CN112375027A - Indolesulfonamide derivative and medical application thereof - Google Patents

Abstract

The invention discloses an indole sulfonamide compound with FABP4/5 inhibitory activity, a preparation method and medical application thereof, wherein the indole sulfonamide compound is a compound with a structural formula shown as a formula I, and a pharmaceutically acceptable salt, ester or solvate thereof. The compound of formula I is a novel FABP4/5 inhibitor, and can be used for preparing medicaments for preventing or treating FABP4/5 related diseases.

Description

Indolesulfonamide derivative and medical application thereof

Technical Field

The invention relates to the field of biomedicine, in particular to an inhibitor of Fatty Acid Binding Protein (FABP)4 and/or 5, and more particularly relates to a novel FABP4/5 inhibitor of indole sulfonamides and a medical application of the inhibitor as FABP4/5 inhibitor.

Background

Fatty Acid Binding Proteins (FABPs) as intracellular lipid chaperones can reversibly bind to lipids, increase the solubility in cytoplasm, and reduce lipotoxicity. FABP family subtypes are many, of which FABP4(adipocyte-FABP, A-FABP) and FABP5(epidermal-FABP, E-FABP) are members of the fatty acid binding protein family. FABP4 was mainly distributed in adipocytes and macrophages, accounting for 1% of total adipose tissue protein. FABP5 has a wide range of tissue distribution. FABP4/5 is closely related to the occurrence and development of metabolic inflammation diseases, including atherosclerosis, hyperlipidemia, type II diabetes, non-alcoholic steatohepatitis, etc. In 1996, Hotamistigl et al first reported FABP4 knock-out (FABP 4)^-/-) The mouse of (4) shows good insulin sensitivity under metabolic stress conditions such as high-fat diet, and compared with the control group, FABP4^-/-Tumor necrosis factor- α (TNF- α) expression was also significantly down-regulated in adipose tissue of mice, but expression of FABP5 was increased complementarily in adipocytes (Science 1996,274,1377). FABP4/5 double knockout (FABP 4-5)^-/-) Mice alter cellular and systemic lipid trafficking and composition, leading to increased insulin receptor signaling, increased adenylate activated protein kinase (AMPK) agonism in muscle tissue, decreased expression of hepatic stearoyl-coa desaturase 1(SCD1), improved hepatic lipid infiltration, and strong protection against diet-induced insulin resistance, type ii diabetes, and fatty liver disease (Cell metab.2005,1, 107). In addition in apolipoprotein E deletion (ApoE)^-/-) FABP4/5 in mice^-/-Ratio FABP4^-/-The effect of protecting vascular lesions is more remarkable (nat. med.2001,7,699). FABP4/5 also mediates inflammation and stabilizes leukotriene A4 to promote inflammatory response (J Lipid Res.2004,45,2138; J Lipid Res.2004,279, 7420). In addition, in genetic studies, it was found that the genetic variation (T-87C) of the human FABP4 promoter reduces the expression of FABP4, and compared with the FABP4 wild-type population, the T-87C-carrying population has a reduced probability of suffering from coronary heart disease and type II diabetes, and the serum TG level is also reduced (Proc Natl Acad Sci USA.2006,103, 6970). FABP4 and FABP5 are also associated with various tumorsThe occurrence and development of tumors including breast cancer, ovarian cancer, prostate cancer and the like and tumor metabolism are closely related (Gene.2018,676, 171). In conclusion, FABP4/5 is expected to be a potential target for treating obesity and related metabolic diseases and tumors.

At present, a lot of reports are provided for FABP4 small-molecule inhibitors, but the FABP4 inhibitor BMS309403 developed by Baishi Guibao corporation is in an early biological activity test stage, so that the FABP4 inhibitor BMS309403 can be deeply researched, can improve atherosclerosis and insulin resistance, and can treat diseases such as nonalcoholic steatohepatitis (Nature.2007,447, 959; Journal of hepatology.2013,58,358), but the safety of the FABP4 small-molecule inhibitor is to be further verified. While the FABP4/5 dual inhibitor is rarely reported, the FABP4/5 dual inhibitor RO6806051 developed by Roche has stronger enzyme inhibition activity (Bioorg Med Chem Lett.2016,26,5092), but the in vivo curative effect of the FABP4/5 dual inhibitor is not reported. FABP4/5 dual inhibitor developed by Merck company can reduce Triglyceride (TG) and Free Fatty Acid (FFA) levels in plasma of mice induced by high-fat diet, and improve Lipid metabolism disorder (J Lipid Res.2011,52,646). In addition, inhibition of FABP3 has been reported in the literature as potentially causing cardiotoxicity (faeb j.1999,13,805). Therefore, the development of a novel FABP4/5 inhibitor with strong selectivity, high activity and small toxic and side effects is urgently needed in clinic.

Disclosure of Invention

The purpose of the invention is as follows: in view of the prior art, the application provides an indole sulfonamide compound with FABP4/5 inhibitory activity and medical application thereof.

The technical scheme is as follows: the invention discloses a compound shown as the following formula I, and a pharmaceutically acceptable salt, ester or solvate thereof:

wherein R is¹Selected from: H. f, Cl, Br, I, OCH₃；

R²Selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, fused ring aryl, or substituted fused ring aryl, wherein said substituted phenyl, substituted heteroaryl, or substituted fused ring aryl may independently be substituted with 1 to 3 of the following substituents: F. cl, Br, I, CN, NO₂、NH₂、OH、OR¹²、C₁-C₃Alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, halocycloalkyl, halocycloalkylalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkylalkoxyalkyl, cycloalkoxyalkyl, alkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylalkyl or substituted amino;

R¹²selected from: cycloalkyl, heterocycloalkyl, or substituted or unsubstituted C₁-C₄Alkyl, said substituted C₁-C₄Alkyl is substituted with one or two or three substituents independently selected from the group consisting of: OH, (O), C (O) OH, CN, NH₂F, alkylsulfonyl, haloalkylsulfonyl, substituted amino, C (O) NH₂Alkylsulfonylamino, sulfamoyl, NHC (O) NH₂Pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl or NHC (O) CH (CH)₃)NHC(O)CH(CH₃)NH；

R³Selected from: H. f, Cl, Br, I, CN, NO₂、NH₂、OH、N₃、C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₁-C₈Alkylcarbonyl group, C₁-C₈Alkoxycarbonyl group, C₁-C₈Alkylsulfonyl radical, C₁-C₈Alkylsulfinyl radical, C₁-C₈Alkylthio radical, C₁-C₅Alkylcarbonylamino, C₁-C₈Alkylaminocarbonyl, di (C)₁-C₃) Alkylaminocarbonyl radical, C₃-C₈Cycloalkyl radicals、C₃-C₈Cycloalkyl oxy, C₃-C₈Heterocycloalkyl radical, C₃-C₈Heterocycloalkyloxy, phenyl, phenyloxy, phenyl (C)₁-C₂) Alkyl, phenyl (C)₁-C₂) Alkoxy, phenylsulfonyl, phenylsulfinyl, C₅-C₆Heteroaryl group, C₅-C₆Heteroaryloxy radical, C₅-C₆Heteroaryl (C)₁-C₃) Alkyl radical, C₅-C₆Heteroaryl (C)₁-C₃) Alkoxy radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkyl radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkoxy radical, C₃-C₈Heterocycloalkyl (C)₁-C₂) Alkyl, heterocycloalkyl (C)₁-C₂) Alkyloxy, wherein R³May be unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C₁-C₈Alkyl and unsubstituted or halogenated C₁-C₈An alkoxy group;

R⁴,R⁵,R⁶independently selected from: H. f, Cl, Br, I, CN, NO₂、NH₂、OH、C₁-C₆Alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, halocycloalkyloxy, alkenyl, cycloalkenyl, alkynyl, alkylsulfonyl, haloalkylsulfonyl, substituted amino, aminoalkyl or substituted aminoalkyl groups which may independently be substituted on nitrogen with 1 to 2 of the following substituents: c₁-C₃Alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl or alkoxyalkyl; or, R⁴,R⁵,R⁶Each two of which, together with the atoms to which they are attached, form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heteroA cycloolefin ring;

R⁷selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted benzyl;

a is selected from: substituted C₃-C₈Cycloalkyl, substituted C₃-C₈Heterocycloalkyl, substituted phenyl, heteroaryl, substituted heteroaryl, fused ring aryl, or substituted fused ring aryl, wherein said substituted phenyl, substituted heteroaryl, or substituted fused ring aryl may independently be substituted with 1 to 3 of the following substituents: H. f, Cl, Br, I, CN, NO₂、NH₂、N₃、OH、-COR⁸、-CONHS(O)₂R⁸、-NHCONHS(O)₂R⁸、-S(O)₂NH₂、-S(O)₂NHCOCH₃、C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, 1H-tetrazol-5-yl, 3H- [1,3,4 ]]Oxadiazol-2-one-5-yl, 3H- [1,3,4 ]]Oxadiazole-2-thione-5-yl, 4H- [1,2,4 [ ]]Oxadiazol-5-one-3-yl, 4H- [1,2,4 ]]Oxadiazole-5-thione-3-yl, 3H- [1,2,3,5]Oxathiadiazol-2-oxide-4-yl, 4H- [1,2,4 ]]Thiadiazol-5-one-3-yl, isoxazol-3-ol-5-yl, 5-alkylisoxazol-3-ol-4-yl, 5-cycloalkylisoxazol-3-ol-4-yl, furan-3-ol-4-yl, 5-alkylsulfonylamino- [1,3, 4-]Oxadiazol-2-yl, 5-cycloalkylsulphonamido- [1,3,4]Oxadiazol-2-yl, 5-alkylsulfonylamino-2H- [1,2,4 ]]Triazol-3-yl, 5-cycloalkylsulfonylamino-2H- [1,2,4]Triazol-3-yl, 5-alkylisothiazol-3-ol-4-yl, 5-cycloalkylisothiazol-3-ol-4-yl, [1,2,5]Thiadiazol-3-ol-4-yl, 1, 4-dihydro-tetrazol-5-one-1-yl, 2H-tetrazol-5-ylcarbamoyl, 2H-tetrazol-5-carbonyl, [1,2,4 ] f]Oxadiazolidine-3, 5-dione-2-yl, 4H- [1,2,4 ]]Oxadiazol-5-one-3-yl, 2, 4-dihydro- [1,2,4 ]]Triazol-3-one-5-ylthio, 4H- [1,2,4 ]]Triazole-3-thio, 4H- [1,2,4 ]]Triazole-3-sulfinyl, 4H- [1,2,4 ]]Triazole-3-sulfonyl, 4-alkyl-pyrazol-1-ol-5-yl, 4-cycloalkyl-pyrazol-1-ol-5-yl, 4-alkyl- [1,2,3]Triazole compounds-1-ol-5-yl, 4-cycloalkyl- [1,2,3]Triazol-1-ol-5-yl, 5-alkyl-imidazol-1-ol-2-yl, 5-cycloalkyl-imidazol-1-ol-2-yl, 4-alkyl-imidazol-1-ol-5-yl, 4-cycloalkyl-imidazol-1-ol-5-yl, 4-alkyl-1, 1-dioxo-1. lambda⁶-[1,2,5]Thiadiazolidin-3-one-5-yl, 4-dialkyl-1, 1-dioxo-1 lambda⁶-[1,2,5]Thiadiazolidin-3-one-5-yl, 4-cycloalkyl-1, 1-dioxo-1 lambda⁶-[1,2,5]Thiadiazolidin-3-one-5-yl, 4-bicycloalkyl-1, 1-dioxo-1 lambda⁶[1,2,5]Thiadiazolidin-3-one-5-yl, thiazolidine-2, 4-dione-5-yl, oxazolidine-2, 4-dione-5-yl, 3- [ 1-hydroxy-methyl- (E) ylidene]-pyrrolidine-2, 4-dione-1-yl, 3- [ 1-hydroxy-methyl- (Z) -ylidene]-pyrrolidine-2, 4-dione-1-yl, 5-methyl-4-hydroxy-5H-furan-2-one-3-yl, 5-dialkyl-4-hydroxy-5H-furan-2-one-3-yl, 5-cycloalkyl-4-hydroxy-5H-furan-2-one-3-yl, 5-bicycloalkyl-4-hydroxy-5H-furan-2-one-3-yl, 3-hydroxy-cyclobut-3-ene-1, 2-dione-4-yl or 3-hydroxy-cyclobut-3-ene-1, 2-diketo-4-amino, wherein each alkyl or alkoxy group may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and unsubstituted or fluorinated C₁-C₃Alkyl or C₁-C₃An alkoxy group;

wherein R is⁸Selected from: OH, OR⁹、NR¹⁰R¹¹、C₁-C₆Alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl;

R⁹selected from: c₁-C₃Alkyl, W substituted C₁-C₃Alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl or alkoxyalkyl; wherein W is selected from: OH, acetylamino, C₁-C₃Alkoxycarbonyloxy or C₁-C₄An alkylcarbonyloxy group;

R¹⁰and R¹¹Independently selected from: H. OH, C₁-C₃Alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

x is-S (O)₂-、-C(O) -or- (CH₂) n-; wherein n is 0, 1 or 2;

m is 0, 1 or 2.

In certain preferred embodiments, the compounds of the present invention are of formula I, a pharmaceutically acceptable salt or ester, or solvate thereof:

R¹selected from: H. f, Cl, Br, I, OCH₃；

R²Selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, fused ring aryl, or substituted fused ring aryl, wherein said substituted phenyl, substituted heteroaryl, or substituted fused ring aryl may independently be substituted with 1 to 3 of the following substituents: F. cl, Br, I, CN, NO₂、NH₂、OH、C₁-C₃Alkyl radical, C₁-C₃Alkoxy, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl;

R³selected from: H. f, Cl, Br, I, CN, NO₂、NH₂、OH、N₃、C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkyl oxy, C₃-C₈Heterocycloalkyl radical, C₃-C₈Heterocycloalkyloxy, phenyl, phenyloxy, phenyl (C)₁-C₂) Alkyl, phenyl (C)₁-C₂) Alkoxy radical, C₅-C₆Heteroaryl group, C₅-C₆Heteroaryloxy radical, C₅-C₆Heteroaryl (C)₁-C₂) Alkyl radical, C₅-C₆Heteroaryl (C)₁-C₂) Alkoxy radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkyl radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkoxy radical, C₃-C₈Heterocycloalkyl (C)₁-C₂) Alkyl, heterocycloalkyl (C)₁-C₂) Alkyloxy, wherein R³Each radical in (A) may be unsubstituted or substituted by one orSubstituted with a plurality of substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C₁-C₆Alkyl and unsubstituted or halogenated C₁-C₆An alkoxy group;

R⁴,R⁵,R⁶independently selected from: H. f, Cl, Br, I, CN, NO₂、NH₂、OH、C₁-C₃Alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, alkenyl, cycloalkenyl, alkynyl, alkylsulfonyl, haloalkylsulfonyl, substituted amino, aminoalkyl, substituted aminoalkyl groups, which substituted amino or substituted aminoalkyl groups may independently be substituted on nitrogen with 1 to 2 substituents from the group consisting of: c₁-C₃Alkyl, haloalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, alkoxyalkyl, hydroxyalkyl; or, R⁴,R⁵,R⁶Each two of which, together with the atoms to which they are attached, form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring;

R⁷selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl;

a is selected from: substituted phenyl, substituted heteroaryl, substituted fused ring aryl, wherein the substituted phenyl, substituted heteroaryl or substituted fused ring aryl may independently be substituted with 1 to 3 of the following substituents: H. f, Cl, Br, I, CN, NO₂、NH₂、N₃、OH、-COR、-CONHS(O)₂R⁸、-NHCONHS(O)₂R⁸、-S(O)₂NH₂、-S(O)₂NHCOCH₃、C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, 1H-tetrazol-5-yl,3H-[1,3,4]Oxadiazol-2-one-5-yl, 3H- [1,3,4 ]]Oxadiazole-2-thione-5-yl, 4H- [1,2,4 [ ]]Oxadiazol-5-one-3-yl;

wherein R is⁸Selected from: OH, OR⁹、NR¹⁰R¹¹、C₁-C₆An alkyl group;

R⁹selected from: c₁-C₃Alkyl or W substituted C₁-C₃Alkyl, wherein W is selected from: OH, acetylamino, C₁-C₃Alkoxycarbonyloxy or C₁-C₄An alkylcarbonyloxy group;

R¹⁰and R¹¹Independently selected from: : H. OH or C₁-C₃An alkyl group;

x is- (CH)₂) n-; wherein n is 0, 1 or 2;

m is 0, 1 or 2.

