tetrahydroquinoline (300 mg), dissolved in 20 mL of methanol, 10% palladium on carbon ( 30 mg) was added to the mixture, and the mixture was reacted at room temperature overnight.

Step 3. Preparation of 4-chloro-2-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide

Take 1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-amine (100 mg), dissolved in 10 mL of pyridine, placed at 100 ° C, 4 -Chloro-2-fluorobenzenesulfonyl chloride (100 mg) was added to the mixture, and the mixture was reacted at 100 ° C overnight, washed once with 10% hydrochloric acid, and extracted three times with ethyl acetate. Drying, column chromatography PE: EA gave 40 mg of product. 1H NMR (400MHz, CDCl3) δ 7.84 (t, J = 8.2 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.26 - 7.24 (m, 2H) , 7.23 (s, 1H), 7.21 (s, 1H), 7.05 (m, 2H), 6.93 - 6.87 (m, 3H), 3.81 - 3.58 (m, 2H), 2.38 (t, J = 6.6 Hz, 2H ), 1.59–1.54 (m, 2H).

Example 2 4-Fluoro-N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl) Preparation of 4-fluoro-N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzenesulfonamide)

Step 1. Preparation of 2H-benzo[b][1,4oxazin-3(4H)-one

2-Aminophenol (3.27g), TEBAC (6.8g), sodium bicarbonate (13g), dissolved in 100mL chloroform, placed in an ice bath, dissolved in chloroacetyl chloride with 5mL chloroform, slowly drip into the mixture After dripping for 30 min, reacting at 0 ° C for 1 hour, heating to 50 ° C for 16 hours, spinning off the solvent, adding water, suction filtration, washing twice with water to obtain a cake, EA/PE recrystallized to obtain 2.1 g of product (Compound 21- 1), the yield was 47%.

Step 2. Preparation

Take 1,2,3,4-tetrahydroquinoline (2g), dissolved in 20mL of DMF, placed in an ice bath, slowly added dropwise to the mixture by adding 10mL of H ₂ SO ₄ , reacted at 0 ° C for 1 hour, then added 5mL HNO ₃ , 0 ° C reaction for 5 hours, adding water, suction filtration, washing twice, to obtain a filter cake, EA / PE recrystallization, 1.9 g of product 7-nitro-1,2,3,4-tetrahydroquinoline .

Step 3. Preparation

Lithium tetrahydrogenate (1.7 g) was taken, dissolved in 5 mL of anhydrous tetrahydrofuran under ice bath, and the compound 19-1 (1.77 g) dissolved in anhydrous tetrahydrofuran was slowly added dropwise, and the mixture was subjected to argon gas and reacted at room temperature for 10 min. Heat to reflux for 4 hours. After cooling, it was quenched with a saturated sodium sulfate solution under ice-cooling, ethyl acetate was added, and filtered, and the filtrate was obtained, and column chromatography PE: EA=10:1 to obtain 1.58 g of product (compound 20-1). 97%.

Step 4. Preparation

Taking 7-nitro-1,2,3,4-tetrahydroquinoline (500 mg), dissolved in 10 mL of pyridine, placed at 100 ° C, and added thiophene-2-sulfonyl chloride (762.6 mg) to the mixture, 100 The reaction mixture was stirred overnight with EtOAc EtOAc EtOAc.

Step 5. Preparation

Take 1-((4-fluorophenyl)sulfonyl)-7-nitro-1,2,3,4-tetrahydroquinoline (300 mg), dissolved in 20 mL of methanol, 10% palladium on carbon ( 30 mg) was added to the mixture, and the mixture was reacted at room temperature overnight.

Step 6. Preparation

Take 7-amino-1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline (100 mg), dissolved in 10 mL of pyridine, placed at 100 ° C, and added (100 mg) The mixture was reacted at 100 ° C overnight, washed with 10% EtOAc EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 7.78 (dd, J = 7.9, 5.4 Hz, 2H), 7.57 (dd, J = 8.0, 5.2 Hz, 2H), 7.51 (s, 1H) ), 7.41 (q, J = 9.0 Hz, 4H), 6.80 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 3.85 (d, J = 4.2 Hz, 2H), 3.69 (d, J = 4.0 Hz, 2H).

Example 3 2,6-Difluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (2, Preparation of 6-difluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic procedure as in Example 1, 39 mg of product was obtained. 1H NMR (400MHz, CDCl3) δ 7.70 - 7.36 (m, 4H), 7.02 (dd, J = 20.5, 8.8 Hz, 5H), 6.93 (d, J = 8.0 Hz, 1H), 3.73 (m, 2H) , 2.39 (m, 2H), 1.58 (m, 2H).

Example 4 5-Methyl-N-(1-(thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-sulfonamide (5-methyl -N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-sulfonamide)

Using a synthetic method as in Example 1, 130 mg of the product was obtained. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.50 (d, J = 5.5Hz, 2H), 7.41 (d, J = 3.5Hz, 1H), 7.35 (d, J = 3.6Hz, 1H), 7.05 (d , J = 8.2 Hz, 1H), 7.00 (t, J = 4.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 3.0 Hz, 1H), 6.65 (s, 1H) ), 3.83–3.75 (m, 2H), 2.45 (d, J = 10.2 Hz, 5H), 1.70–1.62 (m, 2H).

Example 5 N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-7-yl)-5-methylthiophene-2-sulfonamide (N-( Preparation of 1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-methylthiophene-2-sulfonamide)

Using a synthetic method as in Example 1, 65 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.35 (s, 1H), 7.61 (dd, J = 8.5,5.1Hz, 2H), 7.54 (s, 1H), 7.36 (dd, J = 11.0,6.3Hz, 3H ), 6.96 (d, J = 8.2 Hz, 1H), 6.91 - 6.77 (m, 2H), 3.81 - 3.68 (m, 2H), 2.44 (s, 3H), 2.38 (t, J = 6.5 Hz, 2H) , 1.61–1.50 (m, 2H).

Example 6 2-Chloro-4-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (2 Of -chloro-4-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 35 mg of the product was obtained. 1H NMR (400MHz, CDCl3) δ 8.26 - 7.97 (m, 1H), 7.53 (s, 1H), 7.44 (m, 2H), 7.06 (dd, J = 20.3, 12.3 Hz, 4H), 6.89 (t, J = 6.2 Hz, 2H), 3.72 (d, J = 5.5 Hz, 2H), 2.38 (t, J = 6.3 Hz, 2H), 1.62 - 1.46 (m, 2H).

Example 7 N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-sulfonamide (N-(1-( Preparation of (4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-sulfonamide)

Using a synthetic procedure as in Example 1, 76 mg of product was obtained. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.61 (d, J = 3.6Hz, 1H), 7.59-7.53 (m, 3H), 7.52 (s, 31H), 7.12-7.01 (m, 3H), 6.96 ( q, J = 8.2 Hz, 2H), 6.68 (s, 1H), 3.87 - 3.63 (m, 2H), 2.44 (t, J = 6.6 Hz, 2H), 1.63 (dd, J = 12.2, 6.3 Hz, 2H ).

Example 8 N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b][ 1,4]Dihydrohexyl-6-sulfonyl (N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo Preparation of [b][1,4]dioxine-6-sulfonamide)

Using a synthetic method as in Example 1, 105 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.12 (s, 1H), 7.61-7.54 (m, 2H), 7.52 (s, 1H), 7.34 (t, J = 8.9Hz, 2H), 7.23 (d, J =11.0 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 4.24 (d, J = 5.2) Hz, 4H), 3.80–3.66 (m, 2H), 2.35 (t, J = 6.8 Hz, 2H), 1.61–1.47 (m, 2H).

Example 9 N-(4-((4-Fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-A N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylthiophene- Preparation of 2-sulfonamide)

Using a synthetic method as in Example 2, 31 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.17 (s, 1H), 7.66 (dd, J = 8.2,5.1Hz, 2H), 7.62 (s, 1H), 7.41 (t, J = 8.6Hz, 2H), 7.32 (d, J = 3.5 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.8 Hz, 1H), 3.87 (d, J = 4.0 Hz, 2H), 3.72 ( d, J = 4.0 Hz, 2H), 2.44 (s, 3H).

