WO2023202582A1 - Gpcr regulator and use thereof - Google Patents

Gpcr regulator and use thereof Download PDF

Info

Publication number
WO2023202582A1
WO2023202582A1 PCT/CN2023/089013 CN2023089013W WO2023202582A1 WO 2023202582 A1 WO2023202582 A1 WO 2023202582A1 CN 2023089013 W CN2023089013 W CN 2023089013W WO 2023202582 A1 WO2023202582 A1 WO 2023202582A1
Authority
WO
WIPO (PCT)
Prior art keywords
membered
nmr
group
alkyl
methyl
Prior art date
Application number
PCT/CN2023/089013
Other languages
French (fr)
Chinese (zh)
Inventor
焦宁
孙金鹏
于晓
豆晓东
徐国峰
程杰
霍童雨
高明新
赵心怡
王佳乐
张才方
刘雅萌
Original Assignee
北京昌平实验室
北京大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京昌平实验室, 北京大学 filed Critical 北京昌平实验室
Publication of WO2023202582A1 publication Critical patent/WO2023202582A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates to compounds that act as modulators of GPR132, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms.
  • the present invention also relates to methods for the preparation and pharmaceutical uses of said compounds, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms.
  • G protein-coupled receptors are a type of transmembrane protein that transmit chemical signals from extracellular matrix proteins to intracellular cells and participate in and regulate the operation of physiological and pathological functions. More than 800 GPCRs have been identified in the human genome and are divided into categories A, B, C, and F based on amino acid sequence similarity. Among them, class A (also called rhodopsin-like GPCR) family members are the largest and consist of 719 GPCRs.
  • GPCR signal regulation involves ligands, GPCRs, effector proteins and corresponding downstream signaling pathways. After the ligand acts on the GPCR, the GPCR is activated and undergoes conformational rearrangement, recruiting effector proteins and exerting its signaling function. GPCR signaling has a high degree of biological complexity and importance, making GPCRs a valuable drug target.
  • G protein-coupled receptor 132 is a seven-fold transmembrane G protein-coupled receptor that belongs to the rhodopsin family (Class A) GPCR.
  • B cells and T cells could upregulate the expression of GPR132 under stress induction, causing cell cycle arrest in the G2 phase. Therefore, they named the gene encoding this protein G2A (G2 accumulation) and considered it to be a potential inhibitor.
  • GPR132 expression is tissue-specific and cell-type specific, and mainly exists in blood and lymphoid tissues. GPR132 expression is mainly found in blood cells such as macrophages, dendritic cells, neutrophils, T cells, and B lymphocytes, but its expression in immune cells is not specific.
  • GPR132 mainly plays a role in immune cells, regulates immune function, and is closely related to a variety of immune-related diseases and malignant tumors.
  • Le et al. found that GPR132-deficient mice developed delayed autoimmune syndrome and proposed that GPR132 is a potential target for autoimmune diseases.
  • Parks et al. found that GPR132 deletion improved atherosclerosis in low-density lipoprotein receptor-deficient mice.
  • Tabea et al. found that GPR132 deficiency reduces the number of immune cells at the nerve injury site and reduces the release of pro-inflammatory cytokines, thereby reducing the inflammatory response. Therefore, inhibiting GPR132 is expected to be applied to the relief and treatment of neural pain.
  • GPR132 may play an important role in the tumor microenvironment. Chen et al. found that in a mouse breast cancer model, GPR132 deficiency prevented macrophages from polarizing to the M2 type, thereby hindering the invasion and metastasis of tumor cells and inhibiting tumor lung metastasis.
  • the inventor of the present application has obtained a class of benzofuran derivatives, which can serve as GPR132 modulators (such as antagonists) and can be used to prevent or treat GPR132-related diseases, such as arterial disease.
  • GPR132 modulators such as antagonists
  • GPR132-related diseases such as arterial disease.
  • Atherosclerosis, neuropathic pain, breast cancer, hyperlipidemia, type 2 diabetes, etc. thereby providing the following invention.
  • the present invention provides compounds represented by formula (I), their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolites form,
  • A is selected from 6 to 10 membered aryl, 5 to 14 membered heteroaryl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, benzo3 Any _ _ _ _ _
  • the 6- to 10-membered aryl group, the 5- to 14-membered heteroaryl group, the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclyl group, and the benzo 3- to 6-membered cycloalkyl group are substituted by one or more M replaced;
  • R 1 is selected from hydroxyl, -NR 5 R 6 , C 1 -C 6 alkoxy; optionally, the C 1 -C 6 alkoxy is substituted by one or more groups selected from the following: phenyl , halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
  • Q is phenyl or benzo 5-6 membered heteroaryl ring
  • R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; m is selected from 1, 2, 3, 4; when there are multiple R 2s , each R 2 can be the same or different ;
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl and C 1 -C 6 alkyl; optionally, the C 1 -C 6 alkyl is replaced by one or more selected from the following Group substitution: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
  • R 7 and R 8 are each independently selected from C 1 -C 6 alkyl, and q is selected from an integer between 1 and 10;
  • L 1 and L 2 are each independently absent or selected from -(CH 2 ) n -, 3 to 6-membered cycloalkyl, n is an integer selected from 1 to 6; optionally, -(CH 2 ) n - substituted by one or more groups selected from: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, deuterium, tritium, carbonyl; and, the compound is not 3-methyl Base-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid.
  • A is selected from 6 to 10 membered aryl, 5 to 14 membered heteroaryl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, benzo 3 to 6 membered cycloalkyl , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; optionally, the 6 to 10 membered aryl group, 5 to 14 membered heteroaryl group, 3 to 6 membered cycloalkyl group, 3 to 6 membered aryl group Heterocyclyl, benzo 3 to 6-membered cycloalkyl is substituted by one or more M, M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkane Base, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 1 -C 6 haloalkyl group, C 1
  • R 1 is selected from hydroxyl, -NR 5 R 6 , C 1 -C 6 alkoxy; optionally, the C 1 -C 6 alkoxy is substituted by one or more groups selected from the following: phenyl , halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
  • Q is phenyl or benzo 5-6 membered heteroaryl ring
  • R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; m is selected from 1, 2, 3, 4; when there are multiple R 2s , each R 2 can be the same or different ; R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, hydroxyl and C 1 -C 6 alkyl; optionally, the C 1 -C 6 alkyl is one or more selected from the following Group substitution: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
  • L 1 and L 2 are each independently absent or selected from -(CH 2 ) n -, 3 to 6-membered cycloalkyl, n is an integer selected from 1 to 6; optionally, -(CH 2 ) n - substituted by one or more groups selected from: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, deuterium, tritium;
  • the compound is not 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid.
  • A is selected from 6 to 10 membered aryl, 5 to 8 membered monocyclic heteroaryl, 8 to 14 membered fused heteroaryl, 5 to 6 membered cycloalkyl, 5 to 6 membered heterocyclyl, benzo 5 to 6
  • cycloalkyl benzo 5- to 6-membered heterocyclyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 5 to 6 cycloalkenyl , the 6 to 10 membered aryl group, 5 to 8 membered monocyclic heteroaryl group, 8 to 14 membered condensed heteroaryl group, 5 to 6 membered cycloalkyl group, 5 to 6 membered heterocyclyl group, benzo 5 to 6 membered
  • the ring alkyl group is substituted by one or more M;
  • R 7 and R 8 are each methyl, and q is selected from an integer between 1 and 4;
  • A is selected from a 6- to 10-membered aryl group, a 5- to 6-membered sulfur- or nitrogen-containing monocyclic heteroaryl group, an 8- to 10-membered oxygen-containing condensed heteroaryl group (such as a benzo 5- to 6-membered oxygen-containing heteroaryl group).
  • A is selected from phenyl, naphthyl, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxanyl, indolyl, cyclohexenyl, benzocyclohexanyl; optionally, the phenyl, naphthalene base, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 alkenyl
  • halogen eg fluorine, chlorine, bromine, iodine
  • C 1 -C 4 alkyl trifluoromethyl, methoxy,
  • A is selected from 6 to 10 membered aryl, 5 to 8 membered monocyclic heteroaryl, 8 to 14 membered fused heteroaryl, 5 to 6 membered cycloalkyl, 5 to 6 membered heterocycle base, benzo 5 to 6 membered cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; optionally, the 6 to 10 membered aryl group, 5 to 8 membered monocyclic heteroaryl group , 8 to 14 membered fused heteroaryl, 5 to 6 membered cycloalkyl, 5 to 6 membered heterocyclyl, benzo 5 to 6 membered cycloalkyl substituted by one or more M.
  • M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 amido, phenyl, phenoxy.
  • R 3 and R 4 are each independently selected from hydrogen and hydroxyl.
  • the C 1 -C 6 alkoxy group is substituted with one or more groups selected from: C 1 -C 6 fluoroalkyl, cyclopropyl.
  • A is selected from a 6- to 10-membered aryl group, a 5- to 6-membered sulfur- or nitrogen-containing monocyclic heteroaryl group, an 8- to 10-membered oxygen-containing fused heteroaryl group, and a 5- to 6-membered cycloalkyl group.
  • M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 amido, phenyl, phenoxy.
  • A is selected from phenyl, naphthyl, thienyl, pyridyl, benzofuryl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl; optionally, the phenyl, naphthyl, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl A group is substituted with one or more M's.
  • M is selected from the group consisting of: halogen (e.g., fluorine, chlorine, bromine), cyano, -NHCH 3 , C 1 - C 4 alkyl, C 2 -C 4 alkynyl, trifluoromethyl, methoxy, ethoxy, acetyl, phenyl, phenoxy.
  • halogen e.g., fluorine, chlorine, bromine
  • cyano e.g., cyano, -NHCH 3 , C 1 - C 4 alkyl, C 2 -C 4 alkynyl, trifluoromethyl, methoxy, ethoxy, acetyl, phenyl, phenoxy.
  • the methoxy or ethoxy group is substituted with one or more trifluoromethyl or cyclopropyl groups.
  • R1 is hydroxyl or -NHOH.
  • R 2 halo is selected from C 1 -C 6 alkyl (eg, methyl), C 1 -C 6 haloalkyl (eg, fluoromethyl).
  • L 1 is absent or selected from -(CH 2 ) n -, cyclopropyl, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is methyl Substituted or deuterated; optionally, -( CH2 ) n- is substituted or deuterated by methyl or carbonyl.
  • L 2 is absent or selected from -(CH 2 ) n -, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is substituted with methyl or deuterated generation.
  • the 5-6 membered heteroaryl group is selected from the group consisting of furyl, thienyl, and pyrrolyl. In certain embodiments, the 5-6 membered heteroaryl group is furyl.
  • the compound has a structure represented by Formula (II):
  • X is selected from O, S or NH.
  • the compound has a structure represented by Formula (III) or (IV):
  • X is O.
  • X is S.
  • X is NH
  • A is phenyl optionally substituted with one or more M, M as defined above.
  • the compounds of the invention are selected from the compounds shown in Table 1:
  • the compound has a structure represented by Formula (V):
  • Core is X is selected from O, S or NH,
  • R2 is as defined above.
  • R2 is selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine), C 1 -C 6 alkyl (e.g., methyl).
  • halogen e.g., fluorine, chlorine, bromine
  • C 1 -C 6 alkyl e.g., methyl
  • Core is selected from:
  • the compound is selected from the compounds shown in Table 2:
  • the compound has a structure represented by Formula (VI):
  • A is as defined above.
  • A is selected from phenyl optionally substituted with one or more M selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl Oxygen group, nitro group, hydroxyl group, -NR 3 R 4 , R 3 and R 4 are each independently selected from hydrogen and C 1 -C 6 alkyl group.
  • the compound is selected from the compounds shown in Table 3:
  • M is selected from: halogen, C 2
  • the compound is selected from the compounds shown in Table 4:
  • the compound has a structure as shown in formula (VI), wherein A is selected from the following groups optionally substituted with one or more M: phenyl, naphthyl, benzo 5 to 6 Membered heterocyclyl (such as benzo 5- to 6-membered oxygen-containing heterocyclyl), benzo 5- to 6-membered heteroaryl (such as benzo 5- to 6-membered nitrogen-containing or oxygen-containing heteroaryl); M is selected from halogen , C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
  • the compound is selected from the compounds shown in Table 5:
  • the compound has a structure as shown in formula (VI), wherein A is selected from the following groups optionally substituted by one or more M: C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, 5 to 6 membered cycloalkyl, 5 to 6 membered cycloalkenyl, 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl; M is selected from C 1 -C 6 alkyl, halogen.
  • the compound is selected from the compounds shown in Table 6:
  • the structure of the compound of the invention is represented by Formula (VII),
  • A is selected from phenyl, naphthyl, L 1 is absent or selected from -(CH 2 ) n -, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is substituted with one or more groups selected from: halogen, C 1 -C 6 alkyl, carbonyl.
  • the compound is selected from the compounds shown in Table 7:
  • the structure of the compound of the invention is as shown in formula (VII), wherein L 1 is absent and A is selected from the following groups optionally substituted by one or more M: phenyl, naphthyl, Benzo 5- to 6-membered heteroaryl (such as benzo 5- to 6-membered nitrogen-containing or oxygen-containing heteroaryl), benzo 5- to 6-membered cycloalkyl, M selected from C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogen, phenoxy, -NR 3 R 4 , 5 to 6-membered heterocyclyl, R 3 and R 4 are each independently selected from C 1 -C 6 alkyl, the 5 to 6-membered heterocyclic group Heterocyclyl is optionally substituted with C 1 -C 6 alkyl.
  • M selected from C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogen, phenoxy, -NR 3 R 4 , 5 to 6-membere
  • the compound is selected from the compounds shown in Table 8:
  • the pharmaceutically acceptable ester of the compound of the present invention is preferably ethyl carboxylate.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I), which is pharmaceutically acceptable Acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolite forms; optionally, the pharmaceutical composition also includes a pharmaceutically acceptable carrier or excipient agent.
  • the pharmaceutical composition may be in any form known in the medical field.
  • the pharmaceutical composition can be tablets, pills, suspensions, emulsions, solutions, gels, capsules, powders, granules, elixirs, lozenges, suppositories, injections (including injections, lyophilized powder), inhalants, sprays, etc.
  • the preferred dosage form depends on the intended mode of administration and therapeutic use.
  • the compounds, pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, and metabolite forms thereof may be in unit dosage form Present in pharmaceutical compositions to facilitate administration.
  • the compounds, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, their metabolite forms, or the pharmaceutical compositions may be prepared by those skilled in the art. Administration may be carried out by any suitable method known, including, but not limited to, oral, rectal, parenteral or topical administration.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, elixirs, and the like.
  • Liquid dosage forms may contain, in addition to the active compound, inert diluents customary in the art, such as water or other solvents, solubilizers and emulsifiers. Besides inert diluents, liquid dosage forms for oral administration can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents and the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, lozenges, powders, granules, etc.
  • solid dosage forms may contain pharmaceutically acceptable inert excipients or carriers, such as fillers, binders, wetting agents, disintegrating agents, lubricants, and mixtures thereof.
  • the compounds or pharmaceutical compositions of the invention may also be administered parenterally.
  • parenteral administration for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection and infusion.
  • Dosage forms for parenteral administration may be injectable preparations, including injectable solutions, sterile powders for injection, or concentrated solutions for injection.
  • injection dosage forms may contain pharmaceutically acceptable carriers such as sterile water, Ringer's solution and isotonic sodium chloride solution, and may also add appropriate additives such as antioxidants, buffers and Bacteriostat.
  • Topical administration such as transdermal administration (eg, via a transdermal patch or iontophoretic device), intraocular administration, or intranasal or inhaled administration.
  • Dosage forms for transdermal administration may be topical gels, sprays, ointments and creams. Topical dosage forms may contain, in addition to the active compound, ingredients that enhance absorption or penetration of the active compound through the skin or other area of action.
  • administration will be accomplished using patches of the storage and porous film type or solid matrix variety.
  • Dosage forms for topical administration to the eye may be eye drops in which the compound of the invention is dissolved or suspended in a suitable carrier.
  • the compounds of the present invention are conveniently delivered as solutions or suspensions from pressure spray containers by patient compression or pumping, or It is delivered as an aerosol spray formulation from a pressure container or nebulizer using a suitable propellant.
  • Dosage forms for rectal administration may be suppositories.
  • compositions of the present invention can be prepared by any known pharmaceutical process, such as effective formulation and administration methods.
  • effective formulations and methods of administration are well known in the art and are described in standard textbooks.
  • Formulations of drugs are described in, for example, Hoover, John E., Remington's Pharmaceutical Sciences. Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and edited by Kibbe et al., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.
  • the pharmaceutical composition contains a compound of the invention, a pharmaceutically acceptable salt or ester, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form thereof, or a metabolite thereof
  • the amount of the form is 0.01-2000 mg, preferably 0.1-1000 mg, more preferably 1-800 mg, more preferably 10-600 mg, particularly preferably 50-500 mg.
  • the pharmaceutical composition of the present invention may include a "therapeutically effective amount” or a “prophylactically effective amount” of a compound as described herein, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate substances, crystal forms, and their metabolite forms.
  • “Prophylactically effective amount” refers to an amount sufficient to prevent, prevent, or delay the occurrence of disease.
  • a “therapeutically effective amount” means an amount sufficient to cure or at least partially prevent disease and its complications in a patient who is already suffering from the disease.
  • therapeutically effective amounts of compounds as described herein, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, and their metabolite forms It may vary based on factors such as the severity of the disease being treated, the overall status of the patient's own immune system, the patient's general condition such as age, weight, and gender, the manner in which the drug is administered, and other treatments being administered at the same time, etc.
  • the dosing regimen can be adjusted to obtain the optimal desired response (eg, therapeutic or prophylactic response).
  • the dose may be administered as a single dose, may be administered multiple times over a period of time, or may be proportionally reduced or increased according to the exigencies of the treatment situation.
  • Typical non-limiting ranges for therapeutically or prophylactically effective amounts of the compounds of the invention, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms are 0.01 ⁇ 1000mg/kg, such as 0.1 ⁇ 500mg/kg. It should be noted that dosage may vary depending on the type and severity of symptoms requiring treatment. In addition, those skilled in the art understand that for any particular patient, the specific dosage regimen should be adjusted over time based on the needs of the patient and the professional evaluation of the physician; the dosage ranges given here are for illustrative purposes only and are not limiting. Use or scope of the pharmaceutical composition of the present invention.
  • the pharmaceutical compositions may also include additional pharmaceutically active agents.
  • the compound of the invention and the additional pharmaceutically active agent are provided as separate or mixed components in the pharmaceutical composition.
  • the compounds of the invention and the additional pharmaceutically active agent may be administered simultaneously, separately or sequentially.
  • the compounds of the present invention can be used as modulators (eg antagonists) of GPR132 to prevent or treat diseases related to GPR132.
  • the application provides the use of a compound for the preparation of a medicament for preventing or treating diseases related to GPR132, the compound being selected from the group consisting of compounds of formula (I) or the following table, Its pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms
  • the disease associated with GPR132 is selected from the group consisting of tumors, metabolic diseases, immune-related diseases, and neuropathic pain.
  • the tumor is selected from the group consisting of: breast cancer, melanoma, meningioma, soft tissue sarcoma, Salivary gland tumors, primary liver cancer, intraspinal tumors, mediastinal tumors, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumors, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma , pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia, stomach cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulva Cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, Kaposi's sarcoma, non-melanom
  • the metabolic disease is selected from atherosclerosis, obesity, non-alcoholic fatty liver disease (NAFLD) (e.g., simple fatty liver disease or non-alcoholic steatohepatitis (NASH)), metabolic syndrome syndrome, type 2 diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia), and secondary complications of these diseases (e.g., , complications of diabetes, such as retinopathy, neuropathy, nephropathy and delayed wound healing, or cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hypertension, stroke).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • metabolic syndrome syndrome type 2 diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia), and secondary complications of these diseases (e.g., , complications of diabetes, such
  • the immune-related disease is selected from:
  • Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, scleroderma, hyperthyroidism, juvenile diabetes, essential thrombocytopenic purpura, autoimmune hemolytic anemia, ulcerative colitis, skin diseases, chronic liver disease .
  • the invention provides a method for preventing or treating a disease associated with GPR132 in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound, a pharmaceutically acceptable Acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or metabolite forms thereof selected from compounds of formula (I) or the following table
  • the disease associated with GPR132 may be selected from the diseases described above.
  • the application also provides the synthesis of compounds of formula (I), their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolite forms
  • the method includes the following steps: reacting compounds of general formula (IA) and general formula (IB) in the presence of inorganic bases or organic bases to obtain compounds of general formula (I):
  • the organic base is preferably selected from triethylamine and diisopropylethylamine; the reaction solvent is preferably selected from dichloromethane, acetonitrile, and N,N-dimethylformamide.
  • the present invention also provides a method for preparing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which method includes the following steps: in the presence of an inorganic base or an organic base, the general formula (II-A) React with the compound of general formula (II-B) to obtain the compound of general formula (I):
  • rings A, L 1 , L 2 and R 1 -R 6 are as mentioned above respectively;
  • the inorganic base is preferably selected from potassium carbonate, sodium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide and cesium carbonate;
  • the organic base is preferably selected from triethylamine and diisopropylethylamine;
  • the reaction solvent is preferably selected from dichloromethane, acetonitrile, and N,N-dimethylformamide.
  • C 1 -C 6 alkyl refers to a group obtained by removing one hydrogen atom from a straight or branched chain alkane containing 1 to 6 carbon atoms, preferably C 1 -C 6
  • the alkyl group is a C 1 -C 4 alkyl group, and specific examples thereof include but are not limited to: methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl or isobutyl .
  • C 2 -C 6 alkenyl refers to a linear, branched or cyclic alkenyl group containing at least one double bond and having 2 to 6 carbon atoms. Examples include but Not limited to: vinyl, 1-propen-1-yl, allyl, 1-buten-1-yl, 1-penten-1-yl, 1,3-butadien-1-yl, 1, 4-Pentadien-1-yl. Preferred C 2 -C 6 alkenyl groups are C 2 -C 4 alkenyl groups.
  • C 2 -C 6 alkynyl refers to a linear or branched chain alkynyl group with 2 to 6 carbon atoms containing at least one triple bond. Examples include but are not limited to: acetylene base, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl Base-2-hexynyl. Preferred C 2 -C 6 alkynyl groups are C 2 -C 4 alkynyl groups.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • halogenated means that a hydrogen on a group or compound is replaced by one or more halogen atoms, including fully halogenated and partially halogenated.
  • alkoxy refers to a group formed in the alkyl-O- manner, examples include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy, or n-hexyloxy.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. The ring of the cycloalkyl group may contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, including Containing 3 to 20 ring atoms, one or more (eg 1, 2, 3 or 4) of the ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 10 ring atoms; most preferably it contains 5 to 6 ring atoms, of which 1 to 2 are selected from nitrogen, oxygen or Sulfur heteroatoms.
  • the sulfur atoms may be oxosubstituted.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, preferably 6 -10 yuan, such as phenyl, naphthyl.
  • heteroaryl refers to a heteroatom-containing monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, preferably from 5 to 10-membered heteroaryl groups include 5- to 8-membered monocyclic heteroaryl groups and 8- to 14-membered fused heteroaryl groups.
  • the term "5- to 8-membered monocyclic heteroaryl” refers to an aromatic monocyclic cyclic group containing 5 to 8 ring atoms, at least one of which is a heteroatom, e.g. Nitrogen atom, oxygen atom or sulfur atom, including the case where the carbon atom, nitrogen atom and sulfur atom on the ring are substituted by oxygen.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2 ,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, 1,4-dioxanyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, Py
  • the term "8- to 14-membered fused heteroaryl” refers to a group containing 8 to 10 ring atoms formed by two or more cyclic structures sharing two adjacent atoms with each other. , an unsaturated aromatic cyclic structure, in which at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom, and also includes the case where the carbon atoms, nitrogen atoms and sulfur atoms on the ring are oxo-substituted.
  • Examples include, but are not limited to: benzofuryl, benzisofuryl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl , quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazoline base, quinoxalinyl, phenolazine, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, etc.
  • substituted means that one or more hydrogen atoms on a group are replaced by one or more substituents, which may be the same or different.
  • C2 alkyl is substituted means that one or more hydrogen atoms on the C2 alkyl group are replaced by one or more substituents.
  • the term "pharmaceutically acceptable salt” refers to (i) the acidic functional group (such as -COOH) present in the compound provided by the invention and the appropriate inorganic or organic cation (base) formed Salts, and include, but are not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, etc.
  • alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.
  • alkaline earth metal salts such as calcium salts, magnesium salts, etc.
  • other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, etc.
  • inorganic alkali salts such as ammonium salt
  • organic alkali salts such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt , Ethylenediamine salt, N-methylglucosamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroplutide Caine salt, procaine salt, diethanolamine salt, N-benzyl-phenylethylamine salt, piperazine salt, tetramethylamine salt, tris(hydroxymethyl)aminomethane salt.
  • the term "pharmaceutically acceptable ester” refers to the ester of -COOH present in the compounds provided by the present invention with an appropriate alcohol (such as methanol or ethanol), or the ester provided by the present invention.
  • the -OH present in the compound forms an ester with a suitable acid (for example, a carboxylic acid or an oxygenated inorganic acid).
  • suitable ester groups include but Without limitation, formate, acetate, propionate, butyrate, acrylate, ethyl succinate, stearate or palmitate. Esters can undergo hydrolysis reactions in the presence of acids or bases to generate corresponding acids or alcohols.
  • solvate refers to a substance formed by the association of a compound of the invention with a solvent molecule.
  • the solvent can be an organic solvent (such as methanol, ethanol, propanol, acetonitrile, etc.).
  • the compound of the present invention can form an ethanolate with ethanol.
  • the compounds of the present invention can also form hydrates with water.
  • the term "crystalline form" refers to the crystal structure of a substance. During the crystallization of substances, due to the influence of various factors, the bonding methods within or between molecules change, resulting in different arrangements of molecules or atoms in the crystal lattice space, forming different crystal structures.
  • the compound of the present invention can exist in one crystal structure or in multiple crystal structures, that is, it has "polymorphic form".
  • the compounds of the invention may exist in different crystalline forms.
  • stereoisomer includes conformational isomers and configurational isomers, wherein the configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention may exist in stereoisomeric forms and thus encompass all possible stereoisomeric forms, any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above.
  • a compound of the present invention contains an olefinic double bond, it includes both cis and trans isomers, as well as any combination thereof, unless otherwise stated.
  • prodrug refers to a compound of the present invention that can be converted in a subject through reactions such as oxidation, reduction, hydrolysis, and the like.
  • the prodrug itself may or may not have the biological activity of the compound of formula (I) (eg, regulating glucose and lipid metabolism activity, anti-inflammatory activity, antioxidant activity).
  • compounds of formula (I) containing hydroxyl or carboxyl groups may be administered in the form of esters, which are hydrolytically converted in vivo to hydroxyl or carboxyl compounds.
  • compounds of formula (I) including amino groups are acylated, alkylated or phosphorylated to form compounds such as eicosanoylamino, alanylamido, pivaloyloxymethylamino and are administered .
  • prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • prodrugs according to the present invention include: (i) if the compound of formula (I) contains a carboxylic acid function (-COOH), then its esters are included, for example, a (C 1 -C 8 ) alkyl group is substituted for the hydrogen; ( ii) if the compound of formula (I) contains an alcohol functional group (-OH), its ethers are included, for example, (C 1 -C 6 )alkanoyloxymethyl is used instead of hydrogen; and (iii) if the compound of formula (I) Amides containing primary or secondary amino functional groups (-NH 2 or -NHR, where R is not H) include, for example, a (C 1 -C 10 ) alkanoyl group in place of one or two hydrogens. In addition, certain compounds of formula (I) may themselves serve as prodrugs for other compounds of formula (I).
  • the term "pharmaceutically acceptable carrier or excipient” refers to a carrier and/or excipient that is pharmacologically and/or physiologically compatible with the subject and the active ingredient, which are well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed.
  • disintegrants include, but are not limited to: disintegrants, binders, surfactants, glidants , lubricants, pH adjusters, ionic strength enhancers, reagents to maintain osmotic pressure, reagents to delay absorption, diluents, antioxidants, colorants, flavoring agents, preservatives, taste masking agents, etc.
  • the term "subject" refers to a mammal, such as a rat, rabbit, dog, such as a primate mammal, such as a monkey, human.
  • modulator refers to a molecule that can interact directly or indirectly with a target.
  • modulators include, but are not limited to, agonists, partial agonists, inverse agonists, and antagonists.
  • the modulator is an agonist.
  • agonist refers to a molecule that binds to a specific receptor and triggers a response in a cell.
  • Agonists can mimic the effects of endogenous ligands such as LPA, prostaglandins, hormones or neurotransmitters that bind to the same receptor.
  • Antagonist refers to a molecule that attenuates, inhibits, or prevents the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, noncompetitive antagonists, noncompetitive antagonists, partial agonists, and inverse agonists.
  • Step 2 3-Methyl-5-(chlorosulfonyl)benzofuran-2-carboxylic acid ethyl ester
  • Step 3 3-Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate ethyl ester
  • the preparation method was the same as Example 1, except that 4-(2-aminoethyl)tetrahydropyran was used instead of phenylethylamine to prepare the title compound. 0.35g of white solid was obtained, with a yield of 89%.
  • the preparation method was the same as Example 1, except that (1R,2S)-2-phenyl-cyclopropylamine was used instead of phenylethylamine to prepare the title compound. 147 mg of white solid was obtained, with a yield of 99%.
  • the preparation method was the same as Example 1, except that 2-([1,1'-biphenyl]-3-yl)ethane-1-amine was used instead of phenylethylamine to prepare the title compound. 0.39g of white solid was obtained, with a yield of 43%.
  • the preparation method was the same as Example 1, except that 2-(benzofuran-3-yl)ethane-1-amine was used instead of phenylethylamine to prepare the title compound.
  • Step 4 3-Methyl-5-((2-phenylethyl)sulfonamido)benzofuran-2-carboxylic acid ethyl ester
  • the preparation method is the same as in Example 19, except that benzyl sulfonyl chloride is used instead of 2-phenyl-ethanesulfonyl chloride to obtain the title compound compound. 80 mg of light pink solid was obtained, with a yield of 30.3%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(4-phenylbutylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5-(N -Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 164 mg of white solid was obtained, with a yield of 79%.
  • the preparation method is the same as Example 25, except that ethyl 3-methyl-5-(N-(4-phenylbut-2-yl)sulfamoyl)benzofuran-2-carboxylate is used instead of 3- Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, ethyl ester, gave the title compound. 165 mg of white solid was obtained, with a yield of 79%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-cyclohexylethyl)sulfamoyl)benzofuran-
  • the title compound was obtained by substituting ethyl 2-carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 168 mg of white solid was obtained, with a yield of 85%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(but-3-yn-1-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3- Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, ethyl ester, gave the title compound. 147 mg of white solid was obtained, with a yield of 88%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(but-3-en-1-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylate is used instead of 3- Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, ethyl ester, gave the title compound. 103 mg of white solid was obtained, with a yield of 80.5%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)sulfamoyl)benzofuran-2 is used -Ethyl carboxylate was substituted for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate to give the title compound. 161 mg of white solid was obtained, with a yield of 81%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-(thiophen-2-yl)ethyl)sulfamoyl)benzene is used
  • the title compound was obtained by substituting ethyl furan-2-carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 146 mg of white solid was obtained, with a yield of 99%.
  • the preparation method is the same as Example 25, except that ethyl 3-methyl-5-(N-(2-(pyridin-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate is used instead 3-Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 172 mg of white solid was obtained, with a yield of 88%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2,3-dihydro-1H-inden-2-yl)sulfamoyl)benzofuran-2-carboxylic acid is used
  • the title compound was obtained by substituting ethyl ester for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 127 mg of white solid was obtained, with a yield of 79%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(1-naphthyethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl-5- (N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 216 mg of white solid was obtained, with a yield of 83%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-((1R,2S)-2-phenylcyclopropyl)sulfamoyl)benzene is used
  • the title compound was obtained by substituting ethyl furan-2-carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 75 mg of white solid was obtained, with a yield of 57.7%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(4-fluorophenethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 115 mg of white solid was obtained, with a yield of 99%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(4-chlorophenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 116 mg of white solid was obtained, with a yield of 99%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(3-bromopheneethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 148 mg of white solid was obtained, with a yield of 99%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(3-bromophenylethyl)sulfamoyl)benzofuran-2-
  • the title compound was obtained by substituting ethyl carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(3-methoxyphenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl Ethyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate was used to prepare the title compound. 188 mg of white solid was obtained, with a yield of 89%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(3-methylphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 249 mg of white solid was obtained, with a yield of 97%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(naphthalen-1-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5 -(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester to give the title compound. 102 mg of white solid was obtained, with a yield of 92%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(naphthalen-2-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5 -(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester to give the title compound. 181 mg of white solid was obtained, with a yield of 87%.
  • the preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-([1,1'-diphenyl]-3-yl)ethyl)sulfamoyl)benzo Furan-2-carboxylic acid ethyl ester was substituted for 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester to give the title compound. 216 mg of pink solid was obtained, with a yield of 91%.
  • the preparation method is the same as Example 25, except that ethyl 5-(N-(2-(benzofuran-3-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate is used.
  • the title compound was obtained by substituting the ester for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
  • the preparation method is the same as Example 25, except that 3-methyl-5-((2-phenylethyl)sulfonamide)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5-(N -Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 68 mg of light yellow solid was obtained, with a yield of 69%.
  • Example 25 According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-6-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, and the other conditions were the same. 38 mg of white solid was obtained, with a yield of 74%.
  • Example 25 According to the method used in Example 25, the intermediate ethyl ester was replaced with 3-methyl-5-(N-(3-(1-methyl-1H-pyrazol-4-yl)phenylethyl)sulfamoyl) Benzofuran-2-carboxylic acid ethyl ester, the other conditions are the same. 41 mg of yellow solid was obtained, with a yield of 41%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Oncology (AREA)
  • Transplantation (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A compound of a GPR132 regulator, a pharmaceutically acceptable salt or ester, a prodrug, a stereoisomer, a hydrate, a solvate, a crystal form, or a metabolite form thereof, as well as a preparation method therefor and medicinal use thereof.

Description

GPCR调节剂及其应用GPCR modulators and their applications 技术领域Technical field
本发明属于医药技术领域。特别地，本发明涉及可作为GPR132调节剂的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式。本发明还涉及所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的制备方法以及医药用途。The invention belongs to the field of medical technology. In particular, the present invention relates to compounds that act as modulators of GPR132, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms. The present invention also relates to methods for the preparation and pharmaceutical uses of said compounds, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms.
背景技术Background technique
G蛋白偶联受体(G protein-coupled receptors,GPCR)是一类将化学信号从细胞外基质蛋白传递到细胞内的跨膜蛋白，参与和调控生理和病理功能的运作。人类基因组中已鉴定出800多种GPCRs，依据氨基酸序列相似性划分为A、B、C、F类。其中A类(也称视紫红质样GPCR)家族成员最大，由719种GPCR组成。GPCR信号调控涉及配体、GPCR、效应蛋白和下游相应信号通路。配体作用于GPCR后，GPCR激活并发生构象重排，募集效应蛋白，发挥信号传导功能。GPCR信号传导有着高度的生物学复杂性和重要性，因此GPCR成为极具价值的药物靶点。G protein-coupled receptors (GPCRs) are a type of transmembrane protein that transmit chemical signals from extracellular matrix proteins to intracellular cells and participate in and regulate the operation of physiological and pathological functions. More than 800 GPCRs have been identified in the human genome and are divided into categories A, B, C, and F based on amino acid sequence similarity. Among them, class A (also called rhodopsin-like GPCR) family members are the largest and consist of 719 GPCRs. GPCR signal regulation involves ligands, GPCRs, effector proteins and corresponding downstream signaling pathways. After the ligand acts on the GPCR, the GPCR is activated and undergoes conformational rearrangement, recruiting effector proteins and exerting its signaling function. GPCR signaling has a high degree of biological complexity and importance, making GPCRs a valuable drug target.
G蛋白偶联受体132(G protein-coupled receptor 132，GPR132)是七重跨膜的G蛋白偶联受体，属于视紫红质家族(Class A)GPCR。1998年Weng等人发现，B细胞、T细胞在压力诱导下可上调GPR132表达，引起G2期细胞周期阻止，因此将编码该蛋白的基因命名为G2A(G2 accumulation)，并认为可能是潜在的抑癌基因。GPR132表达具有组织特异性和细胞类型特异性，主要存在于血液和淋巴组织。GPR132表达主要被发现在巨噬细胞、树突状细胞、中性粒细胞、T细胞、B淋巴细胞等血液细胞中，但在免疫细胞中的表达并无特异性。G protein-coupled receptor 132 (GPR132) is a seven-fold transmembrane G protein-coupled receptor that belongs to the rhodopsin family (Class A) GPCR. In 1998, Weng et al. discovered that B cells and T cells could upregulate the expression of GPR132 under stress induction, causing cell cycle arrest in the G2 phase. Therefore, they named the gene encoding this protein G2A (G2 accumulation) and considered it to be a potential inhibitor. Oncogene. GPR132 expression is tissue-specific and cell-type specific, and mainly exists in blood and lymphoid tissues. GPR132 expression is mainly found in blood cells such as macrophages, dendritic cells, neutrophils, T cells, and B lymphocytes, but its expression in immune cells is not specific.
据人们目前所了解，GPR132主要在免疫细胞中发挥作用，调节免疫功能，与多种免疫相关疾病和恶性肿瘤有紧密联系。2001年，Le等人发现GPR132缺陷型小鼠发生迟发性自身免疫综合征，提出GPR132是一个潜在的自身免疫病靶点。Parks等人发现在低密度脂蛋白受体缺陷型小鼠种，GPR132缺失可改善动脉粥样硬化病情。Tabea等人发现，GPR132缺陷减少神经损伤部位的免疫细胞数量，降低促炎细胞因子释放，从而减轻炎症反应，因此抑制GPR132有望应用于神经疼痛的缓解和治疗。此外，GPR132可能在肿瘤微环境种扮演重要角色。Chen等人发现在小鼠乳腺癌模型种，GPR132缺陷阻碍巨噬细胞向M2型极化，进而阻碍肿瘤细胞的侵袭和转移，抑制肿瘤肺转移。According to current understanding, GPR132 mainly plays a role in immune cells, regulates immune function, and is closely related to a variety of immune-related diseases and malignant tumors. In 2001, Le et al. found that GPR132-deficient mice developed delayed autoimmune syndrome and proposed that GPR132 is a potential target for autoimmune diseases. Parks et al. found that GPR132 deletion improved atherosclerosis in low-density lipoprotein receptor-deficient mice. Tabea et al. found that GPR132 deficiency reduces the number of immune cells at the nerve injury site and reduces the release of pro-inflammatory cytokines, thereby reducing the inflammatory response. Therefore, inhibiting GPR132 is expected to be applied to the relief and treatment of neural pain. In addition, GPR132 may play an important role in the tumor microenvironment. Chen et al. found that in a mouse breast cancer model, GPR132 deficiency prevented macrophages from polarizing to the M2 type, thereby hindering the invasion and metastasis of tumor cells and inhibiting tumor lung metastasis.
发明内容Contents of the invention
本申请的本发明人通过深入的研究和创造性的发现，得到了一类苯并呋喃衍生物，其可作为GPR132调节剂(例如拮抗剂)，可用于预防或治疗与GPR132相关的疾病，例如动脉粥样硬化、神经性疼痛、乳腺癌、高脂血症、2型糖尿病等，由此提供了下述发明。Through in-depth research and creative discovery, the inventor of the present application has obtained a class of benzofuran derivatives, which can serve as GPR132 modulators (such as antagonists) and can be used to prevent or treat GPR132-related diseases, such as arterial disease. Atherosclerosis, neuropathic pain, breast cancer, hyperlipidemia, type 2 diabetes, etc., thereby providing the following invention.
化合物compound
在第一方面，本发明提供了式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，
In a first aspect, the present invention provides compounds represented by formula (I), their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolites form,
其中：in:
A选自6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3 至6元环烷基、苯并5至6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基；任选地，所述6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基被一个或多个M取代；A is selected from 6 to 10 membered aryl, 5 to 14 membered heteroaryl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, benzo3 Any _ _ _ _ _ Optionally, the 6- to 10-membered aryl group, the 5- to 14-membered heteroaryl group, the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclyl group, and the benzo 3- to 6-membered cycloalkyl group are substituted by one or more M replaced;
M选自以下基团：卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、P(＝O)R7R8、CH3CH2O-(CH2CH2O)q-、4至6元杂环基、5至6元杂芳基；任选地，所述C1-C6烷氧基被一个或多个选自以下的基团取代：C1-C6卤代烷基、3至6元环烷基；所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代；M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 amido , phenyl, phenoxy, P(=O)R 7 R 8 , CH 3 CH 2 O-(CH 2 CH 2 O) q -, 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl; optionally, the C 1 -C 6 alkoxy group is one or more selected from The following groups are substituted: C 1 -C 6 haloalkyl, 3 to 6 membered cycloalkyl; the phenyl, phenoxy, 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl are optionally substituted by Halogen or C 1 -C 6 alkyl substitution;
R1选自羟基、-NR5R6、C1-C6烷氧基；任选地，所述C1-C6烷氧基被一个或多个选自以下的基团取代：苯基、卤素、硝基、氰基、羟基、C1-C6烷基；R 1 is selected from hydroxyl, -NR 5 R 6 , C 1 -C 6 alkoxy; optionally, the C 1 -C 6 alkoxy is substituted by one or more groups selected from the following: phenyl , halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
Q为苯基或苯并5-6元杂芳基环；Q is phenyl or benzo 5-6 membered heteroaryl ring;
R2选自氢、卤素、C1-C6烷基、C1-C6卤代烷基；m选自1、2、3、4；当有多个R2时，各个R2可以相同或不同；R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; m is selected from 1, 2, 3, 4; when there are multiple R 2s , each R 2 can be the same or different ;
R3、R4、R5、R6各自独立地选自氢、羟基和C1-C6烷基；任选地，所述C1-C6烷基被一个或多个选自以下的基团取代：苯基、卤素、硝基、氰基、羟基、C1-C6烷基；R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl and C 1 -C 6 alkyl; optionally, the C 1 -C 6 alkyl is replaced by one or more selected from the following Group substitution: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
R7、R8各自独立地选自C1-C6烷基，q选自1至10之间的整数；R 7 and R 8 are each independently selected from C 1 -C 6 alkyl, and q is selected from an integer between 1 and 10;
L1、L2各自独立地为不存在或选自-(CH2)n-、3至6元环烷基，n为选自1至6的整数；任选地，-(CH2)n-被一个或多个选自以下的基团取代：苯基、卤素、硝基、氰基、羟基、C1-C6烷基、氘、氚、羰基；并且，所述化合物不是3-甲基-5-(N-苯乙基氨磺酰)苯并呋喃-2-羧酸。L 1 and L 2 are each independently absent or selected from -(CH 2 ) n -, 3 to 6-membered cycloalkyl, n is an integer selected from 1 to 6; optionally, -(CH 2 ) n - substituted by one or more groups selected from: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, deuterium, tritium, carbonyl; and, the compound is not 3-methyl Base-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid.
在某些实施方案中，A选自6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基、C2-C6烯基、C2-C6炔基；任选地，所述6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基被一个或多个M取代，M选自以下基团：卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基；任选地，所述C1-C6烷氧基被一个或多个选自以下的基团取代：C1-C6卤代烷基、3至6元环烷基；In certain embodiments, A is selected from 6 to 10 membered aryl, 5 to 14 membered heteroaryl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, benzo 3 to 6 membered cycloalkyl , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; optionally, the 6 to 10 membered aryl group, 5 to 14 membered heteroaryl group, 3 to 6 membered cycloalkyl group, 3 to 6 membered aryl group Heterocyclyl, benzo 3 to 6-membered cycloalkyl is substituted by one or more M, M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkane Base, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 1 -C 6 haloalkyl group, C 1 -C 6 alkoxy group, C 1 -C 6 alkanoyl group, C 1 -C 6 amide group , phenyl, phenoxy; optionally, the C 1 -C 6 alkoxy group is substituted by one or more groups selected from the following: C 1 -C 6 haloalkyl, 3 to 6-membered cycloalkyl ;
R1选自羟基、-NR5R6、C1-C6烷氧基；任选地，所述C1-C6烷氧基被一个或多个选自以下的基团取代：苯基、卤素、硝基、氰基、羟基、C1-C6烷基；R 1 is selected from hydroxyl, -NR 5 R 6 , C 1 -C 6 alkoxy; optionally, the C 1 -C 6 alkoxy is substituted by one or more groups selected from the following: phenyl , halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
Q为苯基或苯并5-6元杂芳基环；Q is phenyl or benzo 5-6 membered heteroaryl ring;
R2选自氢、卤素、C1-C6烷基、C1-C6卤代烷基；m选自1、2、3、4；当有多个R2时，各个R2可以相同或不同；R3、R4、R5、R6各自独立地选自氢、羟基和C1-C6烷基；任选地，所述C1-C6烷基被一个或多个选自以下的基团取代：苯基、卤素、硝基、氰基、羟基、C1-C6烷基；R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; m is selected from 1, 2, 3, 4; when there are multiple R 2s , each R 2 can be the same or different ; R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, hydroxyl and C 1 -C 6 alkyl; optionally, the C 1 -C 6 alkyl is one or more selected from the following Group substitution: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
L1、L2各自独立地为不存在或选自-(CH2)n-、3至6元环烷基，n为选自1至6的整数；任选地，-(CH2)n-被一个或多个选自以下的基团取代：苯基、卤素、硝基、氰基、羟基、C1-C6烷基、氘、氚；L 1 and L 2 are each independently absent or selected from -(CH 2 ) n -, 3 to 6-membered cycloalkyl, n is an integer selected from 1 to 6; optionally, -(CH 2 ) n - substituted by one or more groups selected from: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, deuterium, tritium;
并且，所述化合物不是3-甲基-5-(N-苯乙基氨磺酰)苯并呋喃-2-羧酸。Furthermore, the compound is not 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid.
A选自6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基、苯并5至6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基；任选地，所述6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基被一个或多个M取代；A is selected from 6 to 10 membered aryl, 5 to 8 membered monocyclic heteroaryl, 8 to 14 membered fused heteroaryl, 5 to 6 membered cycloalkyl, 5 to 6 membered heterocyclyl, benzo 5 to 6 Optionally, cycloalkyl, benzo 5- to 6-membered heterocyclyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 5 to 6 cycloalkenyl , the 6 to 10 membered aryl group, 5 to 8 membered monocyclic heteroaryl group, 8 to 14 membered condensed heteroaryl group, 5 to 6 membered cycloalkyl group, 5 to 6 membered heterocyclyl group, benzo 5 to 6 membered The ring alkyl group is substituted by one or more M;
优选地，M选自以下基团：卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、P(＝O)R7R8、CH3CH2O-(CH2CH2O)q-、4至6元杂环基、5至6元杂芳基；所述苯基、苯氧基、4至6元 杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代；Preferably, M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy group, C 1 -C 6 alkanoyl group, C 1 -C 6 amide group, phenyl group, phenoxy group, P(=O)R 7 R 8 , CH 3 CH 2 O- (CH 2 CH 2 O) q -, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl; the phenyl, phenoxy, 4- to 6-membered Heterocyclyl and 5- to 6-membered heteroaryl are optionally substituted by halogen or C 1 -C 6 alkyl;
优选地，R7、R8各自为甲基，q选自1至4之间的整数；Preferably, R 7 and R 8 are each methyl, and q is selected from an integer between 1 and 4;
优选地，A选自6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基(例如苯并5至6元含氧杂芳基)、8至10元含氮稠杂芳基(例如苯并5至6元含氮杂芳基)、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基、苯并5至6元含氧杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基；任选地，所述6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基(例如苯并5至6元含氧杂芳基)、8至10元含氮稠杂芳基(例如苯并5至6元含氮杂芳基)、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基或苯并5至6元含氧杂环基被一个或多个M取代；Preferably, A is selected from a 6- to 10-membered aryl group, a 5- to 6-membered sulfur- or nitrogen-containing monocyclic heteroaryl group, an 8- to 10-membered oxygen-containing condensed heteroaryl group (such as a benzo 5- to 6-membered oxygen-containing heteroaryl group). base), 8- to 10-membered nitrogen-containing fused heteroaryl (such as benzo 5- to 6-membered nitrogen-containing heteroaryl), 5- to 6-membered cycloalkyl, 5- to 6-membered oxygen-containing heterocyclic group, 5- to 6-membered Nitrogen-containing heterocyclic group, benzo 5- to 6-membered cycloalkyl group, benzo 5- to 6-membered oxygen-containing heterocyclic group, C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkyne base, 5- to 6-membered cycloalkenyl; optionally, the 6- to 10-membered aryl group, 5- to 6-membered sulfur-containing or nitrogen-containing monocyclic heteroaryl group, 8- to 10-membered oxygen-containing fused heteroaryl group (such as Benzo 5- to 6-membered oxygen-containing heteroaryl), 8- to 10-membered nitrogen-containing condensed heteroaryl (such as benzo 5- to 6-membered nitrogen-containing heteroaryl), 5- to 6-membered cycloalkyl, 5- to 6-membered An oxygen-containing heterocyclic group, a 5- to 6-membered nitrogen-containing heterocyclic group, a benzo 5- to 6-membered cycloalkyl group, or a benzo 5- to 6-membered oxygen-containing heterocyclic group is substituted by one or more M;
优选地，M选自以下基团：卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、-P(＝O)(CH3)2、CH3CH2O-(CH2CH2O)-；Preferably, M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy group, C 1 -C 6 alkanoyl group, C 1 -C 6 amide group, phenyl group, phenoxy group, -P(=O)(CH 3 ) 2 , CH 3 CH 2 O- (CH 2 CH 2 O)-;
优选地，A选自苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基、C1-C6烷基、2,3-二氢苯并呋喃基、2,3-二氢苯并[b][1,3]二氧杂环戊烷基、2,3-二氢苯并[b][1,4]二氧杂环己烷基、吲哚基、环己烯基、苯并环己烷基；任选地，所述苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基、C1-C6烷基、2,3-二氢苯并呋喃基、2,3-二氢苯并[b][1,3]二氧杂环戊烷基、2,3-二氢苯并[b][1,4]二氧杂环己烷基、吲哚基、环己烯基或苯并环己烷基被一个或多个M取代；Preferably, A is selected from phenyl, naphthyl, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxanyl, indolyl, cyclohexenyl, benzocyclohexanyl; optionally, the phenyl, naphthalene base, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 alkyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1,3]dioxolyl, 2,3-dihydrobenzo[b ][1,4]dioxanyl, indolyl, cyclohexenyl or benzocyclohexanyl group is substituted by one or more M;
优选地，M选自以下基团：卤素(例如氟、氯、溴、碘)、C1-C4烷基、三氟甲基、甲氧基、乙氧基、苯基、C2-C4炔基、C1-C6烷酰基、硝基、羟基、氰基、-NR3R4、-P(＝O)(CH3)2、CH3CH2O-(CH2CH2O)-、4至6元杂环基、5至6元杂芳基、苯氧基；所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代。Preferably, M is selected from the following groups: halogen (eg fluorine, chlorine, bromine, iodine), C 1 -C 4 alkyl, trifluoromethyl, methoxy, ethoxy, phenyl, C 2 -C 4 alkynyl, C 1 -C 6 alkanoyl, nitro, hydroxyl, cyano, -NR 3 R 4 , -P(=O)(CH 3 ) 2 , CH 3 CH 2 O-(CH 2 CH 2 O )-, 4 to 6-membered heterocyclyl, 5 to 6-membered heteroaryl, phenoxy; the phenyl, phenoxy, 4 to 6-membered heterocyclyl, 5 to 6-membered heteroaryl optionally Substituted by halogen or C 1 -C 6 alkyl.
在某些实施方案中，A选自6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基、C2-C6烯基、C2-C6炔基；任选地，所述6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基被一个或多个M取代。In certain embodiments, A is selected from 6 to 10 membered aryl, 5 to 8 membered monocyclic heteroaryl, 8 to 14 membered fused heteroaryl, 5 to 6 membered cycloalkyl, 5 to 6 membered heterocycle base, benzo 5 to 6 membered cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; optionally, the 6 to 10 membered aryl group, 5 to 8 membered monocyclic heteroaryl group , 8 to 14 membered fused heteroaryl, 5 to 6 membered cycloalkyl, 5 to 6 membered heterocyclyl, benzo 5 to 6 membered cycloalkyl substituted by one or more M.
在某些实施方案中，M选自以下基团：卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基。In certain embodiments, M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 amido, phenyl, phenoxy.
在某些实施方案中，R3、R4各自独立地选自氢和羟基。In certain embodiments, R 3 and R 4 are each independently selected from hydrogen and hydroxyl.
在某些实施方案中，所述C1-C6烷氧基被一个或多个选自以下的基团取代：C1-C6氟代烷基、环丙基。In certain embodiments, the C 1 -C 6 alkoxy group is substituted with one or more groups selected from: C 1 -C 6 fluoroalkyl, cyclopropyl.
在某些实施方案中，A选自6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基、C2-C6烯基、C2-C6炔基；任选地，所述6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基被一个或多个M取代。In certain embodiments, A is selected from a 6- to 10-membered aryl group, a 5- to 6-membered sulfur- or nitrogen-containing monocyclic heteroaryl group, an 8- to 10-membered oxygen-containing fused heteroaryl group, and a 5- to 6-membered cycloalkyl group. , 5- to 6-membered oxygen-containing heterocyclic group, 5- to 6-membered nitrogen-containing heterocyclic group, benzo 5- to 6-membered cycloalkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group; optionally , the 6- to 10-membered aryl group, the 5- to 6-membered sulfur-containing or nitrogen-containing monocyclic heteroaryl group, the 8- to 10-membered oxygen-containing condensed heteroaryl group, the 5- to 6-membered cycloalkyl group, the 5- to 6-membered oxygen-containing monocyclic heteroaryl group Heterocyclyl, 5- to 6-membered nitrogen-containing heterocyclyl, and benzo 5- to 6-membered cycloalkyl are substituted by one or more M.
在某些实施方案中，M选自以下基团：卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基。In certain embodiments, M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 amido, phenyl, phenoxy.
在某些实施方案中，A选自苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基；任选地，所述苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基被一个或多个M取代。In certain embodiments, A is selected from phenyl, naphthyl, thienyl, pyridyl, benzofuryl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl; optionally, the phenyl, naphthyl, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl A group is substituted with one or more M's.
在某些实施方案中，M选自以下基团：卤素(例如氟、氯、溴)、氰基、-NHCH3、C1- C4烷基、C2-C4炔基、三氟甲基、甲氧基、乙氧基、乙酰基、苯基、苯氧基。在某些实施方案中，所述甲氧基或乙氧基被一个或多个三氟甲基或环丙基取代。In certain embodiments, M is selected from the group consisting of: halogen (e.g., fluorine, chlorine, bromine), cyano, -NHCH 3 , C 1 - C 4 alkyl, C 2 -C 4 alkynyl, trifluoromethyl, methoxy, ethoxy, acetyl, phenyl, phenoxy. In certain embodiments, the methoxy or ethoxy group is substituted with one or more trifluoromethyl or cyclopropyl groups.
在某些实施方案中，R1为羟基或-NHOH。In certain embodiments, R1 is hydroxyl or -NHOH.
在某些实施方案中，R2卤素、选自C1-C6烷基(例如甲基)、C1-C6卤代烷基(例如氟代甲基)。In certain embodiments, R 2 halo is selected from C 1 -C 6 alkyl (eg, methyl), C 1 -C 6 haloalkyl (eg, fluoromethyl).
在某些实施方案中，L1不存在或选自-(CH2)n-、环丙基，n为选自1至4的整数；任选地，-(CH2)n-被甲基取代或被氘代；任选地，-(CH2)n-被甲基或羰基取代或被氘代。在某些实施方案中，L2不存在或选自-(CH2)n-、n为选自1至4的整数；任选地，-(CH2)n-被甲基取代或被氘代。In certain embodiments, L 1 is absent or selected from -(CH 2 ) n -, cyclopropyl, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is methyl Substituted or deuterated; optionally, -( CH2 ) n- is substituted or deuterated by methyl or carbonyl. In certain embodiments, L 2 is absent or selected from -(CH 2 ) n -, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is substituted with methyl or deuterated generation.
在某些实施方案中，所述5-6元杂芳基选自呋喃基、噻吩基、吡咯基。在某些实施方案中，所述5-6元杂芳基为呋喃基。In certain embodiments, the 5-6 membered heteroaryl group is selected from the group consisting of furyl, thienyl, and pyrrolyl. In certain embodiments, the 5-6 membered heteroaryl group is furyl.
在某些实施方案中，所述化合物的结构如式(II)所示：
In certain embodiments, the compound has a structure represented by Formula (II):
其中，X选自O、S或NH。Wherein, X is selected from O, S or NH.
在某些实施方案中，所述化合物的结构如式(III)或(IV)所示：
In certain embodiments, the compound has a structure represented by Formula (III) or (IV):
在某些实施方案中，X为O。In certain embodiments, X is O.
在某些实施方案中，X为S。In certain embodiments, X is S.
在某些实施方案中，X为NH。In certain embodiments, X is NH.
在某些实施方案中，A为任选被一个或多个M取代的苯基，M如上文所定义。In certain embodiments, A is phenyl optionally substituted with one or more M, M as defined above.
在某些实施方案中，本发明的化合物选自表1所示的化合物：In certain embodiments, the compounds of the invention are selected from the compounds shown in Table 1:
表1






Table 1






在某些实施方案中，所述化合物的结构如式(V)所示：
In certain embodiments, the compound has a structure represented by Formula (V):
其中，in,
Core为X选自O、S或NH，Core is X is selected from O, S or NH,
R2如上文所定义。 R2 is as defined above.
在某些实施方案中，R2选自氢、卤素(例如氟、氯、溴)、C1-C6烷基(例如甲基)。In certain embodiments, R2 is selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine), C 1 -C 6 alkyl (e.g., methyl).
在某些实施方案中，Core选自：
In certain embodiments, Core is selected from:
在某些实施方案中，所述化合物选自表2所示的化合物：In certain embodiments, the compound is selected from the compounds shown in Table 2:
表2

Table 2

在某些实施方案中，所述化合物的结构如式(VI)所示：
In certain embodiments, the compound has a structure represented by Formula (VI):
其中，A如上文所定义。Where, A is as defined above.
在某些实施方案中，A选自任选被一个或多个M取代的苯基，M选自卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、硝基、羟基、-NR3R4，R3、R4各自独立地选自氢、C1-C6烷基。In certain embodiments, A is selected from phenyl optionally substituted with one or more M selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl Oxygen group, nitro group, hydroxyl group, -NR 3 R 4 , R 3 and R 4 are each independently selected from hydrogen and C 1 -C 6 alkyl group.
在某些实施方案中，所述化合物选自表3所示的化合物：In certain embodiments, the compound is selected from the compounds shown in Table 3:
表3


table 3


在某些实施方案中，所述化合物的结构如式(VI)所示，其中，A选自任选被一个或多个M取代的以下基团：苯基、5至6元含氮杂芳基；M选自：卤素、C2-C6炔基、C1-C6烷氧基、氰基、P(＝O)R7R8、C1-C6烷酰基、CH3CH2O-(CH2CH2O)q-、苯基、4至6元杂环基、5至6元杂芳基，其中，R7、R8各自独立地选自C1-C6烷基，q选自1至10之间的整数，所述苯基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代。In certain embodiments, the compound has a structure as shown in formula (VI), wherein A is selected from the following groups optionally substituted by one or more M: phenyl, 5- to 6-membered nitrogen-containing heteroaromatic Base; M is selected from: halogen, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, cyano, P(=O)R 7 R 8 , C 1 -C 6 alkanoyl, CH 3 CH 2 O-(CH 2 CH 2 O) q -, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein R 7 and R 8 are each independently selected from C 1 -C 6 alkyl , q is selected from an integer between 1 and 10, and the phenyl group, 4- to 6-membered heterocyclyl group, and 5- to 6-membered heteroaryl group are optionally substituted by halogen or C 1 -C 6 alkyl group.
在某些实施方案中，所述化合物选自表4所示的化合物：In certain embodiments, the compound is selected from the compounds shown in Table 4:
表4

Table 4

在某些实施方案中，所述化合物的结构如式(VI)所示，其中，A选自任选被一个或多个M取代的以下基团：苯基、萘基、苯并5至6元杂环基(例如苯并5至6元含氧杂环基)、苯并5至6元杂芳基(例如苯并5至6元含氮或含氧杂芳基)；M选自卤素、C1-C6烷基、C1-C6烷氧基。In certain embodiments, the compound has a structure as shown in formula (VI), wherein A is selected from the following groups optionally substituted with one or more M: phenyl, naphthyl, benzo 5 to 6 Membered heterocyclyl (such as benzo 5- to 6-membered oxygen-containing heterocyclyl), benzo 5- to 6-membered heteroaryl (such as benzo 5- to 6-membered nitrogen-containing or oxygen-containing heteroaryl); M is selected from halogen , C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
在某些实施方案中，所述化合物选自表5所示的化合物：In certain embodiments, the compound is selected from the compounds shown in Table 5:
表5


table 5


在某些实施方案中，所述化合物的结构如式(VI)所示，其中，A选自任选被一个或多个M取代的以下基团：C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烷基、5至6元环烯基、5至6元杂芳基、5至6元杂环基；M选自C1-C6烷基、卤素。In certain embodiments, the compound has a structure as shown in formula (VI), wherein A is selected from the following groups optionally substituted by one or more M: C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, 5 to 6 membered cycloalkyl, 5 to 6 membered cycloalkenyl, 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl; M is selected from C 1 -C 6 alkyl, halogen.
在某些实施方案中，所述化合物选自表6所示的化合物：In certain embodiments, the compound is selected from the compounds shown in Table 6:
表6