In certain more preferred embodiments, the compounds of the present invention are of formula I, a pharmaceutically acceptable salt or ester, or solvate thereof:

R¹selected from: H. f, Cl or Br;

R²selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, wherein said substituted phenyl or substituted heteroaryl may independently be substituted with 1 to 3 substituents as follows: F. cl, Br, I, CN, NO₂、NH₂、OH、C₁-C₃An alkyl group;

R³selected from: H. f, Cl, Br, I, CN, C₁-C₈Alkoxy radical, C₃-C₈Cycloalkyl oxy, C₃-C₈Heterocycloalkyloxy, phenyloxy, phenyl (C)₁-C₂) Alkoxy radical, C₅-C₆Heteroaryloxy radical, C₅-C₆Heteroaryl (C)₁-C₂) Alkoxy radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkoxy, heterocycloalkyl (C)₁-C₂) Alkyloxy, wherein R³Each of (1) toEach group may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C₁-C₆Alkyl and unsubstituted or halogenated C₁-C₆An alkoxy group.

R⁴,R⁵,R⁶Independently selected from: H. f, Cl, OH, Br, I, CN, C₁-C₃Alkyl, alkoxy;

R⁷selected from: H. c₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group;

a is selected from: substituted phenyl, substituted heteroaryl, wherein said substituted phenyl or substituted heteroaryl may independently be substituted with 1 to 3 substituents as follows: H. f, Cl, Br, I, CN, NO₂、OH、-COR⁸、C₁-C₆Alkyl radical, C₁-C₆Alkoxy, 1H-tetrazol-5-yl, 3H- [1,3,4 ] methyl]Oxadiazol-2-one-5-yl;

wherein R is⁸Selected from: OH, OR⁹、NR¹⁰R¹¹；

R⁹Selected from: c₁-C₃Alkyl or W substituted C₁-C₃Alkyl, wherein W is selected from: OH, acetylamino, C₁-C₃Alkoxycarbonyloxy or C₁-C₄An alkylcarbonyloxy group;

R¹⁰and R¹¹Independently selected from: H. OH or C₁-C₃An alkyl group;

x is- (CH)₂) n-; wherein n is 0, 1 or 2;

m is 0, 1 or 2.

In certain most preferred embodiments, the compounds of the present invention, or pharmaceutically acceptable salts or esters or solvates thereof, are selected from the group consisting of compounds 1-95:

the compounds of the present invention may also be used as pharmaceutically acceptable salts. The salt may be an acid salt of at least one of the following acids: galactaric acid, D-glucuronic acid, glycerophosphoric acid, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharinic acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecylenic acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid. Alternatively, the salts may be formed with metal (including but not limited to sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amines (including but not limited to ethylenediamine, tromethamine, etc.), ammonium ions or choline of the compounds of the present invention.

The compounds of the present invention may also be comprised in pharmaceutical compositions in the form of esters, prodrugs, N-oxides or solvates thereof.

The invention also provides application of the indole sulfonamide compound in preparation of a medicament for preventing or treating FABP4/5 mediated diseases.

The compound of the formula I or the pharmaceutically acceptable salt, ester or solvate thereof is a novel FABP4/5 inhibitor, and therefore can be used for preparing medicaments for preventing or treating FABP4/5 mediated diseases.

The FABP4/5 mediated diseases, such as metabolic diseases and cardiovascular and cerebrovascular diseases, comprise: insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, diabetic complications (including diabetic cardiomyopathy, diabetic nephropathy, diabetic ulcer, retinopathy, neuropathy and the like), non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic fatty liver disease, liver cirrhosis, hyperuricemia, gout, osteoporosis, polycystic ovary syndrome (PCOS), stroke, cerebral infarction and the like.

Such FABP4/5 mediated diseases, such as inflammatory diseases, autoimmune diseases, organ fibrotic diseases, neurological injury diseases or secondary diseases caused by infection by pathogens, including: pneumonia, tuberculosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, allergic rhinitis, chronic rhinitis, sinusitis, systemic lupus erythematosus, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendonitis, thromboangiitis obliterans, phlebitis, intermittent claudication, keloid, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, septicemia, gangrenous skin disease, uveitis, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary disease, Parkinson's disease, Alzheimer's disease, alpha-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, Neuralgia, Down's syndrome, Harlervorden-Spatz disease, Huntington's chorea or Wilson's disease, etc.

Such FABP4/5 mediated diseases, such as mitochondrial dysfunction and disorder diseases, including: myasthenia, myoclonus, exercise intolerance, cahns-seire syndrome, chronic fatigue syndrome, li's syndrome, mitochondrial myopathy-encephalopathy-hyperlactacidemia, stroke syndrome, or stroke-like episodes. Likewise, the compounds of the invention may also be useful in the treatment of muscular dystrophy states, for example, duchenne muscular dystrophy, conchal muscular dystrophy or friedrich's ataxia.

Such FABP4/5 mediated diseases, such as tumors, include: bone cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, hodgkin's lymphoma, non-hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningiosarcoma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, fibroma, sarcoma, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, colon cancer, rectal cancer, renal cancer, prostate cancer, lymphatic cancer, testicular cancer, interstitial cell cancer, lung cancer, liver cancer, skin cancer, malignant melanoma, basal cell carcinoma, and the like.

The invention also provides a pharmaceutical composition for preventing or treating FABP4/5 mediated diseases, which comprises a therapeutically effective amount of a compound shown in the formula I or a pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient and pharmaceutically acceptable auxiliary materials.

The adjuvant which can be arbitrarily mixed in the pharmaceutical composition of the present invention may vary depending on the dosage form, administration form, etc. The adjuvants include excipient, binder, disintegrating agent, lubricant, correctant, flavoring agent, colorant, sweetener, etc. The administration route of the pharmaceutical composition can be oral, sublingual, transdermal, intramuscular or subcutaneous, cutaneous mucosa or vein, etc. The pharmaceutical composition can be in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, creams, ointments, suppositories, patches and other pharmaceutically conventional preparations.

The preparation of the compounds of the invention can be carried out with reference to the following synthetic routes or modified methods.

Scheme 1.

Firstly, substituted aniline is used as a raw material and reacts with N-iodosuccinimide under an acidic condition to obtain a corresponding single or two o-iodoaniline isomer mixture, N-hexane is used for beating and separating according to the property difference of isomers to obtain a pure product, then corresponding carbamate is obtained under the condition of ethyl chloroformate, corresponding substituted alkyne is obtained by a Sonogashira coupling reaction and reacts with trimethylacetylene silicon, corresponding indole is obtained by a Larock indole synthesis method, and then the substituted alkyne reacts with aryl boric acid at room temperature through a Chan-Evans-Lam coupling reaction, and aryl is introduced into the 1-position of the indole. This reaction proceeds as the oxygen in the air continuously oxidizes copper, and the reaction is difficult to proceed under the protection of an inert gas. The concentration of oxygen in the solution determines the progress of the reaction, so that the yield tends to vary depending on the stirring efficiency. Then, the obtained compound is treated with sulfur trioxide pyridine to obtain corresponding pyridinium sulfonate, then the corresponding sulfonyl chloride is obtained under the condition of phosphorus oxychloride, and the obtained product is condensed with corresponding aniline to obtain the target product.

Scheme 2.

Condensing indole obtained by Larock indole synthesis with corresponding halogenated hydrocarbon at normal temperature under the condition of potassium hydroxide, introducing corresponding aliphatic chain into indole 1 position, and the rest steps are similar to the steps in the scheme 1

Scheme 3.

Because the nitrogen negative ion formed at the position of indole 1 has weaker affinity and the secondary carbon positive ion has weaker reaction activity, an aliphatic ring cannot be introduced at the position of indole 1 by the method of the route 2, the obtained indole is firstly reduced under the conditions of borane tetrahydrofuran and trifluoroacetic acid to obtain corresponding indoline, then the corresponding aliphatic ring is introduced at the position of indoline 1 by the normal-temperature reaction under the conditions of corresponding alicyclic ketone, sodium triacetoxyborohydride and sodium cyanoborohydride, and then the obtained indoline is oxidized into the corresponding indole under the condition of dichloro dicyanobenzoquinone. The remaining steps are similar to route 2.

Scheme 4.

The sulfonyl chloride in the route 1 is used as a raw material, condensed with corresponding aminobenzoate at normal temperature to obtain a corresponding ester compound, hydrolyzed under an alkaline condition to obtain a corresponding acid, then obtained under a sulfoxide chloride condition to obtain a corresponding acyl chloride, and then reacted with ammonia water to obtain amide. And (3) dehydrating the amide with phosphorus oxychloride to obtain a cyano compound, and carrying out Click reaction with sodium azide to obtain a target product.

Scheme 5.

Firstly, substituted indole is used as a raw material, corresponding N-trimethylacetyl indole is obtained under the conditions of trimethylacetyl chloride, 4-dimethylpyridine and triethylamine, then under the condition of boron tribromide, a lone pair electron on a carbonyl oxygen atom in the trimethylacetyl can form a coordinate bond with an empty orbit of boron, so that a boron dibromide group can be selectively arranged on the 7 site of the indole, then, corresponding phenylboronic acid pinacol ester is obtained under the conditions of pinacol and pyridine, and then, the corresponding 7-hydroxyindole is obtained through hydrogen peroxide oxidation under the alkaline condition. And secondly, respectively carrying out nucleophilic substitution twice, namely firstly introducing corresponding aliphatic groups on the phenolic hydroxyl at the 7-position of the indole by heating at 70 ℃ under the condition of corresponding halogenated hydrocarbon and potassium carbonate, and then introducing corresponding substituent groups on the N at the 1-position of the indole by reacting at normal temperature under the condition of corresponding halogenated hydrocarbon and potassium hydroxide. The remaining steps are similar to route 1.

Scheme 6.

The obtained indole sulfonamide compound, sodium hydride and alkyl iodide react in N, N-dimethylformamide in ice bath at room temperature to obtain the product substituted on the indole sulfonamide N, and the rest steps are similar to the steps in the scheme 6.

In the above synthetic scheme, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²X and m are as defined above for compounds of formula I.

In the agent for preventing or treating a FABP 4/5-mediated disease of the present invention, the amount of the compound of formula I or a pharmaceutically acceptable salt or ester or solvate thereof may be appropriately changed depending on the age, body weight, condition, administration route, and the like of the patient. When administered orally to an adult (about 60kg), the compound of formula I or a pharmaceutically acceptable salt or ester or solvate thereof is preferably administered in an amount of 1mg to 500mg per time, more preferably 5mg to 60mg per time, 1 to 3 times per day. This dosage range may also vary depending on the degree of disease and dosage form.

Has the advantages that: the invention provides an indole sulfonamide compound with FABP4/5 inhibitory activity, which can be used for preparing a medicament for preventing or treating FABP4/5 related diseases and has wide market application and development prospects.

Detailed Description

The present invention will be described in detail with reference to examples. In the present invention, the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention. Various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The experimental methods described in the following examples are all conventional reagents unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

Example 14 Ethyl- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) benzoate (Compound 1)

Compound I-1(10g, 68.7mmol) was placed in a solanaceous bottle and dissolved with glacial acetic acid (137mL), N-iodosuccinimide (NIS) (15.6g, 69.4mmol) was slowly added under ice bath, and after completion of addition, stirring was carried out at room temperature for 1 hour. After completion of the reaction, ethyl acetate (50mL) was added to the reaction solution for dilution, a saturated sodium bicarbonate solution (500mL) was added until no bubble was generated, sodium thiosulfate (50mL) was further added to remove excess N-iodosuccinimide, followed by washing with a saturated sodium chloride solution (50mL × 2), drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate 200:1) to obtain compound I-2 (white solid, 8.1g, yield 43%):¹H NMR(300MHz,DMSO-d₆)δ7.61(d,J＝8.8Hz,1H),6.87(d,J＝6.9Hz,1H),5.31(s,2H).

compound I-2(7.6g, 27.99mmol) was dissolved in pyridine (42mL), ethyl chloroformate (3mL, 30.79mmol) was added slowly under ice bath, and after addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50mL), washed with 2N hydrochloric acid (50mL × 3) until no pyridine remained, washed with a saturated sodium chloride solution (30mL × 3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 100:1) to obtain compound I-4 (white solid, 11.1mg, yield 99%):¹H NMR(300MHz,DMSO-d₆)δ9.01(s,1H),7.98(d,J＝8.7Hz,1H),7.61(d,J＝7.3Hz,1H),4.13(q,J＝7.1Hz,2H),1.25(t,J＝7.1Hz,3H).

compound I-4(11.1g, 32.2mmol), bis (triphenylphosphine) palladium chloride (565.7mg, 0.8mmol), cuprous iodide (307mg, 1.6mmol) were dissolved in tetrahydrofuran (129mL) under argon protection, triethylamine (13.4mL, 96.7mmol) and trimethylethynyl silicon (TMSA) (6.8mL, 48.4mmol) were added, and after addition, stirring was carried out at room temperature for 2 hours. After completion of the reaction, filtration was carried out with celite, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether: dichloromethane:ethyl acetate 500:1:0.1) to give compound I-5 (yellow solid, 8.2g, 81% yield):¹H NMR(300MHz,CDCl₃)δ8.27(d,J＝6.9Hz,1H),7.30(s,1H),7.15(d,J＝8.9Hz,1H),4.25(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H),0.29(s,9H).

compound I-5(7.1g, 22.6mmol) and sodium ethoxide (5.5g, 81.4mmol) were dissolved in absolute ethanol (284mL) and refluxed at 80 ℃ for 4 hours under the protection of argon. After completion of the reaction, the solvent was distilled off under reduced pressure, extracted with ethyl acetate (40mL × 3), washed with saturated sodium chloride (30mL × 2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 25:1) to obtain compound I-6 (brown solid, 3.96g, 91%):¹H NMR(300MHz,CDCl₃)δ8.15(s,1H),7.39(dd,J＝14.4,7.8Hz,2H),7.25(d,J＝4.0Hz,1H),6.51(s,1H).

compound I-6(200mg, 1.18mmol), phenylboronic acid (288mg, 2.36mmol), copper acetate (428mg, 2.36mmol), 4A molecular sieves (4A MS) (1.6g) were dissolved in anhydrous dichloromethane (10mL), pyridine (190. mu.L) and triethylamine (328. mu.L) were added, and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction solution was suction-filtered through celite, the filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: dichloromethane ═ 20:1) to give compound I-7 (colorless liquid, 225mg, yield 78%):¹H NMR(300MHz,CDCl₃)δ7.57(d,J＝6.8Hz,2H),7.54(d,J＝2.2Hz,1H),7.48(s,1H),7.44(d,J＝8.1Hz,2H),7.39(dd,J＝9.9,4.0Hz,2H),6.64(d,J＝3.1Hz,1H).

compound I-7(55mg, 0.21mmol) was dissolved in pyridine (1mL), pyridine sulfur trioxide (102mg, 0.64mmol) was added, and the mixture was heated in a sealed tube at 105 ℃ for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained solid product was used directly in the next step.

