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WO2024145931A1 - SMALL MOLECULE INHIBITOR FOR β-CATENIN/BCL9 PROTEIN-PROTEIN INTERACTION AND USE THEREOF - Google Patents

SMALL MOLECULE INHIBITOR FOR β-CATENIN/BCL9 PROTEIN-PROTEIN INTERACTION AND USE THEREOF Download PDF

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Publication number
WO2024145931A1
WO2024145931A1 PCT/CN2023/071067 CN2023071067W WO2024145931A1 WO 2024145931 A1 WO2024145931 A1 WO 2024145931A1 CN 2023071067 W CN2023071067 W CN 2023071067W WO 2024145931 A1 WO2024145931 A1 WO 2024145931A1
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Prior art keywords
group
substituted
alkyl
membered
piperidin
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PCT/CN2023/071067
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French (fr)
Chinese (zh)
Inventor
李建其
朱棣
张庆伟
刘成龙
张�浩
沈栎安
王冠
Original Assignee
上海医药工业研究院有限公司
复旦大学
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Priority to PCT/CN2023/071067 priority Critical patent/WO2024145931A1/en
Publication of WO2024145931A1 publication Critical patent/WO2024145931A1/en

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    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • 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
    • C07D409/10—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 carbon chain containing aromatic rings
    • 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

Definitions

  • ⁇ -catenin/BCL9 protein-protein inhibitors are divided into peptides and small molecules.
  • Peptide inhibitors are difficult to prepare and have poor oral absorption, while small molecule inhibitors are easy to prepare, can be orally absorbed, and have high targeting, which is the current research focus of ⁇ -catenin/BCL9 PPI inhibitors.
  • R1 and R2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, -ORa , substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring;
  • Ra is a 4- to 6-membered heterocycloalkyl group
  • R3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
  • R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted amine, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring;
  • Ring A is a saturated aliphatic ring, an aromatic ring or a heteroaromatic ring
  • R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring.
  • the compound represented by formula (I-1) is a compound represented by formula (II), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;
  • R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring.
  • the aryl group/aromatic ring or aromatic hetero group/heteroaromatic ring are independently phenyl, biphenyl, naphthyl, anthracenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, morpholinyl, piperidinyl or piperazinyl, thienyl, benzothienyl, pyrazolyl, benzopyrazolyl, indolyl, dioxolanyl, benzo[1,3]dioxolanyl, oxazolyl, benzoxazolyl, furanyl, benzofuranyl, thiazolyl or benzothiazolyl, which may be optionally substituted;
  • the alkyl group is an alkyl group containing 1 to 6 carbon atoms
  • the small molecule inhibitor that interacts with the ⁇ -catenin/BCL9 protein has a general structural formula as shown in formula (I-1), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof,
  • Ring A is a saturated aliphatic ring, an aromatic ring or a heteroaromatic ring
  • the ring A may be cyclohexane, benzene, biphenyl, naphthalene or quinoline.
  • R1 and R2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle; R1 and R2 may be the same or different.
  • R 1 and R 2 can be independently selected from hydrogen, halogen, C 1 -C 4 alkyl, alkoxy, thienyl, benzothienyl, pyrazolyl, halogenated aryl and Any two of; Further preferably, R 1 and R 2 can be the combination shown in the following table:
  • R3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
  • R4 can be hydrogen, amino, amide, carboxyl,
  • R 5 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring.
  • R 5 can be hydrogen, alkyl, piperazine or benzenesulfonyl.
  • the alkyl group is a C 1 -C 6 alkyl group.
  • the compound represented by formula (I) is a compound represented by formula (III),
  • Ring A is a saturated aliphatic ring group, an aromatic ring group or a heteroaryl group,
  • the aromatic ring group is a 6- to 14-membered aromatic group
  • R1 and R2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, -ORa , substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring,
  • the saturated or unsaturated alkyl group is a C 1 -C 6 alkyl group
  • the haloalkyl group is a C 1 -C 6 alkyl group substituted by one or more halogens,
  • the haloalkoxy group is a C 1 -C 6 alkoxy group substituted by one or more halogens
  • the aryl group in the substituted or unsubstituted aryl group is a 6- to 14-membered aryl group, wherein the substituted aryl group is a 6- to 14-membered aryl group substituted by one or more R b ,
  • the heterocycle in the substituted or unsubstituted saturated or unsaturated heterocycle is a 4-10-membered heterocycloalkyl, wherein the substituted saturated or unsaturated heterocycle is a 4-10-membered heterocycloalkyl substituted by one or more Re ;
  • R d is hydrogen, 6- to 14-membered aryl, 5- to 12-membered heteroaryl, or 4- to 6-membered heterocycloalkyl;
  • R c-1-1 and R c-1-2 are independently halogen;
  • ring A is a 6- to 14-membered aryl group.
  • R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, 5- to 12-membered heteroaryl, 3- to 6-membered cycloalkyl, 6- to 14-membered aryl, -OR a , or 6- to 14-membered aryl substituted with one or more R b .
  • R 1 is a 5- to 12-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a 6- to 14-membered aryl group, or a 6- to 14-membered aryl group substituted with one or more R b .
  • R 1 and R 2 are each independently hydrogen, 5- to 12-membered heteroaryl, 3- to 6-membered cycloalkyl, 6- to 14-membered aryl, -OR a , or 6- to 14-membered aryl substituted with one or more R b .
  • X is a carbonyl group, and the compound represented by formula (III) is not:
  • each n is independently 0, 1, or 3.
  • each m is independently 1.
  • R 3 is For example
  • R4 is hydroxy, 4- to 10-membered heterocycloalkyl, -NH-( SO2 ) -Rc , -NH-( CH2 ) k - Rd , or 4- to 10-membered heterocycloalkyl substituted by one or more Re .
  • k is 0 or 1.
  • R c is a 6- to 14-membered aryl group, a 6- to 14-membered aryl group substituted with one or more R c-1 , or a 5- to 12-membered heteroaryl group.
  • the 4- to 6-membered cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane.
  • the 6-14 membered aryl group is phenyl or naphthyl, for example phenyl.
  • the heteroatom in the 5- to 12-membered heteroaryl group is N, S or O, and the number of heteroatoms is 1 or 2, and is preferably a 6-membered nitrogen-containing heteroaryl group.
  • the C1 - C6 alkoxy group and the C1 -C6 alkoxy group substituted by one or more halogens is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy.
  • the halogen in the halogen, C1 - C6 alkyl substituted by one or more halogen, C1 - C6 alkoxy substituted by one or more halogen and C1 - C6 alkylthio substituted by one or more halogen is fluorine, chlorine, bromine or iodine.
  • the C1 - C6 alkylthio group substituted by one or more halogens is methylthio, ethylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio, tert-butylthio or isobutylthio.
  • the 6- to 14-membered aryl group and the 6- to 14-membered aryl group substituted by one or more R b is phenyl or naphthyl, for example phenyl.
  • the 5- to 12-membered heteroaryl group and the 5- to 12-membered heteroaryl group substituted by one or more Rf are 5- to 10-membered heteroaryl groups.
  • the heteroatom in the 5- to 10-membered heteroaryl group is N, O or S, and the number of heteroatoms is 1 or 2, such as thienyl, pyrazole or benzothienyl.
  • the heteroatom in the 4- to 6-membered heterocycloalkyl group is N, S or O, and the number of heteroatoms is 1 or 2, and is preferably a 6-membered nitrogen-containing heterocyclohexyl group.
  • the 4- to 6-membered heterocycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • the heteroatom in the 5- to 6-membered heterocycloalkyl is N, O or S, and the number of the heteroatom is 1, such as azacyclopentane.
  • the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine.
  • the C 1 -C 6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example, methyl, isopropyl or tert-butyl.
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy.
  • the C 1 -C 6 alkyl and the C 1 -C 6 alkyl-NH- are methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl.
  • the halogen is fluorine, chlorine, bromine or iodine.
  • the C 1 -C 6 alkoxy group and the C 1 -C 6 alkoxy group substituted by one or more halogens is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy.
  • the halogen in the halogen, C 1 -C 6 alkyl substituted by one or more halogens, C 1 -C 6 alkoxy substituted by one or more halogens and C 1 -C 6 alkylthio substituted by one or more halogens is fluorine, chlorine, bromine or iodine.
  • the C 1 -C 6 alkylthio group substituted by one or more halogens is methylthio, ethylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio, tert-butylthio or isobutylthio.
  • the 6- to 14-membered aryl group is phenyl or naphthyl.
  • the 5- to 12-membered heteroaryl group is a 5- to 10-membered heteroaryl group.
  • the heteroatom in the 5- to 10-membered heteroaryl group is N, O or S, and the number of heteroatoms is 1 or 2.
  • the 4- to 10-membered heterocycloalkyl group and the 4- to 10-membered heterocycloalkyl group substituted by one or more Re are 4- to 7-membered heterocycloalkyl groups, preferably, the heteroatom in the 4- to 7-membered heterocycloalkyl group is O or N, and more preferably, the number of heteroatoms in the 4- to 7-membered heterocycloalkyl group is 1 or 2, for example
  • the compound having the general structural formula (III) is a compound having the general structural formula (III-2).
  • Ra is a 4- to 6-membered heterocycloalkyl group
  • the pharmaceutically acceptable salt of the compound represented by formula (III) is preferably a hydrochloride.
  • X is Chemical bond, methyl
  • R 3 is
  • R 4 is
  • the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of substance A and a pharmaceutical excipient;
  • substance A is the compound represented by formula (I) above, or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;
  • the substance A is a compound represented by the above formula (III) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a use of a substance A in the preparation of a drug, wherein the drug is used to treat and/or prevent tumors, wherein the substance A is a compound as represented by formula (I), an isomer thereof, a pharmaceutically acceptable salt, ester or prodrug thereof;
  • R 1 , R 2 , X and R 3 are as described in any one of the present invention.
  • the present invention also provides a method for treating and/or preventing tumors, comprising administering to a patient a therapeutically effective amount of a substance A, wherein the substance A is a compound represented by formula (I), an isomer thereof, a pharmaceutically acceptable salt, ester or prodrug thereof;
  • R 1 , R 2 , X and R 3 are as described in any one of the present invention.
  • the tumor is breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, blood cancer, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, gastrointestinal stromal tumor or skin cancer, and further preferably, the tumor is breast cancer, colon cancer or liver cancer.
  • the substance A is a compound represented by the above formula (III) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition, comprising substance A and an immune checkpoint inhibitor (ICI), wherein substance A is a compound represented by formula (I), an isomer thereof, a pharmaceutically acceptable salt, ester or a prodrug thereof; preferably, the immune checkpoint inhibitor is PD-1, and further preferably, substance A is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.
  • ICI immune checkpoint inhibitor
  • the present invention also provides the use of the small molecule inhibitor interacting with ⁇ -catenin/BCL9 protein, the small molecule inhibitor interacting with ⁇ -catenin/BCL9 protein prepared by the method described in the aforementioned technical scheme, or the pharmaceutical composition described in the aforementioned technical scheme in the preparation of anti-tumor drugs.
  • the tumors include breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, blood cancer, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, gastrointestinal stromal tumors, and skin cancer.
  • the present invention has confirmed through experiments that the small molecule inhibitor interacting with the ⁇ -catenin/BCL9 protein protein of the present invention has an anti-proliferation inhibitory effect on tumor cell lines such as human breast cancer cells MDA-MB-231, human breast cancer cells MDA-MB-468, human colon cancer cells HCT-116, and human liver cancer cell lines HepG2, and can be used in drugs for treating solid tumors or blood cancers related to human or animal cell proliferation.
  • tumor cell lines such as human breast cancer cells MDA-MB-231, human breast cancer cells MDA-MB-468, human colon cancer cells HCT-116, and human liver cancer cell lines HepG2
  • the present invention also provides a method for preparing the compound represented by the above formula (I), which can be prepared by any of the following schemes:
  • Ring A, K, R 1 , R 2 , X, R d and R c are as described in any one of the present invention.
  • R 4 is a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered heterocycloalkyl group substituted by one or more Re ;
  • Ring A, R 1 , R 2 , Re , X, and 4- to 10-membered heterocycloalkyl are as described in any one of the present invention.
  • the catalyst in the preparation method, in the embodiment (1), is a conventional catalyst for such reactions in the art, such as lithium hydroxide.
  • a Bronsted acid such as hydrochloric acid
  • the pH of the system is 3-4 after the Bronsted acid is added.
  • the compound represented by formula (III-3) obtained can further undergo a salt-forming reaction in a dioxane solution of hydrochloric acid.
  • the solvent is a conventional solvent for such reactions in the art, such as DCM.
  • the solvent is a conventional solvent for such reactions in the art, such as dichloromethane and/or DMF.
  • the catalyst in the preparation method, in the embodiment (3), is a conventional catalyst for such reactions in the art, such as triethylamine and/or HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate).
  • R8 is a group that can react with 1-NH in the piperidine ring
  • the preparation method of the compound of formula (V) comprises:
  • the conditions of the first reaction include heating the reactants under alkaline conditions;
  • pharmaceutically acceptable prodrug refers to a precursor compound that has the ability to form the small molecule inhibitor of the present invention in vitro or in vivo.
  • prevention refers to reducing the risk of developing a disease.
  • the reagents and raw materials used in the present invention are commercially available.
  • Step e Preparation of 3′,4′-dimethyl-[1,1′-biphenyl]-3-carboxylic acid, compound 10
  • Step f Preparation of methyl 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propanoate, compound 11
  • Step g Preparation of 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-1
  • Step c Preparation of 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-21
  • Step d Refer to Example 1 to obtain tert-butyl (3S)-3-((3′,4′-difluoro-5-(3-(3-((1-methoxy-2-methyl-1-oxopropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)oxy)pyrrolidine-1-carboxylate
  • Step a Refer to Example 1 to obtain tert-butyl 4-(2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-carboxylate
  • the electrophysiological stimulation scheme for hERG potassium channels is to first clamp the membrane voltage at -80mV, give the cell a voltage stimulus of +20mV for 2s, activate the hERG potassium channels, and then repolarize to -50mV for 5s to generate an outward tail current.
  • the stimulation frequency is once every 15s.
  • the current value is the peak value of the tail current.
  • T1 /2 and CLint were calculated according to the following formulas, where the slope is measured as the percent compound remaining and the natural logarithm of time, and V/M equals 1/protein concentration.
  • Compound II-39 is stable in liver microsome metabolism
  • CT26 colon cancer cells When they reach the logarithmic phase, digest them and centrifuge them at 800rpm for 5 minutes. Resuspend them in PBS to a cell concentration of 5 ⁇ 10 6 cells/ml. Inoculate them subcutaneously in the right groin of BALB/c mice as soon as possible. Each mouse is injected with 100ul of cell suspension. The cell suspension can be placed in an ice water bath during the operation.
  • mice are randomly grouped according to the tumor volume, and the tumor growth curve is recorded.
  • the positive control compound 37 (Journal of Medicinal Chemistry, 2021, 64, 16, 12109-12131) is administered at a dose of 30 mg/kg, once a day; the test compounds II-25 and II-27 are administered at a dose of 30 mg/kg, once a day.
  • the experimental results are shown in Figure 1.
  • the compound in vivo efficacy test was conducted using a colon cancer mouse model.
  • the test results showed that compounds II-25 and II-27 of the present invention can significantly inhibit the growth of tumors in mice after 5 days of administration, and are superior to the positive control compound 37.
  • the animals in the compound II-25 and II-27 groups were well tolerated and had good safety.
  • the animal experiment operation steps are as follows:
  • CT26 colon cancer cells When they reach the logarithmic phase, digest them and centrifuge them at 800rpm for 5 minutes. Resuspend them in PBS to a cell concentration of 5 ⁇ 10 6 cells/ml. Inoculate them subcutaneously in the right groin of BALB/c mice as soon as possible. Each mouse is injected with 100ul of cell suspension. The cell suspension can be placed in an ice water bath during the operation.
  • mice are randomly divided into groups according to the tumor volume, and the tumor growth curve is recorded.
  • the PD-1 antibody Bio X Cell, BE0146-25MG, InVivoMAb anti-mouse PD-1, clone RMP1-14
  • the tumor volume is measured every day.
  • Tumor volume formula: V L*W*W*1/2. The experiment is terminated when the tumor volume reaches about 1200 mm 3 .
  • the experimental results are shown in Figures 2 and 3.
  • TGI 1-(tumor volume of the treatment group/tumor volume of the control group) ⁇ 100%, reaching 81.1%.
  • the animals in the compound II-39 administration group were well tolerated and safe, and no significant weight loss of mice was observed.
  • the compound II-25 prepared in Example 25 was mixed with a filler, a disintegrant, and a lubricant, granulated, and tableted to obtain a pharmaceutical composition 1 containing the compound II-25 as an active ingredient.
  • Example 27 The compound II-27 prepared in Example 27 is mixed with a solvent and a stabilizer, filtered, and packaged to obtain a pharmaceutical composition 2 containing the compound II-27 as an active ingredient.
  • the compound II-39 prepared in Example 41 was mixed with a filler, a disintegrant, and a lubricant, granulated, and tableted to obtain a pharmaceutical composition 3 containing the compound II-39 as an active ingredient.
  • Compound II-2 prepared in Example 2 and compound II-13 prepared in Example 13 were mixed with a filler, a disintegrant, and a lubricant, granulated, and tableted to obtain a pharmaceutical composition 4 having compounds II-2 and II-13 as active ingredients.

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Abstract

Disclosed are a small molecule inhibitor for β-catenin/BCL9 protein-protein interaction and a use thereof. Specifically provided are a compound as represented by formula (I), or an isomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein the definitions of ring A, X, R1, R2, and R3 are as described in the description. The compound as represented by formula (I) has good β-catenin/BCL9 protein-protein affinity, good anti-tumor activity, and good application prospects.

Description

β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂及其应用Small molecule inhibitors of β-catenin/BCL9 protein-protein interaction and their applications 技术领域Technical Field
本发明涉及抗肿瘤药物技术领域，尤其涉及一种β-catenin/BCL9蛋白蛋白相互作用小分子抑制剂及其制备方法、药物组合物及其抗肿瘤应用。The present invention relates to the technical field of anti-tumor drugs, and in particular to a small molecule inhibitor of β-catenin/BCL9 protein-protein interaction, a preparation method thereof, a pharmaceutical composition and anti-tumor application thereof.
