CN112375027B - Indolesulfonamide derivative and medical application thereof - Google Patents

Indolesulfonamide derivative and medical application thereof Download PDF

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CN112375027B
CN112375027B CN202011415997.9A CN202011415997A CN112375027B CN 112375027 B CN112375027 B CN 112375027B CN 202011415997 A CN202011415997 A CN 202011415997A CN 112375027 B CN112375027 B CN 112375027B
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compound
acid
indole
300mhz
disease
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CN112375027A (en
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王朝鑫
王贺瑶
杨春伟
陈梦婷
袁浩亮
孙宏斌
温小安
李娟红
陈禹绮
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China Pharmaceutical University
Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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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 the FABP4/5 inhibitor.
Background
Fatty Acid Binding Proteins (FABPs) as intracellular lipid chaperones can reversibly bind to lipids, increase the solubility of the proteins 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 is mainly distributed in adipocytes and macrophages, accounting for 1% of the total adipose tissue protein. FABP5 has a wide distribution range of tissues. FABP4/5 is closely related to the occurrence and development of metabolic inflammatory diseases, including atherosclerosis, hyperlipidemia, type II diabetes, nonalcoholic steatohepatitis and the like. In 1996, hotamistigl et al first reported FABP4 knock-out (FABP 4) -/- ) The mice of (1) can show good insulin sensitivity under the condition of metabolic stress such as high fat diet, and compared with the control group, FABP4 -/- Tumor necrosis factor-alpha (TNF-alpha) expression was also significantly down-regulated in adipose tissue of mice, but there was a compensatory increase in FABP5 expression in adipocytes (Science 1996,274,1377). FABP4/5 double knockout (FABP 4-5) -/- ) Mice alter cellular and systemic lipid trafficking and composition, leading to enhanced insulin receptor signaling, increased adenylate-activated protein kinase (AMPK) agonistic activity in muscle tissue, decreased expression of hepatic stearoyl-coa desaturase 1 (SCD 1), improved hepatic lipid infiltration, and strong protection against diet-induced insulin resistance, type ii diabetes, and fatty liver disease (Cell meta b.2005,1, 107). In addition in apolipoprotein E deletion (ApoE) -/- ) FABP4/5 in mice -/- Than 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 responses (J Lipid Res.2004,45, 2138. In addition, in genetic studies, it was found that the genetic variation of the human FABP4 promoter (T-87C) reduces the expression of FABP4, and that the probability of coronary heart disease and type II diabetes in T-87C-bearing people is reduced and the serum TG level is also reduced compared with the FABP4 wild-type people (Proc Natl Acad Sci USA.2006,103, 6)970). FABP4 and FABP5 are also closely related to the development and progression of a variety of tumors including breast, ovarian, prostate, etc., and tumor metabolism (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 inhibitors are in an early biological activity test stage, wherein the FABP4 inhibitor BMS309403 developed by BaishiGuibao company is deeply researched, and the FABP4 inhibitor BMS309403 can improve atherosclerosis and insulin resistance and treat diseases such as nonalcoholic steatohepatitis (Nature.2007, 447,959; journal of hepatology.2013,58,358) but the safety needs to be further verified. While the FABP4/5 dual inhibitor has relatively few reports, 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 to cause 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 invention aims to: in view of the prior art, the application provides an indole sulfonamide compound with FABP4/5 inhibitory activity and a medical application thereof.
The technical scheme is as follows: the invention discloses a compound shown as the following formula I, and pharmaceutically acceptable salt or ester or solvate thereof:
Figure BDA0002820098560000011
wherein R is 1 Selected from: H. f, cl, br, I, OCH 3 ；
R 2 Selected from: H. c 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, 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, NO 2 、NH 2 、OH、OR 12 、C 1 -C 3 Alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, halocycloalkyl, halocycloalkylalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkylalkoxyalkyl, cycloalkoxyalkyl, alkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylalkyl or substituted amino;
R 12 selected from: cycloalkyl, heterocycloalkyl, or substituted or unsubstituted C 1 -C 4 Alkyl, said substituted C 1 -C 4 Alkyl is substituted with one or two or three substituents independently selected from the group consisting of: OH, (O), C (O) OH, CN, NH 2 F, alkylsulfonyl, haloalkylsulfonyl, substituted amino, C (O) NH 2 Alkylsulfonylamino, sulfamoyl, NHC (O) NH 2 Pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholine-1,1-dioxo-4-yl, or NHC (O) CH (CH) 3 )NHC(O)CH(CH 3 )NH；
R 3 Selected from: H. f, cl, br, I, CN, NO 2 、NH 2 、OH、N 3 、C 1 -C 8 Alkyl radical, C 1 -C 8 Alkoxy radical, C 2 -C 8 Alkenyl radical, C 2 -C 8 Alkynyl, C 1 -C 8 Alkyl carbonyl, C 1 -C 8 Alkoxycarbonyl group, C 1 -C 8 Alkylsulfonyl radical, C 1 -C 8 Alkylsulfinyl radical, C 1 -C 8 Alkylthio radical, C 1 -C 5 Alkylcarbonylamino, C 1 -C 8 Alkylaminocarbonyl, di (C) 1 -C 3 ) Alkylaminocarbonyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl oxy, C 3 -C 8 Heterocycloalkyl radical, C 3 -C 8 Heterocycloalkyloxy, phenyl, phenyloxy, phenyl (C) 1 -C 2 ) Alkyl, phenyl (C) 1 -C 2 ) Alkoxy, phenylsulfonyl, phenylsulfinyl, C 5 -C 6 Heteroaryl group, C 5 -C 6 Heteroaryloxy radical, C 5 -C 6 Heteroaryl (C) 1 -C 3 ) Alkyl radical, C 5 -C 6 Heteroaryl (C) 1 -C 3 ) Alkoxy radical, C 3 -C 8 Cycloalkyl (C) 1 -C 2 ) Alkyl radical, C 3 -C 8 Cycloalkyl (C) 1 -C 2 ) Alkoxy radical, C 3 -C 8 Heterocycloalkyl (C) 1 -C 2 ) Alkyl, heterocycloalkyl (C) 1 -C 2 ) Alkyloxy, wherein R 3 May be unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C 1 -C 8 Alkyl and unsubstituted or halogenated C 1 -C 8 An alkoxy group;