Table 6

在某些实施方案中，本发明化合物的结构如式(VII)所示，
In certain embodiments, the structure of the compound of the invention is represented by Formula (VII),
其中，A和L1如上文所定义。where A and L 1 are as defined above.
在某些实施方案中，A选自苯基、萘基，L1不存在或选自-(CH2)n-，n为选自1至4的整数；任选地，-(CH2)n-被一个或多个选自以下的基团取代：卤素、C1-C6烷基、羰基。In certain embodiments, A is selected from phenyl, naphthyl, L 1 is absent or selected from -(CH 2 ) n -, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is substituted with one or more groups selected from: halogen, C 1 -C 6 alkyl, carbonyl.
在某些实施方案中，所述化合物选自表7所示的化合物：In certain embodiments, the compound is selected from the compounds shown in Table 7:
表7
Table 7
在某些实施方案中，本发明化合物的结构如式(VII)所示，其中，L1不存在，A选自任选被一个或多个M取代的以下基团：苯基、萘基、苯并5至6元杂芳基(例如苯并5至6元含氮或含氧杂芳基)、苯并5至6元环烷基，M选自C1-C6烷基、C2-C6炔基、卤素、苯氧基、-NR3R4、5至6元杂环基，R3、R4各自独立地选自C1-C6烷基，所述5至6元杂环基任选地被C1-C6烷基取代。In certain embodiments, the structure of the compound of the invention is as shown in formula (VII), wherein L 1 is absent and A is selected from the following groups optionally substituted by one or more M: phenyl, naphthyl, Benzo 5- to 6-membered heteroaryl (such as benzo 5- to 6-membered nitrogen-containing or oxygen-containing heteroaryl), benzo 5- to 6-membered cycloalkyl, M selected from C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogen, phenoxy, -NR 3 R 4 , 5 to 6-membered heterocyclyl, R 3 and R 4 are each independently selected from C 1 -C 6 alkyl, the 5 to 6-membered heterocyclic group Heterocyclyl is optionally substituted with C 1 -C 6 alkyl.
在某些实施方案中，所述化合物选自表8所示的化合物：In certain embodiments, the compound is selected from the compounds shown in Table 8:
表8
Table 8
本发明的化合物的药学上可接受的酯优选为羧酸乙酯。The pharmaceutically acceptable ester of the compound of the present invention is preferably ethyl carboxylate.
药物组合物pharmaceutical composition
在第二方面，本申请提供了一种药物组合物，其包含式(I)所示的化合物、其药学上可 接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式；任选地，所述药物组合物还包含药学上可接受的载体或赋形剂。In a second aspect, the present application provides a pharmaceutical composition comprising a compound represented by formula (I), which is pharmaceutically acceptable Acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolite forms; optionally, the pharmaceutical composition also includes a pharmaceutically acceptable carrier or excipient agent.
在本发明中，所述药物组合物可以是医学领域已知的任何形式。例如，所述药物组合物可以是片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、冻干粉剂)、吸入剂、喷雾剂等形式。优选剂型取决于预期的给药方式和治疗用途。In the present invention, the pharmaceutical composition may be in any form known in the medical field. For example, the pharmaceutical composition can be tablets, pills, suspensions, emulsions, solutions, gels, capsules, powders, granules, elixirs, lozenges, suppositories, injections (including injections, lyophilized powder), inhalants, sprays, etc. The preferred dosage form depends on the intended mode of administration and therapeutic use.
在某些实施方案中，所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式，可以以单位剂量形式存在于药物组合物中，以便于施用。In certain embodiments, the compounds, pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, and metabolite forms thereof, may be in unit dosage form Present in pharmaceutical compositions to facilitate administration.
所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或者所述药物组合物，可以通过本领域已知的任何合适的方法来施用，包括但不限于，口服、直肠、肠胃外或局部给药。The compounds, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, their metabolite forms, or the pharmaceutical compositions may be prepared by those skilled in the art. Administration may be carried out by any suitable method known, including, but not limited to, oral, rectal, parenteral or topical administration.
一种示例性施用途径是口服给药。用于口服给药的液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、悬浮剂、糖浆剂、酏剂等。除活性化合物以外，液体剂型可含有本领域常用的惰性稀释剂，例如水或其它溶剂、增溶剂和乳化剂。除惰性稀释剂以外，口服给药的液体剂型也可包括助剂，例如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和芳香剂等。用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、锭剂、粉剂、颗粒剂等。除活性化合物以外，固体剂型可含有药学上可接受的惰性赋形剂或载体，例如填充剂、粘合剂、湿润剂、崩解剂、润滑剂及其混合物。One exemplary route of administration is oral administration. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, elixirs, and the like. Liquid dosage forms may contain, in addition to the active compound, inert diluents customary in the art, such as water or other solvents, solubilizers and emulsifiers. Besides inert diluents, liquid dosage forms for oral administration can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents and the like. Solid dosage forms for oral administration include capsules, tablets, pills, lozenges, powders, granules, etc. In addition to the active compound, solid dosage forms may contain pharmaceutically acceptable inert excipients or carriers, such as fillers, binders, wetting agents, disintegrating agents, lubricants, and mixtures thereof.
本发明的化合物或药物组合物也可通过非口服途径给药。The compounds or pharmaceutical compositions of the invention may also be administered parenterally.
因此，另一种示例性的施用途径是肠胃外给药，例如，皮下注射、静脉注射、腹膜内注射、肌肉注射、胸骨内注射和注入。用于肠道外给药的剂型可以为注射制剂，包括注射液、注射用无菌粉末或注射用浓溶液。除活性化合物以外，注射剂型可含有药学上可接受的载体例如无菌水、林格氏液和等渗氯化钠溶液，也可根据药物的性质加入适宜的附加剂例如抗氧化剂、缓冲剂和抑菌剂。Accordingly, another exemplary route of administration is parenteral administration, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection and infusion. Dosage forms for parenteral administration may be injectable preparations, including injectable solutions, sterile powders for injection, or concentrated solutions for injection. In addition to the active compound, injection dosage forms may contain pharmaceutically acceptable carriers such as sterile water, Ringer's solution and isotonic sodium chloride solution, and may also add appropriate additives such as antioxidants, buffers and Bacteriostat.
另一种示例性的施用途径是局部给药，例如经皮给药(如通过经皮贴剂或离子电渗装置给药)、眼内给药或者鼻内或吸入给药。用于经皮给药的剂型可以为局部凝胶剂、喷雾剂、软膏剂和霜剂。除活性化合物以外，局部剂型可含有能够提高该活性化合物通过皮肤或其它作用区域的吸收或渗透的成分。当本发明的化合物通过经皮装置给药时，给药将使用存储和多孔膜类型或者固体基质品种的贴剂完成。用于眼部局部给药的剂型可以为滴眼剂，其中本发明的化合物被溶于或者悬浮于适宜的载体中。对于鼻内给药或吸入给药来说，本发明的化合物以溶液剂或悬浮剂的形式从压力喷雾容器中被方便地递送，所述传递是通过患者压握或者泵送而进行的，或者是作为气溶胶喷雾剂制剂从压力容器或喷雾器中使用适宜的抛射剂而传递的。Another exemplary route of administration is topical administration, such as transdermal administration (eg, via a transdermal patch or iontophoretic device), intraocular administration, or intranasal or inhaled administration. Dosage forms for transdermal administration may be topical gels, sprays, ointments and creams. Topical dosage forms may contain, in addition to the active compound, ingredients that enhance absorption or penetration of the active compound through the skin or other area of action. When the compounds of the present invention are administered via a transdermal device, administration will be accomplished using patches of the storage and porous film type or solid matrix variety. Dosage forms for topical administration to the eye may be eye drops in which the compound of the invention is dissolved or suspended in a suitable carrier. For intranasal or inhaled administration, the compounds of the present invention are conveniently delivered as solutions or suspensions from pressure spray containers by patient compression or pumping, or It is delivered as an aerosol spray formulation from a pressure container or nebulizer using a suitable propellant.
另一种示例性的施用途径是直肠给药。用于直肠给药的剂型可以为栓剂。Another exemplary route of administration is rectal administration. Dosage forms for rectal administration may be suppositories.
此外，还可以使用药学领域已知的其它载体材料和给药方式。本发明的药物组合物可以通过任何公知的制药工艺制备，例如有效的制剂和给药方法。关于有效制剂和给药方法的上述考虑因素是本领域中公知的，并且描述于标准教科书中。药物的制剂描述在，例如，Hoover，John E.，Remington′s Pharmaceutical Sciences.Mack Publishing Co.，Easton，Pennsylvania，1975；Liberman等人编辑，Pharmaceutical Dosage Forms，Marcel Decker，New York，N.Y.，1980；以及Kibbe等人编辑，Handbook of Pharmaceutical Excipients(第3版)，American Pharmaceutical Association，Washington，1999。In addition, other carrier materials and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present invention can be prepared by any known pharmaceutical process, such as effective formulation and administration methods. The above considerations regarding effective formulations and methods of administration are well known in the art and are described in standard textbooks. Formulations of drugs are described in, for example, Hoover, John E., Remington's Pharmaceutical Sciences. Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and edited by Kibbe et al., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.
在某些实施方案中，所述药物组合物含有本发明的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的量为0.01-2000mg，优选为0.1-1000mg，更优选为1-800mg，更优选为10-600mg，特别优选为50-500mg。 In certain embodiments, the pharmaceutical composition contains a compound of the invention, a pharmaceutically acceptable salt or ester, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form thereof, or a metabolite thereof The amount of the form is 0.01-2000 mg, preferably 0.1-1000 mg, more preferably 1-800 mg, more preferably 10-600 mg, particularly preferably 50-500 mg.
本发明的药物组合物可以包括“治疗有效量”或“预防有效量”的如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式。“预防有效量”是指，足以预防，阻止，或延迟疾病的发生的量。“治疗有效量”是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。本领域技术人员理解，如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式的治疗有效量可根据如下因素发生变化：待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄，体重和性别，药物的施用方式，以及同时施用的其他治疗等等。The pharmaceutical composition of the present invention may include a "therapeutically effective amount" or a "prophylactically effective amount" of a compound as described herein, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate substances, crystal forms, and their metabolite forms. "Prophylactically effective amount" refers to an amount sufficient to prevent, prevent, or delay the occurrence of disease. A "therapeutically effective amount" means an amount sufficient to cure or at least partially prevent disease and its complications in a patient who is already suffering from the disease. Those skilled in the art understand that therapeutically effective amounts of compounds as described herein, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, and their metabolite forms It may vary based on factors such as the severity of the disease being treated, the overall status of the patient's own immune system, the patient's general condition such as age, weight, and gender, the manner in which the drug is administered, and other treatments being administered at the same time, etc.
在本发明中，可调整给药方案以获得最佳目的反应(例如治疗或预防反应)。例如，可以单次给药，可以在一段时间内多次给药，或者可以随治疗情况的紧急程度按比例减少或增加剂量。In the present invention, the dosing regimen can be adjusted to obtain the optimal desired response (eg, therapeutic or prophylactic response). For example, the dose may be administered as a single dose, may be administered multiple times over a period of time, or may be proportionally reduced or increased according to the exigencies of the treatment situation.
本发明化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的治疗或预防有效量的典型非极限范围是0.01～1000mg/kg，例如0.1～500mg/kg。应注意的是，剂量可随需要治疗的症状的类型和严重性不同而发生变化。此外，本领域技术人员理解，对于任一特定患者，特定的给药方案应根据患者需要和医生的专业评价而随时间调整；此处给出的剂量范围只用于举例说明目的，而不限定本发明药物组合物的使用或范围。Typical non-limiting ranges for therapeutically or prophylactically effective amounts of the compounds of the invention, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms are 0.01 ~1000mg/kg, such as 0.1~500mg/kg. It should be noted that dosage may vary depending on the type and severity of symptoms requiring treatment. In addition, those skilled in the art understand that for any particular patient, the specific dosage regimen should be adjusted over time based on the needs of the patient and the professional evaluation of the physician; the dosage ranges given here are for illustrative purposes only and are not limiting. Use or scope of the pharmaceutical composition of the present invention.
在某些实施方案中，所述药物组合物还可以包含另外的药学活性剂。In certain embodiments, the pharmaceutical compositions may also include additional pharmaceutically active agents.
在某些实施方案中，在所述药物组合物中，本发明化合物与所述另外的药学活性剂作为分离的组分或混合的组分提供。因此，本发明化合物与所述另外的药学活性剂可以同时、分开或相继施用。In certain embodiments, the compound of the invention and the additional pharmaceutically active agent are provided as separate or mixed components in the pharmaceutical composition. Thus, the compounds of the invention and the additional pharmaceutically active agent may be administered simultaneously, separately or sequentially.
用途use
本发明化合物可作为GPR132的调节剂(例如拮抗剂)，用于预防或治疗与GPR132相关的疾病。The compounds of the present invention can be used as modulators (eg antagonists) of GPR132 to prevent or treat diseases related to GPR132.
因此，在第三方面，本申请提供了化合物用于制备药物中的用途，所述药物用于预防或治疗与GPR132相关的疾病，所述化合物选自式(I)或下表中的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式
Therefore, in a third aspect, the application provides the use of a compound for the preparation of a medicament for preventing or treating diseases related to GPR132, the compound being selected from the group consisting of compounds of formula (I) or the following table, Its pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or their metabolite forms
在某些实施方案中，所述与GPR132相关的疾病选自肿瘤、代谢性疾病、免疫相关疾病、神经性疼痛。In certain embodiments, the disease associated with GPR132 is selected from the group consisting of tumors, metabolic diseases, immune-related diseases, and neuropathic pain.
在某些实施方案中，所述肿瘤选自选自：乳腺癌、黑色素瘤、脑膜瘤、软组织肉瘤、 唾液腺肿瘤、原发性肝癌、椎管内肿瘤、纵隔肿瘤、脑癌、骨癌、阴茎癌、骨肉瘤、颅内肿瘤、舌癌、上颌窦癌、甲状腺癌、恶性淋巴瘤、多发性骨髓瘤、脑垂体腺瘤、睾丸肿瘤、非何杰金氏淋巴癌、膀胱癌、白血病、胃癌、鼻咽癌、喉癌、口腔癌、食管癌、肺癌、肾癌、宫颈癌、绒毛膜癌、外阴癌、皮肤癌、子宫内膜癌、卵巢癌、前列腺癌、胰腺癌、结肠癌、直肠癌、大肠癌、卡波西肉瘤、非黑色素瘤皮肤癌(包括鳞状细胞癌和基底细胞癌)、血管瘤、神经胶质瘤。In certain embodiments, the tumor is selected from the group consisting of: breast cancer, melanoma, meningioma, soft tissue sarcoma, Salivary gland tumors, primary liver cancer, intraspinal tumors, mediastinal tumors, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumors, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma , pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia, stomach cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulva Cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, Kaposi's sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), Hemangioma, glioma.
在某些实施方案中，所述代谢性疾病选自动脉粥样硬化、肥胖、非酒精性脂肪肝病(NAFLD)(例如，单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))、代谢综合征、2型糖尿病、1型糖尿病、胰岛素抵抗、高胰岛素血症、葡萄糖不耐受、高血糖、高脂血症(例如，高胆固醇血症)，及这些疾病的继发性并发症(例如，糖尿病并发症，如视网膜病、神经病、肾病以及延缓的创伤愈合，或者动脉粥样硬化、冠心病、高血压、中风等心脑血管疾病)。In certain embodiments, the metabolic disease is selected from atherosclerosis, obesity, non-alcoholic fatty liver disease (NAFLD) (e.g., simple fatty liver disease or non-alcoholic steatohepatitis (NASH)), metabolic syndrome syndrome, type 2 diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia), and secondary complications of these diseases (e.g., , complications of diabetes, such as retinopathy, neuropathy, nephropathy and delayed wound healing, or cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hypertension, stroke).
在某些实施方案中，所述免疫相关疾病选自：In certain embodiments, the immune-related disease is selected from:
继发性免疫缺陷：例如由感染(例如风疹、麻疹、麻风、结核病、巨细胞病毒感染、艾滋病病毒感染、球孢子菌感染)，蛋白丢失(例如肾病综合征、蛋白丢失性肠病)，免疫球蛋白合成不足，淋巴细胞丢失(例如因药物和/或系统感染引起的淋巴细胞丢失)，其他疾病(如糖尿病、肝硬变、亚急性硬化性全脑炎)和/或免疫抑制治疗引起的继发性免疫缺陷；以及Secondary immune deficiencies: for example caused by infections (e.g. rubella, measles, leprosy, tuberculosis, cytomegalovirus infection, HIV infection, coccidioidomycosis infection), protein loss (e.g. nephrotic syndrome, protein-losing enteropathy), immune Insufficient globulin synthesis, lymphocyte loss (e.g. due to drugs and/or systemic infection), other diseases (e.g. diabetes, cirrhosis, subacute sclerosing panencephalitis) and/or immunosuppressive therapy secondary immunodeficiency; and
自身免疫疾病：例如系统性红斑狼疮、类风湿性关节炎、硬皮病、甲状腺机能亢进、青少年糖尿病、原发性血小板紫癜、自身免疫性溶血性贫血、溃疡性结肠炎、皮肤病、慢性肝病。Autoimmune diseases: such as systemic lupus erythematosus, rheumatoid arthritis, scleroderma, hyperthyroidism, juvenile diabetes, essential thrombocytopenic purpura, autoimmune hemolytic anemia, ulcerative colitis, skin diseases, chronic liver disease .
治疗方法treatment method
在第四方面，本发明提供了一种用于在受试者中预防或治疗与GPR132相关的疾病的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物选自式(I)或下表中的化合物
In a fourth aspect, the invention provides a method for preventing or treating a disease associated with GPR132 in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound, a pharmaceutically acceptable Acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or metabolite forms thereof selected from compounds of formula (I) or the following table
所述与GPR132相关的疾病可以选自上文所述的疾病。The disease associated with GPR132 may be selected from the diseases described above.
制备方法Preparation
在第五方面，本申请还提供了合成式(I)化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的方法，该方法包括以下步骤：在无机碱或有机碱存在的条件下，通式(I-A)和通式(I-B)化合物反应获得通式(I)化合物：
In a fifth aspect, the application also provides the synthesis of compounds of formula (I), their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolite forms The method includes the following steps: reacting compounds of general formula (IA) and general formula (IB) in the presence of inorganic bases or organic bases to obtain compounds of general formula (I):
其中环A、X、L1、R1-R6的定义分别如前文所述；所述无机碱优选自碳酸钾、碳酸钠、氢化钠、氢氧化钠、氢氧化钾、碳酸铯；所述有机碱优选自三乙胺、二异丙基乙基胺；反应溶剂优选自二氯甲烷、乙腈、N,N-二甲基甲酰胺。 The definitions of rings A, The organic base is preferably selected from triethylamine and diisopropylethylamine; the reaction solvent is preferably selected from dichloromethane, acetonitrile, and N,N-dimethylformamide.
本发明还提供一种制备如通式(I)所示的化合物或其可药用盐的方法，该方法包括以下步骤：在无机碱或有机碱存在的条件下，通式(II-A)和通式(II-B)化合物反应获得通式(I)化合物：
The present invention also provides a method for preparing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which method includes the following steps: in the presence of an inorganic base or an organic base, the general formula (II-A) React with the compound of general formula (II-B) to obtain the compound of general formula (I):
其中环A、L1、L2、R1-R6的定义分别如前文所述；所述无机碱优选自碳酸钾、碳酸钠、氢化钠、氢氧化钠、氢氧化钾、碳酸铯；所述有机碱优选自三乙胺、二异丙基乙基胺；反应溶剂优选自二氯甲烷、乙腈、N,N-二甲基甲酰胺。The definitions of rings A, L 1 , L 2 and R 1 -R 6 are as mentioned above respectively; the inorganic base is preferably selected from potassium carbonate, sodium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide and cesium carbonate; The organic base is preferably selected from triethylamine and diisopropylethylamine; the reaction solvent is preferably selected from dichloromethane, acetonitrile, and N,N-dimethylformamide.
术语定义Definition of Terms
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所涉及的实验室操作步骤均为相应领域内广泛使用的常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。In the present invention, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Moreover, the laboratory procedures involved in this article are routine procedures widely used in the corresponding fields. Meanwhile, in order to better understand the present invention, definitions and explanations of relevant terms are provided below.
如本文中所使用的，术语“C1-C6烷基”是指含有1-6个碳原子的直链或支链烷烃去掉一个氢原子后得到的基团，优选的C1-C6烷基是C1-C4烷基，其具体实例包括但不限于：甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、叔丁基或异丁基。As used herein, the term "C 1 -C 6 alkyl" refers to a group obtained by removing one hydrogen atom from a straight or branched chain alkane containing 1 to 6 carbon atoms, preferably C 1 -C 6 The alkyl group is a C 1 -C 4 alkyl group, and specific examples thereof include but are not limited to: methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl or isobutyl .
如本文中所使用的，术语“C2-C6烯基”是指含有至少一个双键的、且碳原子数为2-6的直链、支链或环状的烯基，实例包括但不限于：乙烯基、1-丙烯-1-基、烯丙基、1-丁烯-1-基、1-戊烯-1-基、1,3-丁二烯-1-基、1,4-戊二烯-1-基。优选的C2-C6烯基是C2-C4烯基。As used herein, the term "C 2 -C 6 alkenyl" refers to a linear, branched or cyclic alkenyl group containing at least one double bond and having 2 to 6 carbon atoms. Examples include but Not limited to: vinyl, 1-propen-1-yl, allyl, 1-buten-1-yl, 1-penten-1-yl, 1,3-butadien-1-yl, 1, 4-Pentadien-1-yl. Preferred C 2 -C 6 alkenyl groups are C 2 -C 4 alkenyl groups.
如本文中所使用的，术语“C2-C6炔基”是指含有至少一个三键的、碳原子数为2-6的直链或支链的炔基，实例包括但不限于：乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基、5-甲基-2-己炔基。优选的C2-C6炔基是C2-C4炔基。如本文中所使用的，术语“卤素”包括氟、氯、溴和碘。As used herein, the term "C 2 -C 6 alkynyl" refers to a linear or branched chain alkynyl group with 2 to 6 carbon atoms containing at least one triple bond. Examples include but are not limited to: acetylene base, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl Base-2-hexynyl. Preferred C 2 -C 6 alkynyl groups are C 2 -C 4 alkynyl groups. As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine.
如本文中所使用的，术语“卤代”是指基团或化合物上的氢被一个或多个卤素原子取代，包括全卤代和部分卤代。As used herein, the term "halogenated" means that a hydrogen on a group or compound is replaced by one or more halogen atoms, including fully halogenated and partially halogenated.
如本文中所使用的，术语“烷氧基”是指，以烷基-O-方式形成的基团，实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、新戊氧基、或正己氧基。As used herein, the term "alkoxy" refers to a group formed in the alkyl-O- manner, examples include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy, or n-hexyloxy.
如本文中所使用的，术语“C1-C6酰基”是指以H-(C＝O)-或者C1-C6烷基-(C＝O)-方式形成的基团，实例包括但不限于甲酰基、乙酰基、正丙酰基、正丁酰基、异丁酰基、正戊酰基、新戊酰基等。如本文中所使用的，术语“环烷基”指饱和或部分不饱和的单环或多环环状烃基，环烷基的环可以包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至10个碳原子，最优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。As used herein, the term "C 1 -C 6 acyl" refers to a group formed in the form H-(C=O)- or C 1 -C 6 alkyl-(C=O)-, examples include But it is not limited to formyl, acetyl, n-propionyl, n-butyryl, isobutyryl, n-valeryl, pivaloyl, etc. As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. The ring of the cycloalkyl group may contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms. atoms, more preferably from 3 to 10 carbon atoms, most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
如本文中所使用的，术语“杂环基”指饱和或部分不饱和的单环或多环环状烃基，其包 含3至20个环原子，其中一个或多个(例如1、2、3或4个)环原子为选自氮、氧或硫的杂原子。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至10个环原子；最优选包含5至6个环原子，其中含有1至2个选自氮、氧或硫的杂原子。任选地，所述硫原子可以被氧代。单环杂环基的非限制性实例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, including Containing 3 to 20 ring atoms, one or more (eg 1, 2, 3 or 4) of the ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 10 ring atoms; most preferably it contains 5 to 6 ring atoms, of which 1 to 2 are selected from nitrogen, oxygen or Sulfur heteroatoms. Optionally, the sulfur atoms may be oxosubstituted. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
如本文中所使用的，术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(即共享毗邻碳原子对的环)基团，优选为6-10元，例如苯基、萘基。As used herein, the term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, preferably 6 -10 yuan, such as phenyl, naphthyl.
如本文中所使用的，术语“杂芳基”指具有共轭的π电子体系的包含杂原子的单环或稠合多环(即共享毗邻碳原子对的环)基团，优选为5至10元杂芳基，包括5至8元单环杂芳基和8至14元稠杂芳基。As used herein, the term "heteroaryl" refers to a heteroatom-containing monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, preferably from 5 to 10-membered heteroaryl groups include 5- to 8-membered monocyclic heteroaryl groups and 8- to 14-membered fused heteroaryl groups.
如本文中所使用的，术语“5至8元单环杂芳基”是指含有5至8个环原子的具有芳香性的单环环状基团，其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子，同时包括环上的碳原子、氮原子和硫原子被氧代的情况。实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮、4-吡啶酮、嘧啶基、1,4-二氧杂环己二烯基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等，优选为“5-6元杂芳基”。As used herein, the term "5- to 8-membered monocyclic heteroaryl" refers to an aromatic monocyclic cyclic group containing 5 to 8 ring atoms, at least one of which is a heteroatom, e.g. Nitrogen atom, oxygen atom or sulfur atom, including the case where the carbon atom, nitrogen atom and sulfur atom on the ring are substituted by oxygen. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2 ,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, 1,4-dioxanyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, Pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepantrienyl, 1, 3-diazacyclotrienyl, azacyclotetraenyl, etc. are preferably "5- to 6-membered heteroaryl".
如本文中所使用的，术语“8至14元稠杂芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8至10个环原子的、不饱和的具有芳香性的环状结构，其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子，同时包括环上的碳原子、氮原子和硫原子被氧代的情况。实例包括但不限于：苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮、4-喹啉酮、1-异喹啉酮、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基、吩嗪、吩噻嗪等。As used herein, the term "8- to 14-membered fused heteroaryl" refers to a group containing 8 to 10 ring atoms formed by two or more cyclic structures sharing two adjacent atoms with each other. , an unsaturated aromatic cyclic structure, in which at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom, and also includes the case where the carbon atoms, nitrogen atoms and sulfur atoms on the ring are oxo-substituted. Examples include, but are not limited to: benzofuryl, benzisofuryl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl , quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazoline base, quinoxalinyl, phenolazine, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, etc.
如本文中所使用的，术语“被取代”是指基团上的一个或多个氢原子被一个或多个取代基所取代，所述“多个取代基”之间可以相同或不同。例如，“C2烷基被取代”是指C2烷基上的一个或多个氢原子被一个或多个取代基所取代。As used herein, the term "substituted" means that one or more hydrogen atoms on a group are replaced by one or more substituents, which may be the same or different. For example, " C2 alkyl is substituted" means that one or more hydrogen atoms on the C2 alkyl group are replaced by one or more substituents.
如本文中所使用的，术语“药学上可接受的盐”是指，(i)本发明所提供的化合物中存在的酸性官能团(例如-COOH)与适当的无机或者有机阳离子(碱)形成的盐，并且包括但不限于，碱金属盐，如钠盐、钾盐、锂盐等；碱土金属盐，如钙盐、镁盐等；其他金属盐，如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等；无机碱盐，如铵盐；有机碱盐，如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基胺盐、三(羟甲基)氨基甲烷盐。以及，(ii)本发明所提供的化合物中存在的碱性官能团(例如-NH2)与适当的无机或者有机阴离子(酸)形成的盐，并且包括但不限于，氢卤酸盐，如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等；无机酸盐，如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等；低级烷磺酸盐，如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等；芳基磺酸盐，如苯磺酸盐、对苯磺酸盐等；有机酸盐，如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等；氨基酸盐，如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。As used herein, the term "pharmaceutically acceptable salt" refers to (i) the acidic functional group (such as -COOH) present in the compound provided by the invention and the appropriate inorganic or organic cation (base) formed Salts, and include, but are not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, etc. salt, nickel salt, cobalt salt, etc.; inorganic alkali salts, such as ammonium salt; organic alkali salts, such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt , Ethylenediamine salt, N-methylglucosamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroplutide Caine salt, procaine salt, diethanolamine salt, N-benzyl-phenylethylamine salt, piperazine salt, tetramethylamine salt, tris(hydroxymethyl)aminomethane salt. And, (ii) salts formed by the basic functional groups (such as -NH 2 ) present in the compounds provided by the invention and appropriate inorganic or organic anions (acids), and include, but are not limited to, hydrohalides, such as hydrogen Fluorate, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts, such as nitrate, perchlorate, sulfate, phosphate, etc.; lower alkane sulfonate, such as methanesulfonate , triflate, ethanesulfonate, etc.; aryl sulfonates, such as benzenesulfonate, p-benzenesulfonate, etc.; organic acid salts, such as acetate, malate, fumarate , succinate, citrate, tartrate, oxalate, maleate, etc.; amino acid salts, such as glycinate, trimethylglycinate, arginine, ornithine, glutamate, Aspartate, etc.
如本文中所使用的，术语“药学上可接受的酯”是指，本发明所提供的化合物中存在的-COOH与适当的醇(例如甲醇或乙醇)形成的酯，或者本发明所提供的化合物中存在的-OH与适当的酸(例如，羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但 不限于，甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。酯在酸或者碱存在的条件下，可以发生水解反应生成相应的酸或醇。As used herein, the term "pharmaceutically acceptable ester" refers to the ester of -COOH present in the compounds provided by the present invention with an appropriate alcohol (such as methanol or ethanol), or the ester provided by the present invention. The -OH present in the compound forms an ester with a suitable acid (for example, a carboxylic acid or an oxygenated inorganic acid). Suitable ester groups include but Without limitation, formate, acetate, propionate, butyrate, acrylate, ethyl succinate, stearate or palmitate. Esters can undergo hydrolysis reactions in the presence of acids or bases to generate corresponding acids or alcohols.
如本文中所使用的，术语“溶剂合物”是指本发明化合物与溶剂分子缔合形成的物质。所述溶剂可以是有机溶剂(例如甲醇、乙醇、丙醇、乙腈等)，例如本发明化合物可以与乙醇形成乙醇化物。本发明化合物还可以与水形成水合物。As used herein, the term "solvate" refers to a substance formed by the association of a compound of the invention with a solvent molecule. The solvent can be an organic solvent (such as methanol, ethanol, propanol, acetonitrile, etc.). For example, the compound of the present invention can form an ethanolate with ethanol. The compounds of the present invention can also form hydrates with water.
如本文中所使用的，术语“晶型”是指物质的晶体结构。物质在结晶时由于受各种因素影响，使分子内或分子间键合方式发生改变，致使分子或原子在晶格空间排列不同，形成不同的晶体结构。本发明化合物可以一种晶体结构存在，也可以多种晶体结构存在，即具有“多晶型”。本发明化合物可以不同的晶型存在。As used herein, the term "crystalline form" refers to the crystal structure of a substance. During the crystallization of substances, due to the influence of various factors, the bonding methods within or between molecules change, resulting in different arrangements of molecules or atoms in the crystal lattice space, forming different crystal structures. The compound of the present invention can exist in one crystal structure or in multiple crystal structures, that is, it has "polymorphic form". The compounds of the invention may exist in different crystalline forms.
如本文中所使用的，术语“立体异构体”包括构象异构体和构型异构体，其中所述构型异构体主要包括顺反异构体和旋光异构体。本发明化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，及其任何组合或任何混合物。例如单一对映异构体，单一非对映异构体或以上的混合物。当本发明化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein the configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in stereoisomeric forms and thus encompass all possible stereoisomeric forms, any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above. When a compound of the present invention contains an olefinic double bond, it includes both cis and trans isomers, as well as any combination thereof, unless otherwise stated.
如本文中所使用的，术语“前药”是指可在受试者体内通过例如氧化、还原、水解等反应转化成本发明的化合物。前药自身可或不可具有式(I)化合物的生物活性(例如，调节糖脂代谢活性，抗炎活性，抗氧化活性)。例如，包括羟基或羧基的式(I)化合物可以酯的形式给药，其在体内水解转化成羟基化合物或羧基化合物。类似地，包括氨基的式(I)化合物发生酰化、烷基化或磷酸化，以形成例如二十烷酰基氨基(Eicosanoylamino)、丙氨酰氨基、新戊酰氧甲基氨基的化合物给药。关于前体药物使用的进一步信息可以参见Pro-drugs as Novel Delivery Systems，Vol.14，ACS Symposium Series(T Higuchi and W Stella)和Bioreversible Carriers in Drug Design，Pergamon Press，1987(ed.E B Roche，American Pharmaceutical Association)。根据本发明的一些前体药物实例包括：(i)若式(I)化合物含有羧酸官能团(-COOH)，则包括它的酯，例如用(C1-C8)烷基代替氢；(ii)若式(I)化合物含有醇官能团(-OH)，则包括它的醚，例如用(C1-C6)烷酰氧基甲基代替氢；和(iii)若式(I)化合物含有伯或仲氨基官能团(-NH2或-NHR，其中R不为H)，则包括它的酰胺，例如用(C1-C10)烷酰基代替一个或两个氢。此外，某些式(I)化合物本身可以充当其他式(I)化合物的前体药物。As used herein, the term "prodrug" refers to a compound of the present invention that can be converted in a subject through reactions such as oxidation, reduction, hydrolysis, and the like. The prodrug itself may or may not have the biological activity of the compound of formula (I) (eg, regulating glucose and lipid metabolism activity, anti-inflammatory activity, antioxidant activity). For example, compounds of formula (I) containing hydroxyl or carboxyl groups may be administered in the form of esters, which are hydrolytically converted in vivo to hydroxyl or carboxyl compounds. Similarly, compounds of formula (I) including amino groups are acylated, alkylated or phosphorylated to form compounds such as eicosanoylamino, alanylamido, pivaloyloxymethylamino and are administered . Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Some examples of prodrugs according to the present invention include: (i) if the compound of formula (I) contains a carboxylic acid function (-COOH), then its esters are included, for example, a (C 1 -C 8 ) alkyl group is substituted for the hydrogen; ( ii) if the compound of formula (I) contains an alcohol functional group (-OH), its ethers are included, for example, (C 1 -C 6 )alkanoyloxymethyl is used instead of hydrogen; and (iii) if the compound of formula (I) Amides containing primary or secondary amino functional groups (-NH 2 or -NHR, where R is not H) include, for example, a (C 1 -C 10 ) alkanoyl group in place of one or two hydrogens. In addition, certain compounds of formula (I) may themselves serve as prodrugs for other compounds of formula (I).
如本文中所使用的，术语“药学上可接受的载体或赋形剂”是指，在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂，其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995)，并且包括但不限于：崩解剂、粘合剂、表面活性剂、助流剂、润滑剂、pH调节剂、离子强度增强剂、维持渗透压的试剂、延迟吸收的试剂、稀释剂、抗氧化剂、着色剂、矫味剂、防腐剂、味道掩蔽剂等。As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to a carrier and/or excipient that is pharmacologically and/or physiologically compatible with the subject and the active ingredient, which are well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and include, but are not limited to: disintegrants, binders, surfactants, glidants , lubricants, pH adjusters, ionic strength enhancers, reagents to maintain osmotic pressure, reagents to delay absorption, diluents, antioxidants, colorants, flavoring agents, preservatives, taste masking agents, etc.
如本文中使用的，术语“受试者”是指哺乳动物，例如鼠、兔、犬，例如灵长类哺乳动物，例如猴、人。As used herein, the term "subject" refers to a mammal, such as a rat, rabbit, dog, such as a primate mammal, such as a monkey, human.
如本文中使用的，术语“调节剂”是指可以直接或间接与靶标相互作用的分子。所述调节剂包括但不限于激动剂、部分激动剂、反向激动剂和拮抗剂。在本申请的一些实施方案中，调节剂是激动剂。As used herein, the term "modulator" refers to a molecule that can interact directly or indirectly with a target. Such modulators include, but are not limited to, agonists, partial agonists, inverse agonists, and antagonists. In some embodiments of the present application, the modulator is an agonist.
如本文所用的，术语“激动剂”是指与特定受体结合并且触发在细胞中的反应的分子。激动剂可以模仿与相同受体结合的内源性配体(诸如LPA、前列腺素、激素或神经递质)的作用。As used herein, the term "agonist" refers to a molecule that binds to a specific receptor and triggers a response in a cell. Agonists can mimic the effects of endogenous ligands such as LPA, prostaglandins, hormones or neurotransmitters that bind to the same receptor.
如本文所用的，术语“拮抗剂”是指减弱、抑制或阻止另一种分子的作用或受体位点的活性的分子。拮抗剂包括但不限于竞争性拮抗剂、非竞争性拮抗剂、不竞争性拮抗剂、部分激动剂和反向激动剂。As used herein, the term "antagonist" refers to a molecule that attenuates, inhibits, or prevents the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, noncompetitive antagonists, noncompetitive antagonists, partial agonists, and inverse agonists.
具体实施方式 Detailed ways
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。The embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.
除非特别指明，否则基本上按照本领域内熟知的以及在各种参考文献中描述的常规方法进行实施例中描述的实验和方法。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本领域技术人员知晓，实施例以举例方式描述本发明，且不意欲限制本发明所要求保护的范围。本文中提及的全部公开案和其他参考资料以其全文通过引用合并入本文。Unless otherwise indicated, the experiments and methods described in the examples were performed essentially according to conventional methods well known in the art and described in various references. If the specific conditions are not specified in the examples, the conditions should be carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not indicated, they are all conventional products that can be purchased commercially. Those skilled in the art will appreciate that the examples describe the invention by way of example and are not intended to limit the scope of the invention as claimed. All publications and other references mentioned herein are incorporated by reference in their entirety.
化合物的合成和结构表征Synthesis and structural characterization of compounds
实施例1Example 1
步骤1：3-甲基苯并呋喃-2-羧酸乙酯
Step 1: 3-Methylbenzofuran-2-carboxylic acid ethyl ester
将2-羟基苯乙酮(2.72g,20mmol)，溴乙酸乙酯(5.01g,30mmol)，碳酸钾(5.52g,40mmol)，加入N,N-二甲基甲酰胺(25mL)中加热至160℃反应3h，TLC检测反应完毕后，冷却至室温，减压抽滤出固体，滤饼用乙酸乙酯(25mL)冲洗三次，滤液合并后减压蒸馏除去溶剂，加水(100mL)溶解，乙醚(100mL)萃取三次，有机相用饱和氯化钠水溶液洗，加无水硫酸钠干燥，粗品经柱层析分离(PE/EA＝15/1～10/1)得白色固体1.54g，收率38％。Add 2-hydroxyacetophenone (2.72g, 20mmol), ethyl bromoacetate (5.01g, 30mmol), and potassium carbonate (5.52g, 40mmol) to N,N-dimethylformamide (25mL) and heat until React at 160°C for 3 hours. After TLC detection, the reaction is completed, cool to room temperature, filter out the solid under reduced pressure, rinse the filter cake three times with ethyl acetate (25 mL), combine the filtrate, distill the solvent under reduced pressure, add water (100 mL) to dissolve, and add ethyl ether. (100mL) was extracted three times, the organic phase was washed with saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate. The crude product was separated by column chromatography (PE/EA=15/1~10/1) to obtain 1.54g of white solid, yield 38%.
步骤2：3-甲基-5-(氯磺酰基)苯并呋喃-2-羧酸乙酯
Step 2: 3-Methyl-5-(chlorosulfonyl)benzofuran-2-carboxylic acid ethyl ester
将3-甲基苯并呋喃-2-羧酸乙酯(3.06g,15mmol)加入三氯甲烷(45mL)中，0℃下搅拌10mins后，滴加氯磺酸(8.70g,75mmol)的三氯甲烷(45mL)溶液，室温搅拌4h，TLC检测反应完毕后，将反应液倒入冰水中，用二氯甲烷(150mL)萃取三次，合并有机相用饱和氯化钠水溶液洗，加无水硫酸钠干燥，粗品经石油醚/乙酸乙酯重结晶得白色固体2.07g，收率46％。Add 3-methylbenzofuran-2-carboxylic acid ethyl ester (3.06g, 15mmol) into chloroform (45mL), stir at 0°C for 10mins, and add chlorosulfonic acid (8.70g, 75mmol) dropwise. Methyl chloride (45mL) solution, stirred at room temperature for 4 hours. After TLC detection, the reaction solution was poured into ice water, extracted three times with dichloromethane (150mL), the combined organic phases were washed with saturated sodium chloride aqueous solution, and anhydrous sulfuric acid was added. After drying over sodium, the crude product was recrystallized from petroleum ether/ethyl acetate to obtain 2.07g of white solid, with a yield of 46%.
步骤3：3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯
Step 3: 3-Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate ethyl ester
将5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(2.07g,6.86mmol)，碳酸钾(1.89g,13.72mmol)溶于无水二氯甲烷(80mL)中，室温下滴加苯乙胺(0.97g,8.23mmol)的无水二氯甲烷(20mL)溶液，室温搅拌3h，TLC检测反应完毕后，减压蒸馏除去溶剂，加水(100mL)溶解，乙酸乙酯(100mL)萃取三次，有机相用饱和氯化钠水溶液洗，加无水硫酸钠干燥，粗品经柱层析分离(PE/EA＝10/1～5/1)得白色固体2.33g，收率88％。1H NMR(400MHz,CDCl3)δ8.15(d,J＝1.8Hz,1H),7.84(dd,J＝8.8,1.9Hz,1H),7.59(d,J＝8.8Hz,1H),7.25–7.13(m,3H),7.10–6.99(m,2H),4.77(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.24(q,J＝6.9Hz,2H),2.77(t,J＝7.0Hz,2H),2.59(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.9,155.8,143.0,137.6,135.2,129.4,128.7,126.8,126.2,125.6,121.6,113.0,61.6,44.3,35.8,14.4,9.4.HRMS(ESI)[M+H]+理论值C20H22NO5S:388.1219；实测值：388.1213.Dissolve ethyl 5-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylate (2.07g, 6.86mmol) and potassium carbonate (1.89g, 13.72mmol) in anhydrous dichloromethane (80mL) , add phenylethylamine (0.97g, 8.23mmol) in anhydrous dichloromethane (20mL) dropwise at room temperature, stir for 3 hours at room temperature, and after TLC detection of the reaction, remove the solvent by distillation under reduced pressure, add water (100mL) to dissolve, and acetic acid Extract three times with ethyl ester (100mL), wash the organic phase with saturated sodium chloride aqueous solution, and dry with anhydrous sodium sulfate. The crude product is separated by column chromatography (PE/EA=10/1~5/1) to obtain 2.33g of white solid. Yield 88%. 1 H NMR (400MHz, CDCl 3 ) δ8.15 (d, J＝1.8Hz, 1H), 7.84 (dd, J＝8.8, 1.9Hz, 1H), 7.59 (d, J＝8.8Hz, 1H), 7.25 –7.13(m,3H),7.10–6.99(m,2H),4.77(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.24(q,J＝6.9Hz, 2H), 2.77 (t, J = 7.0Hz, 2H), 2.59 (s, 3H), 1.45 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 159.9, 155.8, 143.0, 137.6 ,135.2,129.4,128.7,126.8,126.2,125.6,121.6,113.0,61.6,44.3,35.8,14.4,9.4.HRMS(ESI)[M+H] + theoretical value C 20 H 22 NO 5 S: 388.1219; actual measurement Value: 388.1213.
实施例2 3-甲基-5-(4-苯基丁基氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 2 3-Methyl-5-(4-phenylbutylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用4-苯基丁胺代替苯乙胺，制得标题化合物，得白色固体0.31g，收率75％。1H NMR(400MHz,DMSO-d6)δ8.26–8.20(m,1H),7.96–7.83(m,2H),7.64(t,J＝5.9Hz,1H),7.24–7.16(m,2H),7.15–7.03(m,3H),4.37(q,J＝7.1Hz,2H),2.78(q,J＝6.6Hz,2H),2.57(s,3H),2.44(t,J＝7.5Hz,2H),1.47(tt,J＝8.6,6.6Hz,2H),1.36(td,J＝7.2,4.4Hz,5H).13C NMR(101MHz,DMSO-d6)δ159.2,154.9,142.1,141.9,136.3,128.6,128.1,128.1,126.2,125.6,125.6,121.0,113.0,61.2,42.4,34.6,28.6,27.9,14.1,9.0.HRMS(ESI)[M+H]+理论值C22H26NO5S:416.1526；实测值：416.1526.The preparation method was the same as Example 1, except that 4-phenylbutylamine was used instead of phenylethylamine to prepare the title compound. 0.31g of white solid was obtained with a yield of 75%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.26–8.20(m,1H),7.96–7.83(m,2H),7.64(t,J＝5.9Hz,1H),7.24–7.16(m,2H ),7.15–7.03(m,3H),4.37(q,J＝7.1Hz,2H),2.78(q,J＝6.6Hz,2H),2.57(s,3H),2.44(t,J＝7.5Hz ,2H),1.47(tt,J＝8.6,6.6Hz,2H),1.36(td,J＝7.2,4.4Hz,5H). 13 C NMR (101MHz, DMSO-d 6 )δ159.2,154.9,142.1,141.9 ,136.3,128.6,128.1,128.1,126.2,125.6,125.6,121.0,113.0,61.2,42.4,34.6,28.6,27.9,14.1,9.0.HRMS(ESI)[M+H] + Theoretical value C 22 H 26 NO 5 S: 416.1526; actual measured value: 416.1526.
实施例3 3-甲基-5-(N-(4-苯基丁-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 3 3-Methyl-5-(N-(4-phenylbut-2-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用1-甲基-3-苯基丙胺代替苯乙胺，制得标题化合物。得白色固体0.43g，收率99％。1H NMR(400MHz,CDCl3)δ8.23(d,J＝1.9Hz,1H),7.95(dd,J＝8.8,1.9Hz,1H),7.62(d,J＝8.8Hz,1H),7.21–7.15(m,3H),7.02–6.95(m,2H),5.04(d,J＝8.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.36(dq,J＝8.2,6.5Hz,1H),2.59(s,5H),1.70(dtd,J＝8.7,6.8,1.8Hz,2H),1.45(t,J＝7.1Hz,3H),1.07(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,155.9,143.0,141.1,136.6,129.4,128.4,128.3,126.3,126.0,125.7,121.6,113.1,61.6,49.8,39.0,31.8,21.8,14.4,9.4.HRMS(ESI)[M+H]-理论值C22H24NO5S:414.1375；实测值：414.1380.The preparation method was the same as Example 1, except that 1-methyl-3-phenylpropylamine was used instead of phenylethylamine to prepare the title compound. 0.43g of white solid was obtained, with a yield of 99%. 1 H NMR (400MHz, CDCl 3 ) δ8.23 (d, J = 1.9 Hz, 1H), 7.95 (dd, J = 8.8, 1.9 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.21 –7.15(m,3H),7.02–6.95(m,2H),5.04(d,J＝8.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.36(dq,J＝8.2,6.5 Hz,1H),2.59(s,5H),1.70(dtd,J＝8.7,6.8,1.8Hz,2H),1.45(t,J＝7.1Hz,3H),1.07(d,J＝6.6Hz,3H ). 13 C NMR (101MHz, CDCl 3 ) δ160.0,155.9,143.0,141.1,136.6,129.4,128.4,128.3,126.3,126.0,125.7,121.6,113.1,61.6,49.8,39.0,31.8,21.8 ,14.4,9.4 .HRMS(ESI)[M+H] -Theoretical value C 22 H 24 NO 5 S: 414.1375; measured value: 414.1380.
实施例4 3-甲基-5-(N-(2-环己基乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 4 3-Methyl-5-(N-(2-cyclohexylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用2-环己基乙胺代替苯乙胺，制得标题化合物。得白色固体0.38g，收率97％。1H NMR(400MHz,CDCl3)δ8.23(dd,J＝1.9,0.6Hz,1H),7.93(dd,J＝8.8,1.9Hz,1H),7.64(dd,J＝8.8,0.6Hz,1H),4.69(t,J＝6.1Hz,1H),4.46(q,J＝7.1Hz,2H),2.97(td,J＝7.1,6.1Hz,2H),2.61(s,3H),1.65–1.50(m,5H),1.44(t,J＝7.1Hz,3H),1.33(q,J＝7.1Hz,2H),1.29–1.00(m,4H),0.85–0.72(m,2H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.1,135.4,129.5,126.4,125.7,121.7,113.2,61.7,41.2,37.1,34.9,33.0,26.5,26.2,14.5,9.5.HRMS(ESI)[M+H]-理论值C20H26NO5S:392.1532；实测值：392.1526.The preparation method was the same as Example 1, except that 2-cyclohexylethylamine was used instead of phenylethylamine to prepare the title compound. 0.38g of white solid was obtained, with a yield of 97%. 1 H NMR (400MHz, CDCl 3 ) δ8.23 (dd, J＝1.9, 0.6Hz, 1H), 7.93 (dd, J＝8.8, 1.9Hz, 1H), 7.64 (dd, J＝8.8, 0.6Hz, 1H),4.69(t,J＝6.1Hz,1H),4.46(q,J＝7.1Hz,2H),2.97(td,J＝7.1,6.1Hz,2H),2.61(s,3H),1.65– 1.50(m,5H),1.44(t,J＝7.1Hz,3H),1.33(q,J＝7.1Hz,2H),1.29–1.00(m,4H),0.85–0.72(m,2H). 13 C NMR (101MHz, CDCl 3 ) δ160.0,156.0,143.1,135.4,129.5,126.4,125.7,121.7,113.2,61.7,41.2,37.1,34.9,33.0,26.5,26.2,14.5,9.5.HRMS(ESI)[M +H] -Theoretical value C 20 H 26 NO 5 S: 392.1532; measured value: 392.1526.
实施例5 3-甲基-5-(N-(丁-3-炔-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 5 3-Methyl-5-(N-(but-3-yn-1-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用丁-3-炔-1-胺代替苯乙胺，制得标题化合物。白色固体0.28g，收率85％。1H NMR(400MHz,CDCl3)δ8.23(dd,J＝1.9,0.6Hz,1H),7.94(dd,J＝8.8,1.9Hz,1H),7.64(dd,J＝8.8,0.6Hz,1H),5.05(t,J＝6.4Hz,1H),4.46(q,J＝7.1Hz,2H),3.14(dd,J＝6.4,6.5Hz,2H),2.60(s,3H),2.36(td,J＝6.5,2.6Hz,2H),1.98(t,J＝2.6Hz,1H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.2,135.4,129.6,126.3,125.7,121.7,113.3,80.3,71.1,61.7,41.8,20.0,14.5,9.5.HRMS(ESI)[M+H]-理论值C16H16NO5S:334.0749；实测值：334.0747.The preparation method was the same as Example 1, except that but-3-yn-1-amine was used instead of phenylethylamine to prepare the title compound. 0.28g of white solid, yield 85%. 1 H NMR (400MHz, CDCl 3 ) δ8.23 (dd, J＝1.9, 0.6Hz, 1H), 7.94 (dd, J＝8.8, 1.9Hz, 1H), 7.64 (dd, J＝8.8, 0.6Hz, 1H),5.05(t,J＝6.4Hz,1H),4.46(q,J＝7.1Hz,2H),3.14(dd,J＝6.4,6.5Hz,2H),2.60(s,3H),2.36( td,J＝6.5,2.6Hz,2H),1.98(t,J＝2.6Hz,1H),1.44(t,J＝7.1Hz,3H). 13 C NMR (101MHz, CDCl 3 ) δ160.0,156.0,143.2 ,135.4,129.6,126.3,125.7,121.7,113.3,80.3,71.1,61.7,41.8,20.0,14.5,9.5.HRMS(ESI)[M+H] -Theoretical value C 16 H 16 NO 5 S: 334.0749; actual measurement Value: 334.0747.
实施例6 5-(N-(丁-3-烯-1-基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
Example 6 5-(N-(but-3-en-1-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用3-丁烯-1-胺代替苯乙胺，制得标题化合物。得白色固体140mg，产率83.8％。1H NMR(400MHz,CDCl3)δ8.22(d,J＝2.0Hz,1H),7.92(dd,J＝8.8,2.0Hz,1H),7.65(d,J＝8.8Hz,1H),5.68-5.54(m,1H),5.12-4.98(m,2H),4.66(s,1H),4.47(q,J＝7.2Hz,2H),3.05(q,J＝6.4Hz,2H),2.61(s,3H),2.21(q,J＝6.4Hz,2H),1.45(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.90,155.88,143.02,135.32,134.04,129.40,126.21,125.56,121.60,118.27,113.09,61.58,42.15,33.63,14.34,9.34.The preparation method was the same as Example 1, except that 3-butene-1-amine was used instead of phenylethylamine to prepare the title compound. 140 mg of white solid was obtained, with a yield of 83.8%. 1 H NMR (400MHz, CDCl 3 ) δ8.22(d,J＝2.0Hz,1H),7.92(dd,J＝8.8,2.0Hz,1H),7.65(d,J＝8.8Hz,1H),5.68 -5.54(m,1H),5.12-4.98(m,2H),4.66(s,1H),4.47(q,J＝7.2Hz,2H),3.05(q,J＝6.4Hz,2H),2.61( s, 3H), 2.21 (q, J = 6.4Hz, 2H), 1.45 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 159.90, 155.88, 143.02, 135.32, 134.04, 129.40, 126.21,125.56,121.60,118.27,113.09,61.58,42.15,33.63,14.34,9.34.
实施例7 3-甲基-5-(N-(2-(四氢-2H-吡喃-4-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 7 3-Methyl-5-(N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用4-(2-氨乙基)四氢吡喃代替苯乙胺，制得标题化合物。得白色固体0.35g，收率89％。1H NMR(400MHz,CDCl3)δ8.22(dd,J＝1.9,0.6Hz,1H),7.93(dd,J＝8.8,1.9Hz,1H),7.64(dd,J＝8.8,0.6Hz,1H),4.79(t,J＝6.2Hz,1H),4.47(q,J＝7.2Hz,2H),3.91–3.83(m,2H),3.27(td,J＝11.9,2.2Hz,2H),3.04–2.93(m,2H),2.61(s,3H),1.62–1.37(m,8H),1.33–1.12(m,2H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.2,135.3,129.6,126.3,125.6,121.7,113.2,67.9,61.7,40.6,36.6,32.8,32.2,14.5,9.5.HRMS(ESI)[M+H]-理论值C19H24NO6S:394.1324；实测值：394.1326.The preparation method was the same as Example 1, except that 4-(2-aminoethyl)tetrahydropyran was used instead of phenylethylamine to prepare the title compound. 0.35g of white solid was obtained, with a yield of 89%. 1 H NMR (400MHz, CDCl 3 ) δ8.22 (dd, J＝1.9, 0.6Hz, 1H), 7.93 (dd, J＝8.8, 1.9Hz, 1H), 7.64 (dd, J＝8.8, 0.6Hz, 1H),4.79(t,J＝6.2Hz,1H),4.47(q,J＝7.2Hz,2H),3.91–3.83(m,2H),3.27(td,J＝11.9,2.2Hz,2H), 3.04–2.93(m,2H),2.61(s,3H),1.62–1.37(m,8H),1.33–1.12(m,2H). 13 C NMR(101MHz, CDCl 3 )δ160.0,156.0,143.2,135.3 ,129.6,126.3,125.6,121.7,113.2,67.9,61.7,40.6,36.6,32.8,32.2,14.5,9.5.HRMS(ESI)[M+H] -Theoretical value C 19 H 24 NO 6 S: 394.1324; actual measurement Value: 394.1326.
实施例8 3-甲基-5-(N-(2-(噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 8 3-Methyl-5-(N-(2-(thiophen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用2-噻吩乙胺代替苯乙胺，制得标题化合物。得白色固体0.19g，收率49％。1H NMR(400MHz,CDCl3)δ8.18(d,J＝1.9Hz,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.61(d,J＝8.8Hz,1H),7.10(dd,J＝5.2,1.2Hz,1H),6.87(dd,J＝5.2,3.4Hz,1H),6.73(dd,J＝3.4,1.2Hz,1H),4.83(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H),3.26(q,J＝6.6Hz,2H),2.98(t,J＝6.7Hz,2H),2.60(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.1,139.9,135.3,129.5,127.2,126.3,126.0,125.7,124.5,121.7,113.2,61.7,44.5,30.2,14.5,9.5.HRMS(ESI)[M+H]-理论值C18H18NO5S2:392.0626；实测值：392.0625.The preparation method was the same as Example 1, except that 2-thienethylamine was used instead of phenethylamine to prepare the title compound. 0.19g of white solid was obtained, with a yield of 49%. 1 H NMR (400MHz, CDCl 3 ) δ8.18(d,J＝1.9Hz,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.61(d,J＝8.8Hz,1H),7.10 (dd,J＝5.2,1.2Hz,1H),6.87(dd,J＝5.2,3.4Hz,1H),6.73(dd,J＝3.4,1.2Hz,1H),4.83(t,J＝6.3Hz, 1H),4.47(q,J＝7.1Hz,2H),3.26(q,J＝6.6Hz,2H),2.98(t,J＝6.7Hz,2H),2.60(s,3H),1.45(t, J=7.1Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ160.0,156.0,143.1,139.9,135.3,129.5,127.2,126.3,126.0,125.7,124.5,121.7,113.2,61.7,44.5,30.2, 14.5 ,9.5.HRMS(ESI)[M+H] - Theoretical value C 18 H 18 NO 5 S 2 :392.0626; Actual value: 392.0625.
实施例9 3-甲基-5-(N-(2-(吡啶-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 9 3-Methyl-5-(N-(2-(pyridin-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用3-(2-氨基乙基)吡啶代替苯乙胺，制得标题化合物。得白色固体0.29g，收率76％。1H NMR(400MHz,CDCl3)δ8.37–8.29(m,2H),8.18–8.14(m,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.63–7.56(m,1H),7.43(dt,J＝7.8,2.0Hz,1H),7.13(dd,J＝7.8,4.7Hz,1H),5.61(t,J＝6.2Hz,1H),4.46(q,J＝7.1Hz,2H),3.25(q,J＝6.7Hz,2H),2.80(t,J＝6.9Hz,2H),2.58(s,3H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,150.1,148.1,143.1,136.6,135.5,133.7,129.5,126.2,125.6,123.6,121.6,113.2,61.7,44.0,33.5,14.5,9.5.HRMS(ESI)[M+H]-理论值C19H19N2O5S:387.1015；实测值：387.1017.The preparation method was the same as Example 1, except that 3-(2-aminoethyl)pyridine was used instead of phenylethylamine to prepare the title compound. 0.29g of white solid was obtained, with a yield of 76%. 1 H NMR (400MHz, CDCl 3 ) δ8.37–8.29(m,2H),8.18–8.14(m,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.63–7.56(m,1H ),7.43(dt,J＝7.8,2.0Hz,1H),7.13(dd,J＝7.8,4.7Hz,1H),5.61(t,J＝6.2Hz,1H),4.46(q,J＝7.1Hz ,2H),3.25(q,J＝6.7Hz,2H),2.80(t,J＝6.9Hz,2H),2.58(s,3H),1.44(t,J＝7.1Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ160.0,156.0,150.1,148.1,143.1,136.6,135.5,133.7,129.5,126.2,125.6,123.6,121.6,113.2,61.7,44.0,33.5,14.5,9.5.HRMS (ESI)[M +H] -Theoretical value C 19 H 19 N 2 O 5 S: 387.1015; measured value: 387.1017.
实施例10 3-甲基-5-(N-(2,3-二氢-1H-茚-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 10 3-Methyl-5-(N-(2,3-dihydro-1H-inden-2-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用2-氨基茚代替苯乙胺，制得标题化合物。得白色固体0.36g，收率91％。1H NMR(400MHz,DMSO-d6)δ8.30(d,J＝1.9Hz,1H),8.09(d,J＝6.9Hz,1H),7.99(dd,J＝8.8,1.9Hz,1H),7.92(d,J＝8.8Hz,1H),7.14–7.04(m,4H),4.38(q,J＝7.1Hz,2H),3.93(h,J＝7.0Hz,1H),2.92(dd,J＝15.9,7.0Hz,2H),2.71(dd,J＝15.9,7.0Hz,2H),2.60(s,3H),1.36(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ159.1,155.0,142.1,140.3,136.8,128.6,126.4,126.2,125.6,124.2,121.1,113.1,61.1,53.9,39.2,14.1,9.0.HRMS(ESI)[M+H]-理论值C21H20NO5S:398.1062；实测值：398.1062.The preparation method was the same as Example 1, except that 2-aminoindene was used instead of phenylethylamine to prepare the title compound. 0.36g of white solid was obtained, with a yield of 91%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.30(d,J＝1.9Hz,1H),8.09(d,J＝6.9Hz,1H),7.99(dd,J＝8.8,1.9Hz,1H) ,7.92(d,J＝8.8Hz,1H),7.14–7.04(m,4H),4.38(q,J＝7.1Hz,2H),3.93(h,J＝7.0Hz,1H),2.92(dd, J＝15.9,7.0Hz,2H),2.71(dd,J＝15.9,7.0Hz,2H),2.60(s,3H),1.36(t,J＝7.1Hz,3H). 13 C NMR (101MHz, DMSO -d 6 )δ159.1,155.0,142.1,140.3,136.8,128.6,126.4,126.2,125.6,124.2,121.1,113.1,61.1,53.9,39.2,14.1,9.0.HRMS(ESI)[M+H] -Theoretical value C 21 H 20 NO 5 S: 398.1062; measured value: 398.1062.
实施例11 5-(N-(1-萘乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
Example 11 5-(N-(1-naphthyethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用1-萘乙胺代替苯乙胺，制得标题化合物。得白色固体280mg，收率33％。1H NMR(400MHz,CDCl3)δ8.07(d,J＝1.5Hz,1H),7.82(dd,J＝6.2,3.5Hz,1H),7.78–7.73(m,2H),7.67(d,J＝8.3Hz,1H),7.47(d,J＝8.7Hz,1H),7.40(dd,J＝6.3,3.3Hz,2H),7.32(t,J＝7.6Hz,1H),7.23(d,J＝6.9Hz,1H),4.93(s,1H),4.49(q,J＝7.1Hz,2H),3.40(q,J＝6.7Hz,2H),3.26(t,J＝6.9Hz,2H),2.54(s,3H),1.48(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.9,155.7,142.8,134.93,133.8,133.5,131.4,129.2,128.8,127.6,127.1,126.1,126.0,125.7,125.6,125.4,123.0,121.4,112.9,61.6,43.5,33.1,14.4,9.3.The preparation method was the same as Example 1, except that 1-naphthyl ethylamine was used instead of phenylethylamine to prepare the title compound. 280 mg of white solid was obtained, with a yield of 33%. 1 H NMR (400MHz, CDCl 3 ) δ8.07 (d, J＝1.5Hz, 1H), 7.82 (dd, J＝6.2, 3.5Hz, 1H), 7.78–7.73 (m, 2H), 7.67 (d, J＝8.3Hz,1H),7.47(d,J＝8.7Hz,1H),7.40(dd,J＝6.3,3.3Hz,2H),7.32(t,J＝7.6Hz,1H),7.23(d, J＝6.9Hz,1H),4.93(s,1H),4.49(q,J＝7.1Hz,2H),3.40(q,J＝6.7Hz,2H),3.26(t,J＝6.9Hz,2H) ,2.54(s,3H),1.48(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ159.9,155.7,142.8,134.93,133.8,133.5,131.4,129.2,128.8,127.6,127.1 ,126.1,126.0,125.7,125.6,125.4,123.0,121.4,112.9,61.6,43.5,33.1,14.4,9.3.
实施例12 3-甲基-5-(N-((1R，2S)-2-苯基环丙基)氨磺酰)苯并呋喃-2-羧酸乙酯
Example 12 3-Methyl-5-(N-((1R,2S)-2-phenylcyclopropyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用(1R,2S)-2-苯基-环丙胺代替苯乙胺，制得标题化合物。得白色固体147mg，产率99％。1H NMR(400MHz,CDCl3)δ8.13(d,J＝2.0Hz,1H),7.92(dd,J＝8.8,2.0Hz,1H),7.58(d,J＝8.8Hz,1H),7.23-7.09(m,3H),6.87(d,J＝6.8Hz,2H),5.66(d,J＝2.0Hz,1H),4.45(q,J＝7.2Hz,2H),2.42(s,3H),2.40-2.34(m,1H),2.11-2.02(m,1H),1.43(t,J＝7.2Hz,3H),1.28-1.20(m,1H),1.09(dd,J＝13.6,6.4Hz,1H).13C NMR(101MHz,CDCl3)δ159.94,155.94,142.90,139.73,134.48,129.33,128.39,126.47,126.29,125.95,125.69,122.37,113.06,61.64,34.09,24.28,15.23,14.36,9.18.The preparation method was the same as Example 1, except that (1R,2S)-2-phenyl-cyclopropylamine was used instead of phenylethylamine to prepare the title compound. 147 mg of white solid was obtained, with a yield of 99%. 1 H NMR (400MHz, CDCl 3 ) δ8.13 (d, J = 2.0Hz, 1H), 7.92 (dd, J = 8.8, 2.0Hz, 1H), 7.58 (d, J = 8.8Hz, 1H), 7.23 -7.09(m,3H),6.87(d,J＝6.8Hz,2H),5.66(d,J＝2.0Hz,1H),4.45(q,J＝7.2Hz,2H),2.42(s,3H) ,2.40-2.34(m,1H),2.11-2.02(m,1H),1.43(t,J＝7.2Hz,3H),1.28-1.20(m,1H),1.09(dd,J＝13.6,6.4Hz ,1H). 13 C NMR (101MHz, CDCl 3 ) δ159.94,155.94,142.90,139.73,134.48,129.33,128.39,126.47,126.29,125.95,125.69,122.37,113.06,61.64,3 4.09,24.28,15.23,14.36,9.18 .
实施例13 5-(N-(4-氟代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
Example 13 5-(N-(4-fluorophenethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用4-氟苯乙胺代替苯乙胺，制得标题化合物。得白色固体115mg，收率57％。1H NMR(400MHz,CDCl3)δ8.17(s,1H),7.87(dd,J＝8.8,1.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.10–6.96(m,2H),6.87(t,J＝8.6Hz,2H),5.05(s,1H),4.47(q,J＝7.1Hz,2H),3.21(q,J＝6.7Hz,2H),2.75(t,J＝7.0Hz,2H),2.58(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ161.7(d,J＝245.1Hz),159.9,155.8,143.0,135.2,133.4(d,J＝3.4Hz),130.2(d,J＝7.9Hz),129.4,126.1,125.5,121.5,115.4(d,J＝21.2Hz),113.0,61.6,44.4,35.0,14.3,9.3.The preparation method was the same as Example 1, except that 4-fluorophenylethylamine was used instead of phenylethylamine to prepare the title compound. 115 mg of white solid was obtained, with a yield of 57%. 1 H NMR (400MHz, CDCl 3 ) δ8.17(s,1H),7.87(dd,J＝8.8,1.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.10–6.96(m, 2H),6.87(t,J＝8.6Hz,2H),5.05(s,1H),4.47(q,J＝7.1Hz,2H),3.21(q,J＝6.7Hz,2H),2.75(t, J＝7.0Hz, 2H), 2.58 (s, 3H), 1.45 (t, J＝7.1Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 161.7 (d, J＝245.1Hz), 159.9, 155.8,143.0,135.2,133.4(d,J＝3.4Hz),130.2(d,J＝7.9Hz),129.4,126.1,125.5,121.5,115.4(d,J＝21.2Hz),113.0,61.6,44.4, 35.0,14.3,9.3.
实施例14 5-(N-(4-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
Example 14 5-(N-(4-chlorophenythylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用4-氯苯乙胺代替苯乙胺，制得标题化合物。得白色固体116mg，收率55％。1H NMR(400MHz,CDCl3)δ8.16(s,1H),7.86(d,J＝10.5Hz,1H),7.60(d,J＝8.8Hz,1H),7.14(d,J＝8.3Hz,2H),6.99(d,J＝8.3Hz,2H),5.04(s,1H),4.47(q,J＝7.1Hz,2H),3.22(q,J＝6.4Hz,2H),2.75(t,J＝7.0Hz,2H),2.58(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.9,155.8,143.0,136.2,135.1,132.5,130.0,129.4,128.7,126.1,125.5,121.5,113.0,61.6,44.1,35.2,14.4,9.3.The preparation method was the same as Example 1, except that 4-chlorophenylethylamine was used instead of phenylethylamine to prepare the title compound. 116 mg of white solid was obtained, with a yield of 55%. 1 H NMR (400MHz, CDCl 3 ) δ8.16 (s, 1H), 7.86 (d, J = 10.5Hz, 1H), 7.60 (d, J = 8.8Hz, 1H), 7.14 (d, J = 8.3Hz ,2H),6.99(d,J＝8.3Hz,2H),5.04(s,1H),4.47(q,J＝7.1Hz,2H),3.22(q,J＝6.4Hz,2H),2.75(t , J＝7.0Hz, 2H), 2.58 (s, 3H), 1.46 (t, J＝7.1Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 159.9, 155.8, 143.0, 136.2, 135.1, 132.5, 130.0 ,129.4,128.7,126.1,125.5,121.5,113.0,61.6,44.1,35.2,14.4,9.3.
实施例15 3-甲基-5-(N-(3-溴苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 15 3-Methyl-5-(N-(3-bromophenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用3-溴苯乙胺代替苯乙胺，制得标题化合物。无色油状液体0.21g，收率45％。1H NMR(400MHz,CDCl3)δ8.17(d,J＝1.9Hz,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.61(d,J＝8.8Hz,1H),7.31–7.24(m,1H),7.17(t,J＝1.9Hz,1H),7.07(t,J＝7.7Hz,1H),7.00(dt,J＝7.7,1.4Hz,1H),5.01(t,J＝6.2Hz,1H),4.47(q,J＝7.2Hz,2H),3.24(q,J＝6.8Hz,2H),2.75(t,J＝7.0Hz,2H),2.59(s,3H),1.46(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,155.9,143.1,140.1,135.2,131.8,130.2,129.9,129.5,127.5,126.2,125.6,122.7,121.6,113.2,61.7,44.1,35.5,14.4,9.4.HRMS(ESI)[M-H]-理论值C20H19NO5SBr:464.0167；实测值：464.0168.The preparation method was the same as Example 1, except that 3-bromophenylethylamine was used instead of phenylethylamine to prepare the title compound. 0.21g of colorless oily liquid, yield 45%. 1 H NMR (400MHz, CDCl 3 ) δ8.17(d,J＝1.9Hz,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.61(d,J＝8.8Hz,1H),7.31 –7.24(m,1H),7.17(t,J＝1.9Hz,1H),7.07(t,J＝7.7Hz,1H),7.00(dt,J＝7.7,1.4Hz,1H),5.01(t, J＝6.2Hz,1H),4.47(q,J＝7.2Hz,2H),3.24(q,J＝6.8Hz,2H),2.75(t,J＝7.0Hz,2H),2.59(s,3H) , 1.46 (T, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCL 3 ) Δ160.0, 1155.9,140.1,135.2,130.2,129.9.5, 127.5, 125.6,122.7,121 .6, 113.2,61.7,44.1,35.5,14.4,9.4.HRMS(ESI)[MH] -Theoretical value C 20 H 19 NO 5 SBr: 464.0167; measured value: 464.0168 .
实施例16 3-甲基-5-(N-(3-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 16 3-Methyl-5-(N-(3-(trifluoromethyl)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用3-(三氟甲基)苯乙胺代替苯乙胺，制得标题化合物。得无色油状液体0.18g，收率40％。1H NMR(400MHz,CDCl3)δ8.19(d,J＝1.9Hz,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.60(d,J＝8.8Hz,1H),7.43(d,J＝7.7Hz,1H),7.36–7.25(m,3H),5.05(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H),3.28(q,J＝6.8Hz,2H),2.86(t,J＝7.0Hz,2H),2.59(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.2,138.8,135.2,132.3,131.0(q,J＝32.3Hz),129.5,129.2,126.2,125.6,125.5(q,J＝4.9Hz),123.7(q,J＝3.9Hz),122.7,121.6,113.2,61.7,44.1,35.8,14.4,9.4.19F NMR(376MHz,CDCl3)δ-62.66.HRMS(ESI)[M-H]-理论值C21H19NO5SF3:454.0936；实测值：454.0935.The preparation method was the same as Example 1, except that 3-(trifluoromethyl)phenylethylamine was used instead of phenylethylamine to prepare the title compound. 0.18g of colorless oily liquid was obtained, with a yield of 40%. 1 H NMR (400MHz, CDCl 3 ) δ8.19(d,J＝1.9Hz,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.60(d,J＝8.8Hz,1H),7.43 (d,J＝7.7Hz,1H),7.36–7.25(m,3H),5.05(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H),3.28(q,J＝ 6.8Hz, 2H), 2.86 (t, J = 7.0Hz, 2H), 2.59 (s, 3H), 1.46 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 160.0, 156.0, 143.2,138.8,135.2,132.3,131.0(q,J＝32.3Hz),129.5,129.2,126.2,125.6,125.5(q,J＝4.9Hz),123.7(q,J＝3.9Hz),122.7,121.6, 113.2, 61.7, 44.1, 35.8, 14.4, 9.4. 19 F NMR (376MHz, CDCl 3 ) δ-62.66.HRMS (ESI) [MH] - theoretical value C 21 H 19 NO 5 SF 3 : 454.0936; measured value: 454.0935 .
实施例17 3-甲基-5-(N-(3-甲氧基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 17 3-Methyl-5-(N-(3-methoxyphenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用3-甲氧基苯乙胺代替苯乙胺，制得标题化合物。得白色固体0.30g，收率72％。1H NMR(400MHz,CDCl3)δ8.15(d,J＝1.9Hz,1H),7.84(dd,J＝8.7,1.9Hz,1H),7.60(d,J＝8.7Hz,1H),7.14(t,J＝7.9Hz,1H),6.71(dd,J＝8.5,2.1Hz,1H),6.66–6.60(m,1H),6.56(t,J＝2.1Hz,1H),4.59(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.72(s,3H),3.25(q,J＝6.7Hz,2H),2.73(t,J＝6.8Hz,2H),2.60(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,160.0,156.0,143.1,139.2,135.3,129.9,129.5,126.3,125.7,121.7,121.1,114.7,113.1,112.1,61.7,55.2,44.2,35.8,14.5,9.5.HRMS(ESI)[M-H]-理论值C21H22NO6S:416.1168；实测值：416.1170.The preparation method was the same as Example 1, except that 3-methoxyphenylethylamine was used instead of phenethylamine to prepare the title compound. 0.30g of white solid was obtained, with a yield of 72%. 1 H NMR (400MHz, CDCl 3 ) δ8.15(d,J＝1.9Hz,1H),7.84(dd,J＝8.7,1.9Hz,1H),7.60(d,J＝8.7Hz,1H),7.14 (t,J＝7.9Hz,1H),6.71(dd,J＝8.5,2.1Hz,1H),6.66–6.60(m,1H),6.56(t,J＝2.1Hz,1H),4.59(t, J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.72(s,3H),3.25(q,J＝6.7Hz,2H),2.73(t,J＝6.8Hz,2H) ,2.60(s,3H),1.45(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ160.0,160.0,156.0,143.1,139.2,135.3,129.9,129.5,126.3,125.7,121.7 ,121.1,114.7,113.1,112.1,61.7,55.2,44.2,35.8,14.5,9.5.HRMS(ESI)[MH] -Theoretical value C 21 H 22 NO 6 S: 416.1168; measured value: 416.1170.
实施例18 5-(N-(3-甲基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
Example 18 5-(N-(3-methylphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用3-甲基苯乙胺代替苯乙胺，制得标题化合物。得白色固体277mg，收率35％。1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.89(d,J＝8.6Hz,1H),7.54(d,J＝8.7Hz,1H),7.15–6.77(m,5H),5.45(d,J＝5.6Hz,1H),4.44(q,J＝6.9Hz,2H),3.23(q,J＝6.9Hz,2H),2.73(t,J＝7.3Hz,2H),2.55(s,3H),2.19(s,3H),1.43(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.9,155.7,142.8,138.1,137.8,135.3,129.4,129.3,128.4,127.3,126.3,125.6,125.6,121.5,112.9,61.6,44.5,35.7,21.2,14.3,9.3.The preparation method was the same as Example 1, except that 3-methylphenylethylamine was used instead of phenylethylamine to prepare the title compound. 277 mg of white solid was obtained, with a yield of 35%. 1 H NMR (400MHz, CDCl 3 ) δ8.19(s,1H),7.89(d,J＝8.6Hz,1H),7.54(d,J＝8.7Hz,1H),7.15–6.77(m,5H) ,5.45(d,J＝5.6Hz,1H),4.44(q,J＝6.9Hz,2H),3.23(q,J＝6.9Hz,2H),2.73(t,J＝7.3Hz,2H),2.55 (s, 3H), 2.19 (s, 3H), 1.43 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 159.9, 155.7, 142.8, 138.1, 137.8, 135.3, 129.4, 129.3, 128.4,127.3,126.3,125.6,125.6,121.5,112.9,61.6,44.5,35.7,21.2,14.3,9.3.
实施例19 3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 19 3-Methyl-5-(N-(naphth-1-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用1-萘胺代替苯乙胺，制得标题化合物。得黄色固体67mg，收率16％。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.10–8.01(m,2H),7.91–7.74(m,4H),7.50–7.34(m,3H),7.14(dd,J＝7.4,1.1Hz,1H),4.36(q,J＝7.1Hz,2H),2.47(s,3H),1.34(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ159.0,155.0,142.1,135.7,133.9,132.3,129.5,128.4,127.9,126.8,126.4,126.2,126.0,125.5,125.4,123.4,123.1,121.2,113.0,61.1,14.1,8.9.HRMS(ESI)[M-H]-理论值C22H18NO5S:408.0906；实测值：408.0911.The preparation method was the same as Example 1, except that 1-naphthylamine was used instead of phenylethylamine to prepare the title compound. 67 mg of yellow solid was obtained, with a yield of 16%. 1 H NMR (400MHz, DMSO-d 6 ) δ10.29(s,1H),8.10–8.01(m,2H),7.91–7.74(m,4H),7.50–7.34(m,3H),7.14(dd ,J＝7.4,1.1Hz,1H),4.36(q,J＝7.1Hz,2H),2.47(s,3H),1.34(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO- d 6 )δ159.0,155.0,142.1,135.7,133.9,132.3,129.5,128.4,127.9,126.8,126.4,126.2,126.0,125.5,125.4,123.4,123.1,121.2,113.0,61 .1,14.1,8.9.HRMS(ESI )[MH] -Theoretical value C 22 H 18 NO 5 S: 408.0906; measured value: 408.0911.
实施例20 3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 20 3-Methyl-5-(N-(naphth-2-yl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
制备方法同实施例1，不同之处为用2-萘胺代替苯乙胺，制得标题化合物。得粉色固体0.38g，收率47％。1H NMR(400MHz,CDCl3)δ8.19–8.14(m,1H),7.85(dd,J＝8.8,1.9Hz,1H),7.78–7.65(m,3H),7.60–7.34(m,4H),7.28–7.20(m,1H),4.43(q,J＝7.1Hz,2H),2.47(s,3H),1.66(s,1H),1.42(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.1,143.1,134.4,133.9,133.7,131.4,129.6,129.5,127.8,127.6,126.9,126.4,125.8,125.6,122.0,121.4,119.2,113.1,61.7,14.4,9.3.HRMS(ESI)[M-H]-理论值C22H18NO5S:408.0906；实测值：408.0906.The preparation method was the same as Example 1, except that 2-naphthylamine was used instead of phenylethylamine to prepare the title compound. 0.38g of pink solid was obtained, with a yield of 47%. 1 H NMR (400MHz, CDCl 3 ) δ8.19–8.14(m,1H),7.85(dd,J＝8.8,1.9Hz,1H),7.78–7.65(m,3H),7.60–7.34(m,4H ),7.28–7.20(m,1H),4.43(q,J＝7.1Hz,2H),2.47(s,3H),1.66(s,1H),1.42(t,J＝7.2Hz,3H). 13 C NMR (101MHz, CDCl 3 ) δ160.0,156.1,143.1,134.4,133.9,133.7,131.4,129.6,129.5,127.8,127.6,126.9,126.4,125.8,125.6,122.0,121.4,119.2 ,113.1,61.7,14.4, 9.3.HRMS(ESI)[MH] -Theoretical value C 22 H 18 NO 5 S: 408.0906; measured value: 408.0906.
实施例21 3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
Example 21 3-Methyl-5-(N-(2-([1,1'-diphenyl]-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate
制备方法同实施例1，不同之处为用2-([1,1'-联苯]-3-基)乙烷-1-胺代替苯乙胺，制得标题化合物。得白色固体0.39g，收率43％。1H NMR(400MHz,CDCl3)δ8.15(d,J＝1.9Hz,1H),7.84(dd,J＝8.9,1.9Hz,1H),7.57(d,J＝8.9Hz,1H),7.51–7.37(m,5H),7.36–7.27(m,2H),7.22(t,J＝1.9Hz,1H),7.08–6.98(m,1H),4.61(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.31(q,J＝6.8Hz,2H),2.83(t,J＝6.8Hz,2H),2.55(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.1,141.8,140.7,138.1,135.4,129.5,129.3,128.9,127.7,127.6,127.5,127.1,126.3,125.8,125.7,121.6,113.2,61.7,44.4,35.9,14.5,9.4.HRMS(ESI)[M-H]-理论值C26H26NO5S:464.1532；实测值：464.1525.The preparation method was the same as Example 1, except that 2-([1,1'-biphenyl]-3-yl)ethane-1-amine was used instead of phenylethylamine to prepare the title compound. 0.39g of white solid was obtained, with a yield of 43%. 1 H NMR (400MHz, CDCl 3 ) δ8.15(d,J＝1.9Hz,1H),7.84(dd,J＝8.9,1.9Hz,1H),7.57(d,J＝8.9Hz,1H),7.51 –7.37(m,5H),7.36–7.27(m,2H),7.22(t,J＝1.9Hz,1H),7.08–6.98(m,1H),4.61(t,J＝6.2Hz,1H), 4.47(q,J＝7.1Hz,2H),3.31(q,J＝6.8Hz,2H),2.83(t,J＝6.8Hz,2H),2.55(s,3H),1.45(t,J＝7.1 Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ160.0,156.0,143.1,141.8,140.7,138.1,135.4,129.5,129.3,128.9,127.7,127.6,127.5,127.1,126.3,125.8,1 25.7,121.6, 113.2,61.7,44.4,35.9,14.5,9.4.HRMS(ESI ) [MH] -Theoretical value C 26 H 26 NO 5 S: 464.1532; measured value: 464.1525.