背景技术Background technique
研究发现人和其他哺乳动物中存在19种Wnt蛋白，它们具有27％-83％的氨基酸序列同源性以及23或24个半胱氨酸残基的保守序列。Wnt信号至少通过三条不同的细胞内通路进行传递：(1)Wnt/β-catenin信号通路；(2)Wnt/Ca 2+信号通路；(3)Wnt/pcp(planar cell polarity)信号通路。其中对于Wnt/β-catenin信号通路的研究最为广泛，该通路也被称为经典Wnt通路或β-catenin依赖的Wnt通路。 Studies have found that there are 19 Wnt proteins in humans and other mammals, which have 27%-83% amino acid sequence homology and a conserved sequence of 23 or 24 cysteine residues. Wnt signals are transmitted through at least three different intracellular pathways: (1) Wnt/β-catenin signaling pathway; (2) Wnt/Ca 2+ signaling pathway; (3) Wnt/pcp (planar cell polarity) signaling pathway. Among them, the Wnt/β-catenin signaling pathway has been the most widely studied, and this pathway is also called the classical Wnt pathway or the β-catenin-dependent Wnt pathway.
研究显示，Wnt/β-catenin信号通路通过调控细胞的增殖、迁移、分化、存活、粘附和干细胞的再生，促进胚胎的发育和维持体内稳态。Wnt/β-catenin信号通路在生命活动中发挥重要作用，当该通路被异常激活时，主要会导致癌症相关疾病的发生。因此，开发作用于Wnt/β-catenin信号通路的药物对肿瘤的治疗具有重要意义。目前，多个作用于Wnt/β-catenin信号通路的小分子化合物被报道用于癌症相关疾病，这类抑制剂主要作用于Wnt/β-catenin通路中的上游组分，由于β-catenin蛋白是Wnt通路的效应器，因此这类抑制剂会影响β-catenin蛋白对细胞之间的粘附作用，导致一系列副反应的发生。而作用于细胞核内蛋白的抑制剂，可以很好的避免此类副作用的产生。Studies have shown that the Wnt/β-catenin signaling pathway promotes embryonic development and maintains homeostasis in the body by regulating cell proliferation, migration, differentiation, survival, adhesion, and stem cell regeneration. The Wnt/β-catenin signaling pathway plays an important role in life activities. When the pathway is abnormally activated, it mainly leads to the occurrence of cancer-related diseases. Therefore, the development of drugs that act on the Wnt/β-catenin signaling pathway is of great significance for the treatment of tumors. At present, a number of small molecule compounds that act on the Wnt/β-catenin signaling pathway have been reported for cancer-related diseases. This type of inhibitor mainly acts on the upstream components of the Wnt/β-catenin pathway. Since the β-catenin protein is an effector of the Wnt pathway, this type of inhibitor will affect the adhesion of the β-catenin protein to cells, leading to a series of side effects. Inhibitors that act on proteins in the cell nucleus can effectively avoid the occurrence of such side effects.
在Wnt/β-catenin信号通路中，细胞核内的蛋白都是以与β-catenin相互作用的形式存在的，其中BCL9作为通路中的细胞核内转录共激活因子，由1350个氨基酸组成。研究显示，结肠癌、肝癌或多发性骨髓瘤的小鼠敲除BCL9后，可以显著地抑制肿瘤的生长和延长小鼠的存活时间，同时，下游的Myc、Ccnd1、Cd44和Vegfa基因也被抑制，且不会影响正常细胞的生长。β-catenin/BCL9复合物晶体结构显示，两个蛋白结合表面达到
Figure PCTCN2023071067-appb-000001
亲和力为0.5μM，适合小分子停留。以上研究都说明β-catenin/BCL9蛋白-蛋白相互作用可以作为抑制Wnt通路的一个抗肿瘤新靶标。 In the Wnt/β-catenin signaling pathway, proteins in the cell nucleus all exist in the form of interacting with β-catenin. BCL9, as a transcriptional coactivator in the cell nucleus in the pathway, is composed of 1,350 amino acids. Studies have shown that knocking out BCL9 in mice with colon cancer, liver cancer, or multiple myeloma can significantly inhibit tumor growth and prolong the survival of mice. At the same time, downstream Myc, Ccnd1, Cd44, and Vegfa genes are also inhibited without affecting the growth of normal cells. The crystal structure of the β-catenin/BCL9 complex shows that the binding surface of the two proteins reaches
Figure PCTCN2023071067-appb-000001
The affinity is 0.5 μM, which is suitable for small molecule retention. The above studies all indicate that the β-catenin/BCL9 protein-protein interaction can be used as a new anti-tumor target for inhibiting the Wnt pathway.
根据结构类型，β-catenin/BCL9蛋白-蛋白抑制剂分为肽类和小分子。肽类抑制剂制备困难、口服吸收差，而小分子抑制剂制备简便，可口服吸收，靶向性高，为目前β-catenin/BCL9PPI抑制剂研究重点。According to the structural type, β-catenin/BCL9 protein-protein inhibitors are divided into peptides and small molecules. Peptide inhibitors are difficult to prepare and have poor oral absorption, while small molecule inhibitors are easy to prepare, can be orally absorbed, and have high targeting, which is the current research focus of β-catenin/BCL9 PPI inhibitors.
现有研究中关于β-catenin/BCL9小分子抑制剂报道较少。化合物a(J Am Chem Soc，2015，137，12249-60)对蛋白亲和力为Ki＝0.41μM，selectivity＝125，但该化合物骨架刚性片段多，成药性较差。There are few reports on β-catenin/BCL9 small molecule inhibitors in existing studies. Compound a (J Am Chem Soc, 2015, 137, 12249-60) has a protein affinity of Ki = 0.41 μM and selectivity = 125, but the compound has many rigid skeleton fragments and poor drugability.
Figure PCTCN2023071067-appb-000002
Figure PCTCN2023071067-appb-000002
β-catenin/BCL9小分子抑制剂化合物b(Nat Commun，2012，3，680)和化合物c(Anal Biochem，2015，469，43-53)是通过体外筛选获得的。化合物b含苯二酚结构，存在假阳性可能；化合物c是通过高通量筛选得到的，可用于阻断β-catenin/BCL9蛋白-蛋白相互作用，但细胞试验中化合物c无活性(Journal of Medicinal Chemistry，2021，64(9))，推测其可能难以透过细胞膜而发挥作用。The β-catenin/BCL9 small molecule inhibitors compound b (Nat Commun, 2012, 3, 680) and compound c (Anal Biochem, 2015, 469, 43-53) were obtained through in vitro screening. Compound b contains a hydroquinone structure and may have false positives; compound c was obtained through high-throughput screening and can be used to block β-catenin/BCL9 protein-protein interactions, but compound c was inactive in cell experiments (Journal of Medicinal Chemistry, 2021, 64(9)), suggesting that it may be difficult to penetrate the cell membrane to exert its effect.
Figure PCTCN2023071067-appb-000003
Figure PCTCN2023071067-appb-000003
目前亟需一种靶向亲和力高、细胞膜透过性好的β-catenin/BCL9蛋白蛋白相互作用小分子抑制剂。Currently, there is an urgent need for a small molecule inhibitor of β-catenin/BCL9 protein-protein interaction with high targeting affinity and good cell membrane permeability.
发明内容Summary of the invention
本发明提供了一种如式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药；The present invention provides a compound as shown in formula (I), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;
Figure PCTCN2023071067-appb-000004
Figure PCTCN2023071067-appb-000004
其中，in,
环A为饱和脂肪环基、芳环基或杂芳基；Ring A is a saturated aliphatic ring group, an aromatic ring group or a heteroaryl group;
X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-CH(OH)-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-，其中各个n独立地为0、1、2、3或4；m为0、1或2； X is -C(=O)-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -, -CH(OH)-(CH 2 ) n -, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(=O)-(CH=CH) m -(CH 2 ) n -, or -(CH 2 ) n -, wherein each n is independently 0, 1, 2, 3 or 4; m is 0, 1 or 2;
R 1和R 2相互独立地为氢、饱和或不饱和烷基、烷氧基、烷氧羰基、羟基、卤素、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代环烷基、取代或非取代芳基、-OR a、取代或非取代杂芳基或取代或非取的饱和或不饱和杂环； R1 and R2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, -ORa , substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring;
R a为4～6元杂环烷基； Ra is a 4- to 6-membered heterocycloalkyl group;
R 3为烷氧基、取代或非取代烷基、卤素、硝基、胺基、烷胺基、羧基、 R3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
Figure PCTCN2023071067-appb-000005
其中，R 4为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代烷胺基、取代或非取代胺基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环；
Figure PCTCN2023071067-appb-000005
wherein R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted amine, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring;
结构通式如式(I)所示的化合物不为：The compound with the general structural formula (I) is not:
[根据细则26改正 31.03.2023]
Figure WO-DOC-FIGURE-1
[Corrected 31.03.2023 in accordance with Rule 26]
Figure WO-DOC-FIGURE-1
[根据细则26改正 31.03.2023]
Figure WO-DOC-FIGURE-2
[Corrected 31.03.2023 in accordance with Rule 26]
Figure WO-DOC-FIGURE-2
优选地，所述异构体为式(I)所示化合物的对映异构体或非对映异构体。Preferably, the isomer is an enantiomer or a diastereomer of the compound represented by formula (I).
某一方案中，所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药中的某些基团具有如下定义，未提及的基团的定义如本发明中任一方案所述(本段内容以下简称为“某一方案中”)：In a certain embodiment, certain groups in the compound represented by formula (I), or its isomers, or its pharmaceutically acceptable salts, esters or prodrugs have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "a certain embodiment"):
本发明提供了一种与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂，其为式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药。The present invention provides a small molecule inhibitor that interacts with β-catenin/BCL9 protein, which is a compound represented by formula (I), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof.
某一方案中，所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂，结构通式如式(I-1)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药；In a certain embodiment, the small molecule inhibitor that interacts with the β-catenin/BCL9 protein has a general structural formula as shown in formula (I-1), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;
Figure PCTCN2023071067-appb-000008
Figure PCTCN2023071067-appb-000008
其中，in,
环A为饱和脂肪环、芳环或杂芳环；Ring A is a saturated aliphatic ring, an aromatic ring or a heteroaromatic ring;
X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-CH(OH)-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-或-(CH 2) n-，其中n为0、1、2、3或4； X is -C(=O)-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -, -CH(OH)-(CH 2 ) n -, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n - or -(CH 2 ) n -, wherein n is 0, 1, 2, 3 or 4;
R 1、R 2相互独立地为氢、饱和或不饱和烷基、烷氧基、烷氧羰基、羟基、卤素、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代环烷基、取代或非取代芳基、取代或非取代杂芳基或取代或非取的饱和或不饱和杂环； R 1 and R 2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring;
R 3为烷氧基、取代或非取代烷基、卤素、硝基、胺基、烷胺基、羧基、 R3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
Figure PCTCN2023071067-appb-000009
其中，R 4为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环。
Figure PCTCN2023071067-appb-000009
wherein R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring.
优选的，所述式(I-1)所示化合物的结构通式(II)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药；Preferably, the compound represented by formula (I-1) is a compound represented by formula (II), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;
Figure PCTCN2023071067-appb-000010
Figure PCTCN2023071067-appb-000010
其中，in,
X、R 1和R 2的定义如式(I-1)所示； X, R 1 and R 2 are defined as shown in formula (I-1);
R 4为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环。 R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring.
优选地，所述脂肪环或环烷基相互独立地为含有5个碳原子以上的环烷基；Preferably, the aliphatic ring or cycloalkyl group is independently a cycloalkyl group containing 5 or more carbon atoms;
优选地，所述芳基/芳环或芳杂基/杂芳环相互独立地为苯基、联苯基、萘基、蒽基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、吡咯基、吗啉基、哌啶基或哌嗪基、噻吩基、苯并噻吩基、吡唑基、苯并吡唑基、吲哚基、二氧戊环基、苯并[1，3]二氧戊环基、噁唑基、苯并噁唑基、呋喃基、苯并呋喃基、噻唑基或苯并噻唑基，其可任选被取代；Preferably, the aryl group/aromatic ring or aromatic hetero group/heteroaromatic ring are independently phenyl, biphenyl, naphthyl, anthracenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, morpholinyl, piperidinyl or piperazinyl, thienyl, benzothienyl, pyrazolyl, benzopyrazolyl, indolyl, dioxolanyl, benzo[1,3]dioxolanyl, oxazolyl, benzoxazolyl, furanyl, benzofuranyl, thiazolyl or benzothiazolyl, which may be optionally substituted;
优选地，所述卤素或卤代中的卤素相互独立地为氟、氯或溴；Preferably, the halogen or the halogen in the halo is independently fluorine, chlorine or bromine;
优选地，所述烷基为含有1-6个碳原子的烷基；Preferably, the alkyl group is an alkyl group containing 1 to 6 carbon atoms;
优选地，所述杂环或杂环基独立地为含有至少1个O、N或S的五元环或六元环。Preferably, the heterocyclic ring or heterocyclic group is independently a five-membered ring or a six-membered ring containing at least one O, N or S.
优选地，所述药学上可接受的盐包括所述小分子抑制剂与下列酸中的一种或多种形成的酸加成盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸和杏仁酸。Preferably, the pharmaceutically acceptable salt includes an acid addition salt formed by the small molecule inhibitor with one or more of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid and mandelic acid.
进一步优选地，包括下述化合物：More preferably, the following compounds are included:
2-(3-(1-((3′，4′-二甲基苄基)氨基甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′,4′-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-(3-(3′，4′-二甲基苯基)丙基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3-(3′,4′-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-(3-(苯并[b]噻吩-6-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3-(Benzo[b]thiophen-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-甲基-2-(3-(1-(3-(噻吩-3-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸；2-Methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propanoic acid;
2-甲基-2-(3-(1-(3-(噻吩-2-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸；2-Methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propanoic acid;
2-(3-(1-(3-(1H-吡唑-4-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-(4′-异丙基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(4′-isopropyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-([1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-([1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-([1，1′-联苯基]-4-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-([1,1′-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-甲基-2-(3-(1-((3-(噻吩-3-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸；2-Methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoic acid;
2-(3-(1-([1，1′-联苯基]-3-基磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-([1,1′-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-((3-环己基苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-甲基-2-(3-(1-((3-(噻吩-2-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸；2-Methyl-2-(3-(1-((3-(thiophen-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoic acid;
2-(3-(1-((3-(苯并[b]噻吩-6-基)苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3-(Benzo[b]thiophen-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-((3′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-((4′-(叔丁基)-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)甲基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
(3S)-3-((5-(3-(3-((2-羧基丙烷-2-基)氧基)苯基)哌啶-1-羰基)-3′，4′-二氟-[1，1′-联苯]-2-基)氧基)吡咯烷-1-氯化铵；(3S)-3-((5-(3-(3-((2-carboxypropan-2-yl)oxy)phenyl)piperidine-1-carbonyl)-3′,4′-difluoro-[1,1′-biphenyl]-2-yl)oxy)pyrrolidine-1-ammonium chloride;
(3S)-3-(4-(3-(3-((2-羧基丙烷-2-基)氧基)苯基)哌啶-1-羰基)-2-环己基苯氧基)吡咯烷-1-氯化铵；(3S)-3-(4-(3-(3-((2-carboxypropan-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-cyclohexylphenoxy)pyrrolidine-1-ammonium chloride;
4-(2-(3-(1-((3′，4′-二甲基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-氯化铵；4-(2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-ammonium chloride;
4-(2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-氯化铵；4-(2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-ammonium chloride;
2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基-N-(苯磺酰基)丙酰胺；2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(phenylsulfonyl)propionamide;
2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基-N-(苯磺酰基)丙酰胺；2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(phenylsulfonyl)propionamide;
2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-N-(苯磺酰基)丙酰胺。2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(phenylsulfonyl)propionamide.
某一方案中，所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂，结构通式如式(I-1)所 示，或其异构体，或其药学上可接受的盐、酯或前药中，In a certain embodiment, the small molecule inhibitor that interacts with the β-catenin/BCL9 protein has a general structural formula as shown in formula (I-1), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof,
环A为饱和脂肪环、芳环或杂芳环；Ring A is a saturated aliphatic ring, an aromatic ring or a heteroaromatic ring;
所述环A可为环己烷、苯、联苯、萘或喹啉。The ring A may be cyclohexane, benzene, biphenyl, naphthalene or quinoline.
某一方案中，X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-CH(OH)-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-或-(CH 2) n-，其中n为0、1、2、3或4。 In one embodiment, X is -C(=O)-( CH2 ) n- , -C(=O)-NH-( CH2 ) n- , -CH(OH)-(CH2) n- , -SO2- ( CH2 ) n- , -SO2 -NH-( CH2 ) n- or -( CH2 ) n- , wherein n is 0, 1, 2, 3 or 4.
某一方案中，所述X可为-C(＝O)-、-C(＝O)-(CH 2) 2-、-SO 2-、-CH 2-或-(CH 2) 3-，也可以无X(即-(CH 2) 0-)。 In one embodiment, X may be -C(=O)-, -C(=O)-(CH 2 ) 2 -, -SO 2 -, -CH 2 - or -(CH 2 ) 3 -, or there may be no X (ie, -(CH 2 ) 0 -).
某一方案中，R 1和R 2相互独立地为氢、饱和或不饱和烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代环烷基、取代或非取代芳基、取代或非取代杂芳基或取代或非取的饱和或不饱和杂环；R 1、R 2可以是相同的，也可以不同的。 In one embodiment, R1 and R2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle; R1 and R2 may be the same or different.