R 4 ,R 5 ,R 6 independently selected from: H. f, cl, br, I, CN, NO 2 、NH 2 、OH、C 1 -C 6 Alkyl, 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: c 1 -C 3 Alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl or alkoxyalkyl; or, R 4 ,R 5 ,R 6 Each 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 heterocycloalkyl ringA hydrocarbon ring or a substituted or unsubstituted heterocyclic olefin ring;
R 7 selected from: H. c 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted benzyl;
a is selected from: substituted C 3 -C 8 Cycloalkyl, substituted C 3 -C 8 Heterocycloalkyl, 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, NO 2 、NH 2 、N 3 、OH、-COR 8 、-CONHS(O) 2 R 8 、-NHCONHS(O) 2 R 8 、-S(O) 2 NH 2 、-S(O) 2 NHCOCH 3 、C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, 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-Thion-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-cycloalkylsulfonamido-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]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. Lamda. 6 -[1,2,5]Thiadiazolidin-3-one-5-yl, 4,4-dialkyl-1,1-dioxo-1 lambda 6 -[1,2,5]Thiadiazolidin-3-one-5-yl, 4-cycloalkyl-1,1 dioxo-1 lambda 6 -[1,2,5]Thiadiazolidin-3-one-5-yl, 4,4-bicycloalkyl-1,1 dioxo-1 lambda 6 [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-diketo-1-yl, 3- [ 1-hydroxy-meth- (Z) -ylidene]-pyrrolidine-2,4-dione-1-yl, 5-methyl-4-hydroxy-5H-furan-2-one-3-yl, 5,5-dialkyl-4-hydroxy-5H-furan-2-one-3-yl, 5-cycloalkyl-4-hydroxy-5H-furan-2-one-3-yl, 5,5-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-dione-4-amino, wherein each alkyl or alkoxy group may be unsubstituted or substituted with one or more substituents selected from halogen and unsubstituted or fluorinated C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group;
wherein R is 8 Selected from: OH, OR 9 、NR 10 R 11 、C 1 -C 6 Alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl;
R 9 selected from: c 1 -C 3 Alkyl, W substituted C 1 -C 3 Alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl or alkoxyalkyl; wherein W is selected from: OH, acetylamino, C 1 -C 3 Alkoxycarbonyloxy or C 1 -C 4 An alkylcarbonyloxy group;
R 10 and R 11 Independently selected from: H. OH, C 1 -C 3 Alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
x is-S (O) 2 -, -C (O) -or- (CH) 2 ) n-; wherein n =0, 1 or 2;
m =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:
R 1 selected from: H. f, cl, br, I, OCH 3 ；
R 2 Selected from: H. c 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl, 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, NO 2 、NH 2 、OH、C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl;
R 3 selected from: H. f, cl, br, I, CN, NO 2 、NH 2 、OH、N 3 、C 1 -C 8 Alkyl radical, C 1 -C 8 Alkoxy radical, C 3 -C 8 Cycloalkyl, C 3 -C 8 Cycloalkyl oxy, C 3 -C 8 Heterocycloalkyl radical, C 3 -C 8 Heterocycloalkyloxy, phenyl, phenyloxy, phenyl (C) 1 -C 2 ) Alkyl, phenyl (C) 1 -C 2 ) Alkoxy radical, C 5 -C 6 Heteroaryl group, C 5 -C 6 Heteroaryloxy radical, C 5 -C 6 Heteroaryl (C) 1 -C 2 ) Alkyl radical, C 5 -C 6 Heteroaryl (C) 1 -C 2 ) Alkoxy radical, C 3 -C 8 Cycloalkyl (C) 1 -C 2 ) Alkyl radical, C 3 -C 8 Cycloalkyl (C) 1 -C 2 ) Alkoxy radical, C 3 -C 8 Heterocycloalkyl (C) 1 -C 2 ) Alkyl, heterocycloalkyl (C) 1 -C 2 ) Alkyloxy, wherein R 3 Each group in (1) mayTo be unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl and unsubstituted or halogenated C 1 -C 6 An alkoxy group;
R 4 ,R 5 ,R 6 independently selected from: H. f, cl, br, I, CN, NO 2 、NH 2 、OH、C 1 -C 3 Alkyl, 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: c 1 -C 3 Alkyl, haloalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, alkoxyalkyl, hydroxyalkyl; or, R 4 ,R 5 ,R 6 Each 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;
R 7 selected from: H. c 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl, 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, NO 2 、NH 2 、N 3 、OH、-COR、-CONHS(O) 2 R 8 、-NHCONHS(O) 2 R 8 、-S(O) 2 NH 2 、-S(O) 2 NHCOCH 3 、C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, 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 is 8 Selected from: OH, OR 9 、NR 10 R 11 、C 1 -C 6 An alkyl group;
R 9 selected from: c 1 -C 3 Alkyl or W substituted C 1 -C 3 Alkyl, wherein W is selected from: OH, acetylamino, C 1 -C 3 Alkoxycarbonyloxy or C 1 -C 4 An alkylcarbonyloxy group;
R 10 and R 11 Independently selected from: : H. OH or C 1 -C 3 An alkyl group;
x is- (CH) 2 ) n-; wherein n =0, 1 or 2;
m =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:
R 1 selected from the group consisting of: H. f, cl or Br;
R 2 selected from the group consisting of: H. c 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl, 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, NO 2 、NH 2 、OH、C 1 -C 3 An alkyl group;
R 3 selected from: H. f, cl, br, I, CN, C 1 -C 8 Alkoxy radical, C 3 -C 8 Cycloalkyloxy radical, C 3 -C 8 Heterocycloalkyloxy, phenyloxy, phenyl (C) 1 -C 2 ) Alkoxy radical, C 5 -C 6 Heteroaryloxy radical, C 5 -C 6 Heteroaryl (C) 1 -C 2 ) Alkoxy radical, C 3 -C 8 Cycloalkyl (C) 1 -C 2 ) Alkoxy, heterocycloalkyl (C) 1 -C 2 ) Alkyl oxygenIn which R is 3 May be unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl and unsubstituted or halogenated C 1 -C 6 An alkoxy group.