Example 10 N-(4-((4-Fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzenesulfonamide ( Preparation of N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzenesulfonamide)

Using a synthetic method as in Example 2, 93 mg of product was obtained. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.81 (d, J = 7.4Hz, 2H), 7.61-7.51 (m, 4H), 7.48 (t, J = 7.6Hz, 2H), 7.10 (t, J = 8.5 Hz, 2H), 6.87 (dd, J = 8.7, 2.5 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.44 (s, 1H), 3.85 - 3.80 (m, 2H), 3.76 - 3.69 (m, 2H).

Example 11 N-(4-((4-Fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)thiophene-2- Preparation of N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)thiophene-2-sulfonamide)

Using a synthetic method as in Example 2, 23 mg of product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 - 7.56 (m, 4H), 7.54 (d, J = 3.7 Hz, 1H), 7.13 (t, J = 8.4 Hz, 2H), 7.05 (t, J = 4.3 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.48 (s, 1H), 3.89 - 3.81 (m, 2H), 3.80 - 3.71 ( m, 2H).

Example 12 N-(4-((4-Fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3 -Dihydrobenzo[b][1,4]dioxine-6-sulfonamide-3,4-dihydro-2H-benzo[b-[4-(4-fluorophenyl)sulfonyl) Preparation of [1,4]oxazin-6-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide)

Using a synthetic method as in Example 2, 85 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ9.94 (s, 1H), 7.62 (dd, J = 8.7,5.1Hz, 2H), 7.57 (d, J = 2.3Hz, 1H), 7.39 (t, J = 8.7 Hz, 2H), 7.26–7.12 (m, 2H), 7.01 (d, J=8.4 Hz, 1H), 6.78 (dd, J=8.8, 2.4 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H) ), 4.24 (d, J = 4.3 Hz, 4H), 3.91 - 3.80 (m, 2H), 3.72 - 3.64 (m, 2H).

Example 13 N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-1-(4-(trifluoromethyl)benzene Of N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-1-(trifluoromethyl)phenyl)methanesulfonamide)

Using a synthetic method as in Example 1, 8 mg of the product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (dd, J = 8.4, 5.1 Hz, 2H), 7.65 - 7.56 (m, 3H), 7.49 (d, J = 7.9 Hz, 2H), 7.13 (t, J = 8.4 Hz, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.66 (s, 1H), 4.45 (s, 2H), 3.99 - 3.62 ( m, 2H), 2.52 (t, J = 6.5 Hz, 2H), 1.80 - 1.65 (m, 2H).

Example 14 N-(4-((4-Fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-( 4-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- Preparation of yl)-1-(4-(trifluoromethyl)phenyl)methanesulfonamide)

Using a synthetic method as in Example 2, 18 mg of the product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 - 7.69 (m, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.16 (t, J = 8.5 Hz, 2H), 6.95 (dd, J = 8.8, 2.6 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.64 (s, 1H) , 4.40(s, 2H), 3.92–3.80 (m, 4H).

Example 15 N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzenesulfonamide ( Preparation of N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzenesulfonamide)

Using a synthetic procedure as in Example 1, 32 mg of product was obtained. _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.02 (d, J = 7.0Hz, 2H), 7.70 (d, J = 7.0Hz, 2H), 7.55 (d, J = 24.1Hz, 4H), 7.05 (d , J = 7.1 Hz, 2H), 6.91 (s, 2H), 3.75 (s, 2H), 2.41 (s, 2H), 1.60 (s, 2H).

Example 16 N-(4-((4-Fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-( N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-( Method for preparing trifluoromethyl)benzenesulfonamide)

Using a synthetic procedure as in Example 2, 87 mg of product was obtained. ¹ H NMR (500MHz, CDCl ₃ ) δ 7.95 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.64 - 7.52 (m, 3H), 7.12 (t, J = 8.5 Hz, 2H), 6.85 (dd, J = 8.7, 2.5 Hz, 2H), 6.72 (d, J = 8.8 Hz, 1H), 3.86 - 3.79 (m, 2H), 3.78 - 3.69 (m, 2H).

Example 17 N-(1-(2-(3,4-Dichlorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzene And [b][1,4]dioxine-6-sulfonamide (N-(1-(2-(3,4-dichlorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7- Method for preparing yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide)

Step 1. Preparation of 7-nitro-1,2,3,4-tetrahydroquinoline

Take 1,2,3,4-tetrahydroquinoline (5g), dissolved in 20mL of DMF, placed in an ice bath, slowly added dropwise to the mixture by adding 10mL of H ₂ SO ₄ , reacted at 0 ° C for 1 hour, then added 5mL HNO ₃ , 0 ° C reaction for 5 hours, adding water, suction filtration, washing twice, to obtain a filter cake, EA / PE recrystallization, to give 5.1 g of the product 7-nitro-1,2,3,4-tetrahydroquinoline .

Step 2. Preparation of 2-(3,4-dichlorophenyl)-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone

3,4-Dichlorophenylacetic acid (68 mg) was added to DMF to dissolve, then HATU (152 mg) and DIPEA (1 mL) were added, stirred at room temperature for 30 min, then the compound 1-((4-fluorophenyl)sulfonyl)- 7-Nitro-1,2,3,4-tetrahydroquinoline (100 mg) was stirred overnight at room temperature. After completion of the reaction, the mixture was washed with EtOAc (EtOAc)EtOAc.

Step 3. Preparation of 1-(7-amino-3,4-dihydroquinolin-1(2H)-yl)-2-(3,4-dichlorophenyl)ethanone

Take 7-nitro-1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline (300 mg), dissolved in 20 mL of methanol, 10% palladium on carbon (30 mg) The mixture was added to the mixture, and the mixture was stirred at room temperature overnight.

Step 4. Preparation of N-(1-(2-(3,4-dichlorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrogen Benzo[b][1,4]dioxine-6-sulfonamide

Take 7-amino-1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline (100 mg), dissolved in 10 mL of pyridine, placed at 100 ° C, 5-methyl The thiophene-2-sulfonyl chloride (100 mg) was added to the mixture, and the mixture was reacted at 100 ° C overnight, washed with 10% hydrochloric acid, and extracted with EtOAc EtOAc. Chromatography of PE: EA gave 84 mg of product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.13 (s, 1H), 7.35 - 7.21 (m, 5H), 7.07 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.99 - 6.95 ( m,1H), 6.91 (dd, J=8.2, 1.9 Hz, 1H), 4.17 (s, 4H), 3.73 (s, 2H), 3.65 (t, J = 6.3 Hz, 2H), 2.51 (d, J) =6.6 Hz, 2H), 1.76 (p, J = 6.6 Hz, 2H).

Example 18 N-(1-(2-(2,4-Dichlorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzene And [b][1,4]dioxine-6-sulfonamide (N-(1-(2-(2,4-dichlorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7- Method for preparing yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide)

Using the synthetic procedure as in Example 17, the product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.12 (s, 1H), 7.34 - 7.19 (m, 5H), 7.07 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.97 (d, J = 9.1 Hz, 1H), 6.91 (dd, J = 8.2, 1.9 Hz, 1H), 4.18 (s, 4H), 3.74 (s, 2H), 3.66 (t, J = 6.3 Hz, 2H), 2.51 ( d, J = 7.0 Hz, 2H), 1.76 (p, J = 6.6 Hz, 2H).

Example 19 Methyl 4-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfonyl)benzoate Preparation method of 4-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate)

Using a synthetic method as in Example 1, 96 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.44 (s, 1H), 8.10 (d, J = 8.3Hz, 2H), 7.88 (d, J = 8.3Hz, 2H), 7.51 (dd, J = 8.6,5.2 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 7.33 (t, J = 8.7 Hz, 2H), 6.93 (d, J = 8.1 Hz, 1H), 6.88 - 6.75 (m, 1H), 3.84(s,3H), 3.79–3.63 (m, 2H), 2.35 (t, J=6.7 Hz, 2H), 1.59–1.44 (m, 2H).

Example 20 Methyl 3-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfonyl)benzoate Preparation of 3-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate)

Using a synthetic method as in Example 1, 80 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.41 (s, 1H), 8.34 (s, 1H), 8.16 (d, J = 7.6Hz, 1H), 7.99 (d, J = 7.8Hz, 1H), 7.72 ( t, J = 7.8 Hz, 1H), 7.58 - 7.40 (m, 3H), 7.31 (t, J = 8.6 Hz, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.0) Hz, 1H), 3.85 (s, 3H), 3.76 - 3.63 (m, 2H), 2.33 (t, J = 6.4 Hz, 2H), 1.51 (dd, J = 11.7, 6.1 Hz, 2H).