某一方案中，R 1、R 2可以独立地选自氢、卤素、C 1-C 4烷基、烷氧基、噻吩基、苯并噻吩基、吡唑基、卤代芳基和
Figure PCTCN2023071067-appb-000011
中的任意两种；进一步优选地，所述R 1、R 2可为下表所示的组合： In one embodiment, R 1 and R 2 can be independently selected from hydrogen, halogen, C 1 -C 4 alkyl, alkoxy, thienyl, benzothienyl, pyrazolyl, halogenated aryl and
Figure PCTCN2023071067-appb-000011
Any two of; Further preferably, R 1 and R 2 can be the combination shown in the following table:
Figure PCTCN2023071067-appb-000012
Figure PCTCN2023071067-appb-000012
Figure PCTCN2023071067-appb-000013
Figure PCTCN2023071067-appb-000013
R 3为烷氧基、取代或非取代烷基、卤素、硝基、胺基、烷胺基、羧基、
Figure PCTCN2023071067-appb-000014
Figure PCTCN2023071067-appb-000015
 R3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
Figure PCTCN2023071067-appb-000014
Figure PCTCN2023071067-appb-000015
某一方案中，R 4可为氢、氨基、酰胺基、羧基、
Figure PCTCN2023071067-appb-000016
In one embodiment, R4 can be hydrogen, amino, amide, carboxyl,
Figure PCTCN2023071067-appb-000016
某一方案中，R 5为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环。 In one embodiment, R 5 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring.
某一方案中，R 5可为氢、烷基、哌嗪或苯磺酰基。 In one embodiment, R 5 can be hydrogen, alkyl, piperazine or benzenesulfonyl.
某一方案中，所述如式(II)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药中，In one embodiment, the compound represented by formula (II), or its isomer, or its pharmaceutically acceptable salt, ester or prodrug,
X、R 1和R 2的定义如式(I-1)所示； X, R 1 and R 2 are defined as shown in formula (I-1);
R 4为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环。 R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring.
某一方案中R 4可为羟基、烷氧基、烷胺基或苯磺酰基。 In one embodiment, R4 can be hydroxy, alkoxy, alkylamino or benzenesulfonyl.
某一方案中，所述烷基为C 1-C 6的烷基。 In one embodiment, the alkyl group is a C 1 -C 6 alkyl group.
某一方案中，所述药学上可接受的盐包括所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂与下列酸中的一种多种形成的酸加成盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸和杏仁酸。In a certain embodiment, the pharmaceutically acceptable salt includes an acid addition salt formed by the small molecule inhibitor that interacts with the β-catenin/BCL9 protein and one or more of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid and mandelic acid.
某一方案中，所述如式(I)所示化合物为如式(III)所示化合物，In one embodiment, the compound represented by formula (I) is a compound represented by formula (III),
Figure PCTCN2023071067-appb-000017
Figure PCTCN2023071067-appb-000017
其中，in,
环A为饱和脂肪环基、芳环基或杂芳基，Ring A is a saturated aliphatic ring group, an aromatic ring group or a heteroaryl group,
所述饱和脂肪环基为4～6元环烷基，The saturated aliphatic ring group is a 4- to 6-membered cycloalkyl group,
所述芳环基为6～14元芳基，The aromatic ring group is a 6- to 14-membered aromatic group,
所述杂芳基为5～12元杂芳基；The heteroaryl group is a 5- to 12-membered heteroaryl group;
X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-CH(OH)-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-，其中各个n独立地为0、1、2、3或4；m为0、1或2； X is -C(=O)-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -, -CH(OH)-(CH 2 ) n -, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(=O)-(CH=CH) m -(CH 2 ) n -, or -(CH 2 ) n -, wherein each n is independently 0, 1, 2, 3 or 4; m is 0, 1 or 2;
R 1和R 2相互独立地为氢、饱和或不饱和烷基、烷氧基、烷氧羰基、羟基、卤素、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代环烷基、取代或非取代芳基、-OR a、取代或非取代杂芳基或取代或非取的饱和或不饱和杂环， R1 and R2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, -ORa , substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring,
所述饱和或不饱和烷基为C 1-C 6烷基， The saturated or unsaturated alkyl group is a C 1 -C 6 alkyl group,
所述烷氧基为C 1-C 6烷氧基， The alkoxy group is a C 1 -C 6 alkoxy group,
所述烷氧羰基为C 1-C 6烷基-O-C(＝O)-， The alkoxycarbonyl group is a C 1 -C 6 alkyl-OC(=O)-,
所述烷胺基为C 1-C 6烷基-NH-， The alkylamino group is a C 1 -C 6 alkyl-NH-,
所述酰基为C 1-C 6烷基-C(＝O)-、C 1-C 6烷基-SO 2-或苯磺酰基， The acyl group is C 1 -C 6 alkyl-C(═O)-, C 1 -C 6 alkyl-SO 2 - or benzenesulfonyl,
所述酰胺基为C 1-C 6烷基-C(＝O)NH-、C 1-C 6烷基-SO 2NH-或苯磺酰胺基， The amide group is C 1 -C 6 alkyl-C(=O)NH-, C 1 -C 6 alkyl-SO 2 NH- or benzenesulfonamide,
所述卤代烷基为被一个或多个卤素取代的C 1-C 6烷基， The haloalkyl group is a C 1 -C 6 alkyl group substituted by one or more halogens,
所述卤代烷氧基为被一个或多个卤素取代的C 1-C 6烷氧基， The haloalkoxy group is a C 1 -C 6 alkoxy group substituted by one or more halogens,
所述卤代烷硫基为被一个或多个卤素取代的C 1-C 6烷硫基， The haloalkylthio group is a C 1 -C 6 alkylthio group substituted by one or more halogens.
所述取代或非取代环烷基中环烷基为3～6元环烷基，The cycloalkyl group in the substituted or unsubstituted cycloalkyl group is a 3- to 6-membered cycloalkyl group,
所述取代或非取代芳基中芳基为6～14元芳基，其中，取代芳基为被一个或多个R b取代的6～14元芳基， The aryl group in the substituted or unsubstituted aryl group is a 6- to 14-membered aryl group, wherein the substituted aryl group is a 6- to 14-membered aryl group substituted by one or more R b ,
所述取代或非取代杂芳基中杂芳基为5～12元杂芳基，其中取代杂芳基为被一个或多个Rf取代的5～12元杂芳基，The heteroaryl in the substituted or unsubstituted heteroaryl is a 5- to 12-membered heteroaryl, wherein the substituted heteroaryl is a 5- to 12-membered heteroaryl substituted by one or more Rf,
所述取代或非取饱和或不饱和杂环中杂环为4～6元杂环烷基；The heterocyclic ring in the substituted or unsubstituted saturated or unsaturated heterocyclic ring is a 4-6-membered heterocycloalkyl group;
R a为4～6元杂环烷基； Ra is a 4- to 6-membered heterocycloalkyl group;
各个R b和R f独立地为卤素或C 1-C 6烷基； Each R b and R f is independently halogen or C 1 -C 6 alkyl;
R 3为烷氧基、取代或非取代烷基、卤素、硝基、胺基、烷胺基、羧基、
Figure PCTCN2023071067-appb-000018
Figure PCTCN2023071067-appb-000019
 R3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
Figure PCTCN2023071067-appb-000018
Figure PCTCN2023071067-appb-000019
所述烷氧基为C 1-C 6烷氧基， The alkoxy group is a C 1 -C 6 alkoxy group,
所述取代或非取代烷基中烷基为C 1-C 6烷基， The alkyl group in the substituted or unsubstituted alkyl group is a C 1 -C 6 alkyl group,
所述烷胺基为C 1-C 6烷基-NH-； The alkylamino group is C 1 -C 6 alkyl-NH-;
R 4为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代烷胺基、取代或非取代胺基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环， R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring,
所述烷基为C 1-C 6烷基， The alkyl group is a C 1 -C 6 alkyl group,
所述烷氧基为C 1-C 6烷氧基， The alkoxy group is a C 1 -C 6 alkoxy group,
所述烷氧羰基为C 1-C 6烷基-O-C(＝O)-， The alkoxycarbonyl group is a C 1 -C 6 alkyl-OC(=O)-,
所述烷胺基烷胺基为C 1-C 6烷基-NH-， The alkylamino group is C 1 -C 6 alkyl-NH-,
所述酰基为C 1-C 6烷基-C(＝O)-、C 1-C 6烷基-SO 2-或苯磺酰基， The acyl group is C 1 -C 6 alkyl-C(═O)-, C 1 -C 6 alkyl-SO 2 - or benzenesulfonyl,
所述酰胺基为C 1-C 6烷基-C(＝O)NH-、C 1-C 6烷基-SO 2NH-或苯磺酰胺基， The amide group is C 1 -C 6 alkyl-C(=O)NH-, C 1 -C 6 alkyl-SO 2 NH- or benzenesulfonamide,
所述卤代烷基为被一个或多个卤素取代的C 1-C 6烷基， The haloalkyl group is a C 1 -C 6 alkyl group substituted by one or more halogens,
所述卤代烷氧基为被一个或多个卤素取代的C 1-C 6烷氧基， The haloalkoxy group is a C 1 -C 6 alkoxy group substituted by one or more halogens,
所述卤代烷硫基为被一个或多个卤素取代的C 1-C 6烷硫基， The haloalkylthio group is a C 1 -C 6 alkylthio group substituted by one or more halogens.
所述取代或非取代烷胺基中烷胺基为-NH-(CH 2) k，其中，取代烷胺基为-NH-(CH 2) k-R d，k为1、2、3或4， The alkylamino group in the substituted or unsubstituted alkylamino group is -NH-(CH 2 ) k , wherein the substituted alkylamino group is -NH-(CH 2 ) k -R d , k is 1, 2, 3 or 4,
所述取代的胺基为-NH-(CH 2) k-R d，k为0， The substituted amine group is -NH-(CH 2 ) k -R d , k is 0,
所述取代的磺酰氨基为-NH-(SO 2)-R c， The substituted sulfonylamino group is -NH-(SO 2 )-R c ,
所述取代或非取代芳基中芳基为6～14元芳基，The aryl group in the substituted or unsubstituted aryl group is a 6- to 14-membered aryl group,
所述取代或非取代杂芳基中杂芳基为5～12元杂芳基，The heteroaryl group in the substituted or unsubstituted heteroaryl group is a 5- to 12-membered heteroaryl group,
所述取代或非取代的饱和或不饱和杂环中杂环为4～10元杂环烷基，其中取代的饱和或不饱和杂环为被一个或多个R e取代的4～10元杂环烷基； The heterocycle in the substituted or unsubstituted saturated or unsaturated heterocycle is a 4-10-membered heterocycloalkyl, wherein the substituted saturated or unsaturated heterocycle is a 4-10-membered heterocycloalkyl substituted by one or more Re ;
R c为氢、6～14元芳基、4～6元杂环烷基、5～12元杂芳基、被一个或多个R c-1取代的6～14元芳基或被一个或多个R c-2取代的5～12元杂芳基； R c is hydrogen, 6- to 14-membered aryl, 4- to 6-membered heterocycloalkyl, 5- to 12-membered heteroaryl, 6- to 14-membered aryl substituted by one or more R c-1 , or 5- to 12-membered heteroaryl substituted by one or more R c-2 ;
R d为氢、6～14元芳基、5～12元杂芳基或4～6元杂环烷基； R d is hydrogen, 6- to 14-membered aryl, 5- to 12-membered heteroaryl, or 4- to 6-membered heterocycloalkyl;
各个R c-1和R c-2独立地为羟基、氰基、C 1-C 6烷基、被一个或多个R c-1-1取代的C 1-C 6烷基、C 1-C 6烷氧基、硝基、卤素、被一个或多个R c-1-2取代的C 1-C 6烷氧基或-NHC(＝O)-R c-1-3； each of R c-1 and R c-2 is independently hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R c-1-1 , C 1 -C 6 alkoxy, nitro, halogen, C 1 -C 6 alkoxy substituted by one or more R c-1-2 , or -NHC(=O)-R c-1-3 ;
各个R e独立地为氧代基(C＝O)、羟基或氨基； Each Re is independently oxo (C=O), hydroxyl or amino;
各个R c-1-1和R c-1-2独立地为卤素； Each of R c-1-1 and R c-1-2 is independently halogen;
R c-1-3为C 1-C 6烷基； R c-1-3 is C 1 -C 6 alkyl;
各个5～12元杂芳基、4～6元杂环烷基和4～10元杂环烷基中杂原子选自N、O或S，杂原子数为1个、2个或3个。In each of the 5- to 12-membered heteroaryl, 4- to 6-membered heterocycloalkyl and 4- to 10-membered heterocycloalkyl, the heteroatom is selected from N, O or S, and the number of the heteroatoms is 1, 2 or 3.
某一方案中，环A为6～14元芳基。In one embodiment, ring A is a 6- to 14-membered aryl group.
某一方案中，R 1和R 2各自独立地为氢、C 1-C 6烷基、5～12元杂芳基、3～6元环烷基、6～14元芳基、-OR a或被一个或多个R b取代的6～14元芳基。 In one embodiment, R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, 5- to 12-membered heteroaryl, 3- to 6-membered cycloalkyl, 6- to 14-membered aryl, -OR a , or 6- to 14-membered aryl substituted with one or more R b .
某一方案中，R 1为5～12元杂芳基、3～6元环烷基、6～14元芳基或被一个或多个R b取代的6～14元芳基。 In one embodiment, R 1 is a 5- to 12-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a 6- to 14-membered aryl group, or a 6- to 14-membered aryl group substituted with one or more R b .
某一方案中，R 1和R 2各自独立地为氢、5～12元杂芳基、3～6元环烷基、6～14元芳基、-OR a或被一个或多个R b取代的6～14元芳基。 In one embodiment, R 1 and R 2 are each independently hydrogen, 5- to 12-membered heteroaryl, 3- to 6-membered cycloalkyl, 6- to 14-membered aryl, -OR a , or 6- to 14-membered aryl substituted with one or more R b .
某一方案中，X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-。 In one embodiment, X is -C(=O)-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(=O)-(CH=CH) m -(CH 2 ) n -, or -(CH 2 ) n -.
某一方案中，X为-C(＝O)-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-。 In one embodiment, X is -C(=O)-, -SO2- ( CH2 ) n- , -SO2 -NH-( CH2 ) n- , -C(=O)-(CH=CH) m- ( CH2 ) n- , or -( CH2 ) n- .
某一方案中，X为羰基，式(III)所示化合物不为：In one embodiment, X is a carbonyl group, and the compound represented by formula (III) is not:
Figure PCTCN2023071067-appb-000020
Figure PCTCN2023071067-appb-000020
某一方案中，X为-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-。 In one embodiment, X is -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(=O)-(CH=CH) m -(CH 2 ) n -, or -(CH 2 ) n -.
某一方案中，各个n独立地为0、1、3。In one embodiment, each n is independently 0, 1, or 3.
某一方案中，各个m独立地为1。In one embodiment, each m is independently 1.
某一方案中，R 3为
Figure PCTCN2023071067-appb-000021
例如
Figure PCTCN2023071067-appb-000022
In one embodiment, R 3 is
Figure PCTCN2023071067-appb-000021
For example
Figure PCTCN2023071067-appb-000022
某一方案中，R 4为羟基、C 1-C 6烷基、4～10元杂环烷基、-NH-(SO 2)-R c、-NH-(CH 2) k-R d或被一个或多个R e取代的4～10元杂环烷基，例如，R 4为羟基、4～10元杂环烷基、-NH-(SO 2)-R c或-NH-(CH 2) k-R d，又如R 4为羟基、4～10元杂环烷基、-NH-(SO 2)-R c、-NH-(CH 2) k-R d或被一个或多个R e取代的4～10元杂环烷基。 In one embodiment, R4 is hydroxy, C1 - C6 alkyl, 4- to 10-membered heterocycloalkyl, -NH-( SO2 ) -Rc , -NH-( CH2 ) k - Rd, or 4- to 10-membered heterocycloalkyl substituted by one or more Re . For example, R4 is hydroxy, 4- to 10-membered heterocycloalkyl, -NH-( SO2 ) -Rc , or -NH-( CH2 ) k - Rd . For another example, R4 is hydroxy, 4- to 10-membered heterocycloalkyl, -NH-( SO2 ) -Rc , -NH-( CH2 ) k - Rd , or 4- to 10-membered heterocycloalkyl substituted by one or more Re .
某一方案中，k为0或1。In one embodiment, k is 0 or 1.
某一方案中，R c为6～14元芳基、被一个或多个R c-1取代的6～14元芳基或5～12元杂芳基。 In one embodiment, R c is a 6- to 14-membered aryl group, a 6- to 14-membered aryl group substituted with one or more R c-1 , or a 5- to 12-membered heteroaryl group.
某一方案中，R d为6～14元芳基或4～6元杂环烷基，例如，R d为4～6元杂环烷基，又如R d为6～14元芳基。 In one embodiment, R d is a 6- to 14-membered aryl group or a 4- to 6-membered heterocycloalkyl group. For example, R d is a 4- to 6-membered heterocycloalkyl group. In another example, R d is a 6- to 14-membered aryl group.
某一方案中，各个R c-1独立地为氰基、被一个或多个R c-1-1取代的C 1-C 6烷基、C 1-C 6烷氧基、硝 基、卤素、被一个或多个R c-1-2取代的C 1-C 6烷氧基或-NHC(＝O)-R c-1-3，或者，各个R c-1独立地为羟基、被一个或多个R c-1-1取代的C 1-C 6烷基或C 1-C 6烷氧基。 In one embodiment, each R c-1 is independently cyano, C 1 -C 6 alkyl substituted by one or more R c-1-1 , C 1 -C 6 alkoxy, nitro, halogen, C 1 -C 6 alkoxy substituted by one or more R c-1-2 , or -NHC(＝O)-R c-1-3 ; or, each R c-1 is independently hydroxy, C 1 -C 6 alkyl substituted by one or more R c-1-1 , or C 1 -C 6 alkoxy.
某一方案中，环A中，所述4～6元环烷基为环丙烷基、环丁烷基、环戊烷基或环己烷基。In one embodiment, in ring A, the 4- to 6-membered cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane.
某一方案中，环A中，所述6～14元芳基为苯基或萘基，例如苯基。In one embodiment, in ring A, the 6-14 membered aryl group is phenyl or naphthyl, for example phenyl.
某一方案中，环A中，所述5～12元杂芳基中杂原子为N、S或O，杂原子数为1个或2个，优选为6元含氮杂芳基。In one embodiment, in ring A, the heteroatom in the 5- to 12-membered heteroaryl group is N, S or O, and the number of heteroatoms is 1 or 2, and is preferably a 6-membered nitrogen-containing heteroaryl group.