R 4 ,R 5 ,R 6 Independently selected from: H. f, cl, OH, br, I, CN, C 1 -C 3 Alkyl, alkoxy;
R 7 selected from the group consisting of: H. c 1 -C 6 Alkyl radical, C 3 -C 6 A 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, NO 2 、OH、-COR 8 、C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, 1H-tetrazol-5-yl, 3H- [1,3,4]Oxadiazol-2-one-5-yl;
wherein R is 8 Selected from the group consisting of: OH, OR 9 、NR 10 R 11 ；
R 9 Selected from the group consisting of: c 1 -C 3 Alkyl or W substituted C 1 -C 3 Alkyl, wherein W is selected from: OH, acetylamino, C 1 -C 3 Alkoxycarbonyloxy or C 1 -C 4 An alkylcarbonyloxy group;
R 10 and R 11 Independently selected from: H. OH or C 1 -C 3 An alkyl group;
x is- (CH) 2 ) n-; wherein n =0, 1 or 2;
m =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:
Figure BDA0002820098560000041
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Figure BDA0002820098560000051
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Figure BDA0002820098560000061
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 formula I or pharmaceutically acceptable salt or ester or solvate thereof is a novel FABP4/5 inhibitor, and thus 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, nerve injury diseases or secondary diseases caused by infection with 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, sepsis, gangrenous dermatosis, uveitis, idiopathic pulmonary fibrosis, cystic fibrosis, parkinson's disease, alzheimer's disease, alpha-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, down syndrome, haller wadding-Shi Pabing, huntington's disease, or wilson's disease, and the like.
Such FABP4/5 mediated diseases, such as mitochondrial dysfunction and disorder diseases, include: 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.
Adjuvants which can be arbitrarily mixed in the pharmaceutical composition of the present invention may vary depending on the dosage form, administration form, and the like. 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 capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, cream, ointment, suppository or patch.
The preparation of the compounds of the invention can be carried out with reference to the following synthetic routes or improved methods.
Scheme 1.
Figure BDA0002820098560000071
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.
Figure BDA0002820098560000081
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.
Figure BDA0002820098560000091
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.
Figure BDA0002820098560000101
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.
Figure BDA0002820098560000111
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.
Figure BDA0002820098560000112
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, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 X and m are as defined above for compounds of formula I.
In the medicament for preventing or treating a FABP4/5 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, symptoms, administration route, and the like of the patient. When administered orally to an adult (about 60 kg), the compound of formula I or a pharmaceutically acceptable salt or ester or solvate thereof is preferably administered in a dose of 1mg to 500mg per time, more preferably 5mg to 60mg per time, 1 to 3 times per day. The dosage range may also vary depending on the degree of disease and dosage form.
Has the beneficial effects 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 prospect.
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 can 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 1 Ethyl 4- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonamide) benzoate (Compound 1)
Figure BDA0002820098560000121
Compound I-1 (10g, 68.7mmol) was placed in a eggplant-shaped bottle, and glacial acetic acid (137 mL) was added to dissolve the compound, and N-iodosuccinimide (NIS) (15.6 g,69.4 mmol) was slowly added in ice bath, and after the addition, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate (50 mL) was added to the reaction solution for dilution, a saturated sodium bicarbonate solution (500 mL) was added until no bubble was generated, sodium thiosulfate (50 mL) was further added to remove excess N-iodosuccinimide, followed by washing with a saturated sodium chloride solution (50 mL × 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) to obtain compound I-2 (white solid, 8.1g, yield 43%): 1 H NMR(300MHz,DMSO-d 6 )δ7.61(d,J＝8.8Hz,1H),6.87(d,J＝6.9Hz,1H),5.31(s,2H).
compound I-2 (7.6 g, 27.99mmol) was dissolved in pyridine (42 mL), and ethyl chloroformate (3 mL, 30.79mmol) was slowly added under ice bath, and after completion of addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (50 mL), washed with 2N hydrochloric acid (50 mL × 3) until no pyridine remained, washed with a saturated sodium chloride solution (30 mL × 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) to obtain compound I-4 (white solid, 11.1mg, yield 99%): 1 H NMR(300MHz,DMSO-d 6 )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) and cuprous iodide (307mg, 1.6 mmol) were dissolved in tetrahydrofuran (129 mL) under argon protection, triethylamine (13.4mL, 96.7mmol) and trimethylacetylene silicon (TMSA) (6.8mL, 48.4mmol) were added and the mixture was stirred at room temperature for 2 hours after completion of the addition. After the reaction is finished, filtering the diatomite by suction, evaporating the solvent from the filtrate under reduced pressure, and passing the residue throughColumn chromatography (petroleum ether: dichloromethane: ethyl acetate = 500) gave compound I-5 (yellow solid, 8.2g, yield 81%): 1 H NMR(300MHz,CDCl 3 )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, 22.6 mmol) and sodium ethoxide (5.5g, 81.4 mmol) were dissolved in absolute ethanol (284 mL) 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 (40 mL × 3), washed with saturated sodium chloride (30 mL × 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%): 1 H NMR(300MHz,CDCl 3 )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) and 4A molecular sieves (4A MS) (1.6 g) were dissolved in anhydrous dichloromethane (10 mL), and pyridine (190. Mu.L) and triethylamine (328. Mu.L) were added thereto 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 distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: dichloromethane = 20) to obtain compound I-7 (colorless liquid, 225mg, yield 78%): 1 H NMR(300MHz,CDCl 3 )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 (1 mL), 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 previous step is dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (0.5mL + 1mL), under the protection of argon, phosphorus oxychloride (43 uL, 0.45 mmol) is added under ice bath, and then the mixture is 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, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate =50: 1) to obtain compound I-9 (white solid, 52mg, two-step yield 67%): 1 H NMR(300MHz,CDCl 3 )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 (2 mL), and the mixture was stirred at room temperature for 30 minutes, followed by addition of pyridine (20. Mu.L, 0.24 mmol) and stirring 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 H NMR(300MHz,DMSO-d 6 )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 2 Ethyl 5- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoate (Compound 2)
Compound 2 was prepared according to the procedure of example 1: 1 H 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 3- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) -4-fluorobenzoic acid ethyl ester (Compound 3)
Compound 3 was prepared according to the procedure of example 1: 1 H 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 4- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 4)
Figure BDA0002820098560000131
Compound 1 (43.1mg, 0.09mmol) was dissolved in 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 the pH to acidity, dichloromethane (10 mL × 3) was extracted, saturated sodium chloride (10 mL × 1) was washed, 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 obtain compound 4 (white solid, 38.7mg, yield 95%): 1 H NMR(300MHz,DMSO-d 6 )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 5- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 6- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonamide) -4-fluorobenzoic acid (Compound 6)
Figure BDA0002820098560000141
Compound I-9 (42mg, 0.12mmol) and ethyl 4-aminobenzoate (40mg, 0.24mmol) were dissolved in dichloromethane (2 mL), and the mixture was stirred at room temperature for 30 minutes, followed by addition of pyridine (20. Mu.L, 0.24 mmol) and stirring 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 obtain compound 6 (pale yellow solid, 86.2mg, yield 99%): 1 H NMR(300MHz,DMSO-d 6 )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)
Figure BDA0002820098560000142
Compound 1 (100mg, 0.21mmol) is dissolved in a methanol-tetrahydrofuran mixed solvent (0.5mL +1.0 mL), 1M sodium hydroxide solution (0.5 mL) is added, and the mixture is heated and stirred 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 (5 mL × 3) was extracted, the organic phases were combined, washed with saturated sodium chloride (5 mL × 2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained product was used in the next reaction without purification.