The solid obtained in the above step was dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (0.5mL +1mL), added with phosphorus oxychloride (43 μ L,0.45mmol) under argon protection in ice bath, and then heated to 70 ℃ for reaction for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (10 mL. times.3), washed with ice water (10 mL. times.3), washed with saturated sodium chloride (10 mL. times.1), dried over anhydrous sodium sulfate, and evaporated under reduced pressureThe solvent and residue were purified by column chromatography (petroleum ether: ethyl acetate 50:1) to give compound I-9 (white solid, 52mg, two-step yield 67%):¹H NMR(300MHz,CDCl₃)δ8.07(s,1H),7.84(d,J＝8.7Hz,1H),7.68–7.57(m,3H),7.51(dd,J＝13.0,6.6Hz,3H).

compound I-9(42mg, 0.12mmol) and ethyl 4-aminobenzoate (40mg, 0.24mmol) were dissolved in dichloromethane (2mL), stirred at room temperature for 30 minutes, then pyridine (20. mu.L, 0.24mmol) was added, and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 50:1) to give compound 1 (pale yellow solid, 86.2mg, yield 99%):¹H NMR(300MHz,DMSO-d₆)δ10.98(s,1H),8.58(s,1H),7.88(d,J＝9.6Hz,1H),7.81(d,J＝8.7Hz,2H),7.71–7.57(m,6H),7.29(d,J＝8.7Hz,2H),4.22(q,J＝7.1Hz,2H),1.25(t,J＝7.1Hz,3H).ESI-MS:m/z 495.1[M+Na]⁺.

example 25- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid ethyl ester (Compound 2)

Compound 2 was prepared according to the procedure of example 1:¹H NMR(300MHz,CDCl3)δ7.75(s,1H),7.64–7.51(m,4H),7.47(d,J＝6.0Hz,1H),7.42–7.32(m,3H),7.05(t,J＝9.4Hz,1H),6.82(s,1H),4.34(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H).

example 33 Ethyl- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) -4-fluorobenzoate (Compound 3)

Compound 3 was prepared according to the procedure of example 1:¹H NMR(300MHz,CDCl3)δ8.35(dd,J＝7.7,2.0Hz,1H),7.96(s,1H),7.90–7.81(m,1H),7.71(d,J＝9.0Hz,1H),7.69–7.61(m,2H),7.53(d,J＝6.0Hz,1H),7.46(d,J＝7.1Hz,2H),7.10(t,1H),7.03(s,1H),4.43(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H).

example 44- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 4)

Taking out the compound1(43.1mg, 0.09mmol) was dissolved in a methanol-tetrahydrofuran mixed solvent (0.4mL +0.8mL), and 1M sodium hydroxide solution (400. mu.L) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution to adjust pH to acidity, dichloromethane (10mL × 3) was extracted, washed with saturated sodium chloride (10mL × 1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol ═ 20:1) to give compound 4 (white solid, 38.7mg, yield 95%):¹H NMR(300MHz,DMSO-d₆)δ7.93–7.83(m,1H),7.73–7.63(m,3H),7.63–7.54(m,5H),7.48–7.41(m,1H),7.37(d,J＝5.7Hz,2H).

example 55- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 5)

Compound 5 was prepared according to the procedure of example 4:¹H NMR(300MHz,DMSO-d₆)δ13.28(s,1H),10.58(s,1H),8.36(s,1H),7.82(d,J＝9.7Hz,1H),7.65(d,J＝6.1Hz,1H),7.63–7.56(m,5H),7.56–7.48(m,1H),7.44–7.34(m,1H),7.18(t,J＝9.7Hz,1H).

example 63- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) -4-fluorobenzoic acid (compound 6)

Compound I-9(42mg, 0.12mmol) and ethyl 4-aminobenzoate (40mg, 0.24mmol) were dissolved in dichloromethane (2mL), stirred at room temperature for 30 minutes, then pyridine (20. mu.L, 0.24mmol) was added, and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 50:1) to give compound 6 (pale yellow solid, 86.2mg, yield 99%):¹H NMR(300MHz,DMSO-d₆)δ13.09(s,1H),10.43(s,1H),8.26(s,1H),7.87(d,J＝7.5Hz,1H),7.79(d,J＝9.8Hz,1H),7.76–7.68(m,1H),7.65(d,J＝6.2Hz,1H),7.62–7.46(m,5H),7.27(t,J＝9.3Hz,1H).

EXAMPLE 7N- (4- (2H-tetrazol-5-yl) phenyl) -6-chloro-5-fluoro-1-phenyl-1H-indole-3-sulfonamide (Compound 7)

Compound 1(100mg, 0.21mmol) was dissolved in a methanol-tetrahydrofuran mixed solvent (0.5mL +1.0mL), and 1M sodium hydroxide solution (0.5mL) was added thereto, followed by stirring at 70 ℃ for 3 hours. After the reaction was completed, 2N hydrochloric acid was added to the reaction solution to adjust the pH to acidity, ethyl acetate (5mL × 3) was extracted, the organic phases were combined, washed with saturated sodium chloride (5mL × 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the obtained product was used in the next reaction without purification.

The above product was dissolved in toluene (1mL), thionyl chloride (32. mu.L, 0.43mmol) was added to the solution, and after the addition was completed, stirring was carried out at 75 ℃ for 1 hour. After the reaction is finished, the solvent is evaporated under reduced pressure, and the obtained product is directly used for the next reaction without purification.

The product was slowly added to aqueous ammonia (5mL) and stirred overnight at room temperature after the addition. After the reaction, ethyl acetate (5 mL. times.3) was added to the reaction solution for extraction, the organic phases were combined, washed with a saturated sodium chloride solution (5 mL. times.2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a product which was used in the next reaction without purification.

The above-mentioned product was dissolved in chloroform (2mL), and phosphorus oxychloride (2mL) was added to the reaction mixture, followed by heating at 110 ℃ for 5 hours. After completion of the reaction, the reaction solution was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (5mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (5mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to obtain compound II-3 (white solid, 54mg, yield 60% in four steps).

Sodium azide (76mg, 1.17mmol) and zinc chloride (64mg, 0.47mmol) were suspended in n-butanol (2mL), stirred at room temperature for 30 minutes, compound II-3(100mg, 0.23mmol) was added, and the mixture was sealed and heated at 120 ℃ for 48 hours. After the reaction of the starting materials was completed, heating was stopped, the reaction mixture was cooled to room temperature, 2N HCl (10mL) was added to the reaction mixture, the mixture was stirred for 30 minutes, extracted with ethyl acetate (5 mL. times.4), the organic phases were combined, washed with saturated brine (5 mL. times.2), dried over anhydrous sodium sulfate,the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (dichloromethane: methanol: acetic acid 200:4:1) and slurried with diethyl ether (5mL) to give compound 7 (beige solid, 66.5mg, 60% yield):¹H NMR(300MHz,DMSO-d₆)δ16.68(s,1H),10.89(s,1H),8.59(s,1H),7.89(t,J＝9.1,5.0Hz,3H),7.71–7.59(m,5H),7.57–7.46(m,1H),7.38(d,J＝8.7Hz,2H).ESI-MS:m/z507.9[M+K]⁺.

EXAMPLE 86-chloro-5-fluoro-N- (4-fluoro-3- (1H-tetrazol-5-yl) phenyl) -1-phenyl-1H-indole-3-sulfonamide (Compound 8)

Compound 8 was prepared according to the procedure of example 7:¹H NMR(300MHz,DMSO-d₆)δ16.83(s,1H),10.64(s,1H),8.42(s,1H),7.89–7.79(m,2H),7.65(d,J＝6.2Hz,1H),7.60(d,J＝4.3Hz,4H),7.57–7.48(m,1H),7.44–7.34(m,2H).ESI-MS:m/z485.1[M-H]^-.

example 95- ((6-chloro-1- (2-cyclohexylethyl) -5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 9)

Compound I-6(150mg, 0.88mmol) was dissolved in dimethylformamide (3mL), and 2-cyclohexylbromoethane (254mg, 1.33mmol) and potassium hydroxide (74mg, 1.33mmol) were added to the solution, which was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with water (30mL), extracted with ethyl acetate (8mL × 3), the organic phases were combined, washed with water (5mL × 2), washed with a saturated sodium chloride solution (5mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate 75:1) to give compound III-1 (colorless oily liquid, 310.4mg, yield 94%).

Compound III-1(300mg, 1.07mmol) was dissolved in pyridine (3mL), pyridine sulfur trioxide (512mg, 3.22mmol) was added, and the mixture was heated in a sealed tube at 110 ℃ for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained product was used in the next step without purification.

The product obtained in the above step is dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (2mL +4mL), under the protection of argon, and phosphorus oxychloride (200. mu.L, 2.14mmol) is added under ice bath, and then heated to 70 ℃ for reaction for 6 hours. After completion of the reaction, the reaction solution was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (10mL × 3), washed with ice water (10mL × 3), washed with saturated sodium chloride (10mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give compound III-3 (yellow oily liquid, 164mg, two-step yield 40%).

Compound III-3(82mg, 0.22mmol) and 5-amino-2-fluorobenzoic acid (67mg, 0.43mmol) were dissolved in dichloromethane (2mL), stirred at room temperature for 30 minutes, then added pyridine (52. mu.L, 0.65mmol), and stirred at room temperature for 12 hours. After completion of the reaction, 2N HCl (20mL), ethyl acetate (5mL × 3) extraction, 2N HCl (5mL × 2) washing, saturated sodium chloride (5mL × 2) washing, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and purification of the residue by column chromatography (dichloromethane: methanol: acetic acid ═ 200:3:1), and the resulting solid was slurried with ether to obtain compound 9 (white solid, 63.5mg, yield 59%):¹H NMR(300MHz,DMSO-d₆)δ13.23(s,1H),10.27(s,1H),8.07(s,1H),7.95(d,J＝6.2Hz,1H),7.71(d,J＝9.8Hz,1H),7.55(dd,J＝6.3,2.8Hz,1H),7.34–7.24(m,1H),7.14(t,1H),4.22(t,J＝7.1Hz,2H),1.68–1.45(m,7H),1.11–0.99(m,3H),0.99–0.92(m,1H),0.91–0.79(m,2H).

example 104- ((6-chloro-1- (2-cyclohexylethyl) -5-fluoro-1H-indole) -3-sulfonamido) benzoic acid (Compound 10)

Compound 10 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ12.62(s,1H),10.72(s,1H),8.28(s,1H),7.95(d,J＝6.2Hz,1H),7.79–7.72(m,3H),7.18(d,J＝8.7Hz,2H),4.24(t,J＝7.1Hz,2H),1.65–1.52(m,7H),1.12–0.99(m,3H),0.95–0.79(m,3H).

example 114- ((6-chloro-1- (cyclohexylmethyl) -5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 11)

Compound 11 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ12.63(s,1H),10.68(s,1H),8.20(s,1H),7.99(d,J＝6.2Hz,1H),7.75(t,J＝8.9Hz,3H),7.17(d,J＝8.6Hz,2H),4.05(d,J＝7.3Hz,2H),1.69–1.50(m,4H),1.19(d,J＝10.4Hz,2H),1.07–0.95(m,3H),0.80(d,2H).ESI-MS:m/z 463.1[M-H]^-.

example 125- ((6-chloro-1- (cyclohexylmethyl) -5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 12)

Compound 12 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ13.20(s,1H),10.25(s,1H),7.99(d,J＝6.6Hz,2H),7.71(d,J＝9.8Hz,1H),7.55(dd,J＝6.3,2.7Hz,1H),7.30–7.20(m,1H),7.12(t,1H),4.03(d,J＝7.2Hz,2H),1.73–1.45(m,4H),1.21–1.11(m,2H),1.11–0.92(m,3H),0.88–0.66(m,2H).ESI-MS:m/z 481.1[M-H]^-.

example 134- ((6-chloro-5-fluoro-1-octyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 13)

Compound 13 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ12.61(s,1H),10.70(s,1H),8.30(s,1H),7.97(d,J＝6.2Hz,1H),7.79–7.72(m,3H),7.17(d,J＝8.7Hz,2H),4.22(t,J＝6.7Hz,2H),1.72–1.60(m,2H),1.25–1.09(m,8H),1.03–0.92(m,2H),0.81(t,J＝7.0Hz,3H).ESI-MS:m/z 479.1[M-H]^-.

example 145- ((6-chloro-5-fluoro-1-octyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 14)

Compound 14 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ13.20(s,1H),10.27(s,1H),8.08(s,1H),7.97(d,J＝6.2Hz,1H),7.70(d,J＝9.8Hz,1H),7.54(dd,J＝6.2,2.7Hz,1H),7.30–7.23(m,1H),7.12(t,J＝9.6Hz,1H),4.20(t,J＝6.6Hz,2H),1.68–1.57(m,2H),1.25–1.09(m,8H),1.00–0.90(m,2H),0.81(t,J＝7.0Hz,3H).ESI-MS:m/z497.1[M-H]^-.

example 155- ((4-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 15)

Compound 15 was prepared according to the procedure of example 1:¹H NMR(300MHz,DMSO-d₆)δ13.29(s,1H),10.39(s,1H),8.46(s,1H),7.70–7.51(m,6H),7.48–7.30(m,3H),7.18(t,1H).

example 164- ((6-chloro-1-cycloheptyl-5-fluoro-1H-indole) -3-sulfonamido) benzoic acid (Compound 16)

Compound I-6(450mg, 2.65mmol) was dissolved in borane in tetrahydrofuran (4mL) and stirred in ice bath for 30 min, trifluoroacetic acid (TFA) (4mL) was added and stirred for 30 min while maintaining ice bath. After completion of the reaction, the reaction mixture was diluted with saturated sodium bicarbonate (30mL), extracted with ethyl acetate (8mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (5mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give compound IV-1 (brown oily liquid, 454.8mg, yield 90%).

Compound IV-1(272mg, 1.59mmol) and cycloheptanone (374. mu.L, 3.17mmol) were dissolved in 1, 2-Dichloroethane (DCE) (5mL), stirred at room temperature for 30 minutes, added Sodium Triacetoxyborohydride (STAB) (669mg, 3.17mmol), and stirred at room temperature overnight. To the reaction solution was added sodium cyanoborohydride (190mg, 3.17mmol), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate 50:1) to give compound IV-2 (colorless oily liquid, 146.4mg, yield 34%).

Compound IV-2(134mg, 1.50mmol) and 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (DDQ) (125mg, 0.55mmol) were dissolved in dry dichloromethane (3mL) and stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate: 100:1) to give compound IV-3 (colorless oily liquid, 101.3mg, yield 76%).

Compound IV-3(96mg, 0.36mmol) was dissolved in pyridine (1mL), pyridine sulfur trioxide (172mg, 1.08mmol) was added, and the mixture was heated in a sealed tube at 110 ℃ for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained product was used in the next step without purification.

The product obtained in the above step was dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (1mL +2mL), added with phosphorus oxychloride (67. mu.L, 0.72mmol) under argon protection in ice bath, and then heated to 70 ℃ for reaction for 5 hours. After completion of the reaction, the reaction solution was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (10mL × 3), washed with ice water (10mL × 3), washed with saturated sodium chloride (10mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give compound IV-4 (yellow oily liquid, 130.5mg, yield in two steps 99%).

