WO2021012689A1 - 一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用 - Google Patents

一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用 Download PDF

Info

Publication number
WO2021012689A1
WO2021012689A1 PCT/CN2020/079854 CN2020079854W WO2021012689A1 WO 2021012689 A1 WO2021012689 A1 WO 2021012689A1 CN 2020079854 W CN2020079854 W CN 2020079854W WO 2021012689 A1 WO2021012689 A1 WO 2021012689A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
substituted
independently
formula
Prior art date
Application number
PCT/CN2020/079854
Other languages
English (en)
French (fr)
Inventor
王任小
洪然
樊文杰
田杰
李嫣
周宓
李晴
孔文娜
李杨峰
李婕
Original Assignee
中国科学院上海有机化学研究所
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 中国科学院上海有机化学研究所 filed Critical 中国科学院上海有机化学研究所
Publication of WO2021012689A1 publication Critical patent/WO2021012689A1/zh

Links

Images

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/90—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. amino-diphenylethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/257—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings
    • C07C43/29—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/257—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings
    • C07C43/295—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings containing hydroxy or O-metal groups
    • 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
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the invention relates to a phenylthiophene sulfonamide compound, a pharmaceutical composition, a preparation method and application thereof.
  • Targeted anti-tumor drugs currently on the market include small molecule kinase inhibitors and macromolecular monoclonal antibodies, and are mainly used for common cancers with high incidence, such as liver cancer, lung cancer, and gastric cancer.
  • cancers with high incidence such as liver cancer, lung cancer, and gastric cancer.
  • malignant tumors such as cervical cancer, acute leukemia, etc.
  • apoptosis mechanism is closely related to the apoptosis mechanism (Okada, H.; Mak, T.W. Nat. Rev. Cancer 2004, 4, 592-603). Studies have shown that apoptosis mechanisms are inhibited in a variety of tumor cells, and tumor cells can be over-proliferated. In addition, the inhibition of apoptosis mechanisms also makes tumor cells more resistant to chemotherapy drugs (Igney, FH; Krammer, PHNat. Rev. Cancer 2002, 2, 277-288).
  • the Bcl-2 protein family is a key regulator in the apoptosis pathway.
  • Typical anti-apoptotic members such as Bcl-2, Bcl-XL, Mcl-1 and Bcl-W.
  • Venetoclax is currently the only drug molecule approved by the FDA to inhibit Bcl-2, but it has shown drug resistance on tumor cells overexpressing Mcl-1. Therefore, the development of selective inhibitors targeting other anti-apoptotic proteins (such as Mcl-1, Bcl-W, etc.) can be a powerful supplement to the existing anti-tumor treatment methods.
  • the present invention aims to solve the technical problem of lack of specificity of anti-tumor drugs and low killing effect on human cervical cancer cells HeLa, and provides a phenylthiophene sulfonamide compound, pharmaceutical composition, preparation method and application thereof
  • Such compounds can effectively and selectively inhibit Bcl-xL, Bcl-2 or Mcl-1, especially Mcl-1, in the Bcl-2 family of key proteins in the process of apoptosis at the molecular level.
  • they have obvious killing effect and high selectivity against cancer cells, especially human cervical cancer cell HeLa, human acute lymphocytic leukemia cell line RS4;11 or human promyelocytic leukemia cell line HL-60, and have a high selectivity.
  • the potential of new anti-tumor drugs has a good market prospect.
  • the present invention solves the above technical problems through the following technical solutions.
  • the invention provides a phenylthiophene sulfonamide compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • R 1 is C 6 ⁇ C 10 aryl, R 1a substituted C 6 ⁇ C 10 aryl, R 1b substituted C 1 ⁇ C 3 alkyl, C 4 ⁇ C 6 cycloalkyl, or R 1c substituted C 4 ⁇ C 6 cycloalkyl;
  • R 1b is a C 6 ⁇ C 10 aryl group or a C 6 ⁇ C 10 aryl group substituted by R 1b-1 ;
  • R 1a , R 1b-1 and R 1c are independently hydroxy, nitro, halogen, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkyl or halogen substituted C 1 ⁇ C 6 alkyl;
  • the number of R 1a , R 1b , R 1c and R 1b-1 is independently one or more. When the number of R 1a is more than one, the R 1a is the same or different; when the When the number of R 1b is multiple, the R 1b is the same or different; when the number of R 1c is multiple, the R 1c is the same or different; when the number of R 1b-1 is When there are more than one, the R 1b-1 is the same or different;
  • R 2 and R 3 are independently H, C 1 ⁇ C 6 alkyl, or R 2 and R 3 are connected to form a -(CH 2 ) m -structure, and m is 0, 1 or 2;
  • Each R B is independently halogen, nitro, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, or halogen substituted C 1 ⁇ C 6 alkyl;
  • Each R A is independently C 1 ⁇ C 6 alkyl group.
  • n is preferably 2.
  • R 1 is a C 6 ⁇ C 10 aryl group and the substituted R 1a is C 6 ⁇ C 10 aryl group in the C 6 ⁇ C 10 aryl group are independently preferably phenyl or naphthyl, more preferably phenyl base.
  • R 1 the number of R 1a is preferably 1 to 4, and more preferably 1 to 2. When the number of R 1a is plural, it is preferable that R 1a are the same.
  • the C 1 -C 3 alkyl group in the C 1 -C 3 alkyl group substituted by R 1b is preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group (for example, a methyl group).
  • R 1 the number of R 1b is preferably 1 to 2, and more preferably one. When the number of R 1b is plural, it is preferable that R 1b are the same.
  • R 1b, the C 6 ⁇ C 10 aryl group and the substituent R 1b-1 to C 6 ⁇ C 10 aryl group in the C 6 ⁇ C 10 aryl group are independently preferably phenyl.
  • R 1b the number of R 1b-1 is preferably 1 to 4, and more preferably 1 to 2. When the number of R 1b-1 is plural, it is preferable that R 1b-1 are the same.
  • R 1 is a C 4 ⁇ C 6 cycloalkyl group and R 1c substituted C 4 ⁇ C 6 cycloalkyl group, C 4 ⁇ C 6 cycloalkyl group independently preferably is C 5 ⁇ C 6 cycloalkyl, For example, cyclopentyl or cyclohexyl.
  • R 1 the number of R 1c is preferably 1 to 4, and more preferably 1 to 2. When the number of R 1c is plural, it is preferable that R 1c are the same.
  • the C 1 ⁇ C 6 alkoxy group is preferably C 1 ⁇ C 3 alkoxy group, more preferably methoxy group, ethoxy group, n-propoxy group or iso Propoxy (e.g. methoxy).
  • the halogen and the halogen in the halogen-substituted C 1 -C 6 alkyl group are independently preferably fluorine, chlorine, bromine or iodine, and more preferably fluorine.
  • R 1a, R 1b-1 and R 1c, the C 1 ⁇ C 6 alkyl and the halogen substituted C 1 ⁇ C 6 alkyl C 1 ⁇ C 6 alkyl groups is independently preferably C 1 ⁇ C 3 alkyl, more preferably independently methyl, ethyl, n-propyl or isopropyl (e.g. methyl).
  • the halogen-substituted C 1 -C 6 alkyl group is preferably CF 3 .
  • R 1 , R 1a , R 1b-1 and R 1c are independently preferably a hydroxyl group, a nitro group or a C 1 -C 6 alkoxy group (for example, a methoxy group), and further independently are preferably a hydroxyl group or C 1 -C 6 Alkoxy (e.g. methoxy).
  • R 1 is preferably a C 6 ⁇ C 10 aryl group substituted by R 1a (for example, phenyl), a C 1 ⁇ C 3 alkyl group substituted by R 1b (for example, methyl), or R 1c substituted C 4 ⁇ C 6 cycloalkyl (for example, cyclohexyl),
  • R 1b is a C 6 to C 10 aryl group (for example, phenyl) substituted by R 1b-1 , wherein R 1a , R 1b-1 and R 1c are independently preferably hydroxyl , Nitro or C 1 ⁇ C 6 alkoxy (for example, methoxy), further independently preferably hydroxy or C 1 ⁇ C 6 alkoxy (for example, methoxy);
  • R 1 is further preferably substituted by R 1a C 6 -C 10 aryl group (for example, phenyl), wherein R 1a is preferably a hydroxyl group or a C 1 -C 6 alkoxy group; R 1 is more
  • the C 1 -C 6 alkoxy group is preferably a C 1 -C 3 alkoxy group, and more preferably Methoxy, ethoxy, n-propoxy or isopropoxy (e.g. methoxy).
  • R 1-1 , R 1-2 , R 1-3 , R 1-4 and R 1-5 are H
  • R 1- 2 and R 1-3 are independently a hydroxy group or a C 1 -C 6 alkoxy group (for example, a C 1 -C 3 alkoxy group, and another example is a methoxy group).
  • the C 1 to C 6 alkyl group is preferably a C 1 to C 3 alkyl group, more preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group (for example, a methyl group).
  • m is preferably 2.
  • R 2 and R 3 are independently preferably H or a C 1 -C 3 alkyl group (e.g., methyl), and further independently are preferably H.
  • R B are, independently, said halogen and halo-substituted C 1 ⁇ C 6 alkyl group halogen is preferably fluoro, chloro, bromo or iodo, more preferably independently fluorine or chlorine.
  • said C 1 ⁇ C 6 alkyl and halogen-substituted C 1 ⁇ C 6 alkyl C 1 ⁇ C 6 alkyl groups is independently preferably C 1 ⁇ C 3 alkyl group, more preferably independently Methyl, ethyl, n-propyl or isopropyl (e.g. methyl).
  • the C 1 ⁇ C 6 alkoxy group is preferably C 1 ⁇ C 3 alkoxy group, more preferably methoxy group, ethoxy group, n-propoxy group or isopropoxy group (for example, methoxy group ).
  • the halogen-substituted C 1 ⁇ C 6 alkyl group is preferably a fluorine-substituted C 1 ⁇ C 3 alkyl group, more preferably CF 3.
  • q is preferably 1, 2, 3, 4 or 5; more preferably, it is 1 or 2.
  • each R B is independently preferably a halogen, a nitro group, a C 1 ⁇ C 6 alkoxy group (for example, a C 1 ⁇ C 3 alkoxy group, and another example of a methoxy group) or a halogen substituted C 1 ⁇ C 6 alkyl, and q is 1, 2, 3, 4, or 5. It is further independently preferably a halogen or fluorine-substituted C 1 -C 3 alkyl group (for example, CF 3 ), and q is 1 or 2.
  • R 4 , R 6 and R 8 are H
  • R 5 and R 7 are independently halogen, nitro, C 1 ⁇ C 6 alkoxy (such as C 1 ⁇ C 3 alkoxy, and another example of methoxy ) Or halogen-substituted C 1 ⁇ C 6 alkyl; or, R 4 and R 8 are H, and one of R 5 , R 6 and R 7 is halogen, nitro, C 1 ⁇ C 6 alkoxy (for example C 1 ⁇ C 3 alkoxy, for example methoxy) or halogen substituted C 1 ⁇ C 6 alkyl, the other two are H.
  • R 4 , R 6 and R 8 are H, R 5 and R 7 are independently halogen or fluorine substituted C 1 ⁇ C 3 alkyl; or, R 4 and R 8 are H, R 5 , R One of 6 and R 7 is C 1 -C 3 alkoxy (e.g. methoxy) or nitro, and the other two are H.
  • the C 1 ⁇ C 6 alkyl group is preferably C 1 ⁇ C 3 alkyl group, more preferably methyl, ethyl, n-propyl or isopropyl (e.g. methyl or isopropyl).
  • p is preferably 1 or 2; more preferably, it is 1.
  • R 10 and R 11 are a C 1 -C 6 alkyl group, and the other is H; R 9 and R 12 are H; R 1 is defined as described above.
  • R 10 and R 11 is a C 1 -C 3 alkyl group (such as methyl, ethyl, n-propyl or isopropyl), the other is H; R 9 and R 12 are H.
  • n 2
  • R 3 are H.
  • R A is a C 1 -C 3 alkyl group, and p is 1 or 2 (for example, 1).
  • R 2 and R 3 are H, for One of R 10 and R 11 is a C 1 -C 3 alkyl group (for example, methyl, ethyl, n-propyl or isopropyl), the other is H; R 9 and R 12 are H.
  • n 2 and R 3 is H, R 1 is substituted with R 1a is C 6 ⁇ C 10 aryl group (e.g. phenyl), R 1a is hydroxy or C 1 ⁇ C 6 alkoxy group (e.g. methoxy ).
  • R 1 is a C 6 -C 10 aryl group substituted by R 1a (for example, phenyl), R 1a is a hydroxyl group or C 1 -C 6 alkoxy (for example, methoxy), for One of R 10 and R 11 is a C 1 -C 3 alkyl group (for example, methyl, ethyl, n-propyl or isopropyl), the other is H; R 9 and R 12 are H.
  • R 1 is substituted with R 1a is C 6 ⁇ C 10 aryl group (e.g. phenyl), R 1a is hydroxy or C 1 ⁇ C 6 alkoxy group (e.g. methoxy ), for One of R 10 and R 11 is a C 1 -C 3 alkyl group (for example, methyl, ethyl, n-propyl or isopropyl), the other is H; R 9 and R 12 are H.
  • R 2 and R 3 are H
  • R 1 is R 1-1
  • R 1-4 and R 1-5 are H
  • R 1-2 and R 1-3 are independently hydroxyl or C 1 ⁇ C 6 alkoxy (for example, C 1 ⁇ C 3 alkoxy, Another example is methoxy)
  • R 10 and R 11 is a C 1 -C 3 alkyl group (for example, methyl, ethyl, n-propyl or isopropyl), the other is H
  • R 9 and R 12 are H.
  • R 1 is R 1a is a substituted C 6 ⁇ C 10 aryl group (e.g. phenyl), R 1a is hydroxy or C 1 ⁇ C 6 alkoxy
  • R 1a is a hydroxy group
  • each R B is independently a C 1 ⁇ C 3 alkyl group (such as CF 3 ) substituted with halogen or fluorine
  • R 1a is a C 1 ⁇ C 6 alkoxy group.
  • group e.g. methoxy
  • each R B is independently a C 1 -C 3 alkyl group (e.g. CF 3 ) substituted with halogen, nitro or fluorine.
  • R 10 and R 11 is a C 1 -C 3 alkyl group (such as methyl, ethyl, n-propyl or isopropyl), the other is H;
  • R 9 and R 12 are H;
  • each R B Are independently halogen, nitro, C 1 ⁇ C 3 alkoxy (such as methoxy) or fluorine substituted C 1 ⁇ C 3 alkyl (such as CF 3 ), and q is 1, 2, 3, 4 or 5 (e.g. 1 or 2).
  • n 2 and R 3 is H
  • R 1 is substituted with R 1a is C 6 ⁇ C 10 aryl group (e.g. phenyl)
  • R 1a is hydroxy or C 1 ⁇ C 6 alkoxy group (e.g. methoxy )
  • each R B is independently halogen, nitro, C 1 -C 3 alkoxy (e.g. methoxy) or fluorine-substituted C 1 -C 3 alkyl (e.g. CF 3 )
  • q is 1, 2, 3, 4 or 5 (e.g.
  • R 10 and R 11 are H.
  • R 2 and R 3 are H
  • R 1 is for for One of R 10 and R 11 is a C 1 -C 3 alkyl group (for example, methyl, ethyl, n-propyl or isopropyl), the other is H
  • R 9 and R 12 are H.
  • the phenylthiophene sulfonamide compound represented by formula I is any one of the following compounds:
  • the present invention also provides a preparation method of the phenylthiophene sulfonamide compound shown in formula I, which comprises: subjecting compound II and compound III to the following reaction in an organic solvent to obtain the formula The phenylthiophene sulfonamide compound shown in I, that is;
  • R 1, R 2, R 3, R A, R B, p, q, X and n are as defined above.
  • the compound II when the compound II contains a hydroxyl substituent, it is preferable to protect the hydroxyl group before performing the reaction.
  • the amount of the compound II and the compound III can be the conventional amount in the art.
  • the molar ratio of the compound II and the compound III is 1: (1 to 1.5), for example, 1: 1.2.
  • the organic solvent may be a conventional solvent in the field. In the present invention, it is preferably a halogenated alkane, and more preferably methylene chloride.
  • the temperature of the reaction may be a conventional temperature of this type of reaction in the art, and preferably, the reaction is carried out at room temperature.
  • the room temperature refers to 20°C to 30°C.
  • the progress of the reaction can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC or NMR).
  • the reaction end point is when the compound II is no longer reacting, and the reaction time can be 1h-5h.
  • the present invention also provides a compound represented by formula II, IV, V, VI, VII or VIII,
  • R 1, R 2, R 3, R A, p and n are as defined above.
  • the compound represented by formula II is any of the following compounds:
  • the compound represented by formula IV is any of the following compounds:
  • the compound represented by formula V is any of the following compounds:
  • the compound represented by formula VI is any of the following compounds:
  • the compound represented by formula VII is any of the following compounds:
  • the compound represented by formula VIII is the following compound:
  • the present invention also provides a preparation method of the compound II, which includes: subjecting the compound IV to the deprotection reaction shown below in an organic solvent to obtain the compound II;
  • R 1, R 2, R 3, R A, p and n are as defined above.
  • the present invention also provides the use of the phenylthiophene sulfonamide compound represented by formula II or a pharmaceutically acceptable salt thereof in the preparation of a Bcl anti-apoptotic protein inhibitor.
  • the present invention also provides the use of the phenylthiophene sulfonamide compound represented by formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and/or prevention of diseases related to Bcl anti-apoptotic protein application.
  • the "Bcl anti-apoptotic protein” is, for example, one or more of Bcl-xL, Bcl-2 and Mcl-1 proteins.
  • the "disease associated with the Bcl anti-apoptotic protein" is for example cancer; the cancer is for example human cervical cancer or leukemia; the leukemia is for example human acute lymphoblastic leukemia or human protomyelogenous leukemia.
  • the Bcl anti-apoptotic protein inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard or control sample to provide comparison, or according to the book
  • the conventional method in the field makes a kit to provide rapid detection for the inhibitory effect of Bcl anti-apoptotic protein.
  • the present invention also provides the use of the phenylthiophene sulfonamide compound represented by formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and/or prevention of human cervical cancer and/or leukemia .
  • the human cervical cancer cells are, for example, human cervical cancer cells HeLa.
  • the leukemia cells are, for example, human acute lymphocytic leukemia cells RS4; 11 or human promyelocytic leukemia cells HL-60.
  • the present invention further provides a pharmaceutical composition, which comprises the phenylthiophene sulfonamide compound represented by formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.
  • the mass percentage of the phenylthiophene sulfonamide compound shown in formula I or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.1% to 99.9%, and the mass percentage refers to the The phenylthiophene sulfonamide compound represented by formula I or a pharmaceutically acceptable salt thereof accounts for the percentage of the total mass of the pharmaceutical composition.
  • the total mass fraction of the phenylthiophene sulfonamide compound represented by formula I or its pharmaceutically acceptable salt and the pharmaceutical excipients is 100%.
  • the choice of the pharmaceutical excipients varies with the route of administration and the action characteristics, and they are usually fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers or suspending agents.
  • composition of the present invention can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.
  • the pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant Into, subcutaneous, intravenous, intraarterial, intramuscular) administration.
  • the pharmaceutical composition of the present invention can also be a controlled release or delayed release dosage form (for example, liposomes or microspheres).
  • solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets.
  • liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions.
  • topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations.
  • preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
  • suitable preparations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges Agent.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that: the phenylthiophene sulfonamide compound represented by formula II of the present invention or a pharmaceutically acceptable salt thereof can be prepared for treating and/or preventing diseases related to Bcl anti-apoptotic protein Drugs or Bcl anti-apoptotic protein inhibitors, these compounds can effectively and selectively inhibit Bcl-xL, Bcl-2 or Mcl-xL, Bcl-2 or Mcl- 1.
  • human cervical cancer cell HeLa human acute lymphocytic leukemia cell RS4;11 or human promyelocytic leukemia cell HL-60, it presents the advantages of high activity and low toxicity.
  • the phenylthiophene sulfonamide compound is convenient to prepare and has low production cost.
  • FIG 1 shows the effect of compounds on tumor volume in mice
  • Figure 2 shows the effect of compounds on mouse body weight
  • Figure 3 shows the results of Ki67 immunofluorescence staining of frozen sections of tumor tissue under the action of different doses of compounds, in which: (A) solvent group; (B) ABT-199 at a dose of 12.5 mg/kg; (C) compound I-3 at a dose (D) Compound I-3, the dose is 25 mg/kg; (E) Compound I-3, the dose is 50 mg/kg.
  • room temperature mentioned in all the following examples refers to 20°C to 30°C.
  • Ph 3 PCH 3 Br (375mg, 1.05mmol) to a 25ml Shrek tube, ventilate 3 times, add anhydrous tetrahydrofuran (4ml) under an ice-water bath, and slowly add a solution of potassium tert-butoxide in tetrahydrofuran (1.05ml) with stirring. , 1.05mmol), after dropping, move to room temperature and stir for 1h. Drop the tetrahydrofuran solution of 1-(4-(3,4-dimethoxyphenoxy)-3-nitrophenyl)ethyl-1-one (222mg, 0.7mmol) into the reaction system and stir for 3h .
  • N-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)ethyl)-3-(2-(3,4-dimethoxyphenoxy)- 5-isopropylphenyl)thiophen-2-sulfonamide is replaced by N-(2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)ethyl)-3-( 2-(3,4-Dimethoxyphenoxy)-5-isopropylphenyl)thiophene-2-sulfonamide, other required raw materials, reagents and preparation methods are the same as those in Example 33 to obtain product N- (2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)ethyl)-3-(2-(3,4-diphenolyl)-5-isopropylbenzene Yl)thiophene-2-sulfonamide, the yield is 98%.
  • N-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)ethyl)-3-(2-(3,4-dimethoxyphenoxy)- 5-isopropylphenyl)thiophen-2-sulfonamide is replaced by N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-3-(2-(3,4- Dimethoxyphenoxy)-5-isopropylphenyl)thiophene-2-sulfonamide, other required raw materials, reagents and preparation methods are the same as those in Example 33 to obtain the product N-(2-(3-( 4-nitrophenyl)thioureido)ethyl)-3-(2-(3,4-diphenolyl)-5-isopropylphenyl)thiophene-2-sulfonamide, the yield is 90%.
  • N-(2-aminoethyl)-3-(2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenoxy)-4-methylphenyl)thiophene- 2-sulfonamide is replaced by N-(2-aminoethyl)-3-(2-(3,4-bis(tert-butyldimethylsiloxy)phenoxy)phenyl)thiophene-2-sulfon
  • the other required raw materials, reagents and preparation methods are the same as those in Example 10 to obtain the product N-(2-(3-(3,5-ditrifluoromethyl)thioureido)ethyl)-3-(2 -(3,4-Dihydroxyphenoxy)phenyl)thiophene-2-sulfonamide, the yield is 71%.
  • N-(2-aminoethyl)-3-(2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenoxy)-4-methylphenyl)thiophene- 2-sulfonamide is replaced by N-(2-aminoethyl)-3-(2-(3,4-bis(tert-butyldimethylsiloxy)phenoxy)phenyl)thiophene-2-sulfon Amide, replace 3,5-ditrifluoromethylphenyl isothiocyanate with 3,5-dichlorophenyl isocyanate, and other required raw materials, reagents and preparation methods are the same as in Example 10 to obtain product N- (2-(3-(3,5-Dichlorophenyl)ureido)ethyl)-3-(2-(3,4-dimethoxyphenoxy)phenyl)thiophene-2-sulfonamide , The yield is 94%.
  • a Bid BH3 polypeptide with 26 amino acid residues (amino acids 79-104: QEDIIRNIARHLAQVGDSMDRSIPPG) was synthesized, and 6-carboxyfluorescein succinimidyl ester (FAM) was labeled at the N-terminus as a fluorescent label (FAM-Bid).
  • FAM-Bid 6-carboxyfluorescein succinimidyl ester
  • the final concentrations of His-Bcl-X L protein, His-Bcl-2 protein, His-Mcl-1 protein and FAM-Bid polypeptide were 230nM, 425nM, 200nM and 10nM, respectively.
  • the final concentrations of the compounds in the system were 1 nM, 10 nM, 100 nM, 1 ⁇ M, 10 ⁇ M, 50 ⁇ M and 100 ⁇ M, respectively.
  • Two control groups were set up at the same time.
  • One control group was the reaction system containing only Bcl-xL or Bcl-2 or Mcl-1 and FAM-Bid (equivalent to 0% inhibition rate), and the other control group was the reaction system containing only FAM-Bid polypeptide.
  • the protein inhibition rate was calculated based on the measurement results of the control group and the polarization value of the tested compound.
  • [I] 50 is the compound concentration when the protein inhibition rate is 50%
  • [L] 50 is the free FAM-Bid concentration when the protein inhibition rate is 50%
  • K d is the dissociation of the target protein from the FAM-Bid polypeptide
  • [P] 0 is the free protein concentration when the protein inhibition rate is 0%.
  • N.A means that there is basically no affinity.
  • test results in Table 1 show that the compound of the present invention has a significant affinity for at least one of Bcl-xL, Bcl-2 and Mcl-1, and some compounds show selectivity for Mcl-1 protein.
  • the human cervical cancer cells HeLa, human acute lymphocytic leukemia cells RS4; 11 and human promyelocytic leukemia cells HL-60 to be tested will be cultured in RPMI1640 medium containing 10% fetal bovine serum, and human embryonic kidney cells 293T cells will be cultured with DMEM culture medium with 10% fetal bovine serum. Seed cells in a 96-well culture plate.
  • the cell concentration of RS4; 11 and HL-60 was 16000 cells/50 ⁇ L, and the concentration of HeLa and 293T cells was 8000 cells/100 ⁇ L; the zero adjustment group only added medium.
  • test results in Table 2 show that the compound of the present invention has a significant improvement in the proliferation inhibition effect on HeLa cells.
  • test results in Table 3 show that the compounds of the present invention show significant proliferation inhibition effects on two acute leukemia cell lines, and the inhibitory effects of some compounds on human promyelocytic leukemia cell line HL-60 are 4-6 that of normal cells. Times, showing good selectivity.
  • test compound (set two different concentrations of 10 ⁇ M and 20 ⁇ M) with human acute lymphoblastic leukemia cells RS4;11 for 48 hours. Then centrifuge at 1000rpm for 5 minutes, discard the supernatant, collect the cells, gently resuspend the cells in ice PBS and count.
  • Annexin V-FITC is green fluorescence
  • PI is red fluorescence
  • the cells appear in the corresponding position by adjusting the relevant settings and parameters of the flow cytometer. Count the percentage of cells in each area. The specific results are shown in Table 4.
  • test results in Table 4 show that the compound of the present invention has a better effect on promoting the apoptosis of human acute lymphoblastic leukemia cells RS4;11.
  • the cell line RS4;11 cells in the logarithmic growth phase were digested, centrifuged, discarded the old medium, and resuspended in PBS.
  • the random number table is used to group the mice, and the mice are weighed at the same time. There should be no statistical difference in body weight.
  • Nine nude mice with good growth conditions were randomly selected as the solvent group, and the others were the experimental group; the solvent group was administered 60% PEG400; the experimental group was administered 12.5 mg/kg, 25 mg/kg and 50 mg/kg.
  • the cycle is once every other day, and the mode of administration is intraperitoneal administration.
  • the experimental results are shown in Figure 1 and Figure 2.
  • Compound I-3 can significantly inhibit the growth of tumor volume and is dose-dependent. Compared with the solvent group at the highest dose of 50mg/kg, the tumor shrinks by about 3/4, and There is no effect on the weight of the mice.
  • the tumor tissue is taken and frozen sectioned, it is used for immunofluorescence staining. Wash the sections with PBS for 3 ⁇ 5 min. Place the citric acid solution in a beaker, wrap the mouth of the beaker with tin foil, and boil on high heat in a microwave oven for about 5 minutes. Place the slices on the cutting rack until the solution continues to boil for 10 minutes. Take out the beaker and leave the slices in the solution until the solution in the beaker cools naturally to room temperature for about 2 hours. Wash with PBS for 3 ⁇ 5min. Add a drop of immunohistochemical blocking solution to the tissue section and block for 1 hour at room temperature. Absorb the liquid and configure the primary antibodies according to the working concentration.
  • Ki67 in tumors from the solvent group was significantly higher than that in the compound I-3 administration group (low-dose group (12.5mg/kg), medium-dose group (25mg/kg) and high-dose group (50mg/kg).
  • the expression level of Ki67 in each dose group After compound I-3 was added, Ki67 expression decreased in a concentration-dependent manner, indicating that compound I-3 can attenuate the proliferation of RS4;11 xenograft tumors.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明公开了一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用。本发明化合物能够在分子水平上有效地、选择性地抑制细胞凋亡过程中的关键蛋白Bcl-2家族中的Bcl-xL、Bcl-2或Mcl-1，尤其是Mcl-1。同时，它们对癌细胞，尤其是人子宫颈癌细胞HeLa、人急性淋巴细胞白血病细胞株RS4；11或人原髓细胞白血病细胞株HL-60具有明显的杀伤作用和高选择性，具有制备成为新型抗肿瘤药物的潜力，具有较好的市场化前景。