The above product was dissolved in toluene (1 mL), thionyl chloride (32. Mu.L, 0.43 mmol) was added to the solution, and after addition, 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 ammonia (5 mL) 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 (2 mL), and phosphorus oxychloride (2 mL) 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 (5 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (5 mL × 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, four-step yield 60%).
Sodium azide (76mg, 1.17mmol) and zinc chloride (64mg, 0.47mmol) were suspended in n-butanol (2 mL), 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 raw materials was completed, heating was stopped, the reaction mixture was cooled to room temperature, 2N HCl (10 mL) was added to the reaction mixture, the mixture was stirred for 30 minutes, extracted with ethyl acetate (5 mL. Times.4), and the organic phases were combined with a saturated common salt solution(5 mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol: acetic acid =200: 1) and slurried with diethyl ether (5 mL) to give compound 7 (beige solid, 66.5mg, yield 60%): 1 H NMR(300MHz,DMSO-d 6 )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 8-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: 1 H NMR(300MHz,DMSO-d 6 )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 9- ((6-chloro-1- (2-cyclohexylethyl) -5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 9)
Figure BDA0002820098560000151
Compound I-6 (150mg, 0.88mmol) was dissolved in dimethylformamide (3 mL), 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 solution was diluted with water (30 mL), extracted with ethyl acetate (8 mL × 3), the organic phases were combined, washed with water (5 mL × 2), washed with a saturated sodium chloride solution (5 mL × 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) to obtain compound III-1 (colorless oily liquid, 310.4mg, yield 94%).
Compound III-1 (300mg, 1.07mmol) was dissolved in pyridine (3 mL), 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.
Dissolving the product obtained in the previous step in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (2mL +4 mL), adding phosphorus oxychloride (200 mu L,2.14 mmol) under the protection of argon, and heating to 70 ℃ for reaction for 6 hours. After completion of the reaction, the reaction liquid was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (10 mL × 3), washed with ice water (10 mL × 3), washed with saturated sodium chloride (10 mL × 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) to obtain 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 methylene chloride (2 mL), and the mixture was stirred at room temperature for 30 minutes, followed by addition of pyridine (52. Mu.L, 0.65 mmol) and stirring at room temperature for 12 hours. After completion of the reaction, 2N HCl (20 mL), ethyl acetate (5 mL × 3) extraction, 2N HCl (5 mL × 2) washing, saturated sodium chloride (5 mL × 2) washing, anhydrous sodium sulfate drying, evaporation of the solvent under reduced pressure, and purification of the residue by column chromatography (dichloromethane: methanol: acetic acid =200: 1), the resulting solid was slurried with ether to obtain compound 9 (white solid, 63.5mg, yield 59%): 1 H NMR(300MHz,DMSO-d 6 )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 10- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 11- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 12- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 13- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 14- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 15- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 16- ((6-chloro-1-cycloheptyl-5-fluoro-1H-indole) -3-sulfonamido) benzoic acid (Compound 16)
Figure BDA0002820098560000171
Compound I-6 (450mg, 2.65mmol) was dissolved in borane in tetrahydrofuran (4 mL) and stirred in ice bath for 30 min, trifluoroacetic acid (TFA) (4 mL) was added and stirred for 30 min while maintaining ice bath. After completion of the reaction, the reaction solution was diluted with saturated sodium bicarbonate (30 mL), extracted with ethyl acetate (8 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (5 mL × 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) to obtain compound IV-1 (brown oily liquid, 454.8mg, yield 90%).
Compound IV-1 (272mg, 1.59mmol) and cycloheptanone (374. Mu.L, 3.17 mmol) were dissolved in 1,2-Dichloroethane (DCE) (5 mL), 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 the 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).
Compound IV-2 (134mg, 1.50mmol) and 2,3-dichloro-5,6-dicyan-p-benzoquinone (DDQ) (125mg, 0.55mmol) were dissolved in anhydrous dichloromethane (3 mL) 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) to obtain compound IV-3 (colorless oily liquid, 101.3mg, yield 76%).
Compound IV-3 (96mg, 0.36mmol) was dissolved in pyridine (1 mL), 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.
Dissolving the product obtained in the above step in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (1mL + 2mL), adding phosphorus oxychloride (67 μ L,0.72 mmol) under argon protection under ice bath, and heating 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 (10 mL × 3), washed with ice water (10 mL × 3), washed with saturated sodium chloride (10 mL × 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) to obtain compound IV-4 (yellow oily liquid, 130.5mg, two-step yield 99%).
Compound IV-4 (82mg, 0.22mmol) and 4-amino-benzoic acid (49mg, 0.36mmol) were dissolved in anhydrous dichloromethane (2 mL), and the mixture was stirred at room temperature for 30 minutes, followed by addition of pyridine (43. Mu.L, 0.54 mmol) and stirring at room temperature for 12 hours. After completion of the reaction, 2N HCl (20 mL), ethyl acetate (5 mL × 3) extraction, 2N HCl (5 mL × 2) washing, saturated sodium chloride (5 mL × 2) washing, anhydrous sodium sulfate drying, solvent removal by evaporation under reduced pressure, and purification of the residue by column chromatography (dichloromethane: methanol: acetic acid =200: 1), and the resulting solid was slurried with ether to obtain compound 16 (white solid, 60mg, yield 85%): 1 H NMR(300MHz,DMSO-d 6 )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 17- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 18- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 19- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 20- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 21- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 22 Ethyl 3- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 23- (((7- (cyclohexylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 23)
Figure BDA0002820098560000181
Compound V-1 (2g, 14.8mmol) and 4-Dimethylaminopyridine (DMAP) (181mg, 1.48mmol) were dissolved in anhydrous dichloromethane (24 mL), triethylamine (3.1mL, 22.2mmol) was added to the solution, pivaloyl 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).
Compound V-2 (1g, 4.56mmol) was placed in a dry three-necked flask, dissolved by adding anhydrous dichloromethane (9 mL) under argon, and a 1M solution of boron tribromide in dichloromethane (10 mL) was added to the solution and stirred at room temperature for 3 hours. To the reaction mixture was added a triethylamine solution (9.6mL, 68.41mmol) of Pinacol (Pinacol) (1.89g, 15.92mmol) and 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).