Compound IV-4(82mg, 0.22mmol) and 4-amino-benzoic acid (49mg, 0.36mmol) were dissolved in anhydrous dichloromethane (2mL), stirred at room temperature for 30 minutes, then pyridine (43. mu.L, 0.54mmol) was added, and stirred at room temperature for 12 hours. After completion of the reaction, 2N HCl (20mL), ethyl acetate (5mL × 3) extraction, 2N HCl (5mL × 2) washing, saturated sodium chloride (5mL × 2) washing, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, purification of the residue by column chromatography (dichloromethane: methanol: acetic acid ═ 200:3:1), and beating of the resulting solid with ether, compound 16 (white solid, 60mg, yield 85%) was obtained:¹H NMR(300MHz,DMSO-d₆)δ12.64(s,1H),10.69(s,1H),8.33(s,1H),8.06(d,J＝6.3Hz,1H),7.78–7.71(m,3H),7.18(d,J＝8.7Hz,2H),4.65–4.56(m,1H),1.99–1.83(m,4H),1.74–1.51(m,8H).ESI-MS:m/z463.2[M-H]^-.

example 175- ((6-chloro-1-cycloheptyl-5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 17)

Compound 17 was prepared according to the procedure of example 16:¹H NMR(300MHz,DMSO-d₆)δ13.26(s,1H),10.24(s,1H),8.13–8.02(m,2H),7.66(d,J＝9.8Hz,1H),7.49(dd,J＝6.2,2.6Hz,1H),7.31–7.23(m,1H),7.20–7.10(m,1H),4.61(s,1H),1.94–1.80(m,4H),1.72–1.48(m,8H).ESI-MS:m/z 481.2[M-H]^-.

example 184- ((6-chloro-1-cyclohexyl-5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 18)

Compound 18 was prepared according to the procedure of example 16:¹H NMR(300MHz,DMSO-d₆)δ12.65(s,1H),10.72(s,1H),8.35(s,1H),8.08(d,J＝6.2Hz,1H),7.86–7.67(m,3H),7.18(d,J＝8.5Hz,2H),4.52–4.36(m,1H),1.96–1.61(m,7H),1.59–1.37(m,2H),1.37–1.16(m,1H).ESI-MS:m/z 449.1[M-H]^-.

example 195- ((6-chloro-1-cyclohexyl-5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 19)

Compound 19 was prepared according to the procedure of example 16:¹H NMR(300MHz,DMSO-d₆)δ13.27(s,1H),10.27(s,1H),8.17–8.02(m,2H),7.66(d,J＝9.8Hz,1H),7.50(d,J＝3.7Hz,1H),7.35–7.21(m,1H),7.15(t,J＝9.6Hz,1H),4.43(s,1H),1.89–1.63(m,7H),1.54–1.39(m,2H),1.28–1.20(m,1H).ESI-MS:m/z 467.1[M-H]^-.

example 204- ((6-chloro-5-fluoro-1-heptyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 20)

Compound 20 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ12.51(s,1H),10.69(s,1H),8.29(s,1H),7.97(d,J＝6.0Hz,1H),7.81–7.68(m,3H),7.17(d,J＝8.2Hz,2H),4.21(t,J＝6.4Hz,2H),1.74–1.57(m,2H),1.28–1.04(m,6H),1.03–0.89(m,2H),0.80(t,J＝6.7Hz,3H).

example 215- ((6-chloro-5-fluoro-1-heptyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 21)

Compound 21 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ13.23(s,1H),10.27(s,1H),8.07(s,1H),7.97(d,J＝6.2Hz,1H),7.70(d,J＝9.8Hz,1H),7.54(dd,J＝6.2,2.6Hz,1H),7.32–7.22(m,1H),7.12(t,J＝9.6Hz,1H),4.19(t,J＝6.6Hz,2H),1.71–1.52(m,2H),1.28–1.01(m,6H),1.02–0.87(m,2H),0.80(t,J＝6.9Hz,3H).

example 223 Ethyl- ((6-chloro-5-fluoro-1-heptyl-1H-indole) -3-sulfonylamino) -4-fluorobenzoate (Compound 22)

Compound 22 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ10.24(s,1H),8.11–7.93(m,2H),7.82(d,J＝7.6Hz,1H),7.70(d,J＝9.9Hz,2H),7.24(t,J＝9.3Hz,1H),4.31–4.15(m,4H),1.69–1.54(m,2H),1.26(t,J＝7.1Hz,3H),1.21–1.04(m,6H),1.04–0.91(m,2H),0.81(t,J＝6.8Hz,3H).

EXAMPLE 234- (((7- (cyclohexylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 23)

Compound V-1(2g, 14.8mmol) and 4-Dimethylaminopyridine (DMAP) (181mg, 1.48mmol) were dissolved in anhydrous dichloromethane (24mL), triethylamine (3.1mL, 22.2mmol) was added to the solution, trimethylacetyl chloride (PivCl) (2.17mL, 17.8mmol) was added under ice bath, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give compound V-2 (white solid, 2.94g, yield 91%).

Compound V-2(1g, 4.56mmol) was placed in a dry three-necked flask, dissolved by adding anhydrous dichloromethane (9mL) under argon, and a 1M solution of boron tribromide in dichloromethane (10mL) was added to the solution and stirred at room temperature for 3 hours. To the reaction mixture was added a solution of Pinacol (Pinacol) (1.89g, 15.92mmol) in triethylamine (9.6mL, 68.41mmol), and the mixture was stirred at room temperature for 5.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate: 30:1) to give compound V-3 (colorless oily liquid, 873mg, yield 55%).

Compound V-3(550mg, 1.59mmol) was dissolved in tetrahydrofuran (8mL), and to the reaction solution was added 0.5M aqueous sodium hydroxide solution (3.4mL), followed by slowly dropwise addition of 30% aqueous hydrogen peroxide solution (797. mu.L), and the mixture was stirred at room temperature overnight. After completion of the reaction, 2N HCl (10mL) was added to the reaction solution, the pH of the solution was adjusted to acidity, ethyl acetate (10mL × 2) was extracted, the organic phases were combined, washed with saturated sodium chloride (8mL × 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to obtain compound V-4 (colorless oily liquid, 188.4mg, yield 49%).

Compound V-4(107mg, 0.71mmol) was dissolved in N, N-dimethylformamide (4mL), and anhydrous potassium carbonate (196mg, 1.42mmol) and bromomethylcyclohexane (149. mu.L, 1.07mmol) were added to the solution, which was heated to 70 ℃ for 12 hours. After completion of the reaction, suction filtration was performed, water (40mL) was added for dilution, extraction was performed with ethyl acetate (8mL × 3), the organic phases were combined, washed with water (5mL × 2), washed with saturated sodium chloride (8mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 30:1) to obtain compound V-5 (colorless oily liquid, 44.7mg, yield 26%).

Compound V-5(44.7mg, 0.18mmol) was dissolved in N, N-dimethylformamide (2mL), and potassium hydroxide (20mg, 0.36mmol) and iodomethane (17. mu.L, 0.27mmol) were added to the solution, followed by stirring at room temperature overnight. After completion of the reaction, methyl iodide was distilled off under reduced pressure, diluted with water (20mL), extracted with ethyl acetate (5mL × 3), the organic phases were combined, washed with water (5mL × 2), washed with saturated sodium chloride (5mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate 75:1) to give compound V-6 (pale yellow solid, 44mg, yield 93%).

Compound V-6(43mg, 0.16mmol) was dissolved in pyridine (1mL), pyridine sulfur trioxide (78mg, 0.49mmol) was added, and the mixture was heated in a sealed tube at 110 ℃ for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained product was used in the next step without purification.

The product obtained in the above step was dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (0.5mL +1mL), added with phosphorus oxychloride (31. mu.L, 0.33mmol) under argon protection in ice bath, and heated to 70 ℃ for reaction for 6 hours. After completion of the reaction, the reaction solution was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (5mL × 3), washed with ice water (5mL × 3), washed with saturated sodium chloride (5mL × 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give compound V-8 (white solid, 57.5mg, yield in two steps 97%).

Compound V-8(82mg, 0.22mmol) and 4-aminobenzoic acid (22mg, 0.16mmol) were dissolved in anhydrous dichloromethane (1mL), stirred at room temperature for 30 minutes, followed by addition of pyridine (19. mu.L, 0.24mmol) and stirring at room temperature for 12 hours. After completion of the reaction, 2N HCl (10mL) was added to the reaction solution, ethyl acetate (5mL × 3) was extracted, 2N HCl (5mL × 2) was washed, saturated sodium chloride (5mL × 2) was washed, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (dichloromethane: methanol: acetic acid ═ 200:3:1), and the obtained solid was slurried with ether to give compound 23 (white solid)26mg, yield 71%):¹H NMR(300MHz,DMSO-d₆)δ12.65(s,1H),10.70(s,1H),8.08(s,1H),7.76(d,J＝8.6Hz,2H),7.22–7.10(m,3H),6.71(dd,J＝11.6,2.0Hz,1H),3.99(s,3H),3.89(d,J＝5.5Hz,2H),1.85–1.62(m,6H),1.30–1.06(m,5H).ESI-MS:m/z 459.1[M-H]^-.

example 245- ((7- (cyclohexylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 24)

Compound 24 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.26(s,1H),10.26(s,1H),7.91(s,1H),7.56(dd,J＝6.4,2.8Hz,1H),7.33–7.26(m,1H),7.15(t,1H),7.07(dd,J＝9.3,2.1Hz,1H),6.71(dd,J＝11.6,2.1Hz,1H),3.98(s,3H),3.90(d,J＝5.6Hz,2H),1.84–1.61(m,6H),1.30–1.07(m,5H)ESI-MS:m/z 477.1[M-H]^-.

EXAMPLE 254- (((7- (2-cyclohexylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 25)

Compound 25 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.54(s,1H),10.68(s,1H),8.08(s,1H),7.76(d,J＝8.6Hz,2H),7.27–7.07(m,3H),6.73(dd,J＝11.5,2.1Hz,1H),4.09(t,J＝6.5Hz,2H),3.97(s,3H),1.79–1.54(m,7H),1.54–1.36(m,1H),1.30–1.09(m,3H),1.02–0.83(m,2H).ESI-MS:m/z 473.2[M-H]^-.

example 265- ((7- (2-cyclohexylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 26)

Compound 26 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.26(s,1H),10.26(s,1H),7.91(s,1H),7.56(dd,J＝6.3,2.8Hz,1H),7.34–7.24(m,1H),7.15(t,1H),7.07(dd,J＝9.3,2.0Hz,1H),6.73(dd,J＝11.5,2.0Hz,1H),4.10(t,J＝6.5Hz,2H),3.95(s,3H),1.80–1.55(m,7H),1.47(s,1H),1.29–1.12(m,3H),1.03–0.84(m,2H).ESI-MS:m/z 491.2[M-H]^-.

example 272-chloro-5- ((6-chloro-5-fluoro-1-octyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 27)

Compounds prepared according to the procedure of example 927：¹H NMR(300MHz,DMSO-d₆)δ13.37(s,1H),10.51(s,1H),8.18(s,1H),7.98(d,J＝6.2Hz,1H),7.73(d,J＝9.8Hz,1H),7.49(d,J＝2.2Hz,1H),7.33(d,J＝8.7Hz,1H),7.22(dd,J＝8.7,2.4Hz,1H),4.21(t,J＝6.6Hz,2H),1.72–1.56(m,2H),1.31–1.05(m,8H),1.05–0.90(m,2H),0.80(t,J＝6.9Hz,3H).

Example 282-chloro-5- ((6-chloro-1- (2-cyclohexylethyl) -5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 28)

Compound 28 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ13.34(s,1H),10.52(s,1H),8.18(s,1H),7.97(d,J＝6.2Hz,1H),7.75(d,J＝9.8Hz,1H),7.51(s,1H),7.36(d,J＝8.6Hz,1H),7.24(d,J＝8.7Hz,1H),4.24(t,J＝7.0Hz,2H),1.75–1.46(m,7H),1.19–0.72(m,6H).

example 292-chloro-5- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 29)

Compound 29 was prepared according to the procedure of example 6:¹H NMR(300MHz,DMSO-d₆)δ13.47(s,1H),10.75(s,1H),8.49(s,1H),7.84(d,J＝9.6Hz,1H),7.70–7.57(m,5H),7.57–7.48(m,2H),7.39(d,J＝8.7Hz,1H),7.32(dd,J＝8.7,2.3Hz,1H).

example 302-chloro-5- ((6-chloro-1-cycloheptyl-5-fluoro-1H-indole) -3-sulfonamido) benzoic acid (Compound 30)

Compound 30 was prepared according to the procedure of example 16:¹H NMR(300MHz,DMSO-d₆)δ13.41(s,1H),10.49(s,1H),8.20(s,1H),8.06(d,J＝6.2Hz,1H),7.69(d,J＝9.7Hz,1H),7.45(d,J＝2.3Hz,1H),7.34(d,J＝8.7Hz,1H),7.27–7.14(m,1H),4.75–4.44(m,1H),2.00–1.79(m,4H),1.79–1.38(m,8H).

example 312-bromo-5- ((6-chloro-5-fluoro-1-octyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 31)

Compound 31 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ13.38(s,1H),10.54(s,1H),8.20(s,1H),7.99(d,J＝6.2Hz,1H),7.73(d,J＝9.8Hz,1H),7.57–7.38(m,2H),7.14(dd,J＝8.6,2.3Hz,1H),4.21(t,J＝6.6Hz,2H),1.74–1.55(m,2H),1.34–1.06(m,8H),1.05–0.89(m,2H),0.81(t,J＝6.9Hz,3H).

example 322-bromo-5- ((6-chloro-1- (2-cyclohexylethyl) -5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 32)

Compound 32 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ13.40(s,1H),10.54(s,1H),8.20(s,1H),7.98(d,J＝6.2Hz,1H),7.75(d,J＝9.8Hz,1H),7.52(d,J＝8.7Hz,1H),7.46(d,J＝2.2Hz,1H),7.16(dd,J＝8.6,2.4Hz,1H),4.25(t,J＝7.1Hz,2H),1.72–1.49(m,7H),1.18–0.76(m,6H).ESI-MS:m/z 555.1[M-H]^-.

example 332-bromo-5- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 33)

Compound 33 was prepared according to the procedure of example 6:¹H NMR(300MHz,DMSO-d₆)δ13.45(s,1H),10.75(s,1H),8.49(s,1H),7.84(d,J＝9.6Hz,1H),7.73–7.59(m,5H),7.59–7.40(m,3H),7.24(dd,J＝8.6,2.5Hz,1H).

example 342-bromo-5- ((6-chloro-1-cycloheptyl-5-fluoro-1H-indole) -3-sulfonamido) benzoic acid (Compound 34)

Compound 34 was prepared according to the procedure of example 16:¹H NMR(300MHz,DMSO-d₆)δ10.49(s,1H),8.20(s,1H),8.06(d,J＝6.2Hz,1H),7.69(d,J＝9.8Hz,1H),7.48(d,J＝8.7Hz,1H),7.41–7.34(m,1H),7.09(d,J＝8.6Hz,1H),4.67–4.53(m,1H),2.01–1.79(m,4H),1.79–1.43(m,8H).ESI-MS:m/z 541.1[M-H]^-.

example 355- ((6-chloro-5-fluoro-1-octyl-1H-indole) -3-sulfonylamino) -2- (trifluoromethyl) benzoic acid (Compound 35)

Compound 35 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ13.55(s,1H),10.95(s,1H),8.33(s,1H),8.00(d,J＝6.2Hz,1H),7.74(d,J＝9.8Hz,1H),7.63(d,J＝8.7Hz,1H),7.46(s,1H),7.39(d,J＝8.3Hz,1H),4.23(t,J＝6.8Hz,2H),1.74–1.60(m,2H),1.28–1.05(m,8H),1.05–0.93(m,2H),0.79(t,J＝6.9Hz,3H).ESI-MS:m/z 547.2[M-H]^-.

example 365- ((6-chloro-1- (2-cyclohexylethyl) -5-fluoro-1H-indole) -3-sulfonylamino) -2- (trifluoromethyl) benzoic acid (Compound 36)

Compound 36 was prepared according to the procedure of example 9:¹H NMR(300MHz,DMSO-d₆)δ13.60(s,1H),10.97(s,1H),8.33(s,1H),7.99(d,J＝6.2Hz,1H),7.75(d,J＝9.8Hz,1H),7.65(d,J＝8.6Hz,1H),7.46(s,1H),7.41(d,J＝8.6Hz,1H),4.25(t,J＝7.1Hz,2H),1.72–1.46(m,7H),1.15–0.93(m,4H),0.91–0.70(m,2H).ESI-MS:m/z 545.2[M-H]^-.

example 375- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) -2- (trifluoromethyl) benzoic acid (Compound 37)

Compound 37 was prepared according to the procedure of example 6:¹H NMR(300MHz,DMSO-d₆)δ13.65(s,1H),11.17(s,1H),8.61(s,1H),7.86(d,J＝9.6Hz,1H),7.74–7.58(m,6H),7.58–7.42(m,3H).

example 385- ((6-chloro-1-cycloheptyl-5-fluoro-1H-indole) -3-sulfonylamino) -2- (trifluoromethyl) benzoic acid (Compound 38)

Compound 38 was prepared according to the procedure of example 16:¹H NMR(300MHz,DMSO-d₆)δ13.58(s,1H),10.94(s,1H),8.34(s,1H),8.08(d,J＝6.3Hz,1H),7.71(d,J＝9.7Hz,1H),7.64(d,J＝8.7Hz,1H),7.44(s,1H),7.36(d,J＝8.5Hz,1H),4.72–4.55(m,1H),2.01–1.81(m,4H),1.79–1.46(m,8H).

example 394- (((7- (2-cyclohexylethoxy) -1-ethyl-5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 39)

Compound 39 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.64(s,1H),10.69(s,1H),8.16(s,1H),7.75(d,J＝8.4Hz,2H),7.28–7.07(m,3H),6.76(d,J＝11.0Hz,1H),4.49–4.30(m,2H),4.12(t,J＝6.1Hz,2H),1.84–1.56(m,7H),1.55–1.39(m,1H),1.29(t,J＝6.9Hz,3H),1.24–1.07(m,3H),1.04–0.82(m,2H).ESI-MS:m/z 487.2[M-H]^-.

example 405- ((7- (2-Cyclohexylethoxy) -1-ethyl-5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 40)