Example 21 Methyl 2-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate Preparation of 2-(N-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate)

Using a synthetic procedure as in Example 1, 38 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.12 (s, 1H), 8.39 (d, J = 7.4Hz, 1H), 8.21 (d, J = 7.5Hz, 1H), 8.12 (d, J = 7.5Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 22.9 Hz, 3H), 7.67 (d, J = 5.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 1H) , 6.84 (d, J = 8.2 Hz, 1H), 3.85 (s, 7H), 3.71 (s, 3H), 2.61 (d, J = 6.7 Hz, 3H), 2.34 (d, J = 6.3 Hz, 2H) .

Example 22 N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(methylsulfonyl)benzenesulfonamide ( Preparation of N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(methylsulfonyl)benzenesulfonamide)

Using a synthetic method as in Example 1, 85 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.48 (s, 1H), 8.27 (s, 1H), 8.20 (d, J = 7.7Hz, 1H), 8.07 (d, J = 7.7Hz, 1H), 7.87 ( t, J = 7.8 Hz, 1H), 7.49 (dd, J = 13.0, 8.0 Hz, 3H), 7.34 (t, J = 8.5 Hz, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.84 ( d, J = 8.0 Hz, 1H), 3.79 - 3.60 (m, 2H), 3.25 (s, 3H), 2.34 (t, J = 6.2 Hz, 2H), 1.61 - 1.41 (m, 2H).

Example 23 4-((N-(1-(4-)4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoic acid Preparation of Methyl-4-((N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoate)

Using a synthetic method as in Example 1, 50 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ9.93 (s, 1H), 7.93 (d, J = 8.1Hz, 2H), 7.76 (dd, J = 8.6,5.2Hz, 2H), 7.56 (s, 1H), 7.42 (t, J = 8.6 Hz, 4H), 7.03 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 4.54 (s, 2H), 3.86 (s, 3H), 3.81–3.73 (m, 2H), 2.43 (t, J = 6.6 Hz, 2H), 1.62 (dd, J = 12.0, 6.1 Hz, 2H).

Example 24 3-((N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfonyl)methyl)benzoic acid Preparation of methyl ester

Using a synthetic procedure as in Example 1, 73 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ9.89 (s, 1H), 7.93 (d, J = 6.0Hz, 1H), 7.87 (s, 1H), 7.75 (s, 2H), 7.58 (s, 1H), 7.51 (d, J = 6.4 Hz, 2H), 7.40 (t, J = 8.3 Hz, 2H), 7.02 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 4.55 ( s, 2H), 3.85 (s, 3H), 3.78 (s, 2H), 2.43 (s, 2H), 1.61 (s, 2H).

Example 25 N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethoxy)benzenesulfonamide Preparation of (N-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethoxy)benzenesulfonamide)

Using a synthetic method as in Example 1, 50 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.40 (s, 1H), 7.89 (d, J = 8.8Hz, 2H), 7.57 (d, J = 8.6Hz, 2H), 7.51 (dd, J = 8.8,5.2 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.34 (t, J = 8.7 Hz, 2H), 6.95 (d, J = 8.3 Hz, 1H), 6.85 (dd, J = 8.1, 1.9 Hz, 1H), 3.82–3.60 (m, 2H), 2.35 (t, J = 6.5 Hz, 2H), 1.53 (dt, J = 12.3, 6.2 Hz, 2H).

Example 26 N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-nitrobenzenesulfonamide (N-(1) -((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-nitrobenzenesulfonamide)

Using a synthetic method as in Example 1, 95 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.60 (s, 1H), 8.38 (d, J = 8.4Hz, 2H), 8.00 (d, J = 8.4Hz, 2H), 7.58-7.47 (m, 2H), 7.44 (s, 1H), 7.35 (t, J = 8.5 Hz, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 3.78 - 3.62 (m, 2H) ), 2.36 (t, J = 6.3 Hz, 2H), 1.58 - 1.44 (m, 2H).

Example 27 2,4-Difluoro-N-(1-((3-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (2, Preparation of 4-difluoro-N-(1-((3-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 30 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.60 (s, 1H), 7.87 (s, 1H), 7.52 (s, 1H), 7.40 (s, 2H), 7.22 (s, 2H), 6.98 (d, J =23.6 Hz, 3H), 6.79 (s, 1H), 4.51 (s, 2H), 3.37 (s, 2H), 2.51 (s, 2H), 1.61 (s, 2H).

Example 28 2,4-Difluoro-N-(1-((4-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (2, Preparation of 4-difluoro-N-(1-((4-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic procedure as in Example 1, 42 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.59 (s, 1H), 7.87 (dd, J = 14.9,8.3Hz, 1H), 7.53 (t, J = 8.9Hz, 1H), 7.39 (s, 1H), 7.29–7.12 (m, 5H), 7.02 (d, J=8.2 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 4.48 (s, 2H), 3.45–3.36 (m, 2H), 2.57 (t, J = 6.3 Hz, 2H), 1.68 - 1.52 (m, 2H).

Example 29 Methyl 4-(((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)methyl)benzoate Preparation of (methyl 4-((7-(2,4-difluorophenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)methyl)benzoate)

Using a synthetic method as in Example 1, 9 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.60 (s, 1H), 7.92 (d, J = 8.0Hz, 2H), 7.89-7.82 (m, 1H), 7.53 (t, J = 9.2Hz, 1H), 7.39 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.4) Hz, 1H), 4.58 (s, 2H), 3.86 (s, 3H), 3.41 (s, 2H), 2.55 (d, J = 6.2 Hz, 2H), 1.61 (s, 2H).

Example 30 Methyl 3-(((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)methyl)benzoate Preparation

Using a synthetic procedure as in Example 1, 28 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.60 (s, 1H), 8.03-7.79 (m, 2H), 7.67 (s, 1H), 7.51 (s, 2H), 7.42 (s, 2H), 7.22 (s , 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 4.59 (s, 2H), 3.83 (s, 3H), 3.34 (s, 2H), 2.50 (s, 2H), 1.56 (s, 2H).

Example 31 Methyl 2-((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate (methyl 2- Preparation of (7-(2,4-difluorophenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)

Using a synthetic method as in Example 1, 21 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.61 (s, 1H), 7.83 (dd, J = 15.2,8.5Hz, 1H), 7.73 (t, J = 7.5Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.50 (dd, J = 18.3, 9.0 Hz, 2H), 7.37 (s, 1H), 7.22 (t, J = 8.3 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 3.75 - 3.58 (m, 5H), 2.39 (t, J = 6.6 Hz, 2H), 1.53 - 1.42 (m) , 2H).

Example 32 Methyl 3-((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate (methyl 3- Preparation of (7-(2,4-difluorophenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)

Using a synthetic procedure as in Example 1, 38 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.65 (s, 1H), 8.19 (d, J = 7.7Hz, 1H), 7.98 (s, 1H), 7.85 (dd, J = 14.9,8.3Hz, 1H), 7.71–7.55 (m, 2H), 7.55–7.43 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 7.8 Hz) , 1H), 3.86 (s, 3H), 3.77–3.64 (m, 2H), 2.31 (t, J = 6.4 Hz, 2H), 1.58–1.41 (m, 2H).

Example 33 Methyl 4-((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate (methyl 4- Preparation of (7-(2,4-difluorophenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)

Using a synthetic procedure as in Example 1, 38 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.64 (s, 1H), 8.00 (d, J = 8.2Hz, 2H), 7.86 (dd, J = 14.9,8.4Hz, 1H), 7.55 (t, J = 11.2 Hz, 3H), 7.46 (s, 1H), 7.24 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.88 ( s, 3H), 3.80–3.66 (m, 2H), 2.32 (t, J = 6.6 Hz, 2H), 1.58–1.44 (m, 2H).

Example 34 2,4-Difluoro-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzene Preparation of 2,4-difluoro-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 50 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.67 (s, 1H), 8.22 (d, J = 7.8Hz, 1H), 8.03 (s, 1H), 7.86 (dd, J = 14.8,8.1Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.50 (dd, J = 19.3, 9.3 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 3.76 (s, 2H), 3.25 (s, 3H), 2.32 (t, J = 6.2 Hz, 2H), 1.60–1.44 (m, 2H).