Compound V-3 (550mg, 1.59mmol) was dissolved in tetrahydrofuran (8 mL), and 0.5M aqueous sodium hydroxide (3.4 mL) was added to the reaction solution, followed by slowly dropwise addition of 30% aqueous hydrogen peroxide (797. Mu.L) and stirring at room temperature overnight. After completion of the reaction, 2N HCl (10 mL) was added to the reaction solution, the pH of the solution was adjusted to acidity, ethyl acetate (10 mL. Times.2) was extracted, the organic phases were combined, washed with saturated sodium chloride (8 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: 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 (4 mL), and anhydrous potassium carbonate (196mg, 1.42mmol) and bromomethylcyclohexane (149. Mu.L, 1.07 mmol) were added to the solution, which was heated to 70 ℃ for 12 hours. After completion of the reaction, suction filtration, dilution with water (40 mL), extraction with ethyl acetate (8 mL × 3), combination of organic phases, washing with water (5 mL × 2), washing with saturated sodium chloride (8 mL × 2), drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and purification of the residue by column chromatography (petroleum ether: ethyl acetate = 30) gave compound V-5 (colorless oily liquid, 44.7mg, yield 26%).
Compound V-5 (44.7mg, 0.18mmol) was dissolved in N, N-dimethylformamide (2 mL), and potassium hydroxide (20mg, 0.36mmol) and iodomethane (17. Mu.L, 0.27 mmol) 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 (20 mL), extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with water (5 mL × 2), washed with saturated sodium chloride (5 mL × 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) to obtain compound V-6 (pale yellow solid, 44mg, yield 93%).
Compound V-6 (43mg, 0.16mmol) was dissolved in pyridine (1 mL), 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.
Dissolving the product obtained in the previous step in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (0.5mL + 1mL), adding phosphorus oxychloride (31 mu L,0.33 mmol) under argon protection and heating 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 (5 mL × 3), washed with ice water (5 mL × 3), washed with saturated sodium chloride (5 mL × 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) to obtain compound V-8 (white solid, 57.5mg, two-step yield 97%).
Compound V-8 (82mg, 0.22mmol) and 4-aminobenzoic acid (22mg, 0.16mmol) were dissolved in anhydrous dichloromethane (1 mL), and the mixture was stirred at room temperature for 30 minutes, followed by addition of pyridine (19. Mu.L, 0.24 mmol) and stirring at room temperature for 12 hours. After completion of the reaction, 2N HCl (10 mL), ethyl acetate (5 mL × 3) extraction, 2N HCl (5 mL × 2) washing, saturated sodium chloride (5 mL × 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) to obtain a solid which is purified by column chromatography (dichloromethaneEther slurried to give compound 23 (white solid, 26mg, 71% yield): 1 H NMR(300MHz,DMSO-d 6 )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 24- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 25- (((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: 1 H NMR(300MHz,DMSO-d 6 )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 26- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 27-chloro-5- ((6-chloro-5-fluoro-1-octyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 27)
Compound 27 was prepared according to the procedure of example 9: 1 H NMR(300MHz,DMSO-d 6 )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 28-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: 1 H NMR(300MHz,DMSO-d 6 )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 29-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: 1 H NMR(300MHz,DMSO-d 6 )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 30-chloro-5- ((6-chloro-1-cycloheptyl-5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 30)
Compound 30 was prepared according to the procedure of example 16: 1 H NMR(300MHz,DMSO-d 6 )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 31-bromo-5- ((6-chloro-5-fluoro-1-octyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 31)
Compound 31 was prepared according to the procedure of example 9: 1 H NMR(300MHz,DMSO-d 6 )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 32-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: 1 H NMR(300MHz,DMSO-d 6 )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 33-bromo-5- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 33)
Compound 33 was prepared according to the procedure of example 6: 1 H NMR(300MHz,DMSO-d 6 )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 34-bromo-5- ((6-chloro-1-cycloheptyl-5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 34)
Compound 34 was prepared according to the procedure of example 16: 1 H NMR(300MHz,DMSO-d 6 )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 35- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 36- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 37- ((6-chloro-5-fluoro-1-phenyl-1H-indole) -3-sulfonylamino) -2- (trifluoromethyl) benzoic acid (Compound 37)
Compound 37 was prepared according to the method of example 6: 1 H NMR(300MHz,DMSO-d 6 )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 38- ((6-chloro-1-cycloheptyl-5-fluoro-1H-indole) -3-sulfonylamino) -2- (trifluoromethyl) benzoic acid (Compound 38)
Compound 38 was prepared according to the method of example 16: 1 H NMR(300MHz,DMSO-d 6 )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 39- (((7- (2-cyclohexylethoxy) -1-ethyl-5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 39)
Compound 39 was prepared according to the method of example 23: 1 H NMR(300MHz,DMSO-d 6 )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 40- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 41- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 24 H 26 F 2 N 2 O 5 S:493.1609,found:493.1611.
example 42- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 43- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 26 H 31 FN 2 O 5 S:503.2016,found:503.2019.
example 44- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 26 H 30 F 2 N 2 O 5 S:543.1741,found:543.1738.
example 45- ((7- (2-cyclohexylethyl) -5-fluoro-1-methyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 45)
Figure BDA0002820098560000221
Taking a dry three-necked bottle, adding an anhydrous tetrahydrofuran solution (20 mL) of the compound VI-1 (2g, 3.93mmol) under the protection of argon, and cooling to-78 ℃. To the solution was slowly added 1M vinylmagnesium bromide in tetrahydrofuran (1M in THF, 31.44mL) and stirred at-78 ℃ for 3 hours. After completion of the reaction, a saturated ammonium chloride solution (30 mL), ethyl acetate (10 mL × 3) extraction, washing with a saturated sodium chloride solution (10 mL × 2), drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 75) of the residue to obtain compound VI-2 (pale yellow solid, 1.03g, yield 61%).
Compound VI-2 (900mg, 4.20mmol) was dissolved in dimethylformamide (8 mL), and methyl iodide (320. Mu.L, 6.31 mmol) and potassium hydroxide (472mg, 8.41mmol) were added to the solution, which was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with water (80 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL × 2), washed with a saturated sodium chloride solution (10 mL × 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) to obtain compound VI-3 (colorless oily liquid, 677.4mg, yield 71%).