Compound 40 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.26(s,1H),10.25(s,1H),7.96(s,1H),7.53(d,J＝3.2Hz,1H),7.35–7.22(m,1H),7.17(d,J＝9.7Hz,1H),7.09(t,1H),6.76(d,J＝11.3Hz,1H),4.45–4.29(m,2H),4.13(t,J＝6.1Hz,2H),1.84–1.56(m,7H),1.48(s,1H),1.26(t,J＝6.8Hz,3H),1.21–1.08(m,3H),1.04–0.86(m,2H).ESI-HRMS:m/z 507.1766[M+H]⁺.

example 413- ((7- (2-cyclohexylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -4-fluorobenzoic acid (compound 41)

Compound 41 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.06(s,1H),10.15(s,1H),7.93(dd,J＝7.8,2.1Hz,1H),7.83(s,1H),7.69(ddd,J＝8.4,4.7,2.2Hz,1H),7.22(t,J＝10.0,8.7Hz,1H),7.03(dd,J＝9.3,2.1Hz,1H),6.74(dd,J＝11.6,2.1Hz,1H),4.12(t,J＝6.5Hz,2H),3.96(s,3H),1.82–1.56(m,7H),1.56–1.39(m,1H),1.32–1.13(m,3H),0.98(t,J＝11.6Hz,2H).ESI-HRMS[M+H]⁺calcd for C₂₄H₂₆F₂N₂O₅S:493.1609,found:493.1611.

example 425- ((7- (2-cyclohexylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2, 4-difluorobenzoic acid (compound 42)

Compound 42 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.35(s,1H),10.03(s,1H),7.85–7.71(m,2H),7.31(t,J＝10.4Hz,1H),6.98(dd,J＝9.3,2.1Hz,1H),6.75(dd,J＝11.5,2.1Hz,1H),4.13(t,J＝6.5Hz,2H),3.96(s,3H),1.80–1.57(m,7H),1.48(dd,J＝9.0,5.5Hz,1H),1.30–1.10(m,3H),1.05–0.88(m,2H).

example 434- ((7- (2-Cyclohexylethoxy) -5-fluoro-1-isopropyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 43)

Compound 43 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.62(s,1H),10.67(s,1H),8.20(s,1H),7.75(d,J＝8.6Hz,2H),7.19(s,1H),7.18–7.10(m,2H),6.82–6.73(m,1H),5.36–5.20(m,1H),4.12(t,J＝6.4Hz,2H),1.81–1.54(m,7H),1.43(d,J＝6.6Hz,6H),1.28–1.07(m,4H),0.95(dd,J＝22.2,10.6Hz,2H).ESI-HRMS[M+H]⁺calcd for C₂₆H₃₁FN₂O₅S:503.2016,found:503.2019.

example 445- ((7- (2-Cyclohexylethoxy) -5-fluoro-1-isopropyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 44)

Compound 44 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.23(s,1H),10.25(s,1H),7.98(s,1H),7.53(dd,J＝6.3,2.8Hz,1H),7.31–7.22(m,1H),7.14(t,1H),7.08(dd,J＝9.1,2.2Hz,1H),6.77(dd,J＝11.6,2.1Hz,1H),5.37–5.22(m,1H),4.14(t,J＝6.4Hz,2H),1.84–1.55(m,7H),1.53–1.45(m,1H),1.40(d,J＝6.7Hz,6H),1.30–1.08(m,3H),1.03–0.83(m,2H).ESI-HRMS[M+Na]⁺calcd for C₂₆H₃₀F₂N₂O₅S:543.1741,found:543.1738.

example 454- ((7- (2-cyclohexylethyl) -5-fluoro-1-methyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 45)

A dry three-necked flask is taken, added with anhydrous tetrahydrofuran solution (20mL) of the compound VI-1(2g, 3.93mmol) under the protection of argon, and cooled to-78 ℃. To the solution was slowly added 1M vinylmagnesium bromide in tetrahydrofuran (1M in THF, 31.44mL) and stirred at-78 deg.C for 3 hours. After completion of the reaction, a saturated ammonium chloride solution (30mL) was added to the reaction solution, extracted with ethyl acetate (10mL × 3), washed with a saturated sodium chloride solution (10mL × 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate 75:1) to give compound VI-2 (pale yellow solid, 1.03g, yield 61%).

Compound VI-2(900mg, 4.20mmol) was dissolved in dimethylformamide (8mL), and methyl iodide (320. mu.L, 6.31mmol) and potassium hydroxide (472mg, 8.41mmol) were added to the solution, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (80mL), extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water (10mL × 2), washed with a saturated sodium chloride solution (10mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate 300:1) to give compound VI-3 (colorless oily liquid, 677.4mg, yield 71%).

Compound VI-3(670mg, 2.94mmol) was dissolved in pyridine (6mL), pyridine sulfur trioxide (1.40g, 8.81mmol) was added, and the mixture was heated in a sealed tube at 105 ℃ for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained solid product was used directly in the next step.

The solid obtained in the above step was dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (3mL +6mL), added with phosphorus oxychloride (548. mu.L, 5.88mmol) under argon protection in ice bath, and then heated to 70 ℃ for reaction for 4 hours. After completion of the reaction, the reaction solution was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (10mL × 3), washed with ice water (10mL × 2), washed with saturated sodium chloride (10mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 30:1) to obtain compound VI-5 (pink solid, 346.8mg, two-step yield 74%).

Compound VI-5(173mg, 0.53mmol) and ethyl 4-aminobenzoate (175mg, 1.06mmol) were dissolved in anhydrous dichloromethane (3mL), stirred at room temperature for 30 minutes, then pyridine (128. mu.L, 1.59mmol) was added, and stirred at room temperature for 12 hours. After completion of the reaction, 2N hydrochloric acid (10mL), ethyl acetate (10mL × 3) was added, extraction was performed, a saturated sodium chloride solution (5mL × 2) was washed, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give compound VI-6 (white solid, 240.8mg, yield 99%).

A dry three-necked flask was taken, and added with compound VI-6(50mg, 0.11mmol), bis (triphenylphosphine) palladium chloride (8mg, 0.011mmol), cuprous iodide (4mg, 0.022mmol) and triphenylphosphine (3mg, 0.011mmol), and under the protection of argon, anhydrous N, N-dimethylformamide (2mL) was added, and to the solution were added cyclohexylacetylene (43. mu.L, 0.33mmol) and triethylamine (46. mu.L, 0.33mmol), and after completion of addition, the mixture was heated at 80 ℃ for 12 hours. After completion of the reaction, water (20mL) was added for dilution, ethyl acetate (5mL × 3) was extracted, water (5mL × 2) was washed, a saturated sodium chloride solution (5mL × 2) was washed, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give compound VI-7 (pale yellow solid, 52mg, yield 98%).

Compound VI-7(43mg, 0.089mmol) was dissolved in methanol (2mL), palladium on carbon (5mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered with suction through celite, the filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate 3:1) to give compound VI-8 (white solid, 28.2mg, 65%).

Compound VI-8(23mg, 0.047mmol) was dissolved in a methanol-tetrahydrofuran mixed solvent (0.4mL +0.8mL), and 1M sodium hydroxide solution (400. mu.L) was added thereto and heated at 70 ℃ for 6 hours. After completion of the reaction, part of the solvent was distilled off under reduced pressure, and 2N hydrochloric acid was added to the reaction solution to adjust pH to acidity, followed by suction filtration and ether beating to obtain compound 45 (white solid, 14mg, yield 65%): ESI-HRMS [ M + H ]]⁺calcd for C₂₄H₂₇FN₂O₄S:459.1754,found:459.1748.

Example 464- ((5-fluoro-1-methyl-7-phenyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 46)

A dry three-necked bottle was taken, and compound VI-6(60mg, 0.13mmol), phenylboronic acid (19mg, 0.16mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (11mg, 0.013mmol) and potassium carbonate (55mg, 0.40mmol) were added under argon protection, dioxane and water (1.6mL +0.4mL) were added, and after completion of addition, heating was carried out at 100 ℃ for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate 4:1) to give compound VII-1 (white solid, 47.5mg, yield 80%).

Compound VII-1(40.5mg, 0.090mmol) was dissolved in a methanol-tetrahydrofuran mixed solvent (0.5mL +1mL), and 1M sodium hydroxide solution (0.5mL) was added and heated at 60 ℃ for 6 hours. After completion of the reaction, part of the solvent was distilled off under reduced pressure, and 2N hydrochloric acid was added to the reaction solution to adjust pH to acidity, followed by suction filtration and ether beating to obtain compound 46 (brown solid, 23.2mg, yield 61%): :¹H NMR(300MHz,DMSO-d₆)δ12.57(s,1H),10.82(s,1H),8.23(s,1H),7.79(d,J＝8.7Hz,2H),7.66(dd,J＝9.2,2.5Hz,1H),7.53–7.38(m,5H),7.24(d,J＝8.7Hz,2H),6.94(dd,J＝9.7,2.5Hz,1H),3.26(s,3H).ESI-HRMS[M+H]⁺calcd for C₂₂H₁₇FN₂O₄S:425.0971,found:425.0972.

example 472-fluoro-5- ((5-fluoro-7- (furan-3-yl) -1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 47)

Compound 47 was prepared according to the procedure of example 46:¹H NMR(300MHz,DMSO-d₆)δ13.17(s,1H),10.37(s,1H),8.08(s,1H),7.90(s,1H),7.79(t,J＝1.5Hz,1H),7.64–7.54(m,2H),7.40–7.30(m,1H),7.25–7.12(m,1H),6.96(dd,J＝9.8,2.5Hz,1H),6.79(s,1H),3.31(s,3H).ESI-HRMS[M+NH₄]⁺calcd for C₂₀H₁₄F₂N₂O₅S:450.0935,found:450.0929.

example 484- (((7- (3-cyclohexylpropyl) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 48)

Compound 48 was prepared according to the procedure of example 45:¹H NMR(300MHz,DMSO-d₆)δ12.61(s,1H),10.71(s,1H),8.17(s,1H),7.76(d,J＝8.7Hz,2H),7.43(dd,J＝9.1,2.5Hz,1H),7.19(d,J＝8.7Hz,2H),6.91(dd,J＝10.5,2.4Hz,1H),4.01(s,3H),3.05–2.89(m,2H),1.75–1.49(m,7H),1.31–1.18(m,4H),1.18–1.01(m,2H),0.93–0.70(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₅H₂₉FN₂O₄S:473.1910,found:473.1899.

example 495- ((7- (2-cyclohexylethyl) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 49)

Compound 49 was prepared according to the procedure of example 45:¹H NMR(300MHz,DMSO-d₆)δ13.25(s,1H),10.29(s,1H),8.00(s,1H),7.57(dd,J＝6.3,2.8Hz,1H),7.38(dd,J＝9.2,2.5Hz,1H),7.35–7.26(m,1H),7.20–7.11(m,1H),6.90(dd,J＝10.5,2.5Hz,1H),4.01(s,3H),3.11–2.92(m,2H),1.77(d,J＝12.3Hz,2H),1.72–1.56(m,3H),1.56–1.42(m,2H),1.38–1.31(m,1H),1.25–1.23(m,1H),1.21–1.15(m,2H),1.01–0.91(m,2H).ESI-HRMS[M+Na]⁺calcd for C₂₄H₂₆F₂N₂O₄S:499.1479,found:499.1474.

example 502-fluoro-5- ((5-fluoro-1-methyl-7-phenyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 50)

Compound 50 was prepared according to the procedure of example 46:¹H NMR(300MHz,DMSO-d₆)δ13.23(s,1H),10.38(s,1H),8.05(s,1H),7.60(dd,J＝6.3,2.8Hz,2H),7.52–7.41(m,5H),7.38(dd,J＝8.6,3.6Hz,1H),7.19(t,J＝9.7Hz,1H),6.94(dd,J＝9.7,2.3Hz,1H),3.31(s,3H).ESI-HRMS[M+H]⁺calcd for C₂₂H₁₆F₂N₂O₄S:443.0877,found:443.0876.

example 514- ((5-fluoro-7- (furan-3-yl) -1-methyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 51)

Compound 51 was prepared according to the procedure of example 46:¹H NMR(300MHz,DMSO-d₆)δ12.64(s,1H),10.79(s,1H),8.26(s,1H),7.90(s,1H),7.78(d,J＝8.0Hz,3H),7.70–7.61(m,1H),7.23(d,J＝8.4Hz,2H),7.01–6.92(m,1H),6.79(s,1H),3.56(s,3H).ESI-HRMS[M+H]⁺calcd for C₂₀H₁₅FN₂O₅S:415.0764,found:415.0765.

example 525- ((7- (3-Cyclohexylpropyl) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 52)

Compound 52 was prepared according to the procedure of example 45:¹H NMR(300MHz,DMSO-d₆)δ13.25(s,1H),10.29(s,1H),8.00(s,1H),7.58(dd,J＝6.3,2.8Hz,1H),7.38(dd,J＝9.2,2.5Hz,1H),7.35–7.27(m,1H),7.24–7.10(m,1H),6.91(dd,J＝10.4,2.4Hz,1H),4.00(s,3H),3.05–2.91(m,2H),1.78–1.52(m,6H),1.30–1.10(m,7H),0.94–0.66(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₅H₂₈F₂N₂O₄S:491.1816,found:491.1810.

example 534- ((5-fluoro-7- (furan-2-yl) -1-methyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 53)

Compound 53 was prepared according to the procedure of example 46:¹H NMR(300MHz,DMSO-d₆)δ10.88(s,1H),8.26(s,1H),7.85(s,1H),7.79–7.74(m,2H),7.74–7.70(m,1H),7.18(t,J＝11.1Hz,3H),6.75(d,J＝3.1Hz,1H),6.66(d,J＝1.7Hz,1H),3.50(s,3H).ESI-HRMS[M+H]⁺calcd for C₂₀H₁₅FN₂O₅S:415.0764,found:415.0757.

example 542-fluoro-5- ((5-fluoro-7- (furan-2-yl) -1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 54)

Compound 54 was prepared according to the procedure of example 46:¹H NMR(300MHz,DMSO-d₆)δ13.28(s,1H),10.39(s,1H),8.12(s,1H),7.86(s,1H),7.65(dd,J＝9.1,2.5Hz,1H),7.60(dd,J＝6.3,2.8Hz,1H),7.39–7.29(m,1H),7.25–7.12(m,2H),6.76(d,J＝3.3Hz,1H),6.67(dd,J＝3.1,1.9Hz,1H),3.48(s,3H).

example 554- (((7- (2-cyclohexylethoxy) -5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 55)

Compound V-4(512mg, 3.39mmol) was dissolved in N, N-dimethylformamide (7mL), and anhydrous potassium carbonate (936mg, 6.78mmol) and 2-cyclohexylbromoethane (796. mu.L, 5.08mmol) were added to the solution under argon, and the mixture was heated to 70 ℃ for 12 hours. After completion of the reaction, suction filtration was performed, water (40mL) was added for dilution, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, washed with water (10mL × 2), washed with saturated sodium chloride (10mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 50:1) to obtain compound VIII-1 (yellow oily liquid, 494mg, yield 56%).

Compound VIII-1(120mg, 0.46mmol), acetic anhydride (82. mu.L, 0.87mmol) and 4-dimethylaminopyridine (11mg, 0.087mmol) were dissolved in 1, 2-dichloroethane (2mL), triethylamine (96. mu.L, 0.69mmol) was added to the solution, and the mixture was heated to 80 ℃ for reaction for 8 hours. After completion of the reaction, it was diluted with saturated sodium bicarbonate solution (20mL), extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with saturated sodium chloride (10mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate 75:1) to give compound VIII-2 (pale yellow oily liquid, 113.5mg, yield 81%).

Compound VIII-2(108mg, 0.36mmol) was dissolved in pyridine (2mL), pyridine sulfur trioxide (57mg, 0.36mmol) was added, and the mixture was heated in a sealed tube at 110 ℃ for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained product was used in the next step without purification.

The product obtained in the above step is dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (1mL +2mL), under the protection of argon, phosphorus oxychloride (66. mu.L, 0.71mmol) is added under ice bath, and the mixture is heated to 70 ℃ for reaction for 2 hours. After completion of the reaction, the reaction solution was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (5mL × 3), washed with ice water (5mL × 3), washed with saturated sodium chloride (5mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 50:1) to give compound VIII-4 (colorless oily liquid, 45.5mg, yield in two steps 32%).