Example 35 N-(1-((4-(tert-butyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,4-difluorobenzene ( Preparation of N-(1-((4-(tert-butyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,4-difluorobenzenesulfonamide)

Using a synthetic method as in Example 1, 21 mg of the product was obtained. ¹ H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 7.78 (s, 1H), 7.51 (d, J = 34.5 Hz, 4H), 7.29 (d, J = 38.8 Hz, 3H), 6.88 ( d, J = 28.8 Hz, 2H), 3.80 (s, 2H), 2.33 (s, 2H), 1.50 (s, 2H), 1.26 (s, 9H).

Example 36 2,4-Difluoro-N-(1-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (2,4- Preparation of difluoro-N-(1-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 7.5 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.65 (s, 1H), 8.26 (s, 1H), 8.10 (s, 2H), 7.82 (d, J = 29.8Hz, 2H), 7.70-7.43 (m, 3H ), 7.37 (s, 1H), 7.24 (s, 1H), 7.09 (s, 1H), 6.85 (s, 2H), 3.71 (s, 2H), 2.21 (s, 2H), 1.36 (s, 2H) .

Example 37 2,4-Difluoro-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzene Preparation of 2,4-difluoro-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 16 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.65 (s, 1H), 7.93-7.80 (m, 3H), 7.67 (d, J = 8.0Hz, 2H), 7.54 (t, J = 8.6Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.25 (t, J = 7.3 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.90 - 6.81 (m, 1H), 3.86 - 3.66 (m) , 2H), 2.35 (t, J = 6.6 Hz, 2H), 1.66 - 1.43 (m, 2H).

Example 38 2,4-Difluoro-N-(1-((4-methylbenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (2 ,4-difluoro-N-(1-((4-methylbenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 4 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.60 (s, 1H), 7.94-7.81 (m, 1H), 7.53 (t, J = 9.9Hz, 1H), 7.46 (s, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 7.8 Hz, 2H), 6.79 (s, 1H), 4.40 (s, 2H), 3.34 (s, 2H), 2.54 (d, J = 6.1 Hz, 2H), 2.29 (s, 3H), 1.55 (s, 2H).

Example 39 2,4-Difluoro-N-(1-((4-(trifluoromethyl)benzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzene Preparation of 2,4-difluoro-N-(1-((4-(trifluoromethyl)benzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)Benzenesulfonamide)

Using a synthetic method as in Example 1, 10 mg of the product was obtained. ¹ H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 7.78 (dd, J = 15.0, 8.1 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 9.7 Hz, 1H), 7.40 (d, J = 7.4 Hz, 3H), 7.25 (t, J = 8.2 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 4.60 (s, 2H), 3.59–3.42 (m, 2H), 2.59 (t, J = 6.3 Hz, 2H), 1.66 (m, 2H).

Example 40 2,4-Difluoro-N-(1-((2-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (2, Preparation of 4-difluoro-N-(1-((2-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 31 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.58 (s, 1H), 7.86 (dd, J = 15.0,8.5Hz, 1H), 7.52 (t, J = 8.8Hz, 1H), 7.43 (dd, J = 13.4 , 6.5 Hz, 1H), 7.37 (s, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.22 (q, J = 8.6 Hz, 3H), 7.02 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 4.51 (s, 2H), 3.47 - 3.37 (m, 2H), 2.60 (t, J = 6.4 Hz, 2H), 1.74 - 1.59 (m, 2H).

Example 41 2,4-Difluoro-N-(1-(2-(4-fluorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide ( Preparation of 2,4-difluoro-N-(1-(2-(4-fluorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic procedure as in Example 1, 48 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.56 (s, 1H), 7.85 (dd, J = 15.1,8.5Hz, 1H), 7.48 (t, J = 9.8Hz, 1H), 7.29 (s, 1H), 7.10 (ddd, J = 23.3, 16.2, 8.2 Hz, 5H), 6.84 (d, J = 8.3 Hz, 1H), 3.72 (s, 2H), 3.62 (t, J = 6.2 Hz, 2H), 2.52 (d) , J = 14.1 Hz, 2H), 1.74 (p, J = 6.0 Hz, 2H).

Example 42 4-(N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid (4-( Preparation of N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid)

Using a synthetic method as in Example 1, 5 mg of the product was obtained. ¹ H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), δ 8.05 (d, J = 7.2 Hz, 2H), 7.83 (d, J = 6.6 Hz, 2H), 7.48 (s, 3H), 7.32 (s, 2H), 6.91 (s, 1H), 6.84 (s, 1H), 3.72 (s, 2H), 2.34 (s, 2H), 1.52 (s, 2H).

Example 43 3-(N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid (3-( Preparation of N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid)

Using a synthetic procedure as in Example 1, 7.8 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.39 (s, 1H), 8.32 (s, 1H), 8.14 (d, J = 7.1Hz, 1H), 7.97 (d, J = 6.9Hz, 1H), 7.69 ( d, J = 7.8 Hz, 1H), 7.47 (s, 3H), 7.32 (d, J = 7.6 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 3.70 (s, 2H), 2.32 (s, 2H), 1.50 (s, 2H).

Example 44 2-(N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid (2-( Preparation of N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid)

Using a synthetic method as in Example 1, 2.7 mg of the product was obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.27 (s, 1H), 7.95 (m, 2H), 7.63 - 7.46 (m, 3H), 7.45 - 7.40 (m, 2H), 7.09 - 6.95 (m, 3H) ), 6.87 (d, J = 8.0 Hz, 1H), 3.83 - 3.62 (m, 2H), 2.37 (t, J = 6.5 Hz, 2H), 1.59 (dd, J = 12.3, 6.4 Hz, 2H).

Example 45 4-((N-(1-(4-)4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoic acid Preparation of 4-((4-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoic acid)

Using a synthetic method as in Example 1, 6 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ12.97 (s, 1H), 9.92 (s, 1H), 7.91 (d, J = 7.1Hz, 2H), 7.76 (s, 2H), 7.57 (s, 1H), 7.48–7.32 (m, 4H), 7.04 (d, J=8.4 Hz, 1H), 6.94 (s, 1H), 4.52 (s, 2H), 3.77 (s, 2H), 2.44 (s, 2H), 1.61 (s, 2H).

Example 46 3-((N-(1-(4-)4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoic acid Preparation of (3-((1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoic acid)

Using a synthetic method as in Example 1, 5.6 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ9.90 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.75 (dd, J = 8.5,5.2Hz, 2H), 7.58 (s, 1H ), 7.48 (d, J = 4.5 Hz, 2H), 7.41 (t, J = 8.7 Hz, 2H), 7.01 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.54(s, 2H), 3.83–3.71 (m, 2H), 2.42 (t, J = 6.5 Hz, 2H), 1.66–1.54 (m, 2H).

Example 47 3-((7-(2,4-Difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoic acid (3-((7) -(2,4-difluorophenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoic acid)

Using a synthetic method as in Example 1, 3 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.64 (s, 1H), 8.17 (d, J = 7.6Hz, 1H), 8.02 (s, 1H), 7.84 (dd, J = 15.1,8.6Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.51 (dd, J = 22.5, 9.5 Hz, 3H), 7.22 (t, J = 8.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 3.82 - 3.64 (m, 2H), 2.32 (t, J = 6.5 Hz, 2H), 1.60 - 1.39 (m, 2H).

Example 48 N-(1-(Thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b][1, 4] N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b] Preparation of [1,4]dioxine-6-sulfonamide)

Using a synthetic method as in Example 1, 70 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.14 (s, 1H), 7.93 (d, J = 5.0Hz, 1H), 7.57 (s, 1H), 7.35 (d, J = 3.2Hz, 1H), 7.24 ( d, J = 7.7 Hz, 2H), 7.12 (t, J = 4.4 Hz, 1H), 6.97 (dd, J = 16.6, 8.5 Hz, 2H), 6.84 (d, J = 8.2 Hz, 1H), 4.24 ( d, J = 5.0 Hz, 4H), 3.81 - 3.63 (m, 2H), 2.35 (t, J = 6.6 Hz, 2H), 1.65 - 1.45 (m, 2H).

Example 49 2,4-Difluoro-N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (2,4- Preparation of difluoro-N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 12 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.65 (s, 1H), 7.90 (dd, J = 20.4,6.6Hz, 1H), 7.56 (dd, J = 20.9,11.8Hz, 3H), 7.32 (d, J = 4.4 Hz, 1H), 7.24 (t, J = 10.5 Hz, 1H), 7.12 (t, J = 4.4 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.88 (d, J = 7.5) Hz, 1H), 3.76–3.64 (m, 2H), 2.35 (t, J = 6.6 Hz, 2H), 1.53 (dd, J = 11.9, 6.2 Hz, 2H).