Compound VI-3 (670mg, 2.94mmol) was dissolved in pyridine (6 mL), pyridine sulfur trioxide (1.40g, 8.81mmol) was added, and the mixture was heated at 105 ℃ for 6 hours in a sealed tube. 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 previous step is dissolved in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (3mL +6 mL), under the protection of argon, phosphorus oxychloride (548 μ L,5.88 mmol) is added under ice bath, and then the mixture is 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 (10 mL × 3), washed with ice water (10 mL × 2), washed with saturated sodium chloride (10 mL × 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) 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 (3 mL), stirred at room temperature for 30 minutes, then pyridine (128. Mu.L, 1.59 mmol) was added, and stirred at room temperature for 12 hours. After completion of the reaction, 2N hydrochloric acid (10 mL), ethyl acetate (10 mL × 3) extraction, saturated sodium chloride solution (5 mL × 2) washing, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and purification of the residue by column chromatography (petroleum ether: ethyl acetate = 10) were added to obtain compound VI-6 (white solid, 240.8mg, yield 99%).
A dry three-necked flask was charged 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 an argon atmosphere, anhydrous N, N-dimethylformamide (2 mL) was added, cyclohexylacetylene (43. Mu.L, 0.33 mmol) and triethylamine (46. Mu.L, 0.33 mmol) were added to the solution, and the mixture was heated at 80 ℃ for 12 hours. After completion of the reaction, it was diluted with water (20 mL), extracted with ethyl acetate (5 mL × 3), washed with water (5 mL × 2), washed with a saturated sodium chloride solution (5 mL × 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 = 5:1) to give compound VI-7 (pale yellow solid, 52mg, yield 98%).
Compound VI-7 (43mg, 0.089mmol) was dissolved in methanol (2 mL), and palladium on carbon (5 mg) was added thereto, followed by stirring under hydrogen atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered with suction through celite, the filtrate was distilled off 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, 0.047 mmol) is dissolved in methanol-tetrahydrofuran mixed solvent (0.4mL + 0.8mL), and 1M sodium hydroxide solution (400. Mu.L) is added 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 C 24 H 27 FN 2 O 4 S:459.1754,found:459.1748.
Example 46- ((5-fluoro-1-methyl-7-phenyl-1H-indole) -3-sulfonamido) benzoic acid (Compound 46)
Figure BDA0002820098560000231
Taking a dry three-neck bottle, adding the compound VI-6 (60mg, 0.13mmol), phenylboronic acid (19mg, 0.111mmol), 1,1' -bis diphenylphosphine ferrocene palladium dichloride (11mg, 0.013mmol) and potassium carbonate (55mg, 0.40mmol) under the protection of argon, adding dioxane and water (1.6mL + 0.4mL), and heating at 100 ℃ for 12 hours after adding. 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) is dissolved in a methanol-tetrahydrofuran mixed solvent (0.5mL + 1mL), and 1M sodium hydroxide solution (0.5 mL) is 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%): : 1 H NMR(300MHz,DMSO-d 6 )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 C 22 H 17 FN 2 O 4 S:425.0971,found:425.0972.
example 47 2-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: 1 H NMR(300MHz,DMSO-d 6 )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+NH 4 ] + calcd for C 20 H 14 F 2 N 2 O 5 S:450.0935,found:450.0929.
EXAMPLE 48 4- (((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 25 H 29 FN 2 O 4 S:473.1910,found:473.1899.
example 49- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 24 H 26 F 2 N 2 O 4 S:499.1479,found:499.1474.
example 50-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: 1 H NMR(300MHz,DMSO-d 6 )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 C 22 H 16 F 2 N 2 O 4 S:443.0877,found:443.0876.
example 51- ((5-fluoro-7- (furan-3-yl) -1-methyl-1H-indole) -3-sulfonamide) benzoic acid (Compound 51)
Compound 51 was prepared according to the procedure of example 46: 1 H NMR(300MHz,DMSO-d 6 )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 C 20 H 15 FN 2 O 5 S:415.0764,found:415.0765.
example 52- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 25 H 28 F 2 N 2 O 4 S:491.1816,found:491.1810.
example 53- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 20 H 15 FN 2 O 5 S:415.0764,found:415.0757.
example 54-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: 1 H NMR(300MHz,DMSO-d 6 )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 55 4- (((7- (2-cyclohexylethoxy) -5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 55)
Figure BDA0002820098560000251
The compound V-4 (512mg, 3.39mmol) was dissolved in N, N-dimethylformamide (7 mL), and anhydrous potassium carbonate (936mg, 6.78mmol) and 2-cyclohexylbromoethane (796. Mu.L, 5.08 mmol) were added to the solution under argon protection, and the mixture was heated to 70 ℃ for 12 hours. After completion of the reaction, suction filtration, dilution with water (40 mL), extraction with ethyl acetate (10 mL × 3), combination of organic phases, washing with water (10 mL × 2), washing with saturated sodium chloride (10 mL × 2), drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and purification of the residue by column chromatography (petroleum ether: ethyl acetate = 50) gave compound VIII-1 (yellow oily liquid, 494mg, yield 56%).
Compound VIII-1 (120mg, 0.46mmol), acetic anhydride (82. Mu.L, 0.87 mmol) and 4-dimethylaminopyridine (11mg, 0.087mmol) were dissolved in 1,2 dichloroethane (2 mL), triethylamine (96. Mu.L, 0.69 mmol) 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 a saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride (10 mL × 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) to obtain compound VIII-2 (light yellow oily liquid, 113.5mg, yield 81%).
Compound VIII-2 (108mg, 0.36mmol) was dissolved in pyridine (2 mL), 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.
Dissolving the product obtained in the previous step in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (1mL + 2mL), adding phosphorus oxychloride (66 mu L,0.71 mmol) under argon protection under ice bath, and heating to 70 ℃ for reaction for 2 hours. After completion of the reaction, the reaction liquid was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (5 mL × 3), washed with ice water (5 mL × 3), washed with saturated sodium chloride (5 mL × 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) to obtain compound VIII-4 (colorless oily liquid, 45.5mg, two-step yield 32%).