某一方案中，R 1和R 2中，所述C 1-C 6烷基、C 1-C 6烷基-O-C(＝O)-、C 1-C 6烷基-NH-、C 1-C 6烷基-C(＝O)-、C 1-C 6烷基-C(＝O)NH-和被一个或多个卤素取代的C 1-C 6烷基中C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如甲基或异丙基。 In one embodiment, in R1 and R2 , the C1 - C6 alkyl, C1 - C6 alkyl-OC(＝O)-, C1 - C6 alkyl-NH-, C1 - C6 alkyl-C(＝O)-, C1 - C6 alkyl-C(＝O)NH- and C1 - C6 alkyl substituted by one or more halogens is methyl , ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example , methyl or isopropyl.
某一方案中，R 1和R 2中，所述C 1-C 6烷氧基和被一个或多个卤素取代的C 1-C 6烷氧基中C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基。 In one embodiment, in R1 and R2 , the C1 - C6 alkoxy group and the C1 -C6 alkoxy group substituted by one or more halogens is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy.
某一方案中，R 1和R 2中，所述卤素、被一个或多个卤素取代的C 1-C 6烷基、被一个或多个卤素取代的C 1-C 6烷氧基和被一个或多个卤素取代的C 1-C 6烷硫基中卤素为氟、氯、溴或碘。 In one embodiment, in R1 and R2 , the halogen in the halogen, C1 - C6 alkyl substituted by one or more halogen, C1 - C6 alkoxy substituted by one or more halogen and C1 - C6 alkylthio substituted by one or more halogen is fluorine, chlorine, bromine or iodine.
某一方案中，R 1和R 2中，所述被一个或多个卤素取代的C 1-C 6烷硫基中C 1-C 6烷硫基为甲硫基、乙硫基、异丙硫基、正丙硫基、正丁硫基、仲丁硫基、叔丁硫基或异丁硫基。 In one embodiment, in R1 and R2 , the C1 - C6 alkylthio group substituted by one or more halogens is methylthio, ethylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio, tert-butylthio or isobutylthio.
某一方案中，R 1和R 2中，所述3～6元环烷基为环丙烷基、环丁烷基、环戊烷基或环己烷基，例如环己烷基。 In one embodiment, in R1 and R2 , the 3- to 6-membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclohexyl.
某一方案中，R 1和R 2中，所述6～14元芳基和被一个或多个R b取代的6～14元芳基中6～14元芳基为苯基或萘基，例如苯基。 In one embodiment, in R 1 and R 2 , the 6- to 14-membered aryl group and the 6- to 14-membered aryl group substituted by one or more R b is phenyl or naphthyl, for example phenyl.
某一方案中，R 1和R 2中，所述5～12元杂芳基和被一个或多个R f取代的5～12元杂芳基中5～12元杂芳基为5～10元杂芳基，优选地，所述5～10元杂芳基中杂原子为N、O或S，杂原子数为1个或2个，例如噻吩基、吡唑或苯并噻吩基。 In one embodiment, in R1 and R2 , the 5- to 12-membered heteroaryl group and the 5- to 12-membered heteroaryl group substituted by one or more Rf are 5- to 10-membered heteroaryl groups. Preferably, the heteroatom in the 5- to 10-membered heteroaryl group is N, O or S, and the number of heteroatoms is 1 or 2, such as thienyl, pyrazole or benzothienyl.
某一方案中，R 1和R 2中，所述4～6元杂环烷基中杂原子为N、S或O，杂原子数为1个或2个，优选为6元含氮杂环己基。 In one embodiment, in R1 and R2 , the heteroatom in the 4- to 6-membered heterocycloalkyl group is N, S or O, and the number of heteroatoms is 1 or 2, and is preferably a 6-membered nitrogen-containing heterocyclohexyl group.
某一方案中，R a中，所述4～6元杂环烷基为5～6元杂环烷基，优选地，所述5～6元杂环烷基中杂原子为N、O或S，杂原子数为1个，例如氮杂环戊烷。 In one embodiment, in Ra , the 4- to 6-membered heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Preferably, the heteroatom in the 5- to 6-membered heterocycloalkyl is N, O or S, and the number of the heteroatom is 1, such as azacyclopentane.
某一方案中，R b和R f中，所述卤素为氟、氯、溴或碘，例如为氟。 In one embodiment, in R b and R f , the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine.
某一方案中，R b和R f中，所述C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如为甲基、异丙基或叔丁基。 In one embodiment, in R b and R f , the C 1 -C 6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example, methyl, isopropyl or tert-butyl.
某一方案中，R 2中，所述C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基。 In one embodiment, in R 2 , the C 1 -C 6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy.
某一方案中，R 3中，所述C 1-C 6烷基和C 1-C 6烷基-NH-中C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基。 In one embodiment, in R 3 , the C 1 -C 6 alkyl and the C 1 -C 6 alkyl-NH- are methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl.
某一方案中，R 3中，所述卤素为氟、氯、溴或碘。 In one embodiment, in R 3 , the halogen is fluorine, chlorine, bromine or iodine.
某一方案中，R 4中，所述C 1-C 6烷基、C 1-C 6烷基-O-C(＝O)-、C 1-C 6烷基-NH-、C 1-C 6烷基-C(＝O)-、C 1-C 6烷基-SO 2-、C 1-C 6烷基-C(＝O)NH-、C 1-C 6烷基-SO 2NH-和被一个或多个卤素取代的C 1-C 6烷基中C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如甲基。 In one embodiment, in R4 , the C1 - C6 alkyl, C1 - C6 alkyl-OC(＝O)-, C1 - C6 alkyl-NH-, C1 - C6 alkyl-C(＝O)-, C1 - C6 alkyl- SO2- , C1 - C6 alkyl-C( ＝ O)NH-, C1 - C6 alkyl- SO2NH- and C1- C6 alkyl substituted by one or more halogens, the C1 - C6 alkyl is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example, methyl.
某一方案中，R 4中，所述C 1-C 6烷氧基和被一个或多个卤素取代的C 1-C 6烷氧基中C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基。 In one embodiment, in R 4 , the C 1 -C 6 alkoxy group and the C 1 -C 6 alkoxy group substituted by one or more halogens is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy.
某一方案中，R 4中，所述卤素、被一个或多个卤素取代的C 1-C 6烷基、被一个或多个卤素取代的C 1-C 6烷氧基和被一个或多个卤素取代的C 1-C 6烷硫基中卤素为氟、氯、溴或碘。 In one embodiment, in R 4 , the halogen in the halogen, C 1 -C 6 alkyl substituted by one or more halogens, C 1 -C 6 alkoxy substituted by one or more halogens and C 1 -C 6 alkylthio substituted by one or more halogens is fluorine, chlorine, bromine or iodine.
某一方案中，R 4中，所述被一个或多个卤素取代的C 1-C 6烷硫基中C 1-C 6烷硫基为甲硫基、乙硫基、异丙硫基、正丙硫基、正丁硫基、仲丁硫基、叔丁硫基或异丁硫基。 In one embodiment, in R 4 , the C 1 -C 6 alkylthio group substituted by one or more halogens is methylthio, ethylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio, tert-butylthio or isobutylthio.
某一方案中，R 4中，所述6～14元芳基中6～14元芳基为苯基或萘基。 In one embodiment, in R 4 , the 6- to 14-membered aryl group is phenyl or naphthyl.
某一方案中，R 4中，所述5～12元杂芳基中5～12元杂芳基为5～10元杂芳基，优选地，所述5～10元杂芳基中杂原子为N、O或S，杂原子数为1个或2个。 In one embodiment, in R 4 , the 5- to 12-membered heteroaryl group is a 5- to 10-membered heteroaryl group. Preferably, the heteroatom in the 5- to 10-membered heteroaryl group is N, O or S, and the number of heteroatoms is 1 or 2.
某一方案中，R 4中，所述4～10元杂环烷基和被一个或多个R e取代的4～10元杂环烷基中4～10元杂环烷基为4～7元杂环烷基，优选地，所述4～7元杂环烷基中杂原子为O或N，进一步优选地，所述4～7元杂环烷基中杂原子数为1个或2个，例如
Figure PCTCN2023071067-appb-000023
In one embodiment, in R4 , the 4- to 10-membered heterocycloalkyl group and the 4- to 10-membered heterocycloalkyl group substituted by one or more Re are 4- to 7-membered heterocycloalkyl groups, preferably, the heteroatom in the 4- to 7-membered heterocycloalkyl group is O or N, and more preferably, the number of heteroatoms in the 4- to 7-membered heterocycloalkyl group is 1 or 2, for example
Figure PCTCN2023071067-appb-000023
某一方案中，R c中，所述6～14元芳基和被一个或多个R c-1取代的6～14元芳基中6～14元芳基为苯基或萘基，例如苯基或萘基。 In one embodiment, in R c , the 6- to 14-membered aryl group and the 6- to 14-membered aryl group substituted by one or more R c-1 is phenyl or naphthyl, for example phenyl or naphthyl.
某一方案中，R c中，所述4～6元杂环烷基为5～6元杂环烷基，优选地，所述5～6元杂环烷基中杂原子为N，进一步优选地，所述5～6元杂环烷基中杂原子数为1个。 In one embodiment, in R c , the 4- to 6-membered heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group, preferably, the heteroatom in the 5- to 6-membered heterocycloalkyl group is N, and more preferably, the number of heteroatoms in the 5- to 6-membered heterocycloalkyl group is 1.
某一方案中，R c中，所述5～12元杂芳基和被一个或多个R c-2取代的5～12元杂芳基中5～12元杂芳基为5～10元杂芳基，优选地，所述5～10元杂芳基中杂原子为S或O，进一步优选地，所述5～10元杂芳基中杂原子数为1个，例如，所述5～10元杂芳基为噻吩。 In one embodiment, in R c , the 5- to 12-membered heteroaryl group and the 5- to 12-membered heteroaryl group substituted by one or more R c-2 are 5- to 10-membered heteroaryl groups, preferably, the heteroatom in the 5- to 10-membered heteroaryl group is S or O, and further preferably, the number of heteroatoms in the 5- to 10-membered heteroaryl group is 1, for example, the 5- to 10-membered heteroaryl group is thiophene.
某一方案中，R d中，所述6～14元芳基为苯基或萘基，例如苯基。 In one embodiment, in R d , the 6-14 membered aryl group is phenyl or naphthyl, for example phenyl.
某一方案中，R d中，所述5～12元杂芳基为5～6元杂芳基，优选地，所述5～6元杂芳基中杂原子为N、S或O，进一步优选地，所述5～6元杂芳基中杂原子数为1个。 In one embodiment, in R d , the 5- to 12-membered heteroaryl group is a 5- to 6-membered heteroaryl group. Preferably, the heteroatom in the 5- to 6-membered heteroaryl group is N, S or O. More preferably, the number of heteroatoms in the 5- to 6-membered heteroaryl group is 1.
某一方案中，R d中，所述4～6元杂环烷基为5～6元杂环烷基，优选地，所述5～6元杂环烷基中杂原子为N，进一步优选地，所述5～6元杂环烷基中杂原子数为1个，例如氮杂环己烷。 In one embodiment, in R d , the 4- to 6-membered heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group, preferably, the heteroatom in the 5- to 6-membered heterocycloalkyl group is N, and more preferably, the number of heteroatoms in the 5- to 6-membered heterocycloalkyl group is 1, such as azacyclohexane.
某一方案中，R c-1和R c-2中，所述C 1-C 6烷基和被一个或多个R c-1-1取代的C 1-C 6烷基中C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如甲基。 In one embodiment, in R c-1 and R c-2 , the C 1 -C 6 alkyl group and the C 1 -C 6 alkyl group substituted by one or more R c-1-1 are methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example, methyl.
某一方案中，R c-1和R c-2中，所述C 1-C 6烷氧基和被一个或多个R c-1-2取代的C 1-C 6烷氧基中C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基，例如甲氧基。 In one embodiment, in R c-1 and R c-2 , the C 1 -C 6 alkoxy group and the C 1 -C 6 alkoxy group substituted by one or more R c-1-2 is methoxy, ethoxy, isopropoxy , n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy, for example, methoxy.
某一方案中，R c-1和R c-2中，所述卤素为氟、氯、溴或碘，例如氟或氯。 In one embodiment, in R c-1 and R c-2 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.
某一方案中，R c-1-1和R c-1-2中，所述卤素为氟、氯、溴或碘，例如氟。 In one embodiment, in R c-1-1 and R c-1-2 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
某一方案中，R c-1-3中，所述C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如甲基。 In one embodiment, in R c-1-3 , the C 1 -C 6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example, methyl.
某一方案中，所述结构通式如式(III)所示化合物为如式(III-1)所示化合物，In one embodiment, the compound having the general structural formula (III) is a compound having the general structural formula (III-1).
Figure PCTCN2023071067-appb-000024
Figure PCTCN2023071067-appb-000024
其中，R 1为5～12元杂芳基、3～6元环烷基、6～14元芳基或被一个或多个R b取代的6～14元芳基； Wherein, R 1 is a 5- to 12-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a 6- to 14-membered aryl group, or a 6- to 14-membered aryl group substituted by one or more R b ;
各个R b独立地为卤素或C 1-C 6烷基； Each R b is independently halogen or C 1 -C 6 alkyl;
R 4为羟基、4～10元杂环烷基、-NH-(SO 2)-R c或-NH-(CH 2) k-R d；k为0、1、2、3或4； R 4 is hydroxy, 4- to 10-membered heterocycloalkyl, -NH-(SO 2 )-R c or -NH-(CH 2 ) k -R d ; k is 0, 1, 2, 3 or 4;
R c为6～14元芳基、被一个或多个R c-1取代的6～14元芳基或5～12元杂芳基； R c is a 6- to 14-membered aryl group, a 6- to 14-membered aryl group substituted by one or more R c-1 groups, or a 5- to 12-membered heteroaryl group;
R d为6～14元芳基； R d is a 6- to 14-membered aromatic group;
各个R c-1独立地为氰基、被一个或多个R c-1-1取代的C 1-C 6烷基、C 1-C 6烷氧基、硝基、卤素、被一个或多个R c-1-2取代的C 1-C 6烷氧基或-NHC(＝O)-R c-1-3； each R c-1 is independently cyano, C 1 -C 6 alkyl substituted by one or more R c-1-1 , C 1 -C 6 alkoxy, nitro, halogen, C 1 -C 6 alkoxy substituted by one or more R c-1-2 , or -NHC(═O)-R c-1-3 ;
各个R c-1-1和R c-1-2独立地为卤素； Each of R c-1-1 and R c-1-2 is independently halogen;
R c-1-3为C 1-C 6烷基； R c-1-3 is C 1 -C 6 alkyl;
各个5～12元杂芳基和4～10元杂环烷基中杂原子选自N、O或S，杂原子数为1个、2个或3个。The heteroatom in each of the 5- to 12-membered heteroaryl and the 4- to 10-membered heterocycloalkyl is selected from N, O or S, and the number of the heteroatoms is 1, 2 or 3.
某一方案中，所述结构通式如式(III)所示化合物为如式(III-2)所示化合物，In one embodiment, the compound having the general structural formula (III) is a compound having the general structural formula (III-2).
Figure PCTCN2023071067-appb-000025
Figure PCTCN2023071067-appb-000025
R 1和R 2各自独立地为氢、5～12元杂芳基、3～6元环烷基、6～14元芳基、-OR a或被一个或多个R b取代的6～14元芳基； R1 and R2 are each independently hydrogen, 5- to 12-membered heteroaryl, 3- to 6-membered cycloalkyl, 6- to 14-membered aryl, -ORa, or 6- to 14-membered aryl substituted with one or more Rb ;
R a为4～6元杂环烷基； Ra is a 4- to 6-membered heterocycloalkyl group;
各个R b独立地为卤素或C 1-C 6烷基； Each R b is independently halogen or C 1 -C 6 alkyl;
R 4为羟基、4～10元杂环烷基、-NH-(SO 2)-R c、-NH-(CH 2) k-R d或被一个或多个R e取代的4～10元杂环烷基；k为0、1、2、3或4； R 4 is hydroxy, 4- to 10-membered heterocycloalkyl, -NH-(SO 2 )-R c , -NH-(CH 2 ) k -R d or 4- to 10-membered heterocycloalkyl substituted by one or more Re ; k is 0, 1, 2, 3 or 4;
R c为6～14元芳基、被一个或多个R c-1取代的6～14元芳基或5～12元杂芳基； R c is a 6- to 14-membered aryl group, a 6- to 14-membered aryl group substituted by one or more R c-1 groups, or a 5- to 12-membered heteroaryl group;
R d为4～6元杂环烷基； R d is a 4- to 6-membered heterocycloalkyl group;
各个R c-1独立地为羟基、被一个或多个R c-1-1取代的C 1-C 6烷基或C 1-C 6烷氧基； Each R c-1 is independently hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy substituted with one or more R c-1-1 ;
各个R e独立地为氧代基(C＝O)、羟基或氨基； Each Re is independently oxo (C=O), hydroxyl or amino;
各个R c-1-1和R c-1-2独立地为卤素； Each of R c-1-1 and R c-1-2 is independently halogen;
各个5～12元杂芳基、4～6元杂环烷基和4～10元杂环烷基中杂原子选自N、O或S，杂原子数为1个、2个或3个。In each of the 5- to 12-membered heteroaryl, 4- to 6-membered heterocycloalkyl and 4- to 10-membered heterocycloalkyl, the heteroatom is selected from N, O or S, and the number of the heteroatoms is 1, 2 or 3.