Compound VIII-4(22.5mg, 0.056mmol) and 4-aminobenzoic acid (15mg, 0.12mmol) were dissolved in anhydrous dichloromethane (1.5mL), stirred at room temperature for 30 minutes, then pyridine (14. mu.L, 0.17mmol) was added, and stirred at room temperature for 12 hours. After completion of the reaction, 2N HCl (10mL), ethyl acetate (5mL × 3) extraction, 2N HCl (5mL × 2) washing, saturated sodium chloride (5mL × 2) washing, drying over anhydrous sodium sulfate, removing the solvent by evaporation under reduced pressure, and purifying the residue by column chromatography (dichloromethane: methanol: acetic acid ═ 60:2:1) to obtain compound 55 (white solid, 17.3mg, yield 67%):¹H NMR(300MHz,DMSO-d₆)δ12.59(s,1H),12.25(s,1H),10.68(s,1H),7.99(s,1H),7.75(d,J＝8.4Hz,2H),7.16(dd,J＝15.1,8.9Hz,3H),6.74(d,J＝11.3Hz,1H),4.14(t,J＝6.2Hz,2H),1.67(dd,J＝13.0,6.4Hz,6H),1.57–1.50(m,1H),1.29–1.10(m,4H),0.94(d,J＝11.6Hz,2H).ESI-HRMS[M+H]⁺calcd for C₂₃H₂₅FN₂O₅S:461.1546found:461.1548.

example 565- ((7- (2-cyclohexylethoxy) -5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 56)

Compound 56 was prepared according to the procedure of example 55:¹H NMR(300MHz,DMSO-d₆)δ13.22(s,1H),12.20(s,1H),10.26(s,1H),7.79(d,J＝2.9Hz,1H),7.56(dd,J＝6.3,2.7Hz,1H),7.29(dd,J＝8.5,3.5Hz,1H),7.18–7.05(m,2H),6.74(d,J＝11.5Hz,1H),4.14(t,J＝6.4Hz,2H),1.77–1.63(m,6H),1.58–1.51(m,1H),1.21(dd,J＝18.1,5.2Hz,4H),1.01–0.91(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₃H₂₄F₂N₂O₅S:479.1452,found:479.1447.

example 574- ((7- (2-Cyclohexylethoxy) -1-cyclopropyl-5-fluoro-1H-indole) -3-sulfonamido) benzoic acid (Compound 57)

A dry three-necked flask was charged with cyclopropylboronic acid (79mg, 0.92mmol), copper acetate (8mg, 0.046mmol), cyclopropylboronic acid (79mg, 0.92mmol) and 4-dimethylaminopyridine (168mg, 1.38mmol), and a toluene solution (2mL) of compound VIII-1(120mg, 0.46mmol) was added under an argon atmosphere, and a 1M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (459. mu.L, 0.46mmol) was added to the solution, stirred at room temperature for 10 minutes, and heated to 95 ℃ for reaction for 48 hours. After completion of the reaction, 2N HCl (20mL), ethyl acetate (5mL × 3) and extraction were added to the reaction mixture, the organic phases were combined, washed with saturated sodium chloride (5mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 150:1) to obtain compound IX-1 (pale yellow oily liquid, 73.1mg, yield 51%).

Compound IX-1(126mg, 0.42mmol) was dissolved in pyridine (2mL), pyridine sulfur trioxide (67mg, 0.42mmol) was added, and the mixture was heated in a sealed tube at 110 ℃ for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained product was used in the next step without purification.

The product obtained in the above step is dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (1mL +2mL), added with phosphorus oxychloride (78. mu.L, 0.84mmol) under argon protection and heated to 70 ℃ for reaction for 3 hours. After completion of the reaction, the reaction solution was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (5mL × 3), washed with ice water (5mL × 3), washed with saturated sodium chloride (5mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 50:1) to obtain compound IX-4 (brown solid, 85.3mg, two-step yield 51%).

Compound IX-4(42.5mg, 0.11mmol) and 4-aminobenzoic acid (29mg, 0.21mmol) were dissolved in anhydrous dichloromethane (2mL), stirred at room temperature for 30 minutes, followed by addition of pyridine (26. mu.L, 0.32mmol) and stirring at room temperature for 12 hours. After completion of the reaction, 2N HCl (10mL), ethyl acetate (5mL × 3) extraction, 2N HCl (5mL × 2) washing, saturated sodium chloride (5mL × 2) washing, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and purification of the residue by column chromatography (dichloromethane: methanol: acetic acid 300:4:1) followed by ether trituration gave compound 57 (white solid, 26.7mg, yield 50%):¹H NMR(300MHz,DMSO-d₆)δ12.63(s,1H),10.70(s,1H),7.99(s,1H),7.76(d,J＝8.7Hz,2H),7.18(d,J＝8.7Hz,2H),7.12(dd,J＝9.1,2.1Hz,1H),6.77(dd,J＝11.6,2.0Hz,1H),4.10(t,J＝6.4Hz,2H),3.81–3.73(m,1H),1.69(dd,J＝18.8,12.1Hz,7H),1.48(s,1H),1.22–1.05(m,5H),0.97(dd,J＝17.7,11.3Hz,4H).ESI-HRMS[M+H]⁺calcd for C₂₆H₂₉FN₂O₅S:501.1859found:501.1850.

example 585- ((7- (2-Cyclohexylethoxy) -1-cyclopropyl-5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 58)

Compound 58 was prepared according to the procedure of example 57:¹H NMR(300MHz,DMSO-d₆)δ13.29(s,1H),10.28(s,1H),7.79(s,1H),7.57–7.47(m,1H),7.29(d,J＝8.7Hz,1H),7.15(t,J＝9.6Hz,1H),7.06(d,J＝9.1Hz,1H),6.77(d,J＝11.6Hz,1H),4.11(t,J＝6.2Hz,2H),3.76(d,J＝4.7Hz,1H),1.70(dd,J＝19.2,12.5Hz,7H),1.48(s,1H),1.25–1.12(m,3H),1.05–0.85(m,6H).ESI-HRMS[M+H]⁺calcd for C₂₆H₂₈F₂N₂O₅S:519.1765,found:519.1761.

example 594- ((7- (2-cyclohexylethoxy) -5-fluoro-N, 1-dimethyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 59)

Compound VIII-1(500mg, 1.91mmol) was dissolved in N, N-dimethylformamide (4mL), and potassium hydroxide (215mg, 3.83mmol) and iodomethane (179. mu.L, 2.87mmol) were added to the solution, followed by stirring at room temperature for 8 hours. After completion of the reaction, it was diluted with water (20mL), extracted with ethyl acetate (10 mL. times.3), the organic phases were combined, washed with saturated sodium chloride (10 mL. times.2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give compound X-1 (colorless oily liquid, 107.4mg, yield 20%).

Compound X-1(106mg, 0.38mmol) was dissolved in pyridine (2mL), pyridine sulfur trioxide (65mg, 0.38mmol) was added, and the mixture was heated in a sealed tube at 110 ℃ for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained product was used in the next step without purification.

The product obtained in the previous step is dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (1mL +2mL), under the protection of argon, phosphorus oxychloride (72 μ L, 0.77mmol) is added under ice bath, and the mixture is heated to 70 ℃ for reaction for 2 hours. After completion of the reaction, the reaction solution was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (5mL × 3), washed with ice water (5mL × 3), washed with saturated sodium chloride (5mL × 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 50:1) to give compound X-3 (pale yellow solid, 68mg, yield in two steps 47%).

Compound X-3(68mg, 0.18mmol) and ethyl 4-aminobenzoate (60mg, 0.36mmol) were dissolved in anhydrous dichloromethane (2mL), stirred at room temperature for 30 minutes, then pyridine (44. mu.L, 0.55mmol) was added, and stirred at room temperature for 12 hours. After completion of the reaction, 2N HCl (10mL), ethyl acetate (5mL × 3) extraction, 2N HCl (5mL × 2) washing, saturated sodium chloride (5mL × 2) washing, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and purification of the residue by column chromatography (dichloromethane: methanol: acetic acid: 300:4:1) gave compound X-4 (white solid, 45mg, yield 49%).

Taking a dry three-necked bottle, adding sodium hydride (4mg, 0.11mmol) under the protection of argon and cooling in iceTo the bath, a solution of compound X-4(45mg, 0.09mmol) in N, N-dimethylformamide (2mL) was added, and the mixture was stirred at room temperature for 1 hour, and methyl iodide (9. mu.L, 0.13mmol) was added to the solution and stirred at room temperature for 6 hours. After completion of the reaction, 2N HCl (10mL) was added for dilution, ethyl acetate (5mL × 3) was extracted, the organic phases were combined, washed with saturated sodium chloride (5mL × 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (dichloromethane: methanol: acetic acid 300:4:1), and the residue was slurried with ether to give compound 59 (white solid, 32.7mg, yield 75%):¹H NMR(300MHz,DMSO-d₆)δ12.87(s,1H),7.92–7.80(m,3H),7.29(d,J＝8.6Hz,2H),6.69(d,J＝11.4Hz,1H),6.25–6.18(m,1H),4.11(t,J＝6.4Hz,2H),4.02(s,3H),3.15(s,3H),1.80–1.62(m,7H),1.49(s,1H),1.27–1.15(m,3H),0.99(t,J＝11.5Hz,2H).ESI-HRMS[M+Na]⁺calcd for C₂₅H₂₉FN₂O₅S:511.1679,found:511.1679.

example 602- (4- ((7- (2-cyclohexylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonamido) phenyl) acetic acid (Compound 60)

Compound 60 was prepared according to the procedure of example 23: ESI-HRMS [ M + H ]]⁺calcd for C₂₅H₂₉FN₂O₅S:489.1859,found:489.1857.

Example 615- ((7- (2-Cyclohexylethoxy) -5-fluoro-N, 1-dimethyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 61)

Compound 61 was prepared according to the procedure of example 59:¹H NMR(300MHz,DMSO-d₆)δ13.34(s,1H),7.86(s,1H),7.55(dd,J＝6.4,2.8Hz,1H),7.35(dd,J＝8.4,3.6Hz,1H),7.28–7.18(m,1H),6.71(d,J＝11.5Hz,1H),6.25(dd,J＝9.3,2.0Hz,1H),4.12(t,J＝6.5Hz,2H),4.02(s,3H),3.09(s,3H),1.81–1.64(m,7H),1.50(s,1H),1.28–1.16(m,3H),1.05–0.92(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₅H₂₈F₂N₂O₅S:507.1765,found:507.1764.

example 625- ((7- (2-Cyclohexylethoxy) -N-ethyl-5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 62)

Reference to realCompound 62 was prepared by the method of example 59:¹H NMR(300MHz,DMSO-d₆))δ13.34(s,1H),7.86(s,1H),7.55(dd,J＝6.4,2.8Hz,1H),7.35(dd,J＝8.4,3.6Hz,1H),7.28–7.18(m,1H),6.71(d,J＝11.5Hz,1H),6.25(dd,J＝9.3,2.0Hz,1H),4.12(t,J＝6.5Hz,2H),4.02(s,3H),3.09(s,3H),1.81–1.64(m,7H),1.50(s,1H),1.28–1.16(m,3H),1.05–0.92(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₆H₃₀F₂N₂O₅S:521.1922,found:521.1914.

example 632- (5- ((7- (2-cyclohexylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorophenyl) acetic acid (Compound 63)

Compound 63 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.43(s,1H),10.10(s,1H),7.90(s,1H),7.12–7.05(m,2H),7.03–6.93(m,2H),6.73(d,J＝11.5Hz,1H),4.10(t,J＝6.4Hz,2H),3.95(s,3H),3.51(s,2H),1.78–1.62(m,7H),1.47(s,1H),1.26–1.13(m,3H),0.97(t,J＝11.5Hz,2H).ESI-HRMS[M+H]⁺calcd for C₂₅H₂₈F₂N₂O₅S:507.1765,found:507.1767.

example 644- ((7- (2-cyclohexylethoxy) -N-ethyl-5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 64)

Compound 64 was prepared according to the procedure of example 59:¹H NMR(300MHz,DMSO-d₆)δ12.97(s,1H),7.90–7.81(m,3H),7.23(d,J＝8.5Hz,2H),6.71(dd,J＝11.5,2.0Hz,1H),6.37(dd,J＝9.3,2.0Hz,1H),4.13(t,J＝6.5Hz,2H),4.02(s,3H),3.62(q,J＝7.0Hz,2H),1.80–1.61(m,7H),1.51(d,J＝3.4Hz,1H),1.22(dd,J＝13.6,6.2Hz,3H),0.99(dd,J＝14.8,7.9Hz,5H).ESI-HRMS[M+Na]⁺calcd for C₂₆H₃₁FN₂O₅S:525.1835,found:525.1832.

example 655- (((7- (2-cyclohexylethoxy) -5-fluoro-N-isopropyl-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 65)

Compound 65 was prepared according to the procedure of example 59:¹H NMR(300MHz,DMSO-d₆)δ13.38(s,1H),7.87(s,1H),7.48(dd,J＝6.6,2.2Hz,1H),7.36–7.26(m,2H),6.76(dd,J＝10.3,8.6Hz,2H),4.48(dd,J＝13.3,6.7Hz,1H),4.16(t,J＝6.5Hz,2H),4.01(s,3H),1.81–1.64(m,7H),1.51(s,1H),1.27–1.18(m,3H),0.97(t,J＝8.8Hz,8H).ESI-HRMS[M+H]⁺calcd for C₂₇H₃₂F₂N₂O₅S:535.2078,found:535.2081.

example 665- ((7- (benzyloxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 66)

Compound 66 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.25(s,1H),10.27(s,1H),7.93(s,1H),7.57(dd,J＝6.4,2.8Hz,1H),7.51(d,J＝7.0Hz,2H),7.44–7.27(m,4H),7.19–7.09(m,2H),6.89–6.82(m,1H),5.23(s,2H),3.96(s,3H).ESI-HRMS[M+H]⁺calcd for C₂₄H₂₆F₂N₂O₄S:473.0983,found:473.0983.

example 674- ((7- (benzyloxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (compound 67)

Compound 67 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.63(s,1H),10.70(s,1H),8.10(s,1H),7.76(d,J＝8.6Hz,2H),7.51(d,J＝7.0Hz,2H),7.44–7.34(m,3H),7.18(dd,J＝7.6,4.2Hz,3H),6.89–6.83(m,1H),5.22(s,2H),3.98(s,3H).

example 684- (((7- (cyclopentylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 68)

Compound 68 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.56(s,1H),10.69(s,1H),8.08(s,1H),7.76(d,J＝8.4Hz,2H),7.16(dd,J＝14.6,8.8Hz,3H),6.71(d,J＝11.6Hz,1H),4.02–3.92(m,5H),2.40–2.30(m,1H),1.78(m,2H),1.57(m,J＝7.0Hz,4H),1.36(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₅H₂₃FN₂O₅S:447.1390,found:447.1389.

example 695- (((7- (cyclopentylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 69)

Method according to example 23Compound 69 was prepared:¹H NMR(300MHz,DMSO-d₆)δ13.28(s,1H),10.27(s,1H),7.91(s,1H),7.56(dd,J＝6.3,2.8Hz,1H),7.34–7.27(m,1H),7.19–7.11(m,1H),7.07(dd,J＝9.3,1.9Hz,1H),6.75–6.68(m,1H),3.97(s,3H),3.95(s,2H),2.38(dd,J＝14.9,7.5Hz,1H),1.79(d,J＝5.8Hz,2H),1.58(dd,J＝14.2,6.7Hz,4H),1.42–1.30(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₂H₂₂F₂N₂O₅S:465.1296,found:465.1299.

example 704- ((7- (2-cyclohexylethoxy) -5-fluoro-N-isopropyl-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 70)

Compound 70 was prepared according to the procedure of example 59:¹H NMR(300MHz,DMSO-d₆)δ13.07(s,1H),7.93(d,J＝8.4Hz,2H),7.88(s,1H),7.20(s,1H),7.17(s,1H),6.79(d,J＝4.3Hz,1H),6.76(d,J＝1.9Hz,1H),4.49(dd,J＝13.2,6.6Hz,1H),4.16(t,J＝6.5Hz,2H),4.02(s,3H),1.81–1.61(m,7H),1.51(s,1H),1.28–1.17(m,3H),1.00(t,J＝11.7Hz,8H).ESI-HRMS[M+Na]⁺calcd for C₂₇H₃₃FN₂O₅S:539.1992,found:539.1388.