Example 50 2-((7-(4-(Trifluoromethoxy)phenylsulfonylamino)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzoic acid methyl ester ( Preparation of methyl 2-((7-(4-(trifluoromethoxy)phenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)

Using a synthetic procedure as in Example 1, 52 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.41 (s, 1H), 7.89 (d, J = 8.7Hz, 2H), 7.73 (t, J = 7.5Hz, 1H), 7.64 (d, J = 7.4Hz, 1H), 7.53 (dd, J = 19.6, 8.0 Hz, 3H), 7.37 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.89 ( d, J = 8.0 Hz, 1H), 3.66 (d, J = 8.4 Hz, 5H), 2.40 (t, J = 6.5 Hz, 2H), 1.58 - 1.43 (m, 2H).

Example 51 2-((7-((4-(methoxycarbonyl)phenyl)methylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoic acid Preparation of methyl 2-((7-(4-(methoxycarbonyl)phenyl)methylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)

Using a synthetic method as in Example 1, 35 mg of the product was obtained. ^{1 H NMR (400MHz, DMSO)} δ9.90 (s, 1H), 7.93 (d, J = 7.6Hz, 2H), 7.84-7.72 (m, 1H), 7.71-7.60 (m, 3H), 7.57 (d , J = 7.3 Hz, 1H), 7.52 - 7.35 (m, 3H), 7.08 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 4.52 (s, 2H), 3.86 (s, 3H), 3.72 (d, J = 20.3 Hz, 5H), 1.61 (d, J = 5.3 Hz, 2H).

Example 52 2-((7-(2,3-Dihydrobenzo[b][1,4]dioxine-6-sulfonyl)-3,4-dihydroquinolin-1 ( 2H)-yl)sulfonyl)benzoic acid methyl ester (Methyl 2-((7-(2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamido)-3,4-dihydroquinolin-1 (2H Preparation of -yl)sulfonyl)benzoate)

Using a synthetic procedure as in Example 1, 72 mg of product was obtained. ^{1 H NMR (400MHz, DMSO)} δ10.14 (s, 1H), 7.73 (t, J = 7.4Hz, 1H), 7.63 (d, J = 7.5Hz, 1H), 7.50 (t, J = 7.7Hz, 1H), 7.43 (s, 1H), 7.21 (dd, J = 18.3, 9.3 Hz, 3H), 7.02 - 6.93 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.22 (d, J) = 6.3 Hz, 4H), 3.67 (s, 5H), 2.38 (t, J = 6.7 Hz, 2H), 1.60 - 1.40 (m, 2H).

Example 53 2-((7-(3-Chloro-2-fluorophenylsulfonylamino)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzoic acid methyl ester (methyl2- Preparation of (7-(3-chloro-2-fluorophenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)

Using a synthetic procedure as in Example 1, 67 mg of product was obtained. ¹ H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.07 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.91 ( d, J = 8.1 Hz, 1H), 3.74 - 3.60 (m, 5H), 2.39 (t, J = 6.8 Hz, 2H), 1.57 - 1.41 (m, 2H).

Example 54 Methyl 2-((7-(2,6-dichlorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate (methyl 2- Preparation of ((7-(2,6-dichlorophenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)

Using a synthetic procedure as in Example 1, 55 mg of product was obtained. . ^{1 H NMR (400MHz, DMSO)} δ10.76 (s, 1H), 7.72 (t, J = 7.6Hz, 1H), 7.61 (d, J = 8.5Hz, 3H), 7.55-7.43 (m, 2H), 7.38 (s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 3.75 - 3.58 (m, 5H) ), 2.37 (t, J = 6.7 Hz, 2H), 1.56 - 1.39 (m, 2H).

Example 55 Methyl 2-((7-((4-methoxyphenyl)sulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate (Methyl2- Preparation of (7-((4-methoxyphenyl)sulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)

Using a synthetic method as in Example 1, 80 mg of the product was obtained. 1H NMR (400MHz, DMSO) δ 10.13 (s, 1H), 7.72 (m, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.42 (s) , 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.3 Hz, 1H) ), 3.76 (s, 3H), 3.70 - 3.58 (m, 5H), 2.38 (t, J = 6.7 Hz, 2H), 1.56 - 1.43 (m, 2H).

Example 56 Methyl 2-((7-((2,5-dimethoxyphenyl)sulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate Preparation of (Methyl-2-((7-(2,5-dimethoxyphenyl)sulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)

Using a synthetic method as in Example 1, 81 mg of the product was obtained. 1H NMR (400MHz, CDCl3) δ 7.51 (t, J = 7.4 Hz, 1H), 7.42 (d, J = 7.1 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.15 (t, J = 7.6 Hz) , 2H), 7.05 (s, 1H), 6.96 (s, 2H), 6.91 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 4.07 (s, 3H), 3.78 (s, 3H), 3.72 (m, 5H), 2.37 (t, J = 6.7 Hz, 2H), 1.61 - 1.48 (m, 2H).

Example 57 2,4-Difluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonamide (2, Preparation of 4-difluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 20 mg of the product was obtained. 1H NMR (500MHz, CDCl3) δ 7.93 - 7.78 (m, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.54 - 7.41 (m, 2H), 7.04 (t, J = 8.6 Hz, 2H) , 7.00–6.91 (m, 2H), 6.89–6.78 (m, 3H), 3.73 (dd, J=6.7, 5.2 Hz, 2H), 2.37 (t, J=6.6 Hz, 2H), 1.60–1.52 (m) , 2H).

Example 58 N-(1,2,3,4-Tetrahydroquinolin-6-yl)-1-(p-tolyl)methanesulfonamide (N-(1,2,3,4-tetrahydroquinolin-6-) Preparation of yl)-1-(p-tolyl)methanesulfonamide)

Using a synthetic method as in Example 1, 18 mg of the product was obtained. 1H NMR (500MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 1H), 7.78 - 7.67 (m, 2H), 7.38 (s, 1H), 7.22 (dd, J = 14.4, 5.9 Hz, 2H) , 7.04–6.92 (m, 2H), 6.67 (s, 1H), 4.40 (s, 2H), 4.02–3.74 (m, 2H), 2.54 (t, J = 6.6 Hz, 2H), 2.45 (s, 3H) ), 1.80–1.66 (m, 2H).

Example 59 N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b][ 1,4]Dihydrohexyl-6-sulfonamide (N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo Preparation of [b][1,4]dioxine-6-sulfonamide)

Using a synthetic procedure as in Example 1, 44 mg of the product was obtained. 1H NMR (400MHz, CDCl3) δ 7.66 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 8.9, 5.1 Hz, 2H), 7.30 - 7.25 (m, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.08 (t, J = 8.6 Hz, 2H), 6.89 (dd, J = 9.1, 5.4 Hz, 2H), 6.76 (dd, J = 8.8, 2.5 Hz, 1H), 6.47 (s, 1H), 4.34–4.28 (m, 2H), 4.28–4.21 (m, 2H), 3.80–3.69 (m, 2H), 2.35 (t, J=6.7 Hz, 2H), 1.61–1.52 (m, 2H) .

Example 60 N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-sulfonamide (N-(1-( Preparation of (4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-sulfonamide)

Using a synthetic procedure as in Example 1, 59 mg of product was obtained. 1H NMR (500MHz, CDCl3) δ 7.69 (d, J = 8.8 Hz, 1H), 7.58 (dd, J = 5.0, 1.0 Hz, 1H), 7.56 - 7.52 (m, 2H), 7.51 (dd, J = 3.7, 1.1 Hz, 1H), 7.10 - 7.02 (m, 3H), 6.90 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.8, 2.6 Hz, 1H), 6.63 (s, 1H), 3.93–3.32 (m, 2H), 2.39 (t, J = 6.7 Hz, 2H), 1.77–1.20 (m, 2H).