某一方案中，所述结构通式如式(III)所示化合物，或其药学上可接受的盐中，In one embodiment, the compound of the general structural formula is represented by formula (III), or a pharmaceutically acceptable salt thereof,
R 1和R 2各自独立地为氢、C 1-C 6烷基、5～12元杂芳基、3～6元环烷基、6～14元芳基、-OR a或被一个或多个R b取代的6～14元芳基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, 5- to 12-membered heteroaryl, 3- to 6-membered cycloalkyl, 6- to 14-membered aryl, -OR a , or 6- to 14-membered aryl substituted with one or more R b ;
R a为4～6元杂环烷基； Ra is a 4- to 6-membered heterocycloalkyl group;
各个R b独立地为卤素或C 1-C 6烷基； Each R b is independently halogen or C 1 -C 6 alkyl;
X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-，其中各个n独立地为0、1、2、3或4；m为0、1或2； X is -C(=O)-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(=O)-(CH=CH) m -(CH 2 ) n -, or -(CH 2 ) n -, wherein each n is independently 0, 1, 2, 3 or 4; m is 0, 1 or 2;
R 4为羟基、C 1-C 6烷基、4～10元杂环烷基、-NH-(SO 2)-R c、-NH-(CH 2) k-R d或被一个或多个R e取代的4～10元杂环烷基；k为0、1、2、3或4； R 4 is hydroxy, C 1 -C 6 alkyl, 4- to 10-membered heterocycloalkyl, -NH-(SO 2 )-R c , -NH-(CH 2 ) k -R d or 4- to 10-membered heterocycloalkyl substituted by one or more Re ; k is 0, 1, 2, 3 or 4;
R c为6～14元芳基、被一个或多个R c-1取代的6～14元芳基或5～12元杂芳基； R c is a 6- to 14-membered aryl group, a 6- to 14-membered aryl group substituted by one or more R c-1 groups, or a 5- to 12-membered heteroaryl group;
R d为6～14元芳基或4～6元杂环烷基； R d is a 6- to 14-membered aryl group or a 4- to 6-membered heterocycloalkyl group;
各个R c-1独立地为羟基、氰基、C 1-C 6烷基、被一个或多个R c-1-1取代的C 1-C 6烷基、C 1-C 6烷氧基、硝基、卤素、被一个或多个R c-1-2取代的C 1-C 6烷氧基或-NHC(＝O)-R c-1-3； Each R c-1 is independently hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R c-1-1 , C 1 -C 6 alkoxy, nitro, halogen, C 1 -C 6 alkoxy substituted by one or more R c-1-2 , or -NHC(=O)-R c-1-3 ;
各个R e独立地为氧代基(C＝O)、羟基或氨基； Each Re is independently oxo (C=O), hydroxyl or amino;
各个R c-1-1和R c-1-2独立地为卤素； Each of R c-1-1 and R c-1-2 is independently halogen;
R c-1-3为C 1-C 6烷基； R c-1-3 is C 1 -C 6 alkyl;
各个5～12元杂芳基、4～6元杂环烷基和4～10元杂环烷基中杂原子选自N、O或S，杂原子数为1个、2个或3个。In each of the 5- to 12-membered heteroaryl, 4- to 6-membered heterocycloalkyl and 4- to 10-membered heterocycloalkyl, the heteroatom is selected from N, O or S, and the number of the heteroatoms is 1, 2 or 3.
某一方案中，R a为4～6元杂环烷基，盐酸与所述4～6元杂环烷基中N原子结合得到所述式(III)所示化合物的盐酸盐。 In one embodiment, Ra is a 4- to 6-membered heterocycloalkyl group, and hydrochloric acid combines with the nitrogen atom in the 4- to 6-membered heterocycloalkyl group to obtain the hydrochloride of the compound represented by the formula (III).
某一方案中，R e为氨基，盐酸与氨基结合得到所述结构通式如式(III)所示化合物的盐酸盐。 In one embodiment, Re is an amino group, and hydrochloric acid combines with the amino group to obtain the hydrochloride of the compound with the general structural formula shown in formula (III).
某一方案中，所述式(III)所示化合物药学上可接受的盐优选为盐酸盐。In one embodiment, the pharmaceutically acceptable salt of the compound represented by formula (III) is preferably a hydrochloride.
某一方案中，X为
Figure PCTCN2023071067-appb-000026
化学键、甲基、
Figure PCTCN2023071067-appb-000027
In one solution, X is
Figure PCTCN2023071067-appb-000026
Chemical bond, methyl,
Figure PCTCN2023071067-appb-000027
某一方案中，R 1和R 2各自独立地为氢、甲基、
Figure PCTCN2023071067-appb-000028
Figure PCTCN2023071067-appb-000029
In one embodiment, R1 and R2 are each independently hydrogen, methyl,
Figure PCTCN2023071067-appb-000028
Figure PCTCN2023071067-appb-000029
某一方案中，R 3为
Figure PCTCN2023071067-appb-000030
Figure PCTCN2023071067-appb-000031
In one embodiment, R 3 is
Figure PCTCN2023071067-appb-000030
Figure PCTCN2023071067-appb-000031
某一方案中，R 4为
Figure PCTCN2023071067-appb-000032
Figure PCTCN2023071067-appb-000033
Figure PCTCN2023071067-appb-000034
In one embodiment, R 4 is
Figure PCTCN2023071067-appb-000032
Figure PCTCN2023071067-appb-000033
Figure PCTCN2023071067-appb-000034
某一方案中，所述如式(III)所示的化合物，或其药学上可接受的盐为如下任一化合物：In one embodiment, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is any of the following compounds:
Figure PCTCN2023071067-appb-000035
Figure PCTCN2023071067-appb-000035
Figure PCTCN2023071067-appb-000036
Figure PCTCN2023071067-appb-000036
Figure PCTCN2023071067-appb-000037
Figure PCTCN2023071067-appb-000037
Figure PCTCN2023071067-appb-000038
Figure PCTCN2023071067-appb-000038
Figure PCTCN2023071067-appb-000039
Figure PCTCN2023071067-appb-000039
本发明还提供了一种药物组合物，其包含治疗有效量的物质A和药用辅料；所述物质A为上述如式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药；The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of substance A and a pharmaceutical excipient; the substance A is the compound represented by formula (I) above, or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;
优选地，所述物质A为上述式(III)所示化合物或其药学上可接受的盐。Preferably, the substance A is a compound represented by the above formula (III) or a pharmaceutically acceptable salt thereof.
本发明还提供了一种物质A在制备药物中的应用，所述药物用于治疗和/或预防肿瘤，所述物质A为如式(I)所示化合物、其异构体、其药学上可接受的盐、酯或其前药；The present invention also provides a use of a substance A in the preparation of a drug, wherein the drug is used to treat and/or prevent tumors, wherein the substance A is a compound as represented by formula (I), an isomer thereof, a pharmaceutically acceptable salt, ester or prodrug thereof;
Figure PCTCN2023071067-appb-000040
Figure PCTCN2023071067-appb-000040
其中，R 1、R 2、X和R 3如本发明任一项所述； wherein R 1 , R 2 , X and R 3 are as described in any one of the present invention;
优选地，所述肿瘤为乳腺癌、结肠癌、肝癌、多发性骨髓瘤、肉瘤、肺癌、前列腺癌、直肠癌、肾癌、胰腺癌、血癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、卵巢癌、外阴癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤或皮肤癌，进一步优选地，所述肿瘤为乳腺癌、结肠癌或肝癌。Preferably, the tumor is breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, blood cancer, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, gastrointestinal stromal tumor or skin cancer, and further preferably, the tumor is breast cancer, colon cancer or liver cancer.
某一方案中，所述应用中，所述物质A为上述式(III)所示化合物或其药学上可接受的盐。In one embodiment, in the application, the substance A is a compound represented by the above formula (III) or a pharmaceutically acceptable salt thereof.
本发明还提供了一种治疗和/或预防肿瘤的方法，其包括向患者施用治疗有效量的物质A，所述物质A为式(I)所示化合物、其异构体、其药学上可接受的盐、酯或其前药；The present invention also provides a method for treating and/or preventing tumors, comprising administering to a patient a therapeutically effective amount of a substance A, wherein the substance A is a compound represented by formula (I), an isomer thereof, a pharmaceutically acceptable salt, ester or prodrug thereof;
Figure PCTCN2023071067-appb-000041
Figure PCTCN2023071067-appb-000041
其中，R 1、R 2、X和R 3如本发明任一项所述； wherein R 1 , R 2 , X and R 3 are as described in any one of the present invention;
优选地，所述肿瘤为乳腺癌、结肠癌、肝癌、多发性骨髓瘤、肉瘤、肺癌、前列腺癌、直肠癌、肾癌、胰腺癌、血癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、卵巢癌、外阴癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤或皮肤癌，进一步优选地，所述肿瘤为乳腺癌、结肠癌或肝癌。Preferably, the tumor is breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, blood cancer, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, gastrointestinal stromal tumor or skin cancer, and further preferably, the tumor is breast cancer, colon cancer or liver cancer.
某一方案中，所述方法中，所述物质A为上述式(III)所示化合物或其药学上可接受的盐。In one embodiment, in the method, the substance A is a compound represented by the above formula (III) or a pharmaceutically acceptable salt thereof.
本发明还提供了一种药物组合物，其包含物质A和免疫检查点抑制剂(immune checkpoint inhibitor，ICI)，其中所述物质A为式(I)所示化合物、其异构体、其药学上可接受的盐、酯或其前药；优选地，所述免疫检查点抑制剂为PD-1，进一步优选地，所述物质A为式(III)所示化合物或其药学上可接受的盐。The present invention also provides a pharmaceutical composition, comprising substance A and an immune checkpoint inhibitor (ICI), wherein substance A is a compound represented by formula (I), an isomer thereof, a pharmaceutically acceptable salt, ester or a prodrug thereof; preferably, the immune checkpoint inhibitor is PD-1, and further preferably, substance A is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.
本发明还提供了一种药物组合物，包括至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂；所述活性组分包括前述技术方案所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂或 上述技术方案所述方法制备得到的与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂，及上述小分子抑制剂的异构体、药学上可接受的盐或酯中的任意一种或多种。The present invention also provides a pharmaceutical composition, comprising at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients; the active ingredient comprises the small molecule inhibitor interacting with β-catenin/BCL9 protein as described in the aforementioned technical solution or the small molecule inhibitor interacting with β-catenin/BCL9 protein prepared by the method described in the aforementioned technical solution, and any one or more of the isomers, pharmaceutically acceptable salts or esters of the aforementioned small molecule inhibitor.
在本发明中，所述药物组合物中的活性组分还可以与其他具有治疗效果或增强治疗效果、降低毒副作用、延长代谢时间的有效成分共同组成药物组合物。In the present invention, the active component in the pharmaceutical composition can also be combined with other effective ingredients that have therapeutic effects or enhance therapeutic effects, reduce toxic side effects, and prolong metabolic time to form a pharmaceutical composition.
本发明还提供了所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂、前述技术方案所述方法制备得到的与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂或上述技术方案所述药物组合物在制备抗肿瘤药物中的应用。The present invention also provides the use of the small molecule inhibitor interacting with β-catenin/BCL9 protein, the small molecule inhibitor interacting with β-catenin/BCL9 protein prepared by the method described in the aforementioned technical scheme, or the pharmaceutical composition described in the aforementioned technical scheme in the preparation of anti-tumor drugs.
本发明优选的，所述肿瘤包括乳腺癌、结肠癌、肝癌、多发性骨髓瘤、肉瘤、肺癌、前列腺癌、直肠癌、肾癌、胰腺癌、血癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、卵巢癌、外阴癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤、皮肤癌。Preferably, the tumors include breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, blood cancer, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, gastrointestinal stromal tumors, and skin cancer.
本发明通过实验证实，本发明所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂对人乳腺癌细胞MDA-MB-231、人乳腺癌细胞MDA-MB-468、人结肠癌细胞HCT-116、人肝癌细胞株HepG2等肿瘤细胞株具有抗增殖抑制作用，可应用于治疗人或动物细胞增殖性相关的实体瘤或血癌的药物中。The present invention has confirmed through experiments that the small molecule inhibitor interacting with the β-catenin/BCL9 protein protein of the present invention has an anti-proliferation inhibitory effect on tumor cell lines such as human breast cancer cells MDA-MB-231, human breast cancer cells MDA-MB-468, human colon cancer cells HCT-116, and human liver cancer cell lines HepG2, and can be used in drugs for treating solid tumors or blood cancers related to human or animal cell proliferation.
本发明还提供了上述式(I)所示化合物的制备方法，其可由如下任一方案制备得到：The present invention also provides a method for preparing the compound represented by the above formula (I), which can be prepared by any of the following schemes:
方案(1)：溶剂中，在催化剂作用下，将式(III-4)所示化合物进行如下所示水解反应，得到式(III-3)所示化合物Scheme (1): In a solvent, in the presence of a catalyst, the compound represented by formula (III-4) is subjected to a hydrolysis reaction as shown below to obtain a compound represented by formula (III-3)
Figure PCTCN2023071067-appb-000042
Figure PCTCN2023071067-appb-000042
其中，环A、R 1、R 2、X和R 4如本发明任一项所述； wherein Ring A, R 1 , R 2 , X and R 4 are as described in any one of the present invention;
方案(2)：溶剂中，在催化剂作用下，将式(III-3)所示化合物与NH2-Rg进行如下所示的酰胺化反应得到式(III-5)所示化合物；Scheme (2): In a solvent, in the presence of a catalyst, the compound represented by formula (III-3) is subjected to an amidation reaction with NH2-Rg as shown below to obtain a compound represented by formula (III-5);
Figure PCTCN2023071067-appb-000043
Figure PCTCN2023071067-appb-000043
其中，R g为-(CH 2) k-R d或-(SO 2)-R c； wherein Rg is -( CH2 ) k - Rd or -( SO2 ) -Rc ;
环A、K、R 1、R 2、X、R d和R c如本发明任一项所述； Ring A, K, R 1 , R 2 , X, R d and R c are as described in any one of the present invention;
方案(3)：溶剂中，在催化剂作用下，将式(III-3)所示化合物与H-R 4进行如下所示的酰化反应得到式(III-6)所示化合物； Scheme (3): In a solvent, in the presence of a catalyst, the compound represented by formula (III-3) is subjected to an acylation reaction with HR 4 as shown below to obtain a compound represented by formula (III-6);
Figure PCTCN2023071067-appb-000044
Figure PCTCN2023071067-appb-000044
其中，R 4为4～10元杂环烷基或被一个或多个R e取代的4～10元杂环烷基； Wherein, R 4 is a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered heterocycloalkyl group substituted by one or more Re ;
环A、R 1、R 2、R e、X、4～10元杂环烷基如本发明任一项所述。 Ring A, R 1 , R 2 , Re , X, and 4- to 10-membered heterocycloalkyl are as described in any one of the present invention.
某一方案中，所述制备方法中，所述方案(1)中，所述溶剂为本领域此类反应常规溶剂，例如四氢呋喃、甲醇和水中一种或多种，优选为四氢呋喃/甲醇/水＝3∶1∶1的混合溶剂。In one embodiment, in the preparation method, in the embodiment (1), the solvent is a conventional solvent for such reactions in the art, such as one or more of tetrahydrofuran, methanol and water, preferably a mixed solvent of tetrahydrofuran/methanol/water = 3:1:1.
某一方案中，所述制备方法中，所述方案(1)中，所述催化剂为本领域此类反应常规催化剂，例如氢氧化锂。In one embodiment, in the preparation method, in the embodiment (1), the catalyst is a conventional catalyst for such reactions in the art, such as lithium hydroxide.
某一方案中，所述制备方法中，所述方案(1)中，所述水解反应结束后加入布朗斯特酸，例如盐酸，所述布朗斯特酸加入后体系pH为3-4。In one embodiment, in the preparation method, in the embodiment (1), after the hydrolysis reaction is completed, a Bronsted acid, such as hydrochloric acid, is added, and the pH of the system is 3-4 after the Bronsted acid is added.
某一方案中，所述制备方法中，所述方案(1)中，所得式(III-3)所示化合物可进一步在盐酸的二氧六环溶液发生成盐反应。In one embodiment, in the preparation method, in the embodiment (1), the compound represented by formula (III-3) obtained can further undergo a salt-forming reaction in a dioxane solution of hydrochloric acid.
某一方案中，所述制备方法中，所述方案(2)中，所述溶剂为本领域此类反应常规溶剂，例如DCM。In one embodiment, in the preparation method, in the embodiment (2), the solvent is a conventional solvent for such reactions in the art, such as DCM.
某一方案中，所述制备方法中，所述方案(2)中，所述催化剂为本领域此类反应常规催化剂，例如1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和/或4-二甲氨基吡啶。In one embodiment, in the preparation method, in the embodiment (2), the catalyst is a conventional catalyst for such reactions in the art, such as 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and/or 4-dimethylaminopyridine.
某一方案中，所述制备方法中，所述方案(3)中，所述溶剂为本领域此类反应常规溶剂，例如二氯甲烷和/或DMF。In one embodiment, in the preparation method, in the embodiment (3), the solvent is a conventional solvent for such reactions in the art, such as dichloromethane and/or DMF.
某一方案中，所述制备方法中，所述方案(3)中，所述催化剂为本领域此类反应常规催化剂，例如三乙胺和/或HATU(2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯)。In one embodiment, in the preparation method, in the embodiment (3), the catalyst is a conventional catalyst for such reactions in the art, such as triethylamine and/or HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate).
某一方案中，所述制备方法中，所述方案(3)中，所得所述式(III-6)所示化合物可进一步在盐酸的二氧六环溶液发生成盐反应。In one embodiment, in the preparation method, in the embodiment (3), the compound represented by the formula (III-6) obtained can further undergo a salt-forming reaction in a dioxane solution of hydrochloric acid.
本发明提供了一种式(III-4)所示化合物，The present invention provides a compound represented by formula (III-4),
Figure PCTCN2023071067-appb-000045
Figure PCTCN2023071067-appb-000045
其中，R 4为C 1-C 6烷氧基，环A、X、R 1和R 2如本发明任一项所述。 Wherein, R 4 is C 1 -C 6 alkoxy, and ring A, X, R 1 and R 2 are as described in any one of the present invention.
某一方案中，所述式(III-4)所示化合物中，R 4中，所述C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基，例如甲氧基。 In one embodiment, in the compound represented by formula (III-4), in R 4 , the C 1 -C 6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy, such as methoxy.