Description

一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用
本申请要求申请日为2019年7月19日的中国专利申请201910655053X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用。
背景技术
近年来，受到环境变化、生存压力增大等多种客观因素的影响，癌症(即恶性肿瘤)的发病率不断上升，预计将取代心血管疾病成为全球第一大死亡原因。在此大背景下，抗肿瘤药物市场急速发展。传统的抗肿瘤药物以细胞毒类药物和激素类药物为主，缺乏特异性，有较大的副作用。靶向药物针对特定靶点产生作用，可以根据病人的情况选用合适的靶向药物，一定程度上实现对肿瘤的个性化治疗。靶向抗肿瘤药物的研发与临床应用已经成为该行业的主要发展方向之一。
目前已上市的靶向抗肿瘤药物包括小分子激酶抑制剂和大分子单克隆抗体，并且主要用于发病率较高的常见癌症，如肝癌、肺癌、胃癌等。对于相对小众的恶性肿瘤(如宫颈癌、急性白血病等)，上市药物种类相对较少。因此，亟需开发一批针对新靶点的抗肿瘤药物，发展新的抗肿瘤治疗方法。
从上世纪90年代以来，人们逐渐认识到肿瘤的发生与细胞凋亡机制密切相关(Okada,H.；Mak,T.W.Nat.Rev.Cancer2004,4,592-603)。研究表明在多种肿瘤细胞中凋亡机制被抑制，肿瘤细胞因而得以过度增生；另外，凋亡机制被抑制也使得肿瘤细胞对化疗药物的耐受性增强(Igney,F.H.；Krammer,P.H.Nat.Rev.Cancer2002,2,277-288)。因此，以细胞凋亡过程中的关键调控因子为分子靶标，设法恢复肿瘤细胞中的凋亡机制，已成为近二十年来抗肿瘤药物发展的新策略(Reed，J.C.Nat.Rev.Drug Discov.2002,1,111-121；Andersen,M.H.；Becker,J.C.；Straten,P.Nat.Rev.DrugDiscov.2005,4,399-409；Belmar,J.；Fesik,S.W.Pharmacol.Therapeut.2015,145,76-84；Pelz,N.F.；Bian,Z.et al.J.Med.Chem.2016,59,2054-2066.)。Bcl-2蛋白家族是细胞凋亡通路中的一类关键调控因子。典型的抗凋亡成员如Bcl-2、Bcl-XL、Mcl-1和Bcl-W等。Venetoclax是目前唯一一个被FDA批准的抑制Bcl-2的药物分子，但它在Mcl-1过表达的肿瘤细胞上表现出抗药性。因此，发展靶向其他抗凋亡蛋白(如Mcl-1，Bcl-W等)的选择性抑制剂可以作为现有的抗肿瘤治疗方法的有力补充。
发明内容
本发明所要解决的是抗肿瘤药物缺乏特异性、对人子宫颈癌细胞HeLa杀伤作用较低的技术问题，而提供了一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用，该类化合物能够在分子水平上有效地、选择性地抑制细胞凋亡过程中的关键蛋白Bcl-2家族中的Bcl-xL、Bcl-2或Mcl-1，尤其是Mcl-1。同时，它们对癌细胞，尤其是人子宫颈癌细胞HeLa、人急性淋巴细胞白血病细胞株RS4；11或人原髓细胞白血病细胞株HL-60具有明显的杀伤作用和高选择性，具有制备成为新型抗肿瘤药物的潜力，具有较好的市场化前景。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐，
Figure PCTCN2020079854-appb-000001
其中，X为O或S；n为1或2；p为1、2、3或4；q为0、1、2、3、4或5；
R 1为C 6～C 10芳基、R 1a取代的C 6～C 10芳基、R 1b取代的C 1～C 3烷基、C 4～C 6环烷基或R 1c取代的C 4～C 6环烷基；
R 1b为C 6～C 10芳基或R 1b-1取代的C 6～C 10芳基；
R 1a、R 1b-1和R 1c独立地为羟基、硝基、卤素、C 1～C 6烷氧基、C 1～C 6烷基或卤素取代的C 1～C 6烷基；
所述R 1a、R 1b、R 1c和R 1b-1的个数独立地为一个或多个，当所述R 1a的个数为多个时，所述R 1a相同或不同；当所述R 1b的个数为多个时，所述R 1b相同或不同；当所述R 1c的个数为多个时，所述R 1c相同或不同；当所述R 1b-1的个数为多个时，所述R 1b-1相同或不同；
R 2和R 3独立地为H、C 1～C 6烷基、或R 2和R 3连接形成-(CH 2) m-结构，m为0、1或2；
每个R B独立地为卤素、硝基、C 1～C 6烷基、C 1～C 6烷氧基或卤素取代的C 1～C 6烷基；
每个R A独立地为C 1～C 6烷基。
式I中，n优选为2。
R 1中，所述C 6～C 10芳基和所述R 1a取代的C 6～C 10芳基中的C 6～C 10芳基独立地优选为苯基或萘基，进一步优选为苯基。
R 1中，所述R 1a的个数优选为1～4个，进一步优选为1～2个。当所述R 1a的个数为多个时，优选为R 1a相同。
R 1中，所述R 1b取代的C 1～C 3烷基中的C 1～C 3烷基优选为甲基、乙基、正丙基或异丙基(例如甲基)。
R 1中，所述R 1b的个数优选为1～2个，进一步优选为1个。当所述R 1b的个数为多个时，优选为R 1b相同。
R 1b中，所述C 6～C 10芳基和所述R 1b-1取代的C 6～C 10芳基中的C 6～C 10芳基独立地优选为苯基。
R 1b中，所述R 1b-1的个数优选为1～4个，进一步优选为1～2个。当所述R 1b-1的个数为多个时，优选为R 1b-1相同。
R 1中，所述C 4～C 6环烷基和R 1c取代的C 4～C 6环烷基中的C 4～C 6环烷基独立地优选为C 5～C 6环烷基，例如环戊基或环己基。
R 1中，所述R 1c的个数优选为1～4个，进一步优选为1～2个。当所述R 1c的个数为多个时，优选为R 1c相同。
R 1a、R 1b-1和R 1c中，所述C 1～C 6烷氧基优选为C 1～C 3烷氧基，进一步优选为甲氧基、乙氧基、正丙氧基或异丙氧基(例如甲氧基)。
R 1a、R 1b-1和R 1c中，所述卤素和所述卤素取代的C 1～C 6烷基中的卤素独立地优选为氟、氯、溴或碘，进一步优选为氟。
R 1a、R 1b-1和R 1c中，所述C 1～C 6烷基和所述卤素取代的C 1～C 6烷基中的C 1～C 6烷基独立地优选为C 1～C 3烷基，进一步独立地优选为甲基、乙基、正丙基或异丙基(例如甲基)。
R 1a、R 1b-1和R 1c中，所述卤素取代的C 1～C 6烷基优选为CF 3。
R 1中，R 1a、R 1b-1和R 1c独立地优选为羟基、硝基或C 1～C 6烷氧基(例如甲氧基)，进一步独立地优选为羟基或C 1～C 6烷氧基(例如甲氧基)。
式I中，R 1优选为R 1a取代的C 6～C 10芳基(例如苯基)、R 1b取代的C 1～C 3烷基(例如甲基)、或R 1c取代的C 4～C 6环烷基(例如环己基)，R 1b为R 1b-1取代的C 6～C 10芳基(例如苯基)，其中，R 1a、R 1b-1和R 1c独立地优选为羟基、硝基或C 1～C 6烷氧基(例如甲氧基)，进一步独立地优选为羟基或C 1～C 6烷氧基(例如甲氧基)；R 1进一步优选为R 1a取代的C 6～C 10芳基(例如苯基)，其中，R 1a优选为羟基或C 1～C 6烷氧基；R 1更优选为
Figure PCTCN2020079854-appb-000002
其中，R 1-1、R 1-2、R 1-3、R 1-4和R 1-5独立地为H、羟基或C 1～C 6烷氧基，且R 1-1、R 1-2、R 1-3、R 1-4和R 1-5不同时为H。
R 1-1、R 1-2、R 1-3、R 1-4和R 1-5中，所述C 1～C 6烷氧基优选为C 1～C 3烷氧基，进一步优选为甲氧基、乙氧基、正丙氧基或异丙氧基(例如甲氧基)。
R 1-1、R 1-2、R 1-3、R 1-4和R 1-5中，较佳地，R 1-1、R 1-4和R 1-5为H，R 1-2和R 1-3独立地为羟基或C 1～C 6烷氧基(例如C 1～C 3烷氧基，再例如甲氧基)。更佳地，
Figure PCTCN2020079854-appb-000003
为
Figure PCTCN2020079854-appb-000004
R 2和R 3中，所述C 1～C 6烷基优选为C 1～C 3烷基，进一步优选为甲基、乙基、正丙基或异丙基(例如甲基)。
当R 2和R 3连接形成-(CH 2) m-结构时，m优选为2。
式I中，R 2和R 3独立地优选为H或C 1～C 3烷基(例如甲基)，进一步独立地优选为H。
R B中，所述卤素和卤素取代的C 1～C 6烷基时中的卤素独立地优选为氟、氯、溴或碘，进一步独立地优选为氟或氯。
R B中，所述C 1～C 6烷基和卤素取代的C 1～C 6烷基中的C 1～C 6烷基独立地优选为C 1～C 3烷基，进一步独立地优选为甲基、乙基、正丙基或异丙基(例如甲基)。
R B中，所述C 1～C 6烷氧基优选为C 1～C 3烷氧基，进一步优选为甲氧基、乙氧基、正丙氧基或异丙氧基(例如甲氧基)。
R B中，所述卤素取代的C 1～C 6烷基优选为氟取代的C 1～C 3烷基，进一步优选为CF 3。
式I中，q优选为1、2、3、4或5；进一步优选为1或2。
式I中，每个R B独立地优选为卤素、硝基、C 1～C 6烷氧基(例如C 1～C 3烷氧基，再例如甲氧基)或卤素取代的C 1～C 6烷基，且q为1、2、3、4或5。进一步独立地优选为卤素、或氟取代的C 1～C 3烷基(例如CF 3)，且q为1或2。
进一步地，
Figure PCTCN2020079854-appb-000005
为
Figure PCTCN2020079854-appb-000006
其中，R 4、R 6和R 8为H，R 5和R 7独立地为卤素、硝基、C 1～C 6烷氧基(例如C 1～C 3烷氧基，再例如甲氧基)或卤素取代的C 1～C 6烷基；或，R 4和R 8为H，R 5、R 6和R 7中的一个为卤素、硝基、C 1～C 6烷氧基(例如C 1～C 3烷氧基，再例如甲氧基)或卤素取代的C 1～C 6烷基，另外两个为H。
更进一步地，R 4、R 6和R 8为H，R 5和R 7独立地为卤素或氟取代的C 1～C 3烷基；或，R 4和R 8为H，R 5、R 6和R 7中的一个为C 1～C 3烷氧基(例如甲氧基)或硝基，另外两个为H。
式I中，
Figure PCTCN2020079854-appb-000007
优选为
Figure PCTCN2020079854-appb-000008
Figure PCTCN2020079854-appb-000009
R A中，所述C 1～C 6烷基优选为C 1～C 3烷基，进一步优选为甲基、乙基、正丙基或异丙基(例如甲基或异丙基)。
式I中，p优选为1或2；进一步优选为1。
进一步地，
Figure PCTCN2020079854-appb-000010
为
Figure PCTCN2020079854-appb-000011
其中，R 10和R 11中的一个为C 1～C 6烷基，另一个为H；R 9和R 12为H；R 1的定义如前所述。
更进一步地，R 10和R 11中的一个为C 1～C 3烷基(例如甲基、乙基、正丙基或异丙基)，另一个为H；R 9和R 12为H。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
n为2，R 2和R 3为H。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
R A为C 1～C 3烷基，p为1或2(例如1)。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
n为2，R 2和R 3为H，
Figure PCTCN2020079854-appb-000012
为
Figure PCTCN2020079854-appb-000013
R 10和R 11中的一个为C 1～C 3烷基(例如甲基、乙基、正丙基或异丙基)，另一个为H；R 9和R 12为H。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
n为2，R 2和R 3为H，R 1为R 1a取代的C 6～C 10芳基(例如苯基)，R 1a为羟基或C 1～C 6烷氧基(例如甲氧基)。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
R 1为R 1a取代的C 6～C 10芳基(例如苯基)，R 1a为羟基或C 1～C 6烷氧基(例如甲氧基)，
Figure PCTCN2020079854-appb-000014
为
Figure PCTCN2020079854-appb-000015
R 10和R 11中的一个为C 1～C 3烷基(例如甲基、乙基、正丙基或异丙基)，另一个为H；R 9和R 12为H。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
n为2，R 2和R 3为H，R 1为R 1a取代的C 6～C 10芳基(例如苯基)，R 1a为羟基或C 1～C 6烷氧基(例如甲氧基)，
Figure PCTCN2020079854-appb-000016
为
Figure PCTCN2020079854-appb-000017
R 10和R 11中的一个为C 1～C 3烷基(例如甲基、乙基、正丙基或异丙基)，另一个为H；R 9和R 12为H。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
n为2，R 2和R 3为H，R 1为
Figure PCTCN2020079854-appb-000018
R 1-1、R 1-4和R 1-5为H，R 1-2和R 1-3独 立地为羟基或C 1～C 6烷氧基(例如C 1～C 3烷氧基，再例如甲氧基)，
Figure PCTCN2020079854-appb-000019
为
Figure PCTCN2020079854-appb-000020
R 10和R 11中的一个为C 1～C 3烷基(例如甲基、乙基、正丙基或异丙基)，另一个为H；R 9和R 12为H。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
q为1、2、3、4或5(例如1或2)；R 1为R 1a取代的C 6～C 10芳基(例如苯基)，R 1a为羟基或C 1～C 6烷氧基(例如甲氧基)，当R 1a为羟基时，每个R B独立地为卤素或氟取代的C 1～C 3烷基(例如CF 3)；R 1a为C 1～C 6烷氧基(例如甲氧基)时，每个R B独立地为卤素、硝基或氟取代的C 1～C 3烷基(例如CF 3)。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2020079854-appb-000021
为
Figure PCTCN2020079854-appb-000022
R 10和R 11中的一个为C 1～C 3烷基(例如甲基、乙基、正丙基或异丙基)，另一个为H；R 9和R 12为H；每个R B独立地为卤素、硝基、C 1～C 3烷氧基(例如甲氧基)或氟取代的C 1～C 3烷基(例如CF 3)，且q为1、2、3、4或5(例如1或2)。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
n为2，R 2和R 3为H，R 1为R 1a取代的C 6～C 10芳基(例如苯基)，R 1a为羟基或C 1～C 6烷氧基(例如甲氧基)，每个R B独立地为卤素、硝基、C 1～C 3烷氧基(例如甲氧基)或氟取代的C 1～C 3烷基(例如CF 3)，且q为1、2、3、4或5(例如1或2)；
Figure PCTCN2020079854-appb-000023
为
Figure PCTCN2020079854-appb-000024
R 10和R 11中的一个为C 1～C 3烷基(例如甲基、乙基、正丙基或异丙基)， 另一个为H；R 9和R 12为H。
在某一方案中，如式I所示的苯基噻吩磺酰胺类化合物某些基团的定义如下，未定义的基团如前任一方案所述：
n为2，R 2和R 3为H，R 1为
Figure PCTCN2020079854-appb-000025
为
Figure PCTCN2020079854-appb-000026
Figure PCTCN2020079854-appb-000027
为
Figure PCTCN2020079854-appb-000028
R 10和R 11中的一个为C 1～C 3烷基(例如甲基、乙基、正丙基或异丙基)，另一个为H；R 9和R 12为H。
较佳地，所述式I所示的苯基噻吩磺酰胺类化合物为如下任一化合物：
Figure PCTCN2020079854-appb-000029
Figure PCTCN2020079854-appb-000030
本发明还提供了所述如式I所示的苯基噻吩磺酰胺类化合物的制备方法，其包括：在有机溶剂中，将化合物II和化合物III进行如下所示的反应，得到所述的式I所示的苯基噻吩磺酰胺类化合物，即可；
Figure PCTCN2020079854-appb-000031
其中，R 1、R 2、R 3、R A、R B、p、q、X和n的定义均如上所述。
所述制备方法中，当化合物II中含有羟基取代基时，优选为对羟基进行保护后再进行所述的反应。
所述制备方法中，所述化合物II和化合物III的用量可为本领域常规的用量，较佳地，所述化合物II和化合物III的摩尔比为1：(1～1.5)，例如为1：1.2。
所述制备方法中，所述有机溶剂可为本领域常规的溶剂，本发明优选为卤代烷烃，进一步优选为二氯甲烷。
所述制备方法中，所述反应的温度可为本领域此类反应的常规温度，较佳的，所述反应在室温下进行。本发明中，所述室温是指20℃～30℃。
所述反应的进程可采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以化合物II不再反应时为反应终点，反应时间可为1h～5h。
本发明还提供了一种如式II、IV、V、VI、VII或VIII所示的化合物，
Figure PCTCN2020079854-appb-000032
其中，R 1、R 2、R 3、R A、p和n的定义均如上所述。
较佳地，所述式II所示的化合物为如下任一化合物：
Figure PCTCN2020079854-appb-000033
较佳地，所述式IV所示的化合物为如下任一化合物：
Figure PCTCN2020079854-appb-000034
较佳地，所述式V所示的化合物为如下任一化合物：
Figure PCTCN2020079854-appb-000035
较佳地，所述式VI所示的化合物为如下任一化合物：
Figure PCTCN2020079854-appb-000036
较佳地，所述式VII所示的化合物为如下任一化合物：
Figure PCTCN2020079854-appb-000037
较佳地，所述式VIII所示的化合物为如下化合物：
Figure PCTCN2020079854-appb-000038
本发明还提供了所述化合物II的制备方法，其包括：在有机溶剂中，将化合物IV进行如下所示的脱保护反应，得到所述的化合物II，即可；
Figure PCTCN2020079854-appb-000039