Example 61 N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)cyclohexanesulfonamide (N-(1-(( Preparation of 4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)cyclohexanesulfonamide)

Using a synthetic procedure as in Example 1, 39 mg of product was obtained. 1H NMR (500MHz, CDCl3) δ 7.73 (d, J = 8.7 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.09 (t, J = 8.5 Hz, 2H), 6.99 - 6.86 (m, 2H) , 6.39 (s, 1H), 3.90 - 3.56 (m, 2H), 2.99 (tt, J = 12.1, 3.4 Hz, 1H), 2.44 (t, J = 6.7 Hz, 2H), 2.15 (d, J = 11.9) Hz, 2H), 1.89 (d, J = 12.3 Hz, 2H), 1.71 (d, J = 7.9 Hz, 2H), 1.68 - 1.38 (m, 4H), 1.24 - 1.11 (m, 2H).

Example 62 N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)butane-1-sulfonamide (N-(1- Preparation of ((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)butane-1-sulfonamide)

Using a synthetic method as in Example 1, 8 mg of the product was obtained. 1H NMR (500MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 1H), 7.65 - 7.49 (m, 2H), 7.09 (t, J = 8.5 Hz, 2H), 6.99 (dd, J = 8.8, 2.5 Hz, 1H), 6.94 (d, J = 2.2 Hz, 1H), 6.73 (s, 1H), 3.93 - 3.50 (m, 2H), 3.18 - 2.91 (m, 2H), 2.44 (t, J = 6.7) Hz, 2H), 1.86 - 1.71 (m, 2H), 1.69 - 1.52 (m, 2H), 1.43 (dd, J = 15.0, 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H).

Example 63 2,4-Difluoro-N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonamide (2,4- Preparation of difluoro-N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonamide)

Using a synthetic procedure as in Example 1, 28 mg of product was obtained. 1H NMR (400MHz, CDCl3) δ 7.84 (dd, J = 14.8, 8.3 Hz, 1H), 7.67 (d, J = 9.4 Hz, 1H), 7.48 (dd, J = 5.0, 1.2 Hz, 1H), 7.29 (dd, J = 3.7, 1.2 Hz, 1H), 6.97 (dt, J = 17.8, 6.7 Hz, 3H), 6.87 (m, 2H), 6.81 (s, 1H), 3.95 - 3.64 (m, 2H), 2.39 (t, J = 6.6 Hz, 2H), 1.71 - 1.50 (m, 2H).

Example 64 N-(1-(Thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1-(p-tolyl)methanesulfonamide (N-( Preparation of 1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1-(p-tolyl)methanesulfonamide)

Using a synthetic procedure as in Example 1, 58 mg of product was obtained. 1H NMR (400MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 4.2 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.26 (s, 1H) ), 7.16 (m, 3H), 7.06 - 7.00 (m, 1H), 6.90 (s, 1H), 6.85 (dd, J = 8.8, 2.4 Hz, 1H), 6.36 (s, 1H), 4.28 (s, 2H), 3.96–3.64 (m, 2H), 2.45 (t, J = 6.6 Hz, 2H), 2.35 (s, 3H), 1.69 (dt, J = 12.6, 6.5 Hz, 2H).

Example 65 N-(1-(Thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b][1, 4] N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b] Preparation of [1,4]dioxine-6-sulfonamide)

Using a synthetic method as in Example 1, 26 mg of the product was obtained. 1H NMR (400MHz, CDCl3) δ 7.65 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 4.1 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.28 - 7.23 (m, 2H) , 7.05–6.99 (m, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.75 (dd, J=8.7, 2.4 Hz, 1H), 6.64 ( s, 1H), 4.28 (dd, J = 13.8, 5.0 Hz, 4H), 4.00 - 3.62 (m, 2H), 2.39 (t, J = 6.6 Hz, 2H), 1.79 - 1.48 (m, 2H).

Example 66 N-(1-(Thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b][1, 4] N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b] Preparation of [1,4]dioxine-6-sulfonamide)

Using a synthetic procedure as in Example 1, 43 mg of product was obtained. 1H NMR (400MHz, CDCl3) δ 7.69 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 4.1 Hz, 1H), 7.50 (t, J = 3.3 Hz, 2H), 7.32 (d, J) =2.7 Hz, 1H), 7.06–6.98 (m, 2H), 6.93 (s, 1H), 6.86 (dd, J=8.8, 2.4 Hz, 1H), 3.87–3.76 (m, 2H), 2.42 (t, J = 6.6 Hz, 2H), 1.74 - 1.57 (m, 2H).

Example 67 N-(1-(Thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)butane-1-sulfonamide (N-(1-(thiophen) Preparation of -2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)butane-1-sulfonamide)

Using a synthetic method as in Example 1, 49 mg of the product was obtained. 1H NMR (400MHz, CDCl3) δ 7.76 (d, J = 8.7 Hz, 1H), 7.57 - 7.47 (m, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.06 - 6.94 (m, 3H) , 6.81 (s, 1H), 3.95 - 3.64 (m, 2H), 3.24 - 2.94 (m, 2H), 2.46 (t, J = 6.6 Hz, 2H), 1.87 - 1.74 (m, 2H), 1.67 (dt , J = 12.7, 6.5 Hz, 2H), 1.50 - 1.37 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H).

Example 68 2-Fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (2-fluoro-N) -(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)

Using a synthetic method as in Example 1, 50 mg of the product was obtained. 1H NMR (400MHz, CDCl3) δ 7.90 (t, J = 7.5 Hz, 1H), 7.58 - 7.47 (m, 2H), 7.39 (dd, J = 8.5, 5.1 Hz, 2H), 7.31 - 7.17 (m, 2H), 7.02 (t, J = 8.5 Hz, 2H), 6.99 - 6.93 (m, 2H), 6.89 (d, J = 8.3 Hz, 1H), 4.02 - 3.25 (m, 2H), 2.36 (t, J) =6.6 Hz, 2H), 1.60–1.51 (m, 2H).

Example 69

In vitro activity assay: The present invention uses the AlphaScreen detection technique to verify the inhibitory ability of the compounds of the invention.

1. Experimental purpose

The inhibitory activity of the compound of the present invention against the RORγ protein was determined.

2, experimental materials

The final concentration of the target protein RORγ was 100 nM; assay buffer (10×) MOPS (500 mM) pH 7.4, CHAPS (0.5 mM), NaF (500 mM), BSA (1 mg/ml); final concentration of donor microbeads in the kit 50 μg/mL, the final concentration of the receptor microbeads was 50 μg/mL; the co-agonistic factor of RORγ, the short peptide bSRC1-4 (Biotin-QKPTSGPQTPQAQQKSLLQQLLTE) was at a final concentration of 20 nM. 150 μL reaction system: RORγ: 15 μL, assay buffer: 15 μL, deionized water: 60 μL, small molecule compound: 15 μL, donor microbead: 15 μL, acceptor microbead: 15 μL; positive inhibitor: T1317 (purchased, The product name is T0901317 and the brand is cayman).

3. Experimental methods

Incubate in the dark for 2 hours, transfer to a 384-well plate, transfer 40 μL of liquid per well, and make 3 replicate wells per sample. The detection wavelength is 680 nm and the emission wavelength is 520-620 nm.

4. Experimental results

The inhibitory activity data of the compounds of the present invention 1-68 (compounds prepared in Examples 1-68, respectively) against the RORy protein are shown in Fig. 1.

The IC ₅₀ values of the inhibitory activity of the compounds of the present invention which are more active against RORγ protein are shown in Table 1 below:

Table 1: IC ₅₀ values of inhibitory activity of the _more active compounds of the invention against RORγ protein

Serial number name IC ₅₀ μΜ 1 Example 5 0.95 2 Example 23 0.74 3 Example 30 0.21 4 Example 31 0.07 5 Example 32 0.40 6 Example 33 0.12 7 Example 34 0.34 8 Example 36 0.60 9 Example 37 0.79 10 Example 38 0.32 11 Example 39 0.26 12 Positive inhibitor T1317 2.50

The experimental results show that the compound of the present invention has a very good inhibitory effect on the RORγ protein, particularly the inhibitory activity of the compound 30 (representing the compound prepared in Example 30, the same below), 31, 33, 34, 38, 39 on the RORγ protein. Better than the comparator T1317.

Example 70

In vitro activity assay: The present invention uses the Luciferase detection technique to verify the inhibitory ability of the compounds of the invention.

1. Experimental purpose

The inhibitory activity of the compounds of the invention against nuclear receptor RORy cell levels was determined.