Compound VIII-4 (22.5mg, 0.056 mmol) and 4-aminobenzoic acid (15mg, 0.12mmol) were dissolved in anhydrous dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 30 minutes, followed by addition of pyridine (14. Mu.L, 0.17 mmol) and stirring at room temperature for 12 hours. After completion of the reaction, 2N HCl (10 mL), ethyl acetate (5 mL × 3) extraction, 2N HCl (5 mL × 2) washing, saturated sodium chloride (5 mL × 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, yield 67%) to obtain compound 55 (white solid: 1 H NMR(300MHz,DMSO-d 6 )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 C 23 H 25 FN 2 O 5 S:461.1546found:461.1548.
example 56- ((7- (2-cyclohexylethoxy) -5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 56)
Reference example 55 preparationTo obtain a compound 56: 1 H NMR(300MHz,DMSO-d 6 )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 C 23 H 24 F 2 N 2 O 5 S:479.1452,found:479.1447.
example 57- ((7- (2-Cyclohexylethoxy) -1-cyclopropyl-5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 57)
Figure BDA0002820098560000261
A dry three-necked flask was charged with cyclopropylboronic acid (79mg, 0.92mmol), copper acetate (8mg, 0.046 mmol), cyclopropylboronic acid (79mg, 0.92mmol) and 4-dimethylaminopyridine (168mg, 1.38mmol), and a toluene solution (2 mL) of compound VIII-1 (120mg, 0.46mmol) was added under argon, and a 1M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (459. Mu.L, 0.46 mmol) 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 (20 mL), ethyl acetate (5 mL × 3) and extraction were added to the reaction solution, the organic phases were combined, washed with saturated sodium chloride (5 mL × 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 (2 mL), 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.
Dissolving the product obtained in the previous step in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (1mL + 2mL), adding phosphorus oxychloride (78 mu L,0.84 mmol) under argon protection and heating to 70 ℃ for reaction for 3 hours. After completion of the reaction, the reaction liquid was poured into ice water, stirred at room temperature for 10 minutes, extracted with ethyl acetate (5 mL × 3), washed with ice water (5 mL × 3), washed with saturated sodium chloride (5 mL × 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) 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 (2 mL), and the mixture was stirred at room temperature for 30 minutes, followed by addition of pyridine (26. Mu.L, 0.32 mmol) and stirring at room temperature for 12 hours. After completion of the reaction, 2N HCl (10 mL), ethyl acetate (5 mL × 3) extraction, 2N HCl (5 mL × 2) washing, saturated sodium chloride (5 mL × 2) washing, anhydrous sodium sulfate drying, solvent removal by evaporation under reduced pressure, and residue purification by column chromatography (dichloromethane: methanol: acetic acid =300: 1) followed by ether beating to obtain compound 57 (white solid, 26.7mg, yield 50%): 1 H NMR(300MHz,DMSO-d 6 )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 C 26 H 29 FN 2 O 5 S:501.1859found:501.1850.
example 58- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 26 H 28 F 2 N 2 O 5 S:519.1765,found:519.1761.
example 59- ((7- (2-Cyclohexylethoxy) -5-fluoro-N, 1-dimethyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 59)
Figure BDA0002820098560000271
Compound VIII-1 (500mg, 1.91mmol) was dissolved in N, N-dimethylformamide (4 mL), and potassium hydroxide (215mg, 3.83mmol) and iodomethane (179. Mu.L, 2.87 mmol) were added to the solution, followed by stirring at room temperature for 8 hours. After completion of the reaction, it was diluted with water (20 mL), 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 (2 mL), 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.
Dissolving the product obtained in the previous step in Sulfolane-acetonitrile mixed solution (Sulfolane-ACN) (1mL + 2mL), adding phosphorus oxychloride (72 mu L,0.77 mmol) under the protection of argon, and heating 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 (5 mL × 3), washed with ice water (5 mL × 3), washed with saturated sodium chloride (5 mL × 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) to obtain compound X-3 (light 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 (2 mL), and the mixture was stirred at room temperature for 30 minutes, followed by addition of pyridine (44. Mu.L, 0.55 mmol) and stirring at room temperature for 12 hours. After completion of the reaction, 2N HCl (10 mL), ethyl acetate (5 mL × 3) extraction, 2N HCl (5 mL × 2) washing, saturated sodium chloride (5 mL × 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 =300: 1) to obtain compound X-4 (white solid, 45mg, yield 49%).
Taking a dry three-necked bottle, and adding hydrogenSodium chloride (4 mg, 0.11mmol), a solution of compound X-4 (45mg, 0.09mmol) in N, N-dimethylformamide (2 mL) was added under argon atmosphere in an ice bath, and the mixture was stirred at room temperature for 1 hour, and methyl iodide (9. Mu.L, 0.13 mmol) was added to the solution and stirred at room temperature for 6 hours. After completion of the reaction, it was diluted with 2N HCl (10 mL), extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with saturated sodium chloride (5 mL × 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 =300, 1) and slurried with ether to give compound 59 (white solid, 32.7mg, yield 75%): 1 H NMR(300MHz,DMSO-d 6 )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 C 25 H 29 FN 2 O 5 S:511.1679,found:511.1679.
example 60- (4- ((7- (2-cyclohexylethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) phenyl) acetic acid (Compound 60)
Compound 60 was prepared according to the procedure of example 23: ESI-HRMS [ M + H ]] + calcd for C 25 H 29 FN 2 O 5 S:489.1859,found:489.1857.
Example 61- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 25 H 28 F 2 N 2 O 5 S:507.1765,found:507.1764.
example 62- ((7- (2-Cyclohexylethoxy) -N-ethyl-5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 62)
Compound 62 was prepared according to the procedure of example 59: 1 H NMR(300MHz,DMSO-d 6 ))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 C 26 H 30 F 2 N 2 O 5 S:521.1922,found:521.1914.
example 63- (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: 1 H NMR(300MHz,DMSO-d 6 )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 C 25 H 28 F 2 N 2 O 5 S:507.1765,found:507.1767.
example 64- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 26 H 31 FN 2 O 5 S:525.1835,found:525.1832.
example 65- (((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 27 H 32 F 2 N 2 O 5 S:535.2078,found:535.2081.
example 66- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 24 H 26 F 2 N 2 O 4 S:473.0983,found:473.0983.
example 67- ((7- (benzyloxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonamide) benzoic acid (compound 67)
Compound 67 was prepared according to the procedure of example 23: 1 H NMR(300MHz,DMSO-d 6 )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 68- (((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 25 H 23 FN 2 O 5 S:447.1390,found:447.1389.