其中，R 1、R 2、R 3、R A、p和n的定义均如上所述。
本发明还提供了所述如式II所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐在制备Bcl抗凋亡蛋白抑制剂中的应用。
本发明还提供了所述如式II所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐在制备用于治疗和/或预防与Bcl抗凋亡蛋白相关的疾病的药物中的应用。
所述的“Bcl抗凋亡蛋白”例如Bcl-xL、Bcl-2和Mcl-1蛋白中的一种或多种。
所述的“与Bcl抗凋亡蛋白相关的疾病”例如癌症；所述的癌症例如人子宫颈癌或白血病；所述的白血病例如人急性淋巴细胞白血病或人原髓细胞白血病。
在所述的应用中，所述的Bcl抗凋亡蛋白抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为Bcl抗凋亡蛋白抑制效果提供快速检测。
本发明还提供了所述如式II所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐在制备用于治疗和/或预防人子宫颈癌和/或白血病的药物中的应用。
所述人子宫颈癌细胞例如人子宫颈癌细胞HeLa。
所述的白血病的细胞例如人急性淋巴细胞白血病细胞RS4；11或人原髓细胞白血病细胞HL-60。
本发明进一步还提供了一种药物组合物，其包括所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐，和至少一种药用辅料。
所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐在药物组合物中的质量百分比为0.1％-99.9％，所述的质量百分比是指所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐占药物组合物总质量的百分比。所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐与所述的药用辅料的质量分数之和为100％。所述的药用辅料的选择因施用途径和作用特点而异，通常是填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、乳化剂或助悬剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药，包括注射(静脉内)、粘膜、口服(固体 和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的如式II所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐可制备用于治疗和/或预防与Bcl抗凋亡蛋白相关的疾病的药物或Bcl抗凋亡蛋白抑制剂，该类化合物能够在分子水平上有效地、选择性地抑制细胞凋亡过程中的关键蛋白Bcl-2家族中的Bcl-xL、Bcl-2或Mcl-1。同时，对人子宫颈癌细胞HeLa、人急性淋巴细胞白血病细胞RS4；11或人原髓细胞白血病细胞HL-60而言，其呈现活性高、毒性低等优点。另外，该苯基噻吩磺酰胺类化合物制备方便、生产成本低。
附图说明
图1为化合物对小鼠肿瘤体积的影响；
图2为化合物对小鼠体重的影响；
图3为不同剂量化合物作用下肿瘤组织冷冻切片的Ki67免疫荧光染色结果，其中：(A)溶剂组；(B)ABT-199，剂量为12.5mg/kg；(C)化合物I-3，剂量为12.5mg/kg；(D)化合物I-3，剂量为25mg/kg；(E)化合物I-3，剂量为50mg/kg。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照 商品说明书选择。
除非另有特别说明，以下所有实施例中所提到的室温是指20℃～30℃。
实施例1 2-(3,4-二甲氧基苯氧基)-4-甲基-1-硝基苯
Figure PCTCN2020079854-appb-000040
25ml蛋形瓶中加入3,4-二甲氧基苯酚(200mg，1.29mmol)，60％氢化钠(79mg，1.98mmol)，四氢呋喃(3ml)及3氟-4-硝基甲苯(181.4mg，1.17mmol)，搅拌下加热回流3h。冰水浴下缓慢加水淬灭反应。浓缩除去四氢呋喃，加入水(3ml)，二氯甲烷(3ml)萃取3次。干燥，过滤，浓缩。石油醚：乙酸乙酯＝25:1柱层析得黄色固体2-(3,4-二甲氧基苯氧基)-4-甲基-1-硝基苯(288mg,85％)。
1HNMR(400MHz,Acetone-d 6)δ7.88(d,J＝8.3Hz,1H),7.09(d,J＝8.3Hz,1H),6.98(d,J＝8.7Hz,1H),6.88(s,1H),6.81(d,J＝2.7Hz,1H),6.60(dd,J＝8.7,2.8Hz,1H),3.82(s,3H),3.81(s,3H),2.35(s,3H)。
13CNMR(100MHz,CDCl 3)δ151.8,150.0,148.8,146.2,145.9,125.8,123.1,119.3,111.6,111.1,104.6,56.2,56.0,21.7。
ESI-MS m/z 290.05(M+H) +。
实施例2 2-(3,4-二甲氧基苯氧基)-4-甲基苯胺
Figure PCTCN2020079854-appb-000041
100ml蛋形瓶中加入2-(3,4-二甲氧基苯氧基)-4-甲基-1-硝基苯(2.11g，7.66mmol),10％Pd/C(211mg)，乙醇(25ml)，氮气保护下加入水合肼(0.7ml)，室温搅拌过夜。硅藻土过滤掉Pd/C，浓缩除去乙醇，加入水(25ml)，乙酸乙酯(25ml)萃取3次。干燥，过滤，浓缩。得淡黄色固体2-(3,4-二甲氧基苯氧基)-4-甲基苯胺(1.85g，93％)。
1HNMR(400MHz,Acetone-d 6)δ6.85(d,J＝8.7Hz,1H),6.76–6.65(m,3H),6.59(s,1H),6.39(dd,J＝8.7,2.8Hz,1H),4.30(s,2H),3.77(s,3H),3.76(s,3H),2.14(s,3H)。
13CNMR(100MHz,CDCl 3)δ151.0,149.8,144.9,144.3,135.3,128.5,124.5,119.3,116.4,111.7,108.7,103.1,56.3,55.9,20.6。
ESI-MS m/z 260.05(M+H) +。
实施例3 2-(3,4-二甲氧基苯氧基)-1-碘-4-甲基苯
Figure PCTCN2020079854-appb-000042
将250ml蛋形瓶置于冰水浴中，向其中加入2-(3,4-二甲氧基苯氧基)-4-甲基苯胺(2.03g，7.8mmol)，浓硫酸(1.24ml溶于30ml水中，23.4mmol)，搅拌下缓慢滴加亚硝酸钠溶液(1.06g，15.6mmol)，保持冰水浴搅拌1h；冰水浴下缓慢滴加碘化钾水溶液(2.58g，15.6mmol)；0.5h后去掉冰水浴，搅拌1h。加入二氯甲烷(100ml)萃取3次；硫代硫酸钠洗涤，干燥，过滤，浓缩。石油醚:乙酸乙酯＝10:1柱层析得白色固体2-(3,4-二甲氧基苯氧基)-1-碘-4-甲基苯(2.26g，78％)。
1HNMR(400MHz,Acetone-d 6)δ7.73(d,J＝8.0Hz,1H),6.93(d,J＝8.7Hz,1H),6.72(m,3H),6.45(dd,J＝8.7,2.7Hz,1H),3.81(s,3H),3.80(s,3H),2.24(s,3H)。
13CNMR(100MHz,CDCl 3)δ157.2,150.3,149.9,145.5,140.0,139.2,129.3,125.7,118.6,111.5,110.2,104.1,56.2,55.9,21.1。
ESI-MS m/z 370.90(M+H) +,392.90(M+Na) +。
实施例4 4-(2-碘-5-甲基苯氧基)苯-1,2-二醇
Figure PCTCN2020079854-appb-000043
将100ml蛋形瓶置于冰水浴下，向其中加2-(3,4-二甲氧基苯氧基)-1-碘-4-甲基苯(2.16g，5.83mmol)，二氯甲烷(45ml)，氮气保护下加入三溴化硼的二氯甲烷溶液(18ml，17.49mmol)，五分钟后撤掉冰水浴，搅拌1h。缓慢加水淬灭反应，二氯甲烷萃取(50ml)3次，干燥，过滤，浓缩，得无色油状物4-(2-碘-5-甲基苯氧基)苯-1,2-二醇(1.7g，98％)。
1HNMR(400MHz,Acetone-d 6)δ8.09(s,1H),7.82(s,1H),7.71(d,J＝8.0Hz,1H),6.76-6.73(m,3H),6.52(d,J＝2.8Hz,1H),6.35(dd,J＝8.6,2.7Hz,1H),2.24(s,3H)。
ESI-MS m/z 340.85(M-H) +。
实施例5 2-(3,4-二(叔丁基二甲基硅氧基)苯氧基)碘苯
Figure PCTCN2020079854-appb-000044
向250ml蛋形瓶中加入4-(2-碘-5-甲基苯氧基)苯-1,2-二醇(1.99g，5.83mmol)，冰水浴下加入二氯甲烷(45ml)，咪唑(873mg，12.826mmol)，DMAP(213mg，1.749mmol)，缓慢加入TBSCl(1.93g，12.826mmol)，撤掉冰水浴，反应2h。加入水(45ml)，二氯甲烷(45ml)萃取3次，干燥，过滤，浓缩。纯石油醚柱层析得无色油状液体2-(3,4-二(叔丁基二甲基硅氧基)苯氧基)碘苯(2.13g，65％)。
1HNMR(400MHz,Acetone-d 6)δ7.22(t,J＝7.8Hz,1H),6.93–6.87(m,2H),6.78(s,1H),6.53(dd,J＝6.6,2.9Hz,2H),2.29(s,3H),1.01(s,9H),0.98(s,9H),0.23(s,6H),0.20(s,6H)。
13CNMR(100MHz,CDCl 3)δ158.2,150.4,147.4,143.1,139.6,129.2,123.2,121.1,118.3,114.7,113.0,112.2,25.9,25.9,21.4,18.4,18.4,-4.1,-4.2。
ESI-MS m/z 571.10(M+H) +。
实施例6 2-(3,4-二((叔丁基二甲基甲硅烷基)氧基)苯氧基)-4-甲基苯基)硼酸
Figure PCTCN2020079854-appb-000045
向100ml蛋形瓶中加入2-(3,4-二(叔丁基二甲基硅氧基)苯氧基)碘苯(2.13g，3.73mmol)，充分抽换气除氧除水氩气保护下加入无水THF(15ml)，在-78℃氩气保护下缓慢滴加正丁基锂溶液(2.5M，2.98ml,7.46mmol)，反应1h后，在-78℃下一次性加入硼酸三甲酯(1.04ml，9.32mmol)，2h后将反应管移至室温搅拌过夜。加入盐酸(1N,15ml)，二氯甲烷(15ml)萃取3次。干燥，过滤，浓缩。石油醚：乙酸乙酯＝20:1柱层析得白色固体2-(3,4-二((叔丁基二甲基甲硅烷基)氧基)苯氧基)-4-甲基苯基)硼酸(917mg，70％)。
1HNMR(400MHz,Acetone-d 6)δ7.76(d,J＝7.6Hz,1H),6.96–6.91(m,3H),6.65–6.60(m,2H),6.56(s,1H),2.24(s,3H),1.02(s,9H),0.99(s,9H),0.24(s,6H),0.21(s,6H)。
13CNMR(100MHz,CDCl 3)δ164.2,148.5,147.6,144.2,143.4,136.6,123.4,121.3,115.7,114.0,113.4,25.9,25.8,21.6,18.4,18.4,-4.1,-4.2。
ESI-MS m/z 487.15(M-H) +。
实施例7 2-(3-溴,2-噻吩基)磺酰胺基N-Boc乙胺
Figure PCTCN2020079854-appb-000046
向20ml蛋形瓶中加入N-Boc保护2-氨基乙胺138.6mg(0.86mmol)，CH 2Cl 23ml,三乙胺0.16ml(1.12mmol)，在冰浴搅拌下缓慢加入3-溴,2-噻吩基氯化砜200.8mg(0.77mmol)。5分钟后移至室温搅拌一个小时。停止搅拌。加水50ml,CH 2Cl 2100ml×3萃取,干燥、过滤、浓缩得产物2-(3-溴,2-噻吩基)磺酰胺基N-Boc乙胺(淡黄色固体,290.1mg,产率为98.1％)。
1H NMR(400MHz,CDCl 3)δ7.51(d,J＝5.2Hz,1H),7.11(d,J＝5.2Hz,1H),5.66(s,1H),4.83(s,1H),3.28(dd,J＝11.2,5.6Hz,2H),3.17(dd,J＝11.4,5.8Hz,2H),1.48(s,9H)。
ESI-MS m/z,407.1(M+Na) +。
实施例8(2-((3-(2-(3,4-双((叔丁基二甲基甲硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩)-2-磺酰氨基)乙基)氨基甲酸叔丁酯
Figure PCTCN2020079854-appb-000047
向250ml蛋形瓶中加入2-(3,4-二((叔丁基二甲基甲硅烷基)氧基)苯氧基)-4-甲基苯基)硼酸(3.1g，6.34mmol)，2-(3-溴,2-噻吩基)磺酰胺基N-Boc乙胺(2g，5.28mmol)，醋酸钯(237mg，1.056mmol)，三苯基膦(553mg，2.112mmol)，磷酸钾(3.36g，15.84mmol)，充分抽氧后加入四氢呋喃(60ml)，水(10ml)，搅拌下加热回流3h。浓缩出去四氢呋喃，加水(20ml)，二氯甲烷(30ml)萃取3次。干燥，过滤，浓缩。石油醚：乙酸乙酯＝10:1至6:1，得白色固体(2-((3-(2-(3,4-双((叔丁基二甲基甲硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩)-2-磺酰氨基)乙基)氨基甲酸叔丁酯(3.045g，77.1％)。
1HNMR(400MHz,Acetone-d 6)δ7.75(d,J＝5.1Hz,1H),7.37(d,J＝7.7Hz,1H),7.13(d,J＝5.1Hz,1H),6.95(d,J＝8.2Hz,1H),6.86(d,J＝8.7Hz,1H),6.68(s,1H),6.61(d,J＝2.9Hz,1H),6.56(dd,J＝8.6,3.0Hz,1H),6.34(s,1H),5.98(s,1H),3.18–3.12(m,2H),3.03(q,J＝6.0Hz,2H),2.30(s,3H),1.39(s,9H),1.00(s,9H),0.98(s,9H),0.22(s,6H),0.21(s,6H)。
13CNMR(100MHz,CDCl 3)δ154.8,150.1,147.5,143.4,140.6,140.5,136.1,131.9,131.5,128.8,123.8,121.7,121.2,118.4,112.5,111.8,43.5,28.3,25.8,25.8,21.3,18.4,18.4,-4.1,-4.2。
ESI-MS m/z 771.20(M+Na) +。
实施例9 N-(2-氨基乙基)-3-(2-(3,4-双((叔丁基二甲基硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩-2-磺酰胺
Figure PCTCN2020079854-appb-000048
向100ml蛋形瓶中加入(2-((3-(2-(3,4-双((叔丁基二甲基甲硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩)-2-磺酰氨基)乙基)氨基甲酸叔丁酯(2g，2.67mmol)，二氯甲烷(20ml)，三氟乙酸(2.7ml)，室温搅拌1h。加入碳酸钾饱和溶液中和体系至碱性，加水(20ml)，二氯甲烷(20ml)萃取3次，干燥，过滤，浓缩。得白色固体N-(2-氨基乙基)-3-(2-(3,4-双((叔丁基二甲基硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(1.728g，99.9％)。
1HNMR(400MHz,CDCl 3)δ7.46(d,J＝5.1Hz,1H),7.39(d,J＝7.8Hz,1H),7.05(d,J＝5.1Hz,1H),6.95(d,J＝8.0Hz,1H),6.75(d,J＝8.6Hz,1H),6.67(s,1H),6.47(d,J＝2.8Hz,1H),6.43(dd,J＝8.6,2.9Hz,1H),2.96(t,J＝5.6Hz,2H),2.73(t,J＝5.6Hz,2H),2.28(s,3H),0.98(s,9H),0.95(s,9H),0.18(s,6H),0.16(s,6H)。
ESI-MS m/z 647.15(M-H) +。
实施例10 N-(2-(3-(3,5-双(三氟甲基)苯基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-1)
Figure PCTCN2020079854-appb-000049
向25mL蛋形瓶中加入N-(2-氨基乙基)-3-(2-(3,4-双((叔丁基二甲基硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩-2-磺酰胺60mg、二氯甲烷(3mL)，加入3,5-二三氟甲基苯基异硫氰酸酯约1.2eq.，室温搅拌至其反应完全。不经处理直接湿法上样，柱层析得到除去过量异氰酸酯或异硫氰酸酯的粗产物后，加入乙腈(2mL)，40％的HF水溶液约0.2mL，室温反应完全后，乙酸乙酯萃取，水洗，饱和食盐水洗涤，干燥、过滤、浓缩后石油醚:乙酸乙酯＝1:1柱层析，收集得到产物N-(2-(3-(3,5-双(三氟甲基)苯基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率78％。
1HNMR(400MHz,CDCl 3)δ7.82(s,2H),7.68(s,1H),7.55(d,J＝5.1Hz,1H),7.23(d,J＝7.7Hz,1H),7.10(d,J＝5.0Hz,1H),6.93(d,J＝7.5Hz,1H),6.78–6.72(m,2H),6.51(d,J＝2.3Hz,1H),6.33–6.27(m,1H),3.70(s,2H),3.15(s,2H),2.29(s,3H)。
13CNMR(100MHz,CDCl 3)δ179.52,152.03,149.94,148.42,140.44,138.15,137.74, 136.85,133.94,131.66,129.42,128.45,126.96,125.78,124.44,122.60,122.02,119.16,118.43,116.86,112.81,106.63,45.47,42.32,21.64。
ESI-MS m/z 690.00(M-H) -。
实施例11 N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-2)
Figure PCTCN2020079854-appb-000050
将3,5-二三氟甲基苯基异硫氰酸酯换为3,5-二三氟甲基苯基异氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率88％。