某一方案中，所述式(III-4)所示化合物为如下任一化合物：In one embodiment, the compound represented by formula (III-4) is any of the following compounds:
2-(3-(1-(3′，4′-二甲基-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
2-(3-(1-(3-(苯并[b]噻吩-6-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(3-(benzo[b]thiophen-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-甲基-2-(3-(1-(3-(噻吩-3-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸甲酯；Methyl 2-methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propanoate;
2-甲基-2-(3-(1-(3-(噻吩-2-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸甲酯；Methyl 2-methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propanoate;
2-(3-(1-(3-(1H-吡唑-4-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-(3-(1-(4′-异丙基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-(4′-isopropyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
2-(3-(1-([1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-([1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-(3-(1-([1，1′-联苯基]-4-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-([1,1′-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-甲基-2-(3-(1-((3-(噻吩-3-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸甲酯；2-methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoic acid methyl ester;
2-(3-(1-([1，1′-联苯基]-3-基磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-([1,1′-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-(3-(1-((3-环己基苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-甲基-2-(3-(1-((3-(噻吩-2-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸甲酯；Methyl 2-methyl-2-(3-(1-((3-(thiophen-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoate;
2-(3-(1-((3-(苯并[b]噻吩-6-基)苯基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((3-(Benzo[b]thiophen-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
2-(3-(1-((3′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-((3′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-(3-(1-((4′-(叔丁基)-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)甲基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
2-(3-(1-((3，4-二甲基苄基)氨基甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-(3-(1-(3-(3，4-二甲基苯基)丙基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
2-(3-(1-2-(4-异丙基苯基乙酰基)哌啶-3-基苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-2-(4-isopropylphenylacetyl)piperidin-3-ylphenoxy)-2-methylpropanoate;
3-(3-(3-(4-异丙基苯基丙烯酰基)哌啶-3-基苯氧基-2-甲基丙酸甲酯；3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy-2-methylpropionic acid methyl ester;
2-(3-(1-(4-异丙基苯甲酰基)哌啶-3-基苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(4-isopropylbenzoyl)piperidin-3-ylphenoxy)-2-methylpropanoate;
2-(3-(1-(4-异丙基苄基)氨甲酰基哌啶-3-基苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropanoate;
2-(3-1-联苯)-4-羰基哌啶-3-苯氧基-2-甲基丙酸甲酯；2-(3-1-biphenyl)-4-carbonylpiperidinyl-3-phenoxy-2-methylpropionic acid methyl ester;
2-(3-1-(3′-异丙基联苯)-3-磺酰基哌啶-3-基苯氧基-2-甲基丙酸甲酯；2-(3-1-(3′-isopropylbiphenyl)-3-sulfonylpiperidin-3-ylphenoxy-2-methylpropionic acid methyl ester;
2-(3-1-叔丁基)-3-磺酰基-3-磺酰基哌啶-2-甲基丙酸甲酯；Methyl 2-(3-1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidin-2-methylpropanoate;
2-(3-(1-(3-异丙基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯。Methyl 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate.
本发明还提供了上述技术方案所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂的制备 方法，包括以下步骤：The present invention also provides a method for preparing the small molecule inhibitor interacting with β-catenin/BCL9 protein according to the above technical solution, comprising the following steps:
将式(V)化合物与式(VI)化合物进行偶联反应，得到式(VII)中间体化合物；Carrying out a coupling reaction between the compound of formula (V) and the compound of formula (VI) to obtain an intermediate compound of formula (VII);
所述偶联反应试剂选自三乙胺、二氯甲烷、HATU(2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯)、DMF、钯碳和Xantphos(4，5-双(二苯基膦)-9，9-二甲基氧杂蒽)中的一种或多种；The coupling reaction reagent is selected from one or more of triethylamine, dichloromethane, HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), DMF, palladium carbon and Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethylxanthene);
Figure PCTCN2023071067-appb-000046
Figure PCTCN2023071067-appb-000046
其中，in,
环A’选自环A或环A的前体化合物；Ring A' is selected from Ring A or a precursor compound of Ring A;
Y选自X或X的前体基团；Y is selected from X or a precursor group of X;
R 5选自R 3或R 3的前体基团，或可被R 3或R 3的前体基团取代的卤素、羟基、羧基、氨基、酰基、酰胺基、烷氧基、烷胺基、巯基、磺酰基、烃基、芳基、杂芳基或杂环基； R 5 is selected from R 3 or a precursor group of R 3 , or a halogen , hydroxyl , carboxyl, amino, acyl, amide, alkoxy, alkylamino, mercapto, sulfonyl, hydrocarbon, aryl, heteroaryl or heterocyclic group which may be substituted by R 3 or a precursor group of R 3;
R8为能与哌啶环中1-NH反应的基团；R8 is a group that can react with 1-NH in the piperidine ring;
R6、R7独立地选自R6/R7或R6/R7的前体基团，或可被R6/R7或R6/R7的前体基取代的卤素、羟基、羧基、氨基、酰基、酰胺基、烷氧基、烷胺基、巯基、磺酰基、烃基、芳基、杂芳基或杂环基。R6 and R7 are independently selected from R6/R7 or a precursor group of R6/R7, or a halogen, hydroxyl, carboxyl, amino, acyl, amide, alkoxy, alkylamino, thiol, sulfonyl, hydrocarbon, aryl, heteroaryl or heterocyclic group which can be substituted by R6/R7 or a precursor group of R6/R7.
优选的，式(V)化合物的制备方法包括：Preferably, the preparation method of the compound of formula (V) comprises:
5-吡啶硼酸与式(III)化合物进行第一反应，得到式(IV)化合物；5-pyridineboronic acid and the compound of formula (III) undergo a first reaction to obtain a compound of formula (IV);
式(IV)化合物进行第二反应，得到式(V)化合物；The compound of formula (IV) undergoes a second reaction to obtain a compound of formula (V);
所述第一反应的条件包括反应物在碱性条件下加热；The conditions of the first reaction include heating the reactants under alkaline conditions;
所述第二反应为催化加氢反应，催化剂选自Pt、Pd或Ni类催化剂；The second reaction is a catalytic hydrogenation reaction, and the catalyst is selected from Pt, Pd or Ni catalysts;
Figure PCTCN2023071067-appb-000047
Figure PCTCN2023071067-appb-000047
优选地，式(II)化合物的制备方法包括以下步骤：Preferably, the preparation method of the compound of formula (II) comprises the following steps:
将式(VIII)化合物与式(VI)化合物偶联，得到式(IX)中间体化合物；coupling the compound of formula (VIII) with the compound of formula (VI) to obtain an intermediate compound of formula (IX);
所述偶联反应试剂选自三乙胺、二氯甲烷、HATU、DMF、钯碳和Xantphos中的一种或多种；The coupling reaction reagent is selected from one or more of triethylamine, dichloromethane, HATU, DMF, palladium carbon and Xantphos;
Figure PCTCN2023071067-appb-000048
Figure PCTCN2023071067-appb-000048
其中，in,
环A”选自取代或非取代的苯或其前体基团；Ring A" is selected from substituted or unsubstituted benzene or its precursor group;
R9选自R4或R4的前体基团，或可被R4或R4的前体基团取代的卤素、羟基、羧基、氨基、酰基、酰胺基、烷氧基、烷胺基、巯基、磺酰基、烃基、芳基、杂芳基或杂环基。R9 is selected from R4 or a precursor group of R4, or a halogen, hydroxyl, carboxyl, amino, acyl, amide, alkoxy, alkylamino, thiol, sulfonyl, hydrocarbon, aryl, heteroaryl or heterocyclic group which can be substituted by R4 or a precursor group of R4.
优选的，式(VIII)化合物的制备方法包括：Preferably, the preparation method of the compound of formula (VIII) comprises:
5-吡啶硼酸与式(X)化合物进行第三反应，得到式(XI)化合物；5-pyridineboronic acid and the compound of formula (X) undergo a third reaction to obtain a compound of formula (XI);
式(XI)化合物与2-溴异丁酸甲酯进行第四反应，得到式(XII)化合物；The compound of formula (XI) is subjected to a fourth reaction with methyl 2-bromoisobutyrate to obtain a compound of formula (XII);
式(XII)化合物进行第五反应，得到式(VIII)化合物；The compound of formula (XII) is subjected to a fifth reaction to obtain a compound of formula (VIII);
所述第三反应的条件包括反应物在碱性条件下加热；The conditions of the third reaction include heating the reactants under alkaline conditions;
所述第四反应的条件包括反应物在碱性条件下加热；The conditions of the fourth reaction include heating the reactants under alkaline conditions;
所述第五反应为催化加氢反应，催化剂选自Pt、Pd或Ni类催化剂；The fifth reaction is a catalytic hydrogenation reaction, and the catalyst is selected from Pt, Pd or Ni catalysts;
Figure PCTCN2023071067-appb-000049
Figure PCTCN2023071067-appb-000049
其中，in,
R10选自可与2-溴异丁酸甲酯发生取代反应的基团；R10 is selected from a group that can undergo a substitution reaction with methyl 2-bromoisobutyrate;
R9选自R4或R4的前体基团，或可被R4或R4的前体基团取代的卤素、羟基、羧基、氨基、酰基、酰胺基、烷氧基、烷胺基、巯基、磺酰基、烃基、芳基、杂芳基或杂环基。R9 is selected from R4 or a precursor group of R4, or a halogen, hydroxyl, carboxyl, amino, acyl, amide, alkoxy, alkylamino, thiol, sulfonyl, hydrocarbon, aryl, heteroaryl or heterocyclic group which can be substituted by R4 or a precursor group of R4.
术语解释：Terminology explanation:
除非另有说明，本发明中术语有如下定义：Unless otherwise specified, the terms used in this invention have the following definitions:
术语“异构体”包括但不限于对映异构体、非对映异构体、对映异构体和非对映异构体的混合物、互变异构体、外消旋混合物与非对映异构体的混合物，及其药学上可接受的盐。除非另做说明，当未具体指明异构体组分时，包括所有可能的异构体。The term "isomer" includes, but is not limited to, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, tautomers, mixtures of racemic mixtures and diastereomers, and pharmaceutically acceptable salts thereof. Unless otherwise specified, when the isomeric component is not specifically indicated, all possible isomers are included.
术语“药学上可接受的盐”是指通过形成本发明所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂其酸式或碱式盐修饰的化合物，包括但不限于无机酸的盐，选自例如，盐酸盐、磷酸盐、磷酸氢盐、氢溴酸盐、硫酸盐、亚硫酸盐和硝酸盐；以及有机盐的盐，选自例如苹果酸盐、马来酸盐、延胡索酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙基磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐、链烷酸盐如乙酸盐，以及HOOC-(CH 2)n-COOH的盐，其中n选自0-4。如果化合物作为酸加成盐获得，则游离碱可以通过碱化酸式盐的溶液而获得。相反地，如果产物是游离碱，加成盐(例如药学上可接受的加成盐)可以通过将游离碱溶于合适的有机溶剂并且用酸处理溶液而制备，与由碱性化合物制备酸加成盐的常规过程一致。本领域技术人员应了解无需过度实验而可用于制备无毒的药学上可接受的加成盐的各种合成方法。具体可参见Handbook of Pharmaceutical Salts：Properties，Selection，and Use(P.Heinrich Stahl，Camille G.Wermuth，2011，2nd Revised Edition)，例如盐酸盐。 The term "pharmaceutically acceptable salt" refers to a compound modified by forming an acid or basic salt of the small molecule inhibitor of the invention that interacts with the β-catenin/BCL9 protein, including but not limited to salts of inorganic acids, selected from, for example, hydrochlorides, phosphates, hydrogen phosphates, hydrobromides, sulfates, sulfites and nitrates; and salts of organic salts, selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoate such as acetate, and salts of HOOC-(CH 2 )n-COOH, wherein n is selected from 0 to 4. If the compound is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. On the contrary, if the product is a free base, an addition salt (e.g., a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, consistent with the conventional process for preparing acid addition salts from basic compounds. Those skilled in the art will appreciate the various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition), for example, hydrochloride.
术语“药学上可接受的酯”是指通过形成本发明所述小分子抑制剂的酯类衍生物，例如小分子抑制剂与甲醇酯化反应得到甲酯衍生物。The term "pharmaceutically acceptable ester" refers to the formation of an ester derivative of the small molecule inhibitor of the present invention, for example, a methyl ester derivative is obtained by esterification of the small molecule inhibitor with methanol.
术语“药学上可接受的前药”是具有在体内外形成本发明所述小分子抑制剂的前体化合物。The term "pharmaceutically acceptable prodrug" refers to a precursor compound that has the ability to form the small molecule inhibitor of the present invention in vitro or in vivo.
术语“芳环”或“芳基”是指5-12个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳环的非限制性实例有：苯环、联苯、萘环和蒽环。The term "aromatic ring" or "aryl group" refers to an all-carbon monocyclic or fused polycyclic group of 5-12 carbon atoms with a completely conjugated π electron system. Non-limiting examples of aromatic rings are: benzene ring, biphenyl ring, naphthalene ring and anthracene ring.
术语“杂芳环”或“杂芳基”是指5-12个环原子的不饱和的碳环，其中一个或多个碳被杂原子例如氧、氮、硫等置换。杂芳环可以是单环，也可以是双环，即通过两个环稠合而成。具体的杂环芳基可以是：吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、吡咯基、吗啉基、哌啶基或哌嗪基、噻吩基、苯并噻吩基、吡唑基、苯并吡唑基、吲哚基、二氧戊环基、苯并[1，3]二氧戊环基、噁唑基、苯并噁唑基、呋喃基、苯并呋喃基、噻唑基或苯并噻唑基等。The term "heteroaromatic ring" or "heteroaryl" refers to an unsaturated carbocyclic ring of 5-12 ring atoms, wherein one or more carbon atoms are replaced by heteroatoms such as oxygen, nitrogen, sulfur, etc. The heteroaromatic ring can be a monocyclic ring or a bicyclic ring, i.e., formed by the fusion of two rings. Specific heterocyclic aromatic groups can be: pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, morpholinyl, piperidinyl or piperazinyl, thienyl, benzothienyl, pyrazolyl, benzopyrazolyl, indolyl, dioxolanyl, benzo[1,3]dioxolanyl, oxazolyl, benzoxazolyl, furyl, benzofuranyl, thiazolyl or benzothiazolyl, etc.
术语“脂肪环”或“环烷基”是指具有3碳原子以上的饱和单环碳环，除非指明不同数目的原子及饱和度。“脂肪环”或“环烷基”包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。The term "aliphatic ring" or "cycloalkyl" refers to a saturated monocyclic carbon ring having more than 3 carbon atoms, unless a different number of atoms and degree of saturation are specified. "Aliphatic ring" or "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
术语“烷氧基”是指-O-烷基基团，其中烷基如上所定义。本发明所用“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。The term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" used in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
术语“卤素”或“卤代”表示氟、氯、溴或碘，优选为氟、氯或溴。The term "halogen" or "halo" denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
术语“杂环的”或“杂环”或“杂环基”指的是选自如下的环：4-12元的单环、双环和三环的饱和和部分不饱和的环，其除了选自氧、硫和氮的1、2、3或者4个杂原子外包含至少一个碳原子。“杂环的”或“杂环”或“杂环基”也指与5、6和/或7元环烷基、碳环芳族或杂芳族环稠合并包含至少一个选自N、O和S的杂原子的5-7元杂环，条件是当杂环与碳环芳族或杂芳族环稠合时连接点在杂环上，且当杂环与环烷基稠合时连接点可在环烷基或杂环上。“杂环的”或“杂环”或“杂环基”也指包含至少一个选自N、O和S的杂原子的脂族螺环，条件是连接点在杂环上。连接点可以是杂环中的 碳原子或杂原子。杂环不是本文中定义的杂芳基。The term "heterocyclic" or "heterocycle" or "heterocyclyl" refers to a ring selected from the following: 4-12 membered monocyclic, bicyclic and tricyclic saturated and partially unsaturated rings, which contain at least one carbon atom in addition to 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen. "Heterocyclic" or "heterocycle" or "heterocyclyl" also refers to a 5-7 membered heterocycle fused to a 5, 6 and/or 7 membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring and containing at least one heteroatom selected from N, O and S, provided that when the heterocycle is fused to the carbocyclic aromatic or heteroaromatic ring, the point of attachment is on the heterocycle, and when the heterocycle is fused to the cycloalkyl, the point of attachment can be on the cycloalkyl or heterocycle. "Heterocyclic" or "heterocycle" or "heterocyclyl" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O and S, provided that the point of attachment is on the heterocycle. The point of attachment can be a carbon atom or a heteroatom in the heterocycle. A heterocycle is not a heteroaryl as defined herein.
术语“稠环”指的是如下的多环体系例如二环或三环体系，其中两个环仅共享两个环原子和一个键。稠环的实例可以包括稠合的双环烷基环，如由7-12个环原子排列组成的选自上述[4，4]、[4，5]、[5，5]、[5，6]和[6，6]环体系的双环；稠合双环芳基环，例如上述7-12元双环芳基环体系，稠合的三环芳基环，例如上述10-15元三环芳基环体系；稠合的双环杂芳基环，例如上述8-12元双环杂芳基环，稠合的三环杂芳基环，例如上述11-14元三环杂芳基环；以及上述稠合的双环或三环杂环基环。The term "fused ring" refers to a polycyclic ring system such as a bicyclic or tricyclic ring system in which the two rings share only two ring atoms and one bond. Examples of fused rings may include fused bicyclic alkyl rings, such as bicyclic rings composed of 7-12 ring atoms arranged in a [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems described above; fused bicyclic aryl rings, such as the 7-12 membered bicyclic aryl ring system described above, fused tricyclic aryl rings, such as the 10-15 membered tricyclic aryl ring system described above; fused bicyclic heteroaryl rings, such as the 8-12 membered bicyclic heteroaryl rings described above, fused tricyclic heteroaryl rings, such as the 11-14 membered tricyclic heteroaryl rings described above; and fused bicyclic or tricyclic heterocyclyl rings described above.
术语“-”是指该基团通过该位点与分子其余部分相连。例如，“CH 3O-”是指烷氧基。 The term "-" refers to the site through which the group is attached to the rest of the molecule. For example, " CH3O- " refers to an alkoxy group.
术语
Figure PCTCN2023071067-appb-000050
是指该结构片段通过该位点与分子其余部分相连。 the term
Figure PCTCN2023071067-appb-000050
It means that the structural fragment is connected to the rest of the molecule through this site.
术语“药学上可接受”是指相对无毒、安全、适合于患者使用。The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.