实施例22 5-(N-(2-(苯并呋喃-3-基)乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
Example 22 5-(N-(2-(benzofuran-3-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
制备方法同实施例1，不同之处为用2-(苯并呋喃-3-基)乙烷-1-胺代替苯乙胺，制得标题化合物。The preparation method was the same as Example 1, except that 2-(benzofuran-3-yl)ethane-1-amine was used instead of phenylethylamine to prepare the title compound.
实施例23Example 23
步骤1：2-(4-乙酰氨基-2-乙酰苯氧基)乙酸乙酯
Step 1: Ethyl 2-(4-acetamido-2-acetylphenoxy)acetate
梨形瓶中加入N-(3-乙酰基-4-羟基苯基)乙酰胺(1.01g,5.23mmol),溴乙酸乙酯(1mL,8.98mmol)，碳酸钾(1.33g,9.62mmol)和碘化钾(0.16g,0.97mmol)，加入丙酮(30mL)，60℃回流反应2h，TLC监测反应完全。反应结束后，加入适量水，二氯甲烷萃取3遍，合并有机相，无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(DCM/MeOH＝30:1)，得白色固体1.32g，产率90.4％。Add N-(3-acetyl-4-hydroxyphenyl)acetamide (1.01g, 5.23mmol), ethyl bromoacetate (1mL, 8.98mmol), potassium carbonate (1.33g, 9.62mmol) and Potassium iodide (0.16g, 0.97mmol) was added to acetone (30mL), and the reaction was refluxed at 60°C for 2 hours. TLC monitored the reaction to be complete. After the reaction, add an appropriate amount of water, extract with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (DCM/MeOH=30:1) to obtain 1.32g of white solid, product The rate is 90.4%.
步骤2：5-乙酰氨基-3-甲基苯并呋喃-2-羧酸乙酯
Step 2: 5-acetamido-3-methylbenzofuran-2-carboxylic acid ethyl ester
梨形瓶中加入2-(4-乙酰氨基-2-乙酰苯氧基)乙酸乙酯(1.32g,4.72mmol)，碳酸钾(0.85g,6.15mmol)，加入DMF(41mL)，140℃回流反应1h，TLC监测反应完全。反应结束后，加入少量EA，硅藻土抽滤，滤液加入饱和氯化钠溶液，EA提取3次，合并有机相，饱和氯化钠溶液洗涤2遍，有机相经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(DCM/MeOH＝50:1)，得白色固体0.78g，产率63.6％。Add 2-(4-acetamido-2-acetylphenoxy)ethyl acetate (1.32g, 4.72mmol) and potassium carbonate (0.85g, 6.15mmol) into the pear-shaped bottle, add DMF (41mL), and reflux at 140°C The reaction lasted for 1 hour, and TLC monitored that the reaction was complete. After the reaction, add a small amount of EA, filter through diatomaceous earth, add saturated sodium chloride solution to the filtrate, extract EA three times, combine the organic phases, wash twice with saturated sodium chloride solution, dry the organic phase over anhydrous sodium sulfate, and filter. Concentrate and purify by silica gel column chromatography (DCM/MeOH=50:1) to obtain 0.78g of white solid with a yield of 63.6%.
步骤3：5-氨基-3-甲基苯并呋喃-2-羧酸乙酯
Step 3: 5-Amino-3-methylbenzofuran-2-carboxylic acid ethyl ester
将5-乙酰氨基-3-甲基苯并呋喃-2-羧酸乙酯(0.78g,2.79mmol)溶于乙醇(16mL)，加入3N HCl(16mL)，80℃回流反应2h，TLC检测反应完全。反应结束后，加入饱和碳酸氢钠溶液调节pH 7～8，EA提取3次，合并有机相无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(DCM/MeOH＝30:1)得淡黄色固体0.44g，产率71.2％.Dissolve 5-acetamido-3-methylbenzofuran-2-carboxylic acid ethyl ester (0.78g, 2.79mmol) in ethanol (16mL), add 3N HCl (16mL), reflux at 80°C for 2h, and detect the reaction with TLC completely. After the reaction, add saturated sodium bicarbonate solution to adjust the pH to 7-8, extract with EA three times, combine the organic phases and dry with anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (DCM/MeOH=30:1) to obtain light yellow. Solid 0.44g, yield 71.2%.
步骤4：3-甲基-5-((2-苯乙基)磺胺基)苯并呋喃-2-羧酸乙酯
Step 4: 3-Methyl-5-((2-phenylethyl)sulfonamido)benzofuran-2-carboxylic acid ethyl ester
将5-氨基-3-甲基苯并呋喃-2-羧酸乙酯(0.14g,0.65mmol)溶于无水DMF(2mL)，依次加入吡啶(0.10g,1.26mmol)，2-苯基-乙烷磺酰氯(0.25g,1.22mmol)，室温搅拌过夜。反应结束后，EA提取3次，合并有机相，饱和氯化钠溶液洗涤2遍，有机相经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(DCM/MeOH＝30:1)，得淡黄色油状液体0.10g，产率51.5％。Dissolve 5-amino-3-methylbenzofuran-2-carboxylic acid ethyl ester (0.14g, 0.65mmol) in anhydrous DMF (2mL), then add pyridine (0.10g, 1.26mmol), 2-phenyl -Ethanesulfonyl chloride (0.25g, 1.22mmol), stir at room temperature overnight. After the reaction, EA was extracted three times, the organic phases were combined, washed twice with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (DCM/MeOH=30:1) to obtain 0.10g of light yellow oily liquid, yield 51.5%.
实施例24 3-甲基-5-((苯甲基)磺胺基)苯并呋喃-2-羧酸乙酯
Example 24 3-Methyl-5-((phenylmethyl)sulfonamido)benzofuran-2-carboxylic acid ethyl ester
制备方法同实施例19，不同之处为用苄磺酰氯代替2-苯基-乙烷磺酰氯，制得标题化 合物。得浅粉色固体80mg,产率30.3％。1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.8Hz,1H),7.41(d,J＝2.4Hz,1H),7.35–7.27(m,5H),7.15(dd,J＝8.8,2.4Hz,1H),6.90(s,1H),4.45(q,J＝7.2Hz,2H),4.32(s,2H),2.54(s,3H),1.44(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.32,151.85,142.16,132.40,130.89,129.90,129.01,128.88,128.44,125.46,122.18,113.36,112.99,61.37,57.67,14.40,9.46.The preparation method is the same as in Example 19, except that benzyl sulfonyl chloride is used instead of 2-phenyl-ethanesulfonyl chloride to obtain the title compound compound. 80 mg of light pink solid was obtained, with a yield of 30.3%. 1 H NMR (400MHz, CDCl 3 ) δ7.46 (d, J＝8.8Hz, 1H), 7.41 (d, J＝2.4Hz, 1H), 7.35–7.27 (m, 5H), 7.15 (dd, J＝ 8.8,2.4Hz,1H),6.90(s,1H),4.45(q,J＝7.2Hz,2H),4.32(s,2H),2.54(s,3H),1.44(t,J＝7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ160.32,151.85,142.16,132.40,130.89,129.90,129.01,128.88,128.44,125.46,122.18,113.36,112.99,61.37,57 .67,14.40,9.46.
实施例25 3-甲基-5-(N-苯乙基氨磺酰)苯并呋喃-2-羧酸(GPR132-B-160)
Example 25 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-160)
将3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(0.10g,0.27mmol)溶于乙醇(8mL)中，加入氢氧化钠(0.06g,1.46mmol，溶于2mL水)，加热至回流反应4h。TLC检测反应完毕后，减压蒸馏除去溶剂，加水(50mL)溶解，调节pH 1～2，大量白色固体析出。抽滤，滤饼减压干燥得白色固体0.67g，收率69％。1H NMR(400MHz,DMSO-d6)δ13.48(s,1H),9.91(s,1H),7.63(d,J＝8.8Hz,1H),7.55(d,J＝2.4Hz,1H),7.38(dd,J＝8.8,2.4Hz,1H),7.29–7.22(m,2H),7.21–7.15(m,3H),3.36–3.32(m,2H),3.04–2.97(m,2H),2.49(s,3H).13C NMR(101MHz,DMSO-d6)δ161.40,151.23,142.62,138.58,134.15,129.69,128.97,128.85,127.00,124.77,122.78,113.42,113.13,51.80,29.53,9.59.Dissolve ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate (0.10g, 0.27mmol) in ethanol (8mL), and add sodium hydroxide (0.06g ,1.46mmol, dissolved in 2mL water), heated to reflux for 4h. After the reaction was detected by TLC, the solvent was evaporated under reduced pressure, dissolved in water (50 mL), and the pH was adjusted to 1 to 2. A large amount of white solid precipitated. After suction filtration, the filter cake was dried under reduced pressure to obtain 0.67g of white solid, with a yield of 69%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.48 (s, 1H), 9.91 (s, 1H), 7.63 (d, J = 8.8Hz, 1H), 7.55 (d, J = 2.4Hz, 1H) ,7.38(dd,J＝8.8,2.4Hz,1H),7.29–7.22(m,2H),7.21–7.15(m,3H),3.36–3.32(m,2H),3.04–2.97(m,2H) ,2.49(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ161.40,151.23,142.62,138.58,134.15,129.69,128.97,128.85,127.00,124.77,122.78,113.42,113.1 3,51.80,29.53,9.59 .
实施例26 3-甲基-5-(N-(4-苯基丁基)氨磺酰)苯并呋喃-2-羧酸(GPR132-B-1)
Example 26 3-methyl-5-(N-(4-phenylbutyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-1)
制备方法同实施例25，不同之处为用3-甲基-5-(4-苯基丁基氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体164mg，收率79％。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.20(d,J＝1.7Hz,1H),7.94–7.80(m,2H),7.62(t,J＝5.9Hz,1H),7.20(t,J＝7.4Hz,2H),7.14–7.04(m,3H),2.77(q,J＝6.6Hz,2H),2.56(s,3H),2.45(t,J＝7.5Hz,2H),1.52–1.43(m,2H),1.35(p,J＝6.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,141.9,136.1,128.8,128.1,128.1,125.8,125.6,124.6,120.8,112.9,42.4,34.6,28.6,27.9,9.0.HRMS(ESI)[M-H]-理论值C20H20NO5S:386.1068；实测值：386.1059.The preparation method is the same as Example 25, except that 3-methyl-5-(4-phenylbutylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5-(N -Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 164 mg of white solid was obtained, with a yield of 79%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.72 (s, 1H), 8.20 (d, J = 1.7Hz, 1H), 7.94–7.80 (m, 2H), 7.62 (t, J = 5.9Hz, 1H),7.20(t,J＝7.4Hz,2H),7.14–7.04(m,3H),2.77(q,J＝6.6Hz,2H),2.56(s,3H),2.45(t,J＝7.5 Hz, 2H), 1.52–1.43 (m, 2H), 1.35 (p, J = 6.9Hz, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ 160.7, 154.8, 143.1, 141.9, 136.1, 128.8, 128.1 ,128.1,125.8,125.6,124.6,120.8,112.9,42.4,34.6,28.6,27.9,9.0.HRMS(ESI)[MH] -Theoretical value C 20 H 20 NO 5 S: 386.1068; measured value: 386.1059.
实施例27 3-甲基-5-(N-(4-苯基丁-2-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-2)
Example 27 3-methyl-5-(N-(4-phenylbut-2-yl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-2)
制备方法同实施例25，不同之处为用3-甲基-5-(N-(4-苯基丁-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体165mg，收率79％。1H NMR(400MHz,DMSO-d6)δ13.79(s,1H),8.18(d,J＝2.0Hz,1H),7.94–7.81(m,1H),7.69(d,J＝7.7Hz,1H),7.26–7.04(m,3H),6.97(dd,J＝6.8,1.9Hz,2H),3.20–3.11(m,1H),2.56(s,3H),2.48–2.32(m,2H),1.55(q,J＝7.5Hz,2H),0.93(d,J＝6.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ160.8,154.7,143.5,141.5,137.3,128.8,128.1,128.0,125.8,125.6,124.3,120.6,112.9,48.8,38.3,31.2,21.1,9.0.HRMS(ESI)[M-H]-理论值C20H20NO5S:386.1068；实测值：386.1064.The preparation method is the same as Example 25, except that ethyl 3-methyl-5-(N-(4-phenylbut-2-yl)sulfamoyl)benzofuran-2-carboxylate is used instead of 3- Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, ethyl ester, gave the title compound. 165 mg of white solid was obtained, with a yield of 79%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.79 (s, 1H), 8.18 (d, J = 2.0Hz, 1H), 7.94–7.81 (m, 1H), 7.69 (d, J = 7.7Hz, 1H),7.26–7.04(m,3H),6.97(dd,J＝6.8,1.9Hz,2H),3.20–3.11(m,1H),2.56(s,3H),2.48–2.32(m,2H) ,1.55(q,J＝7.5Hz,2H),0.93(d,J＝6.5Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ160.8,154.7,143.5,141.5,137.3,128.8,128.1, 128.0,125.8,125.6,124.3,120.6,112.9,48.8,38.3,31.2,21.1,9.0.HRMS(ESI)[MH] -Theoretical value C 20 H 20 NO 5 S: 386.1068; measured value: 386.1064.
实施例28 3-甲基-5-(N-(2-环己基乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-3)
Example 28 3-methyl-5-(N-(2-cyclohexylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-3)
制备方法同实施例25，不同之处为用3-甲基-5-(N-(2-环己基乙基)氨磺酰基)苯并呋喃- 2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体168mg，收率85％。1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝1.9Hz,1H),7.92–7.81(m,2H),7.54(t,J＝5.8Hz,1H),2.75(q,J＝6.5Hz,2H),2.57(s,3H),1.59–1.46(m,5H),1.25–0.96(m,6H),0.73(q,J＝10.4,9.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ160.8,154.8,143.6,135.9,128.9,125.8,124.2,120.8,112.8,40.2,36.3,34.0,32.4,26.0,25.6,9.0.HRMS(ESI)[M-H]-理论值C18H22NO5S:364.1219；实测值：364.1216.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-cyclohexylethyl)sulfamoyl)benzofuran- The title compound was obtained by substituting ethyl 2-carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 168 mg of white solid was obtained, with a yield of 85%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.20 (d, J＝1.9Hz, 1H), 7.92–7.81 (m, 2H), 7.54 (t, J＝5.8Hz, 1H), 2.75 (q, 13 C NMR (101MHz, DMSO-d 6 )δ160.8,154.8,143.6,135.9,128.9,125.8,124.2,120.8,112.8,40.2,36.3,34.0,32.4,26.0,25.6,9.0.HRMS(ESI)[MH] -Theoretical value C 18 H 22 NO 5 S: 364.1219; measured value: 364.1216.
实施例29 3-甲基-5-(N-(丁-3-炔-1-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-4)
Example 29 3-methyl-5-(N-(but-3-yn-1-yl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-4)
制备方法同实施例25，不同之处为用3-甲基-5-(N-(丁-3-炔-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体147mg，收率88％。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.23(d,J＝1.8Hz,1H),7.94–7.82(m,3H),2.93–2.84(m,2H),2.81(t,J＝2.6Hz,1H),2.58(s,3H),2.28(td,J＝7.1,2.6Hz,2H).113C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.2,135.8,128.9,125.9,124.7,121.0,113.0,81.5,72.4,41.6,19.3,9.0.HRMS(ESI)[M-H]-理论值C14H12NO5S:306.0436；实测值：306.0435.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(but-3-yn-1-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3- Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, ethyl ester, gave the title compound. 147 mg of white solid was obtained, with a yield of 88%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.71 (s, 1H), 8.23 (d, J = 1.8Hz, 1H), 7.94–7.82 (m, 3H), 2.93–2.84 (m, 2H), 2.81(t,J＝2.6Hz,1H),2.58(s,3H),2.28(td,J＝7.1,2.6Hz,2H). 113 C NMR(101MHz,DMSO-d 6 )δ160.7,154.9,143.2, 135.8,128.9,125.9,124.7,121.0,113.0,81.5,72.4,41.6,19.3,9.0.HRMS(ESI)[MH] -Theoretical value C 14 H 12 NO 5 S: 306.0436; measured value: 306.0435.
实施例30 5-(N-(丁-3-烯-1-基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-5)
Example 30 5-(N-(but-3-en-1-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-5)
制备方法同实施例25，不同之处为用5-(N-(丁-3-烯-1-基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体103mg，产率80.5％。1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝1.6Hz,1H),7.90(dd,J＝8.8,1.6Hz,1H),7.86(d,J＝8.7Hz,1H),7.67(t,J＝6.0Hz,1H),5.76-5.64(m,1H),5.06–4.92(m,2H),2.86-2.76(m,2H),2.57(s,3H),2.16-2.07(m,2H).13C NMR(101MHz,DMSO-d6)δ161.14,155.33,143.59,136.39,135.78,129.29,126.37,125.18,121.14,117.14,113.41,42.58,33.85,9.50.HRMS(ESI)[M-H]-理论值C14H14NO5S:308.0598；实测值：308.0590.The preparation method is the same as Example 25, except that ethyl 5-(N-(but-3-en-1-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylate is used instead of 3- Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, ethyl ester, gave the title compound. 103 mg of white solid was obtained, with a yield of 80.5%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.22(d,J＝1.6Hz,1H),7.90(dd,J＝8.8,1.6Hz,1H),7.86(d,J＝8.7Hz,1H) ,7.67(t,J＝6.0Hz,1H),5.76-5.64(m,1H),5.06–4.92(m,2H),2.86-2.76(m,2H),2.57(s,3H),2.16-2.07 (m,2H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.14,155.33,143.59,136.39,135.78,129.29,126.37,125.18,121.14,117.14,113.41,42.58,33.85,9.50.H RMS(ESI)[ MH] - theoretical value C 14 H 14 NO 5 S: 308.0598; measured value: 308.0590.
实施例31 3-甲基-5-(N-(2-(四氢-2H-吡喃-4-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-6)
Example 31 3-methyl-5-(N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-6 )
制备方法同实施例25，不同之处为用3-甲基-5-(N-(2-(四氢-2H-吡喃-4-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体161mg，收率81％。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.26–8.16(m,1H),7.94–7.83(m,2H),7.58(t,J＝5.9Hz,1H),3.80–3.68(m,2H),3.20–3.09(m,2H),2.78(q,J＝6.7Hz,2H),2.57(s,3H),1.55–1.36(m,3H),1.29(t,J＝6.9Hz,2H),1.09–0.94(m,2H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,136.0,128.8,125.9,124.7,120.9,112.9,66.9,39.7,35.9,32.3,31.4,9.0.HRMS(ESI)[M-H]-理论值C17H20NO6S:366.1011；实测值：366.1015.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)sulfamoyl)benzofuran-2 is used -Ethyl carboxylate was substituted for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate to give the title compound. 161 mg of white solid was obtained, with a yield of 81%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.70 (s, 1H), 8.26–8.16 (m, 1H), 7.94–7.83 (m, 2H), 7.58 (t, J = 5.9Hz, 1H), 3.80–3.68(m,2H),3.20–3.09(m,2H),2.78(q,J＝6.7Hz,2H),2.57(s,3H),1.55–1.36(m,3H),1.29(t, J＝6.9Hz, 2H), 1.09–0.94 (m, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ160.7,154.8,143.1,136.0,128.8,125.9,124.7,120.9,112.9,66.9,39.7, 35.9,32.3,31.4,9.0.HRMS(ESI)[MH] -Theoretical value C 17 H 20 NO 6 S: 366.1011; measured value: 366.1015.
实施例32 3-甲基-5-(N-(2-(噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-7)
Example 32 3-methyl-5-(N-(2-(thiophen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-7)
制备方法同实施例25，不同之处为用3-甲基-5-(N-(2-(噻吩-2-基)乙基)氨磺酰基)苯 并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体146mg，收率99％。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.21(dd,J＝1.8,0.7Hz,1H),7.95–7.79(m,3H),7.29(dd,J＝5.1,1.2Hz,1H),6.90(dd,J＝5.1,3.3Hz,1H),6.84(dq,J＝3.3,1.2Hz,1H),3.03–2.96(m,2H),2.90(t,J＝7.2Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.2,140.7,135.8,128.9,126.9,125.9,125.5,124.8,124.2,121.0,113.0,44.2,29.6,9.1.HRMS(ESI)[M-H]-理论值C16H14NO5S2:364.0313；实测值：364.0318.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-(thiophen-2-yl)ethyl)sulfamoyl)benzene is used The title compound was obtained by substituting ethyl furan-2-carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 146 mg of white solid was obtained, with a yield of 99%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.71 (s, 1H), 8.21 (dd, J = 1.8, 0.7Hz, 1H), 7.95–7.79 (m, 3H), 7.29 (dd, J = 5.1 ,1.2Hz,1H),6.90(dd,J＝5.1,3.3Hz,1H),6.84(dq,J＝3.3,1.2Hz,1H),3.03–2.96(m,2H),2.90(t,J＝ 7.2Hz, 2H), 2.57 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ160.7,154.9,143.2,140.7,135.8,128.9,126.9,125.9,125.5,124.8,124.2,121.0,113.0, 44.2, 29.6, 9.1.HRMS(ESI)[MH] -Theoretical value C 16 H 14 NO 5 S 2 :364.0313; measured value: 364.0318.
实施例33 3-甲基-5-(N-(2-(吡啶-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-8)
Example 33 3-methyl-5-(N-(2-(pyridin-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-8)
制备方法同实施例25，不同之处为用3-甲基-5-(N-(2-(吡啶-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体172mg，收率88％。1H NMR(400MHz,DMSO-d6)δ8.36(s,2H),8.17(d,J＝2.0Hz,1H),7.90–7.79(m,2H),7.75(t,J＝5.9Hz,1H),7.57(dt,J＝7.8,2.0Hz,1H),7.24(dd,J＝7.8,4.7Hz,1H),3.05(q,J＝6.7Hz,2H),2.70(t,J＝7.0Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,149.8,147.3,143.2,136.3,135.7,134.3,128.8,125.8,124.6,123.3,120.9,112.9,43.5,32.2,9.0.HRMS(ESI)[M-H]-理论值C17H15N2O5S:359.0702；实测值：359.0708.The preparation method is the same as Example 25, except that ethyl 3-methyl-5-(N-(2-(pyridin-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate is used instead 3-Methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 172 mg of white solid was obtained, with a yield of 88%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.36 (s, 2H), 8.17 (d, J = 2.0Hz, 1H), 7.90–7.79 (m, 2H), 7.75 (t, J = 5.9Hz, 1H),7.57(dt,J＝7.8,2.0Hz,1H),7.24(dd,J＝7.8,4.7Hz,1H),3.05(q,J＝6.7Hz,2H),2.70(t,J＝7.0 Hz, 2H), 2.57 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ160.7,154.8,149.8,147.3,143.2,136.3,135.7,134.3,128.8,125.8,124.6,123.3,120.9,112.9 ,43.5,32.2,9.0.HRMS(ESI)[MH] -Theoretical value C 17 H 15 N 2 O 5 S: 359.0702; measured value: 359.0708.
实施例34 3-甲基-5-(N-(2,3-二氢-1H-茚-2-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-9)
Example 34 3-methyl-5-(N-(2,3-dihydro-1H-inden-2-yl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-9)
制备方法同实施例25，不同之处为用3-甲基-5-(N-(2,3-二氢-1H-茚-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体127mg，收率79％。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.28(d,J＝1.9Hz,1H),8.07(d,J＝6.8Hz,1H),7.97(dd,J＝8.8,1.9Hz,1H),7.89(d,J＝8.8Hz,1H),7.08(p,J＝4.6Hz,4H),3.99–3.87(m,1H),2.93(dd,J＝15.9,7.0Hz,2H),2.71(dd,J＝15.9,7.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.2,140.4,136.7,128.8,126.5,126.0,124.7,124.2,121.0,113.0,54.0,39.2,9.0.HRMS(ESI)[M-H]-理论值C19H16NO5S:370.0749；实测值：370.0747.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(2,3-dihydro-1H-inden-2-yl)sulfamoyl)benzofuran-2-carboxylic acid is used The title compound was obtained by substituting ethyl ester for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 127 mg of white solid was obtained, with a yield of 79%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.70 (s, 1H), 8.28 (d, J = 1.9Hz, 1H), 8.07 (d, J = 6.8Hz, 1H), 7.97 (dd, J = 8.8,1.9Hz,1H),7.89(d,J＝8.8Hz,1H),7.08(p,J＝4.6Hz,4H),3.99–3.87(m,1H),2.93(dd,J＝15.9,7.0 Hz, 2H), 2.71 (dd, J = 15.9, 7.0Hz, 2H), 2.58 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 160.7, 154.9, 143.2, 140.4, 136.7, 128.8, 126.5 ,126.0,124.7,124.2,121.0,113.0,54.0,39.2,9.0.HRMS(ESI)[MH] -Theoretical value C 19 H 16 NO 5 S: 370.0749; measured value: 370.0747.
实施例35 5-(N-(1-萘乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-10)
Example 35 5-(N-(1-naphthyethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-10)
制备方法同实施例25，不同之处为用5-(N-(1-萘乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体216mg，收率83％。1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.93–7.81(m,4H),7.78(d,J＝8.8Hz,1H),7.72(d,J＝8.0Hz,1H),7.50–7.42(m,2H),7.37(t,J＝7.5Hz,1H),7.32(d,J＝6.6Hz,1H),3.24–3.05(m,4H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.2,143.6,136.1,134.9,133.8,131.7,129.2,129.0,127.4,127.4,126.5,126.2,126.0,125.9,125.0,123.7,121.3,113.3,43.8,33.0,9.5.The preparation method is the same as Example 25, except that ethyl 5-(N-(1-naphthyethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl-5- (N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 216 mg of white solid was obtained, with a yield of 83%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.16 (s, 1H), 7.93–7.81 (m, 4H), 7.78 (d, J = 8.8Hz, 1H), 7.72 (d, J = 8.0Hz, 1H),7.50–7.42(m,2H),7.37(t,J＝7.5Hz,1H),7.32(d,J＝6.6Hz,1H),3.24–3.05(m,4H),2.53(s,3H ). 13 C NMR (101MHz, DMSO-d 6 ) δ161.2,155.2,143.6,136.1,134.9,133.8,131.7,129.2,129.0,127.4,127.4,126.5,126.2,126.0,125.9,125.0,123. 7,121.3,113.3 ,43.8,33.0,9.5.
实施例36 3-甲基-5-(N-((1R，2S)-2-苯基环丙基)氨磺酰)苯并呋喃-2-羧酸(GPR132-B-11)
Example 36 3-methyl-5-(N-((1R,2S)-2-phenylcyclopropyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-11)
制备方法同实施例25，不同之处为用3-甲基-5-(N-((1R，2S)-2-苯基环丙基)氨磺酰)苯 并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体75mg，产率57.7％。1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝4.0Hz,1H),8.04(t,J＝1.2Hz,1H),7.86(d,J＝1.2Hz,2H),7.20-7.07(m,3H),6.84-6.76(m,2H),2.39(s,3H),2.32-2.25(m,1H),1.77-1.70(m,1H),1.14-1.04(m,2H).13C NMR(101MHz,DMSO-d6)δ161.77,155.45,143.73,140.78,135.67,129.27,128.58,126.42,126.19,125.96,124.92,121.95,113.51,34.91,23.78,14.83,9.30.HRMS(ESI)[M-H]-理论值C19H16NO5S:370.0755；实测值：370.0746.The preparation method is the same as Example 25, except that 3-methyl-5-(N-((1R,2S)-2-phenylcyclopropyl)sulfamoyl)benzene is used The title compound was obtained by substituting ethyl furan-2-carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 75 mg of white solid was obtained, with a yield of 57.7%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.16 (d, J = 4.0 Hz, 1H), 8.04 (t, J = 1.2 Hz, 1H), 7.86 (d, J = 1.2 Hz, 2H), 7.20 -7.07(m,3H),6.84-6.76(m,2H),2.39(s,3H),2.32-2.25(m,1H),1.77-1.70(m,1H),1.14-1.04(m,2H) . 13 C NMR (101MHz, DMSO-d 6 ) δ161.77,155.45,143.73,140.78,135.67,129.27,128.58,126.42,126.19,125.96,124.92,121.95,113.51,34.91,23. 78,14.83,9.30.HRMS(ESI) [MH] -Theoretical value C 19 H 16 NO 5 S: 370.0755; measured value: 370.0746.
实施例37 5-(N-(4-氟代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-12)
Example 37 5-(N-(4-fluorophenethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-12)
制备方法同实施例25，不同之处为用5-(N-(4-氟代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得到白色固体115mg，收率99％。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.16(s,1H),7.92–7.78(m,2H),7.73(t,J＝5.8Hz,1H),7.16(dd,J＝8.5,5.7Hz,2H),7.01(t,J＝8.9Hz,2H),3.00(q,J＝7.0Hz,2H),2.66(t,J＝7.1Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.3(d,J＝241.7Hz),161.2,155.3,143.6,136.3,135.3(d,J＝3.0Hz),130.9(d,J＝7.9Hz),129.3,126.3,125.1,121.3,115.3(d,J＝21.0Hz),113.3,44.5,34.7,9.5.The preparation method is the same as Example 25, except that ethyl 5-(N-(4-fluorophenethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 115 mg of white solid was obtained, with a yield of 99%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.70 (s, 1H), 8.16 (s, 1H), 7.92–7.78 (m, 2H), 7.73 (t, J = 5.8Hz, 1H), 7.16 ( dd,J＝8.5,5.7Hz,2H),7.01(t,J＝8.9Hz,2H),3.00(q,J＝7.0Hz,2H),2.66(t,J＝7.1Hz,2H),2.56( s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 161.3 (d, J = 241.7Hz), 161.2, 155.3, 143.6, 136.3, 135.3 (d, J = 3.0Hz), 130.9 (d, J＝7.9Hz),129.3,126.3,125.1,121.3,115.3(d,J＝21.0Hz),113.3,44.5,34.7,9.5.
实施例38 5-(N-(4-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-13)
Example 38 5-(N-(4-chlorophenythylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-13)
制备方法同实施例25，不同之处为用5-(N-(4-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得到白色固体116mg，收率99％。1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),8.15(s,1H),7.89–7.78(m,1H),7.73(t,J＝5.8Hz,1H),7.30–7.09(m,4H),3.01(q,J＝6.9Hz,2H),2.66(t,J＝7.0Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,137.7,135.8,130.8,130.6,128.8,128.0,125.8,124.6,120.8,112.8,43.7,34.4,9.0.The preparation method is the same as Example 25, except that ethyl 5-(N-(4-chlorophenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 116 mg of white solid was obtained, with a yield of 99%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.69 (s, 1H), 8.15 (s, 1H), 7.89–7.78 (m, 1H), 7.73 (t, J = 5.8Hz, 1H), 7.30– 7.09 (m, 4H), 3.01 (q, J = 6.9Hz, 2H), 2.66 (t, J = 7.0Hz, 2H), 2.56 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ160 .7,154.8,143.1,137.7,135.8,130.8,130.6,128.8,128.0,125.8,124.6,120.8,112.8,43.7,34.4,9.0.
实施例39 3-甲基-5-(N-(3-溴苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-14)
Example 39 3-methyl-5-(N-(3-bromophenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-14)
制备方法同实施例25，不同之处为用3-甲基-5-(N-(3-溴苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体148mg，收率99％。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.16(d,J＝1.7Hz,1H),7.89–7.79(m,2H),7.73(t,J＝5.8Hz,1H),7.32(tq,J＝3.7,1.7Hz,2H),7.20–7.11(m,2H),3.02(q,J＝6.7Hz,2H),2.67(t,J＝7.0Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ160.8,154.9,143.3,141.7,135.8,131.5,130.3,129.1,128.9,127.9,125.9,124.6,121.5,120.9,112.9,43.6,34.6,9.1.HRMS(ESI)[M-H]-理论值C18H15NO5SBr:435.9854；实测值：435.9857.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(3-bromopheneethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 148 mg of white solid was obtained, with a yield of 99%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.72 (s, 1H), 8.16 (d, J = 1.7Hz, 1H), 7.89–7.79 (m, 2H), 7.73 (t, J = 5.8Hz, 1H),7.32(tq,J＝3.7,1.7Hz,2H),7.20–7.11(m,2H),3.02(q,J＝6.7Hz,2H),2.67(t,J＝7.0Hz,2H), 2.57 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ160.8,154.9,143.3,141.7,135.8,131.5,130.3,129.1,128.9,127.9,125.9,124.6,121.5,120.9,112.9, 43.6, 34.6,9.1.HRMS(ESI)[MH] -Theoretical value C 18 H 15 NO 5 SBr: 435.9854; measured value: 435.9857.
实施例40 3-甲基-5-(N-(3-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-15)
Example 40 3-methyl-5-(N-(3-(trifluoromethyl)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-15)
制备方法同实施例25，不同之处为用3-甲基-5-(N-(3-溴苯乙基)氨磺酰基)苯并呋喃-2- 羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.16(d,J＝1.8Hz,1H),7.88–7.72(m,3H),7.52–7.43(m,4H),3.07(q,J＝6.6Hz,2H),2.78(t,J＝6.9Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,140.2,135.8,133.0,129.1(d,J＝5.5Hz),128.8(d,J＝5.8Hz),125.8,125.6,125.3(d,J＝4.0Hz),124.6,122.9(d,J＝3.9Hz),120.9,112.9,43.5,34.7,9.0.19F NMR(376MHz,DMSO-d6)δ-61.06.HRMS(ESI)[M-H]-理论值C19H15NO5SF3:426.0623；实测值：426.0622.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(3-bromophenylethyl)sulfamoyl)benzofuran-2- The title compound was obtained by substituting ethyl carboxylate for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, DMSO-d 6 ) δ13.70 (s, 1H), 8.16 (d, J = 1.8Hz, 1H), 7.88–7.72 (m, 3H), 7.52–7.43 (m, 4H), 3.07 (q, J＝6.6Hz, 2H), 2.78 (t, J＝6.9Hz, 2H), 2.56 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ160.7, 154.8, 143.1, 140.2, 135.8,133.0,129.1(d,J＝5.5Hz),128.8(d,J＝5.8Hz),125.8,125.6,125.3(d,J＝4.0Hz),124.6,122.9(d,J＝3.9Hz), 120.9, 112.9, 43.5, 34.7, 9.0. 19 F NMR (376MHz, DMSO-d 6 ) δ-61.06.HRMS (ESI) [MH] - Theoretical value C 19 H 15 NO 5 SF 3 : 426.0623; measured value: 426.0622 .
实施例41 3-甲基-5-(N-(3-甲氧基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-16)
Example 41 3-methyl-5-(N-(3-methoxyphenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-16)
制备方法同实施例25，不同之处为用3-甲基-5-(N-(3-甲氧基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体188mg，收率89％。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.18(d,J＝1.7Hz,1H),7.91–7.79(m,2H),7.72(t,J＝5.8Hz,1H),7.12(t,J＝7.7Hz,1H),6.73–6.66(m,3H),3.68(s,3H),3.05–2.95(m,2H),2.64(t,J＝7.3Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,159.2,154.8,143.2,140.2,135.8,129.2,128.8,125.8,124.6,120.9,114.3,112.9,111.6,54.8,43.9,35.2,9.0.HRMS(ESI)[M-H]-理论值C19H18NO6S:388.0855；实测值：388.0862.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(3-methoxyphenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl Ethyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate was used to prepare the title compound. 188 mg of white solid was obtained, with a yield of 89%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.72 (s, 1H), 8.18 (d, J = 1.7Hz, 1H), 7.91–7.79 (m, 2H), 7.72 (t, J = 5.8Hz, 1H),7.12(t,J＝7.7Hz,1H),6.73–6.66(m,3H),3.68(s,3H),3.05–2.95(m,2H),2.64(t,J＝7.3Hz,2H ), 2.56 (s, 3H). 13 C NMR (101MHz, DMSO-D 6 ) Δ160.7,159.2,143.2,140.2,135.8,129.2,125.8,124.6,114.3,111.6,54. 8, 43.9,35.2,9.0.HRMS(ESI)[MH] -Theoretical value C 19 H 18 NO 6 S: 388.0855; measured value: 388.0862.
实施例42 5-(N-(3-甲基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧(GPR132-B-17)
Example 42 5-(N-(3-methylphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxy (GPR132-B-17)
制备方法同实施例25，不同之处为用5-(N-(3-甲基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体249mg，收率97％。1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.85(q,J＝8.8Hz,2H),7.74(t,J＝5.7Hz,1H),7.10(t,J＝7.4Hz,1H),6.97–6.87(m,3H),2.98(q,J＝7.0Hz,2H),2.62(t,J＝7.4Hz,2H),2.57(s,3H),2.20(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,143.8,139.0,137.7,136.3,129.7,129.3,128.6,127.3,126.3,126.1,124.9,121.3,113.3,44.5,35.6,21.4,9.5.The preparation method is the same as Example 25, except that ethyl 5-(N-(3-methylphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylate is used instead of 3-methyl- 5-(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 249 mg of white solid was obtained, with a yield of 97%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.18 (s, 1H), 7.85 (q, J = 8.8Hz, 2H), 7.74 (t, J = 5.7Hz, 1H), 7.10 (t, J = 7.4Hz,1H),6.97–6.87(m,3H),2.98(q,J＝7.0Hz,2H),2.62(t,J＝7.4Hz,2H),2.57(s,3H),2.20(s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.2,155.3,143.8,139.0,137.7,136.3,129.7,129.3,128.6,127.3,126.3,126.1,124.9,121.3,113.3,44.5,35 .6,21.4, 9.5.
实施例43 3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸
Example 43 3-methyl-5-(N-(naphth-1-yl)sulfamoyl)benzofuran-2-carboxylic acid
制备方法同实施例25，不同之处为用3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体102mg，收率92％。1H NMR(400MHz,DMSO-d6)δ13.68(s,1H),10.27(s,1H),8.08–7.99(m,2H),7.90–7.71(m,4H),7.50–7.33(m,3H),7.13(dd,J＝7.5,1.1Hz,1H),2.46(s,3H).13C NMR(101MHz,DMSO-d6)δ160.6,155.0,143.2,135.5,133.9,132.3,129.5,128.7,127.9,126.8,126.2,126.1,126.0,125.5,124.5,123.3,123.1,121.1,112.9,8.9.HRMS(ESI)[M-H]-理论值C20H14NO5S:380.0593；实测值：380.0600.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(naphthalen-1-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5 -(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester to give the title compound. 102 mg of white solid was obtained, with a yield of 92%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.68(s,1H),10.27(s,1H),8.08–7.99(m,2H),7.90–7.71(m,4H),7.50–7.33(m ,3H),7.13(dd,J＝7.5,1.1Hz,1H),2.46(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ160.6,155.0,143.2,135.5,133.9,132.3,129.5, 128.7,127.9,126.8,126.2,126.1,126.0,125.5,124.5,123.3,123.1,121.1,112.9,8.9.HRMS(ESI)[MH] - Theoretical value C 20 H 14 NO 5 S: 380.0593; Actual value: 380.060 0 .
实施例44 3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸
Example 44 3-methyl-5-(N-(naphthalen-2-yl)sulfamoyl)benzofuran-2-carboxylic acid
制备方法同实施例25，不同之处为用3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体181mg，收率87％。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),10.57(s,1H),8.29(d,J＝1.9Hz,1H),7.90(dd,J＝8.8,1.9Hz,1H),7.83–7.71(m,4H),7.62(d,J＝2.2Hz,1H),7.46–7.29(m,3H),2.50(s,3H).13C NMR(101MHz,DMSO-d6)δ160.6,155.0,143.4,135.3,134.8,133.2,130.0,129.1,128.8,127.4,127.2,126.6,125.8,125.0,124.4,121.4,120.4,116.1,113.0,8.9.HRMS(ESI)[M-H]-理论值C20H14NO5S:380.0593；实测值：380.0594.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(naphthalen-2-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5 -(N-Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester to give the title compound. 181 mg of white solid was obtained, with a yield of 87%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.72 (s, 1H), 10.57 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 7.90 (dd, J = 8.8, 1.9 Hz, 1H),7.83–7.71(m,4H),7.62(d,J＝2.2Hz,1H),7.46–7.29(m,3H),2.50(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ160.6,155.0,143.4,135.3,134.8,133.2,130.0,129.1,128.8,127.4,127.2,126.6,125.8,125.0,124.4,121.4,120.4,116.1,113.0,8.9.HRMS (ESI)[MH] - Theory Value C 20 H 14 NO 5 S: 380.0593; measured value: 380.0594.
实施例45 3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸
Example 45 3-methyl-5-(N-(2-([1,1'-diphenyl]-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid
制备方法同实施例25，不同之处为用3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得粉色固体216mg，收率91％。1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝1.9Hz,1H),7.88–7.71(m,3H),7.62–7.56(m,2H),7.46–7.40(m,4H),7.32(dt,J＝10.4,7.5Hz,2H),7.13(d,J＝7.5Hz,1H),3.07(q,J＝6.8Hz,2H),2.75(t,J＝6.8Hz,2H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ161.6,154.5,140.2,139.4,135.4,129.4,128.8,127.8,127.3,127.1,126.7,124.9,124.6,120.4,112.5,44.0,35.2,9.0.HRMS(ESI)[M-H]-理论值C24H22NO5S:436.1219；实测值：436.1211.The preparation method is the same as Example 25, except that 3-methyl-5-(N-(2-([1,1'-diphenyl]-3-yl)ethyl)sulfamoyl)benzo Furan-2-carboxylic acid ethyl ester was substituted for 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester to give the title compound. 216 mg of pink solid was obtained, with a yield of 91%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.13 (d, J = 1.9 Hz, 1H), 7.88–7.71 (m, 3H), 7.62–7.56 (m, 2H), 7.46–7.40 (m, 4H) ),7.32(dt,J＝10.4,7.5Hz,2H),7.13(d,J＝7.5Hz,1H),3.07(q,J＝6.8Hz,2H),2.75(t,J＝6.8Hz,2H ), 2.53 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.6,154.5,140.2,139.4,135.4,129.4,128.8,127.8,127.3,127.1,126.7,124.9,124.6,120.4,112.5 , 44.0,35.2,9.0.HRMS(ESI)[MH] -Theoretical value C 24 H 22 NO 5 S: 436.1219; measured value: 436.1211.
实施例46 5-(N-(2-(苯并呋喃-3-基)乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-21)
Example 46 5-(N-(2-(benzofuran-3-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-21)
制备方法同实施例25，不同之处为用5-(N-(2-(苯并呋喃-3-基)乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。The preparation method is the same as Example 25, except that ethyl 5-(N-(2-(benzofuran-3-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate is used. The title compound was obtained by substituting the ester for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
实施例47 3-甲基-5-((2-苯乙基)磺胺基)苯并呋喃-2-羧酸(GPR132-B-161)
Example 47 3-methyl-5-((2-phenylethyl)sulfonamido)benzofuran-2-carboxylic acid (GPR132-B-161)
制备方法同实施例25，不同之处为用3-甲基-5-((2-苯乙基)磺胺基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得浅黄色固体68mg，产率69％。1H NMR(400MHz,DMSO-d6)δ13.48(s,1H),9.91(s,1H),7.63(d,J＝8.8Hz,1H),7.55(d,J＝2.4Hz,1H),7.38(dd,J＝8.8,2.4Hz,1H),7.29–7.22(m,2H),7.21-7.16(m,3H),3.37-3.31(m,2H),3.04–2.97(m,2H),2.49(s,3H).13C NMR(101MHz,DMSO-d6)δ161.40,151.23,142.62,138.58,134.15,129.69,128.97,128.84,126.99,124.77,122.78,113.42,113.13,51.80,29.53,9.59.HRMS(ESI)[M-H]-理论值C18H16NO5S:358.0755；实测值：358.0743.The preparation method is the same as Example 25, except that 3-methyl-5-((2-phenylethyl)sulfonamide)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5-(N -Phenethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester gave the title compound. 68 mg of light yellow solid was obtained, with a yield of 69%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.48 (s, 1H), 9.91 (s, 1H), 7.63 (d, J = 8.8Hz, 1H), 7.55 (d, J = 2.4Hz, 1H) ,7.38(dd,J＝8.8,2.4Hz,1H),7.29–7.22(m,2H),7.21-7.16(m,3H),3.37-3.31(m,2H),3.04–2.97(m,2H) ,2.49(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ161.40,151.23,142.62,138.58,134.15,129.69,128.97,128.84,126.99,124.77,122.78,113.42,113.1 3,51.80,29.53,9.59 .HRMS(ESI)[MH] -Theoretical value C 18 H 16 NO 5 S: 358.0755; measured value: 358.0743.
实施例48 3-甲基-5-((苯甲基)磺胺基)苯并呋喃-2-羧酸(GPR132-B-22)
Example 48 3-methyl-5-((phenylmethyl)sulfonamido)benzofuran-2-carboxylic acid (GPR132-B-22)
制备方法同实施例25，不同之处为用3-甲基-5-((苯甲基)磺胺基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，制得标题化合物。得白色固体73mg,产率99％。1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.60(d,J＝8.8Hz,1H),7.45(d,J＝2.4Hz,1H),7.38–7.27(m,6H),4.48(s,2H),2.49(s,3H).13C NMR(101MHz,CDCl3)δ 161.45,150.89,142.54,134.46,131.45,130.01,129.59,128.82,128.66,124.79,122.11,112.95,112.23,57.43,9.59.HRMS(ESI)[M-H]-理论值C17H14NO5S:344.0598；实测值：344.0596.The preparation method is the same as Example 25, except that 3-methyl-5-((phenylmethyl)sulfonamide)benzofuran-2-carboxylic acid ethyl ester is used instead of 3-methyl-5-(N-phenyl). Ethyl ethylsulfamoyl)benzofuran-2-carboxylate gave the title compound. 73 mg of white solid was obtained, with a yield of 99%. 1 H NMR (400MHz, DMSO-d 6 ) δ9.88 (s, 1H), 7.60 (d, J = 8.8Hz, 1H), 7.45 (d, J = 2.4Hz, 1H), 7.38–7.27 (m, 6H), 4.48 (s, 2H), 2.49 (s, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 161.45,150.89,142.54,134.46,131.45,130.01,129.59,128.82,128.66,124.79,122.11,112.95,112.23,57.43,9.59.HRMS ( ESI)[MH] -Theoretical value C 17 H 1 4 NO 5 S:344.0598; Actual measured value: 344.0596.
实施例49Example 49
3-甲基-6-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-52)
3-Methyl-6-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-52)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-6-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体38mg，收率74％。1H NMR(400MHz,DMSO-d6)δ7.98(d,J＝1.5Hz,1H),7.91(d,J＝8.3Hz,1H),7.82(t,J＝5.8Hz,1H),7.71(dd,J＝8.3,1.5Hz,1H),7.25–7.18(m,2H),7.19–7.10(m,3H),3.03–2.93(m,2H),2.67(t,J＝7.5Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO-d6)δ152.1,138.6,132.5,130.8,128.7,128.6,128.3,128.3,126.2,122.0,121.0,110.5,44.1,35.2,9.1.HRMS(ESI)[M-H]-calcd for C18H17NO5S:358.0749；found:358.0744.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-6-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, and the other conditions were the same. 38 mg of white solid was obtained, with a yield of 74%. 1 H NMR (400MHz, DMSO-d 6 ) δ7.98 (d, J = 1.5 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.82 (t, J = 5.8 Hz, 1H), 7.71 (dd,J＝8.3,1.5Hz,1H),7.25–7.18(m,2H),7.19–7.10(m,3H),3.03–2.93(m,2H),2.67(t,J＝7.5Hz,2H ), 2.54 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ152.1,138.6,132.5,130.8,128.7,128.6,128.3,128.3,126.2,122.0,121.0,110.5,44.1,35.2,9.1. HRMS(ESI)[MH] - calcd for C 18 H 17 NO 5 S:358.0749; found:358.0744.
实施例50Example 50
3-甲基-5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸(GPR132-B-53)
3-Methyl-5-(N-phenylethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid (GPR132-B-53)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.1Hz,1H),8.15(d,J＝8.4Hz,1H),7.98(dd,J＝8.5,2.3Hz,1H),7.30–7.19(m,5H),7.15(t,J＝6.6Hz,1H),3.17(dt,J＝6.6,5.8Hz,2H),2.81(tt,J＝5.8,0.9Hz,2H),2.66(s,3H).13C NMR(101MHz,DMSO-d6)δ167.6,145.0,141.7,137.2,137.2,135.2,128.9,128.9,127.2,126.7,126.6,123.9,121.9,44.9,35.7,13.3.HRMS(ESI)[M-H]-calcd for C18H17NO4S2:374.0526；found:374.0526.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.39(d,J＝2.1Hz,1H),8.15(d,J＝8.4Hz,1H),7.98(dd,J＝8.5,2.3Hz,1H) ,7.30–7.19(m,5H),7.15(t,J＝6.6Hz,1H),3.17(dt,J＝6.6,5.8Hz,2H),2.81(tt,J＝5.8,0.9Hz,2H), 2.66 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ167.6,145.0,141.7,137.2,137.2,135.2,128.9,128.9,127.2,126.7,126.6,123.9,121.9,44.9,35.7,13 .3. HRMS(ESI)[MH] - calcd for C 18 H 17 NO 4 S 2 :374.0526; found:374.0526.
实施例51Example 51
5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸(GPR132-B-54)
5-(N-Phenethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid (GPR132-B-54)
将5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯(0.18g,0.46mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体146mg，产率87.4％。Dissolve ethyl 5-(N-phenylethylsulfamoyl)benzo[b]thiophene-2-carboxylate (0.18g, 0.46mmol) in ethanol (8mL), and add lithium hydroxide (0.02g, 0.83mmol) , dissolved in 2mL water), stirred at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 146 mg of white solid, with a yield of 87.4%.
1H NMR(400MHz,DMSO-d6)δ13.76(s,1H),8.48(d,J＝1.8Hz,1H),8.30(s,1H),8.25(d,J＝8.6Hz,1H),7.89–7.79(m,2H),7.29–7.07(m,5H),3.05–2.95(m,2H),2.68(t,J＝7.5Hz,2H).13C NMR(101MHz,DMSO)δ163.6,144.9,139.1,138.8,137.9,137.6,131.1,129.1,128.7,126.6,125.0,124.6,124.4,44.6,35.7.HRMS(ESI)[M-H]-calcd for C17H15NO4S2:360.0370；found:360.0370. 1 H NMR (400MHz, DMSO-d 6 ) δ13.76 (s, 1H), 8.48 (d, J = 1.8Hz, 1H), 8.30 (s, 1H), 8.25 (d, J = 8.6Hz, 1H) ,7.89–7.79(m,2H),7.29–7.07(m,5H),3.05–2.95(m,2H),2.68(t,J＝7.5Hz,2H). 13 C NMR(101MHz,DMSO)δ163. 6,144.9,139.1,138.8,137.9,137.6,131.1,129.1,128.7,126.6,125.0,124.6,124.4,44.6,35.7.HRMS(ESI)[MH] - calcd for C 17 H 15 NO 4 S 2 :360.0370 ;found :360.0370.
实施例52Example 52
6-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸(GPR132-B-55)
6-(N-Phenethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid (GPR132-B-55)
将6-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯(0.12g,0.31mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体105mg，产率94.6％。Dissolve ethyl 6-(N-phenethylsulfamoyl)benzo[b]thiophene-2-carboxylate (0.12g, 0.31mmol) in ethanol (8mL), and add lithium hydroxide (0.02g, 0.83mmol) , dissolved in 2mL water), stirred at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 105 mg of white solid, with a yield of 94.6%.
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.20(s,1H),8.17(d,J＝8.4Hz,1H),7.84(t,J＝6.0Hz,1H),7.80(dd,J＝8.4,1.6Hz,1H),7.27-7.18(m,2H),7.18-7.09(m,3H),3.02(q,J＝6.8Hz,2H),2.68(t,J＝7.2Hz,2H).13C NMR(101MHz,DMSO-d6)δ163.59,141.63,141.47,139.34,139.08,138.99,129.99,129.11,128.72,126.98,126.67,123.03,122.68,44.55,35.75.HRMS(ESI)[M-H]-calcd for C17H14NO4S2:360.0370；found:360.0364. 1 H NMR (400MHz, DMSO-d 6 ) δ8.54 (s, 1H), 8.20 (s, 1H), 8.17 (d, J = 8.4Hz, 1H), 7.84 (t, J = 6.0Hz, 1H) ,7.80(dd,J＝8.4,1.6Hz,1H),7.27-7.18(m,2H),7.18-7.09(m,3H),3.02(q,J＝6.8Hz,2H),2.68(t,J =7.2Hz, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ163.59,141.63,141.47,139.34,139.08,138.99,129.99,129.11,128.72,126.98,126.67,123.03,122.68, 44.55,35.75.HRMS( ESI)[MH] - calcd for C 17 H 14 NO 4 S 2 :360.0370; found:360.0364.
实施例53Example 53
3-氯-5-(N-苯乙基氨基磺酰基)-1H-吲哚-2-羧酸(GPR132-B-56)
3-Chloro-5-(N-phenylethylaminosulfonyl)-1H-indole-2-carboxylic acid (GPR132-B-56)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.06(s,1H),7.73(dd,J＝8.8,2.0Hz,1H),7.69–7.60(m,2H),7.25–7.08(m,5H),2.95(q,J＝7.2Hz,2H),2.66(t,J＝7.2Hz,2H).13C NMR(101MHz,DMSO-d6)δ161.56,139.18,136.55,133.38,129.08,128.72,126.63,126.12,124.83,123.75,119.31,114.42,110.62,44.57,35.66.HRMS(ESI)[M-H]-calcd for C17H15ClN2O4S:377.0368；found:377.0368.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ12.52 (s, 1H), 8.06 (s, 1H), 7.73 (dd, J = 8.8, 2.0Hz, 1H), 7.69–7.60 (m, 2H), 7.25–7.08(m,5H),2.95(q,J＝7.2Hz,2H),2.66(t,J＝7.2Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ161.56,139.18,136.55, 133.38,129.08,128.72,126.63,126.12,124.83,123.75,119.31,114.42,110.62,44.57,35.66.HRMS(ESI)[MH] - calcd for C 17 H 15 ClN 2 O 4 S:377.0368 ;found:377.0368.
实施例54Example 54
2-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-3-羧酸(GPR132-B-57)
2-Methyl-5-(N-phenylethylsulfamoyl)benzofuran-3-carboxylic acid (GPR132-B-57)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.15(d,J＝2.2Hz,1H),7.97(dd,J＝9.1,2.3Hz,1H),7.65(d,J＝9.0Hz,1H),7.30–7.19(m,5H),7.14(t,J＝6.6Hz,1H),3.17(dt,J＝6.6,5.8Hz,2H),2.81(tt,J＝5.8,0.9Hz,2H),2.67(s,3H).13C NMR(101MHz,DMSO-d6)δ167.5,162.8,156.9,137.2,135.5,128.9,128.9,128.6,127.5,126.7,120.8,111.7,110.3,44.9,35.7,14.7.HRMS(ESI)[M-H]-calcd for C18H17NO5S:358.0755；found:358.0755.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.15 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 9.1, 2.3 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H) ,7.30–7.19(m,5H),7.14(t,J＝6.6Hz,1H),3.17(dt,J＝6.6,5.8Hz,2H),2.81(tt,J＝5.8,0.9Hz,2H), 2.67(s,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ167.5,162.8,156.9,137.2,135.5,128.9,128.9,128.6,127.5,126.7,120.8,111.7,110.3,44.9,35.7,14 .7. HRMS(ESI)[MH] - calcd for C 18 H 17 NO 5 S:358.0755; found:358.0755.
实施例55Example 55
3-甲基-5-(N-(2-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-58)
3-Methyl-5-(N-(2-fluorophenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-58)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(2-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体189mg，收率93％。.1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.19(d,J＝1.7Hz,1H),7.92–7.77(m,3H),7.27–7.16(m,2H),7.11–7.02(m,2H),3.04–2.95(m,2H),2.71(t,J＝7.3Hz,2H),2.57(s,3H).13C NMR (101MHz,DMSO-d6)δ160.7,160.6(d,J＝243.5Hz),154.9,143.1,135.8,131.3(d,J＝4.9Hz),128.8,128.4(d,J＝8.2Hz),125.8,125.2(d,J＝15.6Hz),124.7,124.3(d,J＝3.3Hz),120.9,115.0(d,J＝21.9Hz),112.9,42.6,28.7(d,J＝2.1Hz),9.0.19F NMR(376MHz,DMSO-d6)δ-118.87.19F NMR(376MHz,DMSO)δ-118.87.HRMS(ESI)[M-H]-calcd for C18H15NO5SF:376.0655；found:376.0655.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(2-fluorophenylethyl)sulfamoyl)benzofuran-2-carboxylate. consistent. 189 mg of white solid was obtained, with a yield of 93%. . 1 H NMR (400MHz, DMSO-d 6 ) δ13.70 (s, 1H), 8.19 (d, J = 1.7Hz, 1H), 7.92–7.77 (m, 3H), 7.27–7.16 (m, 2H) ,7.11–7.02(m,2H),3.04–2.95(m,2H),2.71(t,J＝7.3Hz,2H),2.57(s,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ160.7,160.6(d,J＝243.5Hz),154.9,143.1,135.8,131.3(d,J＝4.9Hz),128.8,128.4(d,J＝8.2Hz),125.8, 125.2(d,J＝15.6Hz),124.7,124.3(d,J＝3.3Hz),120.9,115.0(d,J＝21.9Hz),112.9,42.6,28.7(d,J＝2.1Hz),9.0. 19 F NMR(376MHz, DMSO-d 6 )δ-118.87. 19 F NMR(376MHz, DMSO)δ-118.87.HRMS(ESI)[MH] - calcd for C 18 H 15 NO 5 SF: 376.0655; found: 376.0655 .
实施例56Example 56
5-(N-(2-溴代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-60)
5-(N-(2-bromophenythylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-60)
将5-(N-(2-溴代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(248.0mg，0.5mmol)，LiOH(24.0mg，1.0mmol)溶于THF(4mL)和H2O(2.5mL)混合溶液中，室温下反应。TLC监测反应完全后，减压蒸馏将THF旋干，向体系中滴加HCl(1M)，直到溶液呈酸性，白色沉淀产生。抽滤得到白色固体124.2mg，收率57％。1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.97–7.81(m,3H),7.50(d,J＝7.9Hz,1H),7.32–7.25(m,2H),7.18–7.07(m,1H),3.04(q,J＝6.9Hz,2H),2.81(t,J＝7.4Hz,2H),2.59(s,3H).13C NMR(101MHz,DMSO-d6)δ160.8,154.8,143.5,137.6,135.7,132.4,131.2,128.9,128.5,127.7,125.8,124.3,123.7,120.9,112.9,42.1,35.5,9.0.HRMS(ESI)[M-H]-calcd for C18H15BrNO5S:435.9860；found:435.9846.Dissolve 5-(N-(2-bromophenythylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (248.0 mg, 0.5 mmol), LiOH (24.0 mg, 1.0 mmol) React in a mixed solution of THF (4 mL) and H 2 O (2.5 mL) at room temperature. After TLC monitors that the reaction is complete, THF is evaporated under reduced pressure and HCl (1M) is added dropwise to the system until the solution becomes acidic and a white precipitate forms. After suction filtration, 124.2 mg of white solid was obtained, with a yield of 57%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.21 (s, 1H), 7.97–7.81 (m, 3H), 7.50 (d, J = 7.9Hz, 1H), 7.32–7.25 (m, 2H), 7.18–7.07(m,1H),3.04(q,J＝6.9Hz,2H),2.81(t,J＝7.4Hz,2H),2.59(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ160.8,154.8,143.5,137.6,135.7,132.4,131.2,128.9,128.5,127.7,125.8,124.3,123.7,120.9,112.9,42.1,35.5,9.0.HRMS(ESI)[MH] - calcd for C 18H 15 BrNO 5 S:435.9860; found:435.9846.
实施例57Example 57
5-(N-(2-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-59)
5-(N-(2-chlorophenythylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-59)
根据GPR132-B-60的合成步骤，得到白色固体51mg，收率46％。1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.82(s,1H),7.78–7.63(m,2H),7.37–7.13(m,4H),2.99(q,J＝7.7,7.2Hz,2H),2.78(t,J＝7.3Hz,2H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ163.7,154.5,136.4,135.0,133.4,131.7,130.6,129.6,128.7,127.6,124.0,120.1,112.5,42.6,33.5,9.5.HRMS(ESI)[M-H]-calcd for C18H15ClNO5S:392.0365；found:392.0356.According to the synthesis procedure of GPR132-B-60, 51 mg of white solid was obtained with a yield of 46%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.02(s,1H),7.82(s,1H),7.78–7.63(m,2H),7.37–7.13(m,4H),2.99(q,J =7.7, 7.2Hz, 2H), 2.78 (t, J = 7.3Hz, 2H), 2.53 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 163.7, 154.5, 136.4, 135.0, 133.4, 131.7 ,130.6,129.6,128.7,127.6,124.0,120.1,112.5,42.6,33.5,9.5.HRMS(ESI)[MH] - calcd for C 18 H 15 ClNO 5 S:392.0365; found:392.0356.
实施例58Example 58
5-(N-(2-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-61)
5-(N-(2-iodophenethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-61)
梨形瓶中加入中间体酯(0.22g,0.44mmol)，LiOH(0.02g,1.0mmol)，加入乙醇(8mL)及H2O(2mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体195mg，产率94％。Add intermediate ester (0.22g, 0.44mmol), LiOH (0.02g, 1.0mmol), ethanol (8mL) and H 2 O (2mL) to the pear-shaped flask, and react overnight at room temperature. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 195 mg of white solid with a yield of 94%.
1H NMR(400MHz,DMSO-d6)δ13.67(br,1H),8.20(d,J＝2.0Hz,1H),7.89(dd,J＝8.8,1.6Hz,1H),7.85–7.82(m,2H),7.73(dd,J＝8.0,1.2Hz,1H),7.30–7.26(m,1H),7.24(dd,J＝7.6,2.0Hz,1H),6.93–6.88(m,1H),3.00(q,J＝6.8Hz,2H),2.77(t,J＝7.6Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ161.14,155.34,143.57,141.34,139.49,136.24,130.70,129.29,128.99,128.89,126.37,125.17,121.45,113.43,101.06,42.86,9.54.HRMS(ESI)[M-H]-calcd for C18H15INO5S-:483.9721；found:483.9712. 1 H NMR (400MHz, DMSO-d 6 ) δ13.67(br,1H),8.20(d,J＝2.0Hz,1H),7.89(dd,J＝8.8,1.6Hz,1H),7.85–7.82( m,2H),7.73(dd,J＝8.0,1.2Hz,1H),7.30–7.26(m,1H),7.24(dd,J＝7.6,2.0Hz,1H),6.93–6.88(m,1H) ,3.00(q,J＝6.8Hz,2H),2.77(t,J＝7.6Hz,2H),2.58(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ161.14,155.34,143.57,141.34 ,139.49,136.24,130.70,129.29,128.99,128.89,126.37,125.17,121.45,113.43,101.06,42.86,9.54.HRMS(ESI)[MH] - calcd for C 18 H 15 INO 5 S - :483 .9721; found: 483.9712.
实施例59Example 59
3-甲基-5-(N-(2-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-62)
3-Methyl-5-(N-(2-methylphenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-62)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(2-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得黄色固体149mg，收率73％。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝1.8Hz,1H),7.92–7.76(m,3H),7.05(d,J＝1.8Hz,4H),2.96–2.88(m,2H),2.71–2.62(m,2H),2.56(s,3H),2.14(s,3H).13C NMR(101MHz,DMSO-d6)δ161.0,154.7,144.2,136.7,135.8,135.7,130.0,129.1,129.0,126.3,125.8,125.6,123.6,120.7,112.8,42.9,32.8,18.7,9.0.HRMS(ESI)[M-H]-calcd for C19H18NO5S:372.0906；found:372.0907.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(2-methylphenylethyl)sulfamoyl)benzofuran-2-carboxylate, and the remaining conditions All consistent. 149 mg of yellow solid was obtained, with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J＝1.8Hz, 1H), 7.92–7.76 (m, 3H), 7.05 (d, J＝1.8Hz, 4H), 2.96–2.88 ( m,2H),2.71–2.62(m,2H),2.56(s,3H),2.14(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ161.0,154.7,144.2,136.7,135.8,135.7 ,130.0,129.1,129.0,126.3,125.8,125.6,123.6,120.7,112.8,42.9,32.8,18.7,9.0.HRMS(ESI)[MH] - calcd for C 19 H 18 NO 5 S:372.0906; found:372.0907 .
实施例60Example 60
3-甲基-5-(N-(2-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-63)
3-Methyl-5-(N-(2-(trifluoromethyl)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-63)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(2-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体212mg，收率92％。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.20(d,J＝1.9Hz,1H),7.94–7.81(m,3H),7.64–7.51(m,2H),7.45–7.33(m,2H),3.05–2.97(m,2H),2.84(t,J＝7.6Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.2,136.8,135.8,132.5,131.8,128.9,127.2(d,J＝29.1Hz),127.0,125.8,125.7(q,J＝5.8,5.4Hz),124.6,123.1,120.9,113.0,43.6,32.2,9.0.19F NMR(376MHz,DMSO-d6)δ-58.44.HRMS(ESI)[M-H]-calcd for C19H15NO5SF3:426.0623；found:426.0628.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(2-(trifluoromethyl)phenylethyl)sulfamoyl)benzofuran-2-carboxylate. ester, other conditions are the same. 212 mg of white solid was obtained, with a yield of 92%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.70 (s, 1H), 8.20 (d, J = 1.9Hz, 1H), 7.94–7.81 (m, 3H), 7.64–7.51 (m, 2H), 7.45–7.33(m,2H),3.05–2.97(m,2H),2.84(t,J=7.6Hz,2H),2.56(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ160. 7,154.9,143.2,136.8,135.8,132.5,131.8,128.9,127.2(d,J＝29.1Hz),127.0,125.8,125.7(q,J＝5.8,5.4Hz),124.6,123.1,120.9,113.0,43.6 , 32.2,9.0. 19 F NMR (376MHz, DMSO-d 6 ) δ-58.44.HRMS (ESI) [MH] - calcd for C 19 H 15 NO 5 SF 3 : 426.0623; found: 426.0628.
实施例61Example 61
5-(N-(2-甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-64)
5-(N-(2-methoxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-64)
根据GPR132-B-60的合成步骤，得到白色固体117mg，收率91％。1H NMR(400MHz,DMSO-d6)δ13.79(s,1H),8.18(s,1H),7.86(q,J＝8.8Hz,2H),7.71(t,J＝5.8Hz,1H),7.14(t,J＝7.7Hz,1H),7.05(d,J＝6.6Hz,1H),6.86(d,J＝8.2Hz,1H),6.80(t,J＝7.4Hz,1H),3.68(s,3H),2.95(q,J＝7.4,7.0Hz,2H),2.64(t,J＝7.5Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,157.5,155.3,143.8,136.4,130.6,129.3,128.2,126.7,126.3,124.9,121.3,120.6,113.3,111.1,55.6,42.9,30.7,9.5.HRMS(ESI)[M-H]-calcd for C19H18NO6S:388.0860；found:388.0854.According to the synthesis procedure of GPR132-B-60, 117 mg of white solid was obtained with a yield of 91%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.79 (s, 1H), 8.18 (s, 1H), 7.86 (q, J = 8.8Hz, 2H), 7.71 (t, J = 5.8Hz, 1H) ,7.14(t,J＝7.7Hz,1H),7.05(d,J＝6.6Hz,1H),6.86(d,J＝8.2Hz,1H),6.80(t,J＝7.4Hz,1H),3.68 (s, 3H), 2.95 (q, J = 7.4, 7.0Hz, 2H), 2.64 (t, J = 7.5Hz, 2H), 2.57 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.2,157.5,155.3,143.8,136.4,130.6,129.3,128.2,126.7,126.3,124.9,121.3,120.6,113.3,111.1,55.6,42.9,30.7,9.5.HRMS(ESI)[MH] - calcd for C 19 H 18 NO 6 S: 388.0860; found: 388.0854.
实施例62Example 62
5-(N-(2-羟基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-65)
5-(N-(2-hydroxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-65)
1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.18(dd,J＝5.2,1.7Hz,1H),7.94–7.86(m,1H),7.83(d,J＝8.6Hz,1H),7.69(t,J＝5.8Hz,1H),7.00–6.87(m,2H),6.74–6.68(m,1H),6.64(t,J＝7.4Hz,1H),2.94(dq,J＝11.6,6.2Hz,2H),2.61(dd,J＝8.7,6.4Hz,2H),2.56(d,J＝5.9Hz,3H).13C NMR(101MHz,DMSO)δ160.7,155.2,154.8,143.3,135.9,130.3,128.8,127.4,125.9,124.6,124.5,120.9,118.8,114.8,112.8,42.5,30.3,9.0.HRMS(ESI)[M-H]-calcd for C18H17NO6S:374.0698；found:374.0702. 1 H NMR (400MHz, DMSO-d 6 ) δ9.31 (s, 1H), 8.18 (dd, J = 5.2, 1.7Hz, 1H), 7.94–7.86 (m, 1H), 7.83 (d, J = 8.6 Hz,1H),7.69(t,J＝5.8Hz,1H),7.00–6.87(m,2H),6.74–6.68(m,1H),6.64(t,J＝7.4Hz,1H),2.94(dq , J＝11.6, 6.2Hz, 2H), 2.61 (dd, J＝8.7, 6.4Hz, 2H), 2.56 (d, J＝5.9Hz, 3H). 13 C NMR (101MHz, DMSO) δ 160.7, 155.2, 154.8 ,143.3,135.9,130.3,128.8,127.4,125.9,124.6,124.5,120.9,118.8,114.8,112.8,42.5,30.3,9.0.HRMS(ESI)[MH] - calcd for C 18 H 17 NO 6 S:374.069 8 ;found:374.0702.
实施例63Example 63
3-甲基-5-(N-(3-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-66)
3-Methyl-5-(N-(3-fluorophenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-66)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(3-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体182mg，收率89％。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.17(d,J＝1.8Hz,1H),7.90–7.79(m,2H),7.74(t,J＝5.8Hz,1H),7.25(q,J＝7.4Hz,1H),6.95(dd,J＝11.3,8.1Hz,3H),3.02(q,J＝6.8Hz,2H),2.69(t,J＝7.1Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ162.1(d,J＝243.0Hz),160.7,154.9,143.1,141.7(d,J＝7.6Hz),135.8,130.0(d,J＝8.5Hz),128.8,125.9,124.9(d,J＝2.6Hz),124.7,120.9,115.4(d,J＝20.9Hz),113.0,112.8(d,J＝7.1Hz),43.6,34.8,9.0.19F NMR(376MHz,DMSO-d6)δ-113.80.HRMS(ESI)[M-H]-calcd for C18H15NO5SF:376.0655；found:376.0660.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(3-fluorophenylethyl)sulfamoyl)benzofuran-2-carboxylate. consistent. 182 mg of white solid was obtained, with a yield of 89%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.70 (s, 1H), 8.17 (d, J = 1.8Hz, 1H), 7.90–7.79 (m, 2H), 7.74 (t, J = 5.8Hz, 1H),7.25(q,J＝7.4Hz,1H),6.95(dd,J＝11.3,8.1Hz,3H),3.02(q,J＝6.8Hz,2H),2.69(t,J＝7.1Hz, 2H), 2.56 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 162.1 (d, J = 243.0Hz), 160.7, 154.9, 143.1, 141.7 (d, J = 7.6Hz), 135.8 ,130.0(d,J＝8.5Hz),128.8,125.9,124.9(d,J＝2.6Hz),124.7,120.9,115.4(d,J＝20.9Hz),113.0,112.8(d,J＝7.1Hz) ,43.6,34.8,9.0. 19 F NMR (376MHz, DMSO-d 6 )δ-113.80.HRMS (ESI) [MH] - calcd for C 18 H 15 NO 5 SF: 376.0655; found: 376.0660.
实施例64Example 64
5-(N-(3-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-67)
5-(N-(3-chlorophenythylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-67)
根据GPR132-B-60的合成步骤，得到白色固体110mg，收率80％。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.16(s,1H),7.84(q,J＝8.7Hz,2H),7.74(t,J＝5.7Hz,1H),7.29–7.06(m,4H),3.03(q,J＝6.6Hz,2H),2.68(t,J＝6.9Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,143.7,141.8,136.2,133.3,130.4,129.3,129.0,127.9,126.6,126.3,125.0,121.3,113.3,44.0,35.1,9.5.HRMS(ESI)[M-H]-calcd for C18H15ClNO5S:392.0365；found:392.0357.According to the synthesis procedure of GPR132-B-60, 110 mg of white solid was obtained with a yield of 80%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.71 (s, 1H), 8.16 (s, 1H), 7.84 (q, J = 8.7Hz, 2H), 7.74 (t, J = 5.7Hz, 1H) ,7.29–7.06(m,4H),3.03(q,J＝6.6Hz,2H),2.68(t,J＝6.9Hz,2H),2.57(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ161.2,155.3,143.7,141.8,136.2,133.3,130.4,129.3,129.0,127.9,126.6,126.3,125.0,121.3,113.3,44.0,35.1,9.5.HRMS(ESI)[MH] - calcd for C 18 H 15 ClNO 5 S: 392.0365; found: 392.0357.
实施例65Example 65
5-(N-(3-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-69)
5-(N-(3-iodophenethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-69)
梨形瓶中加入中间体酯(0.19g,0.36mmol)，LiOH(0.029g,1.2mmol)，加入乙醇(8mL)及H2O(2mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体161mg，产率91％。Add intermediate ester (0.19g, 0.36mmol), LiOH (0.029g, 1.2mmol), ethanol (8mL) and H 2 O (2mL) to the pear-shaped flask, and react at room temperature overnight. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 161 mg of white solid with a yield of 91%.
1H NMR(400MHz,DMSO-d6)δ13.69(br,1H),8.17(d,J＝1.6Hz,1H),7.86(dd,J＝8.8,2.0Hz,1H),7.82(d,J＝8.4Hz,1H),7.73(d,J＝5.6Hz,1H),7.51-7.48(m,2H),7.16(d,J＝7.6Hz,1H),7.02(t,J＝7.6Hz,1H),3.01(q,J＝6.4Hz,2H),2.64(t,J＝7.2Hz,2H),2.57(s, 3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.31,143.57,142.00,137.74,136.24,135.36,130.80,129.29,128.72,126.31,125.19,121.35,113.36,95.20,44.10,34.97,9.56.HRMS(ESI)[M-H]-calcd for C18H15INO5S-:483.9721；found:483.9720. 1 H NMR (400MHz, DMSO-d 6 ) δ13.69(br,1H),8.17(d,J＝1.6Hz,1H),7.86(dd,J＝8.8,2.0Hz,1H),7.82(d, J＝8.4Hz,1H),7.73(d,J＝5.6Hz,1H),7.51-7.48(m,2H),7.16(d,J＝7.6Hz,1H),7.02(t,J＝7.6Hz, 1H),3.01(q,J＝6.4Hz,2H),2.64(t,J＝7.2Hz,2H),2.57(s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.15,155.31,143.57,142.00,137.74,136.24,135.36,130.80,129.29,128.72,126.31,125.19,121.35,113.36 ,95.20,44.10,34.97,9.56. HRMS(ESI)[MH] - calcd for C 18 H 15 INO 5 S - :483.9721; found:483.9720.
实施例66Example 66
3-甲基-5-(N-(3-硝基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-73)
3-Methyl-5-(N-(3-nitrophenethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-73)
1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝1.8Hz,1H),7.96(dd,J＝8.7,1.9Hz,2H),7.78(td,J＝9.6,8.6,7.2Hz,3H),7.60(d,J＝7.6Hz,1H),7.49(t,J＝7.8Hz,1H),3.11(q,J＝6.4Hz,2H),2.81(t,J＝6.7Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO)δ160.9,154.7,147.5,141.1,135.8,135.7,129.5,128.9,125.5,123.9,123.5,121.1,120.7,112.7,43.4,34.4,9.0.HRMS(ESI)[M-H]-calcd for C18H16N2O7S:403.0600；found:403.0602. 1 H NMR (400MHz, DMSO-d 6 ) δ8.10 (d, J＝1.8Hz, 1H), 7.96 (dd, J＝8.7, 1.9Hz, 2H), 7.78 (td, J＝9.6, 8.6, 7.2 Hz,3H),7.60(d,J＝7.6Hz,1H),7.49(t,J＝7.8Hz,1H),3.11(q,J＝6.4Hz,2H),2.81(t,J＝6.7Hz, 2H),2.54(s,3H). 13 C NMR(101MHz,DMSO)δ160.9,154.7,147.5,141.1,135.8,135.7,129.5,128.9,125.5,123.9,123.5,121.1,120.7,112.7,43.4,3 4.4, 9.0.HRMS(ESI)[MH] - calcd for C 18 H 16 N 2 O 7 S:403.0600; found:403.0602.
实施例67Example 67
5-(N-(3-羟基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-74)
5-(N-(3-hydroxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-74)
梨形瓶中加入中间体酯(0.12g,0.29mmol)，LiOH(0.016g,0.58mmol)，加入乙醇(4mL)及H2O(1mL)，室温反应6h，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体56mg，产率50％。Add intermediate ester (0.12g, 0.29mmol), LiOH (0.016g, 0.58mmol), ethanol (4mL) and H 2 O (1mL) to the pear-shaped flask, and react at room temperature for 6 hours. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 56 mg of white solid, with a yield of 50%.
1H NMR(400MHz,DMSO-d6)δ13.66(s,1H),9.23(s,1H),8.23–8.20(m,1H),7.91–7.88(m,1H),7.85(dd,J＝8.8,0.8Hz,1H),7.72(t,J＝6.2Hz,1H),7.01(t,J＝7.6Hz,1H),6.57–6.52(m,3H),2.95(q,J＝6.8Hz,2H),2.60–2.50(m,5H).13C NMR(101MHz,DMSO-d6)δ161.13,157.74,155.34,143.58,140.47,136.30,129.67,129.31,126.37,125.19,121.40,119.66,115.99,113.66,113.37,44.52,35.76,9.49.HRMS(ESI)[M-H]-calcd forC18H16NO6S-:374.0968；found:374.0700. 1 H NMR (400MHz, DMSO-d 6 ) δ13.66(s,1H),9.23(s,1H),8.23–8.20(m,1H),7.91–7.88(m,1H),7.85(dd,J ＝8.8,0.8Hz,1H),7.72(t,J＝6.2Hz,1H),7.01(t,J＝7.6Hz,1H),6.57–6.52(m,3H),2.95(q,J＝6.8Hz ,2H),2.60–2.50(m,5H). 13 C NMR (101MHz, DMSO-d 6 )δ161.13,157.74,155.34,143.58,140.47,136.30,129.67,129.31,126.37,125.19,121.40,119 .66,115.99, 113.66,113.37,44.52,35.76,9.49.HRMS(ESI)[MH] - calcd forC 18 H 16 NO 6 S - :374.0968; found:374.0700.
实施例68Example 68
5-(N-(3-氨基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-75)
5-(N-(3-Aminophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-75)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.14(t,J＝6.6Hz,1H),7.01(t,J＝7.9Hz,1H),6.94(ddq,J＝8.1,2.2,1.1Hz,1H),6.53–6.45(m,2H),4.25(d,J＝5.5Hz,1H),4.13(d,J＝5.5Hz,1H),3.18(dt,J＝6.7,5.7Hz,2H),2.75(tt,J＝5.7,1.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,147.4,143.1,136.6,134.6,128.5,127.6,125.5,125.0,120.2,118.5,115.8,114.4,113.3,45.0,35.3,10.0.HRMS(ESI)[M-H]-calcd for C18H18N2O5S:373.0864；found:373.0864.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.14(t,J＝6.6Hz,1H),7.01(t,J＝7.9Hz,1H),6.94(ddq,J＝8.1,2.2,1.1Hz,1H),6.53–6.45(m,2H), 4.25(d,J＝5.5Hz,1H),4.13(d,J＝5.5Hz,1H),3.18(dt,J＝6.7,5.7Hz,2H),2.75(tt,J＝5.7,1.0Hz,2H ), 2.58 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ165.0,157.9,147.4,143.1,136.6,134.6,128.5,127.6,125.5,125.0,120.2,118.5,115.8,114.4,113.3 , 45.0,35.3,10.0.HRMS(ESI)[MH] - calcd for C 18 H 18 N 2 O 5 S:373.0864; found:373.0864.
实施例69Example 69
3-甲基-5-(N-(3-(甲氨基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-76)
3-Methyl-5-(N-(3-(methylamino)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-76)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.18–7.09(m,2H),6.92(ddq,J＝7.7,2.2,1.1Hz,1H),6.55–6.46(m,2H),5.68(q,J＝4.8Hz,1H),3.18(dt,J＝6.6,5.8Hz,2H),2.94(d,J＝4.8Hz,3H),2.81(tt,J＝5.8,1.1Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,149.5,143.1,135.4,134.6,129.9,127.6,125.5,125.0,122.7,120.2,115.0,113.3,113.2,45.0,35.1,30.3,10.0.HRMS(ESI)[M-H]-calcd for C19H20N2O5S:387.1020；found:387.1020.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.18–7.09(m,2H),6.92(ddq,J＝7.7,2.2,1.1Hz,1H),6.55–6.46(m,2H),5.68(q,J＝4.8Hz,1H),3.18(dt ,J＝6.6,5.8Hz,2H),2.94(d,J＝4.8Hz,3H),2.81(tt,J＝5.8,1.1Hz,2H),2.58(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ165.0,157.9,149.5,143.1,135.4,134.6,129.9,127.6,125.5,125.0,122.7,120.2,115.0,113.3,113.2,45.0,35.1,30.3,10.0.HRMS(ES I)[MH] - calcd for C 19 H 20 N 2 O 5 S:387.1020; found:387.1020.
实施例70Example 70
5-(N-(3-(二甲基氨基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-77)
5-(N-(3-(Dimethylamino)phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-77)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.18–7.08(m,2H),6.91(dtd,J＝7.9,2.1,0.9Hz,1H),6.60(tt,J＝2.3,1.0Hz,1H),6.55(ddd,J＝7.5,2.2,1.1Hz,1H),3.18(dt,J＝6.6,5.8Hz,2H),2.96(s,6H),2.78(tt,J＝5.6,0.9Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,151.6,143.1,138.0,134.6,129.7,127.6,125.5,125.0,122.0,120.2,115.7,113.3,112.6,45.0,40.4,35.1,10.0.HRMS(ESI)[M-H]-calcd for C20H22N2O5S:401.1177；found:401.1177.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.18–7.08(m,2H),6.91(dtd,J＝7.9,2.1,0.9Hz,1H),6.60(tt,J＝2.3,1.0Hz,1H),6.55(ddd,J＝7.5,2.2, 1.1Hz,1H),3.18(dt,J＝6.6,5.8Hz,2H),2.96(s,6H),2.78(tt,J＝5.6,0.9Hz,2H),2.58(s,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ165.0,157.9,151.6,143.1,138.0,134.6,129.7,127.6,125.5,125.0,122.0,120.2,115.7,113.3,112.6,45.0,40.4,35.1,1 0.0.HRMS(ESI )[MH] - calcd for C 20 H 22 N 2 O 5 S:401.1177; found:401.1177.
实施例71Example 71
5-(N-(4-溴苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸(GPR132-B-80)
5-(N-(4-bromophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-80)
根据GPR132-B-60的合成步骤，得到白色固体117.0mg，收率79％。1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.15(s,1H),7.89–7.78(m,2H),7.74(t,J＝5.8Hz,1H),7.37(d,J＝8.3Hz,2H),7.09(d,J＝8.3Hz,2H),3.01(q,J＝6.9Hz,2H),2.65(t,J＝7.0Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,143.7,138.6,136.2,131.4,129.3,126.2,125.0,121.3,119.7,113.3,44.1,34.9,9.5.HRMS(ESI)[M-H]-calcd for C18H15BrNO5S:435.9860；found:435.9850.According to the synthesis procedure of GPR132-B-60, 117.0 mg of white solid was obtained with a yield of 79%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.73 (s, 1H), 8.15 (s, 1H), 7.89–7.78 (m, 2H), 7.74 (t, J = 5.8Hz, 1H), 7.37 ( d,J＝8.3Hz,2H),7.09(d,J＝8.3Hz,2H),3.01(q,J＝6.9Hz,2H),2.65(t,J＝7.0Hz,2H),2.57(s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.2,155.3,143.7,138.6,136.2,131.4,129.3,126.2,125.0,121.3,119.7,113.3,44.1,34.9,9.5.HRMS(ESI)[MH ] - calcd for C 18 H 15 BrNO 5 S:435.9860; found:435.9850.
实施例72Example 72
5-(N-(4-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-81)
5-(N-(4-iodophenethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-81)
梨形瓶中加入中间体酯(0.10g,0.19mmol)，LiOH(0.017g,0.67mmol)，加入乙醇(4mL)及H2O(1mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体94mg，产率97％。 Add intermediate ester (0.10g, 0.19mmol), LiOH (0.017g, 0.67mmol), ethanol (4mL) and H 2 O (1mL) to the pear-shaped flask, and react at room temperature overnight. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 94 mg of white solid with a yield of 97%.
1H NMR(400MHz,DMSO-d6)δ13.70(br,1H),8.15(d,J＝1.6Hz,1H),7.85(dd,J＝8.8,1.6Hz,1H),7.82(d,J＝8.8Hz,1H),7.73(t,J＝6.0Hz,1H),7.54(d,J＝7.6Hz,2H),6.94(d,J＝8.8Hz,2H),2.98(q,J＝6.8Hz,2H),2.62(t,J＝7.2Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.29,143.65,138.99,137.35,136.24,131.65,129.29,126.28,125.08,121.34,113.31,92.35,44.12,35.04,9.52.HRMS(ESI)[M-H]-calcd for C18H15INO5S-:483.9721；found:483.9712. 1 H NMR (400MHz, DMSO-d 6 ) δ13.70(br,1H),8.15(d,J＝1.6Hz,1H),7.85(dd,J＝8.8,1.6Hz,1H),7.82(d, J＝8.8Hz,1H),7.73(t,J＝6.0Hz,1H),7.54(d,J＝7.6Hz,2H),6.94(d,J＝8.8Hz,2H),2.98(q,J＝ 6.8Hz, 2H), 2.62 (t, J = 7.2Hz, 2H), 2.56 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 161.15, 155.29, 143.65, 138.99, 137.35, 136.24, 131.65, 129.29,126.28,125.08,121.34,113.31,92.35,44.12,35.04,9.52.HRMS(ESI)[MH] - calcd for C 18 H 15 INO 5 S - :483.9721; found:483.9712.