1HNMR(400MHz,CDCl 3)δ7.66(s,2H),7.53-7.42(m,4H),7.24(s,1H),7.12(d,J＝5.1Hz,1H),6.88(d,J＝7.7Hz,1H),6.77–6.67(m,2H),6.50(d,J＝2.7Hz,1H),6.29(dd,J＝8.6,2.7Hz,1H),5.88(s,1H),5.80(s,1H),5.40(s,1H),3.31(d,J＝5.1Hz,2H),3.06(d,J＝5.3Hz,2H),2.19(s,3H)。
13CNMR(100MHz,CDCl 3)δ171.29,155.45,154.49,149.15,144.68,142.13,141.18,141.10,139.93,133.84,132.67,132.22,131.89,131.56,131.11,129.98,124.41,123.99,121.60,118.67,115.58,110.57,106.47,43.41,39.71,21.22。
ESI-MS m/z 698.00(M+Na) -。
实施例12 N-(2-(3-(3,5-二三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-4-甲基苯)噻吩-2-磺酰胺(I-3)
Figure PCTCN2020079854-appb-000051
将N-(2-氨基乙基)-3-(2-(3,4-双((叔丁基二甲基甲硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩)-2-磺酰胺换成N-(2-氨基乙基)-3-(2-(3,4-二甲氧基苯氧基)-4-甲基苯基)噻吩)-2-磺酰胺，其余所需原料、试剂和制备方法与实施例11相同，得到产物N-(2-(3-(3,5-二三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-4-甲基苯)噻吩-2-磺酰胺，产率90％。
1H NMR(400MHz,Acetone-d 6)δ8.68(s,1H),8.14(s,2H),7.75(d,J＝5.1Hz,1H),7.54 (s,1H),7.38(d,J＝7.7Hz,1H),7.19(d,J＝5.1Hz,1H),6.92(d,J＝7.7Hz,1H),6.86(d,J＝8.7Hz,1H),6.76–6.65(m,2H),6.55(dd,J＝8.7,2.7Hz,1H),6.46(t,J＝5.8Hz,1H),6.19(s,1H),3.75(s,6H),3.34(q,J＝5.9Hz,2H),3.09(q,J＝6.0Hz,2H)。
13C NMR(100MHz,Acetone-d 6)δ156.17,155.65,151.18,146.62,143.29,141.52,140.73,137.91,133.01,132.33,132.00,129.51,125.66,123.76,122.86,118.47,118.23,114.70,113.14,111.30,105.46,56.27,55.93,43.96,40.30,21.15。
ESI-MS m/z 726.10(M+Na) +；ESI-HRMS C 30H 28O 6N 3F 6S 2(M+H) +的计算值为704.1310。
实施例13 N-(2-(3-(3-硝基苯基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-4)
Figure PCTCN2020079854-appb-000052
将3,5-二三氟甲基苯基异硫氰酸酯换为3-硝基苯基异硫氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(3-硝基苯基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率82％。
1HNMR(400MHz,Acetone-d 6)δ9.33(s,1H),8.62(s,1H),8.01(s,1H),7.98(d,J＝8.1Hz,1H),7.90(d,J＝7.4Hz,1H),7.81(s,1H),7.76(d,J＝5.1Hz,1H),7.59(t,J＝8.1Hz,1H),7.54(s,1H),7.36(d,J＝7.7Hz,1H),7.18(d,J＝5.1Hz,1H),6.91(d,J＝7.6Hz,1H),6.78(d,J＝8.5Hz,1H),6.68(s,1H),6.57(d,J＝2.8Hz,1H),6.48(s,1H),6.41(dd,J＝8.6,2.8Hz,1H),3.75(dd,J＝11.7,5.8Hz,2H),3.19(dd,J＝12.1,6.1Hz,2H),2.28(s,3H)。
ESI-MS m/z 622.90(M+Na) -。
实施例14 N-(2-(3-(4-硝基苯基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-5)
Figure PCTCN2020079854-appb-000053
将3,5-二三氟甲基苯基异硫氰酸酯换为4-硝基苯基异硫氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(4-硝基苯基)硫脲基)乙基)-3-(2-(3,4-二 羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率85％。
1HNMR(400MHz,Acetone-d 6)δ9.51(s,1H),8.19(d,J＝9.2Hz,2H),8.01(s,1H),7.90(d,J＝9.2Hz,2H),7.82(s,1H),7.76(d,J＝5.1Hz,1H),7.67(s,1H),7.36(d,J＝7.7Hz,1H),7.18(d,J＝5.1Hz,1H),6.92(d,J＝7.5Hz,1H),6.78(d,J＝8.6Hz,1H),6.68(s,1H),6.57(d,J＝2.8Hz,1H),6.49(s,1H),6.41(dd,J＝8.6,2.8Hz,1H),3.76(dd,J＝11.7,5.8Hz,2H),3.20(dd,J＝12.0,6.0Hz,2H),2.28(s,3H)。
ESI-MS m/z 623.05(M+Na) -。
实施例15 N-(2-(3-(3-甲氧基苯基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-6)
Figure PCTCN2020079854-appb-000054
将3,5-二三氟甲基苯基异硫氰酸酯换为3-甲氧基苯基异硫氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(3-甲氧基苯基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率83％。
1HNMR(400MHz,Acetone-d 6)δ8.92(s,1H),8.05(s,1H),7.76(dd,J＝14.7,5.1Hz,2H),7.34(dd,J＝14.1,6.4Hz,2H),7.24(t,J＝8.1Hz,1H),7.17(d,J＝5.1Hz,1H),7.03(s,1H),6.90(t,J＝6.7Hz,2H),6.77(dd,J＝15.7,8.9Hz,2H),6.67(s,1H),6.58(d,J＝2.6Hz,1H),6.49–6.36(m,2H),3.82–3.70(m,5H),3.17(dd,J＝12.0,6.1Hz,2H),2.28(s,3H)。
ESI-MS m/z 584.05(M-H) -。
实施例16 N-(2-(3-(4-甲氧基苯基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-7)
Figure PCTCN2020079854-appb-000055
将3,5-二三氟甲基苯基异硫氰酸酯换为4-甲氧基苯基异硫氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(4-甲氧基苯基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率88％。
1HNMR(400MHz,Acetone-d 6)δ8.75(s,1H),8.13(s,2H),7.73(d,J＝5.1Hz,1H),7.36(d,J＝7.7Hz,1H),7.19(dd,J＝17.6,7.0Hz,3H),7.06(d,J＝5.3Hz,1H),6.94–6.87(m, 3H),6.79(d,J＝8.6Hz,1H),6.67(s,1H),6.58(d,J＝2.8Hz,1H),6.46(s,1H),6.41(dd,J＝8.6,2.8Hz,1H),3.79(s,3H),3.73(q,J＝6.1Hz,2H),3.15(q,J＝6.1Hz,2H),2.28(s,3H)。
ESI-MS m/z 584.05(M-H) -。
实施例17 N-(2-(3-(3-甲氧基苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-8)
Figure PCTCN2020079854-appb-000056
将3,5-二三氟甲基苯基异硫氰酸酯换为4-甲氧基苯基异氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(3-甲氧基苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率86％。
1HNMR(400MHz,Acetone-d 6)δ8.26(s,1H),7.81(s,1H),7.72(d,J＝5.1Hz,1H),7.61(s,1H),7.36(d,J＝7.8Hz,1H),7.31(d,J＝9.0Hz,2H),7.18(d,J＝5.1Hz,1H),6.89(d,J＝7.8Hz,1H),6.82(d,J＝9.0Hz,2H),6.76(d,J＝8.6Hz,1H),6.67(s,1H),6.59(d,J＝2.8Hz,1H),6.45–6.37(m,2H),5.90(s,1H),3.74(s,3H),3.30(q,J＝6.0Hz,2H),3.01(q,J＝6.0Hz,2H),2.25(s,3H)。
13CNMR(100MHz,Acetone-d 6)δ156.18,155.58,149.34,145.89,141.64,140.75,139.90,133.05,132.29,131.64,128.64,122.82,121.93,120.72,117.59,115.38,113.79,110.51,107.46,54.69,43.89,39.49,20.48。
ESI-MS m/z 592.15(M+Na) -。
实施例18 N-(2-(3-(4-甲氧基苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-9)
Figure PCTCN2020079854-appb-000057
将3,5-二三氟甲基苯基异硫氰酸酯换为3-甲氧基苯基异氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(4-甲氧基苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率83％。
1HNMR(400MHz,Acetone-d 6)δ8.16(s,1H),8.02(s,1H),7.73(d,J＝5.1Hz,1H),7.68 (s,1H),7.36(d,J＝7.7Hz,1H),7.22(s,1H),7.17(d,J＝5.1Hz,1H),7.11(t,J＝8.1Hz,1H),6.90(d,J＝7.7Hz,2H),6.77(d,J＝8.6Hz,1H),6.67(s,1H),6.58(d,J＝2.8Hz,1H),6.52(dd,J＝8.2,2.1Hz,1H),6.45–6.34(m,2H),5.96(s,1H),3.74(s,3H),3.31(q,J＝5.9Hz,2H),3.02(q,J＝6.0Hz,2H),2.25(s,3H)。
ESI-MS m/z 592.15(M+Na) -。
实施例19 N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-10)
Figure PCTCN2020079854-appb-000058
将3,5-二三氟甲基苯基异硫氰酸酯换为3,5-二氯苯基异氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率86％。
1HNMR(400MHz,Acetone-d 6)δ8.37(s,1H),8.06(s,1H),7.78–7.72(m,2H),7.53(d,J＝1.7Hz,2H),7.35(d,J＝7.7Hz,1H),7.17(d,J＝5.1Hz,1H),7.00(s,1H),6.90(d,J＝7.7Hz,1H),6.78(d,J＝8.6Hz,1H),6.67(s,1H),6.57(d,J＝2.7Hz,1H),6.40(dt,J＝11.7,4.3Hz,2H),6.07(s,1H),3.30(q,J＝5.9Hz,2H),3.04(q,J＝5.9Hz,2H),2.26(s,3H)。
13CNMR(100MHz,Acetone-d 6)δ155.67,155.02,149.54,145.94,142.98,141.58,140.90,139.98,137.13,134.57,132.30,131.64,128.78,122.88,122.03,120.73,117.69,116.16,115.52,110.60,107.50,43.47,39.53,20.49。
ESI-MS m/z 606.05(M-H) -。
实施例20 N-(2-(3-(3-硝基苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-11)
Figure PCTCN2020079854-appb-000059
将3,5-二三氟甲基苯基异硫氰酸酯换为3-硝基苯基异氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(3-硝基苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率88％。
1HNMR(400MHz,Acetone-d 6)δ8.57(t,J＝2.1Hz,1H),8.52(s,1H),8.06(s,1H),7.82–7.77(m,1H),7.74(d,J＝5.9Hz,3H),7.51(t,J＝8.2Hz,1H),7.36(d,J＝7.8Hz,1H),7.17(d,J＝5.1Hz,1H),6.91(d,J＝7.5Hz,1H),6.77(d,J＝8.6Hz,1H),6.67(s,1H),6.57(d,J＝2.8Hz,1H),6.44–6.37(m,2H),6.10(s,1H),3.33(dd,J＝11.9,5.9Hz,2H),3.06(dd,J＝12.0,6.0Hz,2H),2.25(s,3H)。
13CNMR(100MHz,Acetone-d 6)δ155.66,155.24,149.53,148.75,145.94,141.87,141.58,140.90,139.97,137.17,132.29,131.66,129.65,128.76,123.78,122.88,122.04,117.67,115.90,115.51,112.33,110.59,107.51,43.51,39.54,20.48。
ESI-MS m/z 583.10(M-H) -。
实施例21 N-(2-(3-(4-硝基苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺(I-12)
Figure PCTCN2020079854-appb-000060
将3,5-二三氟甲基苯基异硫氰酸酯换为4-硝基苯基异氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(4-硝基苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)-4-甲基苯基)噻吩-2-磺酰胺，产率84％。
1HNMR(400MHz,Acetone-d 6)δ8.72(s,1H),8.15(d,J＝9.2Hz,2H),8.05(s,1H),7.79(s,1H),7.74(d,J＝5.1Hz,1H),7.71(d,J＝9.2Hz,2H),7.36(d,J＝7.7Hz,1H),7.18(d,J＝5.1Hz,1H),6.90(d,J＝7.7Hz,1H),6.77(d,J＝8.6Hz,1H),6.66(s,1H),6.58(d,J＝2.8Hz,1H),6.41(dd,J＝8.5,2.7Hz,2H),6.17(s,1H),3.33(dd,J＝11.8,5.9Hz,2H),3.05(q,J＝5.9Hz,2H),2.25(s,3H)。
13CNMR(100MHz,Acetone-d 6)δ156.68,155.73,150.49,147.89,146.94,142.58,142.52,141.89,140.97,138.14,133.30,132.66,129.78,125.82,123.83,122.97,118.60,118.24,116.50,111.62,108.59,44.33,40.58,21.49。
ESI-MS m/z 607.15(M+Na) -。
实施例22 1-(4-(3,4-二甲氧基苯氧基)-3-硝基苯基)乙基-1-酮
Figure PCTCN2020079854-appb-000061
25ml蛋形瓶中加入3,4-二甲氧基苯酚(3.53g，22.9mmol)，60％氢化钠(1.3g，32.76mmol)，四氢呋喃(50ml)及4-氟-3-硝基苯乙酮(4g，21.84mmol)，搅拌下加热回流3h。冰水浴下缓慢加水淬灭反应。浓缩除去四氢呋喃，加入水(50ml)，二氯甲烷(50ml)萃取3次。干燥，过滤，浓缩。石油醚：乙酸乙酯＝10:1柱层析得产物1-(4-(3,4-二甲氧基苯氧基)-3-硝基苯基)乙基-1-酮(5.2g,75.4％)。
1H NMR(400MHz,CDCl 3)δ8.49(d,J＝2.1Hz,1H),8.03(dd,J＝8.8,2.1Hz,1H),6.92(dd,J＝27.3,8.7Hz,2H),6.67(dt,J＝8.5,2.6Hz,2H),3.90(s,3H),3.85(s,3H),2.60(s,3H)。
13C NMR(100MHz,CDCl 3)δ194.7,155.5,150.2,147.2,147.0,139.5,133.5,130.8,126.3,117.7,111.9,111.6,104.8,56.2,56.1,26.4。
ESI-MS m/z 318.25(M+H) +，ESI-HRMS m/z 318.0970(M+H) +。
实施例23 1-(3,4-二甲氧基苯氧基)-2-硝基-4-(丙-1-烯-2-基)苯
Figure PCTCN2020079854-appb-000062
25ml史莱克管中加入Ph 3PCH 3Br(375mg，1.05mmol)，抽换气3次，冰水浴下加入无水四氢呋喃(4ml)，搅拌下缓慢滴加叔丁醇钾的四氢呋喃溶液(1.05ml，1.05mmol)，滴毕移至室温搅拌1h。将1-(4-(3,4-二甲氧基苯氧基)-3-硝基苯基)乙基-1-酮(222mg，0.7mmol)的四氢呋喃溶液滴入反应体系中，搅拌3h。加入饱和氯化铵溶液淬灭反应，乙酸乙酯(5ml)，水(5ml)萃取3次，干燥，过滤，浓缩。石油醚：乙酸乙酯＝30:1柱层析得产物1-(3,4-二甲氧基苯氧基)-2-硝基-4-(丙-1-烯-2-基)苯(192mg，87.3％)。