术语“药用辅料”是指除活性药物成分以外，包含在药物制剂中的所有物质，一般分为赋形剂和附加剂两大类。具体可参见《中华人民共和国药典(2020年版)》、Handbook of Pharmaceutical Excipients(Paul J Sheskey，Bruno C Hancock，Gary P Moss，David J Goldfarb，2020，9th Edition)。The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than active pharmaceutical ingredients, which are generally divided into two categories: excipients and additives. For details, please refer to the "Pharmacopoeia of the People's Republic of China (2020 Edition)", Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).
术语“治疗”是指消除病因或缓解症状。The term "treating" refers to removing the cause or alleviating the symptoms.
术语“预防”是指降低发生疾病的风险。The term "prevention" refers to reducing the risk of developing a disease.
术语“患者”是指需要接受治疗或预防疾病的任何动物，通常是哺乳动物，例如人类。哺乳动物包括但不限于：牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人类等。The term "patient" refers to any animal, usually a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物种类、疾病种类、疾病的严重度、患者的年龄等变化，但可由本领域技术人员视情况调整。The term "therapeutically effective amount" refers to the amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
表述“被一个或多个基团A取代的基团B”是指基团B中的一个或多个氢原子独立地被基团A替代。当同时出现多个A基团时，如无特别说明，它们的定义互相独立、互不影响。The expression "a group B substituted by one or more groups A" means that one or more hydrogen atoms in the group B are independently replaced by a group A. When multiple groups A appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other.
术语“氧代基”是指＝O，氧原子替代同一原子上的两个氢，例如，亚甲基(-(CH 2-)被氧代后为羰基(-C(＝O)-)。 The term "oxo" refers to =0, where an oxygen atom replaces two hydrogen atoms on the same atom, for example, methylene (-( CH2- ) is oxoed to form carbonyl (-C(=O)-).
术语“烷基”是指具有指定碳原子数的、直链或支链的、饱和的一价烃基。例如，C 1-C 6烷基(C 1-6烷基)或C 4-C 20烷基(C 4-20烷基)，优选C 1-C 4烷基(C 1-4烷基)或C 9-C 15烷基(C 1-6烷基)。烷基包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms. For example, C 1 -C 6 alkyl (C 1-6 alkyl) or C 4 -C 20 alkyl (C 4-20 alkyl), preferably C 1 -C 4 alkyl (C 1-4 alkyl) or C 9 -C 15 alkyl (C 1-6 alkyl). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
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。Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.
本发明的积极进步效果在于：The positive and progressive effects of the present invention are:
1.本发明所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂为一种新型苯基哌啶类化合物，其结构新颖，药理活高、安全性好，具有如下一个或多个优点：1. The small molecule inhibitor of the interaction with β-catenin/BCL9 protein described in the present invention is a novel phenylpiperidine compound, which has a novel structure, high pharmacological activity, good safety, and has one or more of the following advantages:
(1)与β-catenin/BCL9蛋白-蛋白的亲和力较高，具有阻断Wnt通路激活的作用，并可透过细胞膜抑制肿瘤细胞；(1) It has a high affinity for β-catenin/BCL9 protein-protein, has the effect of blocking the activation of the Wnt pathway, and can penetrate the cell membrane to inhibit tumor cells;
(2)对肿瘤细胞具有选择性抑制作用，在体外实验中对人乳腺癌细胞、人结肠癌细胞、人肝癌 细胞均显示出较高的抑制活性，对人正常细胞的抑制活性较低，显示出较低的毒副作用。(2) It has a selective inhibitory effect on tumor cells. In in vitro experiments, it showed high inhibitory activity against human breast cancer cells, human colon cancer cells, and human liver cancer cells, but low inhibitory activity against normal human cells, showing low toxic side effects.
(3)对hERG钾离子通道的抑制浓度较高，潜在的心脏毒性较低；(3) The inhibitory concentration of hERG potassium ion channel is higher and the potential cardiotoxicity is lower;
(4)肝微粒体代谢稳定；(4) stable liver microsomal metabolism;
(5)在动物实验中表现出显著的抑制肿瘤生长作用，可对多种肿瘤细胞产生抑制作用。(5) It has shown significant inhibitory effects on tumor growth in animal experiments and can inhibit a variety of tumor cells.
2.本发明提供的与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂制备方法条件简单，原料易得，制备成本低。2. The preparation method of the small molecule inhibitor that interacts with β-catenin/BCL9 protein provided by the present invention has simple conditions, readily available raw materials and low preparation cost.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为实施例36中结肠癌小鼠模型不同化合物的体内药效结果比较图。FIG1 is a graph comparing the in vivo efficacy results of different compounds in the colon cancer mouse model in Example 36.
图2为结肠癌小鼠模型用药后肿瘤体积变化。Figure 2 shows the changes in tumor volume in the colon cancer mouse model after drug administration.
图3为结肠癌小鼠模型用药后体重变化。Figure 3 shows the changes in body weight of the colon cancer mouse model after drug administration.
具体实施方式Detailed ways
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。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.
实施例1 2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-1的制备Example 1 Preparation of 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-1
Figure PCTCN2023071067-appb-000051
Figure PCTCN2023071067-appb-000051
步骤a：3-(吡啶-3-基)苯酚，化合物3的制备Step a: Preparation of 3-(pyridin-3-yl)phenol, compound 3
将化合物1(200mg，1.16mmol)和化合物2(171mg，1.39mmol)溶解于乙醇/甲苯(1∶2，30mL)的溶液中，随后加入2M的碳酸钠溶液(5mL)，在氮气保护下，110℃反应5h，过滤反应液，减压浓缩，使用乙酸乙酯反复萃取反应液，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗品使用硅胶色谱柱纯化(洗脱剂：石油醚/乙酸乙酯＝5∶1-3∶1)，得到淡黄色固体120mg，收率60％Compound 1 (200 mg, 1.16 mmol) and compound 2 (171 mg, 1.39 mmol) were dissolved in an ethanol/toluene (1:2, 30 mL) solution, and then a 2M sodium carbonate solution (5 mL) was added. The mixture was reacted at 110°C for 5 h under nitrogen protection. The reaction solution was filtered and concentrated under reduced pressure. The reaction solution was repeatedly extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using a silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5:1-3:1) to obtain 120 mg of a light yellow solid with a yield of 60%.
步骤b：2-甲基-2-(3-(吡啶-3-基)苯氧基)丙酸甲酯，化合物5的制备Step b: Preparation of methyl 2-methyl-2-(3-(pyridin-3-yl)phenoxy)propanoate, compound 5
将化合物3(2.5g，14.6mmol)和化合物4(3.2g，17.5mmol)溶解于乙腈(50mL)溶液中，随后加入碳酸钾(4g，29.2mmol)，90℃下反应20h，将反应液减压浓缩得到粗品，粗品使用硅胶色谱柱纯化(洗脱剂：石油醚/乙酸乙酯＝6∶1-4∶1)，得到淡黄色油状物2.5g，收率64％。Compound 3 (2.5 g, 14.6 mmol) and compound 4 (3.2 g, 17.5 mmol) were dissolved in acetonitrile (50 mL) solution, followed by the addition of potassium carbonate (4 g, 29.2 mmol), and the mixture was reacted at 90°C for 20 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate = 6:1-4:1) to obtain 2.5 g of a light yellow oil with a yield of 64%.
步骤c：2-甲基-2-(3-(哌啶-3-基)苯氧基)丙酸甲酯，化合物6的制备Step c: Preparation of methyl 2-methyl-2-(3-(piperidin-3-yl)phenoxy)propanoate, compound 6
将化合物5(2.7g，9.9mmol)的甲醇(30mL)溶液中，加入1N的盐酸溶液(10mL)，加入催化量的二氧化铂200mg，在50psi的氢气压力下反应5h，将反应液过滤，除去二氧化铂，加入饱和的碳酸氢钠水溶液将反应液Ph调至碱性，使用乙酸乙酯反复萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗品使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶1-100∶5)，得到淡黄色油状物1.3g，收率47％。To a solution of compound 5 (2.7 g, 9.9 mmol) in methanol (30 mL) was added 1N hydrochloric acid solution (10 mL), and a catalytic amount of platinum dioxide 200 mg was added, and the mixture was reacted under a hydrogen pressure of 50 psi for 5 h. The reaction solution was filtered to remove platinum dioxide, and a saturated aqueous sodium bicarbonate solution was added to adjust the reaction solution Ph to alkaline. The mixture was repeatedly extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using a silica gel column (dichloromethane/methanol = 100:1-100:5) to obtain 1.3 g of a light yellow oil with a yield of 47%.
步骤d：3′，4′-二甲基-[1，1′-联苯]-3-羧酸甲酯，化合物9的制备Step d: Preparation of methyl 3′,4′-dimethyl-[1,1′-biphenyl]-3-carboxylate, compound 9
将化合物7(800mg，3.7mmol)和化合物8(669mg，4.5mmol)溶解于甲苯/甲醇/2M碳酸钠(2∶1∶1，30mL)的溶液中，加入四三苯基膦钯(129mg，0.11mmol)，氮气保护下，110℃反应3h，过滤，减压蒸干反应液，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到无色油状物870mg，收率98％。Compound 7 (800 mg, 3.7 mmol) and compound 8 (669 mg, 4.5 mmol) were dissolved in a solution of toluene/methanol/2M sodium carbonate (2:1:1, 30 mL), and tetrakistriphenylphosphine palladium (129 mg, 0.11 mmol) was added. Under nitrogen protection, the reaction was carried out at 110°C for 3 h, filtered, and the reaction solution was evaporated under reduced pressure. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to obtain 870 mg of a colorless oil in a yield of 98%.
步骤e：3′，4′-二甲基-[1，1′-联苯]-3-羧酸，化合物10的制备Step e: Preparation of 3′,4′-dimethyl-[1,1′-biphenyl]-3-carboxylic acid, compound 10
将化合物9(868mg，3.6mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(758mg，18mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-6∶1))得到白色固体760mg，收率86％。Compound 9 (868 mg, 3.6 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (758 mg, 18 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-6:1) to obtain 760 mg of a white solid with a yield of 86%.
步骤f：2-(3-(1-(3′，4′-二甲基-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯，化合物11的制备Step f: Preparation of methyl 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propanoate, compound 11
将化合物6(500mg，1.8mmol)溶解于N，N-二甲基甲酰胺(25mL)溶液中，分别加入化合物9(316mg，1.4mmol)、2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(836g，1.2mmol)和三乙胺(364mg，3.6mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-6∶1))得到无色油状物648mg，收率98％。Compound 6 (500 mg, 1.8 mmol) was dissolved in N,N-dimethylformamide (25 mL) solution, and compound 9 (316 mg, 1.4 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (836 g, 1.2 mmol) and triethylamine (364 mg, 3.6 mmol) were added respectively. The mixture was stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-6:1) to obtain 648 mg of a colorless oil with a yield of 98%.
步骤g：2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-1的制备Step g: Preparation of 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-1
将中间体2-(3-(1-(3′，4′-二甲基-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯(671mg，1.4mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(290mg，6.9mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-1∶1)得到白色固体201mg，收率32％。The intermediate 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester (671 mg, 1.4 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (290 mg, 6.9 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-1:1) to give 201 mg of a white solid with a yield of 32%.
1H NMR(400MHz，MeOD)δ7.79-7.60(m，2H)，7.52(dd，J＝15.7，7.9Hz，1H)，7.46-7.28(m，3H)，7.17(dt，J＝15.4，10.0Hz，2H)，7.02-6.86(m，1H)，6.77(dd，J＝20.9，11.6Hz，1H)，6.71(s，1H)，4.70(d，J＝10.4Hz，1H)，3.80(t，J＝12.0Hz，1H)，3.16(dd，J＝27.0，13.6Hz，1H)，2.88(dd，J＝34.1，22.1Hz，2H)，2.33(d，J＝13.0Hz，6H)，2.15-1.67(m，4H)，1.60-1.46(m，6H)。 1 H NMR (400 MHz, MeOD) δ 7.79-7.60 (m, 2H), 7.52 (dd, J=15.7, 7.9 Hz, 1H), 7.46-7.28 (m, 3H), 7.17 (dt, J=15.4, 10.0 Hz, 2H), 7.02-6.86 (m, 1H), 6.77 (dd, J = 20.9, 11.6 Hz, 1H), 6.71 (s , 1H), 4.70 (d, J = 10.4 Hz, 1H), 3.80 (t, J = 12.0 Hz, 1H), 3.16 (dd, J = 27.0, 13.6 Hz, 1H), 2.88 (dd, J = 34.1, 22.1 Hz, 2H), 2.33 (d, J = 13.0 Hz, 6H), 2.15-1.67 (m, 4H), 1.60-1.46 (m, 6H).
实施例2Example 2
2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-2的制备Preparation of 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-2
Figure PCTCN2023071067-appb-000052
Figure PCTCN2023071067-appb-000052
参照实施例1得到中间体2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯Referring to Example 1, the intermediate 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester was obtained.
将中间体2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯(660mg，1.3mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(279mg，6.6mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-2∶1)得到白色固体50mg，收率8％。The intermediate 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester (660 mg, 1.3 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (279 mg, 6.6 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-2:1) to give 50 mg of a white solid with a yield of 8%.
1H NMR(400MHz，MeOD)δ7.76-7.49(m，4H)，7.47-7.27(m，3H)，7.15(dt，J＝51.3，7.8Hz，1H)，7.01-6.85(m，1H)，6.74(dd，J＝21.6，13.1Hz，1H)，6.67(s，1H)，4.68(d，J＝11.9Hz，1H)，3.88-3.63(m，1H)，3.16(dd，J＝26.3，13.6Hz，1H)，2.98-2.69(m，2H)，2.02(t，J＝15.5Hz，1H)，1.88-1.70(m，2H)，1.66-1.41(m，7H)。 1 H NMR (400 MHz, MeOD) δ 7.76-7.49 (m, 4H), 7.47-7.27 (m, 3H), 7.15 (dt, J=51.3, 7.8 Hz, 1H), 7.01-6.85 (m, 1H), 6.74 (dd, J=21.6, 13.1 Hz, 1H), 6.67 (s, 1H), 4.68 (d, J=11.9 Hz, 1H), 3.88-3.63 (m, 1H), 3.16 (dd, J=26.3, 13.6 Hz, 1H), 2.98-2.69 (m, 2H), 2.02 (t, J=15.5 Hz, 1H), 1.88-1.70 (m, 2H), 1.66-1.41 (m, 7H).
实施例3Example 3
2-(3-(1-(3-(苯并[b]噻吩-6-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-3的制备Preparation of 2-(3-(1-(3-(benzo[b]thiophen-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-3
Figure PCTCN2023071067-appb-000053
Figure PCTCN2023071067-appb-000053
参照实施例1得到中间体2-(3-(1-(3-(苯并[b]噻吩-6-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Referring to Example 1, the intermediate 2-(3-(1-(3-(benzo[b]thiophen-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid methyl ester was obtained.
将中间体2-(3-(1-(3-(苯并[b]噻吩-6-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(660mg，1.2mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(245mg，5.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝4∶1-1∶1)得到白色固体130mg，收率22％。The intermediate methyl 2-(3-(1-(3-(benzo[b]thiophen-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (660 mg, 1.2 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (245 mg, 5.8 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 4:1-1:1) to give 130 mg of a white solid with a yield of 22%.
1H NMR(400MHz，MeOD)δ8.16(d，J＝15.1Hz，1H)，8.00-7.85(m，1H)，7.88-7.44(m，5H)，7.39(s，2H)，7.15(dt，J＝53.2，7.7Hz，1H)，7.00-6.83(m，1H)，6.85-6.61(m，2H)，4.69(d，J＝12.0Hz，1H)，3.79(t，J＝14.9Hz，1H)，3.16(dd，J＝26.5，13.6Hz，1H)，2.84(dt，J＝21.9，11.4Hz，2H)，2.02(d，J＝11.3Hz，1H)，1.98-1.72(m，2H)，1.54(dd，J＝47.5，26.4Hz，7H)。 1 H NMR (400 MHz, MeOD) δ 8.16 (d, J = 15.1 Hz, 1H), 8.00-7.85 (m, 1H), 7.88-7.44 (m, 5H), 7.39 (s, 2H), 7.15 (dt , J = 53.2, 7.7 Hz, 1H), 7.00-6.83 (m, 1H), 6.85-6.61 (m, 2H), 4.69 (d, J =12.0 Hz, 1H), 3.79 (t, J =14.9 Hz, 1H), 3.16 (dd, J =26.5, 13.6 Hz, 1H), 2.84 (dt, J =21.9, 11.4 Hz, 2H), 2.02 (d , J = 11.3 Hz, 1H), 1.98-1.72 (m, 2H), 1.54 (dd, J = 47.5, 26.4 Hz, 7H).
实施例4Example 4
2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-4的制备Preparation of 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-4
Figure PCTCN2023071067-appb-000054
Figure PCTCN2023071067-appb-000054
参照实施例1得到中间体2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Refer to Example 1 to obtain the intermediate 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid methyl ester
将中间体22-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(530mg，1.1mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(240mg，5.7mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝4∶1-1∶1)得到白色固体180mg，收率34％。The intermediate methyl 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (530 mg, 1.1 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (240 mg, 5.7 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column (petroleum ether/ethyl acetate = 4:1-1:1) to give 180 mg of a white solid with a yield of 34%.
1H NMR(400MHz，MeOD)δ7.44-7.07(m，5H)，6.92(dd，J＝48.8，20.5Hz，1H)，6.77(dd，J＝24.1，15.9Hz，2H)，4.69(s，1H)，3.85-3.60(m，1H)，3.25-2.98(m，1H)，2.99-2.47(m，3H)，2.12-1.37(m，20H)。 1 H NMR (400 MHz, MeOD) δ 7.44-7.07 (m, 5H), 6.92 (dd, J=48.8, 20.5 Hz, 1H), 6.77 (dd, J=24.1, 15.9 Hz, 2H), 4.69 (s, 1H), 3.85-3.60 (m, 1H), 3.25-2.98 (m, 1H), 2.99-2.47 (m, 3H), 2.12-1.37 (m, 20H).