实施例73Example 73
3-甲基-5-(N-(4-甲基苯基乙基)磺胺基)苯并呋喃-2-羧酸(GPR132-B-82)
3-Methyl-5-(N-(4-methylphenylethyl)sulfonamide)benzofuran-2-carboxylic acid (GPR132-B-82)
将3-甲基-5-(N-(4-甲基苯基乙基)磺胺基)苯并呋喃-2-羧酸乙酯(0.16g,0.41mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体133mg，产率87.5％。Dissolve ethyl 3-methyl-5-(N-(4-methylphenylethyl)sulfonamido)benzofuran-2-carboxylate (0.16g, 0.41mmol) in ethanol (8mL), add hydrogen Lithium oxide (0.02g, 0.83mmol, dissolved in 2mL water), stirred at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 133 mg of white solid, with a yield of 87.5%.
1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝2.0Hz,1H),7.87(dd,J＝8.8,2.0Hz,1H),7.82(d,J＝8.8Hz,1H),7.72(d,J＝5.6Hz,1H),6.99(s,4H),3.01-2.91(m,2H),2.61(t,J＝7.2Hz,2H),2.56(s,3H),2.20(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.31,143.58,136.33,136.00,135.55,129.29,129.23,128.95,126.33,125.12,121.34,113.30,44.62,35.24,21.00,9.48.HRMS(ESI)[M-H]-calcd for C19H19NO5S:372.0911；found:372.0911. 1 H NMR (400MHz, DMSO-d 6 ) δ8.16 (d, J = 2.0Hz, 1H), 7.87 (dd, J = 8.8, 2.0Hz, 1H), 7.82 (d, J = 8.8Hz, 1H) ,7.72(d,J＝5.6Hz,1H),6.99(s,4H),3.01-2.91(m,2H),2.61(t,J＝7.2Hz,2H),2.56(s,3H),2.20( s,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.15,155.31,143.58,136.33,136.00,135.55,129.29,129.23,128.95,126.33,125.12,121.34,113.30,44.6 2,35.24,21.00,9.48. HRMS(ESI)[MH] - calcd for C 19 H 19 NO 5 S:372.0911; found:372.0911.
实施例74Example 74
5-(N-(4-三氟甲基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸(GPR132-B-83)
5-(N-(4-Trifluoromethylphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-83)
根据GPR132-B-60的合成步骤，得到白色固体117.0mg，收率79％。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.20–8.13(m,1H),7.90–7.73(m,3H),7.56(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),3.06(q,J＝6.7Hz,2H),2.78(t,J＝6.9Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,144.2,143.7,136.2,130.0,129.3,127.5,127.2,126.2,125.4(q,J＝3.8Hz),125.0,121.3,113.3,43.9,35.3,9.5.19F NMR(376MHz,DMSO-d6)δ-63.23.HRMS(ESI)[M-H]-calcd for C19H15F3NO5S:426.0629；found:426.0619.According to the synthesis procedure of GPR132-B-60, 117.0 mg of white solid was obtained with a yield of 79%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.71 (s, 1H), 8.20–8.13 (m, 1H), 7.90–7.73 (m, 3H), 7.56 (d, J = 8.0Hz, 2H), 7.37(d,J＝8.0Hz,2H),3.06(q,J＝6.7Hz,2H),2.78(t,J＝6.9Hz,2H),2.56(s,3H). 13 C NMR (101MHz, DMSO -d 6 )δ161.2,155.3,144.2,143.7,136.2,130.0,129.3,127.5,127.2,126.2,125.4(q,J＝3.8Hz),125.0,121.3,113.3,43.9,35.3,9.5. 19 F NMR ( 376MHz, DMSO-d 6 )δ-63.23.HRMS(ESI)[MH] - calcd for C 19 H 15 F 3 NO 5 S: 426.0629; found: 426.0619.
实施例75Example 75
5-(N-(4-甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-84)
5-(N-(4-methoxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-84)
根据GPR132-B-60的合成步骤，得到白色固体114mg，收率59％。1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.16(d,J＝1.5Hz,1H),7.91–7.78(m,2H),7.70(t,J＝5.8Hz,1H),7.03(d,J＝8.5Hz,2H),6.76(d,J＝8.5Hz,2H),3.67(s,3H),2.96(q,J＝7.1Hz,2H),2.60(t,J＝7.3Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,158.1,155.3,143.6,136.3,130.9,130.1,129.3,126.3,125.1,121.3,114.1,113.3,55.3,44.8,34.8,9.5.HRMS(ESI)[M-H]-calcd for C19H18NO6S:388.0860；found:388.0852.According to the synthesis procedure of GPR132-B-60, 114 mg of white solid was obtained with a yield of 59%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.73 (s, 1H), 8.16 (d, J = 1.5Hz, 1H), 7.91–7.78 (m, 2H), 7.70 (t, J = 5.8Hz, 1H),7.03(d,J＝8.5Hz,2H),6.76(d,J＝8.5Hz,2H),3.67(s,3H),2.96(q,J＝7.1Hz,2H),2.60(t, J=7.3Hz, 2H), 2.56 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.2,158.1,155.3,143.6,136.3,130.9,130.1,129.3,126.3,125.1,121.3,114.1, 113.3,55.3,44.8,34.8,9.5.HRMS(ESI)[MH] - calcd for C 19 H 18 NO 6 S:388.0860; found:388.0852.
实施例76Example 76
5-(N-(4-硝基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-85)
5-(N-(4-Nitrophenylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-85)
根据GPR132-B-60的合成步骤，得到白色固体73mg，收率62％。1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.09(s,1H),8.02(d,J＝8.4Hz,2H),7.84–7.75(m,3H),7.39(d,J＝8.4Hz,2H),3.11(q,J＝6.3Hz,2H),2.81(t,J＝6.6Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO-d6)δ161.1,155.3,147.6,146.4,143.7,136.2,130.5,129.3,126.2,124.9,123.6,121.2,113.2,43.7,35.3,9.5.HRMS(ESI)[M-H]-calcd forC18H15N2O7S:403.0605；found:403.0600.According to the synthesis procedure of GPR132-B-60, 73 mg of white solid was obtained with a yield of 62%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.73 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 8.4Hz, 2H), 7.84–7.75 (m, 3H), 7.39 ( d, J＝8.4Hz, 2H), 3.11 (q, J＝6.3Hz, 2H), 2.81 (t, J＝6.6Hz, 2H), 2.54 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) Δ161.1,155.3,147.6,146.4,143.7,136.2,130.5,129.3,126.2,123.6,121.2,43.7,35.3,9.5.Hrms (MH] -Calcd Forc 18 H 15 n 2 o 7 S:403.0605; found:403.0600.
实施例77Example 77
5-(N-(4-羟基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-86)
5-(N-(4-hydroxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-86)
根据GPR132-B-60的合成步骤，得到白色固体147mg，收率87％。1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.17(d,J＝11.8Hz,1H),7.89(s,1H),7.83(d,J＝9.4Hz,1H),7.74–7.66(m,1H),7.13(d,J＝8.6Hz,1H),6.94–6.87(m,2H),6.61(d,J＝8.4Hz,1H),3.01–2.86(m,2H),2.65(t,J＝7.0Hz,1H),2.57–2.54(m,4H).13C NMR(101MHz,DMSO-d6)δ161.1,156.4,155.3,147.9,143.6,138.6,130.7,129.9,129.3,127.5,125.1,122.3,44.1,34.9,9.5.HRMS(ESI)[M-H]-calcd for C18H16NO6S:374.0704；found:374.0702.According to the synthesis procedure of GPR132-B-60, 147 mg of white solid was obtained with a yield of 87%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.32 (s, 1H), 8.17 (d, J = 11.8Hz, 1H), 7.89 (s, 1H), 7.83 (d, J = 9.4Hz, 1H) ,7.74–7.66(m,1H),7.13(d,J＝8.6Hz,1H),6.94–6.87(m,2H),6.61(d,J＝8.4Hz,1H),3.01–2.86(m,2H ), 2.65 (t, J=7.0Hz, 1H), 2.57–2.54 (m, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.1,156.4,155.3,147.9,143.6,138.6,130.7,129.9, 129.3,127.5,125.1,122.3,44.1,34.9,9.5.HRMS(ESI)[MH] - calcd for C 18 H 16 NO 6 S:374.0704; found:374.0702.
实施例78Example 78
5-(N-(4-氨基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-87)
5-(N-(4-Aminophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-87)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.14(t,J＝6.6Hz,1H),6.90(dt,J＝8.0,1.0Hz,2H),6.48–6.42(m,2H),4.04(d,J＝5.7Hz,1H),3.98(d,J＝5.7Hz,1H),3.17(dt,J＝6.7,5.8Hz,2H),2.82(tt,J＝5.7,1.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,145.9,143.1,134.6,129.6,128.3,127.6,125.5,125.0,120.2,115.2,113.3,44.9,35.2,10.0.HRMS(ESI)[M-H]-calcd for C18H18N2O5S:373.0864；found:373.0864.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.14(t,J＝6.6Hz,1H),6.90(dt,J＝8.0,1.0Hz,2H),6.48–6.42(m,2H),4.04(d,J＝5.7Hz,1H),3.98( d, J＝5.7Hz, 1H), 3.17 (dt, J＝6.7, 5.8Hz, 2H), 2.82 (tt, J＝5.7, 1.0Hz, 2H), 2.58 (s, 3H). 13 C NMR (101MHz ,DMSO-d 6 )δ165.0,157.9,145.9,143.1,134.6,129.6,128.3,127.6,125.5,125.0,120.2,115.2,113.3,44.9,35.2,10.0.HRMS(ESI)[MH] - calcd for C 18 H 18 N 2 O 5 S: 373.0864; found: 373.0864.
实施例79Example 79
3-甲基-5-(N-(4-(甲氨基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-88)
3-Methyl-5-(N-(4-(methylamino)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-88)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.14(t,J＝6.6Hz,1H),6.96(dt,J＝7.5,1.1Hz,2H),6.62–6.56(m,2H),5.48(q,J＝4.8Hz,1H),3.17(dt,J＝6.7,5.8Hz,2H),2.91(d,J＝4.8Hz,3H),2.82(tt,J＝5.7,1.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,147.6,143.1,134.6,131.1,130.1,127.6,125.5,125.0,120.2,113.4, 113.3,44.9,35.8,30.2,10.0.HRMS(ESI)[M-H]-calcd for C19H20N2O5S:387.1020；found:387.1020.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.14(t,J＝6.6Hz,1H),6.96(dt,J＝7.5,1.1Hz,2H),6.62–6.56(m,2H),5.48(q,J＝4.8Hz,1H),3.17( dt,J＝6.7,5.8Hz,2H),2.91(d,J＝4.8Hz,3H),2.82(tt,J＝5.7,1.0Hz,2H),2.58(s,3H). 13 C NMR (101MHz ,DMSO-d 6 )δ165.0,157.9,147.6,143.1,134.6,131.1,130.1,127.6,125.5,125.0,120.2,113.4, 113.3,44.9,35.8,30.2,10.0.HRMS(ESI)[MH] - calcd for C 19 H 20 N 2 O 5 S:387.1020; found:387.1020.
实施例80Example 80
5-(N-(2-(5-溴吡啶-3-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-90)
5-(N-(2-(5-bromopyridin-3-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-90)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.51(dt,J＝20.9,1.8Hz,2H),8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.48(t,J＝2.0Hz,1H),7.16(t,J＝6.6Hz,1H),3.23(q,J＝6.2Hz,2H),2.93(t,J＝6.2Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,148.1,148.0,143.1,135.4,134.6,133.7,127.6,125.5,125.0,120.2,119.9,113.3,44.9,32.4,10.0.HRMS(ESI)[M-H]-calcd for C17H15BrN2O5S:436.9812；found:436.9812.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.51 (dt, J＝20.9, 1.8Hz, 2H), 8.19 (d, J＝2.3Hz, 1H), 7.97 (dd, J＝9.0, 2.2Hz, 1H),7.64(d,J＝9.0Hz,1H),7.48(t,J＝2.0Hz,1H),7.16(t,J＝6.6Hz,1H),3.23(q,J＝6.2Hz,2H) ,2.93(t,J＝6.2Hz,2H),2.58(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.0,157.9,148.1,148.0,143.1,135.4,134.6,133.7,127.6,125.5 ,125.0,120.2,119.9,113.3,44.9,32.4,10.0.HRMS(ESI)[MH] - calcd for C 17 H 15 BrN 2 O 5 S:436.9812; found:436.9812.
实施例81Example 81
5-(N-(2-(5-甲氧基吡啶-3-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-91)
5-(N-(2-(5-methoxypyridin-3-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-91)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.30(t,J＝1.8Hz,1H),8.19(d,J＝2.4Hz,1H),8.12(t,J＝1.8Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.16(t,J＝6.6Hz,1H),6.95(t,J＝2.0Hz,1H),3.91(s,2H),3.23(q,J＝6.3Hz,2H),2.92(t,J＝6.2Hz,2H),2.58(s,2H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,155.7,143.1,143.1,135.1,134.6,133.6,127.6,125.5,125.0,120.2,117.9,113.3,55.8,44.9,33.0,10.0.HRMS(ESI)[M-H]-calcd for C18H18N2O6S:389.0813；found:389.0813.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.30(t,J＝1.8Hz,1H),8.19(d,J＝2.4Hz,1H),8.12(t,J＝1.8Hz,1H),7.97 (dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.16(t,J＝6.6Hz,1H),6.95(t,J＝2.0Hz,1H),3.91 (s, 2H), 3.23 (q, J = 6.3Hz, 2H), 2.92 (t, J = 6.2Hz, 2H), 2.58 (s, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ165. 0,157.9,155.7,143.1,143.1,135.1,134.6,133.6,127.6,125.5,125.0,120.2,117.9,113.3,55.8,44.9,33.0,10.0.HRMS(ESI)[MH] - calcd for C 18 H 1 8 N 2 O 6 S:389.0813; found:389.0813.
实施例82Example 82
3-甲基-5-(N-(3-(三氟甲氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸(GPR132-B-92)
3-Methyl-5-(N-(3-(trifluoromethoxy)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-92)
将3-甲基-5-(N-(3-(三氟甲氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸乙酯(0.17g,0.36mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体147mg，产率91.9％。Dissolve 3-methyl-5-(N-(3-(trifluoromethoxy)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (0.17g, 0.36mmol) in ethanol ( 8mL), add lithium hydroxide (0.02g, 0.83mmol, dissolved in 2mL water), stir and react at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 147 mg of white solid, with a yield of 91.9%.
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝1.6Hz,1H),7.86(dd,J＝8.8,2.0Hz,1H),7.80(d,J＝9.2Hz,2H),7.37–7.30(m,1H),7.17(d,J＝7.6Hz,1H),7.11(d,J＝6.4Hz,2H),3.04(q,J＝6.8Hz,2H),2.73(t,J＝7.2Hz,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ161.16,155.31,148.75,143.66,142.08,136.18,130.42,129.29,128.35,126.27,125.02,121.62,121.37,118.97,113.29,43.96,35.04,9.43.19F NMR(376MHz,DMSO-d6)δ-58.72.HRMS(ESI)[M-H]-calcd for C19H16F3NO6S:442.0578；found:442.0578. 1 H NMR (400MHz, DMSO-d 6 ) δ8.18 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 8.8, 2.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 2H) ,7.37–7.30(m,1H),7.17(d,J＝7.6Hz,1H),7.11(d,J＝6.4Hz,2H),3.04(q,J＝6.8Hz,2H),2.73(t, J=7.2Hz, 2H), 2.55 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.16,155.31,148.75,143.66,142.08,136.18,130.42,129.29,128.35,126.27,125.02,121 .62, found _ _ _ _ _ _ :442.0578.
实施例83Example 83
5-(N-(3-乙炔基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-24)
5-(N-(3-ethynylphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-24)
梨形瓶中加入中间体酯(0.18g,0.43mmol)，LiOH(0.034g,1.2mmol)，加入乙醇(6mL)及H2O(1.5mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量淡黄色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得淡黄色固体131mg，产率80％。Add intermediate ester (0.18g, 0.43mmol), LiOH (0.034g, 1.2mmol), ethanol (6mL) and H 2 O (1.5mL) to the pear-shaped flask, and react overnight at room temperature. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of light yellow solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 131 mg of light yellow solid with a yield of 80%.
1H NMR(400MHz,DMSO-d6)δ13.67(br,1H),8.17(d,J＝2.0Hz,1H),7.86(dd,J＝8.8,2.0Hz,1H),7.82(d,J＝8.8Hz,1H),7.73(t,J＝6.0Hz,1H),7.32–7.16(m,4H),4.12(s,1H),3.01(q,J＝6.4Hz,2H),2.67(t,J＝7.2Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.31,143.55,139.78,136.24,132.42,129.99,129.96,129.29,129.01,126.32,125.18,122.04,121.36,113.35,83.95,80.92,44.12,35.17,9.50.HRMS(ESI)[M-H]-calcd for C20H16NO5S-:382.0755；found:382.0749. 1 H NMR (400MHz, DMSO-d 6 ) δ13.67 (br, 1H), 8.17 (d, J = 2.0Hz, 1H), 7.86 (dd, J = 8.8, 2.0Hz, 1H), 7.82 (d, J＝8.8Hz,1H),7.73(t,J＝6.0Hz,1H),7.32–7.16(m,4H),4.12(s,1H),3.01(q,J＝6.4Hz,2H),2.67( T, J = 7.2Hz, 2H), 2.57 (s, 3H). 13 C NMR (101MHz, DMSO-D 6 ) Δ161.15,155.31,143.55,136.24,132.42,129.9.96.29.29.01,126. 32, 125.18,122.04,121.36,113.35,83.95,80.92,44.12,35.17,9.50.HRMS(ESI)[MH] - calcd for C 20 H 16 NO 5 S - :382.0755; found:382.0749.
实施例84Example 84
5-(N-(3-氰基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-26)
5-(N-(3-cyanophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-26)
梨形瓶中加入中间体酯(0.24g,0.59mmol)，LiOH(0.028g,1.2mmol)，加入乙醇(8mL)及H2O(2mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量淡黄色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得淡黄色固体196mg，产率86％。Add intermediate ester (0.24g, 0.59mmol), LiOH (0.028g, 1.2mmol), ethanol (8mL) and H2O (2mL) to the pear-shaped flask, and react at room temperature overnight. TLC monitors the reaction to be complete. After the reaction is completed, add an appropriate amount of 3N HCl to adjust the pH to 1, and a large amount of light yellow solid will precipitate. After suction filtration, the filter cake was washed with distilled water and dried to obtain 196 mg of light yellow solid with a yield of 86%.
1H NMR(400MHz,DMSO-d6)δ13.66(br,1H),8.18–8.15(m,1H),7.86–7.80(m,2H),7.75(t,J＝5.8Hz,1H),7.60–7.58(m,2H),7.49(d,J＝7.6Hz,1H),7.42(t,J＝7.8Hz,1H),3.07(q,J＝6.4Hz,2H),2.74(t,J＝7.0Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.14,155.30,143.59,140.88,136.26,134.37,132.77,130.43,129.78,129.28,126.27,125.14,121.33,119.27,113.35,111.56,43.78,34.91,9.50.HRMS(ESI)[M-H]-calcd for C19H15N2O5S-:383.0707；found:383.0709. 1 H NMR (400MHz, DMSO-d 6 ) δ13.66 (br, 1H), 8.18–8.15 (m, 1H), 7.86–7.80 (m, 2H), 7.75 (t, J = 5.8Hz, 1H), 7.60–7.58(m,2H),7.49(d,J＝7.6Hz,1H),7.42(t,J＝7.8Hz,1H),3.07(q,J＝6.4Hz,2H),2.74(t,J =7.0Hz, 2H), 2.57 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.14,155.30,143.59,140.88,136.26,134.37,132.77,130.43,129.78,129.28,126.27,125 .14,121.33 ,119.27,113.35,111.56,43.78,34.91,9.50.HRMS(ESI)[MH] - calcd for C 19 H 15 N 2 O 5 S - :383.0707; found:383.0709.
实施例85Example 85
5-(N-(3-(二甲基磷酰基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-95)
5-(N-(3-(Dimethylphosphoryl)phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-95)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.44(dddd,J＝13.4,7.3,2.3,1.3Hz,1H),7.32–7.18(m,3H),7.14(t,J＝6.6Hz,1H),3.17(dt,J＝6.6,5.7Hz,2H),2.78(tt,J＝5.7,1.0Hz,2H),2.58(s,3H),1.97(s,6H).13C NMR(101MHz,DMSO-d6)δ165.6,156.7,143.1,139.2,139.1,135.3,134.9,134.3,130.6,130.6,129.8,129.7,129.3,129.3,127.8,127.8,127.8,127.1,126.6,119.4,113.0,45.0,35.4,35.4,18.6,17.9,10.3.31P NMR(202MHz,DMSO-d6)δ34.2.HRMS(ESI)[M-H]-calcd for C20H22NO6PS:434.0833；found:434.0833.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.44(dddd,J＝13.4,7.3,2.3,1.3Hz,1H),7.32–7.18(m,3H),7.14(t,J＝6.6Hz,1H),3.17(dt,J＝6.6,5.7Hz ,2H),2.78(tt,J＝5.7,1.0Hz,2H),2.58(s,3H),1.97(s,6H). 13 C NMR (101MHz, DMSO-d 6 )δ165.6,156.7,143.1,139.2 ,139.1,135.3,134.9,134.3,130.6,130.6,129.8,129.7,129.3,129.3,127.8,127.8,127.8,127.1,126.6,119.4,113.0,45.0,35.4,35.4,18. 6,17.9,10.3. 31P NMR (202MHz, DMSO-d 6 )δ34.2.HRMS(ESI)[MH] - calcd for C 20 H 22 NO 6 PS:434.0833; found:434.0833.
实施例86Example 86
5-(N-(3-(1,1-二氟乙基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-96)
5-(N-(3-(1,1-difluoroethyl)phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-96)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.41–7.30(m,3H),7.21–7.12(m,2H),3.17(dt,J＝6.6,5.7Hz,2H),2.82(tt,J＝5.6,1.0Hz,2H),2.58(s,3H),2.33(t,J＝20.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,138.2(t,J＝32.0Hz),137.3(t,J＝2.0Hz),134.6,130.1(t,J＝2.0Hz),130.0,127.6,126.8(t,J＝3.9Hz),125.5,125.0,124.9(t,J＝3.9Hz),121.5(t,J＝221.1Hz),120.2,113.3,45.0,35.9,25.6(t,J＝27.1Hz),10.0.19F NMR(472MHz,DMSO-d6)δ-95.99.HRMS(ESI)[M-H]-calcd for C20H19F2NO5S:422.0879；found:422.0879.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.41–7.30(m,3H),7.21–7.12(m,2H),3.17(dt,J＝6.6,5.7Hz,2H),2.82(tt,J＝5.6,1.0Hz,2H),2.58(s ,3H),2.33(t,J＝20.9Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.0,157.9,143.1,138.2(t,J＝32.0Hz),137.3(t,J＝2.0 Hz), 134.6, 130.1 (t, J = 2.0Hz), 130.0, 127.6, 126.8 (t, J = 3.9Hz), 125.5, 125.0, 124.9 (t, J = 3.9Hz), 121.5 (t, J = 221.1 Hz), 120.2, 113.3, 45.0, 35.9, 25.6 (t, J = 27.1Hz), 10.0. 19 F NMR (472MHz, DMSO-d 6 ) δ-95.99.HRMS (ESI) [MH] - calcd for C 20 H 19 F 2 NO 5 S: 422.0879; found: 422.0879.
实施例87Example 87
5-(N-(3-乙酰苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-25)
5-(N-(3-acetylphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-25)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.14(d,J＝2.0Hz,1H),7.84(dd,J＝8.8,2.0Hz,1H),7.80(s,1H),7.78(d,J＝4.8Hz,1H),7.73–7.70(m,1H),7.68(d,J＝2.2Hz,1H),7.42–7.41(m,1H),7.36(d,J＝7.6Hz,1H),3.06(q,J＝6.4Hz,2H),2.75(t,J＝7.0Hz,2H),2.55(s,3H),2.51(s,3H).13C NMR(101MHz,DMSO-d6)δ198.25,161.14,155.26,143.55,139.78,137.17,136.24,134.06,129.26,129.00,128.81,126.65,126.29,125.13,121.31,113.30,44.24,35.29,27.08,9.48.HRMS(ESI)[M-H]-calcd for C20H18NO6S-:400.0860；found:400.0862.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.14 (d, J＝2.0Hz, 1H), 7.84 (dd, J＝8.8, 2.0Hz, 1H), 7.80 (s, 1H), 7.78 (d, J＝4.8Hz,1H),7.73–7.70(m,1H),7.68(d,J＝2.2Hz,1H),7.42–7.41(m,1H),7.36(d,J＝7.6Hz,1H), 3.06 (q, J＝6.4Hz, 2H), 2.75 (t, J＝7.0Hz, 2H), 2.55 (s, 3H), 2.51 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ198 .25,161.14,155.26,143.55,139.78,137.17,136.24,134.06,129.26,129.00,128.81,126.65,126.29,125.13,121.31,113.30,44.24,35.29, 27.08,9.48.HRMS(ESI)[MH] - calcd for C 20 H 18 NO 6 S - :400.0860; found: 400.0862.
实施例88Example 88
5-(N-(3-乙氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-98)
5-(N-(3-ethoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-98)
梨形瓶中加入中间体酯(0.19g,0.44mmol)，LiOH(0.022g,0.93mmol)，加入乙醇(4mL)及H2O(1mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体157mg，产率87％。Add intermediate ester (0.19g, 0.44mmol), LiOH (0.022g, 0.93mmol), ethanol (4mL) and H 2 O (1mL) to the pear-shaped flask, and react overnight at room temperature. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 157 mg of white solid with a yield of 87%.
1H NMR(400MHz,DMSO-d6)δ13.69(br,1H),8.18(d,J＝1.6Hz,1H),7.87(dd,J＝8.8,1.6Hz,1H),7.82(d,J＝8.8Hz,1H),7.72(t,J＝5.6Hz,1H),7.11(t,J＝7.8Hz,1H),6.68(dd,J＝8.0,2.0Hz,2H),6.64(t,J＝2.0Hz,1H),3.92(q,J＝6.8Hz,2H),3.00(q,J＝6.8Hz,2H),2.63(t,J＝7.4Hz,2H),2.57(s,3H),1.28(t,J＝6.8Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.15,158.90,155.31,143.54,140.65,136.31,129.66,129.26,126.33,125.18,121.37,121.23,115.18,113.33,112.48,63.15,44.36,35.64,15.09,9.49.HRMS(ESI)[M-H]-calcd forC20H20NO6S-:402.1017；found:402.1018. 1 H NMR (400MHz, DMSO-d 6 ) δ13.69(br,1H),8.18(d,J＝1.6Hz,1H),7.87(dd,J＝8.8,1.6Hz,1H),7.82(d, J＝8.8Hz,1H),7.72(t,J＝5.6Hz,1H),7.11(t,J＝7.8Hz,1H),6.68(dd,J＝8.0,2.0Hz,2H),6.64(t, J＝2.0Hz,1H),3.92(q,J＝6.8Hz,2H),3.00(q,J＝6.8Hz,2H),2.63(t,J＝7.4Hz,2H),2.57(s,3H) " 3,115.18 , 113.33,112.48,63.15,44.36,35.64,15.09,9.49.HRMS(ESI)[MH] - calcd forC 20 H 20 NO 6 S - :402.1017; found:402.1018.
实施例89Example 89
3-甲基-5-(N-(3-(2,2,2-三氟乙氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸(GPR132-B-27)
3-Methyl-5-(N-(3-(2,2,2-trifluoroethoxy)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-27)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ13.68(br,1H),8.19(d,J＝1.6Hz,1H),7.88(dd,J＝8.8,2.0Hz,1H),7.83(d,J＝8.8Hz,1H),7.74(t,J＝5.8Hz,1H),7.20–7.16(m,1H),6.85–6.80(m,3H),4.67(q,J＝8.8Hz,2H),3.02(q,J＝6.8Hz,2H),2.66(t,J＝7.4Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,157.32,155.31,143.56,141.06,136.30,129.89,129.28,126.32,125.17,124.47(q,J＝279.1Hz),122.97,121.38,115.66,113.35,112.95,64.94(q,J＝34.3Hz),44.21,35.56,9.46.19F NMR(376MHz,DMSO-d6)δ-72.63.HRMS(ESI)[M-H]-calcd for C20H17F3NO6S-:456.0734；found:456.0727.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ13.68(br,1H),8.19(d,J＝1.6Hz,1H),7.88(dd,J＝8.8,2.0Hz,1H),7.83(d, J＝8.8Hz,1H),7.74(t,J＝5.8Hz,1H),7.20–7.16(m,1H),6.85–6.80(m,3H),4.67(q,J＝8.8Hz,2H), 3.02(q,J＝6.8Hz,2H),2.66(t,J＝7.4Hz,2H),2.57(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ161.15,157.32,155.31,143.56, 141.06,136.30,129.89,129.28,126.32,125.17,124.47(q,J＝279.1Hz),122.97,121.38,115.66,113.35,112.95,64.94(q,J＝34.3Hz),44.21,35 .56,9.46. 19F NMR(376MHz, DMSO-d 6 )δ-72.63.HRMS(ESI)[MH] - calcd for C 20 H 17 F 3 NO 6 S - :456.0734; found: 456.0727.
实施例90Example 90
5-(N-(3-(2-乙氧基乙氧基)苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-100)
5-(N-(3-(2-ethoxyethoxy)phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-100)
梨形瓶中加入中间体酯(0.18g,0.38mmol)，LiOH(0.020g,0.84mmol)，加入乙醇(4mL)及H2O(1mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体126mg，产率75％。Add intermediate ester (0.18g, 0.38mmol), LiOH (0.020g, 0.84mmol), ethanol (4mL) and H 2 O (1mL) to the pear-shaped flask, and react at room temperature overnight. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 126 mg of white solid with a yield of 75%.
1H NMR(400MHz,DMSO-d6)δ13.68(br,1H),8.18(d,J＝2.0Hz,1H),7.87(dd,J＝8.8,2.0Hz,1H),7.83(d,J＝8.8Hz,1H),7.72(t,J＝5.6Hz,1H),7.12(t,J＝8.0Hz,1H),6.72–6.68(m,3H),3.99(t,J＝4.2Hz,2H),3.65(t,J＝4.8Hz,2H),3.48(q,J＝6.8Hz,2H),3.00(q,J＝6.8Hz,2H),2.63(t,J＝7.4Hz,2H),2.57(s,3H),1.12(t,J＝6.8Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.15,158.87,155.31,143.55,140.70,136.32,129.69,129.27,126.34,125.19,121.43,121.38,115.26,113.36,112.59,68.81,67.35,66.13,44.35,35.64,15.54,9.49.HRMS(ESI)[M-H]-calcd for C22H24NO7S-:446.1279；found:446.1274. 1 H NMR (400MHz, DMSO-d 6 ) δ13.68 (br, 1H), 8.18 (d, J = 2.0Hz, 1H), 7.87 (dd, J = 8.8, 2.0Hz, 1H), 7.83 (d, J＝8.8Hz,1H),7.72(t,J＝5.6Hz,1H),7.12(t,J＝8.0Hz,1H),6.72–6.68(m,3H),3.99(t,J＝4.2Hz, 2H),3.65(t,J＝4.8Hz,2H),3.48(q,J＝6.8Hz,2H),3.00(q,J＝6.8Hz,2H),2.63(t,J＝7.4Hz,2H) ,2.57(s,3H),1.12(t,J＝6.8Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ161.15,158.87,155.31,143.55,140.70,136.32,129.69,129.27,126.34,125.19 ,121.43,121.38,115.26,113.36,112.59,68.81,67.35,66.13,44.35,35.64,15.54,9.49.HRMS(ESI)[MH] - calcd for C 22 H 24 NO 7 S - :446.1279; found:446.1 274.
实施例91Example 91
5-(N-(3-(3,3-二氟氮杂环丁烷-1-基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-101)
5-(N-(3-(3,3-difluoroazetidin-1-yl)phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B -101)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.18–7.11(m,2H),7.00(dddt,J＝7.3,3.5,2.4,1.2Hz,2H),6.74(tt,J＝2.1,1.0Hz,1H),4.02(t,J＝20.9Hz,4H),3.18(dt,J＝6.6,5.8Hz,2H),2.78(tt,J＝5.6,0.9Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,148.7(t,J＝3.9Hz),143.1,138.2,134.6,130.2,127.6,125.5,125.0,122.3,120.2,117.1,116.9(t,J＝216Hz),113.4,113.3,60.9(t,J＝27.1Hz),45.0,35.1,10.0.19F NMR(376MHz,DMSO-d6)δ-122.4.HRMS(ESI)[M-H]-calcd for C21H20F2N2O5S:449.0988；found:449.0988.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.18–7.11(m,2H),7.00(dddt,J＝7.3,3.5,2.4,1.2Hz,2H),6.74(tt,J＝2.1,1.0Hz,1H),4.02(t,J＝20.9Hz ,4H),3.18(dt,J＝6.6,5.8Hz,2H),2.78(tt,J＝5.6,0.9Hz,2H),2.58(s,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ165.0,157.9,148.7(t,J＝3.9Hz),143.1,138.2,134.6,130.2,127.6,125.5,125.0,122.3,120.2,117.1,116.9(t,J＝216Hz),113.4,113.3,60.9 (t , J=27.1Hz), 45.0, 35.1, 10.0. 19 F NMR (376MHz, DMSO-d 6 ) δ-122.4.HRMS (ESI) [MH] - calcd for C 21 H 20 F 2 N 2 O 5 S: 449.0988; found:449.0988.
实施例92Example 92
3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-102)
3-Methyl-5-(N-(2-([1,1'-diphenyl]-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-102 )
按照实施例25所用方法，中间体乙酯替换为3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基) 氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得粉色固体216mg，收率91％。1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝1.9Hz,1H),7.88–7.71(m,3H),7.62–7.56(m,2H),7.46–7.40(m,4H),7.32(dt,J＝10.4,7.5Hz,2H),7.13(d,J＝7.5Hz,1H),3.07(q,J＝6.8Hz,2H),2.75(t,J＝6.8Hz,2H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ161.6,154.5,140.2,139.4,135.4,129.4,128.8,127.8,127.3,127.1,126.7,124.9,124.6,120.4,112.5,44.0,35.2,9.0.HRMS(ESI)[M+H]+calcd for C24H22NO5S:436.1219；found:436.1211.According to the method used in Example 25, the intermediate ethyl ester was replaced with 3-methyl-5-(N-(2-([1,1'-diphenyl]-3-yl)ethyl) Sulfamoyl)benzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 216 mg of pink solid was obtained, with a yield of 91%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.13 (d, J = 1.9 Hz, 1H), 7.88–7.71 (m, 3H), 7.62–7.56 (m, 2H), 7.46–7.40 (m, 4H) ),7.32(dt,J＝10.4,7.5Hz,2H),7.13(d,J＝7.5Hz,1H),3.07(q,J＝6.8Hz,2H),2.75(t,J＝6.8Hz,2H ), 2.53 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.6,154.5,140.2,139.4,135.4,129.4,128.8,127.8,127.3,127.1,126.7,124.9,124.6,120.4,112.5 , 44.0,35.2,9.0.HRMS(ESI)[M+H] + calcd for C 24 H 22 NO 5 S:436.1219; found:436.1211.
实施例93Example 93
3-甲基-5-(N-(3-(噻吩-3-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-103)
3-Methyl-5-(N-(3-(thiophen-3-yl)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-103)
按照实施例25乙酯所用方法合成。1H NMR(00MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.59(t,J＝1.7Hz,1H),7.52–7.35(m,5H),7.20–7.11(m,2H),3.17(dt,J＝6.6,5.7Hz,2H),2.84(tt,J＝5.8,1.0Hz,3H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,141.2,139.1,137.1,134.6,128.7,128.1,128.0,127.6,127.0,126.6,125.6,125.5,125.0,122.9,120.2,113.3,45.0,35.8,10.0.HRMS(ESI)[M-H]-calcd for C22H19NO5S2:440.0632；found:440.0632.The ethyl ester was synthesized according to the method used in Example 25. 1 H NMR (00MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.59(t,J＝1.7Hz,1H),7.52–7.35(m,5H),7.20–7.11(m,2H),3.17(dt,J＝6.6,5.7Hz,2H),2.84(tt,J =5.8,1.0Hz,3H),2.58(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ165.0,157.9,143.1,141.2,139.1,137.1,134.6,128.7,128.1,128.0,127.6,127.0 ,126.6,125.6,125.5,125.0,122.9,120.2,113.3,45.0,35.8,10.0.HRMS(ESI)[MH] - calcd for C 22 H 19 NO 5 S 2 :440.0632; found:440.0632.
实施例94Example 94
3-甲基-5-(N-(3(噻吩-2-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-104)
3-Methyl-5-(N-(3(thiophen-2-yl)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-104)
梨形瓶中加入中间体酯(0.36g,0.78mmol)，LiOH(0.042g,1.7mmol)，加入乙醇(8mL)及H2O(2mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体334mg，产率97％。Add intermediate ester (0.36g, 0.78mmol), LiOH (0.042g, 1.7mmol), ethanol (8mL) and H 2 O (2mL) to the pear-shaped flask, and react at room temperature overnight. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 334 mg of white solid with a yield of 97%.
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝2.0Hz,1H),7.87(dd,J＝8.6,1.6Hz,1H),7.80(d,J＝8.8Hz,1H),7.76(t,J＝5.8Hz,1H),7.50(d,J＝4.8Hz,1H),7.43–7.38(m,3H),7.25(t,J＝7.8Hz,1H),7.10(t,J＝4.4Hz,1H),7.07(d,J＝7.6Hz,1H),3.08(q,J＝6.8Hz,2H),2.72(t,J＝7.2Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO-d6)δ161.13,155.30,143.78,143.56,140.09,136.34,134.13,129.44,129.28,128.80,128.45,126.30,126.20,125.95,125.14,124.00,123.81,121.33,113.31,44.31,35.50,9.47.HRMS(ESI)[M-H]-calcd for C22H18NO5S2 -:440.0700；found:440.0627. 1 H NMR (400MHz, DMSO-d 6 ) δ8.18 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 8.6, 1.6 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H) ,7.76(t,J＝5.8Hz,1H),7.50(d,J＝4.8Hz,1H),7.43–7.38(m,3H),7.25(t,J＝7.8Hz,1H),7.10(t, J＝4.4Hz,1H),7.07(d,J＝7.6Hz,1H),3.08(q,J＝6.8Hz,2H),2.72(t,J＝7.2Hz,2H),2.54(s,3H) . 13 C NMR (101MHz, DMSO-d 6 ) δ161.13,155.30,143.78,143.56,140.09,136.34,134.13,129.44,129.28,128.80,128.45,126.30,126.20,125.95,12 5.14,124.00,123.81,121.33,113.31, 44.31,35.50,9.47.HRMS(ESI)[MH] - calcd for C 22 H 18 NO 5 S 2 - :440.0700; found:440.0627.
实施例95Example 95
3-甲基-5-(N-(3-(1-甲基-1H-吡唑-4-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-105)
3-Methyl-5-(N-(3-(1-methyl-1H-pyrazol-4-yl)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-105 )
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(3-(1-甲基-1H-吡唑-4-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得黄色固体41mg，收率41％。1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝1.8Hz,1H),8.03(s,1H),7.85(dd,J＝8.7,1.8Hz, 1H),7.81–7.72(m,3H),7.39–7.27(m,2H),7.19(t,J＝7.6Hz,1H),6.94(d,J＝7.6Hz,1H),3.84(s,3H),3.11–2.96(m,2H),2.68(t,J＝7.3Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO)δ154.7,139.1,135.9,135.7,132.5,129.0,128.7,127.6,126.3,125.5,125.2,122.8,121.8,120.7,112.7,43.9,38.6,35.2,9.0.HRMS(ESI)[M+H]+calcd for C22H22N3O5S:440.1280；found:440.1273.According to the method used in Example 25, the intermediate ethyl ester was replaced with 3-methyl-5-(N-(3-(1-methyl-1H-pyrazol-4-yl)phenylethyl)sulfamoyl) Benzofuran-2-carboxylic acid ethyl ester, the other conditions are the same. 41 mg of yellow solid was obtained, with a yield of 41%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.16 (d, J＝1.8Hz, 1H), 8.03 (s, 1H), 7.85 (dd, J＝8.7, 1.8Hz, 1H),7.81–7.72(m,3H),7.39–7.27(m,2H),7.19(t,J＝7.6Hz,1H),6.94(d,J＝7.6Hz,1H),3.84(s,3H ),3.11–2.96(m,2H),2.68(t,J＝7.3Hz,2H),2.54(s,3H). 13 C NMR(101MHz,DMSO)δ154.7,139.1,135.9,135.7,132.5,129.0, 128.7,127.6,126.3,125.5,125.2,122.8,121.8,120.7,112.7,43.9,38.6,35.2,9.0.HRMS(ESI)[M+H] + calcd for C 22 H 22 N 3 O 5 S:440.1280; found:440.1273.
实施例96Example 96
3-甲基-5-(N-(3-(1-甲基-1H-吡唑-5-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-106)
3-Methyl-5-(N-(3-(1-methyl-1H-pyrazol-5-yl)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-106 )
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(3-(1-甲基-1H-吡唑-5-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得灰色固体88mg，收率57％。1H NMR(400MHz,DMSO-d6)δ8.23–8.18(m,1H),7.91–7.73(m,3H),7.44(d,J＝1.9Hz,1H),7.39–7.27(m,3H),7.20(dt,J＝7.2,1.7Hz,1H),6.34(d,J＝1.9Hz,1H),3.81(s,3H),3.07(q,J＝6.8Hz,2H),2.75(t,J＝7.1Hz,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.2,142.6,139.4,137.8,135.8,130.1,128.8,128.8,128.7,128.7,126.3,125.8,124.6,120.9,112.9,105.7,43.8,37.4,35.0,9.0.HRMS(ESI)[M+H]+calcd for C22H22N3O5S:440.1280；found:440.1273.According to the method used in Example 25, the intermediate ethyl ester was replaced with 3-methyl-5-(N-(3-(1-methyl-1H-pyrazol-5-yl)phenylethyl)sulfamoyl) Benzofuran-2-carboxylic acid ethyl ester, the other conditions are the same. 88 mg of gray solid was obtained, with a yield of 57%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.23–8.18(m,1H),7.91–7.73(m,3H),7.44(d,J＝1.9Hz,1H),7.39–7.27(m,3H ),7.20(dt,J＝7.2,1.7Hz,1H),6.34(d,J＝1.9Hz,1H),3.81(s,3H),3.07(q,J＝6.8Hz,2H),2.75(t , J=7.1Hz, 2H), 2.55 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ160.7,154.8,143.2,142.6,139.4,137.8,135.8,130.1,128.8,128.8,128.7,128.7 ,126.3,125.8,124.6,120.9,112.9,105.7,43.8,37.4,35.0,9.0.HRMS(ESI)[M+H] + calcd for C 22 H 22 N 3 O 5 S:440.1280; found:440.1273.
实施例97Example 97
5-(N-(2-氟-4-氯苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸(GPR132-B-107)
5-(N-(2-fluoro-4-chlorophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-107)
根据GPR132-B-60的合成步骤，得到白色固体108.6mg，收率80％。1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.90–7.74(m,3H),7.25(t,J＝8.3Hz,2H),7.13(dd,J＝8.2,1.8Hz,1H),3.02(q,J＝6.8Hz,2H),2.69(t,J＝6.9Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,160.9(d,J＝247.3Hz),155.3,143.9,136.2,133.0(d,J＝5.7Hz),132.2(d,J＝10.3Hz),129.3,126.2,1245.0(d,J＝15.7Hz),124.9,124.8,121.2,116.1(d,J＝26.0Hz),113.3.19F NMR(376MHz,DMSO-d6)δ-113.46.HRMS(ESI)[M-H]-calcd forC18H14ClFNO5S:410.0271；found:410.0262.According to the synthesis procedure of GPR132-B-60, 108.6 mg of white solid was obtained with a yield of 80%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.14 (s, 1H), 7.90–7.74 (m, 3H), 7.25 (t, J = 8.3Hz, 2H), 7.13 (dd, J = 8.2, 1.8 Hz, 1H), 3.02 (q, J = 6.8Hz, 2H), 2.69 (t, J = 6.9Hz, 2H), 2.57 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 161.2, 160.9 (d,J＝247.3Hz),155.3,143.9,136.2,133.0(d,J＝5.7Hz),132.2(d,J＝10.3Hz),129.3,126.2,1245.0(d,J＝15.7Hz),124.9 ,124.8,121.2,116.1(d,J=26.0Hz),113.3. 19 F NMR (376MHz, DMSO-d 6 )δ-113.46.HRMS(ESI)[MH] - calcd forC 18 H 14 ClFNO 5 S: 410.0271 ;found:410.0262.
实施例98Example 98
3-甲基-5-(N-(2-氟-3-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-108)
3-Methyl-5-(N-(2-fluoro-3-methylphenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-108)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(2-氟-3-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体143mg，收率68％。1H NMR(400MHz,DMSO-d6)δ8.17–8.13(m,1H),7.86–7.78(m,3H),7.10–6.89(m,3H),3.08–2.86(m,2H),2.67(d,J＝7.9Hz,2H),2.59–2.52(m,3H),2.13(s,3H).13C NMR(101MHz,DMSO-d6)δ161.1,154.7,135.6,129.7,129.0,128.6,125.5,124.9,123.7,120.7,112.8,42.6,28.9,14.1,9.0.19F NMR(376MHz,DMSO-d6)δ-123.64.HRMS(ESI)[M-H]-calcd for C19H18FNO5S:390.0811；found:390.0805. According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(2-fluoro-3-methylphenethyl)sulfamoyl)benzofuran-2-carboxylate. ester, other conditions are the same. 143 mg of white solid was obtained, with a yield of 68%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.17–8.13(m,1H),7.86–7.78(m,3H),7.10–6.89(m,3H),3.08–2.86(m,2H),2.67 (d,J＝7.9Hz,2H),2.59–2.52(m,3H),2.13(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ161.1,154.7,135.6,129.7,129.0,128.6, 125.5,124.9,123.7,120.7,112.8,42.6,28.9,14.1,9.0. 19 F NMR(376MHz,DMSO-d 6 )δ-123.64.HRMS(ESI)[MH] - calcd for C 19 H 18 FNO 5 S :390.0811; found:390.0805.
实施例99Example 99
5-(N-(2-(2,3-二氢苯并呋喃-7-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-109)
5-(N-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-109)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.19(t,J＝6.5Hz,1H),7.10(ddq,J＝16.3,8.1,1.2Hz,2H),7.00–6.93(m,1H),4.49(dd,J＝5.2,3.2Hz,2H),3.26–3.05(m,4H),2.91(td,J＝5.9,1.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,158.9,157.9,143.1,134.6,127.7,127.6,127.6,125.9,125.5,125.0,121.0,120.2,118.2,113.3,73.4,42.3,30.6,29.1,10.0.HRMS(ESI)[M-H]-calcd for C20H19NO6S:400.0860；found:400.0860.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.19(t,J＝6.5Hz,1H),7.10(ddq,J＝16.3,8.1,1.2Hz,2H),7.00–6.93(m,1H),4.49(dd,J＝5.2,3.2Hz,2H ),3.26–3.05(m,4H),2.91(td,J＝5.9,1.0Hz,2H),2.58(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.0,158.9,157.9,143.1 ,134.6,127.7,127.6,127.6,125.9,125.5,125.0,121.0,120.2,118.2,113.3,73.4,42.3,30.6,29.1,10.0.HRMS(ESI)[MH] - calcd for C 20 H 19 NO 6 S :400.0860; found:400.0860.
实施例100Example 100
5-(N-(2-(2,3-二氢苯并[b][1,3]二氧杂环戊烷-5-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-110)
5-(N-(2-(2,3-dihydrobenzo[b][1,3]dioxolan-5-yl)ethyl)sulfamoyl)-3-methylbenzo Furan-2-carboxylic acid (GPR132-B-110)
梨形瓶中加入中间体酯(0.31g,0.75mmol)，LiOH(0.06g,2.8mmol)，加入乙醇(12mL)及H2O(3mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体270mg，产率91％。Add intermediate ester (0.31g, 0.75mmol), LiOH (0.06g, 2.8mmol), ethanol (12mL) and H 2 O (3mL) to the pear-shaped flask, and react at room temperature overnight. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 270 mg of white solid with a yield of 91%.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.18(d,J＝1.8Hz,1H),7.88(dd,J＝8.8,1.8Hz,1H),7.84(d,J＝8.7Hz,1H),7.79(t,J＝5.9Hz,1H),6.73–6.67(m,2H),6.62(dd,J＝5.4,3.7Hz,1H),5.91(s,2H),3.07–2.96(m,2H),2.63(t,J＝7.5Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.14,155.32,147.10,145.72,143.56,136.32,129.28,126.34,125.18,123.16,121.81,121.36,120.14,113.34,107.27,100.89,42.54,29.89,9.49.HRMS(ESI)[M-H]-calcd for C19H17NO7S:402.0653；found:402.0653. 1 H NMR (400MHz, DMSO-d 6 ) δ13.70 (s, 1H), 8.18 (d, J = 1.8Hz, 1H), 7.88 (dd, J = 8.8, 1.8Hz, 1H), 7.84 (d, J＝8.7Hz,1H),7.79(t,J＝5.9Hz,1H),6.73–6.67(m,2H),6.62(dd,J＝5.4,3.7Hz,1H),5.91(s,2H), 3.07–2.96(m,2H),2.63(t,J=7.5Hz,2H),2.57(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ161.14,155.32,147.10,145.72,143.56,136.32 ,129.28,126.34,125.18,123.16,121.81,121.36,120.14,113.34,107.27,100.89,42.54,29.89,9.49.HRMS(ESI)[MH] - calcd for C 19 H 17 NO 7 S:402.06 53;found:402.0653 .
实施例101Example 101
5-(N-(2-(2,2-二氟苯并[d][1,3]二氧杂环戊-4-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-111)
5-(N-(2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)ethyl)sulfamoyl)-3-methylbenzofuran -2-carboxylic acid (GPR132-B-111)
梨形瓶中加入中间体酯(0.24g,0.5mmol)，LiOH(0.07g,0.28mmol)，加入乙醇(8mL)及H2O(2mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体145mg，产率66％。Add intermediate ester (0.24g, 0.5mmol), LiOH (0.07g, 0.28mmol), ethanol (8mL) and H 2 O (2mL) to the pear-shaped flask, and react at room temperature overnight. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 145 mg of white solid, with a yield of 66%.
1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),8.16(s,1H),7.88–7.77(m,3H),7.16(d,J＝7.9Hz,1H),7.07(t,J＝7.9Hz,1H),7.01(d,J＝7.9Hz,1H),3.08(q,J＝6.7Hz,2H),2.75(t,J＝7.0Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.13,155.31,143.59,142.84,141.77,136.21,131.34(t,J＝255.6Hz),129.26,126.24,125.87,125.11,124.54,121.96,121.32, 113.33,108.54,42.30,29.29,9.42.19F NMR(376MHz,CDCl3)δ-49.73.HRMS(ESI)[M-H]-calcd for C19H15F2NO7S:438.0465；found:438.0465. 1 H NMR (400MHz, DMSO-d 6 ) δ13.69 (s, 1H), 8.16 (s, 1H), 7.88–7.77 (m, 3H), 7.16 (d, J = 7.9Hz, 1H), 7.07 ( t,J＝7.9Hz,1H),7.01(d,J＝7.9Hz,1H),3.08(q,J＝6.7Hz,2H),2.75(t,J＝7.0Hz,2H),2.56(s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 161.13, 155.31, 143.59, 142.84, 141.77, 136.21, 131.34 (t, J = 255.6Hz), 129.26, 126.24, 125.87, 125.11, 124.54, 1 21.96,121.32, 113.33,108.54,42.30,29.29,9.42. 19 F NMR (376MHz, CDCl 3 )δ-49.73.HRMS (ESI) [MH] - calcd for C 19 H 15 F 2 NO 7 S: 438.0465; found: 438.0465.
实施例102Example 102
5-(N-(2-(2,3-二氢苯并[b][1,4]二氧杂环己烷-5-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-112)
5-(N-(2-(2,3-dihydrobenzo[b][1,4]dioxan-5-yl)ethyl)sulfamoyl)-3-methylbenzo Furan-2-carboxylic acid (GPR132-B-112)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.4Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.22(t,J＝6.5Hz,1H),6.92–6.85(m,1H),6.78–6.69(m,2H),4.29(s,4H),3.21–3.14(m,2H),2.93(td,J＝6.0,1.1Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,145.6,144.3,143.1,134.6,127.6,125.8,125.5,125.0,124.1,122.9,120.2,113.3,113.2,65.1,63.7,42.2,30.5,10.0.HRMS(ESI)[M-H]-calcd for C20H19NO7S:416.0809；found:416.0809.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.4Hz, 1H), 7.97 (dd, J = 9.0, 2.2Hz, 1H), 7.64 (d, J = 9.0Hz, 1H) ,7.22(t,J＝6.5Hz,1H),6.92–6.85(m,1H),6.78–6.69(m,2H),4.29(s,4H),3.21–3.14(m,2H),2.93(td ,J＝6.0,1.1Hz,2H),2.58(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ165.0,157.9,145.6,144.3,143.1,134.6,127.6,125.8,125.5,125.0,124.1 ,122.9,120.2,113.3,113.2,65.1,63.7,42.2,30.5,10.0.HRMS(ESI)[MH] - calcd for C 20 H 19 NO 7 S:416.0809; found:416.0809.
实施例103Example 103
5-(N-(2,4-二氟苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-114)
5-(N-(2,4-difluorophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-114)
梨形瓶中加入中间体酯(0.10g,0.24mmol)，LiOH(0.013g,0.51mmol)，加入乙醇(4mL)及H2O(1mL)，室温反应2.5h，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体92mg，产率95％。Add the intermediate ester (0.10g, 0.24mmol), LiOH (0.013g, 0.51mmol), ethanol (4mL) and H 2 O (1mL) to the pear-shaped bottle, and react at room temperature for 2.5h. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 92 mg of white solid with a yield of 95%.
1H NMR(400MHz,DMSO-d6)δ13.68(br,1H),8.16(s,1H),7.88–7.82(m,2H),7.79(t,J＝5.8Hz,1H),7.27(dd,J＝15.2,8.8Hz,1H),7.10–7.04(m,1H),6.97–6.92(m,1H),2.99(q,J＝7.8Hz,2H),2.68(t,J＝7.2Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.14,155.32,143.58,136.27,132.78,132.72,132.68,132.62,129.29,126.28,125.13,122.06,121.91,121.32,113.36,111.75,111.71,111.54,111.50,104.22,103.96,103.70,42.96,28.63,9.47.19F NMR(376MHz,DMSO-d6)δ-112.83,-114.35.HRMS(ESI)[M-H]-calcd forC18H14F2NO5S-:394.0566；found:394.0561. 1 H NMR (400MHz, DMSO-d 6 ) δ13.68 (br, 1H), 8.16 (s, 1H), 7.88–7.82 (m, 2H), 7.79 (t, J = 5.8Hz, 1H), 7.27 ( dd,J＝15.2,8.8Hz,1H),7.10–7.04(m,1H),6.97–6.92(m,1H),2.99(q,J＝7.8Hz,2H),2.68(t,J＝7.2Hz ,2H),2.57(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ161.14,155.32,143.58,136.27,132.78,132.72,132.68,132.62,129.29,126.28,125.13,122.06,1 21.91,121.32, 113.36,111.75,111.71,111.54,111.50,104.22,103.96,103.70,42.96,28.63,9.47. 19 F NMR (376MHz, DMSO-d 6 )δ-112.83,-114.35.HRMS(ESI)[MH] - calc d forC 18 H 14 F 2 NO 5 S - :394.0566; found: 394.0561.
实施例104Example 104
5-(N-(5-溴-2-氟苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-115)
5-(N-(5-bromo-2-fluorophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-115)
梨形瓶中加入中间体酯(0.12g,0.25mmol)，LiOH(0.013g,0.51mmol)，加入乙醇(4mL)及H2O(1mL)，室温反应4h，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色略带淡黄色固体96mg，产率85％。Add intermediate ester (0.12g, 0.25mmol), LiOH (0.013g, 0.51mmol), ethanol (4mL) and H 2 O (1mL) to the pear-shaped flask, and react at room temperature for 4 hours. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 96 mg of a white slightly yellowish solid with a yield of 85%.
1H NMR(400MHz,DMSO-d6)δ13.68(s,1H),8.19(d,J＝1.6Hz,1H),7.90–7.80(m,3H),7.24–7.21(m,1H),7.10–7.05(m,2H),3.02–2.97(m,2H),2.72(t,J＝7.4Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ162.25,161.14,159.83,155.33,143.56,136.25,131.76,131.72,129.30,128.93,128.85,126.33,125.75,125.60,125.19,124.77,124.74,121.40,115.61,115.39,113.41,43.04,29.20,9.49.HRMS(ESI)[M-H]-calcd for C18H14FBrNO5S-:453.9766；found:453.9764. 1 H NMR (400MHz, DMSO-d 6 ) δ13.68 (s, 1H), 8.19 (d, J = 1.6Hz, 1H), 7.90–7.80 (m, 3H), 7.24–7.21 (m, 1H), 7.10–7.05(m,2H),3.02–2.97(m,2H),2.72(t,J＝7.4Hz,2H),2.57(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ162. 25,161.14,159.83,155.33,143.56,136.25,131.76,131.72,129.30,128.93,128.85,126.33,125.75,125.60,125.19,124.77,124.74,121.40 ,115.61,115.39,113.41,43.04,29.20,9.49.HRMS(ESI) [MH] - calcd for C 18 H 14 FBrNO 5 S - :453.9766; found:453.9764.
实施例105Example 105
3-甲基-5-(N-(2-氟-5-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-116)
3-Methyl-5-(N-(2-fluoro-5-methylphenylethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-116)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(2-氟-5-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体163mg，收率77％。1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.99–7.68(m,3H),7.12–6.81(m,3H),3.08–2.89(m,2H),2.65(t,J＝7.5Hz,2H),2.56(s,3H),2.18(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,158.8(d,J＝240.6Hz),154.7,135.7,133.2,131.5(d,J＝4.7Hz),129.1,128.6(d,J＝8.4Hz),125.5,124.7(d,J＝16.1Hz),120.7,114.7(d,J＝22.0Hz),112.8,42.7,28.8,20.1,9.0.19F NMR(376MHz,DMSO-d6)δ-124.06.HRMS(ESI)[M-H]-calcd for C19H18FNO5S:390.0811；found:390.0811.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(2-fluoro-5-methylphenylethyl)sulfamoyl)benzofuran-2-carboxylate. ester, other conditions are the same. 163 mg of white solid was obtained, with a yield of 77%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.16(s,1H),7.99–7.68(m,3H),7.12–6.81(m,3H),3.08–2.89(m,2H),2.65(t ,J＝7.5Hz,2H),2.56(s,3H),2.18(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ161.2,158.8(d,J＝240.6Hz),154.7,135.7, 133.2, 131.5 (d, J = 4.7Hz), 129.1, 128.6 (d, J = 8.4Hz), 125.5, 124.7 (d, J = 16.1Hz), 120.7, 114.7 (d, J = 22.0Hz), 112.8, 42.7, 28.8, 20.1, 9.0. 19 F NMR (376MHz, DMSO-d 6 ) δ-124.06.HRMS (ESI) [MH] - calcd for C 19 H 18 FNO 5 S: 390.0811; found: 390.0811.
实施例106Example 106
5-(N-(2-氟-5-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-117)
5-(N-(2-fluoro-5-methoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-117)
将5-(N-(2-氟-5-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯(0.39g,0.40mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体143mg，产率89.9％。Dissolve 5-(N-(2-fluoro-5-methoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (0.39g, 0.40mmol) in ethanol ( 8mL), add lithium hydroxide (0.02g, 0.83mmol, dissolved in 2mL water), stir and react at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 143 mg of white solid, with a yield of 89.9%.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝2.0Hz,1H),7.91-7.72(m,3H),6.96(t,J＝9.2Hz,1H),6.78-6.66(m,2H),3.67(s,3H),3.01(q,J＝6.8Hz,2H),2.67(t,J＝7.2Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.16,155.34(d,J＝236.4Hz),155.32,154.17,143.61,136.30,129.30,126.46(d,J＝17.6Hz),126.26,125.11,121.32,116.60(d,J＝4.6),116.03,115.80,113.33,55.85,42.96,29.36,9.45.19F NMR(376MHz,DMSO-d6)δ-129.74.HRMS(ESI)[M-H]-calcd for C19H17FNO6S:406.0766；found:406.0764. 1 H NMR (400MHz, DMSO-d 6 ) δ8.17 (d, J = 2.0 Hz, 1H), 7.91-7.72 (m, 3H), 6.96 (t, J = 9.2 Hz, 1H), 6.78-6.66 ( m,2H),3.67(s,3H),3.01(q,J＝6.8Hz,2H),2.67(t,J＝7.2Hz,2H),2.56(s,3H). 13 C NMR(101MHz,DMSO -d 6 )δ161.16,155.34(d,J＝236.4Hz),155.32,154.17,143.61,136.30,129.30,126.46(d,J＝17.6Hz),126.26,125.11,121.32,116.60(d,J＝4.6) ,116.03,115.80,113.33,55.85,42.96,29.36,9.45. 19 F NMR (376MHz, DMSO-d 6 )δ-129.74.HRMS(ESI)[MH] - calcd for C 19 H 17 FNO 6 S: 406.0766; found:406.0764.
实施例107Example 107
5-(N-(4-氟-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-118)
5-(N-(4-fluoro-3-methoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-118)
将5-(N-(4-氟-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯(0.18g,0.41mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体158mg，产率94.0％。Dissolve 5-(N-(4-fluoro-3-methoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (0.18g, 0.41mmol) in ethanol ( 8mL), add lithium hydroxide (0.02g, 0.83mmol, dissolved in 2mL water), stir and react at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 158 mg of white solid, with a yield of 94.0%.
1H NMR(400MHz,DMSO-d6)δ8.14(d,J＝1.6Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.81(d,J＝8.8Hz,1H),7.72(t,J＝6.0Hz,1H),6.98(dd,J＝11.6,8.0Hz,1H),6.89(dd,J＝8.4,2.0Hz,1H),6.68-6.62(m,1H),3.74(s,3H),3.03(q,J＝6.8Hz,2H),2.63(t,J＝7.2Hz,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.28,151.81,149.41,147.10(d,J＝10.7Hz),143.57,136.36,135.86(d,J＝3.6Hz),129.26,126.28,125.11,121.27,121.18(d,J＝6.8Hz),115.83,115.66,114.62,113.26,56.17,44.38,35.22,9.45.19F NMR(376MHz,DMSO-d6)δ-139.14.HRMS(ESI)[M-H]-calcd for C19H17FNO6S:406.4766；found:406.0764. 1 H NMR (400MHz, DMSO-d 6 ) δ8.14(d,J＝1.6Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.81(d,J＝8.8Hz,1H) ,7.72(t,J＝6.0Hz,1H),6.98(dd,J＝11.6,8.0Hz,1H),6.89(dd,J＝8.4,2.0Hz,1H),6.68-6.62(m,1H), 3.74 (s, 3H), 3.03 (q, J = 6.8Hz, 2H), 2.63 (t, J = 7.2Hz, 2H), 2.55 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161 .15,155.28,151.81,149.41,147.10(d,J＝10.7Hz),143.57,136.36,135.86(d,J＝3.6Hz),129.26,126.28,125.11,121.27,121.18(d,J＝6.8Hz),11 5.83 ,115.66,114.62,113.26,56.17,44.38,35.22,9.45. 19 F NMR (376MHz, DMSO-d 6 )δ-139.14.HRMS(ESI)[MH] - calcd for C 19 H 17 FNO 6 S: 406.4766; found:406.0764.
实施例108Example 108
5-(N-(4-氯-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-119)
5-(N-(4-chloro-3-methoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-119)
将5-(N-(4-氯-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯(0.14g,0.31mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体117mg，产率89.1％。Dissolve 5-(N-(4-chloro-3-methoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (0.14g, 0.31mmol) in ethanol ( 8mL), add lithium hydroxide (0.02g, 0.83mmol, dissolved in 2mL water), stir and react at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 117 mg of white solid, with a yield of 89.1%.
1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝1.2Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.74(t,J＝5.6Hz,1H),7.18(d,J＝8.0Hz,1H),6.87(d,J＝2.0Hz,1H),6.68(dd,J＝8.0,2.0Hz,1H),3.77(s,3H),3.06(q,J＝6.8Hz,2H),2.66(t,J＝6.8Hz,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ161.17,155.27,154.55,143.67,139.80,136.36,129.76,129.27,126.21,125.00,122.06,121.21,119.26,113.67,113.20,56.24,44.18,35.35,9.45.HRMS(ESI)[M-H]-calcd for C19H17ClNO6S:422.0471；found:422.0470. 1 H NMR (400MHz, DMSO-d 6 ) δ8.13(d,J＝1.2Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.79(d,J＝8.8Hz,1H) ,7.74(t,J＝5.6Hz,1H),7.18(d,J＝8.0Hz,1H),6.87(d,J＝2.0Hz,1H),6.68(dd,J＝8.0,2.0Hz,1H) ,3.77(s,3H),3.06(q,J＝6.8Hz,2H),2.66(t,J＝6.8Hz,2H),2.55(s,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.17,155.27,154.55,143.67,139.80,136.36,129.76,129.27,126.21,125.00,122.06,121.21,119.26,113.67,113.20,56.24,44.18,35. 35,9.45.HRMS(ESI)[MH] - calcd for C 19 H 17 ClNO 6 S: 422.0471; found: 422.0470.
实施例109Example 109
5-(N-(3,4-二甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-120)
5-(N-(3,4-Dimethoxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-120)
根据GPR132-B-60的合成步骤，得到白色固体95mg，收率69％。1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),8.16(d,J＝1.3Hz,1H),7.91–7.77(m,2H),7.70(t,J＝5.7Hz,1H),6.79–6.52(m,3H),3.68(s,6H),3.00(q,J＝7.0Hz,2H),2.60(t,J＝7.3Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.1,155.3,148.9,147.7,143.5,136.4,131.5,129.2,126.3,125.1,121.3,121.0,113.3,113.0,112.1,55.9,55.8,44.7,35.2,9.5.HRMS(ESI)[M-H]-calcd for C20H20NO7S:418.0966；found:418.0954.According to the synthesis procedure of GPR132-B-60, 95 mg of white solid was obtained with a yield of 69%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.69 (s, 1H), 8.16 (d, J = 1.3Hz, 1H), 7.91–7.77 (m, 2H), 7.70 (t, J = 5.7Hz, 1H),6.79–6.52(m,3H),3.68(s,6H),3.00(q,J＝7.0Hz,2H),2.60(t,J＝7.3Hz,2H),2.56(s,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.1,155.3,148.9,147.7,143.5,136.4,131.5,129.2,126.3,125.1,121.3,121.0,113.3,113.0,112.1,55.9,55.8,44 .7,35.2,9.5 .HRMS(ESI)[MH] - calcd for C 20 H 20 NO 7 S:418.0966; found:418.0954.
实施例110Example 110
5-(N-(3,4-亚甲二氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-121)
5-(N-(3,4-methylenedioxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-121)
根据GPR132-B-60的合成步骤，得到白色固体98mg，收率78％。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.16(s,1H),7.90–7.78(m,2H),7.69(t,J＝5.7Hz,1H),6.72(d,J＝7.9Hz,1H),6.68(s,1H),6.57(d,J＝7.9Hz,1H),5.91(s,2H),2.97(q,J＝6.9Hz,2H),2.58(d,J＝10.3Hz,5H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,147.5,146.0,143.6,136.3,132.9,129.3,126.3,125.1,122.1,121.3,113.3,109.5,108.4,101.1,44.7,35.3,9.5.HRMS(ESI)[M-H]-calcd for C19H16NO7S:402.0653；found:402.0643.According to the synthesis procedure of GPR132-B-60, 98 mg of white solid was obtained with a yield of 78%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.71 (s, 1H), 8.16 (s, 1H), 7.90–7.78 (m, 2H), 7.69 (t, J = 5.7Hz, 1H), 6.72 ( d,J＝7.9Hz,1H),6.68(s,1H),6.57(d,J＝7.9Hz,1H),5.91(s,2H),2.97(q,J＝6.9Hz,2H),2.58( d, J＝10.3Hz, 5H). 13 C NMR (101MHz, DMSO-d 6 ) δ161.2,155.3,147.5,146.0,143.6,136.3,132.9,129.3,126.3,125.1,122.1,121.3,113.3,109.5,108 .4 ,101.1,44.7,35.3,9.5.HRMS(ESI)[MH] - calcd for C 19 H 16 NO 7 S:402.0653; found:402.0643.
实施例111Example 111
3-甲基-5-(N-(2-(萘-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-122)
3-Methyl-5-(N-(2-(naphth-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-122)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(2-(萘-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体91mg，收率93％。1H NMR(400 MHz,DMSO-d6)δ13.71(s,1H),8.15(d,J＝1.8Hz,1H),7.92–7.73(m,6H),7.60(s,1H),7.48–7.39(m,2H),7.34–7.26(m,1H),3.15(q,J＝6.8Hz,2H),2.86(t,J＝7.1Hz,2H),2.52(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,136.3,135.9,133.0,131.7,128.8,127.7,127.3,127.3,127.2,126.8,125.9,125.8,125.3,124.6,120.8,112.8,43.9,35.3,9.0.HRMS(ESI)[M-H]-calcd for C22H18NO5S:408.0906；found:408.0908.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(2-(naphthalen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate. ester, other conditions are the same. 91 mg of white solid was obtained, with a yield of 93%. 1 H NMR(400 MHz, DMSO-d 6 )δ13.71(s,1H),8.15(d,J＝1.8Hz,1H),7.92–7.73(m,6H),7.60(s,1H),7.48–7.39(m, 2H), 7.34–7.26 (m, 1H), 3.15 (q, J＝6.8Hz, 2H), 2.86 (t, J＝7.1Hz, 2H), 2.52 (s, 3H). 13 C NMR (101MHz, DMSO -d 6 )δ160.7,154.8,143.1,136.3,135.9,133.0,131.7,128.8,127.7,127.3,127.3,127.2,126.8,125.9,125.8,125.3,124.6,120.8,112.8,43 .9,35.3,9.0.HRMS( ESI)[MH] - calcd for C 22 H 18 NO 5 S:408.0906; found:408.0908.
实施例112Example 112
5-(N-(3,5-二甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-123)
5-(N-(3,5-dimethoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-123)
梨形瓶中加入中间体酯(0.23g,0.52mmol)，LiOH(0.029g,1.2mmol)，加入乙醇(8mL)及H2O(2mL)，室温过夜反应，TLC监测反应完全。反应结束后，加入适量3N HCl调节pH至1，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，干燥后得白色固体162mg，产率74％。Add intermediate ester (0.23g, 0.52mmol), LiOH (0.029g, 1.2mmol), ethanol (8mL) and H 2 O (2mL) to the pear-shaped flask, and react at room temperature overnight. TLC monitors the reaction to be complete. After the reaction, an appropriate amount of 3N HCl was added to adjust the pH to 1, and a large amount of white solid precipitated. After suction filtration, the filter cake was washed with distilled water and dried to obtain 162 mg of white solid, with a yield of 74%.
1H NMR(400MHz,DMSO-d6)δ13.69(br,1H),8.17(d,J＝1.6Hz,1H),7.87(dd,J＝8.8,2.0Hz,1H),7.82(d,J＝8.8Hz,1H),7.71(t,J＝6.0Hz,1H),6.26(d,J＝2.4Hz,2H),6.24(t,J＝2.4Hz,1H),3.66(s,6H),3.02(q,J＝7.2Hz,2H),2.59(t,J＝7.2Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,160.74,155.31,143.53,141.39,136.40,129.26,126.31,125.18,121.32,113.27,107.13,98.43,55.41,44.25,35.87,9.46.HRMS(ESI)[M-H]-calcd for C20H20NO7S-:418.0966；found:418.0966. 1 H NMR (400MHz, DMSO-d 6 ) δ13.69(br,1H),8.17(d,J＝1.6Hz,1H),7.87(dd,J＝8.8,2.0Hz,1H),7.82(d, J＝8.8Hz,1H),7.71(t,J＝6.0Hz,1H),6.26(d,J＝2.4Hz,2H),6.24(t,J＝2.4Hz,1H),3.66(s,6H) ,3.02(q,J＝7.2Hz,2H),2.59(t,J＝7.2Hz,2H),2.56(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ161.15,160.74,155.31,143.53 ,141.39,136.40,129.26,126.31,125.18,121.32,113.27,107.13,98.43,55.41,44.25,35.87,9.46.HRMS(ESI)[MH] - calcd for C 20 H 20 NO 7 S - :418.096 6;found: 418.0966.
实施例113Example 113
5-(N-(3-吲哚基乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-125)
5-(N-(3-Indoylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-125)
根据GPR132-B-60的合成步骤，得到白色固体82mg，收率65％。1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.20(d,J＝10.4Hz,1H),7.94–7.67(m,3H),7.31(dd,J＝22.9,7.8Hz,2H),7.10(s,1H),7.01(t,J＝7.3Hz,1H),6.91(t,J＝7.3Hz,1H),4.38(q,J＝6.9Hz,1H),3.05(q,J＝6.8Hz,2H),2.79(t,J＝7.2Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ159.6,155.3,155.2,136.6,136.3,129.4,127.4,126.6,126.1,123.4,121.3,121.2,118.6,118.3,113.2,111.8,111.3,43.9,25.8,9.5.HRMS(ESI)[M-H]-calcd for C20H17N2O5S:397.0864；found:397.0855.According to the synthesis procedure of GPR132-B-60, 82 mg of white solid was obtained with a yield of 65%. 1 H NMR (400MHz, DMSO-d 6 ) δ10.78 (s, 1H), 8.20 (d, J = 10.4Hz, 1H), 7.94–7.67 (m, 3H), 7.31 (dd, J = 22.9, 7.8 Hz,2H),7.10(s,1H),7.01(t,J＝7.3Hz,1H),6.91(t,J＝7.3Hz,1H),4.38(q,J＝6.9Hz,1H),3.05( q, J＝6.8Hz, 2H), 2.79 (t, J＝7.2Hz, 2H), 2.56 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 159.6, 155.3, 155.2, 136.6, 136.3, 129.4,127.4,126.6,126.1,123.4,121.3,121.2,118.6,118.3,113.2,111.8,111.3,43.9,25.8,9.5.HRMS(ESI)[MH] - calcd for C 20 H 17 N 2 O 5 S: 397.0864; found:397.0855.
实施例114Example 114
5-(正丁基磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-127)
5-(n-Butylsulfonyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-127)
将3-甲基-5-(N-(4-甲基苯基乙基)磺胺基)苯并呋喃-2-羧酸乙酯(0.13g,0.38mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体119mg，产率99％。Dissolve ethyl 3-methyl-5-(N-(4-methylphenylethyl)sulfonamido)benzofuran-2-carboxylate (0.13g, 0.38mmol) in ethanol (8mL), add hydrogen Lithium oxide (0.02g, 0.83mmol, dissolved in 2mL water), stirred at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 119 mg of white solid, with a yield of 99%.
1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝2.0Hz,1H),7.90(dd,J＝8.8,2.0Hz,1H),7.84(d,J＝8.8Hz,1H),7.58(t,J＝6.0Hz,1H),2.73(q,J＝6.8Hz,2H),2.57(s,3H),1.37- 1.27(m,2H),1.27-1.15(m,2H),0.76(t,J＝7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.14,155.28,143.62,136.48,129.26,126.31,125.08,121.31,113.33,42.67,31.50,19.64,13.86,9.46.HRMS(ESI)[M-H]-calcd for C14H17NO5S:310.0755；found:310.0753. 1 H NMR (400MHz, DMSO-d 6 ) δ8.20 (d, J = 2.0Hz, 1H), 7.90 (dd, J = 8.8, 2.0Hz, 1H), 7.84 (d, J = 8.8Hz, 1H) ,7.58(t,J＝6.0Hz,1H),2.73(q,J＝6.8Hz,2H),2.57(s,3H),1.37- 1.27 (m, 2H), 1.27-1.15 (m, 2H), 0.76 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 161.14, 155.28, 143.62, 136.48, 129.26, 126.31 ,125.08,121.31,113.33,42.67,31.50,19.64,13.86,9.46.HRMS(ESI)[MH] - calcd for C 14 H 17 NO 5 S:310.0755; found:310.0753.
实施例115Example 115
5-(N-(3-碘丁-3-烯-1-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-129)
5-(N-(3-iodobut-3-en-1-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-129)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),6.73(t,J＝5.1Hz,1H),5.80(q,J＝1.0Hz,1H),5.72(q,J＝1.0Hz,1H),2.99(q,J＝5.3Hz,2H),2.58(s,3H),2.44(tt,J＝5.4,1.0Hz,2H).13C NMR(101MHz,DMSO-d6)δ165.6,156.7,143.1,134.9,127.8,127.1,126.6,126.3,119.4,113.0,109.5,44.0,41.6,10.3.HRMS(ESI)[M-H]-calcd for C14H14INO5S:433.9565；found:433.9565. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,6.73(t,J＝5.1Hz,1H),5.80(q,J＝1.0Hz,1H),5.72(q,J＝1.0Hz,1H),2.99(q,J＝5.3Hz,2H),2.58 (s, 3H), 2.44 (tt, J = 5.4, 1.0Hz, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ 165.6, 156.7, 143.1, 134.9, 127.8, 127.1, 126.6, 126.3, 119.4, 113.0 ,109.5,44.0,41.6,10.3.HRMS(ESI)[MH] - calcd for C 14 H 14 INO 5 S:433.9565; found:433.9565.
实施例116Example 116
5-(N-(2-环戊基乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-131)
5-(N-(2-cyclopentylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-131)
将5-(N-(2-环戊基乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.39mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体75mg，产率53.9％。Dissolve ethyl 5-(N-(2-cyclopentylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate (0.15g, 0.39mmol) in ethanol (8mL), add hydrogen Lithium oxide (0.02g, 0.83mmol, dissolved in 2mL water), stirred at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 75 mg of white solid, with a yield of 53.9%.
1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝2.0Hz,1H),7.89(dd,J＝8.8,2.0Hz,1H),7.85(d,J＝8.8Hz,1H),7.58(t,J＝6.0Hz,1H),2.73(dd,J＝14.8,6.0Hz,2H),2.56(s,3H),1.75-1.54(m,3H),1.53-1.30(m,7H),0.99-0.86(m,2H).13C NMR(101MHz,DMSO-d6)δ161.15,155.29,143.58,136.42,129.26,126.35,125.13,121.34,113.36,42.40,37.13,35.67,32.32,24.99,9.47.HRMS(ESI)[M-H]-calcd for C17H20NO5S:350.1068；found:350.1057. 1 H NMR (400MHz, DMSO-d 6 ) δ8.20 (d, J = 2.0Hz, 1H), 7.89 (dd, J = 8.8, 2.0Hz, 1H), 7.85 (d, J = 8.8Hz, 1H) ,7.58(t,J＝6.0Hz,1H),2.73(dd,J＝14.8,6.0Hz,2H),2.56(s,3H),1.75-1.54(m,3H),1.53-1.30(m,7H ),0.99-0.86(m,2H). 13 C NMR (101MHz, DMSO-d 6 )δ161.15,155.29,143.58,136.42,129.26,126.35,125.13,121.34,113.36,42.40,37.13,35.67,32. 32,24.99, 9.47.HRMS(ESI)[MH] - calcd for C 17 H 20 NO 5 S:350.1068; found:350.1057.
实施例117Example 117
3-甲基-5-(N-(2-(噻吩-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-133)
3-Methyl-5-(N-(2-(thiophen-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-133)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.27–7.20(m,2H),7.14(t,J＝6.6Hz,1H),6.66(dd,J＝5.2,1.7Hz,1H),3.17(dt,J＝6.7,5.2Hz,2H),2.77(t,J＝5.2Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,137.0,134.6,127.6,127.5,125.5,125.5,125.0,124.5,120.2,113.3,44.7,30.9,10.0.HRMS(ESI)[M-H]-calcd for C16H15NO5S2:364.0319；found:364.0319. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.27–7.20(m,2H),7.14(t,J＝6.6Hz,1H),6.66(dd,J＝5.2,1.7Hz,1H),3.17(dt,J＝6.7,5.2Hz,2H), 2.77 (t, J=5.2Hz, 2H), 2.58 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ165.0,157.9,143.1,137.0,134.6,127.6,127.5,125.5,125.5,125.0, 124.5,120.2,113.3,44.7,30.9,10.0.HRMS(ESI)[MH] - calcd for C 16 H 15 NO 5 S 2 :364.0319; found:364.0319.
实施例118Example 118
5-(N-(2-(5-氯噻吩-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-134)
5-(N-(2-(5-chlorothiophen-2-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-134)
1H NMR(400MHz,DMSO-d6)δ8.07(d,J＝1.8Hz,1H),7.84(t,J＝5.8Hz,1H),7.78(dd,J＝8.7,1.9Hz,1H),7.72(d,J＝8.7Hz,1H),6.87(d,J＝3.8Hz,1H),6.71(dd,J＝3.7,1.0Hz,1H),2.97(q,J＝6.5Hz,2H),2.83(t,J＝6.8Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO)δ162.2,154.3,140.5,134.8,129.9,126.3,125.6,125.5,124.2,120.0,112.2,43.7,29.8,9.0.HRMS(ESI)[M-H]-calcd for C16H14ClNO5S2:400.0080；found:400.0074. 1 H NMR (400MHz, DMSO-d 6 ) δ8.07(d,J＝1.8Hz,1H),7.84(t,J＝5.8Hz,1H),7.78(dd,J＝8.7,1.9Hz,1H) ,7.72(d,J＝8.7Hz,1H),6.87(d,J＝3.8Hz,1H),6.71(dd,J＝3.7,1.0Hz,1H),2.97(q,J＝6.5Hz,2H) ,2.83(t,J＝6.8Hz,2H),2.54(s,3H). 13 C NMR(101MHz,DMSO)δ162.2,154.3,140.5,134.8,129.9,126.3,125.6,125.5,124.2,120.0,112.2, 43.7,29.8,9.0.HRMS(ESI)[MH] - calcd for C 16 H 14 ClNO 5 S 2 :400.0080; found:400.0074.
实施例119Example 119
3-甲基-5-(N-(2-(5-溴噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-135)
3-Methyl-5-(N-(2-(5-bromothiophen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-135)
按照实施例25所用方法，将中间体酯替换为3-甲基-5-(N-(2-(5-溴噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体205mg，收率86％。1H NMR(400MHz,DMSO-d6)δ13.74(s,1H),8.19(d,J＝1.8Hz,1H),7.91–7.80(m,3H),6.97(d,J＝3.7Hz,1H),6.68(d,J＝3.7Hz,1H),3.01–2.93(m,2H),2.85(t,J＝6.7Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.3,143.1,135.7,129.9,128.9,126.6,125.8,124.6,121.0,112.9,108.7,43.7,29.8,9.1.HRMS(ESI)[M-H]-calcd for C16H14BrNO5S2:441.9419；found:441.9413.According to the method used in Example 25, the intermediate ester was replaced with 3-methyl-5-(N-(2-(5-bromothiophen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxy Acid ethyl ester, other conditions are the same. 205 mg of white solid was obtained, with a yield of 86%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.74 (s, 1H), 8.19 (d, J = 1.8Hz, 1H), 7.91–7.80 (m, 3H), 6.97 (d, J = 3.7Hz, 1H), 6.68 (d, J＝3.7Hz, 1H), 3.01–2.93 (m, 2H), 2.85 (t, J＝6.7Hz, 2H), 2.57 (s, 3H). 13 C NMR (101MHz, DMSO -d 6 )δ160.7,154.9,143.3,143.1,135.7,129.9,128.9,126.6,125.8,124.6,121.0,112.9,108.7,43.7,29.8,9.1.HRMS(ESI)[MH] - calcd for C 16 H 14 BrNO 5 S 2 :441.9419; found:441.9413.
实施例120Example 120
3-甲基-5-(N-(2-(4-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-136)
3-Methyl-5-(N-(2-(4-methylthiophen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-136)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(2-(4-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得褐色固体48mg，收率48％。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝1.8Hz,1H),7.92–7.77(m,3H),6.83(s,1H),6.61(s,1H),2.98(q,J＝6.7Hz,2H),2.82(t,J＝7.2Hz,2H),2.57(s,3H),2.09(s,3H).13C NMR(101MHz,DMSO-d6)δ160.9,154.8,143.8,140.5,136.7,135.7,129.0,127.7,125.7,124.1,120.9,119.0,112.9,44.1,29.7,15.3,9.0.HRMS(ESI)[M-H]-calcd for C17H16NO5S2:378.0470；found:378.0473.According to the method used in Example 25, the intermediate ethyl ester was replaced with 3-methyl-5-(N-(2-(4-methylthiophen-2-yl)ethyl)sulfamoyl)benzofuran-2 -Ethyl carboxylate, all other conditions are the same. 48 mg of brown solid was obtained, with a yield of 48%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J＝1.8Hz, 1H), 7.92–7.77 (m, 3H), 6.83 (s, 1H), 6.61 (s, 1H), 2.98 ( q, J＝6.7Hz, 2H), 2.82 (t, J＝7.2Hz, 2H), 2.57 (s, 3H), 2.09 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 160.9, 154.8 ,143.8,140.5,136.7,135.7,129.0,127.7,125.7,124.1,120.9,119.0,112.9,44.1,29.7,15.3,9.0.HRMS(ESI)[MH] - calcd for C 17 H 16 NO 5 S 2 : 378.0470; found:378.0473.
实施例121Example 121
3-甲基-5-(N-(2-(3-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-137)
3-Methyl-5-(N-(2-(3-methylthiophen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-137)
按照实施例25所用方法，中间体乙酯替换为3-甲基-5-(N-(2-(3-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得灰黄色固体161mg，收率79％。1H NMR(400MHz,DMSO-d6)δ8.02(d,J＝1.9Hz,1H),7.83(t,J＝5.8Hz,1H),7.77–7.65(m,2H),6.62–6.53(m,2H),2.95(q,J＝6.8Hz,2H),2.80(t,J＝7.2Hz,2H),2.52(s,3H),2.33(s,3H). 13C NMR(101MHz,DMSO-d6)δ163.0,153.9,151.4,138.5,137.3,134.5,130.4,125.2,124.9,123.4,119.5,116.3,112.0,44.3,29.7,14.9,9.0.HRMS(ESI)[M-H]-calcd for C17H16NO5S2:378.0470；found:378.0465.According to the method used in Example 25, the intermediate ethyl ester was replaced with 3-methyl-5-(N-(2-(3-methylthiophen-2-yl)ethyl)sulfamoyl)benzofuran-2- Ethyl carboxylate, other conditions were the same. 161 mg of grayish-yellow solid was obtained, with a yield of 79%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.02 (d, J = 1.9 Hz, 1H), 7.83 (t, J = 5.8 Hz, 1H), 7.77–7.65 (m, 2H), 6.62–6.53 ( m,2H),2.95(q,J＝6.8Hz,2H),2.80(t,J＝7.2Hz,2H),2.52(s,3H),2.33(s,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ163.0,153.9,151.4,138.5,137.3,134.5,130.4,125.2,124.9,123.4,119.5,116.3,112.0,44.3,29.7,14.9,9.0.HRMS (ESI )[ MH] - calcd for C 17 H 16 NO 5 S 2 :378.0470; found:378.0465.
实施例122Example 122
5-(N-(2-(环己-1-烯-1-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-138)
5-(N-(2-(cyclohex-1-en-1-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-138)
将5-(N-(2-(环己-1-烯-1-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.16g,0.41mmol)溶于乙醇(8mL)，加入氢氧化锂(0.02g,0.83mmol，溶于2mL水)，室温搅拌反应3h。反应结束后，浓缩除去乙醇，加入适量水，搅拌下加入3N HCl调节pH 2～3，析出大量白色固体。抽滤，滤饼用蒸馏水洗涤，烘干得白色固体133mg，产率89.9％。5-(N-(2-(cyclohex-1-en-1-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (0.16g, 0.41mmol) Dissolve in ethanol (8mL), add lithium hydroxide (0.02g, 0.83mmol, dissolved in 2mL of water), stir and react at room temperature for 3h. After the reaction is completed, concentrate to remove ethanol, add an appropriate amount of water, add 3N HCl under stirring to adjust the pH to 2-3, and precipitate a large amount of white solid. After suction filtration, the filter cake was washed with distilled water and dried to obtain 133 mg of white solid, with a yield of 89.9%.