1H NMR(400MHz,CDCl 3)δ7.99(d,J＝2.3Hz,1H),7.55(dd,J＝8.8,2.3Hz,1H),6.90(d,J＝8.8Hz,1H),6.84(d,J＝8.7Hz,1H),6.68(d,J＝2.7Hz,1H),6.59(dd,J＝8.7,2.7Hz,1H),5.39(s,1H),5.16(s,1H),3.88(s,3H),3.84(s,3H),2.14(s,3H)。
13C NMR(100MHz,CDCl 3)δ150.7,150.0,148.8,146.3,140.4,135.8,130.8,122.4,118.8,113.8,111.6,111.0,104.5,56.2,56.0,21.5。
ESI-MS m/z 316.05(M+H) +，ESI-HRMS m/z 316.1179(M+H) +。
实施例24 2-(3,4-二甲氧基苯氧基)-5-异丙基苯胺
Figure PCTCN2020079854-appb-000063
25ml蛋形瓶中加入1-(3,4-二甲氧基苯氧基)-2-硝基-4-(丙-1-烯-2-基)苯(155mg，0.4919mmol)，甲醇(6ml)溶解，40℃下通入氢气搅拌5h。硅藻土过滤除去钯碳，浓缩除去甲醇，得产物2-(3,4-二甲氧基苯氧基)-5-异丙基苯胺(120mg，85.1％)。
1H NMR(400MHz,CDCl 3)δ6.80–6.65(m,4H),6.56(dd,J＝8.2,2.0Hz,1H),6.46(dd,J＝8.7,2.7Hz,1H),3.85(s,3H),3.83(s,3H),3.67(s,2H),2.81(dt,J＝13.8,6.9Hz,1H),1.23(s,3H),1.21(s,3H)。
13C NMR(100MHz,CDCl 3)δ151.3,149.8,145.0,144.7,142.2,137.5,118.6,116.7,114.5,111.6,108.3,102.9,56.2,55.9,33.6,24.1。
ESI-MS m/z 288.05(M+H) +，ESI-HRMS m/z 288.1592(M+H) +。
实施例25 2-(3,4-二甲氧基苯氧基)-5-异丙基碘苯
Figure PCTCN2020079854-appb-000064
将250ml蛋形瓶置于冰水浴中，向其中加入2-(3,4-二甲氧基苯氧基)-5-异丙基苯胺(2.58g，8.98mmol)，浓硫酸(1.44ml溶于50ml水中，26.9mmol)，搅拌下缓慢滴加亚硝酸钠溶液(1.23g，17.96mmol)，保持冰水浴搅拌1h；冰水浴下缓慢滴加碘化钾水溶液(2.98g，17.96mmol)；0.5h后去掉冰水浴，搅拌1h。加入二氯甲烷(100ml)萃取3次；硫代硫酸钠洗涤，干燥，过滤，浓缩。石油醚:乙酸乙酯＝15:1柱层析得产物2-(3,4-二甲氧基苯氧基)-5-异丙基碘苯(2.78g，77.8％)。
1H NMR(400MHz,CDCl 3)δ7.69(d,J＝2.0Hz,1H),7.10(dd,J＝8.4,2.0Hz,1H),6.79(d,J＝8.7Hz,1H),6.73(d,J＝8.4Hz,1H),6.65(d,J＝2.7Hz,1H),6.46(dd,J＝8.7,2.7Hz,1H),3.86(s,3H),3.84(s,3H),2.85(dt,J＝13.8,6.9Hz,1H),1.24(s,3H),1.22(s,3H)。
13C NMR(100MHz,CDCl 3)δ155.1,150.6,149.8,145.6,145.3,137.4,127.5,117.8,111.5, 109.7,103.9,87.8,56.2,55.9,33.1,24.0。
ESI-MS m/z 397.35(M-H) +，ESI-HRMS m/z 399.0451(M+H) +。
实施例26 2-(3,4-二甲氧基苯氧基)-5-异丙基苯硼酸
Figure PCTCN2020079854-appb-000065
向100ml蛋形瓶中加入2-(3,4-二甲氧基苯氧基)-5-异丙基碘苯(2.58g，6.48mmol)，充分抽换气除氧除水氩气保护下加入无水THF(27ml)，在-78℃氩气保护下缓慢滴加正丁基锂溶液(2.5M，5.2ml，13mmol)，反应1h后，在-78℃下一次性加入硼酸三甲酯(1.8ml，16.2mmol)，2h后将反应管移至室温搅拌过夜。加入盐酸(1N,30ml)，二氯甲烷(30ml)萃取3次。干燥，过滤，浓缩。石油醚：乙酸乙酯＝10:1柱层析得产物2-(3,4-二甲氧基苯氧基)-5-异丙基苯硼酸(1.28g，64％)。
1H NMR(400MHz,Acetone-d 6)δ7.76(d,J＝2.2Hz,1H),7.25(dd,J＝8.5,2.4Hz,1H),7.04(s,2H),6.96(d,J＝8.7Hz,1H),6.81(d,J＝2.7Hz,1H),6.65(d,J＝8.5Hz,1H),6.58(dd,J＝8.7,2.7Hz,1H),3.81(s,3H),3.80(s,3H),2.90(dd,J＝13.9,6.9Hz,1H),1.24(s,3H),1.22(s,3H)。
实施例27(2-((3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩)-2-磺酰氨基)乙基)氨基甲酸叔丁酯
Figure PCTCN2020079854-appb-000066
向250ml蛋形瓶中加入2-(3,4-二甲氧基苯氧基)-5-异丙基苯硼酸(200mg，0.6326mmol)，2-(3-溴,2-噻吩基)磺酰胺基N-Boc乙胺(203mg，0.5271mmol)，醋酸钯(24mg，0.1054mmol)，三苯基膦(55mg，0.2108mmol)，磷酸钾(335mg，1.5813mmol)，充分抽氧后加入四氢呋喃(6.3ml)，水(1.8ml)，搅拌下加热回流3h。浓缩出去四氢呋喃，加水(5ml)，二氯甲烷(5ml)萃取3次。干燥，过滤，浓缩。石油醚：乙酸乙酯＝10:1至6:1，得产物(2-((3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩)-2-磺酰氨基)乙基)氨基甲酸叔丁酯(208mg，68.6％)。
1H NMR(400MHz,Acetone-d 6)δ7.75(d,J＝5.1Hz,1H),7.42(s,1H),7.23(dd,J＝11.6, 3.6Hz,2H),6.89(d,J＝8.7Hz,1H),6.79(d,J＝8.5Hz,1H),6.73(d,J＝2.5Hz,1H),6.53(dd,J＝8.7,2.6Hz,1H),6.31(t,J＝5.7Hz,1H),5.99(s,1H),3.77(s,3H),3.76(s,3H),3.12(dd,J＝12.3,6.1Hz,2H),2.96(ddd,J＝20.6,12.9,6.4Hz,3H),1.38(s,9H),1.27(s,3H),1.25(s,3H)。
13C NMR(100MHz,Acetone-d 6)δ156.6,154.2,151.4,151.1,146.5,143.2,141.5,138.4,132.8,130.7,129.3,128.4,125.4,117.8,113.2,111.1,105.4,78.7,56.3,55.9,43.9,40.9,33.8,28.4,24.1。
ESI-MS m/z 477.15(M+H) +。
实施例28 N-(2-氨基乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺
Figure PCTCN2020079854-appb-000067
向100ml蛋形瓶中加入(2-((3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩)-2-磺酰氨基)乙基)氨基甲酸叔丁酯(1.2g，2.08mmol)，二氯甲烷(20ml)，三氟乙酸(2ml)，室温搅拌1h。加入碳酸钾饱和溶液中和体系至碱性，加水(20ml)，二氯甲烷(20ml)萃取3次，干燥，过滤，浓缩。得产物N-(2-氨基乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺(950mg，96％)。
1H NMR(400MHz,Acetone-d 6)δ7.76(d,J＝5.1Hz,1H),7.46(d,J＝2.1Hz,1H),7.27–7.20(m,2H),6.87(d,J＝8.7Hz,1H),6.79(d,J＝8.5Hz,1H),6.74(d,J＝2.6Hz,1H),6.54(dd,J＝8.7,2.7Hz,1H),3.77(s,3H),3.73(s,3H),3.20(t,J＝6.2Hz,2H),3.09(t,J＝6.2Hz,2H),2.93(dd,J＝13.8,6.9Hz,1H),1.27(s,3H),1.25(s,3H)。
13C NMR(100MHz,Acetone-d 6)δ154.2,151.3,151.1,146.5,143.2,141.2,132.7,130.3,129.3,128.4,125.3,117.8,113.1,111.1,105.5,56.3,55.9,50.7,44.6,33.8,24.1。
ESI-MS m/z 449.10(M+H) +。
实施例29 N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺(I-13)
Figure PCTCN2020079854-appb-000068
将N-(2-氨基乙基)-3-(2-(3,4-双((叔丁基二甲基甲硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩)-2-磺酰胺换成N-(2-氨基乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩)-2-磺酰胺，其余所需原料、试剂和制备方法与实施例11相同，得到产物N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺，产率97％。
1H NMR(400MHz,Acetone-d 6)δ8.13(s,2H),7.75(d,J＝5.1Hz,1H),7.53(s,1H),7.42(d,J＝2.1Hz,1H),7.20(dd,J＝12.2,3.6Hz,2H),6.86(d,J＝8.7Hz,1H),6.77(d,J＝8.5Hz,1H),6.72(d,J＝2.6Hz,1H),6.54(dd,J＝8.7,2.7Hz,1H),3.74(d,J＝2.2Hz,6H),3.30(t,J＝5.7Hz,2H),3.04(t,J＝6.0Hz,2H),2.92(dd,J＝13.8,6.9Hz,1H),1.24(d,J＝6.9Hz,6H)。
13C NMR(101MHz,Acetone-d 6)δ155.6,154.2,151.2,146.53,143.2,141.6,138.1,132.8,132.2,131.9,130.7,128.4,125.6,125.2,122.9,118.1,117.7,114.5,113.1,111.1,105.3,56.2,55.9,43.9,40.2,33.83,24.0。
ESI-MS m/z 770.15(M+K) +；ESI-HRMS C 32H 32O 6N 3F 6S 2(M+H) +的计算值为732.1628。
实施例30 N-(2-(3-(3,5-双(三氟甲基)苯基)硫脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺(I-14)
Figure PCTCN2020079854-appb-000069
将3,5-二三氟甲基苯基异氰酸酯换为3,5-二三氟甲基苯基异硫氰酸酯，其余所需原料、试剂和制备方法与实施例29相同，得到产物N-(2-(3-(3,5-双(三氟甲基)苯基)硫脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺，产率78％。
1H NMR(400MHz,Acetone-d 6)δ9.48(s,1H),8.30(s,2H),7.77(d,J＝5.1Hz,1H),7.71(d,J＝10.4Hz,2H),7.42(d,J＝2.3Hz,1H),7.23(q,J＝2.7Hz,2H),6.87(d,J＝8.7Hz,1H),6.79(d,J＝8.5Hz,1H),6.72(d,J＝2.7Hz,1H),6.54(dd,J＝8.7,2.7Hz,1H),6.48(s,1H),3.74(dd,J＝9.9,5.6Hz,8H),3.18(q,J＝6.1Hz,2H),2.93(dd,J＝13.8,6.9Hz,1H),1.25(d,J＝6.9Hz,6H)。
13C NMR(101MHz,Acetone-d 6)δ182.4,154.2,151.3,151.1,146.5,143.2,142.4,141.8,137.8,132.9,131.9,131.5,130.7,129.5,128.4,125.3,123.3,122.7,117.8,117.4,113.1,111.0,105.3,56.3,55.9,44.4,42.7,33.8,24.1。
ESI-MS m/z 746.10(M-H) +；ESI-HRMS C 32H 32O 5N 3F 6S 3(M+H) +的计算值为748.1401。
实施例31 N-(2-(3-(4-硝基苯基)硫脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基 苯基)噻吩-2-磺酰胺(I-15)
Figure PCTCN2020079854-appb-000070
将3,5-二三氟甲基苯基异氰酸酯换为4-硝基苯基异硫氰酸酯，其余所需原料、试剂和制备方法与实施例29相同，得到产物N-(2-(3-(4-硝基苯基)硫脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺，产率86％。
1H NMR(400MHz,Acetone-d 6)δ9.52(s,1H),8.18(d,J＝9.1Hz,2H),7.89(d,J＝9.1Hz,2H),7.80–7.73(m,1H),7.69(s,1H),7.41(s,1H),7.23(d,J＝5.1Hz,2H),6.88(d,J＝8.7Hz,1H),6.79(d,J＝8.5Hz,1H),6.72(d,J＝2.4Hz,1H),6.57–6.45(m,2H),3.75(d,J＝4.9Hz,8H),3.18(dd,J＝11.8,5.9Hz,2H),2.92(dt,J＝14.0,7.0Hz,1H),1.25(d,J＝6.9Hz,6H)。
13C NMR(101MHz,Acetone-d 6)δ181.8,154.2,151.3,151.1,146.5,143.2,141.8,137.9,132.9,130.7,129.6,128.4,125.2,125.0,121.9,117.8,113.1,111.0,105.3,56.3,56.0,44.5,42.7,33.8,24.1。
ESI-MS m/z 657.15(M+H) +；ESI-HRMS C 30H 33O 7N 4S 3(M+H) +的计算值为658.1504。
实施例32 N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺(I-16)
Figure PCTCN2020079854-appb-000071
将3,5-二三氟甲基苯基异氰酸酯换为3,5-二氯苯基异氰酸酯，其余所需原料、试剂和制备方法与实施例29相同，得到产物N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺，产率87％。
1H NMR(400MHz,Acetone-d 6)δ8.39(s,1H),7.75(d,J＝5.1Hz,1H),7.52(d,J＝1.8Hz,2H),7.42(d,J＝2.3Hz,1H),7.24–7.17(m,2H),6.99(t,J＝1.8Hz,1H),6.86(d,J＝8.7Hz,1H),6.74(dd,J＝14.6,5.6Hz,2H),6.54(dd,J＝8.7,2.7Hz,1H),6.38(t,J＝5.6Hz,1H),6.09(t,J＝5.5Hz,1H),3.75(d,J＝3.2Hz,6H),3.27(q,J＝5.9Hz,2H),3.02(q,J＝5.9Hz,2H),2.93(dd,J＝13.8,6.9Hz,1H),1.24(t,J＝7.1Hz,6H)。
13C NMR(101MHz,Acetone-d 6)δ155.6,154.2,151.3,151.1,146.5,143.6,143.1,141.6,138.1,135.1,132.8,130.7,129.4,128.4,125.2,121.2,117.6,116.6,113.1,111.1,105.4,56.2,55.9,44.1,40.2,33.8,24.2。
ESI-MS m/z 662.05(M-H) +；ESI-HRMS C 30H 32O 6N 3Cl 2S 2(M+H) +的计算值为664.1103。
实施例33 N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二苯酚基)-5-异丙基苯基)噻吩-2-磺酰胺(I-17)
Figure PCTCN2020079854-appb-000072
向25ml蛋形瓶中加入N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺(40mg)，加入3ml DCM，冰水浴下缓慢滴加BBr 3(10eq.)搅拌1h。缓慢加水淬灭反应，二氯甲烷(3ml)萃取3次，干燥，过滤，浓缩，获得产物N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二苯酚基)-5-异丙基苯基)噻吩-2-磺酰胺，产率100％。
1H NMR(400MHz,Acetone-d 6)δ8.72(s,1H),8.09(d,J＝23.2Hz,3H),7.74(d,J＝5.1Hz,2H),7.54(s,1H),7.41(d,J＝1.6Hz,1H),7.23–7.14(m,2H),6.77(dd,J＝8.5,4.1Hz,2H),6.56(d,J＝2.5Hz,1H),6.39(dd,J＝8.5,2.6Hz,1H),6.33(t,J＝5.7Hz,1H),6.19(s,1H),3.31(dd,J＝11.3,5.6Hz,2H),3.02(dd,J＝11.9,6.0Hz,2H),2.89(dd,J＝13.8,6.8Hz,1H),1.24(d,J＝6.9Hz,6H)。
13C NMR(100MHz,Acetone-d 6)δ155.4,154.1,150.3,146.3,142.9,141.8,141.6,137.7,132.7,132.1,131.8,130.5,129.3,128.2,125.5,125.0,122.8,118.0,117.6,115.9,114.5,110.8,107.7,43.8,39.9,33.7,23.9。