EXAMPLE 69- (((7- (cyclopentylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 69)
Compound 69 was prepared according to the method of example 23: 1 H NMR(300MHz,DMSO-d 6 )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 C 22 H 22 F 2 N 2 O 5 S:465.1296,found:465.1299.
example 70- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 27 H 33 FN 2 O 5 S:539.1992,found:539.1388.
example 71- (4- ((7- (cyclohexylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonamido) phenyl) acetic acid (Compound 71)
Compound 71 was prepared according to the procedure of example 23: 1 H NMR(300MHz,DMSO-d 6 )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 72- (((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 23 H 25 FN 2 O 5 S:461.1546,found:461.1536.
example 73- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 23 H 24 F 2 N 2 O 5 S:479.1452,found:479.1447.
example 74- ((7- (cyclohexylmethoxy) -5-fluoro-1H-indole) -3-sulfonylamino) benzoic acid (Compound 74)
Compound 74 was prepared according to the procedure of example 56: 1 H NMR(300MHz,DMSO-d 6 )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 C 22 H 23 FN 2 O 5 S:447.1390,found:447.1379.
example 75- ((7- (cyclohexylmethoxy) -5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorobenzoic acid (compound 75)
Compound 75 was prepared according to the procedure of example 56: 1 H NMR(300MHz,DMSO-d 6 )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 C 22 H 22 F 2 N 2 O 5 S:465.1296,found:465.1287.
example 76- (5- ((7- (cyclohexylmethoxy) -5-fluoro-1H-indole) -3-sulfonylamino) -2-fluorophenyl) acetic acid (Compound 76)
Compound 76 was prepared according to the procedure of example 23: 1 H NMR(300MHz,DMSO-d 6 )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 C 24 H 26 F 2 N 2 O 5 S:493.1609,found:493.1604.
example 77- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 24 H 21 FN 2 O 5 S:469.1233,found:469.1222.
example 78-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: 1 H NMR(300MHz,DMSO-d 6 )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 C 24 H 20 F 2 N 2 O 5 S:487.1139,found:487.1135.
example 79- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 23 H 25 FN 2 O 5 S:477.1251,found:477.1247.
example 80- ((4-chloro-7- (2-cyclohexylethoxy) -1-isopropyl-1H-indole) -3-sulfonamide) benzoic acid (Compound 80)
Compound 80 was prepared according to the procedure of example 23: 1 H NMR(300MHz,DMSO-d 6 )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 C 26 H 31 ClN 2 O 5 S:519.1720,found:519.1710.
example 81- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 26 H 30 ClFN 2 O 5 S:537.1626,found:537.1617.
example 82- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 25 H 29 ClN 2 O 5 S:505.1564,found:505.1561.
example 83- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 24 H 27 ClN 2 O 5 S:491.1407,found:491.1394.
example 84- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 24 H 26 ClFN 2 O 5 S:509.1313,found:509.1304.
example 85- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 C 23 H 24 ClFN 2 O 5 S:495.1157,found:495.1147.
example 86- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 87-chloro-7- (2-cyclohexylethoxy) -5-fluoro-N- (4- (hydroperoxy-12-methyl) phenyl) -1-isopropyl-1H-indole-3-sulfonamide (Compound 87)
Compound 87 prepared according to the procedure of example 23: 1 H NMR(300MHz,DMSO-d 6 )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 88- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 89- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 90- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 91- ((4-chloro-7- (cyclohexylmethoxy) -5-fluoro-1-methyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 91)
Compound 91 was prepared according to the procedure of example 23: 1 H NMR(300MHz,DMSO-d 6 )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 92- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 93- ((4-chloro-7- (cyclohexylmethoxy) -5-fluoro-1-isopropyl-1H-indole) -3-sulfonylamino) benzoic acid (Compound 93)
Compound 93 was prepared according to the procedure of example 23: 1 H NMR(300MHz,DMSO-d 6 )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 94- ((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: 1 H NMR(300MHz,DMSO-d 6 )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 95- ((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: 1 H NMR(300MHz,DMSO-d 6 )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).
EXAMPLE 96 test of the inhibitory Activity of Compounds on 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. In the experiment, the inhibition effect of the compound on FABP4 and FABP5 is evaluated by measuring the change of ANS fluorescence signal value. The method for testing the inhibition activity of FABP4 and FABP5 by using ANS substrate competition is correspondingly modified on the basis of the method of Kane and Bernlohr. The His-tagged human FABP4 or FABP5 was expressed in BL21 (DE 3) strain and then purified with Ni-NTA Superflow affinity chromatography resin to obtain the 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, then the compound with gradient concentration is added for incubation for 3min, and finally the excitation wavelength (EX) 370 nm/emission wavelength (EM) 470nm is used for detecting fluorescence signals. Calculating the inhibition rate (%) of the tested compound to FABP4 and FABP5 under 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 software 50 The value is obtained. FABP4 selective inhibitor BMS309403, endogenous FABP5 ligand linoleic acid LA and reported FABP4/5 dual inhibitor RO6806051 were used as positive control compounds. The inhibition (%) was performed according to the following formula:
inhibition (%) = [1- (F) X -F Background )/(F 0 ％-F Background )]*100％
In the above formula F X Represents the fluorescence value (F), F) of the system measured in the presence of compound X Background Indicating the fluorescence of the system with only fluorogenic substrate ANS, F 0 % 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
Figure BDA0002820098560000321
/>
Figure BDA0002820098560000331
Note: "ND" means not detected.
The experimental results (table 1) show that the compounds of the present invention have significant FABP4/5 inhibitory activity. Among them, compounds 4, 5,6, 12, 19 and 29 were able to significantly inhibit the activity of FABP4, compounds 10, 13, 23, 25, 32, 35 and 36 were able to significantly inhibit the activity of FABP5, and compounds 8, 11, 14, 15, 17, 18, 26, 33, 39, 40, 41, 43 and 44 were able to significantly inhibit the activities of FABP4 and FABP5, indicating that the compounds of the present invention are definite FABP4/5 inhibitors.
Example 97
Tablet formulation
Compound 44 (50 g) obtained in example 44, hydroxypropylmethylcellulose E (150 g), starch (200 g), povidone K30 and magnesium stearate (1 g) were mixed, granulated and tabletted.

Claims (7)

1. Indoles 1-95 or pharmaceutically acceptable salts thereof as follows:
Figure FDA0003971751670000011
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Figure FDA0003971751670000021
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Figure FDA0003971751670000031
2. use of the indole of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a FABP4/5 mediated disease.
3. The use according to claim 2, 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.
4. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.
5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is in the form of a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalation, cream, ointment, suppository, or patch.
6. Use of the pharmaceutical composition of claim 4 for the preparation of a medicament for the prevention or treatment of a FABP4/5 mediated disease.
7. The use according to claim 6, wherein the FABP4/5 mediated disease is a metabolic disease, a cardiovascular disease, an inflammatory disease, an autoimmune disease, an organ fibrosis disease, a nerve injury disease, a secondary disease caused by infection with a pathogen, or a tumor.
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