1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝2.0Hz,1H),7.90(dd,J＝8.8,2.0Hz,1H),7.85(d,J＝8.8Hz,1H),7.55(t,J＝6.0Hz,1H),5.30-5.26(m,1H),2.86-2.77(m,2H),2.57(s,3H),1.97(t,J＝6.8Hz,2H),1.89-1.81(m,2H),1.80-1.70(m,2H),1.51–1.35(m,4H).13C NMR(101MHz,DMSO-d6)δ161.15,155.30,143.63,136.51,134.63,129.29,126.36,125.08,122.79,121.35,113.32,41.68,37.82,27.96,25.04,22.73,22.24,9.48.HRMS(ESI)[M-H]-calcd for C18H21NO5S:362.1068；found:362.1068. 1 H NMR (400MHz, DMSO-d 6 ) δ8.21 (d, J = 2.0Hz, 1H), 7.90 (dd, J = 8.8, 2.0Hz, 1H), 7.85 (d, J = 8.8Hz, 1H) ,7.55(t,J＝6.0Hz,1H),5.30-5.26(m,1H),2.86-2.77(m,2H),2.57(s,3H),1.97(t,J＝6.8Hz,2H), 1.89-1.81(m,2H),1.80-1.70(m,2H),1.51–1.35(m,4H). 13 C NMR(101MHz,DMSO-d 6 )δ161.15,155.30,143.63,136.51,134.63,129.29, 126.36,125.08,122.79,121.35,113.32,41.68,37.82,27.96,25.04,22.73,22.24,9.48.HRMS(ESI)[MH] - calcd for C 18 H 21 NO 5 S:362.1068; found:362.106 8.
实施例123Example 123
5-(N-(2-氟-2-苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-23)
5-(N-(2-fluoro-2-phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-23)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.44–7.23(m,5H),6.96(t,J＝7.7Hz,1H),5.41(dt,J＝46.4,4.6Hz,1H),3.76–3.52(m,2H),2.58(s,3H).13C NMR(400MHz,DMSO-d6)δ165.0,157.9,143.1,137.6(d,J＝32.0Hz),135.2,128.9(d,J＝1.9Hz),128.3,127.6,126.3(d,J＝4.1Hz),125.5,125.0,120.2,113.3,91.4(d,J＝268.0Hz),48.1(d,J＝27.2Hz),10.0.HRMS(ESI)[M-H]-calcd for C18H16FNO5S:376.0660；found:376.0660.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.44–7.23(m,5H),6.96(t,J＝7.7Hz,1H),5.41(dt,J＝46.4,4.6Hz,1H),3.76–3.52(m,2H),2.58(s,3H ). 13 C NMR (400MHz, DMSO-d 6 ) δ165.0, 157.9, 143.1, 137.6 (d, J = 32.0Hz), 135.2, 128.9 (d, J = 1.9Hz), 128.3, 127.6, 126.3 (d, J ＝4.1Hz),125.5,125.0,120.2,113.3,91.4(d,J＝268.0Hz),48.1(d,J＝27.2Hz),10.0.HRMS(ESI)[MH] - calcd for C 18 H 16 FNO 5 S:376.0660; found:376.0660.
实施例124Example 124
3-甲基-5-(N-(1-苯基丙-2-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-140)
3-Methyl-5-(N-(1-phenylpropan-2-yl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-140)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝2.3Hz,1H),7.95(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.40–7.11(m,5H),6.72(d,J＝10.1Hz,1H),3.48(dh,J＝10.1,7.0Hz,1H),2.92–2.79(m,2H),2.58(s,3H),1.13(d,J＝7.0Hz,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.8,143.1,137.9,135.3,129.0,128.8,127.5,127.2,125.3,125.0,120.1,113.2,51.6,42.6,20.0,10.0.HRMS(ESI)[M-H]-calcd for C19H19NO5S:372.0911；found:372.0911. 1 H NMR (400MHz, DMSO-d 6 ) δ8.16 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H) ,7.40–7.11(m,5H),6.72(d,J＝10.1Hz,1H),3.48(dh,J＝10.1,7.0Hz,1H),2.92–2.79(m,2H),2.58(s,3H 13 C NMR ,51.6,42.6,20.0,10.0.HRMS(ESI)[MH] - calcd for C 19 H 19 NO 5 S:372.0911; found:372.0911.
实施例125Example 125
3-甲基-5-(N-(2-苯基乙酰基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-141)
3-Methyl-5-(N-(2-phenylacetyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-141)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(2-苯基乙酰基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体61mg，收率55％。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),8.29(d,J＝2.0Hz,1H),7.99(dd,J＝8.8,2.0Hz,1H),7.87(d,J＝8.8Hz,1H),7.33–7.17(m,3H),7.17–7.09(m,2H),3.55(s,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ169.5,160.6,155.4,143.5,134.5,133.9,129.3,128.7,128.3,126.9,126.7,124.6,122.4,112.9,42.0,9.0.HRMS(ESI)[M-H]-calcd for C18H15NO6S:372.0542；found:372.0544.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(2-phenylacetyl)sulfamoyl)benzofuran-2-carboxylate. consistent. 61 mg of white solid was obtained, with a yield of 55%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.07 (s, 1H), 8.29 (d, J = 2.0Hz, 1H), 7.99 (dd, J = 8.8, 2.0Hz, 1H), 7.87 (d, J＝8.8Hz,1H),7.33–7.17(m,3H),7.17–7.09(m,2H),3.55(s,2H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ169.5,160.6,155.4,143.5,134.5,133.9,129.3,128.7,128.3,126.9,126.7,124.6,122.4,112.9,42.0,9.0.HRMS(ESI)[MH] - calcd for C 18 H 15 NO 6 S :372.0542; found:372.0544.
实施例126Example 126
3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-144)
3-Methyl-5-(N-(naphthalen-1-yl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-144)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体102mg，收率92％。1H NMR(400MHz,DMSO-d6)δ13.68(s,1H),10.27(s,1H),8.08–7.99(m,2H),7.90–7.71(m,4H),7.50–7.33(m,3H),7.13(dd,J＝7.5,1.1Hz,1H),2.46(s,3H).13C NMR(101MHz,DMSO-d6)δ160.6,155.0,143.2,135.5,133.9,132.3,129.5,128.7,127.9,126.8,126.2,126.1,126.0,125.5,124.5,123.3,123.1,121.1,112.9,8.9.HRMS(ESI)[M-H]-calcd for C20H14NO5S:380.0593；found:380.0600.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(naphthalen-1-yl)sulfamoyl)benzofuran-2-carboxylate, and the other conditions were consistent. . 102 mg of white solid was obtained, with a yield of 92%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.68(s,1H),10.27(s,1H),8.08–7.99(m,2H),7.90–7.71(m,4H),7.50–7.33(m ,3H),7.13(dd,J＝7.5,1.1Hz,1H),2.46(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ160.6,155.0,143.2,135.5,133.9,132.3,129.5, 128.7,127.9,126.8,126.2,126.1,126.0,125.5,124.5,123.3,123.1,121.1,112.9,8.9.HRMS(ESI)[MH] - calcd for C 20 H 14 NO 5 S:380.0593; found:380.060 0.
实施例127Example 127
3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-145)
3-Methyl-5-(N-(naphthalen-2-yl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-145)
按照实施例25所用方法，将中间体乙酯替换为3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体181mg，收率87％。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),10.57(s,1H),8.29(d,J＝1.9Hz,1H),7.90(dd,J＝8.8,1.9Hz,1H),7.83–7.71(m,4H),7.62(d,J＝2.2Hz,1H),7.46–7.29(m,3H),2.50(s,3H).13C NMR(101MHz,DMSO-d6)δ160.6,155.0,143.4,135.3,134.8,133.2,130.0,129.1,128.8,127.4,127.2,126.6,125.8,125.0,124.4,121.4,120.4,116.1,113.0,8.9.HRMS(ESI)[M-H]-calcd for C20H14NO5S:380.0593；found:380.0594.According to the method used in Example 25, the intermediate ethyl ester was replaced with ethyl 3-methyl-5-(N-(naphthalen-2-yl)sulfamoyl)benzofuran-2-carboxylate, and the other conditions were consistent. . 181 mg of white solid was obtained, with a yield of 87%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.72 (s, 1H), 10.57 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 7.90 (dd, J = 8.8, 1.9 Hz, 1H),7.83–7.71(m,4H),7.62(d,J＝2.2Hz,1H),7.46–7.29(m,3H),2.50(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ160.6,155.0,143.4,135.3,134.8,133.2,130.0,129.1,128.8,127.4,127.2,126.6,125.8,125.0,124.4,121.4,120.4,116.1,113.0,8.9.HRMS (ESI)[MH] -calcd for C 20 H 14 NO 5 S: 380.0593; found: 380.0594.
实施例128Example 128
3-甲基-5-(N-(萘-1-基甲基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-146)
3-Methyl-5-(N-(naphthalen-1-ylmethyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-146)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ8.21–8.11(m,2H),7.98(dd,J＝9.0,2.2Hz,1H),7.92–7.81(m,2H),7.64(d,J＝9.0Hz,1H),7.56–7.46(m,2H),7.43–7.35(m,2H),7.29(t,J＝7.3 Hz,1H),4.36(d,J＝7.3Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,135.3,133.7,133.6,131.6,128.8,128.4,127.7,127.6,127.5,126.4,125.8,125.5,125.0,124.5,120.2,113.3,46.6,10.0.HRMS(ESI)[M-H]-calcd for C21H17NO5S:394.0755；found:394.0755. 1 H NMR (400MHz, DMSO-d 6 ) δ8.21–8.11(m,2H),7.98(dd,J＝9.0,2.2Hz,1H),7.92–7.81(m,2H),7.64(d,J ＝9.0Hz,1H),7.56–7.46(m,2H),7.43–7.35(m,2H),7.29(t,J＝7.3 Hz, 1H), 4.36 (d, J = 7.3Hz, 2H), 2.58 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 165.0, 157.9, 143.1, 135.3, 133.7, 133.6, 131.6, 128.8 ,128.4,127.7,127.6,127.5,126.4,125.8,125.5,125.0,124.5,120.2,113.3,46.6,10.0.HRMS(ESI)[MH] - calcd for C 21 H 17 NO 5 S:394.0755; found:394.07 55 .
实施例129Example 129
5-(N-(2-乙炔基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-28)
5-(N-(2-ethynylphenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-28)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.55(dd,J＝6.7,1.3Hz,1H),7.42–7.32(m,2H),7.25(td,J＝6.6,1.8Hz,1H),3.22(s,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,139.3,134.5,132.5,130.3,127.7,125.0,124.6,124.3,120.3,119.7,113.1,112.8,83.8,78.6,10.0.HRMS(ESI)[M-H]-calcd for C18H13NO5S:354.0442；found:354.0442.Synthesize according to the method used in Example 25. 1 H NMR (400MHz, DMSO-d 6 ) δ9.18 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J＝9.0Hz,1H),7.55(dd,J＝6.7,1.3Hz,1H),7.42–7.32(m,2H),7.25(td,J＝6.6,1.8Hz,1H),3.22(s,1H ), 2.58 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ165.0,157.9,143.1,139.3,134.5,132.5,130.3,127.7,125.0,124.6,124.3,120.3,119.7,113.1,112.8 , 83.8,78.6,10.0.HRMS(ESI)[MH] - calcd for C 18 H 13 NO 5 S:354.0442; found:354.0442.
实施例130Example 130
5-(N-(1H-吲哚-4-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-150)
5-(N-(1H-indol-4-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-150)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝6.6Hz,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.43(t,J＝7.9Hz,1H),7.27(dd,J＝7.9,1.3Hz,1H),7.20(dd,J＝6.6,3.7Hz,1H),7.04(dd,J＝7.7,1.5Hz,1H),6.85(d,J＝3.7Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,135.5,135.0,134.5,127.7,125.0,124.6,123.5,123.4,122.1,120.3,113.1,112.8,107.1,100.6,10.0.HRMS(ESI)[M-H]-calcd for C18H14N2O5S:369.0551；found:369.0551. 1 H NMR (400MHz, DMSO-d 6 ) δ8.52(d,J＝6.6Hz,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H) ,7.65(d,J＝9.0Hz,1H),7.43(t,J＝7.9Hz,1H),7.27(dd,J＝7.9,1.3Hz,1H),7.20(dd,J＝6.6,3.7Hz, 1H), 7.04 (dd, J＝7.7, 1.5Hz, 1H), 6.85 (d, J＝3.7Hz, 1H), 2.58 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 165.0, 157.9 ,143.1,135.5,135.0,134.5,127.7,125.0,124.6,123.5,123.4,122.1,120.3,113.1,112.8,107.1,100.6,10.0.HRMS(ESI)[MH] - calcd for C 18 H 14 N 2 O 5 S:369.0551; found:369.0551.
实施例131Example 131
5-(N-(苯并呋喃-5-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-151)
5-(N-(Benzofuran-5-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-151)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.76(d,J＝1.6Hz,1H),7.67–7.62(m,2H),7.45(d,J＝8.4Hz,1H),7.24(dd,J＝8.4,2.2Hz,1H),6.89(t,J＝1.8Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,152.6,145.2,143.1,134.6,133.9,129.1,127.7,125.0,124.6,120.3,118.2,113.2,113.1,110.8,105.5,10.0.HRMS(ESI)[M-H]-calcd for C18H13NO6S:370.0319；found:370.0319. 1 H NMR (400MHz, DMSO-d 6 ) δ9.84 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.76 (d, J＝1.6Hz,1H),7.67–7.62(m,2H),7.45(d,J＝8.4Hz,1H),7.24(dd,J＝8.4,2.2Hz,1H),6.89(t,J＝1.8 Hz, 1H), 2.58 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ165.0,157.9,152.6,145.2,143.1,134.6,133.9,129.1,127.7,125.0,124.6,120.3,118.2,113.2 ,113.1,110.8,105.5,10.0.HRMS(ESI)[MH] - calcd for C 18 H 13 NO 6 S:370.0319; found:370.0319.
实施例132Example 132
5-(N-(2,3-二甲基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-152)
5-(N-(2,3-dimethylphenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-152)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.02(t,J＝7.8Hz,1H),6.94–6.84(m,2H),2.58(s,3H),2.26(d,J＝0.7Hz,3H),2.08(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,137.9,137.3,134.5,129.3,127.7,126.8,125.0,124.7,124.6,120.3,119.5,113.1,20.3,14.2,10.0.HRMS(ESI)[M-H]-calcd for C18H17NO5S:358.0755；found:358.0755. 1 H NMR (400MHz, DMSO-d 6 ) δ8.99 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J＝9.0Hz,1H),7.02(t,J＝7.8Hz,1H),6.94–6.84(m,2H),2.58(s,3H),2.26(d,J＝0.7Hz,3H),2.08( s,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ165.0,157.9,143.1,137.9,137.3,134.5,129.3,127.7,126.8,125.0,124.7,124.6,120.3,119.5,113.1,20.3, 14.2, 10.0.HRMS(ESI)[MH] - calcd for C 18 H 17 NO 5 S:358.0755; found:358.0755.
实施例133Example 133
5-(N-(2-碘苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-153)
5-(N-(2-iodophenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-153)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.78(dd,J＝7.7,1.3Hz,1H),7.65(d,J＝9.0Hz,1H),7.34–7.22(m,2H),6.93(ddd,J＝7.7,6.7,1.7Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.6,156.8,143.1,140.7,139.0,134.9,128.7,127.8,127.1,126.7,126.4,121.0,119.5,112.8,93.7,10.3.HRMS(ESI)[M-H]-calcd for C16H12INO5S:455.9408；found:455.9408. 1 H NMR (400MHz, DMSO-d 6 ) δ9.54 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.78 (dd, J＝7.7,1.3Hz,1H),7.65(d,J＝9.0Hz,1H),7.34–7.22(m,2H),6.93(ddd,J＝7.7,6.7,1.7Hz,1H),2.58(s ,3H). 13 C NMR (101MHz, DMSO-d 6 ) δ165.6,156.8,143.1,140.7,139.0,134.9,128.7,127.8,127.1,126.7,126.4,121.0,119.5,112.8,93.7,10.3.HRMS (ESI )[MH] - calcd for C 16 H 12 INO 5 S:455.9408; found:455.9408.
实施例134Example 134
5-(N-(4-碘苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-154)
5-(N-(4-iodophenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-154)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.76–7.70(m,2H),7.65(d,J＝8.9Hz,1H),6.99–6.93(m,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.6,156.8,143.1,137.9,137.1,135.0,127.8,127.1,126.4,122.2,119.5,112.9,88.5,10.3.HRMS(ESI)[M-H]-calcd for C16H12INO5S:455.9408；found:455.9408. 1 H NMR (400MHz, DMSO-d 6 ) δ9.66 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.76–7.70 ( m,2H),7.65(d,J＝8.9Hz,1H),6.99–6.93(m,2H),2.58(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.6,156.8,143.1, 137.9,137.1,135.0,127.8,127.1,126.4,122.2,119.5,112.9,88.5,10.3.HRMS(ESI)[MH] - calcd for C 16 H 12 INO 5 S:455.9408; found:455.9408.
实施例135Example 135
3-甲基-5-(N-(3-苯氧基苯基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-155)
3-Methyl-5-(N-(3-phenoxyphenyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-155)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.41–7.26(m,3H),7.10(tt,J＝7.2,1.5Hz,1H),7.05–6.97(m,3H),6.82(t,J＝2.2Hz,1H),6.52(ddd,J＝7.7,2.2,1.1Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,157.4,157.2,143.1,139.6,134.6,129.9,129.8,127.7,125.0,124.6,124.5,120.3,118.9,114.8,113.4,113.1,112.1,10.0.HRMS(ESI)[M-H]-calcd for C22H17NO6S:422.0704；found:422.0704. 1 H NMR (400MHz, DMSO-d 6 ) δ8.26 (d, J = 2.3 Hz, 1H), 8.00 (dd, J = 9.0, 2.2 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H) ,7.41–7.26(m,3H),7.10(tt,J＝7.2,1.5Hz,1H),7.05–6.97(m,3H),6.82(t,J＝2.2Hz,1H),6.52(ddd,J ＝7.7,2.2,1.1Hz,1H),2.58(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ165.0,157.9,157.4,157.2,143.1,139.6,134.6,129.9,129.8,127.7,125.0 ,124.6,124.5,120.3,118.9,114.8,113.4,113.1,112.1,10.0.HRMS(ESI)[MH] - calcd for C 22 H 17 NO 6 S:422.0704; found:422.0704.
实施例136Example 136
3-甲基-5-(N-(3-(4-甲基哌嗪-1-基)苯基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-156)
3-Methyl-5-(N-(3-(4-methylpiperazin-1-yl)phenyl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-156)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.08(dd,J＝8.1,7.2Hz,1H),6.73(ddd,J＝8.1,2.2,1.3Hz,1H),6.50–6.35(m,2H),3.23(ddd,J＝5.3,4.0,1.0Hz,4H),2.85–2.76(m,2H),2.61–2.51(m,5H),2.29(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,151.9,143.1,139.7,134.6,129.5,127.7,125.0,124.6,120.3,116.7,113.1,109.4,107.6,54.1,48.7,45.3,10.0.HRMS(ESI)[M-H]-calcd for C21H23N3O5S:428.1286；found:428.1286. 1 H NMR (400MHz, DMSO-d 6 ) δ9.75 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J＝9.0Hz,1H),7.08(dd,J＝8.1,7.2Hz,1H),6.73(ddd,J＝8.1,2.2,1.3Hz,1H),6.50–6.35(m,2H),3.23(ddd , J＝5.3, 4.0, 1.0Hz, 4H), 2.85–2.76 (m, 2H), 2.61–2.51 (m, 5H), 2.29 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ165 .0,157.9,151.9,143.1,139.7,134.6,129.5,127.7,125.0,124.6,120.3,116.7,113.1,109.4,107.6,54.1,48.7,45.3,10.0.HRMS(ESI)[MH] - calcd for C21H 23 N 3 O 5 S:428.1286; found:428.1286.
实施例137Example 137
3-甲基-5-(N-(5,6,7,8-四氢萘-1-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-157)
3-Methyl-5-(N-(5,6,7,8-tetralin-1-yl)sulfamoyl)benzofuran-2-carboxylic acid (GPR132-B-157)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.08(t,J＝8.1Hz,1H),6.92(dd,J＝8.1,1.2Hz,1H),6.81(dq,J＝7.7,1.0Hz,1H),2.89–2.69(m,4H),2.58(s,3H),1.81–1.68(m,4H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,138.6,138.2,134.5,127.8,127.7,126.2,125.0,124.6,122.2,120.3,119.2,113.1,29.6,24.9,22.8,22.5,10.0.HRMS(ESI)[M-H]-calcd for C20H19NO5S:384.0911；found:384.0911. 1 H NMR (400MHz, DMSO-d 6 ) δ9.21 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J＝9.0Hz,1H),7.08(t,J＝8.1Hz,1H),6.92(dd,J＝8.1,1.2Hz,1H),6.81(dq,J＝7.7,1.0Hz,1H),2.89– 2.69(m,4H),2.58(s,3H),1.81–1.68(m,4H). 13 C NMR(101MHz,DMSO-d 6 )δ165.0,157.9,143.1,138.6,138.2,134.5,127.8,127.7, 126.2,125.0,124.6,122.2,120.3,119.2,113.1,29.6,24.9,22.8,22.5,10.0.HRMS(ESI)[MH] - calcd for C 20 H 19 NO 5 S:384.0911; found:384.0911.
实施例138Example 138
5-(N-(4-乙炔基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-158)
5-(N-(4-ethynylphenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-158)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.53–7.47(m,2H),7.11–7.05(m,2H),3.04(s,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,138.9,134.6,132.4,127.7,125.0,124.6,120.3,120.2,114.0,113.1,81.4,78.9,10.0.HRMS(ESI)[M-H]-calcd for C18H13NO5S:354.0422；found:354.0422. 1 H NMR (400MHz, DMSO-d 6 ) δ9.55 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J＝9.0Hz,1H),7.53–7.47(m,2H),7.11–7.05(m,2H),3.04(s,1H),2.58(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.0,157.9,143.1,138.9,134.6,132.4,127.7,125.0,124.6,120.3,120.2,114.0,113.1,81.4,78.9,10.0.HRMS(ESI)[MH] - calcd for C 18 H 13 NO 5 S :354.0422; found:354.0422.
实施例139Example 139
5-(N-(3-(二甲基氨基)苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-159)
5-(N-(3-(Dimethylamino)phenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (GPR132-B-159)
按照实施例25所用方法合成。Synthesize according to the method used in Example 25.
1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.10(dd,J＝8.2,7.2Hz,1H),6.85(t,J＝2.3Hz,1H),6.76(ddd,J＝8.1,2.2,1.2Hz,1H),6.49(ddd,J＝7.3,2.2,1.2Hz,1H),2.97(s,6H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,152.0,143.1,140.9,134.6,129.2,127.7,125.0,124.6,120.3,116.4,113.1,110.1,107.1,40.4,10.0.HRMS(ESI)[M-H]-calcd for C18H18N2O5S:373.0864；found:373.0864. 1 H NMR (400MHz, DMSO-d 6 ) δ9.76 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J＝9.0Hz,1H),7.10(dd,J＝8.2,7.2Hz,1H),6.85(t,J＝2.3Hz,1H),6.76(ddd,J＝8.1,2.2,1.2Hz,1H), 6.49 (ddd, J=7.3, 2.2, 1.2Hz, 1H), 2.97 (s, 6H), 2.58 (s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 165.0, 157.9, 152.0, 143.1, 140.9 ,134.6,129.2,127.7,125.0,124.6,120.3,116.4,113.1,110.1,107.1,40.4,10.0.HRMS(ESI)[MH] - calcd for C 18 H 18 N 2 O 5 S:373.0864; found:373.0864 .
实施例140Example 140
3-甲基-6-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-6-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成，将氨的甲醇溶液替换为2-苯乙胺，将5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯替换为6-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯，其余条件均一致。得白黄色固体56mg，收率30％。1H NMR(400MHz,Chloroform-d)δ8.01(t,J＝1.1Hz,1H),7.73(t,J＝1.1Hz,2H),7.37–7.11(m,4H),7.08–7.02(m,2H),4.73(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.28–3.19(m,2H),2.76(t,J＝7.1Hz,2H),2.61(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,153.2,143.9,139.2,137.6,132.7,130.6,128.9,128.8,128.8,126.9,125.0,122.1,121.6,111.9,61.7,44.4,35.9,14.4,9.4.HRMS(ESI)[M+H]+calcd for C20H22NO5S:388.1219；found:388.1213.Synthesize according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, replace the methanol solution of ammonia with 2-phenylethylamine, and replace 5-(chloro Sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester was replaced with 6-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, and the other conditions were the same. 56 mg of white-yellow solid was obtained, with a yield of 30%. 1 H NMR(400MHz,Chloroform-d)δ8.01(t,J＝1.1Hz,1H),7.73(t,J＝1.1Hz,2H),7.37–7.11(m,4H),7.08–7.02(m ,2H),4.73(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.28–3.19(m,2H),2.76(t,J＝7.1Hz,2H),2.61 (s, 3H), 1.46 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ 160.0, 153.2, 143.9, 139.2, 137.6, 132.7, 130.6, 128.9, 128.8, 128.8, 126.9, 125.0,122.1,121.6,111.9,61.7,44.4,35.9,14.4,9.4.HRMS(ESI)[M+H] + calcd for C 20 H 22 NO 5 S:388.1219; found:388.1213.
实施例141Example 141
3-甲基-5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯(M-GPR132-B-53)
3-Methyl-5-(N-phenethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid ethyl ester (M-GPR132-B-53)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成合成。1H NMR(400MHz,Chloroform-d)δ8.38(d,J＝2.1Hz,1H),8.14(d,J＝8.4Hz,1H),7.96(dd,J＝8.5,2.3Hz,1H),7.30–7.19(m,5H),7.15(t,J＝6.6Hz,1H),4.32(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.9Hz,2H),2.81(tt,J＝5.8,0.9Hz,2H),2.65(s,3H),1.37(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR(400MHz,Chloroform-d)δ8.38(d,J＝2.1Hz,1H),8.14(d,J＝8.4Hz,1H),7.96(dd,J＝8.5,2.3Hz,1H), 7.30–7.19(m,5H),7.15(t,J＝6.6Hz,1H),4.32(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.9Hz,2H),2.81(tt ,J＝5.8,0.9Hz,2H),2.65(s,3H),1.37(t,J＝6.3Hz,3H).
实施例142Example 142
5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯
5-(N-Phenethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid ethyl ester
将苯乙胺(0.10g,0.82mmol)溶于DMF(2.5mL)，加入6-(氯磺酰基)苯并[b]噻吩-2-羧酸乙酯(0.30g,0.98mmol)，DIPEA(0.25mL)，室温搅拌反应2h。TLC监测反应完全，加入适量水，乙酸乙酯提取3次，有机相合并，经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(PE/DCM/EA＝9:1:1.5)得白色固体179mg，产率55.8％。 Dissolve phenethylamine (0.10g, 0.82mmol) in DMF (2.5mL), add ethyl 6-(chlorosulfonyl)benzo[b]thiophene-2-carboxylate (0.30g, 0.98mmol), DIPEA ( 0.25 mL) and stirred at room temperature for 2 h. TLC monitors that the reaction is complete. Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE/DCM/EA=9:1:1.5) to obtain white color Solid 179 mg, yield 55.8%.
1H NMR(400MHz,CDCl3)δ8.35(d,J＝2.0Hz,1H),8.05(s,1H),7.90(d,J＝8.4Hz,1H),7.82(dd,J＝8.4,2.0Hz,1H),7.25-7.10(m,3H),7.09-7.03(m,2H),5.31(t,J＝6.0Hz,1H),4.42(q,J＝7.2Hz,2H),3.25(q,J＝6.8Hz,2H),2.78(t,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.17,145.53,138.28,137.79,136.97,136.55,130.36,128.74,128.64,126.70,124.88,124.19,123.73,62.12,44.47,35.85,14.34. 1 H NMR (400MHz, CDCl 3 ) δ8.35 (d, J = 2.0Hz, 1H), 8.05 (s, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.82 (dd, J = 8.4, 2.0Hz,1H),7.25-7.10(m,3H),7.09-7.03(m,2H),5.31(t,J＝6.0Hz,1H),4.42(q,J＝7.2Hz,2H),3.25( q, J＝6.8Hz, 2H), 2.78 (t, J＝7.2Hz, 2H), 1.42 (t, J＝7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 162.17, 145.53, 138.28, 137.79 ,136.97,136.55,130.36,128.74,128.64,126.70,124.88,124.19,123.73,62.12,44.47,35.85,14.34.
实施例143Example 143
6-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯
6-(N-Phenethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid ethyl ester
将苯乙胺(0.10g,0.82mmol)溶于DMF(2.5mL)，加入6-(氯磺酰基)苯并[b]噻吩-2-羧酸乙酯(0.30g,0.98mmol)，DIPEA(0.25mL)，室温搅拌反应2h。TLC监测反应完全，加入适量水，乙酸乙酯提取3次，有机相合并，经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(PE/DCM/EA＝9:1:1.5)得白色固体127mg，产率39.6％。Dissolve phenethylamine (0.10g, 0.82mmol) in DMF (2.5mL), add ethyl 6-(chlorosulfonyl)benzo[b]thiophene-2-carboxylate (0.30g, 0.98mmol), DIPEA ( 0.25 mL) and stirred at room temperature for 2 h. TLC monitors that the reaction is complete. Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE/DCM/EA=9:1:1.5) to obtain white color Solid 127 mg, yield 39.6%.
1H NMR(400MHz,CDCl3)δ8.33(s,1H),8.08(s,1H),7.93(d,J＝8.8Hz,1H),7.78(dd,J＝8.8,1.6Hz,1H),7.24-7.13(m,3H),7.09-7.03(m,2H),5.11(t,J＝6.0Hz,1H),4.43(q,J＝7.2Hz,2H),3.26(q,J＝6.8Hz,2H),2.78(t,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.13,141.73,141.33,138.13,137.65,129.54,128.74,128.70,126.80,126.25,122.83,122.49,62.16,44.43,35.85,14.32. 1 H NMR (400MHz, CDCl 3 ) δ8.33 (s, 1H), 8.08 (s, 1H), 7.93 (d, J = 8.8Hz, 1H), 7.78 (dd, J = 8.8, 1.6Hz, 1H) ,7.24-7.13(m,3H),7.09-7.03(m,2H),5.11(t,J＝6.0Hz,1H),4.43(q,J＝7.2Hz,2H),3.26(q,J＝6.8 Hz, 2H), 2.78 (t, J = 7.2Hz, 2H), 1.43 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 162.13, 141.73, 141.33, 138.13, 137.65, 129.54, 128.74,128.70,126.80,126.25,122.83,122.49,62.16,44.43,35.85,14.32.
实施例144Example 144
3-氯-5-(N-苯乙基氨基磺酰基)-1H-吲哚-2-羧酸乙酯(M-GPR132-B-56)
3-Chloro-5-(N-phenylethylaminosulfonyl)-1H-indole-2-carboxylic acid ethyl ester (M-GPR132-B-56)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.47(d,J＝2.3Hz,1H),7.92(dd,J＝7.9,2.2Hz,1H),7.60(d,J＝8.0Hz,1H),7.30–7.19(m,5H),7.14(t,J＝6.6Hz,1H),4.35(q,J＝6.4Hz,2H),3.17(dt,J＝6.5,5.8Hz,2H),2.81(tt,J＝5.8,0.9Hz,2H),1.37(t,J＝6.4Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.47 (d, J＝2.3Hz, 1H), 7.92 (dd, J＝7.9, 2.2Hz, 1H), 7.60 (d, J＝8.0Hz, 1H), 7.30–7.19(m,5H),7.14(t,J＝6.6Hz,1H),4.35(q,J＝6.4Hz,2H),3.17(dt,J＝6.5,5.8Hz,2H),2.81(tt ,J＝5.8,0.9Hz,2H),1.37(t,J＝6.4Hz,3H).
实施例145Example 145
2-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-3-羧酸乙酯(M-GPR132-B-57)
2-Methyl-5-(N-phenylethylsulfamoyl)benzofuran-3-carboxylic acid ethyl ester (M-GPR132-B-57)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝2.2Hz,1H),7.96(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.30–7.19(m,5H),7.14(t,J＝6.6Hz,1H),4.35(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.9Hz,2H),2.81(tt,J＝5.8,0.9Hz,2H),2.70(s,3H),1.36(t,J＝6.4Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.17 (d, J＝2.2Hz, 1H), 7.96 (dd, J＝9.0, 2.2Hz, 1H), 7.65 (d, J＝9.0Hz, 1H), 7.30–7.19(m,5H),7.14(t,J＝6.6Hz,1H),4.35(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.9Hz,2H),2.81(tt ,J＝5.8,0.9Hz,2H),2.70(s,3H),1.36(t,J＝6.4Hz,3H).
实施例146Example 146
3-甲基-5-(N-(2-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-fluorophenylethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，所用胺原料替换为2-氟苯乙胺，其余条件均一致。得白色固体0.32g，收率79％。1H NMR(400MHz,Chloroform-d)δ8.16(dd,J＝1.9,0.6Hz,1H),7.85(dd,J＝8.8,1.9Hz,1H),7.59(dd,J＝8.8,0.6Hz,1H),7.21–6.83(m,4H),4.72(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H),3.26(q,J＝6.8Hz,2H),2.85–2.77(m,2H),2.59(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ162.5,160.0,156.0,143.1,135.4,131.2(d,J＝4.7Hz),129.5,128.8(d,J＝8.2Hz),126.3,125.7,124.7(d,J＝15.5Hz),124.4(d,J＝3.6Hz),121.7,115.5(d,J＝22.0Hz),113.2,61.7,43.2,29.8(d,J＝2.0Hz),14.5,9.4.19F NMR(376MHz,Chloroform-d)δ-118.27.HRMS(ESI)[M-H]-calcd for C20H19NO5SF:404.0968；found:404.0968.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, the amine raw material used was replaced with 2-fluorophenylethylamine, and the other conditions were the same. 0.32g of white solid was obtained, with a yield of 79%. 1 H NMR (400MHz, Chloroform-d) δ8.16 (dd, J＝1.9, 0.6Hz, 1H), 7.85 (dd, J＝8.8, 1.9Hz, 1H), 7.59 (dd, J＝8.8, 0.6Hz ,1H),7.21–6.83(m,4H),4.72(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H),3.26(q,J＝6.8Hz,2H),2.85 –2.77(m,2H),2.59(s,3H),1.45(t,J＝7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ162.5,160.0,156.0,143.1,135.4,131.2(d ,J＝4.7Hz),129.5,128.8(d,J＝8.2Hz),126.3,125.7,124.7(d,J＝15.5Hz),124.4(d,J＝3.6Hz),121.7,115.5(d,J ＝22.0Hz),113.2,61.7,43.2,29.8(d,J＝2.0Hz),14.5,9.4. 19 F NMR(376MHz,Chloroform-d)δ-118.27.HRMS(ESI)[MH] - calcd for C 20 H 19 NO 5 SF: 404.0968; found: 404.0968.
实施例147Example 147
5-(N-(2-溴代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-Bromophenethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
将5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(226mg,0.75mmol)溶于无水二氯甲烷(3mL)中，加入2-(2-溴苯基)乙胺(72μL,0.5mmol),向体系中滴加DIPEA(206μL，1.25mmol)，室温下反应，直到TLC监测反应完全。减压蒸馏除去溶剂，加水(10mL)溶解，乙酸乙酯(10mL)萃取三次，有机相用饱和氯化钠水溶液(10mL)洗一次，加无水硫酸钠干燥，粗产品经柱层析分离(PE/EA＝5/1)，得白色固体248.0mg，收率100％。1H NMR(400MHz,Chloroform-d)δ8.19(s,1H),7.87(d,J＝10.3Hz,1H),7.56(d,J＝8.8Hz,1H),7.37(d,J＝8.0Hz,2H),7.13(d,J＝4.3Hz,2H),7.03–6.94(m,1H),5.21(s,1H),4.47(q,J＝7.1Hz,2H),3.28(q,J＝6.3Hz,2H),2.90(t,J＝7.1Hz,3H),2.58(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,142.9,137.1,135.2,132.8,131.1,129.3,128.4,127.6,126.2,125.6,124.3,121.6,113.0,61.6,42.6,36.3,14.4,9.4.Dissolve 5-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (226 mg, 0.75 mmol) in anhydrous dichloromethane (3 mL), and add 2-(2-bromophenyl ) Ethylamine (72 μL, 0.5 mmol), add DIPEA (206 μL, 1.25 mmol) dropwise to the system, and react at room temperature until the reaction is complete as monitored by TLC. The solvent was evaporated under reduced pressure, dissolved in water (10 mL), extracted three times with ethyl acetate (10 mL), the organic phase was washed once with saturated sodium chloride aqueous solution (10 mL), and dried over anhydrous sodium sulfate. The crude product was separated by column chromatography ( PE/EA=5/1), 248.0 mg of white solid was obtained, the yield was 100%. 1 H NMR (400MHz, Chloroform-d) δ8.19 (s, 1H), 7.87 (d, J = 10.3Hz, 1H), 7.56 (d, J = 8.8Hz, 1H), 7.37 (d, J = 8.0 Hz,2H),7.13(d,J＝4.3Hz,2H),7.03–6.94(m,1H),5.21(s,1H),4.47(q,J＝7.1Hz,2H),3.28(q,J =6.3Hz, 2H), 2.90 (t, J = 7.1Hz, 3H), 2.58 (s, 3H), 1.45 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ 159. 9,155.8,142.9,137.1,135.2,132.8,131.1,129.3,128.4,127.6,126.2,125.6,124.3,121.6,113.0,61.6,42.6,36.3,14.4,9.4.
实施例148Example 148
5-(N-(2-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-Chlorophenythylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照实施例147步骤，得白色固体120mg，收率57％。1H NMR(400MHz,Chloroform-d)δ8.19(d,J＝1.5Hz,1H),7.87(d,J＝10.6Hz,1H),7.56(d,J＝8.8Hz,1H),7.22–7.15(m,1H),7.14–7.05(m,3H),5.20(t,J＝6.1Hz,1H),4.46(q,J＝7.1Hz,2H),3.28(q,J＝6.9Hz,2H),2.90(t,J＝7.1Hz,2H),2.58(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,142.9,135.4,135.2,133.9,131.1,129.5,129.3,128.2,126.9,126.2,125.6,121.6,113.0,61.6,42.6,33.8,14.3,9.3.Following the steps of Example 147, 120 mg of white solid was obtained with a yield of 57%. 1 H NMR (400MHz, Chloroform-d) δ8.19(d,J＝1.5Hz,1H),7.87(d,J＝10.6Hz,1H),7.56(d,J＝8.8Hz,1H),7.22– 7.15(m,1H),7.14–7.05(m,3H),5.20(t,J＝6.1Hz,1H),4.46(q,J＝7.1Hz,2H),3.28(q,J＝6.9Hz,2H ), 2.90 (t, J = 7.1Hz, 2H), 2.58 (s, 3H), 1.45 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ 159.9, 155.8, 142.9, 135.4 ,135.2,133.9,131.1,129.5,129.3,128.2,126.9,126.2,125.6,121.6,113.0,61.6,42.6,33.8,14.3,9.3.
实施例149Example 149
5-(N-(2-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-iodophenethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.18(d,J＝2.0Hz,1H),7.86(dd,J＝8.8,2.0Hz,1H),7.66(dd,J＝7.6Hz,1.6Hz,1H),7.57(d,J＝8.8Hz,2H),7.20-7.16(m,1H),7.11(dd,J＝7.6Hz,2.0Hz,1H),6.84-6.80(m,1H),4.99(t,J＝6.0Hz,1H),4.46(q,J＝7.2Hz,2H),3.24(q,J＝6.8Hz,2H),2.89(t,J＝6.8Hz,2H),2.59(s,3H),1.44(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.93,155.82,142.91,140.32,139.62,135.15,130.24,129.35,128.69,128.59,128.54,128.50,126.19,125.61,121.65,113.08,100.33,61.61,42.81,40.57,14.36,9.42.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.18(d,J＝2.0Hz,1H),7.86(dd,J＝8.8,2.0Hz,1H),7.66(dd,J＝7.6Hz,1.6Hz,1H ),7.57(d,J＝8.8Hz,2H),7.20-7.16(m,1H),7.11(dd,J＝7.6Hz,2.0Hz,1H),6.84-6.80(m,1H),4.99(t ,J＝6.0Hz,1H),4.46(q,J＝7.2Hz,2H),3.24(q,J＝6.8Hz,2H),2.89(t,J＝6.8Hz,2H),2.59(s,3H ), 1.44 (t, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ159.93,155.82,142.91,140.32,139.62,135.15,130.24,129.35,128.69,128.59,128.54,128.50, 126.19,125.61 ,121.65,113.08,100.33,61.61,42.81,40.57,14.36,9.42.
实施例150Example 150
3-甲基-5-(N-(2-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-methylphenethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，所用胺原料替换为2-甲基苯乙胺，其余条件均一致。得黄色固体0.30g，收率74％。1H NMR(400MHz,Chloroform-d)δ8.17(dd,J＝1.9,0.6Hz,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.60(dd,J＝8.8,0.6Hz,1H),7.14–6.98(m,4H),4.68(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.21(td,J＝7.2,6.2Hz,2H),2.80(t,J＝7.2Hz,2H),2.60(s,3H),2.19(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.1,136.4,135.8,135.4,130.7,129.5,129.4,127.1,126.3,126.3,125.7,121.7,113.2,61.7,43.2,33.4,19.3,14.5,9.5.HRMS(ESI)[M-H]-calcd for C21H22NO5S:400.1219；found:400.1218.Follow the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, except that the amine raw material used is replaced by 2-methylphenylethylamine, and the other conditions are the same. 0.30g of yellow solid was obtained, with a yield of 74%. 1 H NMR (400MHz, Chloroform-d) δ8.17 (dd, J＝1.9, 0.6Hz, 1H), 7.86 (dd, J＝8.8, 1.9Hz, 1H), 7.60 (dd, J＝8.8, 0.6Hz ,1H),7.14–6.98(m,4H),4.68(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.21(td,J＝7.2,6.2Hz,2H) ,2.80(t,J＝7.2Hz,2H),2.60(s,3H),2.19(s,3H),1.46(t,J＝7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ160 .0,156.0,143.1,136.4,135.8,135.4,130.7,129.5,129.4,127.1,126.3,126.3,125.7,121.7,113.2,61.7,43.2,33.4,19.3,14.5,9.5.HRMS(ESI )[MH] -calcd for C 21 H 22 NO 5 S:400.1219; found:400.1218.
实施例151Example 151
3-甲基-5-(N-(2-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-(trifluoromethyl)phenylethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，得白色固体0.28g，收率62％。1H NMR(400MHz,Chloroform-d)δ8.19(dd,J＝1.9,0.6Hz,1H),7.88(dd,J＝8.8,1.9Hz,1H),7.64–7.54(m,2H),7.42(t,J＝7.3Hz,1H),7.29(t,J＝7.3Hz,2H),4.77(t,J＝6.4Hz,1H),4.48(q,J＝7.1Hz,2H),3.32–3.22(m,2H),2.98(t,J＝7.3Hz,2H),2.61(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.2,136.4,135.4,132.1,131.7,129.5,128.9(d,J＝29.9Hz),127.1,126.4(d,J＝5.8Hz),126.2,125.7,124.5(d,J＝273.7Hz),121.7,113.2,61.7,44.2,33.2,14.5,9.4.19F NMR(376MHz,Chloroform-d)δ-59.41.HRMS(ESI)[M-H]-calcd for C21H19NO5SF3:454.0936；found:454.0942.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, 0.28 g of white solid was obtained, with a yield of 62%. 1 H NMR (400MHz, Chloroform-d) δ8.19 (dd, J＝1.9, 0.6Hz, 1H), 7.88 (dd, J＝8.8, 1.9Hz, 1H), 7.64–7.54 (m, 2H), 7.42 (t,J＝7.3Hz,1H),7.29(t,J＝7.3Hz,2H),4.77(t,J＝6.4Hz,1H),4.48(q,J＝7.1Hz,2H),3.32–3.22 (m, 2H), 2.98 (t, J = 7.3Hz, 2H), 2.61 (s, 3H), 1.46 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ 160.0, 156.0 ,143.2,136.4,135.4,132.1,131.7,129.5,128.9(d,J＝29.9Hz),127.1,126.4(d,J＝5.8Hz),126.2,125.7,124.5(d,J＝273.7Hz),121.7 ,113.2,61.7,44.2,33.2,14.5,9.4. 19 F NMR(376MHz,Chloroform-d)δ-59.41.HRMS(ESI)[MH] - calcd for C 21 H 19 NO 5 SF 3 :454.0936; found: 454.0942.
实施例152Example 152
5-(N-(2-甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸
5-(N-(2-methoxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid
根据实施例147的合成步骤，得到白色固体137mg，收率66％。1H NMR(400MHz, Chloroform-d)δ8.13(d,J＝1.5Hz,1H),7.81(dd,J＝8.8,1.8Hz,1H),7.55(d,J＝8.8Hz,1H),7.13(t,J＝7.8Hz,1H),6.97(d,J＝7.3Hz,1H),6.83–6.65(m,2H),5.02(t,J＝5.7Hz,1H),4.48(q,J＝7.1Hz,2H),3.70(s,3H),3.24(q,J＝6.6Hz,2H),2.76(t,J＝6.8Hz,2H),2.59(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,157.3,155.7,142.8,135.3,130.6,129.2,128.1,126.2,126.0,125.6,121.5,120.6,112.8,110.3,61.6,55.2,43.2,30.5,14.4,9.4.According to the synthesis procedure of Example 147, 137 mg of white solid was obtained with a yield of 66%. 1 H NMR (400MHz, Chloroform-d)δ8.13(d,J＝1.5Hz,1H),7.81(dd,J＝8.8,1.8Hz,1H),7.55(d,J＝8.8Hz,1H),7.13(t,J＝ 7.8Hz,1H),6.97(d,J＝7.3Hz,1H),6.83–6.65(m,2H),5.02(t,J＝5.7Hz,1H),4.48(q,J＝7.1Hz,2H) ,3.70(s,3H),3.24(q,J＝6.6Hz,2H),2.76(t,J＝6.8Hz,2H),2.59(s,3H),1.46(t,J＝7.1Hz,3H) . 13 C NMR (101MHz, Chloroform-d) δ159.9,157.3,155.7,142.8,135.3,130.6,129.2,128.1,126.2,126.0,125.6,121.5,120.6,112.8,110.3,61.6,55.2, 43.2,30.5,14.4 ,9.4.
实施例153Example 153
5-(N-(2-羟基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-hydroxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.23–8.19(m,1H),7.97–7.83(m,2H),7.70(t,J＝5.8Hz,1H),6.96(ddq,J＝5.6,3.9,1.7Hz,2H),6.74–6.60(m,2H),4.37(q,J＝7.0Hz,2H),2.95(t,J＝6.3Hz,2H),2.66–2.53(m,5H),1.35(t,J＝7.0Hz,3H).13C NMR(101MHz,DMSO)δ159.2,155.2,154.9,142.0,136.1,130.3,128.6,127.4,126.2,125.6,124.6,121.0,118.8,114.8,113.0,61.1,42.5,30.3,14.1,9.0.HRMS(ESI)[M-H]-calcd for C20H21NO6S:402.1011；found:402.1014. 1 H NMR (400MHz, DMSO-d 6 ) δ9.29 (s, 1H), 8.23–8.19 (m, 1H), 7.97–7.83 (m, 2H), 7.70 (t, J = 5.8Hz, 1H), 6.96(ddq,J＝5.6,3.9,1.7Hz,2H),6.74–6.60(m,2H),4.37(q,J＝7.0Hz,2H),2.95(t,J＝6.3Hz,2H),2.66 –2.53(m,5H),1.35(t,J＝7.0Hz,3H). 13 C NMR(101MHz,DMSO)δ159.2,155.2,154.9,142.0,136.1,130.3,128.6,127.4,126.2,125.6,124.6, 121.0,118.8,114.8,113.0,61.1,42.5,30.3,14.1,9.0.HRMS(ESI)[MH]-calcd for C 20 H 21 NO 6 S:402.1011; found:402.1014.
实施例154Example 154
3-甲基-5-(N-(3-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(3-fluorophenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成，所用胺原料替换为3-氟苯乙胺，其余条件均一致。得橙色固体0.31g，收率76％。1H NMR(400MHz,Chloroform-d)δ8.16(dd,J＝1.9,0.6Hz,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.61(dd,J＝8.8,0.6Hz,1H),7.17(ddd,J＝8.4,7.6,6.0Hz,1H),6.90–6.81(m,2H),6.74(dt,J＝9.7,2.0Hz,1H),4.74(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H),3.24(q,J＝6.8Hz,2H),2.77(t,J＝6.9Hz,2H),2.59(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ163.0(d,J＝246.6Hz),160.0,156.0,143.2,140.3(d,J＝7.3Hz),135.3,130.3(d,J＝8.3Hz),129.6,126.2,125.7,124.5(d,J＝2.9Hz),121.7,115.7(d,J＝21.2Hz),113.9(d,J＝21.0Hz),113.2,61.7,44.1,35.7(d,J＝1.8Hz),14.5,9.4.HRMS(ESI)[M-H]-calcd for C20H19NO5SF:404.0968；found:404.0973.Synthesize according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, except that the amine raw material used is replaced by 3-fluorophenylethylamine, and the other conditions are the same. 0.31g of orange solid was obtained, with a yield of 76%. 1 H NMR (400MHz, Chloroform-d) δ8.16 (dd, J＝1.9, 0.6Hz, 1H), 7.86 (dd, J＝8.8, 1.9Hz, 1H), 7.61 (dd, J＝8.8, 0.6Hz ,1H),7.17(ddd,J＝8.4,7.6,6.0Hz,1H),6.90–6.81(m,2H),6.74(dt,J＝9.7,2.0Hz,1H),4.74(t,J＝6.3 Hz,1H),4.47(q,J＝7.1Hz,2H),3.24(q,J＝6.8Hz,2H),2.77(t,J＝6.9Hz,2H),2.59(s,3H),1.45( t, J＝7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ163.0 (d, J＝246.6Hz), 160.0, 156.0, 143.2, 140.3 (d, J＝7.3Hz), 135.3, 130.3(d,J＝8.3Hz),129.6,126.2,125.7,124.5(d,J＝2.9Hz),121.7,115.7(d,J＝21.2Hz),113.9(d,J＝21.0Hz),113.2, 61.7, 44.1, 35.7 (d, J = 1.8Hz), 14.5, 9.4.HRMS (ESI) [MH] - calcd for C 20 H 19 NO 5 SF: 404.0968; found: 404.0973.
实施例155Example 155
5-(N-(3-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3-Chlorophenythylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照实施例147步骤，得白色固体147mg，收率70％。1H NMR(400MHz,Chloroform-d)δ8.17(s,1H),7.87(d,J＝8.8Hz,1H),7.59(d,J＝8.8Hz,1H),7.11(d,J＝5.9Hz,2H),7.00(s,1H),6.95(t,J＝5.0Hz,2H),5.16(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.24(q,J＝6.8Hz,2H),2.75(t,J＝7.0Hz,2H),2.58(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,143.0,139.8,135.1,134.3,129.8,129.4,128.8,126.9,126.8, 126.1,125.6,121.5,113.1,61.6,44.1,35.5,14.3,9.3.Following the steps of Example 147, 147 mg of white solid was obtained with a yield of 70%. 1 H NMR (400MHz, Chloroform-d) δ8.17 (s, 1H), 7.87 (d, J = 8.8Hz, 1H), 7.59 (d, J = 8.8Hz, 1H), 7.11 (d, J = 5.9 Hz,2H),7.00(s,1H),6.95(t,J＝5.0Hz,2H),5.16(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.24( q, J＝6.8Hz, 2H), 2.75 (t, J＝7.0Hz, 2H), 2.58 (s, 3H), 1.45 (t, J＝7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d )δ159.9,155.8,143.0,139.8,135.1,134.3,129.8,129.4,128.8,126.9,126.8, 126.1,125.6,121.5,113.1,61.6,44.1,35.5,14.3,9.3.
实施例156Example 156
5-(N-(3-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3-iodophenethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.17(d,J＝1.6Hz,1H),7.86(dd,J＝8.4,2.0Hz,1H),7.59(d,J＝8.8Hz,1H),7.45(d,J＝7.6Hz,1H),7.36(s,1H),7.03(d,J＝7.6Hz,1H),6.90(t,J＝7.6Hz,1H),5.18(t,J＝6.0Hz,1H),4.46(q,J＝7.2Hz,2H),3.22(q,J＝6.8Hz,2H),2.71(t,J＝7.2Hz,2H),2.58(s,3H),1.45(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.92,155.81,142.95,140.22,137.60,135.74,135.10,130.29,129.40,128.04,126.15,125.61,121.55,113.12,94.60,61.64,44.10,35.34,14.38,9.45.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.17(d,J＝1.6Hz,1H),7.86(dd,J＝8.4,2.0Hz,1H),7.59(d,J＝8.8Hz,1H),7.45 (d,J＝7.6Hz,1H),7.36(s,1H),7.03(d,J＝7.6Hz,1H),6.90(t,J＝7.6Hz,1H),5.18(t,J＝6.0Hz ,1H),4.46(q,J＝7.2Hz,2H),3.22(q,J＝6.8Hz,2H),2.71(t,J＝7.2Hz,2H),2.58(s,3H),1.45(t , J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ159.92,155.81,142.95,140.22,137.60,135.74,135.10,130.29,129.40,128.04,126.15,125.61,121.55, 113.12,94.60,61.64, 44.10,35.34,14.38,9.45.
实施例157Example 157
3-甲基-5-(N-(3-硝基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(
3-Methyl-5-(N-(3-nitrophenethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝1.9Hz,1H),8.01(ddd,J＝8.0,2.4,1.3Hz,1H),7.92(t,J＝2.0Hz,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.60(d,J＝8.8Hz,1H),7.48–7.35(m,2H),4.47(q,J＝7.1Hz,2H),3.30(q,J＝6.8Hz,2H),2.91(t,J＝6.8Hz,2H),2.58(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,148.4,143.2,140.0,135.2,135.1,129.7,129.6,126.2,125.6,123.7,122.0,121.7,113.3,61.8,44.0,35.8,14.5,9.4.HRMS(ESI)[M-H]-calcd for C20H20N2O7S:431.0913；found:431.0913.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.17 (d, J＝1.9Hz, 1H), 8.01 (ddd, J＝8.0, 2.4, 1.3Hz, 1H), 7.92 (t, J＝2.0Hz, 1H ),7.86(dd,J＝8.8,1.9Hz,1H),7.60(d,J＝8.8Hz,1H),7.48–7.35(m,2H),4.47(q,J＝7.1Hz,2H),3.30 (q, J＝6.8Hz, 2H), 2.91 (t, J＝6.8Hz, 2H), 2.58 (s, 3H), 1.45 (t, J＝7.1Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ160.0,156.0,148.4,143.2,140.0,135.2,135.1,129.7,129.6,126.2,125.6,123.7,122.0,121.7,113.3,61.8,44.0,35.8,14.5,9.4.HRMS(ESI) [MH] -calcd for C 20 H 20 N 2 O 7 S:431.0913; found:431.0913.
实施例158Example 158
5-(N-(3-羟基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3-hydroxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.14(d,J＝1.2Hz,1H),7.82(dd,J＝8.8,2.0Hz,1H),7.58(d,J＝8.4Hz,1H),7.06(t,J＝8.0Hz,1H),6.67–6.64(m,1H),6.59–6.56(m,2H),5.77(s,1H),4.80(t,J＝6.0Hz,1H),4.47(q,J＝7.2Hz,2H),3.22(q,J＝6.4Hz,2H),2.70(t,J＝6.8Hz,2H),2.58(s,3H),1.45(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.04,156.10,155.88,142.95,139.35,135.00,129.92,129.40,126.18,125.67,121.57,120.81,115.76,113.88,113.09,61.67,44.08,35.52,14.34,9.34.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.14(d,J＝1.2Hz,1H),7.82(dd,J＝8.8,2.0Hz,1H),7.58(d,J＝8.4Hz,1H),7.06 (t,J＝8.0Hz,1H),6.67–6.64(m,1H),6.59–6.56(m,2H),5.77(s,1H),4.80(t,J＝6.0Hz,1H),4.47( q,J＝7.2Hz,2H),3.22(q,J＝6.4Hz,2H),2.70(t,J＝6.8Hz,2H),2.58(s,3H),1.45(t,J＝7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ160.04,156.10,155.88,142.95,139.35,135.00,129.92,129.40,126.18,125.67,121.57,120.81,115.76,113.88,1 13.09,61.67,44.08,35.52,14.34, 9.34.
实施例159Example 159
5-(N-(3-氨基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-75)
5-(N-(3-Aminophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-75)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.14(t,J＝6.6Hz,1H),7.01(t,J＝7.9Hz,1H),6.94(ddq,J＝8.1,2.3,1.1Hz,1H),6.53–6.45(m,2H),4.34(q,J＝6.4Hz,2H),4.25(d,J＝5.5Hz,1H),4.13(d,J＝5.5Hz,1H),3.18(dt,J＝6.7,5.7Hz,2H),2.75(tt,J＝5.7,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.14(t,J＝6.6Hz,1H),7.01(t,J＝7.9Hz,1H),6.94(ddq,J＝8.1,2.3,1.1Hz,1H),6.53–6.45(m,2H),4.34 (q,J＝6.4Hz,2H),4.25(d,J＝5.5Hz,1H),4.13(d,J＝5.5Hz,1H),3.18(dt,J＝6.7,5.7Hz,2H),2.75 (tt,J＝5.7,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).
实施例160Example 160
3-甲基-5-(N-(3-(甲氨基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-76)
3-Methyl-5-(N-(3-(methylamino)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-76)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.18–7.09(m,2H),6.92(ddq,J＝7.7,2.2,1.1Hz,1H),6.55–6.46(m,2H),5.68(q,J＝4.8Hz,1H),4.34(q,J＝6.4Hz,2H),3.18(dt,J＝6.6,5.8Hz,2H),2.94(d,J＝4.8Hz,3H),2.81(tt,J＝5.8,1.1Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.18–7.09(m,2H),6.92(ddq,J＝7.7,2.2,1.1Hz,1H),6.55–6.46(m,2H),5.68(q,J＝4.8Hz,1H),4.34(q, J＝6.4Hz,2H),3.18(dt,J＝6.6,5.8Hz,2H),2.94(d,J＝4.8Hz,3H),2.81(tt,J＝5.8,1.1Hz,2H),2.60( s,3H),1.39(t,J=6.3Hz,3H).
实施例161Example 161
5-(N-(3-(二甲基氨基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-77)
5-(N-(3-(Dimethylamino)phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-77)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.18–7.08(m,2H),6.91(dtd,J＝7.9,2.1,1.0Hz,1H),6.62–6.52(m,2H),4.34(q,J＝6.4Hz,2H),3.18(dt,J＝6.6,5.8Hz,2H),2.96(s,6H),2.78(tt,J＝5.6,0.9Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.18–7.08(m,2H),6.91(dtd,J＝7.9,2.1,1.0Hz,1H),6.62–6.52(m,2H),4.34(q,J＝6.4Hz,2H),3.18(dt, J＝6.6,5.8Hz,2H),2.96(s,6H),2.78(tt,J＝5.6,0.9Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).
实施例162Example 162
5-(N-(4-溴苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯
5-(N-(4-Bromophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate ethyl ester
按照实施例147步骤，得白色固体156.0mg，收率67％。1H NMR(400MHz,Chloroform-d)δ8.16(d,J＝1.8Hz,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.61(d,J＝8.8Hz,1H),7.30(d,2H),6.93(d,J＝8.3Hz,2H),4.95(t,J＝6.1Hz,1H),4.48(q,J＝7.1Hz,2H),3.23(q,J＝6.6Hz,2H),2.74(t,J＝6.9Hz,2H),2.59(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,143.1,136.7,135.1,131.7,130.4,129.4,126.1,125.5,121.5,120.6,113.0,61.6,44.1,35.3,14.4,9.4.Following the steps of Example 147, 156.0 mg of white solid was obtained with a yield of 67%. 1 H NMR (400MHz, Chloroform-d) δ8.16 (d, J＝1.8Hz, 1H), 7.86 (dd, J＝8.8, 1.9Hz, 1H), 7.61 (d, J＝8.8Hz, 1H), 7.30(d,2H),6.93(d,J＝8.3Hz,2H),4.95(t,J＝6.1Hz,1H),4.48(q,J＝7.1Hz,2H),3.23(q,J＝6.6 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.59 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 159.9, 155.8, 143.1,136.7,135.1,131.7,130.4,129.4,126.1,125.5,121.5,120.6,113.0,61.6,44.1,35.3,14.4,9.4.
实施例163Example 163
5-(N-(4-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(4-iodophenethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J＝2.0Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.60(d,J＝8.8Hz,1H),7.48(d,J＝8.4Hz,2H),6.80(d,J＝8.4Hz,2H),5.06(t,J＝6.0Hz,1H),4.47(q,J＝7.2Hz,2H),3.21(q,J＝6.8Hz,2H),2.72(t,J＝6.8Hz,2H),2.58(s,3H),1.46(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,155.82,143.04,137.62,137.35,135.07,130.76,129.41,126.12,125.53,121.54,113.06,91.98,61.63,44.04,35.36,14.39,9.42.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.15 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.48 (d,J＝8.4Hz,2H),6.80(d,J＝8.4Hz,2H),5.06(t,J＝6.0Hz,1H),4.47(q,J＝7.2Hz,2H),3.21(q , J＝6.8Hz, 2H), 2.72 (t, J＝6.8Hz, 2H), 2.58 (s, 3H), 1.46 (t, J＝7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ159 .91,155.82,143.04,137.62,137.35,135.07,130.76,129.41,126.12,125.53,121.54,113.06,91.98,61.63,44.04,35.36,14.39,9.42.
实施例164Example 164
3-甲基-5-(N-(4-甲基苯基乙基)磺胺基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(4-methylphenylethyl)sulfonamide)benzofuran-2-carboxylate ethyl ester
将对甲基苯乙胺(0.076g,0.56mmol)溶于DMF(2.5mL)，加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol)，DIPEA(0.25mL)，室温搅拌反应2h。TLC监测反应完全，加入适量水，乙酸乙酯提取3次，有机相合并，经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(PE/DCM/EA＝9:1:1)得白色固体160mg，产率80.4％。Dissolve p-methylphenylethylamine (0.076g, 0.56mmol) in DMF (2.5mL), add ethyl 5-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylate (0.15g, 0.49 mmol), DIPEA (0.25 mL), and stirred at room temperature for 2 h. TLC monitors that the reaction is complete. Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE/DCM/EA=9:1:1) to obtain white color Solid 160 mg, yield 80.4%.
1H NMR(400MHz,CDCl3)δ8.17(d,J＝2.4Hz,1H),7.87(dd,J＝8.8,2.0Hz,1H),7.54(d,J＝8.8Hz,1H),6.93(q,J＝8.1Hz,4H),5.31(t,J＝6.1Hz,1H),4.44(q,J＝7.2Hz,2H),3.20(q,J＝7.2Hz,2H),2.71(t,J＝7.2Hz,2H),2.54(s,3H),2.21(s,3H),1.43(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,155.76,142.86,136.11,135.30,134.68,129.31,129.22,128.55,126.27,125.61,121.55,112.90,61.58,44.54,35.33,20.92,14.35,9.31. 1 H NMR (400MHz, CDCl 3 ) δ8.17(d,J＝2.4Hz,1H),7.87(dd,J＝8.8,2.0Hz,1H),7.54(d,J＝8.8Hz,1H),6.93 (q,J＝8.1Hz,4H),5.31(t,J＝6.1Hz,1H),4.44(q,J＝7.2Hz,2H),3.20(q,J＝7.2Hz,2H),2.71(t ,J＝7.2Hz,2H),2.54(s,3H),2.21(s,3H),1.43(t,J＝7.2Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ159.91,155.76,142.86, 136.11,135.30,134.68,129.31,129.22,128.55,126.27,125.61,121.55,112.90,61.58,44.54,35.33,20.92,14.35,9.31.
实施例165Example 165
5-(N-(4-三氟甲基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯
5-(N-(4-Trifluoromethylphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate ethyl ester
按照实施例147步骤，得白色固体158.1mg，收率69％。1H NMR(400MHz,Chloroform-d)δ8.22–8.13(m,1H),7.87(dd,J＝8.8,2.0Hz,1H),7.63–7.56(m,1H),7.44(d,J＝8.1Hz,2H),7.19(d,J＝7.9Hz,2H),5.24(t,J＝6.0Hz,1H),4.46(q,J＝7.1Hz,2H),3.26(q,J＝6.6Hz,2H),2.86(t,J＝7.1Hz,2H),2.57(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,143.0,142.0,135.1,129.4,129.1,129.1,128.8,126.1,125.4(q,J＝4.0Hz),122.7,121.5,113.0,61.6,44.0,35.7,143,9.3.Following the steps of Example 147, 158.1 mg of white solid was obtained with a yield of 69%. 1 H NMR (400MHz, Chloroform-d) δ8.22–8.13 (m, 1H), 7.87 (dd, J＝8.8, 2.0Hz, 1H), 7.63–7.56 (m, 1H), 7.44 (d, J＝ 8.1Hz,2H),7.19(d,J＝7.9Hz,2H),5.24(t,J＝6.0Hz,1H),4.46(q,J＝7.1Hz,2H),3.26(q,J＝6.6Hz ,2H),2.86(t,J＝7.1Hz,2H),2.57(s,3H),1.45(t,J＝7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ159.9,155.8,143.0 ,142.0,135.1,129.4,129.1,129.1,128.8,126.1,125.4(q,J＝4.0Hz),122.7,121.5,113.0,61.6,44.0,35.7,143,9.3.
实施例166Example 166
5-(N-(4-甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(4-Methoxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照实施例147步骤，得白色固体125mg，收率60％。1H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.86(d,J＝10.4Hz,1H),7.58(d,J＝8.8Hz,1H),6.95(d,J＝8.5Hz,2H),6.72(d,J＝8.5Hz,2H),4.99(s,1H),4.47(q,J＝7.1Hz,2H),3.72(s,3H),3.19(d,J＝10.3Hz,2H),2.70(t,J＝6.9Hz,2H),2.58(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,158.4,155.8,142.9,135.2,129.6,129.6,129.3,126.2,125.6,121.5,114.0,112.9,61.6,55.2,44.5,34.8,14.4,9.3.Following the steps of Example 147, 125 mg of white solid was obtained with a yield of 60%. 1 H NMR (400MHz, Chloroform-d) δ8.16 (s, 1H), 7.86 (d, J = 10.4Hz, 1H), 7.58 (d, J = 8.8Hz, 1H), 6.95 (d, J = 8.5 Hz,2H),6.72(d,J＝8.5Hz,2H),4.99(s,1H),4.47(q,J＝7.1Hz,2H),3.72(s,3H),3.19(d,J＝10.3 Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H), 2.58 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 159.9, 158.4, 155.8,142.9,135.2,129.6,129.6,129.3,126.2,125.6,121.5,114.0,112.9,61.6,55.2,44.5,34.8,14.4,9.3.
实施例167 Example 167
5-(N-(4-硝基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(4-Nitrophenylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照实施例147步骤，得白色固体125mg，收率60％。1H NMR(400MHz,Chloroform-d)δ8.21–8.14(m,1H),8.13–8.04(m,2H),7.89(d,J＝8.7Hz,1H),7.65(d,J＝8.7Hz,1H),7.28(d,J＝8.3Hz,2H),4.82(t,J＝5.9Hz,1H),4.49(q,J＝7.1Hz,2H),3.31(q,J＝6.7Hz,2H),2.94(t,J＝6.8Hz,2H),2.61(s,3H),1.48(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.8,155.9,146.9,145.4,143.2,135.0,129.7,129.5,126.0,125.3,123.8,121.5,113.1,61.7,43.7,36.0,14.3,9.3.Following the steps of Example 147, 125 mg of white solid was obtained with a yield of 60%. 1 H NMR (400MHz, Chloroform-d) δ8.21–8.14(m,1H),8.13–8.04(m,2H),7.89(d,J＝8.7Hz,1H),7.65(d,J＝8.7Hz ,1H),7.28(d,J＝8.3Hz,2H),4.82(t,J＝5.9Hz,1H),4.49(q,J＝7.1Hz,2H),3.31(q,J＝6.7Hz,2H ), 2.94 (t, J＝6.8Hz, 2H), 2.61 (s, 3H), 1.48 (t, J＝7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ 159.8, 155.9, 146.9, 145.4 ,143.2,135.0,129.7,129.5,126.0,125.3,123.8,121.5,113.1,61.7,43.7,36.0,14.3,9.3.
实施例168Example 168
5-(N-(4-羟基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(4-hydroxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照实施例147步骤，得白色固体182mg，收率91％。1H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.84(d,J＝8.7Hz,1H),7.59(dd,J＝25.8,8.8Hz,1H),6.99(d,J＝8.4Hz,1H),6.84(dd,J＝20.5,8.4Hz,2H),6.68(d,J＝8.3Hz,1H),4.46(q,J＝7.0Hz,2H),3.17(t,J＝6.9Hz,2H),2.70(dt,J＝28.1,6.9Hz,2H),2.56(s,3H),1.43(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,148.1,143.3,137.2,135.1,130.0,129.7,127.3,126.1,122.4,115.5,113.2,61.7,44.1,35.3,14.3,9.3.Following the steps of Example 147, 182 mg of white solid was obtained with a yield of 91%. 1 H NMR (400MHz, Chloroform-d) δ8.16 (s, 1H), 7.84 (d, J = 8.7Hz, 1H), 7.59 (dd, J = 25.8, 8.8Hz, 1H), 6.99 (d, J ＝8.4Hz,1H),6.84(dd,J＝20.5,8.4Hz,2H),6.68(d,J＝8.3Hz,1H),4.46(q,J＝7.0Hz,2H),3.17(t,J =6.9Hz, 2H), 2.70 (dt, J = 28.1, 6.9Hz, 2H), 2.56 (s, 3H), 1.43 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ159.9,155.8,148.1,143.3,137.2,135.1,130.0,129.7,127.3,126.1,122.4,115.5,113.2,61.7,44.1,35.3,14.3,9.3.
实施例169Example 169
5-(N-(4-氨基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-87)
5-(N-(4-Aminophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-87)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.14(t,J＝6.6Hz,1H),6.90(dt,J＝8.0,1.0Hz,2H),6.48–6.42(m,2H),4.34(q,J＝6.4Hz,2H),4.04(d,J＝5.7Hz,1H),3.98(d,J＝5.7Hz,1H),3.17(dt,J＝6.7,5.8Hz,2H),2.82(tt,J＝5.7,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.14(t,J＝6.6Hz,1H),6.90(dt,J＝8.0,1.0Hz,2H),6.48–6.42(m,2H),4.34(q,J＝6.4Hz,2H),4.04(d ,J＝5.7Hz,1H),3.98(d,J＝5.7Hz,1H),3.17(dt,J＝6.7,5.8Hz,2H),2.82(tt,J＝5.7,1.0Hz,2H),2.60 (s,3H),1.39(t,J＝6.3Hz,3H).
实施例170Example 170
3-甲基-5-(N-(4-(甲氨基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-88)
3-Methyl-5-(N-(4-(methylamino)phenylethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-88)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2 Hz,1H),7.14(t,J＝6.6Hz,1H),6.96(dt,J＝7.5,1.1Hz,2H),6.62–6.56(m,2H),5.48(q,J＝4.8Hz,1H),4.34(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.8Hz,2H),2.91(d,J＝4.8Hz,3H),2.82(tt,J＝5.8,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2 Hz,1H),7.14(t,J＝6.6Hz,1H),6.96(dt,J＝7.5,1.1Hz,2H),6.62–6.56(m,2H),5.48(q,J＝4.8Hz,1H ),4.34(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.8Hz,2H),2.91(d,J＝4.8Hz,3H),2.82(tt,J＝5.8,1.0Hz ,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例171Example 171
5-(N-(2-(5-溴吡啶-3-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-90)
5-(N-(2-(5-bromopyridin-3-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-90)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.54(t,J＝1.9Hz,1H),8.49(t,J＝1.8Hz,1H),8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.48(t,J＝2.0Hz,1H),7.16(t,J＝6.6Hz,1H),4.34(q,J＝6.4Hz,2H),3.23(q,J＝6.3Hz,2H),2.93(t,J＝6.2Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.54(t,J＝1.9Hz,1H),8.49(t,J＝1.8Hz,1H),8.18(d,J＝2.2Hz,1H),7.96( dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.48(t,J＝2.0Hz,1H),7.16(t,J＝6.6Hz,1H),4.34( q,J＝6.4Hz,2H),3.23(q,J＝6.3Hz,2H),2.93(t,J＝6.2Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz, 3H).
实施例172Example 172
5-(N-(2-(5-甲氧基吡啶-3-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-91)
5-(N-(2-(5-methoxypyridin-3-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-91 )
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.30(t,J＝1.8Hz,1H),8.18(d,J＝2.2Hz,1H),8.12(t,J＝1.8Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.16(t,J＝6.6Hz,1H),6.95(t,J＝2.0Hz,1H),4.34(q,J＝6.4Hz,2H),3.91(s,3H),3.23(q,J＝6.3Hz,2H),2.92(t,J＝6.2Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.30(t,J＝1.8Hz,1H),8.18(d,J＝2.2Hz,1H),8.12(t,J＝1.8Hz,1H),7.96( dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.16(t,J＝6.6Hz,1H),6.95(t,J＝2.0Hz,1H),4.34( q,J＝6.4Hz,2H),3.91(s,3H),3.23(q,J＝6.3Hz,2H),2.92(t,J＝6.2Hz,2H),2.60(s,3H),1.39( t,J＝6.3Hz,3H).
实施例173Example 173
3-甲基-5-(N-(3-(三氟甲氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(3-(trifluoromethoxy)phenylethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
将2-(3-(三氟甲氧基)苯基)乙烷-1-胺(0.1g,0.49mmol)溶于DMF(2.5mL)，加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol)，DIPEA(0.25mL)，室温搅拌反应2h。TLC监测反应完全，加入适量水，乙酸乙酯提取3次，有机相合并，经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(PE/DCM/EA＝9:1:1)得白色固体175mg，产率74.9％。Dissolve 2-(3-(trifluoromethoxy)phenyl)ethane-1-amine (0.1g, 0.49mmol) in DMF (2.5mL), and add 5-(chlorosulfonyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (0.15g, 0.49mmol), DIPEA (0.25mL), stirred at room temperature for 2h. TLC monitors that the reaction is complete. Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE/DCM/EA=9:1:1) to obtain white color Solid 175 mg, yield 74.9%.
1H NMR(400MHz,CDCl3)δ8.16(d,J＝2.0Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.53(d,J＝8.8Hz,1H),7.16(t,J＝8.0Hz,1H),7.01-6.92(m,2H),6.87(s,1H),5.45(t,J＝6.0Hz,1H),4.42(q,J＝7.2Hz,2H),3.22(q,J＝6.8Hz,2H),2.77(t,J＝7.2Hz,2H),2.52(s,3H),1.40(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.90,155.80,149.26(d,J＝1.8Hz),142.94,140.25,135.13,129.84,129.35,127.13,126.09,125.50,121.50,121.13,120.33(q,J＝ 258.2Hz),118.92,112.98,61.59,44.05,35.52,14.22,9.18.19F NMR(376MHz,CDCl3)δ-57.81. 1 H NMR (400MHz, CDCl 3 ) δ8.16 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.16 (t,J＝8.0Hz,1H),7.01-6.92(m,2H),6.87(s,1H),5.45(t,J＝6.0Hz,1H),4.42(q,J＝7.2Hz,2H) ,3.22(q,J＝6.8Hz,2H),2.77(t,J＝7.2Hz,2H),2.52(s,3H),1.40(t,J＝7.2Hz,3H). 13 C NMR(101MHz, CDCl 3 )δ159.90,155.80,149.26(d,J＝1.8Hz),142.94,140.25,135.13,129.84,129.35,127.13,126.09,125.50,121.50,121.13,120.33(q,J＝ 258.2Hz), 118.92, 112.98, 61.59, 44.05, 35.52, 14.22, 9.18. 19 F NMR (376MHz, CDCl 3 ) δ-57.81.
实施例174Example 174
5-(N-(3-乙炔基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3-ethynylphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J＝2.0Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.58(d,J＝8.8Hz,1H),7.24(d,J＝7.6Hz,1H),7.14–7.10(m,2H),7.04(d,J＝8.0Hz,1H),5.17(t,J＝6.0Hz,1H),4.45(q,J＝7.2Hz,2H),3.22(q,J＝6.8Hz,2H),3.02(s,1H),2.74(t,J＝6.8Hz,2H),2.57(s,3H),1.44(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.92,155.80,142.91,138.02,135.11,132.23,130.40,129.37,129.29,128.59,126.16,125.63,122.34,121.53,113.06,83.23,77.50,61.60,44.11,35.49,14.35,9.36.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.15 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.24 (d,J＝7.6Hz,1H),7.14–7.10(m,2H),7.04(d,J＝8.0Hz,1H),5.17(t,J＝6.0Hz,1H),4.45(q,J＝ 7.2Hz,2H),3.22(q,J＝6.8Hz,2H),3.02(s,1H),2.74(t,J＝6.8Hz,2H),2.57(s,3H),1.44(t,J＝ 7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ159.92,155.80,142.91,138.02,135.11,132.23,130.40,129.37,129.29,128.59,126.16,125.63,122.34,121 .53,113.06,83.23,77.50,61.60 ,44.11,35.49,14.35,9.36.
实施例175Example 175
5-(N-(3-氰基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3-cyanophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.13(d,J＝2.0Hz,1H),7.83(dd,J＝8.8,2.0Hz,1H),7.53(d,J＝8.8Hz,1H),7.38–7.35(m,1H),7.33–7.30(m,2H),7.25(t,J＝7.6Hz,1H),5.58(t,J＝6.2Hz,1H),4.40(q,J＝7.2Hz,2H),3.20(q,J＝6.8Hz,2H),2.80(t,J＝7.2Hz,2H),2.51(s,3H),1.39(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ159.88,155.75,142.96,139.58,135.08,133.46,132.30,130.30,129.36,129.33,126.09,125.50,121.51,118.65,113.06,112.30,61.64,43.92,35.43,14.31,9.33.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.13(d,J＝2.0Hz,1H),7.83(dd,J＝8.8,2.0Hz,1H),7.53(d,J＝8.8Hz,1H),7.38 –7.35(m,1H),7.33–7.30(m,2H),7.25(t,J＝7.6Hz,1H),5.58(t,J＝6.2Hz,1H),4.40(q,J＝7.2Hz, 2H), 3.20 (q, J＝6.8Hz, 2H), 2.80 (t, J＝7.2Hz, 2H), 2.51 (s, 3H), 1.39 (t, J＝7.0Hz, 3H). 13 C NMR ( 101MHz, CDCl 3 )δ159.88,155.75,142.96,139.58,135.08,133.46,132.30,130.30,129.36,129.33,126.09,125.50,121.51,118.65,113.06,112.3 0,61.64,43.92,35.43,14.31,9.33.
实施例176Example 176
5-(N-(3-(二甲基磷酰基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-95)
5-(N-(3-(Dimethylphosphoryl)phenethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-95)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.44(dddd,J＝13.4,7.3,2.3,1.3Hz,1H),7.31–7.19(m,3H),7.14(t,J＝6.6Hz,1H),4.34(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.7Hz,2H),2.78(tt,J＝5.6,1.0Hz,2H),2.60(s,3H),1.97(s,6H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.44(dddd,J＝13.4,7.3,2.3,1.3Hz,1H),7.31–7.19(m,3H),7.14(t,J＝6.6Hz,1H),4.34(q,J＝6.4Hz,2H) ,3.17(dt,J＝6.6,5.7Hz,2H),2.78(tt,J＝5.6,1.0Hz,2H),2.60(s,3H),1.97(s,6H),1.39(t,J＝6.3 Hz,3H).
实施例177Example 177
5-(N-(3-(1,1-二氟乙基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-96)
5-(N-(3-(1,1-difluoroethyl)phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-96)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.41–7.30(m,3H),7.21–7.12(m,2H),4.34(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.7Hz,2H),2.82(tt,J＝5.6,1.0Hz,2H),2.60(s,3H),2.33(t,J＝20.9Hz,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.41–7.30(m,3H),7.21–7.12(m,2H),4.34(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.7Hz,2H),2.82(tt,J＝ 5.6,1.0Hz,2H),2.60(s,3H),2.33(t,J＝20.9Hz,3H),1.39(t,J＝6.3Hz,3H).
实施例178Example 178
5-(N-(3-乙酰苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3-Acetylphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.12(d,J＝2.0Hz,1H),7.86(dd,J＝8.8,2.0Hz,1H),7.74–7.71(m,1H),7.67(s,1H),7.58(d,J＝8.8Hz,1H),7.31–7.28(m,2H),5.28(br,1H),4.46(q,J＝7.2Hz,2H),3.27(q,J＝5.6Hz,2H),2.85(t,J＝7.0Hz,2H),2.57(s,3H),2.52(s,3H),1.45(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ198.05,159.88,155.79,142.96,138.46,137.32,135.21,133.56,129.37,128.84,128.35,126.89,126.12,125.55,121.51,113.04,61.59,44.13,35.72,26.59,14.33,9.32.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.12 (d, J＝2.0Hz, 1H), 7.86 (dd, J＝8.8, 2.0Hz, 1H), 7.74–7.71 (m, 1H), 7.67 (s, 1H),7.58(d,J＝8.8Hz,1H),7.31–7.28(m,2H),5.28(br,1H),4.46(q,J＝7.2Hz,2H),3.27(q,J＝5.6 Hz, 2H), 2.85 (t, J＝7.0Hz, 2H), 2.57 (s, 3H), 2.52 (s, 3H), 1.45 (t, J＝7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ198.05,159.88,155.79,142.96,138.46,137.32,135.21,133.56,129.37,128.84,128.35,126.89,126.12,125.55,121.51,113.04,61.59, 44.13,35.72,26.59,14.33,9.32.
实施例179Example 179
5-(N-(3-乙氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3-ethoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J＝2.0Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.55(d,J＝8.8Hz,1H),7.07(t,J＝7.8Hz,1H),6.64(dd,J＝8.0,2.4Hz,1H),6.60(d,J＝7.2Hz,1H),6.54(t,J＝6.2Hz,1H),5.23(t,J＝6.0Hz,1H),4.45(q,J＝7.2Hz,2H),3.88(q,J＝6.8Hz,2H),3.22(q,J＝6.8Hz,2H),2.72(t,J＝7.0Hz,2H),2.56(s,3H),1.44(t,J＝7.2Hz,3H),1.33(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ159.90,159.09,155.76,142.85,139.26,135.22,129.55,129.31,126.22,125.61,121.52,120.81,114.94,112.93,112.42,63.21,61.57,44.28,35.75,14.77,14.34,9.31.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.15 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.07 (t,J＝7.8Hz,1H),6.64(dd,J＝8.0,2.4Hz,1H),6.60(d,J＝7.2Hz,1H),6.54(t,J＝6.2Hz,1H),5.23 (t,J＝6.0Hz,1H),4.45(q,J＝7.2Hz,2H),3.88(q,J＝6.8Hz,2H),3.22(q,J＝6.8Hz,2H),2.72(t , J＝7.0Hz, 2H), 2.56 (s, 3H), 1.44 (t, J＝7.2Hz, 3H), 1.33 (t, J＝7.0Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ159 .90,159.09,155.76,142.85,139.26,135.22,129.55,129.31,126.22,125.61,121.52,120.81,114.94,112.93,112.42,63.21,61.57,44.28,3 5.75,14.77,14.34,9.31.
实施例180Example 180
3-甲基-5-(N-(3-(2,2,2-三氟乙氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(3-(2,2,2-trifluoroethoxy)phenylethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J＝2.0Hz,1H),7.84(dd,J＝8.8,2.0Hz,1H),7.54(d,J＝8.8Hz,1H),7.11(t,J＝8.0Hz,1H),6.71(d,J＝7.6Hz,1H),6.68(dd,J＝8.0,2.4Hz,1H),6.63(t,J＝2.0 Hz,1H),5.20(t,J＝6.0Hz,1H),4.44(q,J＝7.2Hz,2H),4.25(q,J＝8.0Hz,2H),3.22(q,J＝6.8Hz,2H),2.73(t,J＝7.2Hz,2H),2.55(s,3H),1.43(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,157.46,155.79,142.95,139.84,135.13,129.85,129.36,126.12,125.55,123.33(q,J＝279.1Hz),122.77,121.52,115.50,113.00,112.75,65.60(q,J＝35.7Hz),61.61,44.15,35.67,14.28,9.25.19F NMR(376MHz,CDCl3)δ-73.98.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.15(d,J＝2.0Hz,1H),7.84(dd,J＝8.8,2.0Hz,1H),7.54(d,J＝8.8Hz,1H),7.11 (t,J＝8.0Hz,1H),6.71(d,J＝7.6Hz,1H),6.68(dd,J＝8.0,2.4Hz,1H),6.63(t,J＝2.0 Hz,1H),5.20(t,J＝6.0Hz,1H),4.44(q,J＝7.2Hz,2H),4.25(q,J＝8.0Hz,2H),3.22(q,J＝6.8Hz, 2H), 2.73 (t, J＝7.2Hz, 2H), 2.55 (s, 3H), 1.43 (t, J＝7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 159.91, 157.46, 155.79, 142.95 ,139.84,135.13,129.85,129.36,126.12,125.55,123.33(q,J＝279.1Hz),122.77,121.52,115.50,113.00,112.75,65.60(q,J＝35.7Hz),61.61,4 4.15,35.67,14.28 ,9.25. 19 F NMR (376MHz, CDCl 3 )δ-73.98.
实施例181Example 181
5-(N-(3-(2-乙氧基乙氧基)苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3-(2-ethoxyethoxy)phenethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,CDCl3)δ8.12(d,J＝1.6Hz,1H),7.82(dd,J＝8.6,2.0Hz,1H),7.53(d,J＝8.8Hz,1H),7.04(t,J＝7.6Hz,1H),6.67–6.64(m,1H),6.58(d,J＝6.8Hz,2H),5.18(t,J＝6.2Hz,1H),4.42(q,J＝7.2Hz,2H),3.97(t,J＝4.8Hz,2H),3.69(t,J＝4.8Hz,2H),3.52(q,J＝7.2Hz,2H),3.17(q,J＝6.8Hz,2H),2.68(t,J＝7.0Hz,2H),2.53(s,3H),1.40(t,J＝7.2Hz,3H),1.17(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ159.89,158.98,155.75,142.84,139.27,135.23,129.54,129.30,126.20,125.62,121.51,121.13,115.16,112.96,112.52,68.85,67.26,66.76,61.55,44.25,35.77,15.12,14.33,9.32. 1 H NMR (400MHz, CDCl 3 ) δ8.12(d,J＝1.6Hz,1H),7.82(dd,J＝8.6,2.0Hz,1H),7.53(d,J＝8.8Hz,1H),7.04 (t,J＝7.6Hz,1H),6.67–6.64(m,1H),6.58(d,J＝6.8Hz,2H),5.18(t,J＝6.2Hz,1H),4.42(q,J＝ 7.2Hz,2H),3.97(t,J＝4.8Hz,2H),3.69(t,J＝4.8Hz,2H),3.52(q,J＝7.2Hz,2H),3.17(q,J＝6.8Hz ,2H),2.68(t,J＝7.0Hz,2H),2.53(s,3H),1.40(t,J＝7.2Hz,3H),1.17(t,J＝7.0Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ159.89,158.98,155.75,142.84,139.27,135.23,129.54,129.30,126.20,125.62,121.51,121.13,115.16,112.96,112.52,68.85 ,67.26,66.76,61.55,44.25,35.77,15.12, 14.33,9.32.
实施例182Example 182
5-(N-(3-(3,3-二氟氮杂环丁烷-1-基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-101)
5-(N-(3-(3,3-Difluoroazetidin-1-yl)phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M -GPR132-B-101)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.18–7.11(m,2H),7.00(dddt,J＝7.3,3.5,2.4,1.2Hz,2H),6.74(tt,J＝2.1,1.0Hz,1H),4.34(q,J＝6.4Hz,2H),4.02(t,J＝20.9Hz,4H),3.18(dt,J＝6.6,5.8Hz,2H),2.78(tt,J＝5.6,0.9Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.18–7.11(m,2H),7.00(dddt,J＝7.3,3.5,2.4,1.2Hz,2H),6.74(tt,J＝2.1,1.0Hz,1H),4.34(q,J＝6.4Hz, 2H),4.02(t,J＝20.9Hz,4H),3.18(dt,J＝6.6,5.8Hz,2H),2.78(tt,J＝5.6,0.9Hz,2H),2.60(s,3H), 1.39(t,J＝6.3Hz,3H).
实施例183Example 183
3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-([1,1'-diphenyl]-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，得白色固体0.39g，收率43％。1H NMR(400MHz,Chloroform-d)δ8.15(d,J＝1.9Hz,1H),7.84(dd,J＝8.9,1.9Hz,1H),7.57(d,J＝8.9Hz,1H),7.51–7.37(m,5H),7.36–7.27(m,2H),7.22(t,J＝1.9Hz,1H),7.08–6.98(m,1H),4.61(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.31(q,J＝6.8Hz,2H),2.83(t,J＝6.8Hz,2H),2.55(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.1,141.8,140.7,138.1,135.4,129.5,129.3,128.9,127.7,127.6,127.5,127.1,126.3,125.8,125.7,121.6,113.2,61.7,44.4,35.9,14.5,9.4.HRMS(ESI)[M+H]+calcd for C26H26NO5S:464.1532；found:464.1525. According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, 0.39g of white solid was obtained, with a yield of 43%. 1 H NMR (400MHz, Chloroform-d) δ8.15 (d, J＝1.9Hz, 1H), 7.84 (dd, J＝8.9, 1.9Hz, 1H), 7.57 (d, J＝8.9Hz, 1H), 7.51–7.37(m,5H),7.36–7.27(m,2H),7.22(t,J＝1.9Hz,1H),7.08–6.98(m,1H),4.61(t,J＝6.2Hz,1H) ,4.47(q,J＝7.1Hz,2H),3.31(q,J＝6.8Hz,2H),2.83(t,J＝6.8Hz,2H),2.55(s,3H),1.45(t,J＝ 7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ160.0,156.0,143.1,141.8,140.7,138.1,135.4,129.5,129.3,128.9,127.7,127.6,127.5,127.1,126.3,12 5.8,125.7, 121.6,113.2,61.7,44.4,35.9,14.5,9.4.HRMS(ESI)[M+H] + calcd for C 26 H 26 NO 5 S:464.1532; found:464.1525.