ESI-MS m/z 704.15(M+H) +；ESI-HRMS C 30H 28O 6N 3F 6S 2(M+H) +的计算值为704.1320。
实施例34 N-(2-(3-(3,5-双(三氟甲基)苯基)硫脲基)乙基)-3-(2-(3,4-二苯酚基)-5-异丙基苯基)噻吩-2-磺酰胺(I-18)
Figure PCTCN2020079854-appb-000073
将N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯 基)噻吩-2-磺酰胺换为N-(2-(3-(3,5-双(三氟甲基)苯基)硫脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺，其余所需原料、试剂和制备方法与实施例33相同，得到产物N-(2-(3-(3,5-双(三氟甲基)苯基)硫脲基)乙基)-3-(2-(3,4-二苯酚基)-5-异丙基苯基)噻吩-2-磺酰胺，产率98％。
1H NMR(400MHz,Acetone-d 6)δ9.51(s,1H),8.31(s,2H),8.01(s,1H),7.80(s,1H),7.77(d,J＝5.1Hz,1H),7.71(d,J＝11.3Hz,2H),7.40(d,J＝2.2Hz,1H),7.24–7.18(m,2H),6.78(t,J＝8.3Hz,2H),6.56(d,J＝2.8Hz,1H),6.48–6.34(m,2H),3.73(dd,J＝11.9,5.9Hz,2H),3.16(q,J＝6.1Hz,2H),2.93(dd,J＝13.8,6.9Hz,1H),1.25(d,J＝6.9Hz,6H)。
ESI-MS m/z 718.05(M-H) +；ESI-HRMS C 30H 26O 5N 3F 6S 3(M-H) +的计算值为718.0955。
实施例35 N-(2-(3-(4-硝基苯基)硫脲基)乙基)-3-(2-(3,4-二苯酚基)-5-异丙基苯基)噻吩-2-磺酰胺(I-19)
Figure PCTCN2020079854-appb-000074
将N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺换为N-(2-(3-(4-硝基苯基)硫脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺，其余所需原料、试剂和制备方法与实施例33相同，得到产物N-(2-(3-(4-硝基苯基)硫脲基)乙基)-3-(2-(3,4-二苯酚基)-5-异丙基苯基)噻吩-2-磺酰胺，产率90％。
1H NMR(400MHz,Acetone-d 6)δ9.62(s,1H),8.18(d,J＝9.0Hz,2H),8.05(s,1H),7.92(d,J＝8.9Hz,2H),7.77(dd,J＝14.0,5.5Hz,3H),7.40(s,1H),7.21(t,J＝7.1Hz,2H),6.78(dd,J＝8.5,3.7Hz,2H),6.58(d,J＝2.4Hz,1H),6.47–6.33(m,2H),3.74(d,J＝5.4Hz,2H),3.22–3.13(m,2H),2.91(dd,J＝13.7,6.8Hz,1H),1.25(d,J＝6.9Hz,6H)。
ESI-MS m/z 629.10(M+H) +；ESI-HRMS C 28H 29O 7N 4S 3(M+H) +的计算值为629.1190。
实施例36 N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二苯酚基)-5-异丙基苯基)噻吩-2-磺酰胺(I-20)
Figure PCTCN2020079854-appb-000075
将N-(2-(3-(3,5-双(三氟甲基)苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺换为N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)-5-异丙基苯基)噻吩-2-磺酰胺，其余所需原料、试剂和制备方法与实施例33相同，得到产物N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二苯酚基)-5-异丙基苯基)噻吩-2-磺酰胺，产率100％。
1H NMR(400MHz,Acetone-d 6)δ7.74(d,J＝5.1Hz,1H),7.52(d,J＝1.8Hz,2H),7.41(d,J＝2.2Hz,1H),7.20(d,J＝5.1Hz,1H),7.16(dd,J＝8.5,2.2Hz,1H),7.01(t,J＝1.8Hz,1H),6.80–6.73(m,2H),6.60(d,J＝2.7Hz,1H),6.39(dd,J＝8.6,2.8Hz,1H),3.28(t,J＝6.0Hz,2H),2.99(t,J＝6.0Hz,2H),2.91(dt,J＝13.8,6.9Hz,1H),1.25(d,J＝6.9Hz,6H)。
13C NMR(100MHz,Acetone-d 6)δ155.5,154.1,150.1,146.4,143.3,142.8,141.8,141.5,137.7,135.0,132.6,130.5,129.2,128.2,124.9,121.1,117.5,116.5,115.8,107.7,43.9,39.8,33.7,23.9。
ESI-MS m/z 658.10(M+Na) +；ESI-HRMS C 28H 28O 6N 3Cl 2S 2(M+H) +的计算值为636.0788。
对比实施例1 N-(2-(3-(3,5-二三氟甲基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)苯基)噻吩-2-磺酰胺(D-1)
Figure PCTCN2020079854-appb-000076
将N-(2-氨基乙基)-3-(2-(3,4-双((叔丁基二甲基硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩-2-磺酰胺换为N-(2-氨基乙基)-3-(2-(3,4-二(叔丁基二甲基硅氧基)苯氧基)苯基)噻吩-2-磺酰胺，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(3,5-二三氟甲基)硫脲基)乙基)-3-(2-(3,4-二羟基苯氧基)苯基)噻吩-2-磺酰胺，产率71％。
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.82(s,2H),7.67(s,1H),7.56(d,J＝5.2Hz,1H),7.37–7.30(m,2H),7.14–7.10(m,2H),6.93(d,J＝8.4Hz,1H),6.80(m,1H),6.76(d,J＝8.4Hz,1H),6.49(d,J＝2.8Hz,1H),6.32(dd,J＝8.8,2.8Hz,1H),5.43(s,1H),5.24(t,J＝6.4Hz,1H),3.72–3.68(m,2H),3.17–3.13(m,2H)。
对比实施例2 N-(2-(3-(3,5-二三氟甲基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)苯基)噻吩-2-磺酰胺(D-2)
Figure PCTCN2020079854-appb-000077
将3,5-二三氟甲基苯基异硫氰酸酯换为3,5-二三氟甲基苯基异氰酸酯，其余所需原料、试剂和制备方法与对比实施例1相同，得到产物N-(2-(3-(3,5-二三氟甲基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)苯基)噻吩-2-磺酰胺，产率67％。
1H NMR(400MHz,CDCl3)δ7.61(s,2H),7.56(d,J＝4.8Hz,1H),7.49(s,1H),7.44(s,2H),7.37(dd,J＝7.6,1.6Hz,1H),7.27–7.23(m,1H),7.15(d,J＝4.8Hz,1H),7.07(td,J＝7.6,0.8Hz,1H),6.88(d,J＝8.4Hz,1H),6.75(d,J＝8.8Hz,1H),6.49(d,J＝2.8Hz,1H),6.30(dd,J＝8.8,2.8Hz,1H),5.76–5.73(m,2H),5.37–5.33(m,1H),3.33–3.29(m,2H),3.07–3.03(m,2H)。
ESI-MS m/z 662.1(M+H) +,684.1(M+Na) +；ESI-HRMS C 27H 22N 3O 6F 6S 2(M+H) +的计算值为662.0849,实测值为662.0881。
对比实施例3 N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)苯基)噻吩-2-磺酰胺(D-3)
Figure PCTCN2020079854-appb-000078
将3,5-二三氟甲基苯基异硫氰酸酯换为3,5-二氯苯基异氰酸酯，其余所需原料、试剂和制备方法与对比实施例1相同，得到产物N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二羟基苯氧基)苯基)噻吩-2-磺酰胺，产率78％。
1H NMR(400MHz,Acetone-d6)δ8.23(s,1H),7.93(s,1H),7.62(d,J＝5.2Hz,1H),7.39(d,J＝1.6Hz,2H),7.33(dd,J＝7.6,1.6Hz,1H),7.20–7.16(m,1H),7.06(d,J＝5.2Hz,1H),6.96(td,J＝7.6,0.8Hz,1H),6.86(t,J＝1.6Hz,1H),6.69(d,J＝8.4Hz,1H),6.65(d,J＝8.4Hz,1H),6.45(d,J＝2.4Hz,1H),6.30–6.27(m,2H),5.93(t,J＝1.2Hz,1H),3.19–3.15(m,2H),2.93–2.89(m,2H)。
ESI-MS m/z 593.9(M+H) +；MALDI-HRMS C 25H 21N 3O 6S 2Cl 2Na(M+Na) +的计算值为616.0141,实测值为616.0147。
对比实施例4 N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)苯基)噻吩-2-磺酰胺(D-4)
Figure PCTCN2020079854-appb-000079
将N-(2-氨基乙基)-3-(2-(3,4-双((叔丁基二甲基硅烷基)氧基)苯氧基)-4-甲基苯基)噻吩-2-磺酰胺换为N-(2-氨基乙基)-3-(2-(3,4-二(叔丁基二甲基硅氧基)苯氧基)苯基)噻吩-2-磺酰胺，将3,5-二三氟甲基苯基异硫氰酸酯换为3,5-二氯苯基异氰酸酯，其余所需原料、试剂和制备方法与实施例10相同，得到产物N-(2-(3-(3,5-二氯苯基)脲基)乙基)-3-(2-(3,4-二甲氧基苯氧基)苯基)噻吩-2-磺酰胺，产率94％。
1H NMR(400MHz,CDCl 3)δ7.54(d,J＝5.2Hz,1H),7.42(dd,J＝7.6,1.6Hz,1H),7.33–7.28(m,1H),7.19(d,J＝1.6Hz,2H),7.14–7.10(m,2H),6.92–6.87(m,3H),6.76(d,J＝8.8Hz,1H),6.55(d,J＝2.4Hz,1H),6.48(dd,J＝8.8,2.8Hz,1H),5.41(s,1H),5.21(s,1H),3.82(s,3H),3.77(s,3H),3.27(t,J＝5.0Hz,2H),3.07(t,J＝4.8Hz,2H)。
13C NMR(100MHz,CDCl 3)δ155.2,155.2,150.2,150.1,145.8,141.4,141.2,135.5,134.9,132.1,131.5,130.4,129.7,124.7,123.0,122.2,117.8,116.9,112.0,110.5,104.3,56.3,56.1,43.7,39.7。
ESI-MS m/z 622.3(M+H) +,644.1(M+Na) +；MALDI-HRMS C 27H 25N 3O 6S 2Cl 2Na(M+Na) +的计算值为644.0454，实测值为644.0460。
效果实施例1部分化合物与Bcl-xL、Bcl-2和Mcl-1的亲合性测试结果
合成一个带有26个氨基酸残基的Bid BH3多肽(氨基酸79-104：QEDIIRNIARHLAQVGDSMDRSIPPG)，并在N端标记上6-羧基荧光素琥珀酰亚胺酯(FAM)作为荧光标签(FAM-Bid)。将His-Bcl-xL蛋白或His-Bcl-2蛋白或His-Mcl-1蛋白和待测小分子化合物溶于磷酸缓冲盐溶液中，在37度避光孵育30分钟，然后再加入FAM-Bid多肽，混匀后37度避光孵育20分钟。His-Bcl-X L蛋白，His-Bcl-2蛋白，His-Mcl-1蛋白和FAM-Bid多肽的终浓度分别为230nM，425nM，200nM和10nM。化合物在体系中的终浓度分别为1nM，10nM，100nM，1μM，10μM，50μM和100μM。将以上反应液各取60μl加入到384孔板中(平行三组)，立即在酶标仪上进行荧光偏振的检测。荧光极化值(mP)在由485nm波长激发产生的535nm发射波长下测量。同时设立两个对照组，一个对照组为反应体系中只含有Bcl-xL或Bcl-2或Mcl-1和FAM-Bid(相当于0％抑制率)，另一对照组为反应体系中只含有FAM-Bid多肽。根据对照组以及受测化合物极化值的测定结果计算蛋白抑制率。以蛋白抑制率对化合物浓度的对数作图求出IC 50值。根据公式K i＝[I] 50/([L] 50/K d+[P] 0/K d+1)推导计算得出化合物与蛋白的竞争抑制常数K i值。公式中[I] 50 为蛋白抑制率为50％时的化合物浓度，[L] 50为蛋白抑制率为50％时的游离FAM-Bid浓度，K d为靶蛋白与FAM-Bid多肽的解离常数，[P] 0为蛋白抑制率为0％时的游离蛋白浓度。具体结果如表1所示。
表1
Figure PCTCN2020079854-appb-000080
表中，“N.A.”表示基本没有亲合性。
表1中的测试结果显示，本发明化合物与Bcl-xL、Bcl-2和Mcl-1中的至少一个有显著的亲合性，部分化合物表现出对Mcl-1蛋白的选择性。
效果实施例2部分化合物在若干肿瘤细胞株上的抑制增殖活性
将要检测的人子宫颈癌细胞HeLa，人急性淋巴细胞白血病细胞RS4；11和人原髓细胞白血病细胞HL-60用含10％胎牛血清的RPMI1640培养液培养，人胚肾细胞293T细胞用含10％胎牛血清的DMEM培养液培养。在96孔培养板中种细胞，RS4；11和HL-60的细胞浓度为16000个/50μL，HeLa和293T细胞浓度为8000个/100μL；调零组只加培 养基。在96孔板中分别加入化合物(设定五个不同浓度40μM，20μM，10μM，5μM和2.5μM，每个浓度下平行三组)，然后在37℃下放在CO 2培养箱中孵育48小时。向每孔加入10μLCCK-8溶液并在37℃下孵育2小时，使用酶标仪在450nm波长处测定各孔光吸收值。计算细胞存活率＝(实验组光吸收值-调零组光吸收值)/(对照组光吸收值-调零组光吸收值)。用细胞存活率对化合物浓度对数作图求出IC 50值。具体结果如表2和表3所示。
表2
Figure PCTCN2020079854-appb-000081
表2测试结果显示，本发明化合物在HeLa细胞上的抑制增殖效果有显著改善。
表3
Figure PCTCN2020079854-appb-000082
Figure PCTCN2020079854-appb-000083
表3的测试结果显示，本发明化合物在两个急性白血病细胞株上显示出明显的抑制增殖效果，部分化合物在人原髓细胞白血病细胞株HL-60上的抑制效果为正常细胞的4-6倍，体现出良好的选择性。
效果实施例3采用PI/Annexin V双染研究化合物对细胞凋亡的影响
(1)将待测化合物(设定两个不同浓度10μM和20μM)与人急性淋巴细胞白血病细胞RS4；11孵育48小时。然后在1000rmp转速下离心5分钟，弃上清，收集细胞，用冰PBS轻轻重悬细胞并计数。
(2)取5-10万重悬的细胞，在1000rmp转速下离心5分钟，弃上清，加入200μL Annexin V-FITC-PI染色液轻轻重悬细胞。(200μL染色液中含有5μLAnnexin V-FITC母液和5μLPI母液)
(3)室温(20-25℃)避光孵育30分钟，随后置于冰浴中。可以使用铝箔进行避光。孵育过程中可以重悬细胞2-3次以改善染色效果。
(4)每个样品中加入200μL不含染料的缓冲液，混匀后等待上机检测。
(5)Annexin V-FITC为绿色荧光，PI为红色荧光，通过调整流式细胞仪的相关设置和参数使细胞出现在相应的位置。统计各个区域中细胞的百分比。具体结果如表4所示。
表4
Figure PCTCN2020079854-appb-000084
Figure PCTCN2020079854-appb-000085
表4的测试结果显示，本发明化合物促进人急性淋巴细胞白血病细胞RS4；11凋亡的效果较好。
效果实施例4化合物对裸鼠移植瘤的抑制增殖效果
(1)细胞悬液的制备
将处于对数生长期的细胞株RS4；11细胞消化，离心，倒掉旧培养基，重悬于PBS中。
(2)裸小鼠接种
用PBS洗细胞两遍，与Matrigel胶按1：1比例混合，调整细胞浓度为5×10 6/mL，取0.2mL接种于裸小鼠右侧腹部皮下。
(3)给药与检测
当肿瘤体积长至250mm 3时，采用随机数字表法分组，同时称量小鼠体重，体重应无统计学差异。将生长状况良好的裸小鼠随机取出9只作为溶剂组，其他均为实验组；溶剂组给药为60％PEG400；实验组给药剂量为12.5mg/kg，25mg/kg和50mg/kg，周期为隔天给药一次，给药方式为腹腔给药。期间测量肿瘤大小及小鼠体重。实验结果如图1、图2所示，化合物I-3可以明显地抑制肿瘤体积的增长，且有剂量依赖性，最高剂量50mg/kg组与溶剂组相比，肿瘤缩小3/4左右，并且对小鼠体重没有影响。
(4)Ki67免疫荧光分析
对肿瘤组织进行取材、冷冻切片后，用于免疫荧光染色。用PBS清洗切片3×5min。将枸橼酸溶液置于烧杯中，锡纸包住烧杯口，微波炉高火煮沸约5min，将切片置于切片 架上放至溶液中继续煮沸10min。取出烧杯，将切片留在溶液中待烧杯内溶液自然冷却约2h至室温。用PBS洗3×5min。加一滴免疫组化封闭液与组织切片上，室温封闭1h。吸干液体，按照工作浓度分别配置一抗。每张切片滴加100μL一抗，完全覆盖待检组织，4℃湿盒中孵育过夜。次日从4℃取出切片，置于37℃烘箱中继续反应1h。用PBS洗3×5min。每张切片加100μL二抗，完全覆盖待检组织，室温孵育1h，然后用PBS洗3×5min。用Anti-Fade Dapi-Fluoromount-G封片。在波长550nm处，用荧光倒置显微镜进行检测分析。Ki67的染色结果如图3所示。溶剂组取材的瘤体中Ki67的表达量明显高于化合物I-3给药组(低剂量组(12.5mg/kg)、中剂量组(25mg/kg)和高剂量组(50mg/kg)三个剂量组)中Ki67的表达量。化合物I-3加入后，Ki67表达量呈现浓度依赖性的降低，说明化合物I-3可以减弱RS4；11移植瘤的增殖。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (11)