2, experimental materials

Human renal epithelial cell line 293T cells; DMEM medium containing 10% fetal bovine serum; 96-well plate transparent plate; double reporter gene detection kit; Opti-MEM reagent; Lipo-fectamine 2000 transfection reagent; recombinant plasmid: Gal4- RORγLBD: 25 ng, RORE_Luc: 25 ng, pG5-luc, Renilla; positive inhibitor: T1317 (purchased, product name T0901317, brand cayman).

3. Experimental methods

Human renal epithelial cell line 293T cells were cultured in DMEM medium containing 10% fetal calf serum. The day before transfection, cells were prepared in 96-well plates with a cell density of 1.5x10 ⁴ cells / well. Transient transfection was carried out 24 hours after adherent growth, using a double reporter gene co-transfection method, the transfection reagent was Lipo-fectamine2000, and the transfection reagent and plasmid were diluted with Opti-MEM reagent, respectively. Gal4-RORγLBD was 25 ng per well; pG5-luc gene was 25 ng per well; Renilla was 5 ng per well. After transfection for 24 hours, different concentrations of compounds were added. After incubation for 24 hours, the Luciferase double reporter assay kit was used to detect the luminescent signal. 3 replicate wells per sample.

The inhibitory activity of the compounds of the present invention 1-68 (compounds prepared in Examples 1-68, respectively) against RORγ cell levels is shown in Figure 2 below.

The IC ₅₀ values for the inhibitory activity of the _more active compounds of the present invention against ROR gamma cell levels are shown in Table 2 below:

Table II: IC ₅₀ of the inhibitory activity of the active compound is preferably on the cellular level RORγ

The experimental results show that the compound of the present invention has a very good inhibitory effect on the RORγ cell level test, and in particular, the inhibitory activity of the compound 31 on the RORγ protein is better than that of the control drug. The inhibitory activity of compounds 22 and 24 on the RORγ protein was comparable to that of the control drug. At the same time, the compound of the present invention has the advantages of novel structure and easy preparation compared with the control drug.

Claims (10)

a tetrahydroquinoline-related bicyclic compound characterized by having the structure represented by Formula I:

In formula I: X is selected from: C, O or N; Y is selected from: CO or SO ₂ ; n is selected from: 0, 1 or 2; R _{1 is} optionally selected from the group consisting of: C ₀ to C ₆ alkylene-R ₃ ; R _{2 is} optionally selected from the group consisting of: C ₀ to C ₆ alkylene-R ₃ ; R _{3 is} optionally selected from the group consisting of: H, cycloalkyl or heterocyclic; The above cycloalkyl group is optionally selected from a saturated or unsaturated ring composed of 3 to 7 carbon atoms, and the cycloalkyl group is selected from 0, 1, 2 or 3, selected from halogen, C ₁ -C ₆ alkane. a group, a C ₁ -C ₆ haloalkyl group, a hydroxyl group, a cyano group, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ ～ C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ Alkyl-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ), or -N(R ₄ a SO ₂ -C ₁ -C ₆ alkyl group substituted; wherein R ₄ , R _{5 are each selected} from H or C ₁ -C ₆ alkyl; R _{6 is selected} from H or C ₁ -C ₆ alkyl; The above heterocyclic group is optionally selected from 1 to 3 of a 5- or 6-membered heterocyclic ring selected from N, O or S heteroatoms, and the heterocyclic group is selected from 0, 1, 2 or 3 Halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )( R ₅ ), -C ₀ -C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ) -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ Or a -N(R ₄ )SO ₂ -C ₁ -C ₆ alkyl group; wherein R ₄ , R _{5 are each selected} from H or C ₁ -C ₆ alkyl; R _{6 is selected} from H or C ₁ ~C ₆ alkyl. The compound according to claim 1, wherein said R ₁ and R _{2 are} independently selected from any one of the following groups: 1) methyl, ethyl, propyl, or butyl; 2) C ₀ - C ₆ alkylene-R ₃ ; said R _{3 is} independently selected from: H, cycloalkyl or heterocyclic; the cycloalkyl is selected from cyclobutane, cyclopentane , cyclohexane, cycloheptane, phenyl, naphthyl, benzyl, etc., wherein the cycloalkyl group is selected from the group consisting of fluorine, chlorine, bromine, iodine, and C ₁ -C ₆ alkane. a group, a C ₁ -C ₆ haloalkyl group, a hydroxyl group, a cyano group, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ ～ C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ Alkyl-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ) or -N(R ₄ ) Substituted with a SO ₂ -C ₁ -C ₆ alkyl group; wherein R ₄ and R _{5 are each selected} from H, methyl, ethyl, propyl or butyl; and R _{6 is selected} from H, methyl, ethyl, a propyl or butyl group; the heterocyclic group is selected from the group consisting of imidazolyl, triazolyl, pyrazolyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, iso Quinolinyl, porphyrin, 1H-carbazolyl, 1H-benzo[d]imidazolyl, 1H-indenyl, benzo[d][1,3]dioxole , Benzo [d] thiazolyl or H- pyrazol -3 (2H) - yl ketone and the like; said heterocyclyl is optionally selected from 2 or 3 fluoro, chloro, bromo, iodo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ -C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ) or -N (R ₄ )SO ₂ -C ₁ -C ₆ alkyl group substituted; wherein R ₄ , R _{5 are each selected} from H, methyl, ethyl, propyl, butyl; R _{6 is selected} from H, methyl , ethyl, propyl or butyl. The compound of claim 1 wherein said compound is selected from the group consisting of compounds of formula IA or formula IB:

In the formula IA: X is selected from: C, O or N; Y is selected from: CO or SO ₂ ; n is selected from: 0; 1 or 2; R ₁ and R _{2 are} independently selected from the group consisting of methyl, ethyl, propyl, butyl or C ₀ -C ₆ alkylene-R ₃ ; said R _{3 is} independently selected from: H, cycloalkyl or a heterocyclic group; the cycloalkyl group is optionally selected from the group consisting of cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, naphthyl or benzyl; the cycloalkyl group is 0, 1, 2 or Three are selected from the group consisting of fluorine, chlorine, bromine, iodine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), —C ₀ —C ₆ alkylene-alkoxy, —C ₀ —C ₆ alkylene-COOR ₆ , —OC ₁ —C ₆ alkylene -N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , _{-SO 2 N (R 4) (} R 5) or _{-N (R 4) SO 2 -C} 1 ~ C 6 alkyl groups; wherein R _4, R ₅ optionally selected from H, methyl, ethyl, a propyl or butyl group; R _{6 is selected} from H, methyl, ethyl, propyl or butyl; the heterocyclic group is selected from the group consisting of imidazolyl, triazolyl, pyrazolyl, thienyl, oxazole , isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, porphyrinyl, 1H-carbazolyl, 1H-benzo[d] Azolyl, 1H-indenyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl or H-pyrazole-3(2H)-one; The heterocyclic group is selected from 0, 1, 2 or 3, and is selected from the group consisting of fluorine, chlorine, bromine, iodine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano and -N(R ₄ ). (R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ -C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ) or -N(R ₄ )SO ₂ -C ₁ -C ₆ alkyl group substituted; wherein R ₄ , R _{5 are} Selected from H, methyl, ethyl, propyl or butyl; R _{6 is selected} from H, methyl, ethyl, propyl or butyl; In the formula IB: X is selected from: C, O or N; Y is selected from: CO or SO ₂ ; n is selected from: 0; 1 or 2; R ₁ and R _{2 are} independently selected from the group consisting of methyl, ethyl, propyl, butyl or C ₀ -C ₆ alkylene-R ₃ ; said R _{3 is} independently selected from: H, cycloalkyl or a heterocyclic group; the cycloalkyl group is optionally selected from the group consisting of cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, naphthyl or benzyl; the cycloalkyl group is 0, 1, 2 or Three are selected from the group consisting of fluorine, chlorine, bromine, iodine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano, -N(R ₄ )(R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), —C ₀ —C ₆ alkylene-alkoxy, —C ₀ —C ₆ alkylene-COOR ₆ , —OC ₁ —C ₆ alkylene -N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , _{-SO 2 N (R 4) (} R 5) or _{-N (R 4) SO 2 -C} 1 ~ C 6 alkyl groups; wherein R _4, R ₅ optionally selected from H, methyl, ethyl, a propyl or butyl group; R _{6 is selected} from H, methyl, ethyl, propyl or butyl; the heterocyclic group is selected from the group consisting of imidazolyl, triazolyl, pyrazolyl, thienyl, oxazole , isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, porphyrinyl, 1H-carbazolyl, 1H-benzo[d] Azolyl, 1H-indenyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl or H-pyrazole-3(2H)-one; The heterocyclic group is selected from 0, 1, 2 or 3, and is selected from the group consisting of fluorine, chlorine, bromine, iodine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, cyano and -N(R ₄ ). (R ₅ ), -C ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -C ₀ -C ₆ alkylene-alkoxy, -C ₀ -C ₆ alkylene-COOR ₆ , -OC ₁ -C ₆ alkylene-N(R ₄ )(R ₅ ), -OC ₀ -C ₆ alkylene-COOR ₆ -COR ₄ , -OR ₄ , -N(R ₄ )COR ₆ , -N(R ₄ )COOR ₆ , -SO ₂ N(R ₄ )(R ₅ ) or -N(R ₄ )SO ₂ -C ₁ -C ₆ alkyl group substituted; wherein R ₄ , R _{5 are} It is selected from H, methyl, ethyl, propyl or butyl; R _{6 is selected} from H, methyl, ethyl, propyl or butyl. The compound according to claim 1, wherein the compound is selected from any one of the following compounds: 4-chloro-2-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, 4-fluoro-N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzamide , 2,6-Difluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, 5-methyl-N-(1-(thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-sulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-7-yl)-5-methylthiophene-2-sulfonamide, 2-Chloro-4-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-sulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b][1,4 Dioxane-6-sulfonamide, N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylthiophene- 2-sulfonamide, N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzenesulfonamide, N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)thiophene-2-sulfonamide, N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-dihydro Benzo[b][1,4]dioxine-6-sulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-1-(4-(trifluoromethyl)phenyl) Sulfonamide, N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(4-( Trifluoromethyl)phenyl)methanesulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzenesulfonamide, N-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-(trifluoromethyl) Phenylsulfonamide N-(1-(2-(3,4-Dichlorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b ][1,4]dioxine-6-sulfonamide, N-(1-(2-(2,4-dichlorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b ][1,4]dioxine-6-sulfonamide, Methyl-4-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate, Methyl-3-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate, Methyl 2-(1-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoate, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(methylsulfonyl)benzenesulfonamide, Methyl 4-((N-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoate, Methyl 4-((N-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoate, Methyl 3-((N-(1-(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfonyl)methyl)benzoate, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-4-nitrobenzenesulfonamide, 2,4-Difluoro-N-(1-((3-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, 2,4-Difluoro-N-(1-((4-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, Methyl 4-(((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)methyl)benzoate, Methyl 3-(((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)methyl)benzoate, Methyl 2-((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate, Methyl 3-((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate, Methyl 4-((7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate, 2,4-Difluoro-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, N-(1-((4-(tert-butyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,4-difluorobenzene, 2,4-Difluoro-N-(1-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, 2,4-Difluoro-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, 2,4-Difluoro-N-(1-((4-methylbenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, 2,4-Difluoro-N-(1-((4-(trifluoromethyl)benzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, 2,4-Difluoro-N-(1-((2-fluorobenzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, 2,4-Difluoro-N-(1-(2-(4-fluorophenyl)acetyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, 4-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid, 3-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid, 2-(N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid, 4-((N-(1-(4-)4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)methyl)benzoic acid, 3-((N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfonyl)methyl)benzoic acid, 3-(7-(2,4-difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoic acid, N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2,3-dihydrobenzo[b][1,4] Oxecyclohexene-6-sulfonamide, 2,4-Difluoro-N-(1-(thien-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, Methyl 2-((7-(4-(trifluoromethoxy)phenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate, Methyl 2-((7-((4-(methoxycarbonyl)phenyl)methylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate, 2-((7-(2,3-Dihydrobenzo[b][1,4]dioxine-6-sulfonyl)-3,4-dihydroquinolin-1(2H)- Methyl)sulfonyl)benzoate, Methyl 2-((7-(3-chloro-2-fluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate, 2-((7-(2,6-Dichlorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoic acid, Methyl 2-((7-((4-methoxyphenyl)sulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate, Methyl 2-((7-((2,5-dimethoxyphenyl)sulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate, 2,4-Difluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonamide, N-(1,2,3,4-tetrahydroquinolin-6-yl)-1-(p-tolyl)methanesulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b][1,4 Dioxane-6-sulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-sulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)cyclohexanesulfonamide, N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)butane-1-sulfonamide, 2,4-Difluoro-N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonamide, N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1-(p-tolyl)methanesulfonamide, N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b][1,4] Oxecyclohexene-6-sulfonamide, N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydrobenzo[b][1,4] Oxecyclohexene-6-sulfonamide, N-(1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)butane-1-sulfonamide, 2-Fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide. A pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate or solvate of the compound according to any one of claims 1 to 4. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal, complex, hydrate or solvate thereof, for inhibiting ROR receptor preparation Application in the agent. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate or solvate thereof, for the preparation of a cancer or an inflammatory disease Or the application of drugs for autoimmune diseases. The use according to claim 7, wherein the cancer is selected from the group consisting of: acoustic neuroma, acral melanoma, acral adenoma, acute eosinophilic leukemia, acute red leukemia, acute lymphoblastic leukemia, Acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumor, adrenocortical carcinoma, adrenal tumor, adult T-cell leukemia/lymphoma, AIDS-related Lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid carcinoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical deformity rod-shaped tumor , B cell chronic lymphocytic leukemia, B cell prolymphocytic leukemia, B cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone tumor, brown tumor, Burkitt's lymphoma, breast cancer, brain Cancer, carcinoma in situ, chondroma, cementum, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus Head tumor, renal clear cell sarcoma, craniopharyngioma, cutaneous t-cell lymphoma, cervical cancer, colon cancer, small round cell tumor, diffuse B-cell lymphoma, neuroepithelial tumor, dysplasia, embryogenic Endocrine gland tumors, endoderm sinus tumors, esophageal cancer, fibroids, fibrosarcoma, follicular lymphoma, follicular astrocytoma, thyroid cancer, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, Giant cell fibroblastoma, giant cell tumor of bone, glioma, glioblastoma multiforme, glioma, granulosa cell tumor, male cell tumor, gallbladder cancer, gastric cancer, hemangioblastoma, Head and neck cancer, hemangiopericoma malignancy, hepatocellular carcinoma, cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer Fatal midline cancer, leukemia, testicular stromal cell tumor, liposarcoma, lung cancer, lymphangioma, lymphoepithelial neoplasia, lymphoma, acute lymphangiosarcoma, lymphocytic leukemia, chronic lymphoid Cell leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, malt lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, marginal b-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, breast medullary carcinoma , medullary thyroid cancer, medulloblastoma, melanoma, meningioma, Merkel cell cancer, mesothelioma, metastatic cell carcinoma, mixed sputum tumor, mucinous tumor, multiple myeloma, muscle tissue tumor , mucus-like liposarcoma, myxoma, mucinous sarcoma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, neuroma, ocular cancer, eosinophilia, optic nerve sheath meningioma, tumor, oral cancer, Osteosarcoma, ovarian cancer, papillary thyroid carcinoma, paraganglioma, tumor pineal cell tumor, pituitary cell tumor, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, peritoneal cancer, Pancreatic cancer, pharyngeal cancer, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyosarcoma, rhabdomyosarcoma, rectal cancer, sarcoma, seminoma, trophoblastic tumor, skin cancer, small round cell tumor, small cell Cancer, soft tissue sarcoma, somatostatin, spinal cord tumor, spleen marginal lymphoma, squamous cell carcinoma, synovial sarcoma, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, prostate cancer, thyroid Cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, genitourinary cancer, uterine cancer, verrucous cancer, visual pathway glioma, vulvar cancer or vaginal cancer. The use according to claim 7, wherein the inflammatory disease or autoimmune disease is selected from the group consisting of: inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, encephalomyelitis. , myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organs Transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune disease, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmunity Hemolytic and thrombocytopenia, pulmonary hemorrhagic nephritis syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, asthma, septic shock, systemic lupus erythematosus, Rheumatoid arthritis, psoriatic arthritis, collagen-induced arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis , allergic dermatitis, degenerative joint disease, Guillain-Barré syndrome, mycosis fungoides or acute inflammatory reactions. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex thereof, hydrated And solvates, and optionally a pharmaceutically acceptable carrier or excipient.

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