example 712- (4- ((7- (cyclohexylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) phenyl) acetic acid (Compound 71)

Compound 71 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.20(s,1H),10.11(s,1H),7.93(s,1H),7.14(d,J＝9.0Hz,1H),7.03(q,J＝8.6Hz,4H),6.68(d,J＝11.3Hz,1H),3.97(s,3H),3.89(d,J＝5.3Hz,2H),3.41(s,2H),1.86–1.63(m,6H),1.32–1.07(m,5H).

example 724- (((7- (2-cyclopentylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 72)

Compound 72 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.64(s,1H),10.70(s,1H),8.08(s,1H),7.76(d,J＝8.5Hz,2H),7.24–7.08(m,3H),6.73(d,J＝11.3Hz,1H),4.13–4.03(m,2H),3.98(s,3H),2.00–1.88(m,1H),1.85–1.70(m,4H),1.65–1.43(m,4H),1.21–1.08(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₃H₂₅FN₂O₅S:461.1546,found:461.1536.

example 735- ((7- (2-cyclopentylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 73)

Compound 73 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.24(s,1H),10.27(s,1H),7.91(s,1H),7.56(d,J＝3.5Hz,1H),7.28(s,1H),7.16(t,J＝9.6Hz,1H),7.07(d,J＝7.5Hz,1H),6.73(d,J＝11.2Hz,1H),4.08(t,J＝6.1Hz,2H),3.96(s,3H),2.02–1.91(m,1H),1.86–1.70(m,4H),1.65–1.40(m,4H),1.23–1.10(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₃H₂₄F₂N₂O₅S:479.1452,found:479.1447.

example 744- ((7- (cyclohexylmethoxy) -5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 74)

Compound 74 was prepared according to the procedure of example 56:¹H NMR(300MHz,DMSO-d₆)δ12.62(s,1H),12.28(s,1H),10.67(s,1H),8.00(d,J＝2.9Hz,1H),7.75(d,J＝8.6Hz,2H),7.22–7.09(m,3H),6.71(d,J＝11.5Hz,1H),3.90(d,J＝6.0Hz,2H),1.86(d,J＝12.3Hz,2H),1.82–1.75(m,1H),1.71(d,J＝11.2Hz,3H),1.30–1.05(m,5H).ESI-HRMS[M+H]⁺calcd for C₂₂H₂₃FN₂O₅S:447.1390,found:447.1379.

example 755- ((7- (cyclohexylmethoxy) -5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 75)

Compound 75 was prepared according to the procedure of example 56:¹H NMR(300MHz,DMSO-d₆)δ13.24(s,1H),12.23(s,1H),10.26(s,1H),7.81(d,J＝3.1Hz,1H),7.57(dd,J＝6.3,2.8Hz,1H),7.32–7.26(m,1H),7.18–7.04(m,2H),6.70(dd,J＝11.5,1.9Hz,1H),3.91(d,J＝6.1Hz,2H),1.87(d,J＝12.1Hz,2H),1.77(d,J＝11.2Hz,1H),1.72(d,J＝11.4Hz,3H),1.28–1.07(m,5H).ESI-HRMS[M+H]⁺calcd for C₂₂H₂₂F₂N₂O₅S:465.1296,found:465.1287.

example 762- (5- ((7- (cyclohexylmethoxy) -5-fluoro-1H-indole) -3-sulfonamido) -2-fluorophenyl) acetic acid (Compound 76)

Compound 76 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.43(s,1H),10.10(s,1H),7.90(s,1H),7.13–7.04(m,2H),7.02–6.89(m,2H),6.70(d,J＝10.0Hz,1H),3.97(s,3H),3.90(d,J＝4.7Hz,2H),3.51(s,2H),1.86–1.63(m,6H),1.27–1.08(m,5H).ESI-HRMS[M+H]⁺calcd for C₂₄H₂₆F₂N₂O₅S:493.1609,found:493.1604.

example 774- ((5-fluoro-1-methyl-7-phenethyloxy-1H-indole) -3-sulfonamido) benzoic acid (Compound 77)

Compound 77 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.62(s,1H),10.68(s,1H),8.03(s,1H),7.75(d,J＝8.5Hz,2H),7.35–7.11(m,8H),6.77(d,J＝11.5Hz,1H),4.34(t,J＝6.3Hz,2H),3.77(s,3H),3.10(t,J＝6.2Hz,2H).ESI-HRMS[M+H]⁺calcd for C₂₄H₂₁FN₂O₅S:469.1233,found:469.1222.

example 782-fluoro-5- ((5-fluoro-1-methyl-7-phenethyloxy-1H-indole) -3-sulfonamido) benzoic acid (Compound 78)

Compound 78 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.24(s,1H),10.25(s,1H),7.87(s,1H),7.55(dd,J＝6.3,2.7Hz,1H),7.34–7.28(m,4H),7.28–7.18(m,2H),7.14(t,1H),7.07(dd,J＝9.2,2.1Hz,1H),6.77(dd,J＝11.5,2.0Hz,1H),4.35(t,J＝6.4Hz,2H),3.76(s,3H),3.10(t,J＝6.3Hz,2H).ESI-HRMS[M+H]⁺calcd for C₂₄H₂₀F₂N₂O₅S:487.1139,found:487.1135.

example 794- ((4-chloro-7- (cyclohexylmethoxy) -1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 79)

Compound 79 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.58(s,1H),10.37(s,1H),8.20(s,1H),7.75(d,J＝8.6Hz,2H),7.19(d,J＝8.6Hz,2H),7.06(d,J＝8.4Hz,1H),6.75(d,J＝8.5Hz,1H),4.05(s,3H),3.86(d,J＝5.3Hz,2H),1.83–1.67(m,5H),1.33-1.04(m,6H).ESI-HRMS[M+H]⁺calcd for C₂₃H₂₅FN₂O₅S:477.1251,found:477.1247.

example 804- ((4-chloro-7- (2-cyclohexylethoxy) -1-isopropyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 80)

Compound 80 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ10.41(s,1H),8.28(s,1H),7.74(d,J＝8.3Hz,2H),7.19(d,J＝8.4Hz,2H),7.09(d,J＝8.2Hz,1H),6.82(d,J＝8.5Hz,1H),5.46–5.36(m,1H),4.10(t,J＝6.3Hz,2H),1.78–1.58(m,7H),1.48(d,J＝6.6Hz,6H),1.31–1.07(m,4H),0.94(d,J＝11.3Hz,2H).ESI-HRMS[M+H]⁺calcd for C₂₆H₃₁ClN₂O₅S:519.1720,found:519.1710.

example 815- ((4-chloro-7- (2-cyclohexylethoxy) -1-isopropyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 81)

Compound 81 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.25(s,1H),10.11(s,1H),8.16(s,1H),7.58(dd,J＝6.2,2.8Hz,1H),7.37–7.24(m,1H),7.22–7.04(m,2H),6.83(d,J＝8.6Hz,1H),5.48–5.31(m,1H),4.11(t,J＝6.4Hz,2H),1.79–1.55(m,7H),1.45(d,J＝6.6Hz,6H),1.30–1.06(m,4H),0.96(t,J＝11.1Hz,2H).ESI-HRMS[M+H]⁺calcd for C₂₆H₃₀ClFN₂O₅S:537.1626,found:537.1617.

example 824- ((4-chloro-7- (cyclohexylmethoxy) -1-isopropyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 82)

Compound 82 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.60(s,1H),10.41(s,1H),8.29(s,1H),7.74(d,J＝8.4Hz,2H),7.19(d,J＝8.4Hz,2H),7.08(d,J＝8.3Hz,1H),6.80(d,J＝8.5Hz,1H),5.47–5.37(m,1H),3.90(d,J＝5.4Hz,2H),1.83–1.62(m,6H),1.49(d,J＝6.6Hz,6H),1.29–1.06(m,5H).ESI-HRMS[M+H]⁺calcd for C₂₅H₂₉ClN₂O₅S:505.1564,found:505.1561.

example 834- ((4-chloro-7- (2-cyclohexylethoxy) -1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 83)

Compound 83 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ10.38(s,1H),8.21(s,1H),7.75(d,J＝8.6Hz,2H),7.19(d,J＝8.6Hz,2H),7.07(d,J＝8.4Hz,1H),6.78(d,J＝8.5Hz,1H),4.10–4.02(m,5H),1.77–1.58(m,7H),1.51–1.42(m,1H),1.26–1.11(m,3H),1.03–0.89(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₄H₂₇ClN₂O₅S:491.1407,found:491.1394.

example 845- ((4-chloro-7- (2-cyclohexylethoxy) -1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 84)

Compound 84 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.13(s,1H),10.00(s,1H),8.09(s,1H),7.60(dd,J＝6.3,2.8Hz,1H),7.45–7.25(m,1H),7.24–6.98(m,2H),6.79(d,J＝8.5Hz,1H),4.08(t,J＝6.5Hz,2H),4.01(s,3H),1.79–1.55(m,7H),1.55–1.37(m,1H),1.31–1.07(m,4H),1.06-0.84(m,2H).ESI-HRMS[M+H]⁺calcd for C₂₄H₂₆ClFN₂O₅S:509.1313,found:509.1304.

example 855- ((4-chloro-7- (cyclohexylmethoxy) -1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 85)

Compound 85 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.21(s,1H),10.01(s,1H),8.10(s,1H),7.60(d,J＝3.5Hz,1H),7.33(d,J＝8.4Hz,1H),7.20–7.05(m,2H),6.76(d,J＝8.5Hz,1H),4.03(s,3H),3.87(d,J＝5.2Hz,2H),1.83–1.65(m,5H),1.29–1.10(m,6H).ESI-HRMS[M+H]⁺calcd for C₂₃H₂₄ClFN₂O₅S:495.1157,found:495.1147.

example 864- ((4-chloro-7- (2-cyclohexylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 86)

Compound 86 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.60(s,1H),10.45(s,1H),8.25(s,1H),7.76(d,J＝8.5Hz,2H),7.19(d,J＝8.5Hz,2H),6.98(d,J＝11.7Hz,1H),4.10(t,J＝6.3Hz,2H),4.01(s,2H),1.79–1.54(m,6H),1.53–1.37(m,1H),1.28–1.07(m,3H),1.04–0.85(m,2H).

example 874-chloro-7- (2-cyclohexylethoxy) -5-fluoro-N- (4- (hydroperoxy-12-methyl) phenyl) -1-isopropyl-1H-indole-3-sulfonamide (Compound 87)

Compound 87 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.59(s,1H),10.48(s,1H),8.31(s,1H),7.75(d,J＝8.6Hz,2H),7.19(d,J＝8.7Hz,2H),7.02(d,J＝11.8Hz,1H),5.43–5.26(m,1H),4.13(t,J＝6.3Hz,2H),1.79–1.54(m,7H),1.47(d,J＝6.6Hz,6H),1.30–1.08(m,4H),1.03–0.83(m,2H).

example 885- ((4-chloro-7- (2-cyclohexylethoxy) -5-fluoro-1-isopropyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 88)

Compound 88 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.23(s,1H),10.17(s,1H),8.18(s,1H),7.65–7.52(m,1H),7.29(d,J＝8.6Hz,1H),7.14(t,J＝9.6Hz,1H),7.02(d,J＝11.8Hz,1H),5.45–5.24(m,1H),4.14(t,J＝6.2Hz,2H),1.84–1.55(m,7H),1.45(d,J＝6.5Hz,6H),1.32–1.07(m,4H),1.06–0.86(m,2H).

example 894- ((5-bromo-7- (cyclohexylmethoxy) -1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 89)

Compound 89 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.64(s,1H),10.73(s,1H),8.09(s,1H),7.76(d,J＝8.6Hz,2H),7.58(d,J＝1.3Hz,1H),7.18(d,J＝8.7Hz,2H),6.89(s,1H),3.99(s,3H),3.90(d,J＝5.5Hz,2H),1.89–1.57(m,6H),1.36–1.08(m,5H).

example 905- ((4-chloro-7- (cyclohexylmethoxy) -1-isopropyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 90)

Compound 90 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.24(s,1H),10.10(s,1H),8.16(s,1H),7.58(dd,J＝6.2,2.8Hz,1H),7.36–7.24(m,1H),7.20–7.05(m,2H),6.80(d,J＝8.6Hz,1H),5.50–5.31(m,1H),3.91(d,J＝5.4Hz,2H),1.91–1.59(m,6H),1.46(d,J＝6.6Hz,6H),1.38–0.99(m,5H).

example 914- ((4-chloro-7- (cyclohexylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 91)

Compound 91 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.61(s,1H),10.45(s,1H),8.25(s,1H),7.76(d,J＝8.6Hz,2H),7.18(d,J＝8.6Hz,2H),6.95(d,J＝11.8Hz,1H),4.03(s,3H),3.89(d,J＝5.5Hz,2H),1.91–1.56(m,6H),1.39–0.97(m,5H).

example 925- ((4-chloro-7- (cyclohexylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 92)

Compound 92 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.28(s,1H),10.08(s,1H),8.14(s,1H),7.63–7.55(m,1H),7.36–7.29(m,1H),7.16(t,J＝9.7Hz,1H),6.96(d,J＝11.7Hz,1H),4.01(s,3H),3.91(d,J＝5.3Hz,2H),1.86–1.59(m,6H),1.30–1.06(m,5H).

example 934- ((4-chloro-7- (cyclohexylmethoxy) -5-fluoro-1-isopropyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 93)

Compound 93 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.62(s,1H),10.48(s,1H),8.32(s,1H),7.75(d,J＝8.5Hz,2H),7.19(d,J＝8.5Hz,2H),6.99(d,J＝11.9Hz,1H),5.41–5.31(m,1H),3.94(d,J＝5.1Hz,2H),1.84–1.60(m,6H),1.48(d,J＝6.5Hz,6H),1.30–1.04(m,5H).

example 945- ((4-chloro-7- (cyclohexylmethoxy) -5-fluoro-1-isopropyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 94)

Compound 94 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ13.26(s,1H),10.18(s,1H),8.20(s,1H),7.58(dd,J＝6.2,2.8Hz,1H),7.30(dd,J＝8.7,3.5Hz,1H),7.14(t,J＝9.7Hz,1H),7.00(d,J＝11.8Hz,1H),5.41–5.29(m,1H),3.94(d,J＝5.5Hz,2H),1.85–1.61(m,6H),1.46(d,J＝6.6Hz,6H),1.31–1.06(m,5H).

example 954- ((5-bromo-7- (2-cyclohexylethoxy) -1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 95)

Compound 95 was prepared according to the procedure of example 23:¹H NMR(300MHz,DMSO-d₆)δ12.66(s,1H),10.74(s,1H),8.09(s,1H),7.77(d,J＝8.6Hz,2H),7.59(s,1H),7.18(d,J＝8.6Hz,2H),6.93(s,1H),4.10(t,J＝6.4Hz,2H),3.98(s,2H),1.82–1.55(m,5H),1.56–1.35(m,1H),1.33–1.08(m,3H),1.03–0.76(m,2H).

test of inhibitory Activity of the Compounds of example 96 against FABP4 and FABP5

The experimental principle and method are as follows: binding of free non-covalent fluorescent probe ANS to FABP4 or FABP5 results in an increase in ANS fluorescence intensity and a blue shift of the spectrum. This experiment evaluated the inhibitory effect of compounds on FABP4 and FABP5 by measuring the change in ANS fluorescence signal value. FABP4 and FABP5 inhibitory activity test the method of ANS substrate competition, the application is based on the method of Kane and Bernlohr and is modified accordingly. His-tagged human FABP4 or FABP5 was expressed in BL21(DE3) strain, and then purified with Ni-NTA Superflow affinity chromatography resin to obtain a protein. The concentration of 1,8-ANS substrate in the detection system is 10 μ M, the final concentration of FABP4 and FABP5 protein is 10 μ M, compounds with gradient concentration are added for incubation for 3min, and finally fluorescence signals are detected at excitation wavelength (EX)370 nm/emission wavelength (EM)470 nm. Calculating the inhibition rate (%) of the tested compound to FABP4 and FABP5 at different concentrations according to the fluorescence signal value, and fitting the IC of the tested compound according to the concentration and the inhibition rate of the compound by using GraphPad Prism software₅₀The value is obtained. BMS309403, a selective FABP4 inhibitor, linoleic acid LA, an endogenous FABP5 ligand, and a reported FABP4/5 dual inhibitor RO6806051 were used as positive control compounds. The inhibition (%) was performed according to the following formula:

inhibition rate (%) ([ 1- (F))_X-F_Background)/(F₀％-F_Background)]*100％

In the above formula F_XRepresents the fluorescence value (F), F) of the system measured in the presence of compound X_BackgroundIndicating the fluorescence of the system with only fluorogenic substrate ANS, F₀% represents the fluorescence value of the system when the inhibition ratio is 0%, i.e., when no compound is added.