  1. 一种如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐，
    Figure PCTCN2020079854-appb-100001
    其中，X为O或S；n为1或2；p为1、2、3或4；q为0、1、2、3、4或5；
    R 1为C 6～C 10芳基、R 1a取代的C 6～C 10芳基、R 1b取代的C 1～C 3烷基、C 4～C 6环烷基或R 1c取代的C 4～C 6环烷基；
    R 1b为C 6～C 10芳基或R 1b-1取代的C 6～C 10芳基；
    R 1a、R 1b-1和R 1c独立地为羟基、硝基、卤素、C 1～C 6烷氧基、C 1～C 6烷基或卤素取代的C 1～C 6烷基；
    所述R 1a、R 1b、R 1c和R 1b-1的个数独立地为一个或多个，当所述R 1a的个数为多个时，所述R 1a相同或不同；当所述R 1b的个数为多个时，所述R 1b相同或不同；当所述R 1c的个数为多个时，所述R 1c相同或不同；当所述R 1b-1的个数为多个时，所述R 1b-1相同或不同；
    R 2和R 3独立地为H、C 1～C 6烷基、或R 2和R 3连接形成-(CH 2) m-结构，m为0、1或2；
    每个R A独立地为C 1～C 6烷基；每个R B独立地为卤素、硝基、C 1～C 6烷基、C 1～C 6烷氧基或卤素取代的C 1～C 6烷基。
  2. 如权利要求1所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐，其特征在于，R 1中，所述C 6～C 10芳基和所述R 1a取代的C 6～C 10芳基中的C 6～C 10芳基独立地为苯基或萘基，优选为苯基；
    和/或，R 1中，所述R 1a的个数为1～4个，优选为1～2个；当所述R 1a的个数为多个时，优选为R 1a相同；
    和/或，R 1中，所述R 1b取代的C 1～C 3烷基中的C 1～C 3烷基为甲基、乙基、正丙基或异丙基；
    和/或，R 1中，所述R 1b的个数为1～2个，优选为1个；当所述R 1b的个数为多个时，优选为R 1b相同；
    和/或，R 1b中，所述C 6～C 10芳基和所述R 1b-1取代的C 6～C 10芳基中的C 6～C 10芳基独 立地为苯基；
    和/或，R 1b中，所述R 1b-1的个数为1～4个，优选为1～2个；当所述R 1b-1的个数为多个时，优选为R 1b-1相同；
    和/或，R 1中，所述C 4～C 6环烷基和R 1c取代的C 4～C 6环烷基中的C 4～C 6环烷基独立地为C 5～C 6环烷基；优选为环戊基或环己基；
    和/或，R 1中，所述R 1c的个数为1～4个，优选为1～2个；当所述R 1c的个数为多个时，优选为R 1c相同；
    和/或，R 1a、R 1b-1和R 1c中，所述C 1～C 6烷氧基为C 1～C 3烷氧基，优选为甲氧基、乙氧基、正丙氧基或异丙氧基；
    和/或，R 1a、R 1b-1和R 1c中，所述卤素和所述卤素取代的C 1～C 6烷基中的卤素独立地为氟、氯、溴或碘，优选为氟；
    和/或，R 1a、R 1b-1和R 1c中，所述C 1～C 6烷基和所述卤素取代的C 1～C 6烷基中的C 1～C 6烷基独立地为C 1～C 3烷基，独立地优选为甲基、乙基、正丙基或异丙基；
    和/或，R 1a、R 1b-1和R 1c中，所述卤素取代的C 1～C 6烷基为CF 3；
    和/或，R 2和R 3中，所述C 1～C 6烷基为C 1～C 3烷基，优选为甲基、乙基、正丙基或异丙基；
    和/或，当R 2和R 3连接形成-(CH 2) m-结构时，m为2；
    和/或，R B中，所述卤素和卤素取代的C 1～C 6烷基时中的卤素独立地为氟、氯、溴或碘，独立地优选为氟或氯；
    和/或，R B中，所述C 1～C 6烷基和卤素取代的C 1～C 6烷基中的C 1～C 6烷基独立地为C 1～C 3烷基，独立地优选为甲基、乙基、正丙基或异丙基；
    和/或，R A中，所述C 1～C 6烷基为C 1～C 3烷基，优选为甲基、乙基、正丙基或异丙基；
    和/或，R B中，所述C 1～C 6烷氧基为C 1～C 3烷氧基，优选为甲氧基、乙氧基、正丙氧基或异丙氧基；
    和/或，R B中，所述卤素取代的C 1～C 6烷基为氟取代的C 1～C 3烷基，优选为CF 3。
  3. 如权利要求1所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐，其特征在于，R 1中，R 1a、R 1b-1和R 1c独立地为羟基、硝基或C 1～C 6烷氧基，进一步独立地优选为羟基或C 1～C 6烷氧基；
    和/或，式I中，n为2；
    和/或，式I中，R 1为R 1a取代的C 6～C 10芳基、R 1b取代的C 1～C 3烷基、或R 1c取代的C 4～C 6环烷基，R 1b为R 1b-1取代的C 6～C 10芳基，其中，R 1a、R 1b-1和R 1c独立地优选为羟 基、硝基或C 1～C 6烷氧基，进一步独立地优选为羟基或C 1～C 6烷氧基；R 1进一步优选为R 1a取代的C 6～C 10芳基，其中，R 1a优选为羟基或C 1～C 6烷氧基；R 1更优选为
    Figure PCTCN2020079854-appb-100002
    其中，R 1-1、R 1-2、R 1-3、R 1-4和R 1-5独立地为H、羟基或C 1～C 6烷氧基，且R 1-1、R 1-2、R 1- 3、R 1-4和R 1-5不同时为H，R 1-1、R 1-2、R 1-3、R 1-4和R 1-5中，所述C 1～C 6烷氧基优选为C 1～C 3烷氧基，进一步优选为甲氧基、乙氧基、正丙氧基或异丙氧基；
    和/或，式I中，R 2和R 3独立地为H或C 1～C 3烷基(例如甲基)，独立地优选为H；
    和/或，式I中，p为1或2；优选为1；
    和/或，式I中，q为1、2、3、4或5；优选为1或2；
    和/或，式I中，每个R B独立地为卤素、硝基、C 1～C 6烷氧基或卤素取代的C 1～C 6烷基，且q为1、2、3、4或5；独立地优选为卤素、或氟取代的C 1～C 3烷基，且q为1或2。
  4. 如权利要求1所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐，其特征在于，
    R 1为
    Figure PCTCN2020079854-appb-100003
    R 1-1、R 1-4和R 1-5为H，R 1-2和R 1-3独立地为羟基或C 1～C 6烷氧基；较佳地，
    Figure PCTCN2020079854-appb-100004
    为
    Figure PCTCN2020079854-appb-100005
    和/或，
    Figure PCTCN2020079854-appb-100006
    为
    Figure PCTCN2020079854-appb-100007
    其中，R 10和R 11中的一个为C 1～C 6烷基，另一个为H；R 9和R 12为H；较佳地，R 10和R 11中的一个为C 1～C 3烷基，另一个为H；R 9和R 12为H，R 1的定义如权利要求1～3中至少一项所述；
    和/或，
    Figure PCTCN2020079854-appb-100008
    为
    Figure PCTCN2020079854-appb-100009
    其中，R 4、R 6和R 8为H，R 5和R 7独立地为卤 素、硝基、C 1～C 6烷氧基或卤素取代的C 1～C 6烷基；或，R 4和R 8为H，R 5、R 6和R 7中的一个为卤素、硝基、C 1～C 6烷氧基或卤素取代的C 1～C 6烷基，另外两个为H；较佳地，R 4、R 6和R 8为H，R 5和R 7独立地为卤素或氟取代的C 1～C 3烷基；或，R 4和R 8为H，R 5、R 6和R 7中的一个为C 1～C 3烷氧基或硝基，另外两个为H；更佳地，
    Figure PCTCN2020079854-appb-100010
    为
    Figure PCTCN2020079854-appb-100011
  5. 如权利要求1～4中至少一项所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐，其特征在于，n为2，R 2和R 3为H；
    或，R A为C 1～C 3烷基，p为1或2；
    或，n为2，R 2和R 3为H，
    Figure PCTCN2020079854-appb-100012
    为
    Figure PCTCN2020079854-appb-100013
    R 10和R 11中的一个为C 1～C 3烷基，另一个为H；R 9和R 12为H；
    或，n为2，R 2和R 3为H，R 1为R 1a取代的C 6～C 10芳基，R 1a为羟基或C 1～C 6烷氧基；
    或，R 1为R 1a取代的C 6～C 10芳基，R 1a为羟基或C 1～C 6烷氧基，
    Figure PCTCN2020079854-appb-100014
    为
    Figure PCTCN2020079854-appb-100015
    R 10和R 11中的一个为C 1～C 3烷基，另一个为H；R 9和R 12为H；
    或，n为2，R 2和R 3为H，R 1为R 1a取代的C 6～C 10芳基，R 1a为羟基或C 1～C 6烷氧基，
    Figure PCTCN2020079854-appb-100016
    为
    Figure PCTCN2020079854-appb-100017
    R 10和R 11中的一个为C 1～C 3烷基，另一个为H；R 9和R 12为H；
    或，n为2，R 2和R 3为H，R 1为
    Figure PCTCN2020079854-appb-100018
    R 1-1、R 1-4和R 1-5为H，R 1-2和R 1- 3独立地为羟基或C 1～C 6烷氧基，
    Figure PCTCN2020079854-appb-100019
    为
    Figure PCTCN2020079854-appb-100020
    R 10和R 11中的一个为C 1～C 3烷基，另一个为H；R 9和R 12为H；
    或，q为1、2、3、4或5；R 1为R 1a取代的C 6～C 10芳基，R 1a为羟基或C 1～C 6烷氧基，当R 1a为羟基时，每个R B独立地为卤素或氟取代的C 1～C 3烷基；R 1a为C 1～C 6烷氧基时，每个R B独立地为卤素、硝基或氟取代的C 1～C 3烷基；
    或，
    Figure PCTCN2020079854-appb-100021
    为
    Figure PCTCN2020079854-appb-100022
    R 10和R 11中的一个为C 1～C 3烷基，另一个为H；R 9和R 12为H；每个R B独立地为卤素、硝基、C 1～C 3烷氧基或氟取代的C 1～C 3烷基，且q为1、2、3、4或5；
    或，n为2，R 2和R 3为H，R 1为R 1a取代的C 6～C 10芳基，R 1a为羟基或C 1～C 6烷氧基，每个R B独立地为卤素、硝基、C 1～C 3烷氧基或氟取代的C 1～C 3烷基，且q为1、2、3、4或5；
    Figure PCTCN2020079854-appb-100023
    为
    Figure PCTCN2020079854-appb-100024
    R 10和R 11中的一个为C 1～C 3烷基，另一个为H；R 9和R 12为H；
    或，n为2，R 2和R 3为H，R 1为
    Figure PCTCN2020079854-appb-100025
    为
    Figure PCTCN2020079854-appb-100026
    Figure PCTCN2020079854-appb-100027
    为
    Figure PCTCN2020079854-appb-100028
    R 10和R 11中的一个为C 1～C 3烷基，另一个为H；R 9和R 12为H。
  6. 如权利要求1～5中至少一项所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐，其特征在于，所述式I所示的苯基噻吩磺酰胺类化合物为如下任一化合物：
    Figure PCTCN2020079854-appb-100029
    Figure PCTCN2020079854-appb-100030
  7. 如权利要求1～6中至少一项所述的如式I所示的苯基噻吩磺酰胺类化合物的制备方法，其特征在于，在有机溶剂中，将化合物II和化合物III进行如下所示的反应，得到所述的式I所示的苯基噻吩磺酰胺类化合物，即可；
    Figure PCTCN2020079854-appb-100031
    其中，R 1、R 2、R 3、R A、R B、p、q、X和n的定义均如权利要求1～6中至少一项所述。
  8. 如权利要求7所述的如式I所示的苯基噻吩磺酰胺类化合物的制备方法，其特征在于，当化合物II中含有羟基取代基时，对羟基进行保护后再进行所述的反应；
    和/或，所述化合物II和化合物III的摩尔比为1：(1～1.5)，优选为1：1.2；
    和/或，所述有机溶剂为卤代烷烃，优选为二氯甲烷；
    和/或，所述反应的温度为20℃～30℃。
  9. 一种如式II、IV、V、VI、VII或VIII所示的化合物，
    Figure PCTCN2020079854-appb-100032
    其中，R 1、R 2、R 3、R A、p和n的定义均如权利要求1～6中至少一项所述；
    较佳地，所述式II所示的化合物为如下任一化合物：
    Figure PCTCN2020079854-appb-100033
    较佳地，所述式IV所示的化合物为如下任一化合物：
    Figure PCTCN2020079854-appb-100034
    较佳地，所述式V所示的化合物为如下任一化合物：
    Figure PCTCN2020079854-appb-100035
    较佳地，所述式VI所示的化合物为如下任一化合物：
    Figure PCTCN2020079854-appb-100036
    较佳地，所述式VII所示的化合物为如下任一化合物：
    Figure PCTCN2020079854-appb-100037
    较佳地，所述式VIII所示的化合物为如下化合物：
    Figure PCTCN2020079854-appb-100038
  10. 如权利要求1～6中至少一项所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐在制备Bcl抗凋亡蛋白抑制剂、或制备用于治疗和/或预防与Bcl抗凋亡蛋白相关的疾病的药物、或制备用于治疗和/或预防人子宫颈癌和/或白血病的药物中的应用。
  11. 一种药物组合物，其特征在于，所述药物组合物包括权利要求1～6中至少一项所述的如式I所示的苯基噻吩磺酰胺类化合物或其药学上可接受的盐，和至少一种药用辅料。
PCT/CN2020/079854 2019-07-19 2020-03-18 一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用 WO2021012689A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910655053.X 2019-07-19
CN201910655053.XA CN110330477B (zh) 2019-07-19 2019-07-19 一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2021012689A1 true WO2021012689A1 (zh) 2021-01-28