实施例184Example 184
3-甲基-5-(N-(3-(噻吩-3-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-103)
3-Methyl-5-(N-(3-(thiophen-3-yl)phenethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-103)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.59(t,J＝1.7Hz,1H),7.52–7.35(m,5H),7.20–7.11(m,2H),4.34(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.7Hz,2H),2.84(tt,J＝5.8,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.59(t,J＝1.7Hz,1H),7.52–7.35(m,5H),7.20–7.11(m,2H),4.34(q,J＝6.4Hz,2H),3.17(dt,J＝6.6, 5.7Hz,2H),2.84(tt,J＝5.8,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).
实施例185Example 185
3-甲基-5-(N-(3(噻吩-2-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(3(thiophen-2-yl)phenylethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
梨形瓶中加入4(0.47g,2.3mmol)，5(0.70g,2.3mmol)，DIPEA(0.43g,3.3mmol)，加入DMF 3ml，室温反应5h，TLC监测反应完全。反应结束后，EA/H2O萃取3次，合并有机相，Na2SO4干燥，过滤浓缩，硅胶柱层析纯化(PE:EA＝4:1)，得白色固体0.36g，产率33％。Add 4 (0.47g, 2.3mmol), 5 (0.70g, 2.3mmol), DIPEA (0.43g, 3.3mmol) into the pear-shaped bottle, add 3ml of DMF, and react at room temperature for 5h. TLC monitors the reaction to be complete. After the reaction, EA/H2O was extracted three times, the organic phases were combined, dried over Na2SO4, filtered and concentrated, and purified by silica gel column chromatography (PE:EA=4:1) to obtain 0.36g of white solid with a yield of 33%.
1H NMR(400MHz,CDCl3)δ8.15(d,J＝2.0Hz,1H),7.86(dd,J＝8.8,2.0Hz,1H),7.59(d,J＝8.8Hz,1H),7.44(d,J＝8.8Hz,1H),7.28–7.25(m,2H),7.23–7.21(m,2H),7.06(dd,J＝5.2,3.6Hz,1H),6.99(d,J＝7.6Hz,1H),4.68(t,J＝6.0Hz,1H),4.49(q,J＝7.2Hz,2H),3.32(q,J＝6.8Hz,2H),2.81(t,J＝6.8Hz,2H),2.57(s,3H),1.48(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.88,155.83,143.72,142.94,138.24,135.14,134.80,129.40,129.27,128.02,127.78,126.16,126.02,125.56,124.98,124.36,123.17,121.48,113.03,61.55,44.15,35.66,14.37,9.33. 1 H NMR (400MHz, CDCl 3 ) δ8.15 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.8, 2.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.44 (d,J＝8.8Hz,1H),7.28–7.25(m,2H),7.23–7.21(m,2H),7.06(dd,J＝5.2,3.6Hz,1H),6.99(d,J＝7.6 Hz,1H),4.68(t,J＝6.0Hz,1H),4.49(q,J＝7.2Hz,2H),3.32(q,J＝6.8Hz,2H),2.81(t,J＝6.8Hz, 2H), 2.57 (s, 3H), 1.48 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 159.88, 155.83, 143.72, 142.94, 138.24, 135.14, 134.80, 129.40, 129.27, 128.02 ,127.78,126.16,126.02,125.56,124.98,124.36,123.17,121.48,113.03,61.55,44.15,35.66,14.37,9.33.
实施例186Example 186
3-甲基-5-(N-(3-(1-甲基-1H-吡唑-4-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(3-(1-methyl-1H-pyrazol-4-yl)phenethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，得黄色固体0.13g，收率23％。1H NMR(400MHz,Chloroform-d)δ8.13(dd,J＝1.9,0.8Hz,1H),7.83(dd,J＝8.8,1.9Hz,1H),7.65(d,J＝0.8Hz,1H),7.59–7.50(m,2H),7.26(d,J＝1.8Hz,1H),7.20(t,J＝7.6Hz,1H),7.11(t,J＝1.8Hz,1H),6.93–6.85(m,1H),4.78(t,J＝6.1Hz,1H),4.47(q,J＝7.1Hz,2H),3.92(s,3H),3.29(q,J＝6.8Hz,2H),2.79(t,J＝6.8Hz,2H),2.56(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ160.0,155.9,143.1,138.3,136.7,135.3,133.2,129.5,129.3,127.0,126.7,126.3,125.8,125.6,124.0,122.8,121.6,113.1,61.7,44.3,39.2,35.9,14.5,9.4.HRMS(ESI)[M+H]+calcd for C24H26N3O5S:468.1593；found:468.1585.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, 0.13 g of yellow solid was obtained, with a yield of 23%. 1 H NMR (400MHz, Chloroform-d) δ8.13 (dd, J＝1.9, 0.8Hz, 1H), 7.83 (dd, J＝8.8, 1.9Hz, 1H), 7.65 (d, J＝0.8Hz, 1H ),7.59–7.50(m,2H),7.26(d,J＝1.8Hz,1H),7.20(t,J＝7.6Hz,1H),7.11(t,J＝1.8Hz,1H),6.93–6.85 (m,1H),4.78(t,J＝6.1Hz,1H),4.47(q,J＝7.1Hz,2H),3.92(s,3H),3.29(q,J＝6.8Hz,2H),2.79 (t, J＝6.8Hz, 2H), 2.56 (s, 3H), 1.46 (t, J＝7.1Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 160.0, 155.9, 143.1, 138.3, 136.7 ,135.3,133.2,129.5,129.3,127.0,126.7,126.3,125.8,125.6,124.0,122.8,121.6,113.1,61.7,44.3,39.2,35.9,14.5,9.4.HRMS(ESI)[M+H] + calcd for C 24 H 26 N 3 O 5 S:468.1593; found:468.1585.
实施例187Example 187
3-甲基-5-(N-(3-(1-甲基-1H-吡唑-5-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(3-(1-methyl-1H-pyrazol-5-yl)phenylethyl)sulfamoyl)benzofuran-2-carboxylate
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，得黄色液体0.18g，收率65％。1H NMR(400MHz,Chloroform-d)δ8.20(dd,J＝1.9,0.6Hz,1H),7.89(dd,J＝8.8,1.9Hz,1H),7.62(dd,J＝8.8,0.6Hz,1H),7.49(d,J＝1.9Hz,1H),7.35(t,J＝7.9Hz,1H),7.28(s,1H),7.18–7.09(m,2H),6.25(d,J＝1.9Hz,1H),4.98(t,J＝6.3Hz,1H),4.48(q,J＝7.1Hz,2H),3.86(s,3H),3.29(q,J＝6.8Hz,2H),2.86(t,J＝7.1Hz,2H),2.60(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.2,138.6,138.5,135.4,131.3,129.5,129.3,129.1,128.9,127.2,126.2,125.6,121.6,113.2,106.2,61.7,44.3,37.6,36.0,14.5,9.5.HRMS(ESI)[M+H]+calcd for C24H26N3O5S:468.1593；found:468.1586.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, 0.18g of yellow liquid was obtained, with a yield of 65%. 1 H NMR (400MHz, Chloroform-d) δ8.20 (dd, J＝1.9, 0.6Hz, 1H), 7.89 (dd, J＝8.8, 1.9Hz, 1H), 7.62 (dd, J＝8.8, 0.6Hz ,1H),7.49(d,J＝1.9Hz,1H),7.35(t,J＝7.9Hz,1H),7.28(s,1H),7.18–7.09(m,2H),6.25(d,J＝ 1.9Hz,1H),4.98(t,J＝6.3Hz,1H),4.48(q,J＝7.1Hz,2H),3.86(s,3H),3.29(q,J＝6.8Hz,2H),2.86 (t,J＝7.1Hz,2H),2.60(s,3H),1.46(t,J＝7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.2,138.6,138.5, 135.4,131.3,129.5,129.3,129.1,128.9,127.2,126.2,121.6,113.2,61.7,44.3,37.6.0,14.5.hrms (ESI) [m + H] + Calcd. for C 24 H 26 N 3 O 5 S:468.1593; found:468.1586.
实施例188Example 188
5-(N-(2-氟-4-氯苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯
5-(N-(2-Fluoro-4-chlorophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate ethyl ester
按照实施例147步骤，得白色固体144.2mg，收率66％。1H NMR(400MHz,Chloroform-d)δ8.16(d,J＝1.8Hz,1H),7.86(dd,J＝8.8,2.0Hz,1H),7.59(d,J＝8.8Hz,1H),7.03(t,J＝8.0Hz,1H),6.92(ddd,J＝17.3,8.9,2.1Hz,2H),5.15(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H),3.24(q,J＝6.8Hz,2H),2.78(t,J＝6.9Hz,2H),2.59(s,3H),1.46(t,J＝7.2Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.80(d,J＝248.9Hz),159.9,155.8,143.0,135.1,133.3(d,J＝10.3Hz),131.9(d,J＝5.7Hz),129.4,126.1,125.5,124.5(d,J＝3.6Hz),123.4(d,J＝15.8Hz),121.5,116.1(d,J＝25.5Hz),113.0,61.6,42.8,29.2,14.3,9.3.Following the steps of Example 147, 144.2 mg of white solid was obtained with a yield of 66%. 1 H NMR (400MHz, Chloroform-d) δ8.16 (d, J＝1.8Hz, 1H), 7.86 (dd, J＝8.8, 2.0Hz, 1H), 7.59 (d, J＝8.8Hz, 1H), 7.03(t,J＝8.0Hz,1H),6.92(ddd,J＝17.3,8.9,2.1Hz,2H),5.15(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H ), 3.24 (q, J＝6.8Hz, 2H), 2.78 (t, J＝6.9Hz, 2H), 2.59 (s, 3H), 1.46 (t, J＝7.2Hz, 3H). 13 C NMR (101MHz ,Chloroform-d)δ160.80(d,J＝248.9Hz),159.9,155.8,143.0,135.1,133.3(d,J＝10.3Hz),131.9(d,J＝5.7Hz),129.4,126.1,125.5 ,124.5(d,J＝3.6Hz),123.4(d,J＝15.8Hz),121.5,116.1(d,J＝25.5Hz),113.0,61.6,42.8,29.2,14.3,9.3.
实施例189Example 189
3-甲基-5-(N-(2-氟-3-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-fluoro-3-methylphenylethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，得黄色固体0.41g，收率33％。1H NMR(400MHz,Chloroform-d)δ8.16(dd,J＝1.9,0.6Hz,1H),7.85(dd,J＝8.8,1.9Hz,1H),7.62–7.52(m,1H),7.01–6.92(m,1H),6.92–6.81(m,2H),4.86(t,J＝6.8Hz,1H),4.46(q,J＝7.1Hz,2H),3.25(q,J＝6.8Hz,2H),2.80–2.71(m,2H),2.58(s,3H),2.14(d,J＝2.2Hz,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,159.7(d,J＝244.2Hz),155.9,143.0,135.3,130.3(d,J＝5.1Hz),129.4,128.5(d,J＝4.6Hz),126.3,125.7,125.0(d,J＝17.7Hz),124.3(d,J＝16.3Hz),123.8(d,J＝4.3Hz),121.6,113.1,61.7,43.2(d,J＝1.7Hz),29.7(d,J＝2.4Hz),14.5(d,J＝4.5Hz),14.4,9.4.19F NMR(376MHz,Chloroform-d)δ-122.90.HRMS(ESI)[M+H]+calcd for C21H23NO5SF:420.1281；found:420.1279.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, 0.41g of yellow solid was obtained, with a yield of 33%. 1 H NMR (400MHz, Chloroform-d) δ8.16 (dd, J＝1.9, 0.6Hz, 1H), 7.85 (dd, J＝8.8, 1.9Hz, 1H), 7.62–7.52 (m, 1H), 7.01 –6.92(m,1H),6.92–6.81(m,2H),4.86(t,J＝6.8Hz,1H),4.46(q,J＝7.1Hz,2H),3.25(q,J＝6.8Hz, 2H), 2.80–2.71 (m, 2H), 2.58 (s, 3H), 2.14 (d, J＝2.2Hz, 3H), 1.45 (t, J＝7.1Hz, 3H). 13 C NMR (101MHz, Chloroform -d) δ160.0,159.7(d,J＝244.2Hz),155.9,143.0,135.3,130.3(d,J＝5.1Hz),129.4,128.5(d,J＝4.6Hz),126.3,125.7,125.0(d ,J＝17.7Hz),124.3(d,J＝16.3Hz),123.8(d,J＝4.3Hz),121.6,113.1,61.7,43.2(d,J＝1.7Hz),29.7(d,J＝2.4 Hz), 14.5 (d, J＝4.5Hz), 14.4, 9.4. 19 F NMR (376MHz, Chloroform-d) δ-122.90.HRMS (ESI) [M+H] + calcd for C 21 H 23 NO 5 SF :420.1281; found:420.1279.
实施例190Example 190
5-(N-(2-(2,3-二氢苯并呋喃-7-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-109)
5-(N-(2-(2,3-Dihydrobenzofuran-7-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132- B-109)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.19(t,J＝6.5Hz,1H),7.10(ddq,J＝16.3,8.1,1.2Hz,2H),7.00–6.93(m,1H),4.49(dd,J＝5.2,3.2Hz,2H),4.34(q,J＝6.4Hz,2H),3.21–3.09(m,4H),2.91(td,J＝5.9,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.19(t,J＝6.5Hz,1H),7.10(ddq,J＝16.3,8.1,1.2Hz,2H),7.00–6.93(m,1H),4.49(dd,J＝5.2,3.2Hz,2H) ,4.34(q,J＝6.4Hz,2H),3.21–3.09(m,4H),2.91(td,J＝5.9,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3 Hz,3H).
实施例191Example 191
5-(N-(2-(2,3-二氢苯并[b][1,3]二氧杂环戊烷-5-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-(2,3-dihydrobenzo[b][1,3]dioxolan-5-yl)ethyl)sulfamoyl)-3-methylbenzo Furan-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.14(d,J＝1.9Hz,1H),7.83(dd,J＝8.8,1.9Hz,1H),7.56(d,J＝8.7Hz,1H),6.67–6.59(m,2H),6.48(dd,J＝7.3,1.8Hz,1H),5.80(s,2H),4.97–4.87(m,1H),4.46(q,J＝7.1Hz,2H),3.26(q,J＝6.6Hz,2H),2.72(t,J＝6.9Hz,2H),2.57(s,3H),1.44(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,155.78,147.10,145.58,142.90,135.25,129.32,126.16,125.58,122.73,121.76,121.49,119.11,112.92,107.36,100.60,61.59,42.67,29.91,14.35,9.34.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.14(d,J＝1.9Hz,1H),7.83(dd,J＝8.8,1.9Hz,1H),7.56(d,J＝8.7Hz,1H),6.67 –6.59(m,2H),6.48(dd,J＝7.3,1.8Hz,1H),5.80(s,2H),4.97–4.87(m,1H),4.46(q,J＝7.1Hz,2H), 3.26 (q, J=6.6Hz, 2H), 2.72 (t, J=6.9Hz, 2H), 2.57 (s, 3H), 1.44 (t, J=7.3Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ159.91,155.78,147.10,145.58,142.90,135.25,129.32,126.16,125.58,122.73,121.76,121.49,119.11,112.92,107.36,100.60,61.59, 42.67,29.91,14.35,9.34.
实施例192Example 192
5-(N-(2-(2,2-二氟苯并[d][1,3]二氧杂环戊-4-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)ethyl)sulfamoyl)-3-methylbenzofuran -2-Carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J＝1.9Hz,1H),7.83(dd,J＝8.7,1.9Hz,1H),7.51(d,J＝8.7Hz,1H),6.86–6.74(m,3H),5.48(t,J＝6.2Hz,1H),4.42(q,J＝7.1Hz,2H),3.27(q,J＝6.8Hz,2H),2.80(t,J＝7.0Hz,2H),2.53(s,3H),1.41(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.93,155.78,143.29,142.90,142.02,135.14,131.23(t,J＝255.6Hz),129.31,126.07,125.54,124.73,123.59,121.47,120.56,112.95,107.90,61.61,42.41,29.64,29.57,14.25,9.18.19F NMR(376MHz,CDCl3)δ-49.72.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.15 (d, J = 1.9 Hz, 1H), 7.83 (dd, J = 8.7, 1.9 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 6.86 –6.74(m,3H),5.48(t,J＝6.2Hz,1H),4.42(q,J＝7.1Hz,2H),3.27(q,J＝6.8Hz,2H),2.80(t,J＝ 7.0Hz, 2H), 2.53 (s, 3H), 1.41 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 159.93, 155.78, 143.29, 142.90, 142.02, 135.14, 131.23 (t, J＝255.6Hz),129.31,126.07,125.54,124.73,123.59,121.47,120.56,112.95,107.90,61.61,42.41,29.64,29.57,14.25,9.18. 19 F NMR (376MHz, CDCl 3 )δ-49.72.
实施例193Example 193
5-(N-(2-(2,3-二氢苯并[b][1,4]二氧杂环己烷-5-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-112)
5-(N-(2-(2,3-dihydrobenzo[b][1,4]dioxan-5-yl)ethyl)sulfamoyl)-3-methylbenzo Furan-2-carboxylic acid ethyl ester (M-GPR132-B-112)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400 MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.22(t,J＝6.6Hz,1H),6.89(t,J＝8.1Hz,1H),6.78–6.69(m,2H),4.34(q,J＝6.4Hz,2H),4.29(s,4H),3.21–3.14(m,2H),2.93(td,J＝5.9,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR(400 MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.22(t, J＝6.6Hz,1H),6.89(t,J＝8.1Hz,1H),6.78–6.69(m,2H),4.34(q,J＝6.4Hz,2H),4.29(s,4H),3.21– 3.14(m,2H),2.93(td,J＝5.9,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).
实施例194Example 194
5-(N-(2,4-二氟苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2,4-Difluorophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J＝1.6Hz,1H),7.86(dd,J＝8.8,1.6Hz,1H),7.58(d,J＝8.8Hz,1H),7.07–7.01(m,1H),6.71–6.61(m,2H),5.07(t,J＝6.4Hz,1H),4.45(q,J＝7.2Hz,2H),3.20(q,J＝6.8Hz,2H),2.76(t,J＝6.8Hz,2H),2.57(s,3H),1.44(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.67(dd,J＝89.1,12.0Hz),160.21(dd,J＝89.1,12.0Hz),159.90,155.83,142.99,135.17,131.73(dd,J＝9.6,6.3Hz),129.39,126.11,125.52,121.51,120.54(dd,J＝16.0,3.7Hz),113.02,111.22(dd,J＝21.1,3.7Hz),103.77(t,J＝25.8Hz),61.61,43.00,29.13,14.32,9.28.19F NMR(376MHz,CDCl3)δ-111.80,-113.99.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.15(d,J＝1.6Hz,1H),7.86(dd,J＝8.8,1.6Hz,1H),7.58(d,J＝8.8Hz,1H),7.07 –7.01(m,1H),6.71–6.61(m,2H),5.07(t,J＝6.4Hz,1H),4.45(q,J＝7.2Hz,2H),3.20(q,J＝6.8Hz, 2H), 2.76 (t, J=6.8Hz, 2H), 2.57 (s, 3H), 1.44 (t, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 162.67 (dd, J = 89.1,12.0Hz), 160.21 (DD, J = 89.1,12.0Hz), 159.90,155.83,142.99,135.17,131.73 (DD, J = 9.6.3Hz), 129.39,126.11, 125.521.51.51,120. 54 (DD , J＝16.0, 3.7Hz), 113.02, 111.22 (dd, J＝21.1, 3.7Hz), 103.77 (t, J＝25.8Hz), 61.61, 43.00, 29.13, 14.32, 9.28. 19 F NMR (376MHz, CDCl 3 )δ-111.80,-113.99.
实施例195Example 195
5-(N-(5-溴-2-氟苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(5-Bromo-2-fluorophenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate ethyl ester
梨形瓶中加入化合物3(0.086g,0.39mmol)，化合物4(0.131g,0.43mmol)，N,N-二异丙基乙胺(DIPEA,0.076g,0.59mmol)，加入无水DMF 2ml，室温过夜反应。TLC监测反应完全。反应结束后，加入适量EA，少量H2O洗涤3次，合并水相，少量EA洗涤两次，合并有机相，Na2SO4干燥，过滤浓缩，硅胶柱层析纯化(PE:EA＝4:1)，得白色固体0.19g，产率99％。Add compound 3 (0.086g, 0.39mmol), compound 4 (0.131g, 0.43mmol), N,N-diisopropylethylamine (DIPEA, 0.076g, 0.59mmol) into the pear-shaped bottle, and add 2ml of anhydrous DMF , react overnight at room temperature. TLC monitored the reaction to be complete. After the reaction, add an appropriate amount of EA, wash three times with a small amount of H 2 O, combine the water phase, wash twice with a small amount of EA, combine the organic phases, dry with Na2SO4, filter and concentrate, and purify by silica gel column chromatography (PE:EA=4:1) , 0.19g of white solid was obtained, with a yield of 99%.
1H NMR(400MHz,CDCl3)δ8.16(d,J＝1.9Hz,1H),7.85(dd,J＝8.7,1.9Hz,1H),7.60(d,J＝8.7Hz,1H),7.17(m,1H),7.08(m,1H),7.01(m,1H),6.93(m,1H),4.48(q,J＝7.0Hz,3H),3.28(q,J＝6.7Hz,2H),2.81(t,J＝6.9Hz,2H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.93,155.88,142.99,135.23,131.17,129.41,128.77,126.15,125.60,124.31,121.56,115.57,115.36,113.08,61.60,43.04,29.68,14.36,9.36.19F NMR(376MHz,CDCl3)δ-118.26,-120.28. 1 H NMR (400MHz, CDCl 3 ) δ8.16 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 8.7, 1.9 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.17 (m,1H),7.08(m,1H),7.01(m,1H),6.93(m,1H),4.48(q,J＝7.0Hz,3H),3.28(q,J＝6.7Hz,2H) ,2.81(t,J＝6.9Hz,2H),1.46(t,J＝7.1Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ159.93,155.88,142.99,135.23,131.17,129.41,128.77,126.15, 125.60,124.31,121.56,115.57,115.36,113.08,61.60,43.04,29.68,14.36,9.36. 19 F NMR (376MHz, CDCl 3 )δ-118.26,-120.28.
实施例196Example 196
3-甲基-5-(N-(2-氟-5-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-fluoro-5-methylphenylethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，得白色固体0.59g，收率45％。1H NMR(400MHz,Chloroform-d)δ8.16(dd,J＝1.9,0.6Hz,1H),7.85(dd,J＝8.7,1.9Hz,1H),7.59(dd,J＝8.7,0.6Hz,1H),6.96–6.88(m,1H),6.84–6.75(m,2H),4.66(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.25(q,J＝6.2Hz,2H),2.79–2.71(m,2H),2.60(s,3H),2.21(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,159.4(d,J＝242.6Hz),156.0,143.1,135.4,133.8,131.6(d,J＝4.7Hz),129.5,129.1(d,J＝7.9Hz),126.3,125.7,124.1(d,J＝15.9Hz),121.7,115.2(d,J＝22.0Hz),113.1,61.7,43.2, 29.7,20.6,14.5,9.5.19F NMR(376MHz,Chloroform-d)δ-123.68.HRMS(ESI)[M+H]+calcd for C21H23NO5SF:420.1281；found:420.1275.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, 0.59g of white solid was obtained, with a yield of 45%. 1 H NMR (400MHz, Chloroform-d) δ8.16 (dd, J＝1.9, 0.6Hz, 1H), 7.85 (dd, J＝8.7, 1.9Hz, 1H), 7.59 (dd, J＝8.7, 0.6Hz ,1H),6.96–6.88(m,1H),6.84–6.75(m,2H),4.66(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.25(q, J＝6.2Hz,2H),2.79–2.71(m,2H),2.60(s,3H),2.21(s,3H),1.45(t,J＝7.1Hz,3H). 13 C NMR (101MHz, Chloroform -d) δ160.0,159.4(d,J＝242.6Hz),156.0,143.1,135.4,133.8,131.6(d,J＝4.7Hz),129.5,129.1(d,J＝7.9Hz),126.3,125.7,124.1 (d,J＝15.9Hz),121.7,115.2(d,J＝22.0Hz),113.1,61.7,43.2, 29.7, 20.6, 14.5, 9.5. 19 F NMR (376MHz, Chloroform-d) δ-123.68.HRMS (ESI) [M+H] + calcd for C 21 H 23 NO 5 SF: 420.1281; found: 420.1275.
实施例197Example 197
5-(N-(2-氟-5-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-Fluoro-5-methoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
将2-(2-氟-5-甲氧基苯基)乙烷-1-胺(0.10g,0.59mmol)溶于DMF(2.5mL)，加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol)，DIPEA(0.25mL)，室温搅拌反应2h。TLC监测反应完全，加入适量水，乙酸乙酯提取3次，有机相合并，经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(PE/DCM/EA＝9:1:2)得白色固体171mg，产率79.2％。Dissolve 2-(2-fluoro-5-methoxyphenyl)ethane-1-amine (0.10g, 0.59mmol) in DMF (2.5mL), and add 5-(chlorosulfonyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (0.15g, 0.49mmol), DIPEA (0.25mL), stirred at room temperature for 2h. TLC monitors that the reaction is complete. Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE/DCM/EA=9:1:2) to obtain white color Solid 171 mg, yield 79.2%.
1H NMR(400MHz,CDCl3)δ8.14(d,J＝2.0Hz,1H),7.84(dd,J＝8.8,2.0Hz,1H),7.53(d,J＝8.8Hz,1H),6.80-6.71(m,1H),6.60-6.52(m,2H),5.27-5.18(m,1H),4.43(q,J＝7.2Hz,2H),3.64(s,3H),3.22(q,J＝6.8Hz,2H),2.73(t,J＝7.2Hz,2H),2.54(s,3H),1.42(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,156.58,155.75,155.51,154.23,142.81,135.27,129.29,126.13,125.62,125.44(d,J＝16.8Hz),121.47,116.08(d,J＝4.4Hz),112.63(d,J＝21.9Hz),112.95,112.86,61.58,55.57,43.01,29.78,14.31,9.27.19F NMR(376MHz,CDCl3)δ-129.34. 1 H NMR (400MHz, CDCl 3 ) δ8.14(d,J＝2.0Hz,1H),7.84(dd,J＝8.8,2.0Hz,1H),7.53(d,J＝8.8Hz,1H),6.80 -6.71(m,1H),6.60-6.52(m,2H),5.27-5.18(m,1H),4.43(q,J＝7.2Hz,2H),3.64(s,3H),3.22(q,J =6.8Hz, 2H), 2.73 (t, J = 7.2Hz, 2H), 2.54 (s, 3H), 1.42 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 159.91, 156.58 ,155.75,155.51,154.23,142.81,135.27,129.29,126.13,125.62,125.44(d,J＝16.8Hz),121.47,116.08(d,J＝4.4Hz),112.63(d,J＝21.9Hz),112. 95 ,112.86,61.58,55.57,43.01,29.78,14.31,9.27. 19 F NMR (376MHz, CDCl 3 )δ-129.34.
实施例198Example 198
5-(N-(4-氟-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(4-Fluoro-3-methoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
将2-(4-氟-3-甲氧基苯基)乙烷-1-胺(0.12g,0.71mmol)溶于DMF(2.5mL)，加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol)，DIPEA(0.25mL)，室温搅拌反应2h。TLC监测反应完全，加入适量水，乙酸乙酯提取3次，有机相合并，经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(PE/DCM/EA＝9:1:2)得白色固体180mg，产率83.4％。Dissolve 2-(4-fluoro-3-methoxyphenyl)ethane-1-amine (0.12g, 0.71mmol) in DMF (2.5mL), and add 5-(chlorosulfonyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (0.15g, 0.49mmol), DIPEA (0.25mL), stirred at room temperature for 2h. TLC monitors that the reaction is complete. Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE/DCM/EA=9:1:2) to obtain white color Solid 180 mg, yield 83.4%.
1H NMR(400MHz,CDCl3)δ8.12(d,J＝2.0Hz,1H),7.83(dd,J＝8.8,2.0Hz,1H),7.53(d,J＝8.8Hz,1H),6.79(dd,J＝11.2,8.2Hz,1H),6.62(dd,J＝8.2,2.0Hz,1H),6.53-6.47(m,1H),5.33(t,J＝6.0Hz,1H),4.41(q,J＝7.2Hz,2H),3.71(s,3H),3.17(q,J＝6.8Hz,2H),2.69(t,J＝7.2Hz,2H),2.51(s,3H),1.40(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.86,155.75,152.36,149.93,147.39(d,J＝10.7Hz),142.94,135.16,134.16(d,J＝3.8Hz),129.34,126.10,125.47,121.44,120.38(d,J＝6.7Hz),115.78(d,J＝18.3Hz),113.85,112.91,61.59,56.04,44.34,35.46,14.28,9.23.19F NMR(376MHz,CDCl3)δ-138.17. 1 H NMR (400MHz, CDCl 3 ) δ8.12(d,J＝2.0Hz,1H),7.83(dd,J＝8.8,2.0Hz,1H),7.53(d,J＝8.8Hz,1H),6.79 (dd,J＝11.2,8.2Hz,1H),6.62(dd,J＝8.2,2.0Hz,1H),6.53-6.47(m,1H),5.33(t,J＝6.0Hz,1H),4.41( q,J＝7.2Hz,2H),3.71(s,3H),3.17(q,J＝6.8Hz,2H),2.69(t,J＝7.2Hz,2H),2.51(s,3H),1.40( t, J＝7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ159.86, 155.75, 152.36, 149.93, 147.39 (d, J＝10.7Hz), 142.94, 135.16, 134.16 (d, J＝3.8Hz) 19 F NMR (3 76MHz ,CDCl 3 )δ-138.17.
实施例199Example 199
5-(N-(4-氯-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(4-Chloro-3-methoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
将2-(4-氯-3-甲氧基苯基)乙烷-1-胺(0.09g,0.48mmol)溶于DMF(2.5mL)，加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.17g,0.56mmol)，DIPEA(0.25mL)，室温搅拌反应2h。TLC监测反应完全，加入适量水，乙酸乙酯提取3次，有机相合并，经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(PE/DCM/EA＝9:1:1.5)得白色固体142mg，产率64.8％。Dissolve 2-(4-chloro-3-methoxyphenyl)ethane-1-amine (0.09g, 0.48mmol) in DMF (2.5mL), and add 5-(chlorosulfonyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (0.17g, 0.56mmol), DIPEA (0.25mL), stirred at room temperature for 2h. TLC monitors that the reaction is complete. Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE/DCM/EA=9:1:1.5) to obtain white color Solid 142 mg, yield 64.8%.
1H NMR(400MHz,CDCl3)δ8.10(d,J＝2.0Hz,1H),7.81(dd,J＝8.8,2.0Hz,1H),7.52(d,J＝8.8Hz,1H),7.05(d,J＝8.0Hz,1H),6.59(d,J＝2.0Hz,1H),6.52(dd,J＝8.0,2.0Hz,1H),5.33(t,J＝6.0Hz,1H),4.41(q,J＝7.2Hz,2H),3.71(s,3H),3.19(q,J＝6.8Hz,2H),2.70(t,J＝6.8Hz,2H),2.51(s,3H),1.40(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.86,155.75,154.81,142.97,137.97,135.10,129.98,129.34,126.06,125.45,121.43,121.36,120.55,112.91,112.62,61.60,55.94,44.16,35.63,14.31,9.27. 1 H NMR (400MHz, CDCl 3 ) δ8.10 (d, J = 2.0Hz, 1H), 7.81 (dd, J = 8.8, 2.0Hz, 1H), 7.52 (d, J = 8.8Hz, 1H), 7.05 (d,J＝8.0Hz,1H),6.59(d,J＝2.0Hz,1H),6.52(dd,J＝8.0,2.0Hz,1H),5.33(t,J＝6.0Hz,1H),4.41 (q,J＝7.2Hz,2H),3.71(s,3H),3.19(q,J＝6.8Hz,2H),2.70(t,J＝6.8Hz,2H),2.51(s,3H),1.40 (t, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ159.86,155.75,154.81,142.97,137.97,135.10,129.98,129.34,126.06,125.45,121.43,121.36,120.55 ,112.91,112.62, 61.60,55.94,44.16,35.63,14.31,9.27.
实施例200Example 200
5-(N-(3,4-二甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3,4-Dimethoxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照实施例147步骤，得白色固体124mg，收率55％。1H NMR(400MHz,Chloroform-d)δ8.15(s,1H),7.84(d,J＝10.4Hz,1H),7.57(d,J＝8.8Hz,1H),6.67(d,J＝8.6Hz,1H),6.57(d,J＝5.1Hz,2H),5.06(t,J＝6.0Hz,1H),4.44(q,J＝7.1Hz,2H),3.75(d,J＝12.6Hz,6H),3.20(q,J＝6.7Hz,2H),2.70(t,J＝6.9Hz,2H),2.55(s,3H),1.43(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.8,155.7,149.0,147.8,142.9,135.2,130.1,129.3,126.1,125.5,121.5,120.7,112.9,111.8,111.38,61.6,55.8,55.8,44.5,35.3,14.3,9.3.Following the steps of Example 147, 124 mg of white solid was obtained with a yield of 55%. 1 H NMR (400MHz, Chloroform-d) δ8.15 (s, 1H), 7.84 (d, J = 10.4Hz, 1H), 7.57 (d, J = 8.8Hz, 1H), 6.67 (d, J = 8.6 Hz,1H),6.57(d,J＝5.1Hz,2H),5.06(t,J＝6.0Hz,1H),4.44(q,J＝7.1Hz,2H),3.75(d,J＝12.6Hz, 6H), 3.20 (q, J=6.7Hz, 2H), 2.70 (t, J=6.9Hz, 2H), 2.55 (s, 3H), 1.43 (t, J=7.1Hz, 3H). 13 C NMR ( 101MHz,Chloroform-d)δ159.8,155.7,149.0,147.8,142.9,135.2,130.1,129.3,126.1,125.5,121.5,120.7,112.9,111.8,111.38,61.6,55.8,55.8,44 .5,35.3,14.3,9.3.
实施例201Example 201
5-(N-(3,4-亚甲二氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3,4-methylenedioxyphenylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照实施例147步骤，得白色固体135mg，收率63％。1H NMR(400MHz,Chloroform-d)δ8.17(dd,J＝1.9,0.6Hz,1H),7.86(dd,J＝8.7,1.9Hz,1H),7.61(dd,J＝8.7,0.6Hz,1H),6.64(d,J＝7.8Hz,1H),6.54–6.47(m,2H),5.87(s,2H),4.85(t,J＝6.2Hz,1H),4.48(q,J＝7.1Hz,2H),3.20(q,J＝6.7Hz,2H),2.68(t,J＝6.8Hz,2H),2.60(s,3H),1.46(t,J＝7.2Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,147.8,146.3,142.9,135.2,131.2,129.3,126.2,125.6,121.7,121.5,113.0,108.9,108.3,101.0,61.6,44.4,35.4,14.4,9.3.Following the steps of Example 147, 135 mg of white solid was obtained with a yield of 63%. 1 H NMR (400MHz, Chloroform-d) δ8.17 (dd, J＝1.9, 0.6Hz, 1H), 7.86 (dd, J＝8.7, 1.9Hz, 1H), 7.61 (dd, J＝8.7, 0.6Hz ,1H),6.64(d,J＝7.8Hz,1H),6.54–6.47(m,2H),5.87(s,2H),4.85(t,J＝6.2Hz,1H),4.48(q,J＝ 7.1Hz,2H),3.20(q,J＝6.7Hz,2H),2.68(t,J＝6.8Hz,2H),2.60(s,3H),1.46(t,J＝7.2Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ159.9,155.8,147.8,146.3,142.9,135.2,131.2,129.3,126.2,125.6,121.7,121.5,113.0,108.9,108.3,101.0,61.6,44.4 ,35.4,14.4,9.3 .
实施例202Example 202
3-甲基-5-(N-(2-(萘-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-(naphth-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，得黄色固体0.12g，收率46％。1H NMR(400MHz,Chloroform-d)δ8.06(dd,J＝1.9,0.6Hz,1H),7.79(dd,J＝8.8,1.9Hz,1H),7.76–7.71(m,1H),7.65(dd,J＝8.8,2.9Hz,2H),7.51(dd,J＝8.8,0.6Hz,1H),7.49–7.36(m,3H),7.13(dd,J＝8.4,1.8Hz,1H),4.62(t,J＝6.1Hz,1H),4.48(q,J＝7.1Hz,2H),3.36(q,J＝6.6Hz,2H),2.92(t,J＝6.7Hz,2H),2.50(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,155.9,143.0,135.3,135.0,133.5,132.4,129.5,128.6,127.7,127.5,127.4,126.8,126.4,126.3,125.9,125.6,121.5,113.0,61.7,44.3,36.0,14.5,9.4.HRMS(ESI)[M-H]-calcd for C24H22NO5S:436.1219；found:436.1217.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, 0.12 g of yellow solid was obtained, with a yield of 46%. 1 H NMR (400MHz, Chloroform-d) δ8.06 (dd, J＝1.9, 0.6Hz, 1H), 7.79 (dd, J＝8.8, 1.9Hz, 1H), 7.76–7.71 (m, 1H), 7.65 (dd,J＝8.8,2.9Hz,2H),7.51(dd,J＝8.8,0.6Hz,1H),7.49–7.36(m,3H),7.13(dd,J＝8.4,1.8Hz,1H), 4.62(t,J＝6.1Hz,1H),4.48(q,J＝7.1Hz,2H),3.36(q,J＝6.6Hz,2H),2.92(t,J＝6.7Hz,2H),2.50( s, 3H), 1.46 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ 160.0, 155.9, 143.0, 135.3, 135.0, 133.5, 132.4, 129.5, 128.6, 127.7, 127.5, 127.4 ,126.8,126.4,126.3,125.9,125.6,121.5,113.0,61.7,44.3,36.0,14.5,9.4.HRMS(ESI)[MH] - calcd for C 24 H 22 NO 5 S:436.1219; found:436.1217.
实施例203Example 203
5-(N-(3,5-二甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3,5-Dimethoxyphenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.13(d,J＝1.6Hz,1H),7.83(dd,J＝8.8,2.0Hz,1H),7.54(d,J＝8.8Hz,1H),6.19(t,J＝2.0Hz,1H),6.14(d,J＝2.4Hz,2H),5.09(t,J＝6.4Hz,1H),4.43(q,J＝7.2Hz,2H),3.65(s,6H),3.20(q,J＝6.8Hz,2H),2.66(t,J＝6.8Hz,2H),2.54(s,3H),1.42(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.83,159.87,155.73,142.81,140.06,135.23,129.29,126.17,125.60,121.45,112.86,106.65,98.33,61.53,55.11,44.18,35.96,14.30,9.24.It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.13(d,J＝1.6Hz,1H),7.83(dd,J＝8.8,2.0Hz,1H),7.54(d,J＝8.8Hz,1H),6.19 (t,J＝2.0Hz,1H),6.14(d,J＝2.4Hz,2H),5.09(t,J＝6.4Hz,1H),4.43(q,J＝7.2Hz,2H),3.65(s ,6H),3.20(q,J＝6.8Hz,2H),2.66(t,J＝6.8Hz,2H),2.54(s,3H),1.42(t,J＝7.2Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ160.83,159.87,155.73,142.81,140.06,135.23,129.29,126.17,125.60,121.45,112.86,106.65,98.33,61.53,55.11,44.18,35 .96,14.30,9.24.
实施例204Example 204
5-(N-(3-吲哚基乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(3-Indoylethylamino)sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
根据实施例147的合成步骤，得到白色固体136mg，收率64％。1H NMR(400MHz,Chloroform-d)δ8.13–8.05(m,2H),7.77(dd,J＝8.8,1.9Hz,1H),7.54(d,J＝8.8Hz,1H),7.34(t,J＝7.4Hz,2H),7.16(t,J＝8.0Hz,1H),7.04–6.95(m,2H),4.57–4.45(m,2H),3.34(q,J＝6.4Hz,2H),2.97(t,J＝6.5Hz,2H),2.58(s,3H),1.49(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,155.8,142.8,136.4,135.0,129.3,126.7,126.1,125.6,122.6,122.4,121.5,119.5,118.3,112.9,111.4,111.3,61.6,43.0,25.5,14.4,9.4.According to the synthesis procedure of Example 147, 136 mg of white solid was obtained with a yield of 64%. 1 H NMR (400MHz, Chloroform-d) δ8.13–8.05(m,2H),7.77(dd,J＝8.8,1.9Hz,1H),7.54(d,J＝8.8Hz,1H),7.34(t ,J＝7.4Hz,2H),7.16(t,J＝8.0Hz,1H),7.04–6.95(m,2H),4.57–4.45(m,2H),3.34(q,J＝6.4Hz,2H) ,2.97(t,J＝6.5Hz,2H),2.58(s,3H),1.49(t,J＝7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ160.0,155.8,142.8,136.4, 135.0,129.3,126.7,126.1,125.6,122.6,122.4,121.5,119.5,118.3,112.9,111.4,111.3,61.6,43.0,25.5,14.4,9.4.
实施例205Example 205
5-(正丁基磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(n-Butylsulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
将正丁胺(0.06g,0.82mmol)溶于DMF(2.5mL)，加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol)，DIPEA(0.25mL)，室温搅拌反应2h。TLC监测反应完全，加入适量水，乙酸乙酯提取3次，有机相合并，经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(PE/DCM/EA＝9:1:1)得白色固体130mg，产率77.4％。Dissolve n-butylamine (0.06g, 0.82mmol) in DMF (2.5mL), add ethyl 5-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylate (0.15g, 0.49mmol), DIPEA (0.25 mL), stirred at room temperature for 2 h. TLC monitors that the reaction is complete. Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE/DCM/EA=9:1:1) to obtain white color Solid 130 mg, yield 77.4%.
1H NMR(400MHz,CDCl3)δ8.20(d,J＝2.0Hz,1H),7.91(dd,J＝8.8,2.0Hz,1H),7.56(d,J＝8.8Hz,1H),5.34(t,J＝6.0Hz,1H),4.40(q,J＝7.2Hz,2H),2.90(q,J＝7.2Hz,2H), 2.53(s,3H),1.45-1.34(m,5H),1.29-1.15(m,2H),0.74(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.89,155.73,142.83,135.36,129.27,126.22,125.58,121.53,112.91,61.53,42.96,31.47,19.62,14.28,13.45,9.26. 1 H NMR (400MHz, CDCl 3 ) δ8.20 (d, J = 2.0Hz, 1H), 7.91 (dd, J = 8.8, 2.0Hz, 1H), 7.56 (d, J = 8.8Hz, 1H), 5.34 (t,J＝6.0Hz,1H),4.40(q,J＝7.2Hz,2H),2.90(q,J＝7.2Hz,2H), 2.53 (s, 3H), 1.45-1.34 (m, 5H), 1.29-1.15 (m, 2H), 0.74 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 159.89, 155.73, 142.83,135.36,129.27,126.22,125.58,121.53,112.91,61.53,42.96,31.47,19.62,14.28,13.45,9.26.
实施例206Example 206
5-(N-(3-碘丁-3-烯-1-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-129)
5-(N-(3-iodobut-3-en-1-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-129)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,CDCl3)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),6.73(t,J＝5.1Hz,1H),5.80(q,J＝1.0Hz,1H),5.72(q,J＝1.0Hz,1H),4.34(q,J＝6.4Hz,2H),2.99(q,J＝5.3Hz,2H),2.60(s,3H),2.44(tt,J＝5.4,1.1Hz,2H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.18 (d, J = 2.2 Hz, 1H), 7.96 (dd, J = 9.2, 2.2 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 6.73 (t,J＝5.1Hz,1H),5.80(q,J＝1.0Hz,1H),5.72(q,J＝1.0Hz,1H),4.34(q,J＝6.4Hz,2H),2.99(q ,J＝5.3Hz,2H),2.60(s,3H),2.44(tt,J＝5.4,1.1Hz,2H),1.39(t,J＝6.3Hz,3H).
实施例207Example 207
5-(N-(2-环戊基乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-Cyclopentyethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester
将2-环戊基-乙胺(0.045g,0.40mmol)溶于DMF(2.5mL)，加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.10g,0.33mmol)和DIPEA(0.25mL)，室温下搅拌反应2h。TLC检测反应完全，加入适量水，乙酸乙酯提取3次，合并有机相，饱和食盐水洗涤一遍，经无水硫酸钠干燥后，过滤浓缩，硅胶柱层析纯化(PE:DCM:EA＝9:1:1)得白色固体151mg，产率99％。Dissolve 2-cyclopentyl-ethylamine (0.045g, 0.40mmol) in DMF (2.5mL), and add ethyl 5-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylate (0.10g ,0.33mmol) and DIPEA (0.25mL), stir and react at room temperature for 2h. TLC detects that the reaction is complete, add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE:DCM:EA=9 :1:1) to obtain 151 mg of white solid, with a yield of 99%.
1H NMR(400MHz,CDCl3)δ8.22(d,J＝2.0Hz,1H),7.93(dd,J＝8.8,2.0Hz,1H),7.60(d,J＝8.8Hz,1H),5.12(t,J＝6.0Hz,1H),4.44(q,J＝7.2Hz,2H),2.93(dd,J＝14.8,6.4Hz,2H),2.57(s,3H),1.74-1.57(m,3H),1.54-1.33(m,9H),1.01-0.88(m,2H).13C NMR(101MHz,CDCl3)δ159.93,155.79,142.89,135.30,129.33,126.24,125.63,121.59,113.00,61.59,42.69,37.20,35.74,32.35,24.94,14.34,9.34. 1 H NMR (400MHz, CDCl 3 ) δ8.22(d,J＝2.0Hz,1H),7.93(dd,J＝8.8,2.0Hz,1H),7.60(d,J＝8.8Hz,1H),5.12 (t,J＝6.0Hz,1H),4.44(q,J＝7.2Hz,2H),2.93(dd,J＝14.8,6.4Hz,2H),2.57(s,3H),1.74-1.57(m, 3H),1.54-1.33(m,9H),1.01-0.88(m,2H). 13 C NMR (101MHz, CDCl 3 ) δ159.93,155.79,142.89,135.30,129.33,126.24,125.63,121.59,113.00,61.5 9, 42.69,37.20,35.74,32.35,24.94,14.34,9.34.
实施例208Example 208
3-甲基-5-(N-(2-(噻吩-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-133)
3-Methyl-5-(N-(2-(thiophen-3-yl)ethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-133)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.2Hz,1H),7.96(dd,J＝9.2,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.27–7.20(m,2H),7.14(t,J＝6.6Hz,1H),6.66(dd,J＝5.2,1.7Hz,1H),4.34(q,J＝6.4Hz,2H),3.17(dt,J＝6.6,5.2Hz,2H),2.77(t,J＝5.2Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J = 2.2Hz, 1H), 7.96 (dd, J = 9.2, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.27–7.20(m,2H),7.14(t,J＝6.6Hz,1H),6.66(dd,J＝5.2,1.7Hz,1H),4.34(q,J＝6.4Hz,2H),3.17(dt ,J＝6.6,5.2Hz,2H),2.77(t,J＝5.2Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).
实施例209Example 209
5-(N-(2-(5-氯噻吩-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-(5-chlorothiophen-2-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ8.18(dd,J＝1.9,0.6Hz,1H),7.88(dd,J＝8.8,1.9Hz,1H),7.63(dd,J＝8.8,0.6Hz,1H),6.66(d,J＝3.7Hz,1H),6.52(dt,J＝3.7,1.0Hz,1H),4.47(q,J＝7.1Hz,2H),3.22(q,J＝6.5Hz,2H),2.89(td,J＝6.6,1.0Hz,2H),2.61(s,3H),1.45(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.1,143.2,138.8,135.2,129.6,128.5,126.3,126.1,125.7,125.5,121.7,113.3,61.7,44.3,30.7,14.5,9.5.HRMS(ESI)[M+H]+calcd for C18H18ClNO5S2:428.0393；found:428.0386. 1 H NMR (400MHz, Chloroform-d) δ8.18 (dd, J＝1.9, 0.6Hz, 1H), 7.88 (dd, J＝8.8, 1.9Hz, 1H), 7.63 (dd, J＝8.8, 0.6Hz ,1H),6.66(d,J＝3.7Hz,1H),6.52(dt,J＝3.7,1.0Hz,1H),4.47(q,J＝7.1Hz,2H),3.22(q,J＝6.5Hz ,2H),2.89(td,J＝6.6,1.0Hz,2H),2.61(s,3H),1.45(t,J＝7.2Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ160.0,156.1, 143.2,138.8,135.2,129.6,128.5,126.3,126.1,125.7,125.5,121.7,113.3,61.7,44.3,30.7,14.5,9.5.HRMS(ESI)[M+H] + calcd for C 18 H 18 ClNO 5 S 2 :428.0393; found:428.0386.
实施例210Example 210
3-甲基-5-(N-(2-(5-溴噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-(5-bromothiophen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，得白色固体296mg，收率34％。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝1.9Hz,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.64(d,J＝8.8Hz,1H),6.80(d,J＝3.6Hz,1H),6.51(d,J＝3.6Hz,1H),4.78(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H),3.26–3.17(m,2H),2.95–2.86(m,2H),2.61(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.2,141.7,135.1,129.9,129.6,126.6,126.3,125.7,121.7,113.3,110.6,61.7,44.2,30.7,14.5,9.5.HRMS(ESI)[M-H]-calcd for C18H17BrNO5S2:469.9732；found:469.9729.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, 296 mg of white solid was obtained, with a yield of 34%. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J＝1.9Hz, 1H), 7.87 (dd, J＝8.8, 1.9Hz, 1H), 7.64 (d, J＝8.8Hz, 1H), 6.80(d,J＝3.6Hz,1H),6.51(d,J＝3.6Hz,1H),4.78(t,J＝6.3Hz,1H),4.47(q,J＝7.1Hz,2H),3.26– 3.17(m,2H),2.95–2.86(m,2H),2.61(s,3H),1.45(t,J＝7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.2 ,141.7,135.1,129.9,129.6,126.6,126.3,125.7,121.7,113.3,110.6,61.7,44.2,30.7,14.5,9.5.HRMS(ESI)[MH] - calcd for C 18 H 17 BrNO 5 S 2 : 469.9732; found:469.9729.
实施例211Example 211
3-甲基-5-(N-(2-(4-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(GPR132-B-1024)
3-Methyl-5-(N-(2-(4-methylthiophen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate (GPR132-B-1024)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，得棕色油状物0.12g，收率17％。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝1.9Hz,1H),7.88(dd,J＝8.7,1.9Hz,1H),7.61(d,J＝8.8Hz,1H),6.65(t,J＝1.3Hz,1H),6.52(d,J＝1.4Hz,1H),4.94(t,J＝6.2Hz,1H),4.46(q,J＝7.1Hz,2H),3.23(q,J＝6.6Hz,2H),2.90(t,J＝6.7Hz,2H),2.59(s,3H),2.13(s,3H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,155.9,143.0,139.7,137.8,135.3,129.5,128.4,126.3,125.7,121.7,119.5,113.1,61.7,44.5,30.3,15.7,14.4,9.4.HRMS(ESI)[M+H]+calcd for C19H22NO5S2:408.0939；found:408.0931.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, 0.12g of brown oil was obtained, with a yield of 17%. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J＝1.9Hz, 1H), 7.88 (dd, J＝8.7, 1.9Hz, 1H), 7.61 (d, J＝8.8Hz, 1H), 6.65(t,J＝1.3Hz,1H),6.52(d,J＝1.4Hz,1H),4.94(t,J＝6.2Hz,1H),4.46(q,J＝7.1Hz,2H),3.23( q,J＝6.6Hz,2H),2.90(t,J＝6.7Hz,2H),2.59(s,3H),2.13(s,3H),1.44(t,J＝7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ160.0,155.9,143.0,139.7,137.8,135.3,129.5,128.4,126.3,125.7,121.7,119.5,113.1,61.7,44.5,30.3,15.7,14.4,9.4 .HRMS(ESI) [M+H] + calcd for C 19 H 22 NO 5 S 2 :408.0939; found:408.0931.
实施例212Example 212
3-甲基-5-(N-(2-(3-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-(3-methylthiophen-2-yl)ethyl)sulfamoyl)benzofuran-2-carboxylate
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，所用胺原料为2-(3- 甲基噻吩)乙胺，其余条件均一致。得黄色固体0.31g，收率38％。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝1.8Hz,1H),7.87(dd,J＝8.7,1.9Hz,1H),7.63(d,J＝8.8Hz,1H),6.50(m,2H),4.69(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.22(q,J＝6.5Hz,2H),2.88(t,J＝6.5Hz,2H),2.61(s,3H),2.37(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.1,139.1,137.5,135.3,129.5,126.4,125.9,125.7,125.2,121.7,113.2,61.7,44.5,30.3,15.3,14.5,9.5.HRMS(ESI)[M+H]+calcd for C19H22NO5S2:408.0939；found:408.0933.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, the amine raw material used is 2-(3- Methylthiophene)ethylamine, other conditions are the same. 0.31g of yellow solid was obtained, with a yield of 38%. 1 H NMR (400MHz, Chloroform-d) δ8.18 (d, J＝1.8Hz, 1H), 7.87 (dd, J＝8.7, 1.9Hz, 1H), 7.63 (d, J＝8.8Hz, 1H), 6.50(m,2H),4.69(t,J＝6.2Hz,1H),4.47(q,J＝7.1Hz,2H),3.22(q,J＝6.5Hz,2H),2.88(t,J＝6.5 Hz, 2H), 2.61 (s, 3H), 2.37 (s, 3H), 1.45 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ 160.0, 156.0, 143.1, 139.1, 137.5 ,135.3,129.5,126.4,125.9,125.7,125.2,121.7,113.2,61.7,44.5,30.3,15.3,14.5,9.5.HRMS(ESI)[M+H] + calcd for C 19 H 22 NO 5 S 2 : 408.0939; found:408.0933.
实施例213Example 213
5-(N-(2-(环己-1-烯-1-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
5-(N-(2-(cyclohex-1-en-1-yl)ethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylate ethyl ester
将2-(1-环己烯基)乙胺(0.07g,0.56mmol)溶于DMF(2.5mL)，加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol)，DIPEA(0.25mL)，室温搅拌反应2h。TLC监测反应完全，加入适量水，乙酸乙酯提取3次，有机相合并，经无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化(PE/DCM/EA＝9:1:1)得白色固体161mg，产率83.0％。Dissolve 2-(1-cyclohexenyl)ethylamine (0.07g, 0.56mmol) in DMF (2.5mL), add ethyl 5-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylate Ester (0.15g, 0.49mmol), DIPEA (0.25mL), stirred at room temperature for 2h. TLC monitors that the reaction is complete. Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (PE/DCM/EA=9:1:1) to obtain white color Solid 161 mg, yield 83.0%.
1H NMR(400MHz,CDCl3)δ8.18(d,J＝2.4Hz,1H),7.89(dd,J＝8.8,2.4Hz,1H),7.56(d,J＝8.8Hz,1H),5.27(s,1H),5.03(t,J＝6.0Hz,1H),4.39(q,J＝7.2Hz,2H),2.96(q,J＝6.8Hz,2H),2.53(s,3H),2.00(t,J＝6.8Hz,2H),1.82(s,2H),1.63(s,2H),1.46-1.33(m,7H).13C NMR(101MHz,CDCl3)δ159.83,155.73,142.86,135.30,133.36,129.27,126.23,125.53,124.44,121.55,112.89,61.51,40.86,37.40,27.57,25.05,22.56,22.10,14.29,9.26. 1 H NMR (400MHz, CDCl 3 ) δ8.18(d,J＝2.4Hz,1H),7.89(dd,J＝8.8,2.4Hz,1H),7.56(d,J＝8.8Hz,1H),5.27 (s,1H),5.03(t,J＝6.0Hz,1H),4.39(q,J＝7.2Hz,2H),2.96(q,J＝6.8Hz,2H),2.53(s,3H),2.00 (t, J=6.8Hz, 2H), 1.82 (s, 2H), 1.63 (s, 2H), 1.46-1.33 (m, 7H). 13 C NMR (101MHz, CDCl 3 ) δ 159.83, 155.73, 142.86, 135.30 ,133.36,129.27,126.23,125.53,124.44,121.55,112.89,61.51,40.86,37.40,27.57,25.05,22.56,22.10,14.29,9.26.
实施例214Example 214
3-甲基-5-(N-(1-苯基丙-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-140)
3-Methyl-5-(N-(1-phenylpropan-2-yl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-140)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J＝2.3Hz,1H),7.94(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.2Hz,1H),7.35–7.09(m,5H),6.72(d,J＝10.1Hz,1H),4.34(q,J＝6.4Hz,2H),3.48(dh,J＝10.1,7.0Hz,1H),2.92–2.79(m,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H),1.13(d,J＝7.0Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.15 (d, J = 2.3Hz, 1H), 7.94 (dd, J = 9.0, 2.2Hz, 1H), 7.64 (d, J = 9.2Hz, 1H), 7.35 –7.09(m,5H),6.72(d,J＝10.1Hz,1H),4.34(q,J＝6.4Hz,2H),3.48(dh,J＝10.1,7.0Hz,1H),2.92–2.79( m,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H),1.13(d,J＝7.0Hz,3H).
实施例215Example 215
5-(N-(2-氟-2-苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-23)
5-(N-(2-Fluoro-2-phenylethyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-23)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.19(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.44–7.23(m,5H),6.96(t,J＝7.7Hz,1H),5.41(dt,J＝46.4,4.6Hz,1H),3.76–3.52(m,2H),3.22(q,J＝6.3Hz,2H),2.58(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, CDCl 3 ) δ8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.44 –7.23(m,5H),6.96(t,J＝7.7Hz,1H),5.41(dt,J＝46.4,4.6Hz,1H),3.76–3.52(m,2H),3.22(q,J＝6.3 Hz, 2H), 2.58 (s, 3H), 1.39 (t, J = 6.3Hz, 3H).
实施例216 Example 216
3-甲基-5-(N-(2-苯基乙酰基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(2-phenylacetyl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，所用胺原料为2-苯基乙酰胺，其余条件均一致。得白色固体33mg，收率8％。1H NMR(400MHz,Chloroform-d)δ8.40(d,J＝2.0Hz,1H),7.99(dd,J＝8.8,2.0Hz,1H),7.56(d,J＝8.8Hz,1H),7.31–7.24(m,3H),7.13(dd,J＝6.5,2.9Hz,2H),4.48(q,J＝7.1Hz,2H),3.59(s,2H),2.59(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ168.9,160.0,156.6,143.2,133.6,132.4,129.4,129.4,129.3,128.0,127.3,125.9,123.8,113.0,61.8,43.6,14.4,9.5.HRMS(ESI)[M+H]+calcd for C20H20NO6S:402.1011；found:402.1004.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, the amine raw material used is 2-phenylacetamide, and the other conditions are the same. 33 mg of white solid was obtained, with a yield of 8%. 1 H NMR (400MHz, Chloroform-d) δ8.40 (d, J＝2.0Hz, 1H), 7.99 (dd, J＝8.8, 2.0Hz, 1H), 7.56 (d, J＝8.8Hz, 1H), 7.31–7.24(m,3H),7.13(dd,J＝6.5,2.9Hz,2H),4.48(q,J＝7.1Hz,2H),3.59(s,2H),2.59(s,3H),1.46 (T, J = 7.1Hz, 3H). 13 C NMR (101MHz, Chloroform-D) Δ168.9,160.0,156.6,143.2,132.4,129.4,129.3,127.3,123.8,113 .0,61.8 ,43.6,14.4,9.5.HRMS(ESI)[M+H] + calcd for C 20 H 20 NO 6 S:402.1011; found:402.1004.
实施例217Example 217
3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(naphth-1-yl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，所用胺原料为1-萘胺，其余条件均一致。得黄色固体67mg，收率16％。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.10–8.01(m,2H),7.91–7.74(m,4H),7.50–7.34(m,3H),7.14(dd,J＝7.4,1.1Hz,1H),4.36(q,J＝7.1Hz,2H),2.47(s,3H),1.34(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ159.0,155.0,142.1,135.7,133.9,132.3,129.5,128.4,127.9,126.8,126.4,126.2,126.0,125.5,125.4,123.4,123.1,121.2,113.0,61.1,14.1,8.9.HRMS(ESI)[M-H]-calcd for C22H18NO5S:408.0906；found:408.0911.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, the amine raw material used is 1-naphthylamine, and the other conditions are the same. 67 mg of yellow solid was obtained, with a yield of 16%. 1 H NMR (400MHz, DMSO-d 6 ) δ10.29(s,1H),8.10–8.01(m,2H),7.91–7.74(m,4H),7.50–7.34(m,3H),7.14(dd ,J＝7.4,1.1Hz,1H),4.36(q,J＝7.1Hz,2H),2.47(s,3H),1.34(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO- d 6 )δ159.0,155.0,142.1,135.7,133.9,132.3,129.5,128.4,127.9,126.8,126.4,126.2,126.0,125.5,125.4,123.4,123.1,121.2,113.0,61 .1,14.1,8.9.HRMS(ESI )[MH] - calcd for C 22 H 18 NO 5 S:408.0906; found:408.0911.
实施例218Example 218
3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
3-Methyl-5-(N-(naphth-2-yl)sulfamoyl)benzofuran-2-carboxylate ethyl ester
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法，所用胺原料为2-萘胺，其余条件均一致。得粉色固体0.38g，收率47％。1H NMR(400MHz,Chloroform-d)δ8.19–8.14(m,1H),7.85(dd,J＝8.8,1.9Hz,1H),7.78–7.65(m,3H),7.60–7.34(m,4H),7.28–7.20(m,1H),4.43(q,J＝7.1Hz,2H),2.47(s,3H),1.66(s,1H),1.42(t,J＝7.2Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.1,143.1,134.4,133.9,133.7,131.4,129.6,129.5,127.8,127.6,126.9,126.4,125.8,125.6,122.0,121.4,119.2,113.1,61.7,14.4,9.3.HRMS(ESI)[M-H]-calcd for C22H18NO5S:408.0906；found:408.0906.According to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate, the amine raw material used is 2-naphthylamine, and the other conditions are the same. 0.38g of pink solid was obtained, with a yield of 47%. 1 H NMR(400MHz,Chloroform-d)δ8.19–8.14(m,1H),7.85(dd,J＝8.8,1.9Hz,1H),7.78–7.65(m,3H),7.60–7.34(m, 4H),7.28–7.20(m,1H),4.43(q,J＝7.1Hz,2H),2.47(s,3H),1.66(s,1H),1.42(t,J＝7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ160.0,156.1,143.1,134.4,133.9,133.7,131.4,129.6,129.5,127.8,127.6,126.9,126.4,125.8,125.6,122.0,121.4, 119.2,113.1,61.7, 14.4,9.3.HRMS(ESI)[MH] - calcd for C 22 H 18 NO 5 S:408.0906; found:408.0906.
实施例219Example 219
3-甲基-5-(N-(萘-1-基甲基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-146)
3-Methyl-5-(N-(naphthalen-1-ylmethyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-146)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400 MHz,Chloroform-d)δ8.21–8.11(m,2H),7.97(dd,J＝9.1,2.3Hz,1H),7.89(dt,J＝7.5,1.5Hz,1H),7.87–7.81(m,1H),7.64(d,J＝9.1Hz,1H),7.56–7.46(m,2H),7.43–7.35(m,2H),7.29(t,J＝7.3Hz,1H),4.38–4.30(m,4H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR(400 MHz,Chloroform-d)δ8.21–8.11(m,2H),7.97(dd,J＝9.1,2.3Hz,1H),7.89(dt,J＝7.5,1.5Hz,1H),7.87–7.81(m ,1H),7.64(d,J＝9.1Hz,1H),7.56–7.46(m,2H),7.43–7.35(m,2H),7.29(t,J＝7.3Hz,1H),4.38–4.30( m,4H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例220Example 220
5-(N-(2-乙炔基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-28)
5-(N-(2-ethynylphenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-28)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.26(d,J＝2.3Hz,1H),8.00(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.55(dd,J＝6.7,1.3Hz,1H),7.42–7.32(m,2H),7.25(td,J＝6.6,1.8Hz,1H),4.34(q,J＝6.3Hz,2H),3.22(s,1H),2.58(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, DMSO-d 6 ) δ9.18 (s, 1H), 8.26 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J＝9.0Hz,1H),7.55(dd,J＝6.7,1.3Hz,1H),7.42–7.32(m,2H),7.25(td,J＝6.6,1.8Hz,1H),4.34(q,J ＝6.3Hz,2H),3.22(s,1H),2.58(s,3H),1.39(t,J＝6.3Hz,3H).
实施例221Example 221
5-(N-(1H-吲哚-4-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-150)
5-(N-(1H-indol-4-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-150)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.52(d,J＝6.6Hz,1H),8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.43(t,J＝7.9Hz,1H),7.27(dd,J＝7.9,1.3Hz,1H),7.20(dd,J＝6.6,3.7Hz,1H),7.04(dd,J＝7.7,1.5Hz,1H),6.85(d,J＝3.6Hz,1H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate. 1 H NMR (400MHz, Chloroform-d) δ8.52 (d, J = 6.6 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 9.0, 2.2 Hz, 1H), 7.65(d,J＝9.0Hz,1H),7.43(t,J＝7.9Hz,1H),7.27(dd,J＝7.9,1.3Hz,1H),7.20(dd,J＝6.6,3.7Hz,1H ),7.04(dd,J＝7.7,1.5Hz,1H),6.85(d,J＝3.6Hz,1H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),1.39(t ,J＝6.3Hz,3H).
实施例222Example 222
5-(N-(苯并呋喃-5-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-151)
5-(N-(Benzofuran-5-yl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-151)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ9.84(s,1H),8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.76(d,J＝1.6Hz,1H),7.67–7.62(m,2H),7.45(d,J＝8.4Hz,1H),7.24(dd,J＝8.4,2.2Hz,1H),6.89(t,J＝1.8Hz,1H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ9.84 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 9.0, 2.2Hz, 1H), 7.76 (d, J ＝1.6Hz,1H),7.67–7.62(m,2H),7.45(d,J＝8.4Hz,1H),7.24(dd,J＝8.4,2.2Hz,1H),6.89(t,J＝1.8Hz ,1H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).
实施例223Example 223
5-(N-(2,3-二甲基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-152)
5-(N-(2,3-dimethylphenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-152)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。 It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.02(t,J＝7.8Hz,1H),6.94–6.84(m,2H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),2.26(d,J＝0.7Hz,3H),2.08(s,3H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ8.99 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J ＝9.0Hz,1H),7.02(t,J＝7.8Hz,1H),6.94–6.84(m,2H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),2.26(d ,J＝0.7Hz,3H),2.08(s,3H),1.39(t,J＝6.3Hz,3H).
实施例224Example 224
5-(N-(2-碘苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-153)
5-(N-(2-iodophenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-153)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ9.54(s,1H),8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.78(dd,J＝7.7,1.3Hz,1H),7.65(d,J＝9.0Hz,1H),7.32–7.22(m,2H),6.93(ddd,J＝7.7,6.7,1.7Hz,1H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ9.54 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 9.0, 2.2Hz, 1H), 7.78 (dd, J ＝7.7,1.3Hz,1H),7.65(d,J＝9.0Hz,1H),7.32–7.22(m,2H),6.93(ddd,J＝7.7,6.7,1.7Hz,1H),4.34(q, J＝6.4Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).
实施例225Example 225
5-(N-(4-碘苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-154)
5-(N-(4-iodophenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-154)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.76–7.70(m,2H),7.65(d,J＝9.0Hz,1H),6.99–6.93(m,2H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ9.66 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 9.0, 2.2Hz, 1H), 7.76–7.70 (m ,2H),7.65(d,J＝9.0Hz,1H),6.99–6.93(m,2H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),1.39(t,J＝ 6.3Hz,3H).
实施例226Example 226
3-甲基-5-(N-(3-苯氧基苯基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-155)
3-Methyl-5-(N-(3-phenoxyphenyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-155)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.39–7.32(m,2H),7.29(t,J＝7.8Hz,1H),7.10(tt,J＝7.2,1.5Hz,1H),7.05–6.99(m,3H),6.82(t,J＝2.2Hz,1H),6.52(ddd,J＝7.7,2.2,1.1Hz,1H),4.34(q,J＝6.4Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ8.25 (d, J＝2.3Hz, 1H), 7.98 (dd, J＝9.0, 2.2Hz, 1H), 7.65 (d, J＝9.0Hz, 1H), 7.39–7.32(m,2H),7.29(t,J＝7.8Hz,1H),7.10(tt,J＝7.2,1.5Hz,1H),7.05–6.99(m,3H),6.82(t,J＝ 2.2Hz, 1H), 6.52 (ddd, J＝7.7, 2.2, 1.1Hz, 1H), 4.34 (q, J＝6.4Hz, 2H), 2.60 (s, 3H), 1.39 (t, J＝6.3Hz, 3H).
实施例227Example 227
3-甲基-5-(N-(3-(4-甲基哌嗪-1-基)苯基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-156)
3-Methyl-5-(N-(3-(4-methylpiperazin-1-yl)phenyl)sulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-156 )
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ9.75(s,1H),8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.08(dd,J＝8.1,7.2Hz,1H),6.72(dd,J＝2.2,1.3Hz,1H),6.46–6.36(m,2H),4.34(q,J＝6.4Hz,2H),3.23(ddd,J＝5.3,4.0,1.0Hz,4H),2.84–2.76(m,2H),2.61–2.53(m,5H),2.29(s,3H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ9.75 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J ＝9.0Hz,1H),7.08(dd,J＝8.1,7.2Hz,1H),6.72(dd,J＝2.2,1.3Hz,1H),6.46–6.36(m,2H),4.34(q,J＝ 6.4Hz,2H),3.23(ddd,J＝5.3,4.0,1.0Hz,4H),2.84–2.76(m,2H),2.61–2.53(m,5H),2.29(s,3H),1.39(t ,J＝6.3Hz,3H).
实施例228Example 228
3-甲基-5-(N-(5,6,7,8-四氢萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-157)
3-Methyl-5-(N-(5,6,7,8-tetralin-1-yl)sulfamoyl)benzofuran-2-carboxylate (M-GPR132-B-157)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ9.21(s,1H),8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.08(t,J＝8.1Hz,1H),6.92(dd,J＝8.1,1.2Hz,1H),6.81(dq,J＝7.7,1.0Hz,1H),4.34(q,J＝6.4Hz,2H),2.89–2.69(m,4H),2.60(s,3H),1.81–1.68(m,4H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ9.21 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J ＝9.0Hz,1H),7.08(t,J＝8.1Hz,1H),6.92(dd,J＝8.1,1.2Hz,1H),6.81(dq,J＝7.7,1.0Hz,1H),4.34(q ,J＝6.4Hz,2H),2.89–2.69(m,4H),2.60(s,3H),1.81–1.68(m,4H),1.39(t,J＝6.3Hz,3H).
实施例229Example 229
5-(N-(4-乙炔基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-158)
5-(N-(4-ethynylphenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-158)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ9.55(s,1H),8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.53–7.47(m,2H),7.11–7.05(m,2H),4.34(q,J＝6.4Hz,2H),3.04(s,1H),2.60(s,3H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ9.55 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J ＝9.0Hz,1H),7.53–7.47(m,2H),7.11–7.05(m,2H),4.34(q,J＝6.4Hz,2H),3.04(s,1H),2.60(s,3H) ,1.39(t,J＝6.3Hz,3H).
实施例230Example 230
5-(N-(3-(二甲基氨基)苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-159)
5-(N-(3-(Dimethylamino)phenyl)sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M-GPR132-B-159)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。It was synthesized according to the method used for ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate.
1H NMR(400MHz,Chloroform-d)δ9.76(s,1H),8.25(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.65(d,J＝9.0Hz,1H),7.10(dd,J＝8.2,7.2Hz,1H),6.85(t,J＝2.3Hz,1H),6.76(ddd,J＝8.1,2.2,1.2Hz,1H),6.49(ddd,J＝7.3,2.2,1.2Hz,1H),4.34(q,J＝6.4Hz,2H),2.97(s,6H),2.60(s,3H),1.39(t,J＝6.3Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ9.76 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 9.0, 2.2Hz, 1H), 7.65 (d, J ＝9.0Hz,1H),7.10(dd,J＝8.2,7.2Hz,1H),6.85(t,J＝2.3Hz,1H),6.76(ddd,J＝8.1,2.2,1.2Hz,1H),6.49 (ddd,J＝7.3,2.2,1.2Hz,1H),4.34(q,J＝6.4Hz,2H),2.97(s,6H),2.60(s,3H),1.39(t,J＝6.3Hz, 3H).
生物活性测试Bioactivity testing
1.1G蛋白激活1.1G protein activation
Gi BRET探针是根据之前的文献报道(Olsen等人，2020)生成的，包括Gαi-RLuc8、Gβ3和Gγ9-GFP2。GPR132和Gi BRET探针在HEK293细胞中瞬时共转染。转染24小时后，将细胞以每孔5×104个细胞的密度分布到96孔微孔板中，再培养24小时。细胞用Tyrode缓冲液洗涤两次，用不同浓度(10-11-10-5M)的化合物配体和Tyrode缓冲液刺激2分钟，再加入10-5M的9-HODE刺激。然后加入荧光素酶底物腔肠素400a(5μM)后，使用配备BRET过滤器组的Mithras LB940酶标仪测量BRET信号。BRET信号计算为510nm/400nm处的发射光比。Gi BRET probes were generated according to previous literature reports (Olsen et al., 2020) and included Gαi-RLuc8, Gβ3, and Gγ9-GFP2. GPR132 and Gi BRET probes were transiently co-transfected in HEK293 cells. 24 hours after transfection, the cells were distributed into a 96-well microplate at a density of 5 × 10 cells per well and cultured for another 24 hours. The cells were washed twice with Tyrode buffer, stimulated with different concentrations (10 -11 -10 -5 M) of compound ligand and Tyrode buffer for 2 minutes, and then stimulated by adding 10 -5 M of 9-HODE. Then after adding the luciferase substrate coelenterazine 400a (5 μM), the BRET signal was measured using a Mithras LB940 microplate reader equipped with a BRET filter set. The BRET signal is calculated as the emission ratio at 510nm/400nm.
上述实验中EC50数值较低的化合物，具有良好的GPR132拮抗活性。 The compounds with lower EC 50 values in the above experiments have good GPR132 antagonistic activity.
1.2细胞培养与传代1.2 Cell culture and passage
人胚胎肾细胞系HEK293A传代培养，培养条件为含有青霉素(终浓度为100U/mL)、链霉素(终浓度为100μg/mL)以及10％FBS的MEM培养基，置于95％空气和5％二氧化碳的湿润气氛下37℃恒温培养。当细胞融合至90％时，弃去旧培养基，用2mL PBS洗涤细胞2次，弃去PBS后加入2mL 0.25％胰蛋白酶-0.25％EDTA混合消化液，置显微镜下观察，当细胞变圆后迅速加入2mL完全培养基终止消化，轻轻吹打，收集细胞。800rpm，4℃，离心5min，弃去上清，用完全培养基重悬细胞，分瓶培养，隔天换液。The human embryonic kidney cell line HEK293A was subcultured in MEM medium containing penicillin (final concentration: 100 U/mL), streptomycin (final concentration: 100 μg/mL) and 10% FBS, placed in 95% air and 5 Incubate at 37°C in a humidified atmosphere of % carbon dioxide. When the cells are 90% confluent, discard the old culture medium and wash the cells twice with 2 mL of PBS. After discarding the PBS, add 2 mL of 0.25% trypsin-0.25% EDTA mixed digestion solution and observe under a microscope. When the cells become round, Quickly add 2 mL of complete culture medium to stop digestion, pipet gently to collect cells. Centrifuge at 800 rpm, 4°C for 5 minutes, discard the supernatant, resuspend the cells in complete culture medium, culture in separate bottles, and change the medium every other day.
人肝癌细胞系HepG2传代培养，培养条件为含有青霉素(终浓度为100U/mL)、链霉素(终浓度为100μg/mL)以及10％FBS的DMEM培养基，余同HEK293A传代培养相同。The human hepatoma cell line HepG2 was subcultured in DMEM medium containing penicillin (final concentration: 100 U/mL), streptomycin (final concentration: 100 μg/mL) and 10% FBS. The conditions were the same as the subculture of HEK293A.
胰岛素细胞株(INS-1细胞)传代培养。培养条件：DMEM(Dulbecco's modified Eagle's medium)培养基中培养，其中还需要添加10％(v/v)胎牛血清(FBS)、2mM L-谷氨酰胺(L-glutamine)、100U/mL青霉素和100μg/mL链霉素。置于37℃、5％CO2、95％空气的细胞培养箱中培养。Insulin cell line (INS-1 cells) was subcultured. Culture conditions: Culture in DMEM (Dulbecco's modified Eagle's medium) medium, which also needs to add 10% (v/v) fetal bovine serum (FBS), 2mM L-glutamine (L-glutamine), 100U/mL penicillin and 100μg/mL streptomycin. Place it in a cell culture incubator at 37°C, 5% CO 2 and 95% air.
1.3细胞增殖抑制实验1.3 Cell proliferation inhibition experiment
通过MTT法检测化合物的细胞增殖抑制能力。HepG2和HEK293细胞以30％的密度接种于96孔板，孵育18h使细胞贴壁后，移除原有培养基，每孔加入给定浓度的待测化合物，对照组加入等量的DMSO。每个化合物设置三个复孔。给药48h后，MTT法检测细胞活力，空白组为不加入细胞的孔，随后用酶标仪在490nm处读取其OD值。细胞活力的计算公式为：细胞活力(％)＝(OD待测-OD空白)/(OD对照-OD空白)×100。The cell proliferation inhibitory ability of compounds was detected by MTT assay. HepG2 and HEK293 cells were seeded in a 96-well plate at a density of 30%. After incubation for 18 hours to allow the cells to adhere, the original culture medium was removed and a given concentration of the compound to be tested was added to each well. An equal amount of DMSO was added to the control group. Three replicate wells were set up for each compound. After 48 hours of administration, the cell viability was detected by the MTT method. The blank group was the well where no cells were added, and then the OD value was read at 490 nm with a microplate reader. The calculation formula of cell viability is: cell viability (%) = (OD to be tested - OD blank) / (OD control - OD blank) × 100.
上述实验中对HEK293细胞活力高、CC50数值较高的化合物，具有良好的安全性。对HepG2细胞抑制率较高、EC50数值较低的化合物，可以较好地抑制肿瘤细胞的增殖。In the above experiments, compounds with high HEK293 cell viability and high CC 50 values have good safety. Compounds with higher inhibition rates on HepG2 cells and lower EC 50 values can better inhibit the proliferation of tumor cells.
1.4细胞胰岛素水平检测1.4 Detection of cellular insulin levels
培养胰岛素分泌细胞：首先选取胰岛素细胞株(INS-1细胞)进行培养。培养条件：DMEM(Dulbecco's modified Eagle's medium)培养基中培养，其中还需要添加10％(v/v)胎牛血清(FBS)、2mM L-谷氨酰胺(L-glutamine)、100U/mL青霉素和100μg/mL链霉素。置于37℃、5％CO2、95％空气的细胞培养箱中培养。INS-1细胞接种于96孔板内培养贴壁，每组3个平行，使用高糖培养基培养细胞24h，随后使用PBS清洗2次后，加入含2％FBS无葡萄糖的KRBH液孵育30min，弃上清，再加入含5mmol/L或25mmol/L葡萄糖的KRBH液刺激1h后取上清，采用大鼠胰岛素酶联免疫分析(ELISA)检测胰岛素含量。具体步骤如下：Culture insulin-secreting cells: First, select an insulin cell line (INS-1 cells) for culture. Culture conditions: Culture in DMEM (Dulbecco's modified Eagle's medium) medium, which also needs to add 10% (v/v) fetal bovine serum (FBS), 2mM L-glutamine (L-glutamine), 100U/mL penicillin and 100μg/mL streptomycin. Place it in a cell culture incubator at 37°C, 5% CO 2 and 95% air. INS-1 cells were seeded in a 96-well plate and cultured in parallel, with 3 cells in each group. The cells were cultured in high-glucose medium for 24 hours. After washing twice with PBS, KRBH solution containing 2% FBS without glucose was added and incubated for 30 minutes. Discard the supernatant, add KRBH solution containing 5mmol/L or 25mmol/L glucose, stimulate for 1 hour, take the supernatant, and detect the insulin content using rat insulin enzyme-linked immunoassay (ELISA). Specific steps are as follows:
■标准品的加样：设置标准品孔和样本孔，标准品孔各加不同浓度的标准品50μL。■Add standard sample: Set standard wells and sample wells, and add 50 μL of standard products of different concentrations to each standard well.
■加样：分别设空白孔(空白对照孔不加样品及酶标试剂，其余各步操作相同)、待测样品孔。在酶标包被板上待测样品孔中先加样品稀释液40μL，然后再加待测样品10μL(样品终稀释度为5倍)。加样将样品加于酶标板孔底部，尽量不触及孔壁，轻轻晃动混匀。■Sample addition: Separately set up blank holes (no sample or enzyme label reagent is added to the blank control hole, and the remaining steps are the same) and the sample hole to be tested. First add 40 μL of sample diluent to the well of the sample to be tested on the enzyme-labeled coated plate, and then add 10 μL of the sample to be tested (the final dilution of the sample is 5 times). Add the sample to the bottom of the well of the enzyme plate, try not to touch the wall of the well, and shake gently to mix.
■加酶：每孔加入酶标试剂100μL，空白孔除外。■Add enzyme: Add 100 μL of enzyme label reagent to each well, except blank wells.
■温育：用封板膜封板后置37℃温育60分钟。■Incubation: Seal the plate with sealing film and incubate at 37°C for 60 minutes.
■配液：将20倍浓缩洗涤液用蒸馏水20倍稀释后备用。■Liquid preparation: Dilute the 20-fold concentrated washing liquid with distilled water 20-fold and set aside.
■洗涤：小心揭掉封板膜，弃去液体，甩干，每孔加满洗涤液，静置30秒后弃去，如此重复5次，拍干。■Washing: Carefully remove the sealing film, discard the liquid, spin dry, fill each well with washing liquid, let it stand for 30 seconds and discard, repeat this 5 times, and pat dry.
■显色：每孔先加入显色剂A50μL，再加入显色剂B50μL，轻轻震荡混匀，37℃避光显色15分钟.■Color development: First add 50μL of chromogen A to each well, then add 50μL of chromogen B, shake gently to mix, and develop color for 15 minutes at 37°C in the dark.
■终止：每孔加终止液50μL，终止反应(此时蓝色立转黄色)。 ■Stop: Add 50 μL of stop solution to each well to stop the reaction (blue turns to yellow immediately).
■测定：以空白孔调零，450nm波长依序测量各孔的吸光度(OD值)。测定应在加终止液后15分钟以内进行。■Measurement: Zero the blank wells and measure the absorbance (OD value) of each well at 450nm wavelength. The measurement should be performed within 15 minutes after adding the stop solution.
根据标准品绘制标准曲线，可计算出待测样品中的胰岛素含量。进一步计算出胰岛素分泌率，胰岛素分泌促进情况计算公式为：分泌促进率(％)＝胰岛素含量待测-胰岛素含量对照/胰岛素含量对照×100。Draw a standard curve based on the standard substance to calculate the insulin content in the sample to be tested. The insulin secretion rate is further calculated, and the formula for calculating insulin secretion promotion is: secretion promotion rate (%) = insulin content to be measured - insulin content control /insulin content control × 100.
上述实验中胰岛素分泌促进率较高，EC50数值较低的化合物，可以较好地促进胰岛素分泌进而提高葡萄糖耐量，改善胰岛素抵抗，降低血糖水平。In the above experiments, compounds with higher insulin secretion promotion rates and lower EC 50 values can better promote insulin secretion, thereby improving glucose tolerance, improving insulin resistance, and lowering blood sugar levels.
1.5细胞TC/TG检测1.5 Cell TC/TG detection
细胞TC/TG用南京建成TG测试盒、TC测试盒检测。HepG2细胞用0.5mmol/L FFA(油酸与棕榈酸酯按照2:1混合)和溶剂或不同浓度(20μM、40μM、80μM)的化合物孵育24h。吸弃培养液，用0.01M,pH 7.4PBS清洗一遍细胞。用细胞刮板刮下细胞，加入2-5mL,0.01M,pH 7.4PBS，收集细胞悬液后，1000×g，4℃，离心10min收集细胞，按照106个细胞加入300-500μL匀浆介质的比例加入异丙醇，进行机械匀浆，充分破碎至无明显的细胞沉淀。10000×g，4℃，离心10min，取上清置于冰上待测。取2.5μL蒸馏水、标准品或样品分别与250μL蒸馏水混匀，37℃孵育10分钟，酶标仪510nm测定各孔吸光度值。TC/TG浓度计算公式：样品浓度(mmol/g protein)＝(OD样品-OD空白)/(OD标准-OD空白)×标准品浓度(mmol/L)/蛋白浓度(g protein/L)。Cellular TC/TG was detected using Nanjing Jiancheng TG test kit and TC test kit. HepG2 cells were incubated with 0.5 mmol/L FFA (oleic acid and palmitate mixed at a ratio of 2:1) and solvent or compounds of different concentrations (20 μM, 40 μM, 80 μM) for 24 h. Aspirate the culture medium and wash the cells with 0.01M, pH 7.4 PBS. Use a cell scraper to scrape off the cells, add 2-5mL, 0.01M, pH 7.4PBS. After collecting the cell suspension, centrifuge at 1000×g, 4℃ for 10 minutes to collect the cells. Add 300-500μL homogenization medium according to 106 cells. Add isopropyl alcohol in appropriate proportion, perform mechanical homogenization, and fully disrupt until there is no obvious cell precipitation. Centrifuge at 10000×g, 4°C for 10 minutes, take the supernatant and place it on ice for testing. Take 2.5 μL of distilled water, standards or samples, mix them with 250 μL of distilled water, incubate at 37°C for 10 minutes, and measure the absorbance value of each well with a microplate reader at 510 nm. TC/TG concentration calculation formula: sample concentration (mmol/g protein) = (OD sample-OD blank)/(OD standard-OD blank) × standard concentration (mmol/L)/protein concentration (g protein/L).
BCA法蛋白定量BCA method protein quantification
蛋白标准品的准备：a.取1.2mL蛋白标准配制液加入到一管蛋白标准(30mg BSA))中，充分溶解后配制成25mg/mL的蛋白标准溶液。b.取适量25mg/mL蛋白标准，稀释至终浓度为0.5mg/mL。BCA工作液配制：根据样品数量，按50体积BCA试剂A加1体积BCA试剂B(50:1)配制适量BCA工作液，充分混匀。蛋白浓度测定：a.将标准品按0、1、2、4、8、12、16、20μL加到96孔板的标准品孔中，加标准品稀释液补足到20μL，相当于标准品浓度分别为0、0.025、0.05、0.1、0.2、0.3、0.4、0.5mg/mL。b.加适当体积样品到96孔板的样品孔中。如果样品不足20μL，需加标准品稀释液补足到20μL。c.各孔加入200μL BCA工作液，37℃放置20-30分钟。d.用酶标仪测定A562nm波长处的吸光度。e.根据标准曲线和使用的样品体积计算出样品的蛋白浓度。Preparation of protein standard: a. Add 1.2mL of protein standard solution into a tube of protein standard (30mg BSA), fully dissolve it and prepare a 25mg/mL protein standard solution. b. Take an appropriate amount of 25mg/mL protein standard and dilute it to a final concentration of 0.5mg/mL. Preparation of BCA working solution: According to the number of samples, prepare an appropriate amount of BCA working solution by adding 50 volumes of BCA reagent A and 1 volume of BCA reagent B (50:1), and mix thoroughly. Determination of protein concentration: a. Add 0, 1, 2, 4, 8, 12, 16, and 20 μL of standard into the standard wells of the 96-well plate, and add standard diluent to make up to 20 μL, which is equivalent to the concentration of the standard. They are 0, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 mg/mL respectively. b. Add appropriate volume of sample to the sample well of the 96-well plate. If the sample is less than 20 μL, add standard diluent to make up to 20 μL. c. Add 200μL BCA working solution to each well and place at 37°C for 20-30 minutes. d. Use a microplate reader to measure the absorbance at the wavelength of A562nm. e. Calculate the protein concentration of the sample based on the standard curve and the sample volume used.
上述实验中TC/TG降低率较高、EC50数值较低的化合物，可以较好地降低血液和/或肝脏中的脂肪含量。In the above experiments, compounds with higher TC/TG reduction rates and lower EC 50 values can better reduce the fat content in the blood and/or liver.
1.6急性高脂血症动物实验1.6 Animal experiments on acute hyperlipidemia
雄性C57BL/6小鼠随机分为8组，Control组、Model组、SIPI-7623组(10mg/kg、30mg/kg和100mg/kg)和受试物组(3个剂量)。Model组、SIPI-7623组和受试物组腹腔注射600mg/kg的Triton WR-1339，Control组注射同等体积生理盐水。在注射诱导剂前1个小时和注射诱导剂后23h灌胃给与化合物处理，1h后，收集血液样品和组织样品。Male C57BL/6 mice were randomly divided into 8 groups, Control group, Model group, SIPI-7623 group (10mg/kg, 30mg/kg and 100mg/kg) and test substance group (3 doses). The Model group, SIPI-7623 group and test group were intraperitoneally injected with 600mg/kg Triton WR-1339, and the Control group was injected with the same volume of normal saline. The compounds were administered intragastrically 1 hour before and 23 hours after the induction agent injection, and blood and tissue samples were collected 1 hour later.
1.7高脂饮食动物实验1.7 High-fat diet animal experiments
雄性C57BL/6小鼠随机分为6组，Control组、HFD组、SIPI-7623组(40mg/kg)和受试物组(3个剂量)。Control组给予正常饮食，HFD组、SIPI-7623组和受试物组给予高脂饮食。Control组和HFD组灌胃给与溶剂，其他组给予相应剂量化合物处理。每天记录小鼠体重。化合物灌胃处理8周后，收集血液样品和组织样品。高脂饮食成分见下表。Male C57BL/6 mice were randomly divided into 6 groups, Control group, HFD group, SIPI-7623 group (40 mg/kg) and test substance group (3 doses). The control group was given a normal diet, and the HFD group, SIPI-7623 group and test substance group were given a high-fat diet. The Control group and HFD group were given solvent by gavage, and the other groups were given corresponding doses of compounds. The mouse body weight was recorded every day. After 8 weeks of oral administration of the compound, blood and tissue samples were collected. The ingredients of a high-fat diet are shown in the table below.
小鼠正常饲料(Standard chow)和高脂饲料(High fat diet)配方组成