The results of the experiment are shown in table 1.

Inhibitory Activity of the Compounds of Table 1 against FABP4 and FABP5

Note: "ND" means not detected.

The experimental results (table 1) show that the compound of the present invention has significant FABP4/5 inhibitory activity. Among them, compounds 4, 5,6, 12, 19 and 29 significantly inhibited FABP4 activity, compounds 10, 13, 23, 25, 32, 35 and 36 significantly inhibited FABP5 activity, and compounds 8, 11, 14, 15, 17, 18, 26, 33, 39, 40, 41, 43 and 44 significantly inhibited FABP4 and FABP5 activity, indicating that the compounds of the present invention are clear FABP4/5 inhibitors.

Example 97

Tablet formulation

Compound 44(50g) obtained in example 44, hydroxypropylmethylcellulose E (150g), starch (200g), povidone K30, and magnesium stearate (1g) were mixed, granulated, and tabletted.

Claims (10)

1. An indole compound represented by formula I, or a pharmaceutically acceptable salt or ester or solvate thereof:

R¹selected from: H. f, Cl, Br, I, OCH₃；

R²Selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, wherein the substituted phenyl, substituted heteroaryl or substituted fused ring arylA group may be independently substituted with 1 to 3 substituents as follows: F. cl, Br, I, CN, NO₂、NH₂、OH、OR¹²、C₁-C₃Alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, halocycloalkyl, halocycloalkylalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkylalkoxyalkyl, cycloalkoxyalkyl, alkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylalkyl or substituted amino;

R¹²selected from: cycloalkyl, heterocycloalkyl, or substituted or unsubstituted C₁-C₄Alkyl, said substituted C₁-C₄Alkyl is substituted with one or two or three substituents independently selected from the group consisting of: OH, (O), C (O) OH, CN, NH₂F, alkylsulfonyl, haloalkylsulfonyl, substituted amino, C (O) NH₂Alkylsulfonylamino, sulfamoyl, NHC (O) NH₂Pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl or NHC (O) CH (CH)₃)NHC(O)CH(CH₃)NH；

R³Selected from: H. f, Cl, Br, I, CN, NO₂、NH₂、OH、N₃、C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₁-C₈Alkylcarbonyl group, C₁-C₈Alkoxycarbonyl group, C₁-C₈Alkylsulfonyl radical, C₁-C₈Alkylsulfinyl radical, C₁-C₈Alkylthio radical, C₁-C₅Alkylcarbonylamino, C₁-C₈Alkylaminocarbonyl, di (C)₁-C₃) Alkylaminocarbonyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkyl oxy, C₃-C₈Heterocycloalkyl radical, C₃-C₈Heterocycloalkyloxy, phenyl, phenyloxy, phenyl (C)₁-C₂) Alkane (I) and its preparation methodPhenyl radical, phenyl radical (C)₁-C₂) Alkoxy, phenylsulfonyl, phenylsulfinyl, C₅-C₆Heteroaryl group, C₅-C₆Heteroaryloxy radical, C₅-C₆Heteroaryl (C)₁-C₃) Alkyl radical, C₅-C₆Heteroaryl (C)₁-C₃) Alkoxy radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkyl radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkoxy radical, C₃-C₈Heterocycloalkyl (C)₁-C₂) Alkyl, heterocycloalkyl (C)₁-C₂) Alkoxy radical, wherein R³May be unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C₁-C₈Alkyl and unsubstituted or halogenated C₁-C₈An alkoxy group;

R⁴,R⁵,R⁶independently selected from: H. f, Cl, Br, I, CN, NO₂、NH₂、OH、C₁-C₆Alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, halocycloalkyloxy, alkenyl, cycloalkenyl, alkynyl, alkylsulfonyl, haloalkylsulfonyl, substituted amino, aminoalkyl or substituted aminoalkyl groups which may independently be substituted on nitrogen with 1 to 2 of the following substituents: c₁-C₃Alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl or alkoxyalkyl; or, R⁴,R⁵,R⁶Each two of which, together with the atoms to which they are attached, form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring;

R⁷selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, orSubstituted phenyl, heteroaryl, substituted benzyl;

a is selected from: substituted C₃-C₈Cycloalkyl, substituted C₃-C₈Heterocycloalkyl, substituted phenyl, heteroaryl, substituted heteroaryl, fused ring aryl, or substituted fused ring aryl, wherein said substituted phenyl, substituted heteroaryl, or substituted fused ring aryl may independently be substituted with 1 to 3 of the following substituents: H. f, Cl, Br, I, CN, NO₂、NH₂、N₃、OH、-COR⁸、-CONHS(O)₂R⁸、-NHCONHS(O)₂R⁸、-S(O)₂NH₂、-S(O)₂NHCOCH₃、C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, 1H-tetrazol-5-yl, 3H- [1,3,4 ]]Oxadiazol-2-one-5-yl, 3H- [1,3,4 ]]Oxadiazole-2-thione-5-yl, 4H- [1,2,4 [ ]]Oxadiazol-5-one-3-yl, 4H- [1,2,4 ]]Oxadiazole-5-thione-3-yl, 3H- [1,2,3,5]Oxathiadiazol-2-oxide-4-yl, 4H- [1,2,4 ]]Thiadiazol-5-one-3-yl, isoxazol-3-ol-5-yl, 5-alkylisoxazol-3-ol-4-yl, 5-cycloalkylisoxazol-3-ol-4-yl, furan-3-ol-4-yl, 5-alkylsulfonylamino- [1,3, 4-]Oxadiazol-2-yl, 5-cycloalkylsulphonamido- [1,3,4]Oxadiazol-2-yl, 5-alkylsulfonylamino-2H- [1,2,4 ]]Triazol-3-yl, 5-cycloalkylsulfonylamino-2H- [1,2,4]Triazol-3-yl, 5-alkylisothiazol-3-ol-4-yl, 5-cycloalkylisothiazol-3-ol-4-yl, [1,2,5]Thiadiazol-3-ol-4-yl, 1, 4-dihydro-tetrazol-5-one-1-yl, 2H-tetrazol-5-ylcarbamoyl, 2H-tetrazol-5-carbonyl, [1,2,4 ] f]Oxadiazolidine-3, 5-dione-2-yl, 4H- [1,2,4 ]]Oxadiazol-5-one-3-yl, 2, 4-dihydro- [1,2,4 ]]Triazol-3-one-5-ylthio, 4H- [1,2,4 ]]Triazole-3-thio, 4H- [1,2,4 ]]Triazole-3-sulfinyl, 4H- [1,2,4 ]]Triazole-3-sulfonyl, 4-alkyl-pyrazol-1-ol-5-yl, 4-cycloalkyl-pyrazol-1-ol-5-yl, 4-alkyl- [1,2,3]Triazol-1-ol-5-yl, 4-cycloalkyl- [1,2,3]Triazol-1-ol-5-yl, 5-alkyl-imidazol-1-ol-2-yl, 5-cycloalkyl-imidazol-1-ol-2-yl, 4-alkyl-imidazol-1-ol-5-yl, 4-cycloalkyl-imidazol-1-ol-5-yl, 4-alkyl-1, 1-dioxo-1. lambda⁶-[1,2,5]Thiadiazolidin-3-one-5-yl, 4-dialkyl-1, 1-dioxo-1 lambda⁶-[1,2,5]Thiadiazolidin-3-one-5-yl, 4-cycloalkyl-1, 1-dioxo-1 lambda⁶-[1,2,5]Thiadiazolidin-3-one-5-yl, 4-bicycloalkyl-1, 1-dioxo-1 lambda⁶[1,2,5]Thiadiazolidin-3-one-5-yl, thiazolidine-2, 4-dione-5-yl, oxazolidine-2, 4-dione-5-yl, 3- [ 1-hydroxy-methyl- (E) ylidene]-pyrrolidine-2, 4-dione-1-yl, 3- [ 1-hydroxy-methyl- (Z) -ylidene]-pyrrolidine-2, 4-dione-1-yl, 5-methyl-4-hydroxy-5H-furan-2-one-3-yl, 5-dialkyl-4-hydroxy-5H-furan-2-one-3-yl, 5-cycloalkyl-4-hydroxy-5H-furan-2-one-3-yl, 5-bicycloalkyl-4-hydroxy-5H-furan-2-one-3-yl, 3-hydroxy-cyclobut-3-ene-1, 2-dione-4-yl or 3-hydroxy-cyclobut-3-ene-1, 2-diketo-4-amino, wherein each alkyl or alkoxy group may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and unsubstituted or fluorinated C₁-C₃Alkyl or C₁-C₃An alkoxy group;

wherein R is⁸Selected from: OH, OR⁹、NR¹⁰R¹¹、C₁-C₆Alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl; r⁹Selected from: c₁-C₃Alkyl, W substituted C₁-C₃Alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl or alkoxyalkyl; wherein W is selected from: OH, acetylamino, C₁-C₃Alkoxycarbonyloxy or C₁-C₄An alkylcarbonyloxy group; r¹⁰And R¹¹Independently selected from: H. OH, C₁-C₃Alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

x is-S (O)_2--C (O) -or- (CH)₂) n-; wherein n is 0, 1 or 2;

m is 0, 1 or 2.

2. The indole compound according to claim 1,

R²selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, fused ring aryl, or substituted fused ring aryl, wherein said substituted phenyl, substituted heteroaryl, or substituted fused ring aryl may independently be substituted with 1 to 3 of the following substituents: F. cl, Br, I, CN, NO₂、NH₂、OH、C₁-C₃Alkyl radical, C₁-C₃Alkoxy, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl;

R³selected from: H. f, Cl, Br, I, CN, NO₂、NH₂、OH、N₃、C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkyl oxy, C₃-C₈Heterocycloalkyl radical, C₃-C₈Heterocycloalkyloxy, phenyl, phenyloxy, phenyl (C)₁-C₂) Alkyl, phenyl (C)₁-C₂) Alkoxy radical, C₅-C₆Heteroaryl group, C₅-C₆Heteroaryloxy radical, C₅-C₆Heteroaryl (C)₁-C₂) Alkyl radical, C₅-C₆Heteroaryl (C)₁-C₂) Alkoxy radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkyl radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkoxy radical, C₃-C₈Heterocycloalkyl (C)₁-C₂) Alkyl, heterocycloalkyl (C)₁-C₂) Alkoxy radical, wherein R³May be unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C₁-C₆Alkyl and unsubstituted or halogenated C₁-C₆An alkoxy group;

R⁴,R⁵,R⁶independently selected from: H. f, Cl, Br, I, CN, NO₂、NH₂、OH、C₁-C₃Alkyl, haloAn alkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, alkenyl, cycloalkenyl, alkynyl, alkylsulfonyl, haloalkylsulfonyl, substituted amino, aminoalkyl, substituted aminoalkyl, which substituted amino or substituted aminoalkyl may independently be substituted on nitrogen with 1 to 2 substituents as follows: c₁-C₃Alkyl, haloalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, alkoxyalkyl, hydroxyalkyl; or, R⁴,R⁵,R⁶Each two of which, together with the atoms to which they are attached, form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring;

R⁷selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl;

a is selected from: substituted phenyl, substituted heteroaryl, substituted fused ring aryl, wherein the substituted phenyl, substituted heteroaryl or substituted fused ring aryl may independently be substituted with 1 to 3 of the following substituents: H. f, Cl, Br, I, CN, NO₂、NH₂、N₃、OH、-COR、-CONHS(O)₂R⁸、-NHCONHS(O)₂R⁸、-S(O)₂NH₂、-S(O)₂NHCOCH₃、C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, 1H-tetrazol-5-yl, 3H- [1,3,4 ]]Oxadiazol-2-one-5-yl, 3H- [1,3,4 ]]Oxadiazole-2-thione-5-yl, 4H- [1,2,4 [ ]]Oxadiazol-5-one-3-yl;

wherein R is⁸Selected from: OH, OR⁹、NR¹⁰R¹¹、C₁-C₆An alkyl group; r⁹Selected from: c₁-C₃Alkyl or W substituted C₁-C₃Alkyl, wherein W is selected from: OH, acetamidoBase, C₁-C₃Alkoxycarbonyloxy or C₁-C₄An alkylcarbonyloxy group; r¹⁰And R¹¹Independently selected from: : H. OH or C₁-C₃An alkyl group;

x is- (CH)₂) n-; wherein n is 0, 1 or 2;

m is 0, 1 or 2.

3. The indole compound according to claim 1,

R¹selected from: H. f, Cl or Br;

R²selected from: H. c₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, wherein said substituted phenyl or substituted heteroaryl may independently be substituted with 1 to 3 substituents as follows: F. cl, Br, I, CN, NO₂、NH₂、OH、C₁-C₃An alkyl group;

R³selected from: H. f, Cl, Br, I, CN, C₁-C₈Alkoxy radical, C₃-C₈Cycloalkyl oxy, C₃-C₈Heterocycloalkyloxy, phenyloxy, phenyl (C)₁-C₂) Alkoxy radical, C₅-C₆Heteroaryloxy radical, C₅-C₆Heteroaryl (C)₁-C₂) Alkoxy radical, C₃-C₈Cycloalkyl (C)₁-C₂) Alkoxy, heterocycloalkyl (C)₁-C₂) Alkyloxy, wherein R³May be unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C₁-C₆Alkyl and unsubstituted or halogenated C₁-C₆An alkoxy group.

R⁴,R⁵,R⁶Independently selected from: H. f, Cl, OH, Br, I, CN, C₁-C₃Alkyl, alkoxy;

R⁷selected from: H. c₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group;

a is selected from: substituted phenyl, substituted heteroaryl, wherein said substituted phenyl or substituted heteroaryl may independently be substituted with 1 to 3 substituents as follows: H. f, Cl, Br, I, CN, NO₂、OH、-COR⁸、C₁-C₆Alkyl radical, C₁-C₆Alkoxy, 1H-tetrazol-5-yl, 3H- [1,3,4 ] methyl]Oxadiazol-2-one-5-yl;

wherein R is⁸Selected from: OH, OR⁹、NR¹⁰R¹¹；R⁹Selected from: c₁-C₃Alkyl or W substituted C₁-C₃Alkyl, wherein W is selected from: OH, acetylamino, C₁-C₃Alkoxycarbonyloxy or C₁-C₄An alkylcarbonyloxy group; r¹⁰And R¹¹Independently selected from: H. OH or C₁-C₃An alkyl group;

x is- (CH)₂) n-; wherein n is 0, 1 or 2;

m is 0, 1 or 2.

4. The indole compound or the pharmaceutically acceptable salt, ester or solvate thereof according to any one of claims 1 to 3, wherein the indole compound is selected from the group consisting of the following compounds 1 to 95:

5. use of the indole of claim 1 or a pharmaceutically acceptable salt, ester or solvate thereof in the manufacture of a medicament for the prevention or treatment of a FABP4/5 mediated disease.

6. The use according to claim 5, wherein the FABP4/5 mediated disease is a metabolic disease, a cardiovascular disease, a cerebrovascular disease, an inflammatory disease, an autoimmune disease, an organ fibrotic disease, a nerve injury disease, a secondary disease caused by infection with a pathogen, or a tumor.

7. A pharmaceutical composition comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is in the form of a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, cream, ointment, suppository, or patch.

9. Use of the pharmaceutical composition of claim 7 or 8 in the manufacture of a medicament for the prevention or treatment of a FABP4/5 mediated disease.

10. The use according to claim 9, wherein the FABP4/5 mediated disease is a metabolic disease, a cardiovascular disease, an inflammatory disease, an autoimmune disease, an organ fibrotic disease, a neurological injury disease, a secondary disease caused by infection with a pathogen, or a tumor.