Family

ID=68146012

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/079854 WO2021012689A1 (zh) 2019-07-19 2020-03-18 一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用

Country Status (2)

Country Link
CN (1) CN110330477B (zh)
WO (1) WO2021012689A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110330477B (zh) * 2019-07-19 2021-03-23 中国科学院上海有机化学研究所 一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103373969A (zh) * 2012-04-27 2013-10-30 中国科学院上海有机化学研究所 苯基唑环取代酰胺类化合物及其制备方法和用途
CN103450149A (zh) * 2012-06-01 2013-12-18 中国科学院上海有机化学研究所 苯基噻吩磺酰胺类化合物及其制备方法和用途
CN109384764A (zh) * 2018-12-12 2019-02-26 中国科学院上海有机化学研究所 苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用
CN110330477A (zh) * 2019-07-19 2019-10-15 中国科学院上海有机化学研究所 一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103373969A (zh) * 2012-04-27 2013-10-30 中国科学院上海有机化学研究所 苯基唑环取代酰胺类化合物及其制备方法和用途
CN103450149A (zh) * 2012-06-01 2013-12-18 中国科学院上海有机化学研究所 苯基噻吩磺酰胺类化合物及其制备方法和用途
CN109384764A (zh) * 2018-12-12 2019-02-26 中国科学院上海有机化学研究所 苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用
CN110330477A (zh) * 2019-07-19 2019-10-15 中国科学院上海有机化学研究所 一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG CHENGWEN ET AL.: "Development of 3-Phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl-2 Family Proteins", CHEMMEDCHEM, vol. 9, no. 7, 29 April 2014 (2014-04-29), pages 1436 - 1452, XP055774640, ISSN: 1860-7187 *

Also Published As

Publication number Publication date
CN110330477B (zh) 2021-03-23
CN110330477A (zh) 2019-10-15

Similar Documents

Publication Publication Date Title
WO2020088357A1 (zh) 联苯类化合物、其中间体、制备方法、药物组合物及应用
Von Angerer et al. 2-Phenylindoles. Relationship between structure, estrogen receptor affinity, and mammary tumor inhibiting activity in the rat
KR100395280B1 (ko) 신규한3환성화합물및그를함유하는의약조성물
WO2017107754A1 (zh) 苯并哌啶类衍生物、其制备方法及其在医药上的应用
KR100335169B1 (ko) 포화 고리를 갖는 신규한 트리시클릭 화합물 및 이를포함하는 의약 조성물
WO2022268066A1 (zh) 一种蛋白降解剂
JP2023503962A (ja) 新規な甲状腺ホルモン模倣物
CN107056799B (zh) 辛二酸单酰苯胺基团氧桥双庚烯磺酰胺类化合物、其合成方法、应用和抗乳腺癌药物组合物
TW201336831A (zh) 作為鈣感測受體調節劑之取代二氫苯並哌喃化合物
JP2022522334A (ja) 新規な甲状腺模倣物
WO2023016484A1 (zh) 磺酰胺衍生物、其制备方法及其在医药上的应用
TW201623257A (zh) 藥理活性之喹唑啉二酮衍生物
CN106478606A (zh) N‑取代吲哚类衍生物及其应用
WO2021012689A1 (zh) 一种苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用
WO2022228286A1 (zh) 一种新型联苯类衍生物及其制备方法与医药用途
JP2023530708A (ja) 甲状腺様作用剤
EP1254106B1 (en) Calcilytic compounds
CN101253146A (zh) 用于治疗肥胖症及相关病症的新的氨基酸衍生物
CN109384764B (zh) 苯基噻吩磺酰胺类化合物、药物组合物、其制备方法和应用
CA2426730A1 (en) Calcilytic compounds
MXPA02009618A (es) Sulfonatos arilicos y heteroarilicos.
WO2017219935A1 (zh) 联芳基脲类衍生物或其盐及其制备方法和用途
CN114292226A (zh) 具有异羟肟酸结构的化合物及其制备方法和应用
WO2021228215A1 (zh) 可用作RORγ调节剂的联芳基类化合物
WO2024146619A1 (zh) 橙酮衍生物或类似物、其制备方法、药物组合物和用途

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: 20842963

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20842963

Country of ref document: EP

Kind code of ref document: A1