Formula composition of mouse normal chow (Standard chow) and high fat diet (High fat diet)

1.8饮食诱导肥胖动物实验1.8 Animal experiments on diet-induced obesity
雄性C57BL/6小鼠分为2组，Control组正常饮食、HFD组给予高脂饮食。高脂饮食12周后，HFD组随机分为9组：HFD组、受试物组(3个剂量)、SIPI-7623(40mg/kg)、Atorvastatin(10mg/kg)和受试物(10mg/kg)+Atorvastatin(10mg/kg)。Control组和HFD组灌胃给与溶剂，其他组给予相应剂量化合物处理。每周记录小鼠体重。化合物灌胃处理8周后，收集血液样品和组织样品。高脂饮食成分见上表。Male C57BL/6 mice were divided into 2 groups, the Control group was fed a normal diet, and the HFD group was given a high-fat diet. After 12 weeks of high-fat diet, the HFD group was randomly divided into 9 groups: HFD group, test substance group (3 doses), SIPI-7623 (40mg/kg), Atorvastatin (10mg/kg) and test substance (10mg/kg). kg)+Atorvastatin(10mg/kg). The Control group and HFD group were given solvent by gavage, and the other groups were given corresponding doses of compounds. The body weight of the mice was recorded weekly. After 8 weeks of oral administration of the compound, blood and tissue samples were collected. The ingredients of high-fat diet are shown in the table above.
1.9 db/db鼠动物实验1.9 db/db mouse animal experiment
雄性db/db小鼠随机分为5组，实验分组为db/db组、受试物组(3个剂量)和吡格列酮(7mg/kg)。db/db组给予溶剂灌胃处理，其他组给予对应化合物灌胃处理4周。每周记录小鼠体重，并检测空腹血糖。化合物灌胃4周后，收集血液样品和组织样品进行后续实验。Male db/db mice were randomly divided into 5 groups, and the experimental groups were db/db group, test substance group (3 doses) and pioglitazone (7mg/kg). The db/db group was given intragastric treatment with solvent, and the other groups were given intragastric treatment with corresponding compounds for 4 weeks. The body weight of the mice was recorded weekly, and fasting blood glucose was measured. Four weeks after compound administration, blood and tissue samples were collected for subsequent experiments.
2.0小鼠血糖测定2.0 Mouse blood glucose measurement
1、罗氏血糖仪包括：血糖仪、采血笔、血糖试纸。1. Roche blood glucose meter includes: blood glucose meter, blood collection pen, and blood glucose test strips.
2、用酒精棉球擦拭小鼠尾尖，打开采血笔上的采样针，扎破小鼠尾尖；用血糖试纸蘸取尾尖血液，血液必须完全覆盖试纸测试区；打开血糖仪，将血糖试纸插入血糖仪，读取并记录血糖值。每只小鼠测定血糖前都应该更换采样针和血糖试纸。2. Wipe the tail tip of the mouse with an alcohol cotton ball, open the sampling needle on the lancing pen, and prick the tail tip of the mouse; dip the blood glucose test paper into the tail tip blood, and the blood must completely cover the test area of the test paper; turn on the blood glucose meter and collect the blood glucose The test strip is inserted into the blood glucose meter to read and record the blood glucose value. The sampling needle and blood glucose test paper should be replaced before measuring blood glucose in each mouse.
2.1葡萄糖耐量试验(Glucose tolerance test,GTT)2.1 Glucose tolerance test (GTT)
葡萄糖耐量试验在受试物灌胃给药后第5周(实验第17周)进行。小鼠禁食16h后，腹腔注射葡萄糖(1.5g/kg)，在注射葡萄糖后0、15、30、60、90、120min分别用血糖仪测定小鼠的血糖水平。The glucose tolerance test was performed on the 5th week after intragastric administration of the test substance (the 17th week of the experiment). After the mice were fasted for 16 hours, glucose (1.5g/kg) was injected intraperitoneally. The blood glucose levels of the mice were measured with a blood glucose meter at 0, 15, 30, 60, 90, and 120 minutes after glucose injection.
2.2胰岛素耐量试验(Insulin tolerance test,ITT)2.2 Insulin tolerance test (ITT)
胰岛素耐量试验在受试物灌胃给药后第6周(实验第18周)进行。小鼠禁食4h后，腹腔注射胰岛素(1U/kg)，在注射胰岛素后0、15、30、60、90、120min分别用血糖仪测定小鼠的血糖水平。The insulin tolerance test was performed on the 6th week after intragastric administration of the test substance (the 18th week of the experiment). After the mice were fasted for 4 hours, insulin (1 U/kg) was injected intraperitoneally. The blood glucose levels of the mice were measured with a blood glucose meter at 0, 15, 30, 60, 90, and 120 minutes after insulin injection.
2.3动物取材2.3 Animal materials
1、小鼠称重后，使用戊巴比妥钠腹腔注射麻醉。1. After weighing the mice, anesthetize them by intraperitoneal injection of sodium pentobarbital.
2、内眦取血，取20μL全血，用全血稀释液进行稀释，进行血常规检测；剩余全血常温静置2h，3000rpm，4℃，离心10min，取上层血清，进行血生化检测。2. Take blood from the inner canthus, take 20 μL of whole blood, dilute it with whole blood diluent, and conduct routine blood tests; the remaining whole blood is allowed to stand at room temperature for 2 hours, 3000 rpm, 4°C, and centrifuged for 10 minutes, and the upper serum is taken for blood biochemical testing.
3、小鼠取完血后，打开胸腔和腹腔，分别取出肝、肠、白色脂肪和褐色脂肪组织。3. After collecting blood from the mice, open the chest and abdominal cavities and remove the liver, intestines, white fat and brown adipose tissue respectively.
4、肝脏分出一部分4％甲醛固定，用于石蜡切片和冰冻切片，剩余组织-80℃冻存。 4. Separate a part of the liver and fix it in 4% formaldehyde for paraffin sectioning and frozen sectioning. The remaining tissue is frozen at -80°C.
5、肠道组织用PBS冲洗后，刮取肠道上皮细胞-80℃冻存。5. After washing the intestinal tissue with PBS, scrape the intestinal epithelial cells and freeze them at -80°C.
6、对白色脂肪和褐色脂肪组织进行称重。6. Weigh the white adipose and brown adipose tissue.
2.4肝脏中胆固醇和甘油三酯检测2.4 Detection of cholesterol and triglycerides in liver
1、取适量肝脏组织，加入研磨珠以PBS为buffer进行组织匀浆。1. Take an appropriate amount of liver tissue, add grinding beads and use PBS as buffer to homogenize the tissue.
2、将匀浆液等分为两部分，一部分加入氯仿甲醇抽提，测定胆固醇和甘油三酯。向其中一管加入4倍体积氯仿甲醇抽提液(氯仿：甲醇＝2:1)，涡旋使其充分混匀，静置至分层，2000rpm，4℃，离心30min，吸出下层液体于新离心管，在真空浓缩仪中挥发干净溶剂，加入适量3％Triton X-100，恒温水浴摇床50-60℃溶解。用TC和TG试剂盒测定浓度。2. Divide the homogenate into two parts, add one part to chloroform and methanol for extraction, and measure cholesterol and triglycerides. Add 4 times the volume of chloroform-methanol extract (chloroform:methanol=2:1) to one of the tubes, vortex to mix thoroughly, let stand until layered, centrifuge at 2000 rpm, 4°C for 30 minutes, suck out the lower liquid and place it in a new tube. Centrifuge the tube, evaporate the clean solvent in a vacuum concentrator, add an appropriate amount of 3% Triton X-100, and dissolve in a constant temperature water bath shaker at 50-60°C. Determine concentration using TC and TG kits.
5、取另一管匀浆液，12000rpm，4℃，离心15min，取上清，用BCA试剂盒测定蛋白浓度。5. Take another tube of homogenate, centrifuge at 12000 rpm, 4°C for 15 minutes, take the supernatant, and use the BCA kit to measure the protein concentration.
6、脂质含量＝脂质浓度/蛋白浓度6. Lipid content = lipid concentration/protein concentration
2.5肝脏油红O染色2.5 Liver Oil Red O staining
1、取相同部位相同大小的新鲜肝脏组织放置于4％中性甲醛中固定，送至检测公司制备切片并进行油红O染色。1. Take fresh liver tissue from the same part and size and fix it in 4% neutral formaldehyde. Send it to a testing company to prepare sections and stain with Oil Red O.
2、取回已经制备好的切片用扫描仪扫描切片并拍照。2. Take back the prepared slices, scan them with a scanner and take pictures.
2.6组织HE染色2.6 Tissue HE staining
1、取相同部位相同大小的新鲜肝脏组织放置于4％中性甲醛中固定，送至检测公司制备切片并进行HE染色。1. Take fresh liver tissue of the same size from the same part, place it in 4% neutral formaldehyde and fix it, then send it to a testing company to prepare sections and perform HE staining.
2、取回已经制备好的切片用扫描仪扫描切片并拍照。2. Take back the prepared slices, scan them with a scanner and take pictures.
表9部分化合物的GPR132拮抗活性

Table 9 GPR132 antagonistic activity of some compounds

表10部分化合物的GPR132拮抗活性Table 10 GPR132 antagonistic activity of some compounds
GPR132拮抗活性结果表示GPR132 antagonistic activity results indicate
A:0.0001μM<EC50<0.1μMA:0.0001μM<EC50<0.1μM
B:0.1μM<EC50<1μMB:0.1μM<EC50<1μM
C:1μM<EC50<10μMC:1μM<EC50<10μM
D:10μM<EC50<100μM


D:10μM<EC50<100μM


表11部分化合物的促进胰岛素分泌活性

Table 11: Insulin secretion-promoting activity of some compounds

表12部分化合物的促进胰岛素分泌活性促进胰岛素分泌活性结果表示Table 12 shows the insulin secretion-promoting activity of some compounds.
A:0.0001μM<EC50<1μMA:0.0001μM<EC50<1μM
B:0.1μM<EC50<10μMB:0.1μM<EC50<10μM
C:1μM<EC50<100μM

C:1μM<EC50<100μM

实验结果表明，本发明化合物具有以下一个或多个方面的效果：Experimental results show that the compound of the present invention has one or more of the following effects:
(1)具有良好的GPR132拮抗活性；(1) Has good GPR132 antagonistic activity;
(2)具有良好的安全性；(2) Has good safety;
(3)可以提高葡萄糖耐量；(3) Can improve glucose tolerance;
(4)可以改善胰岛素抵抗；(4) Can improve insulin resistance;
(5)可以降低血糖水平；(5) Can lower blood sugar levels;
(6)可以降低血脂水平；(6) Can lower blood lipid levels;
(7)可以降低肝脏中的脂肪含量；(7) It can reduce the fat content in the liver;
(8)可以抑制肿瘤细胞的增殖。(8) Can inhibit the proliferation of tumor cells.
综上，本发明的化合物可作为GPR132拮抗剂，用于预防和/或治疗与GPR132相关的疾病，例如肿瘤或代谢性疾病。In summary, the compounds of the present invention can be used as GPR132 antagonists for preventing and/or treating GPR132-related diseases, such as tumors or metabolic diseases.
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解：根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。 Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all teachings that have been disclosed, and these changes are within the scope of the present invention. . The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (20)

  1. 式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，
    Compounds represented by formula (I), their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystal forms or their metabolite forms,
    其中：in:
    A选自6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基、苯并5至6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基；任选地，所述6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基被一个或多个M取代；A is selected from 6 to 10 membered aryl, 5 to 14 membered heteroaryl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, benzo 3 to 6 membered cycloalkyl, benzo 5 to 6 membered Heterocyclyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 5 to 6 membered cycloalkenyl; optionally, the 6 to 10 membered aryl group, 5 To 14-membered heteroaryl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, benzo 3- to 6-membered cycloalkyl substituted by one or more M;
    M选自以下基团：卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、P(＝O)R7R8、CH3CH2O-(CH2CH2O)q-、4至6元杂环基、5至6元杂芳基；任选地，所述C1-C6烷氧基被一个或多个选自以下的基团取代：C1-C6卤代烷基、3至6元环烷基；所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代；M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 amido, phenyl, phenoxy, P(=O)R 7 R 8 , CH 3 CH 2 O-(CH 2 CH 2 O) q -, 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl; optionally, the C 1 -C 6 alkoxy group is one or more selected from The following groups are substituted: C 1 -C 6 haloalkyl, 3 to 6 membered cycloalkyl; the phenyl, phenoxy, 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl are optionally substituted by Halogen or C 1 -C 6 alkyl substitution;
    R1选自羟基、-NR5R6、C1-C6烷氧基；任选地，所述C1-C6烷氧基被一个或多个选自以下的基团取代：苯基、卤素、硝基、氰基、羟基、C1-C6烷基；R 1 is selected from hydroxyl, -NR 5 R 6 , C 1 -C 6 alkoxy; optionally, the C 1 -C 6 alkoxy is substituted by one or more groups selected from the following: phenyl , halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
    Q为苯基或苯并5-6元杂芳基环；Q is phenyl or benzo 5-6 membered heteroaryl ring;
    R2选自氢、卤素、C1-C6烷基、C1-C6卤代烷基；m选自1、2、3、4；当有多个R2时，各个R2可以相同或不同；R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; m is selected from 1, 2, 3, 4; when there are multiple R 2s , each R 2 can be the same or different ;
    R3、R4、R5、R6各自独立地选自氢、羟基和C1-C6烷基；任选地，所述C1-C6烷基被一个或多个选自以下的基团取代：苯基、卤素、硝基、氰基、羟基、C1-C6烷基；R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl and C 1 -C 6 alkyl; optionally, the C 1 -C 6 alkyl is replaced by one or more selected from the following Group substitution: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl;
    R7、R8各自独立地选自C1-C6烷基，q选自1至10之间的整数；R 7 and R 8 are each independently selected from C 1 -C 6 alkyl, and q is selected from an integer between 1 and 10;
    L1、L2各自独立地为不存在或选自-(CH2)n-、3至6元环烷基，n为选自1至6的整数；任选地，-(CH2)n-被一个或多个选自以下的基团取代：苯基、卤素、硝基、氰基、羟基、C1-C6烷基、氘、氚、羰基；并且，所述化合物不是3-甲基-5-(N-苯乙基氨磺酰)苯并呋喃-2-羧酸。L 1 and L 2 are each independently absent or selected from -(CH 2 ) n -, 3 to 6-membered cycloalkyl, n is an integer selected from 1 to 6; optionally, -(CH 2 ) n - substituted by one or more groups selected from: phenyl, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, deuterium, tritium, carbonyl; and, the compound is not 3-methyl Base-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid.
  2. 根据权利要求1所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，A选自6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基、苯并5至6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基；任选地，所述6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基被一个或多个M取代；The compound according to claim 1, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein A is selected from 6 to 10-membered aryl, 5- to 8-membered monocyclic heteroaryl, 8- to 14-membered fused heteroaryl, 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, benzo 5- to 6-membered cycloalkyl, Benzo 5- to 6-membered heterocyclyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 5 to 6-membered cycloalkenyl; optionally, the 6 to 6-membered cycloalkenyl 10-membered aryl, 5- to 8-membered monocyclic heteroaryl, 8- to 14-membered fused heteroaryl, 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, benzo 5- to 6-membered cycloalkyl One or more M substitutions;
    优选地，M选自以下基团：卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、 C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、P(＝O)R7R8、CH3CH2O-(CH2CH2O)q-、4至6元杂环基、5至6元杂芳基；所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代；Preferably, M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 amido, phenyl, phenoxy, P( =O)R 7 R 8 , CH 3 CH 2 O-(CH 2 CH 2 O) q -, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl; the phenyl, phenoxy, 4 To a 6-membered heterocyclyl, a 5- to 6-membered heteroaryl is optionally substituted by halogen or C 1 -C 6 alkyl;
    优选地，R7、R8各自为甲基，q选自1至4之间的整数；Preferably, R 7 and R 8 are each methyl, and q is selected from an integer between 1 and 4;
    优选地，A选自6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基(例如苯并5至6元含氧杂芳基)、8至10元含氮稠杂芳基(例如苯并5至6元含氮杂芳基)、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基、苯并5至6元含氧杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基；任选地，所述6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基(例如苯并5至6元含氧杂芳基)、8至10元含氮稠杂芳基(例如苯并5至6元含氮杂芳基)、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基或苯并5至6元含氧杂环基被一个或多个M取代；Preferably, A is selected from a 6- to 10-membered aryl group, a 5- to 6-membered sulfur- or nitrogen-containing monocyclic heteroaryl group, an 8- to 10-membered oxygen-containing condensed heteroaryl group (such as a benzo 5- to 6-membered oxygen-containing heteroaryl group). base), 8- to 10-membered nitrogen-containing fused heteroaryl (such as benzo 5- to 6-membered nitrogen-containing heteroaryl), 5- to 6-membered cycloalkyl, 5- to 6-membered oxygen-containing heterocyclic group, 5- to 6-membered Nitrogen-containing heterocyclic group, benzo 5- to 6-membered cycloalkyl group, benzo 5- to 6-membered oxygen-containing heterocyclic group, C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkyne base, 5- to 6-membered cycloalkenyl; optionally, the 6- to 10-membered aryl group, 5- to 6-membered sulfur-containing or nitrogen-containing monocyclic heteroaryl group, 8- to 10-membered oxygen-containing fused heteroaryl group (such as Benzo 5- to 6-membered oxygen-containing heteroaryl), 8- to 10-membered nitrogen-containing condensed heteroaryl (such as benzo 5- to 6-membered nitrogen-containing heteroaryl), 5- to 6-membered cycloalkyl, 5- to 6-membered An oxygen-containing heterocyclic group, a 5- to 6-membered nitrogen-containing heterocyclic group, a benzo 5- to 6-membered cycloalkyl group, or a benzo 5- to 6-membered oxygen-containing heterocyclic group is substituted by one or more M;
    优选地，M选自以下基团：卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、-P(＝O)(CH3)2、CH3CH2O-(CH2CH2O)-；Preferably, M is selected from the following groups: halogen, nitro, hydroxyl, cyano, -NR 3 R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy group, C 1 -C 6 alkanoyl group, C 1 -C 6 amide group, phenyl group, phenoxy group, -P(=O)(CH 3 ) 2 , CH 3 CH 2 O- (CH 2 CH 2 O)-;
    优选地，A选自苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基、C1-C6烷基、2,3-二氢苯并呋喃基、2,3-二氢苯并[b][1,3]二氧杂环戊烷基、2,3-二氢苯并[b][1,4]二氧杂环己烷基、吲哚基、环己烯基、苯并环己烷基；任选地，所述苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基、C1-C6烷基、2,3-二氢苯并呋喃基、2,3-二氢苯并[b][1,3]二氧杂环戊烷基、2,3-二氢苯并[b][1,4]二氧杂环己烷基、吲哚基、环己烯基或苯并环己烷基被一个或多个M取代；Preferably, A is selected from phenyl, naphthyl, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxanyl, indolyl, cyclohexenyl, benzocyclohexanyl; optionally, the phenyl, naphthalene base, thienyl, pyridyl, benzofuranyl, cyclohexyl, tetrahydropyranyl, piperazinyl, indenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 alkyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1,3]dioxolyl, 2,3-dihydrobenzo[b ][1,4]dioxanyl, indolyl, cyclohexenyl or benzocyclohexanyl group is substituted by one or more M;
    优选地，M选自以下基团：卤素(例如氟、氯、溴、碘)、C1-C4烷基、三氟甲基、甲氧基、乙氧基、苯基、C2-C4炔基、C1-C6烷酰基、硝基、羟基、氰基、-NR3R4、-P(＝O)(CH3)2、CH3CH2O-(CH2CH2O)-、4至6元杂环基、5至6元杂芳基、苯氧基；所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代。Preferably, M is selected from the following groups: halogen (eg fluorine, chlorine, bromine, iodine), C 1 -C 4 alkyl, trifluoromethyl, methoxy, ethoxy, phenyl, C 2 -C 4 alkynyl, C 1 -C 6 alkanoyl, nitro, hydroxyl, cyano, -NR 3 R 4 , -P(=O)(CH 3 ) 2 , CH 3 CH 2 O-(CH 2 CH 2 O )-, 4 to 6-membered heterocyclyl, 5 to 6-membered heteroaryl, phenoxy; the phenyl, phenoxy, 4 to 6-membered heterocyclyl, 5 to 6-membered heteroaryl optionally Substituted by halogen or C 1 -C 6 alkyl.
  3. 根据权利要求1或2所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，R1为羟基或-NHOH。The compound according to claim 1 or 2, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein R 1 is Hydroxy or -NHOH.
  4. 根据权利要求1-3任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，R2选自卤素、C1-C6烷基(例如甲基)、C1-C6卤代烷基(例如氟代甲基)。The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein, R 2 is selected from halogen, C 1 -C 6 alkyl (eg methyl), C 1 -C 6 haloalkyl (eg fluoromethyl).
  5. 根据权利要求1-4任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，L1不存在或选自-(CH2)n-、环丙基，n为选自1至4的整数；任选地，-(CH2)n-被甲基或羰基取代或被氘代；The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein, L 1 is absent or selected from -(CH 2 ) n -, cyclopropyl, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is substituted by methyl or carbonyl or deuterated ;
    优选地，L2不存在或选自-(CH2)n-、n为选自1至4的整数；任选地，-(CH2)n-被甲基取代或被氘代。 Preferably, L 2 is absent or selected from -(CH 2 ) n -, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is substituted by methyl or deuterated.
  6. 根据权利要求1-5任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，所述5-6元杂芳基选自呋喃基、噻吩基、吡咯基；The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein, The 5-6 membered heteroaryl group is selected from furyl group, thienyl group, and pyrrolyl group;
    优选地，所述化合物的结构如式(II)所示：
    Preferably, the structure of the compound is shown in formula (II):
    其中，X选自O、S或NH，A、R1、R2、L1如权利要求1-5任一项所定义；Wherein, X is selected from O, S or NH, and A, R 1 , R 2 and L 1 are as defined in any one of claims 1-5;
    优选地，所述化合物的结构如式(III)或(IV)所示：
    Preferably, the structure of the compound is shown in formula (III) or (IV):
    优选地，X为O、S或NH，A、R1、R2、L1如权利要求1-5任一项所定义。Preferably, X is O, S or NH, and A, R 1 , R 2 and L 1 are as defined in any one of claims 1-5.
  7. 根据权利要求1-6任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物选自表1所示的化合物：The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, The compound is selected from the compounds shown in Table 1:
    表1





    Table 1





  8. 根据权利要求1-6任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物的结构如式(V)所示：
    The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, The structure of the compound is shown in formula (V):
    其中，Core为X选自O、S或NH，R2如权利要求1或4任一项所定义；Among them, Core is X is selected from O, S or NH, R 2 is as defined in any one of claims 1 or 4;
    优选地，R2选自氢、卤素、C1-C6烷基；Preferably, R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl;
    优选地，Core选自：
    Preferably, Core is selected from:
    优选地，所述化合物选自表2所示的化合物：Preferably, the compound is selected from the compounds shown in Table 2:
    表2
    Table 2
  9. 根据权利要求1-6任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物的结构如式(VI)所示：
    The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, The structure of the compound is shown in formula (VI):
    其中，A如权利要求1或2任一项所定义。Wherein, A is as defined in either claim 1 or 2.
  10. 根据权利要求9所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，A选自任选被一个或多个M取代的苯基，M选自卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、硝基、羟基、-NR3R4，R3、R4各自独立地选自氢、C1-C6烷基；The compound according to claim 9, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein A is selected from optional Phenyl substituted by one or more M, M selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, nitro, hydroxyl, -NR 3 R 4 , R 3 and R 4 are each independently selected from hydrogen and C 1 -C 6 alkyl;
    优选地，所述化合物选自表3所示的化合物：Preferably, the compound is selected from the compounds shown in Table 3:
    表3

    table 3

  11. 根据权利要求9所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，A选自任选被一个或多个M取代的以下基团：苯基、5至6元含氮杂芳基；M选自：卤素、C2-C6炔基、C1-C6烷氧基、氰基、P(＝O)R7R8、C1-C6烷酰基、CH3CH2O-(CH2CH2O)q-、苯基、4至6元杂环基、5至6元杂芳基，其中，R7、R8各自独立地选自C1-C6烷基，q选自1至10之间的整数，所述苯基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代；The compound according to claim 9, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein A is selected from optional The following groups substituted by one or more M: phenyl, 5 to 6-membered nitrogen-containing heteroaryl; M is selected from: halogen, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, cyano , P(＝O)R 7 R 8 , C 1 -C 6 alkanoyl group, CH 3 CH 2 O-(CH 2 CH 2 O) q -, phenyl, 4 to 6-membered heterocyclyl, 5 to 6-membered Heteroaryl, wherein R 7 and R 8 are each independently selected from C 1 -C 6 alkyl, q is selected from an integer between 1 and 10, and the phenyl, 4 to 6-membered heterocyclyl, 5 to 6-membered heteroaryl is optionally substituted by halogen or C 1 -C 6 alkyl;
    优选地，所述化合物选自表4所示的化合物：Preferably, the compound is selected from the compounds shown in Table 4:
    表4

    Table 4

  12. 根据权利要求9所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，A选自任选被一个或多个M取代的以下基团：苯基、萘基、苯并5至6元杂环基(例如苯并5至6元含氧杂环基)、苯并5至6元杂芳基(例如苯并5至6元含氮或含氧杂芳基)；M选自卤素、C1-C6烷基、C1-C6烷氧基；The compound according to claim 9, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein A is selected from optional The following groups substituted by one or more M: phenyl, naphthyl, benzo 5- to 6-membered heterocyclic group (such as benzo 5- to 6-membered oxygen-containing heterocyclic group), benzo 5- to 6-membered heteroaryl group (such as benzo 5- to 6-membered nitrogen-containing or oxygen-containing heteroaryl group); M is selected from halogen, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group;
    优选地，所述化合物选自表5所示的化合物：Preferably, the compound is selected from the compounds shown in Table 5:
    表5


    table 5


  13. 根据权利要求9所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，A选自任选被一个或多个M取代的以下基团：C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烷基、5至6元环烯基、5至6元杂芳基、5至6元杂环基；M选自C1-C6烷基、卤素；The compound according to claim 9, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein A is selected from optional The following groups substituted by one or more M: C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 5 to 6-membered cycloalkyl, 5 to 6-membered cycloalkenyl base, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl; M is selected from C 1 -C 6 alkyl, halogen;
    优选地，所述化合物选自表6所示的化合物：Preferably, the compound is selected from the compounds shown in Table 6:
    表6

    Table 6

  14. 根据权利要求1-6任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物如式(VII)所示，
    The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, The compound is shown in formula (VII),
    其中，A和L1如权利要求1、2或5任一项所定义。Wherein, A and L 1 are as defined in any one of claims 1, 2 or 5.
  15. 根据权利要求14所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，A选自苯基、萘基，L1不存在或选自-(CH2)n-，n为选自1至4的整数；任选地，-(CH2)n-被一个或多个选自以下的基团取代：卤素、C1-C6烷基、羰基；The compound according to claim 14, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, wherein A is selected from phenyl , naphthyl, L 1 is absent or selected from -(CH 2 ) n -, n is an integer selected from 1 to 4; optionally, -(CH 2 ) n - is replaced by one or more groups selected from the following Group substitution: halogen, C 1 -C 6 alkyl, carbonyl;
    优选地，所述化合物选自表7所示的化合物：Preferably, the compound is selected from the compounds shown in Table 7:
    表7

    Table 7

  16. 根据权利要求14所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，其中，L1不存在，A选自任选被一个或多个M取代的以下基团：苯基、萘基、苯并5至6元杂芳基(例如苯并5至6元含氮或含氧杂芳基)、苯并5至6元环烷基，M选自C1-C6烷基、C2-C6炔基、卤素、苯氧基、-NR3R4、5至6元杂环基，R3、R4各自独立地选自C1-C6烷基，所述5至6元杂环基任选地被C1-C6烷基取代；The compound according to claim 14, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystalline form or their metabolite form, wherein L 1 is absent, A is selected from the following groups optionally substituted by one or more M: phenyl, naphthyl, benzo 5- to 6-membered heteroaryl (such as benzo 5- to 6-membered nitrogen-containing or oxygen-containing heteroaryl), Benzo 5- to 6-membered cycloalkyl, M selected from C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogen, phenoxy, -NR 3 R 4 , 5 to 6-membered heterocyclyl, R 3. R 4 is each independently selected from C 1 -C 6 alkyl, and the 5 to 6-membered heterocyclic group is optionally substituted by C 1 -C 6 alkyl;
    优选地，所述化合物选自表8所示的化合物：Preferably, the compound is selected from the compounds shown in Table 8:
    表8

    Table 8

  17. 根据权利要求1-16任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述药学上可接受的酯为羧酸乙酯。The compound according to any one of claims 1 to 16, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or their metabolite form, A pharmaceutically acceptable ester is ethyl carboxylate.
  18. 一种药物组合物，其包含根据权利要求1-17任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式；任选地，所述药物组合物还包含药学上可接受的载体或赋形剂。A pharmaceutical composition comprising a compound according to any one of claims 1-17, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or Their metabolite forms; optionally, the pharmaceutical composition further includes a pharmaceutically acceptable carrier or excipient.
  19. 化合物用于制备药物中的用途，所述药物用于预防或治疗与GPR132相关的疾病，所述化合物选自根据权利要求1-17任一项所述的化合物或下表中的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式：
    The use of compounds in the preparation of medicines for preventing or treating diseases related to GPR132, the compounds being selected from the group consisting of compounds according to any one of claims 1 to 17 or compounds in the table below, pharmaceuticals thereof Acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms or metabolite forms thereof:
  20. 根据权利要求19所述的用途，其中，所述与GPR132相关的疾病选自肿瘤、代谢性疾病、免疫相关疾病、神经性疼痛；The use according to claim 19, wherein the disease related to GPR132 is selected from tumors, metabolic diseases, immune-related diseases, and neuropathic pain;
    优选地，所述肿瘤选自选自：乳腺癌、黑色素瘤、脑膜瘤、软组织肉瘤、唾液腺肿瘤、原发性肝癌、椎管内肿瘤、纵隔肿瘤、脑癌、骨癌、阴茎癌、骨肉瘤、颅内肿瘤、舌癌、上颌窦癌、甲状腺癌、恶性淋巴瘤、多发性骨髓瘤、脑垂体腺瘤、睾丸肿瘤、非何杰金氏淋巴癌、膀胱癌、白血病、胃癌、鼻咽癌、喉癌、口腔癌、食管癌、肺癌、肾癌、宫颈癌、绒毛膜癌、外阴癌、皮肤癌、子宫内膜癌、卵巢癌、前列腺癌、胰腺癌、结肠癌、直肠癌、大肠癌、卡波西肉瘤、非黑色素瘤皮肤癌(包括鳞状细胞癌和基底细胞癌)、血管瘤、神经胶质瘤； Preferably, the tumor is selected from the group consisting of: breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumor, primary liver cancer, intraspinal tumor, mediastinal tumor, brain cancer, bone cancer, penile cancer, osteosarcoma , intracranial tumors, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumors, non-Hodgkin's lymphoma, bladder cancer, leukemia, gastric cancer, nasopharyngeal cancer , laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulvar cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer , Kaposi's sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), hemangioma, glioma;
    优选地，所述代谢性疾病选自动脉粥样硬化、肥胖、非酒精性脂肪肝病(NAFLD)(例如，单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))、代谢综合征、2型糖尿病、1型糖尿病、胰岛素抵抗、高胰岛素血症、葡萄糖不耐受、高血糖、高脂血症(例如，高胆固醇血症)，及这些疾病的继发性并发症(例如，糖尿病并发症，如视网膜病、神经病、肾病以及延缓的创伤愈合，或者动脉粥样硬化、冠心病、高血压、中风等心脑血管疾病)；Preferably, the metabolic disease is selected from the group consisting of atherosclerosis, obesity, non-alcoholic fatty liver disease (NAFLD) (eg, simple fatty liver disease or non-alcoholic steatohepatitis (NASH)), metabolic syndrome, type 2 Diabetes mellitus, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia), and secondary complications of these diseases (e.g., diabetic complications , such as retinopathy, neuropathy, kidney disease and delayed wound healing, or cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hypertension, stroke);
    优选地，所述免疫相关疾病选自：Preferably, the immune-related disease is selected from:
    继发性免疫缺陷：例如由感染(例如风疹、麻疹、麻风、结核病、巨细胞病毒感染、艾滋病病毒感染、球孢子菌感染)，蛋白丢失(例如肾病综合征、蛋白丢失性肠病)，免疫球蛋白合成不足，淋巴细胞丢失(例如因药物和/或系统感染引起的淋巴细胞丢失)，其他疾病(如糖尿病、肝硬变、亚急性硬化性全脑炎)和/或免疫抑制治疗引起的继发性免疫缺陷；以及Secondary immune deficiencies: for example caused by infections (e.g. rubella, measles, leprosy, tuberculosis, cytomegalovirus infection, HIV infection, coccidioidomycosis infection), protein loss (e.g. nephrotic syndrome, protein-losing enteropathy), immune Insufficient globulin synthesis, lymphocyte loss (e.g. due to drugs and/or systemic infection), other diseases (e.g. diabetes, cirrhosis, subacute sclerosing panencephalitis) and/or immunosuppressive therapy secondary immunodeficiency; and
    自身免疫疾病：例如系统性红斑狼疮、类风湿性关节炎、硬皮病、甲状腺机能亢进、青少年糖尿病、原发性血小板紫癜、自身免疫性溶血性贫血、溃疡性结肠炎、皮肤病、慢性肝病。 Autoimmune diseases: such as systemic lupus erythematosus, rheumatoid arthritis, scleroderma, hyperthyroidism, juvenile diabetes, essential thrombocytopenic purpura, autoimmune hemolytic anemia, ulcerative colitis, skin diseases, chronic liver disease .
PCT/CN2023/089013 2022-04-18 2023-04-18 Gpcr regulator and use thereof WO2023202582A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210404725 2022-04-18
CN202210404725.1 2022-04-18

Publications (1)

Publication Number Publication Date
WO2023202582A1 true WO2023202582A1 (en) 2023-10-26

Family

ID=88360964

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/089013 WO2023202582A1 (en) 2022-04-18 2023-04-18 Gpcr regulator and use thereof

Country Status (2)

Country Link
CN (1) CN116903563A (en)
WO (1) WO2023202582A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130053345A1 (en) * 2010-05-06 2013-02-28 Bristol-Myers Squibb Company Bicyclic heteroarly analogues as gpr119 modulators
US20130059858A1 (en) * 2010-05-06 2013-03-07 Bristol-Myers Squibb Company Benzofuranyl analogues as gpr119 modulators
CN105085450A (en) * 2015-09-14 2015-11-25 中国药科大学 Benzofuran derivatives, and preparation method and therapeutic action thereof
CN109705071A (en) * 2017-10-25 2019-05-03 成都先导药物开发有限公司 Hdac inhibitor and its preparation method and application
US20210095293A1 (en) * 2016-05-05 2021-04-01 The Board Of Regents Of The University Of Texas System Methods of treating cancers with gpr132 inhibitors
CN115215823A (en) * 2021-04-16 2022-10-21 青岛睿吉医疗技术有限公司 FXR (FXR) regulator and preparation method, pharmaceutical composition and application thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130053345A1 (en) * 2010-05-06 2013-02-28 Bristol-Myers Squibb Company Bicyclic heteroarly analogues as gpr119 modulators
US20130059858A1 (en) * 2010-05-06 2013-03-07 Bristol-Myers Squibb Company Benzofuranyl analogues as gpr119 modulators
CN105085450A (en) * 2015-09-14 2015-11-25 中国药科大学 Benzofuran derivatives, and preparation method and therapeutic action thereof
US20210095293A1 (en) * 2016-05-05 2021-04-01 The Board Of Regents Of The University Of Texas System Methods of treating cancers with gpr132 inhibitors
CN109705071A (en) * 2017-10-25 2019-05-03 成都先导药物开发有限公司 Hdac inhibitor and its preparation method and application
CN115215823A (en) * 2021-04-16 2022-10-21 青岛睿吉医疗技术有限公司 FXR (FXR) regulator and preparation method, pharmaceutical composition and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry CAS; 19 December 2022 (2022-12-19), ANONYMOUS : "2-Benzofurancarboxylic acid, 3-methyl-5-[[[2- [4-(trifluoromethyl)- 2- thiazolyl]ethyl]amin o]sulfonyl]-", XP093102445, retrieved from STN Database accession no. 2871435-85-5 *
DATABASE Registry CAS; 24 November 2020 (2020-11-24), ANONYMOUS : "1H-Indole-2-carboxylic a cid, 5-[(cyclopropyla mino)sulfonyl]-3-me thyl-", XP093102447, retrieved from STN Database accession no. 2528192-96-1 *
SHEHATA MOHAMED A., BELCIK CHRISTENSEN HANNA, ISBERG VIGNIR, SEJER PEDERSEN DANIEL, BENDER ANDREAS, BRÄUNER-OSBORNE HANS, GLORIAM : "Identification of the first surrogate agonists for the G protein-coupled receptor GPR132", RSC ADVANCES, vol. 5, no. 60, 1 January 2015 (2015-01-01), pages 48551 - 48557, XP093102140, DOI: 10.1039/C5RA04804D *

Also Published As

Publication number Publication date
CN116903563A (en) 2023-10-20

Similar Documents

Publication Publication Date Title
TWI832962B (en) Heterocyclic compound and use thereof
JP5487202B2 (en) Novel thyroid hormone beta receptor agonist
KR100236806B1 (en) Hydroxamic acid derivative based on aromatic sulfonamide
CN113474338A (en) Pyrazine derivative and application thereof in inhibition of SHP2
TW202220959A (en) Substituted piperidine compound and use thereof
JP5847533B2 (en) Novel thyroid hormone beta receptor agonist
WO2014198195A1 (en) Biaryl-substituted 4-amino-butyric acid derivative, preparation method therefor and uses thereof
WO2005113484A1 (en) Phenyl carboxamide compounds useful as beta-secretase inhibitors for the treatment of alzheimer&#39;s disease
TW202021967A (en) Salts of apoptosis signal-regulating kinase 1 inhibitors and crystalline forms thereof
JPWO2008123207A1 (en) Ornithine derivatives
TW202227433A (en) Medium- or macro-cyclic benzyl-substituted heterocycle derivatives and related uses
WO2020063824A1 (en) Nitroxoline prodrug and use thereof
WO2019117148A1 (en) Sulfonamide derivative or pharmaceutically acceptable acid-addition salt
WO2022268066A1 (en) Protein degradation agent
CN110914248A (en) LXR modulators containing amines or (thio) amides
TWI704139B (en) Hydroxytriazine compound and pharmaceutical use thereof
WO2021244582A1 (en) NOVEL THYROID HORMONE β RECEPTOR AGONIST
WO2023202582A1 (en) Gpcr regulator and use thereof
WO2023202583A1 (en) Fxr regulator and use thereof
JP2022550489A (en) Sulfo-substituted biaryl compound or salt thereof and method for preparation and use thereof
KR20220024199A (en) Heterocycloalkyl compounds as CCR2/CCR5 antagonists
CN112689630A (en) Novel LXR modulators with bicyclic core moieties
BRPI0713988A2 (en) biarylcarboxyarylamides as type 1 vanilloid receptor modulators, pharmaceutical composition comprising them and use of said compounds in the preparation of medicaments
CN110903224A (en) Aryl sulfonamide compound, preparation method thereof, pharmaceutical composition and application
TW201823231A (en) Azabicyclo-substituted triazole derivative, a preparation method therefor, and a pharmaceutical use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23791237

Country of ref document: EP

Kind code of ref document: A1