实施例5Example 5
2-甲基-2-(3-(1-(3-(噻吩-3-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸，化合物II-5的制备Preparation of 2-methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propionic acid, compound II-5
Figure PCTCN2023071067-appb-000055
Figure PCTCN2023071067-appb-000055
参照实施例1得到中间体2-甲基-2-(3-(1-(3-(噻吩-3-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸甲酯Refer to Example 1 to obtain the intermediate 2-methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propionic acid methyl ester
将中间体2-甲基-2-(3-(1-(3-(噻吩-3-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸甲酯(600mg，1.3mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(272mg，6.5mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝4∶1-1∶1)得到白色固体230mg，收率38％。The intermediate methyl 2-methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propanoate (600 mg, 1.3 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (272 mg, 6.5 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 4:1-1:1) to give 230 mg of a white solid with a yield of 38%.
1H NMR(600MHz，MeOD)δ7.80-7.69(m，3H)，7.53-7.47(m，3H)，7.34(d，J＝5.4Hz，1H)，7.26-7.07(m，1H)，7.01-6.87(m，1H)，6.78(dd，J＝31.3，7.4Hz，1H)，6.70(s，1H)，4.70(d，J＝11.7Hz，1H)，3.91-3.60(m，1H)，3.22-3.05(m，1H)，3.00-2.63(m，2H)，1.97-1.68(m，3H)，1.54(d，J＝61.5Hz，7H)。 1 H NMR (600 MHz, MeOD) δ 7.80-7.69 (m, 3H), 7.53-7.47 (m, 3H), 7.34 (d, J=5.4 Hz, 1H), 7.26-7.07 (m, 1H), 7.01-6.87 (m, 1H), 6.78 (dd, J=31.3, 7.4 Hz, 1H), 6.70 (s, 1H), 4.70 (d, J=11.7 Hz, 1H), 3.91-3.60 (m, 1H), 3.22-3.05 (m, 1H), 3.00-2.63 (m, 2H), 1.97-1.68 (m, 3H), 1.54 (d, J=61.5 Hz, 7H).
实施例6Example 6
2-甲基-2-(3-(1-(3-(噻吩-2-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸，化合物II-6的制备Preparation of 2-methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propionic acid, compound II-6
Figure PCTCN2023071067-appb-000056
Figure PCTCN2023071067-appb-000056
参照实施例1得到中间体2-甲基-2-(3-(1-(3-(噻吩-2-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸甲酯Refer to Example 1 to obtain the intermediate 2-methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propionic acid methyl ester
将中间体2-甲基-2-(3-(1-(3-(噻吩-2-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸甲酯(510mg，1.1mmol) 溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(231mg，5.5mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体135mg，收率27％。The intermediate methyl 2-methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propanoate (510 mg, 1.1 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (231 mg, 5.5 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to give 135 mg of a white solid with a yield of 27%.
1H NMR(400MHz，MeOD)δ7.80-7.66(m，2H)，7.48(dd，J＝24.4，12.8Hz，3H)，7.34(d，J＝7.2Hz，1H)，7.21(dd，J＝30.9，23.0Hz，2H)，7.02-6.86(m，1H)，6.77(dd，J＝25.1，13.9Hz，2H)，4.69(d，J＝11.3Hz，1H)，3.76(t，J＝12.2Hz，1H)，3.14(dd，J＝26.5，13.3Hz，1H)，2.95-2.64(m，2H)，2.03-1.93(m，1H)，2.01-1.41(m，9H)。 1 H NMR (400 MHz, MeOD) δ 7.80-7.66 (m, 2H), 7.48 (dd, J=24.4, 12.8 Hz, 3H), 7.34 (d, J=7.2 Hz, 1H), 7.21 (dd, J=30.9, 23.0 Hz, 2H), 7.02-6.86 (m, 1H), 6.77 (dd, J=25.1, 13.9 Hz, 2H), 4.69 (d, J=11.3 Hz, 1H), 3.76 (t, J=12.2 Hz, 1H), 3.14 (dd, J=26.5, 13.3 Hz, 1H), 2.95-2.64 (m, 2H), 2.03-1.93 (m, 1H), 2.01-1.41 (m, 9H).
实施例7Example 7
2-(3-(1-(3-(1H-吡唑-4-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-7的制备Preparation of 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-7
Figure PCTCN2023071067-appb-000057
Figure PCTCN2023071067-appb-000057
参照实施例1得到中间体2-(3-(1-(3-(1H-吡唑-4-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Referring to Example 1, the intermediate 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid methyl ester was obtained.
将中间体2-(3-(1-(3-(1H-吡唑-4-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(200mg，0.45mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(93mg，2.2mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体25mg，收率10％。The intermediate methyl 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (200 mg, 0.45 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (93 mg, 2.2 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to give 25 mg of a white solid with a yield of 10%.
1H NMR(400MHz，MeOD)δ7.81-7.45(m，5H)，7.42-7.24(m，3H)，7.28-7.03(m，1H)，7.00-6.86(m，1H)，6.77(dd，J＝30.9，7.9Hz，2H)，4.69(d，J＝11.7Hz，1H)，3.78(t，J＝11.0Hz，1H)，3.21-3.03(m，1H)，3.03-2.62(m，3H)，2.15-1.96(m，1H)，1.77-1.34(m，8H)。 1 H NMR (400 MHz, MeOD) δ 7.81-7.45 (m, 5H), 7.42-7.24 (m, 3H), 7.28-7.03 (m, 1H), 7.00-6.86 (m, 1H), 6.77 (dd, J=30.9, 7.9 Hz, 2H), 4.69 (d, J=11.7 Hz, 1H), 3.78 (t, J=11.0 Hz, 1H), 3.21-3.03 (m, 1H), 3.03-2.62 (m, 3H), 2.15-1.96 (m, 1H), 1.77-1.34 (m, 8H).
实施例8Example 8
2-(3-(1-(4′-异丙基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-8的制备Preparation of 2-(3-(1-(4′-isopropyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-8
Figure PCTCN2023071067-appb-000058
Figure PCTCN2023071067-appb-000058
参照实施例1得到中间体2-(3-(1-(4′-异丙基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯Referring to Example 1, the intermediate 2-(3-(1-(4′-isopropyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester was obtained.
将中间体2-(3-(1-(4′-异丙基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯(400mg，0.66mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(182mg，4.3mmol)， 室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体150mg，收率46％。The intermediate 2-(3-(1-(4′-isopropyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester (400 mg, 0.66 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (182 mg, 4.3 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate=5:1-3:1) to obtain 150 mg of a white solid with a yield of 46%.
1H NMR(400MHz，MeOD)δ7.76-7.62(m，2H)，7.54(dt，J＝19.8，7.8Hz，3H)，7.43-7.28(m，3H)，7.26-7.04(m，1H)，7.06-6.86(m，1H)，6.77(dd，J＝30.9，7.9Hz，2H)，4.69(d，J＝11.7Hz，1H)，3.78(t，J＝11.0Hz，1H)，3.24-3.09(m，1H)，3.01-2.68(m，3H)，2.01(t，J＝19.8Hz，1H)，1.73(dd，J＝38.7，20.3Hz，2H)，1.53(d，J＝36.2Hz，6H)，1.29(t，J＝6.3Hz，6H)。 1 H NMR (400 MHz, MeOD) δ 7.76-7.62 (m, 2H), 7.54 (dt, J=19.8, 7.8 Hz, 3H), 7.43-7.28 (m, 3H), 7.26-7.04 (m, 1H) , 7.06-6.86 (m, 1H), 6.77 (dd, J = 30.9, 7.9 Hz, 2H), 4.69 (d, J = 11.7 Hz, 1H), 3.78 (t, J = 11.0 Hz, 1H), 3.24-3.09 (m, 1H), 3.01-2.68 (m, 3H), 2.01 (t, J = 19.8 Hz, 1H), 1.73 (dd , J = 38.7, 20.3 Hz, 2H), 1.53 (d, J = 36.2 Hz, 6H), 1.29 (t, J = 6.3 Hz, 6H).
实施例9Example 9
2-(3-(1-([1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-9的制备Preparation of 2-(3-(1-([1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-9
Figure PCTCN2023071067-appb-000059
Figure PCTCN2023071067-appb-000059
参照实施例1得到中间体2-(3-(1-([1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Referring to Example 1, the intermediate 2-(3-(1-([1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid methyl ester was obtained.
将中间体2-(3-(1-([1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(425mg，0.92mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(195mg，4.65mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体126mg，收率30％。The intermediate methyl 2-(3-(1-([1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (425 mg, 0.92 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (195 mg, 4.65 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to give 126 mg of a white solid with a yield of 30%.
1H NMR(400MHz，MeOD)δ7.80-7.33(m，9H)，7.20(dd，J＝34.3，26.4Hz，1H)，6.93(dd，J＝42.9，15.1Hz，1H)，6.86-6.62(m，2H)，4.70(d，J＝11.5Hz，1H)，3.80(d，J＝10.9Hz，1H)，3.15(dd，J＝23.8，11.7Hz，1H)，2.93-2.79(m，2H)，2.03(s，1H)，1.98-1.46(m，9H)。 1 H NMR (400 MHz, MeOD) δ 7.80-7.33 (m, 9H), 7.20 (dd, J=34.3, 26.4 Hz, 1H), 6.93 (dd, J=42.9, 15.1 Hz, 1H), 6.86-6.62 (m, 2H), 4.70 (d, J=11.5 Hz, 1H), 3.80 (d, J=10.9 Hz, 1H), 3.15 (dd, J=23.8, 11.7 Hz, 1H), 2.93-2.79 (m, 2H), 2.03 (s, 1H), 1.98-1.46 (m, 9H).
实施例10Example 10
2-(3-(1-([1，1′-联苯基]-4-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-10的制备Preparation of 2-(3-(1-([1,1′-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-10
Figure PCTCN2023071067-appb-000060
Figure PCTCN2023071067-appb-000060
参照实施例1得到中间体2-(3-(1-([1，1′-联苯基]-4-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Referring to Example 1, the intermediate 2-(3-(1-([1,1′-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid methyl ester was obtained.
将中间体2-(3-(1-([1，1′-联苯基]-4-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(350mg，0.76mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(159mg，3.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃 取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体177mg，收率35％。The intermediate methyl 2-(3-(1-([1,1′-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (350 mg, 0.76 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (159 mg, 3.8 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to give 177 mg of a white solid with a yield of 35%.
1H NMR(40)0)MHz，MeOD)δ7.68(d，J＝26.9Hz，4H)，7.55-7.34(m，5H)，7.18(d，J＝42.5Hz，1H)，7.03-6.87(m，1H)，6.76(d，J＝30.5Hz，2H)，4.69(d，J＝10.1Hz，1H)，3.80(s，1H)，3.14(dd，J＝25.8，12.9Hz，1H)，2.86(dd，J＝35.0，23.3Hz，2H)，2.03(t，J＝10.0Hz，1H)，1.81(dd，J＝43.4，32.2Hz，2H)，1.66-1.45(m，7H)。 1 H NMR (40) (20 MHz, MeOD) δ 7.68 (d, J = 26.9 Hz, 4H), 7.55-7.34 (m, 5H), 7.18 (d, J = 42.5 Hz, 1H), 7.03-6.87 (m, 1H), 6.76 (d, J = 30.5 Hz, 2H), 4.69 (d, J = 10.1 Hz, 1H), 3.80 (s, 1H), 3.14 (dd, J = 25.8, 12.9 Hz, 1H), 2.86 (dd, J = 35.0, 23.3 Hz, 2H), 2.03 (t, J = 10.0 Hz, 1H), 1.81 (dd, J = 43.4, 32.2 Hz, 2H), 1.66-1.45 (m, 7H).
实施例11Embodiment 11
2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-11的制备Preparation of 2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-11
Figure PCTCN2023071067-appb-000061
Figure PCTCN2023071067-appb-000061
步骤a：2-(3-(1-((3-溴苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯，化合物13的制备Step a: Preparation of methyl 2-(3-(1-((3-bromophenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate, compound 13
将化合物6(1g，3.6mmol)溶解于二氯甲烷溶液中，加入三乙胺(540mg，5.4mmol)搅拌10min，在氮气保护下，加入化合物12(1.1g，4.3mmol)，室温反应24h，直接将反应液蒸干，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体1.06g，收率62％。Compound 6 (1 g, 3.6 mmol) was dissolved in dichloromethane solution, triethylamine (540 mg, 5.4 mmol) was added and stirred for 10 min. Compound 12 (1.1 g, 4.3 mmol) was added under nitrogen protection, and the mixture was reacted at room temperature for 24 h. The reaction solution was directly evaporated to dryness and purified using a silica gel column (petroleum ether/ethyl acetate = 5:1-3:1) to obtain 1.06 g of a white solid with a yield of 62%.
步骤b：参照实施例1得到2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯Step b: Refer to Example 1 to obtain methyl 2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate
步骤c：2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-11的制备Step c: Preparation of 2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-11
将中间体2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸(1.1g，2.0mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(428mg，10.2mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体500mg，收率48％。The intermediate 2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid (1.1 g, 2.0 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (428 mg, 10.2 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (dichloromethane/methanol = 100:2-100:3) to give 500 mg of a white solid with a yield of 48%.
1H NMR(400MHz，MeOD)δ7.94-7.80(m，2H)，7.72-7.59(m，2H)，7.38(s，1H)，7.36-7.29(m，1H)，7.22-7.16(m，1H)，7.16-7.07(m，1H)，6.81(d，J＝7.7Hz，1H)，6.72(dd，J＝4.1，2.1Hz，2H)，3.85-3.70(m，2H)，2.73(ddd，J＝11.5，8.2，3.5Hz，1H)，2.40-2.20(m，8H)，1.86-1.71(m，2H)，1.71-1.56(m，1H)，1.48(t，J＝11.5Hz，6H)，1.46-1.34(m，1H)。 1 H NMR (400 MHz, MeOD) δ 7.94-7.80 (m, 2H), 7.72-7.59 (m, 2H), 7.38 (s, 1H), 7.36-7.29 (m, 1H), 7.22-7.16 (m, 1H), 7.16-7.07 (m, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.72 (dd, J = 4.1 , 2.1 Hz, 2H), 3.85-3.70 (m, 2H), 2.73 (ddd, J=11.5, 8.2, 3.5 Hz, 1H), 2.40-2.20 (m, 8H), 1.86-1.71 (m, 2H), 1.71-1.56 (m, 1H), 1.48 (t, J=11.5 Hz, 6H), 1.46-1.34 (m, 1H).
实施例12Example 12
2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-12的制备Preparation of 2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-12
Figure PCTCN2023071067-appb-000062
Figure PCTCN2023071067-appb-000062
参照实施例11得到中间体2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯Referring to Example 11, the intermediate 2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester was obtained.
将中间体2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯(377mg，0.71mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(149mg，3.6mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体148mg，收率39％。The intermediate 2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester (377 mg, 0.71 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (149 mg, 3.6 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (dichloromethane/methanol = 100:2-100:3) to give 148 mg of a white solid with a yield of 39%.
1H NMR(400MHz，DMSO-d 6)δ13.04(s，1H)，8.03(dt，J＝7.3，1.6Hz，1H)，7.95(d，J＝1.5Hz，1H)，7.91-7.80(m，1H)，7.82-7.65(m，2H)，7.64-7.43(m，2H)，7.21-7.08(m，1H)，6.84(d，J＝7.7Hz，1H)，6.70(d，J＝1.5Hz，1H)，6.64(dd，J＝8.1，2.1Hz，1H)，3.69(dt，J＝20.0，14.2Hz，2H)，2.81-2.64(m，1H)，2.41-2.30(m，2H)，1.80-1.26(m，10H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 8.03 (dt, J=7.3, 1.6 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.91-7.80 ( m, 1H), 7.82-7.65 (m, 2H), 7.64-7.43 (m, 2H), 7.21-7.08 (m, 1H), 6.84 (d, J =7.7 Hz, 1H), 6.70 (d, J =1.5 Hz, 1H), 6.64 (dd, J =8.1, 2.1 Hz, 1H), 3.69 (dt, J =20.0, 14.2 Hz, 2H), 2.81-2.64 (m, 1H), 2.41-2.30 (m, 2H), 1.80-1.26 (m, 10H).
实施例13Example 13
2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-13的制备Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-13
Figure PCTCN2023071067-appb-000063
Figure PCTCN2023071067-appb-000063
参照实施例11得到中间体2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Referring to Example 11, the intermediate 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid methyl ester was obtained.
将中间体2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(330mg，0.61mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(129mg，3.1mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体101mg，收率32％。The intermediate methyl 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (330 mg, 0.61 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (129 mg, 3.1 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column (dichloromethane/methanol = 100:2-100:3) to give 101 mg of a white solid with a yield of 32%.
1H NMR(400MHz，MeOD)δ7.80-7.66(m，2H)，7.48(dd，J＝24.4，12.8Hz，3H)，7.34(d，J＝7.2Hz，1H)，7.21(dd，J＝30.9，23.0Hz，2H)，7.02-6.86(m，1H)，6.77(dd，J＝25.1，13.9Hz，2H)，4.69(d，J＝11.3Hz，1H)，3.76(t，J＝12.2Hz，1H)，3.14(dd，J＝26.5，13.3Hz，1H)，2.95-2.64(m，2H)，1.99 (dd，J＝34.5，7.5Hz，1H)，2.01-1.41(m，9H)。 1 H NMR (400 MHz, MeOD) δ 7.80-7.66 (m, 2H), 7.48 (dd, J = 24.4, 12.8 Hz, 3H), 7.34 (d, J = 7.2 Hz, 1H), 7.21 (dd, J = 30.9, 23.0 Hz, 2H), 7.02-6.86 (m, 1H), 6.77 (dd, J = 25.1, 13.9 Hz, 2H), 4.69 (d, J = 11.3 Hz, 1H), 3.76 (t, J = 12.2 Hz, 1H), 3.14 (dd, J = 26.5, 13.3 Hz, 1H), 2.95-2.64 (m, 2H), 1.99 (dd, J=34.5, 7.5 Hz, 1H), 2.01-1.41 (m, 9H).
实施例14Embodiment 14
2-甲基-2-(3-(1-((3-(噻吩-3-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸，化合物II-14的制备Preparation of 2-methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionic acid, compound II-14
Figure PCTCN2023071067-appb-000064
Figure PCTCN2023071067-appb-000064
参照实施例11得到中间体2-甲基-2-(3-(1-((3-(噻吩-3-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸甲酯Referring to Example 11, the intermediate methyl 2-methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoate was obtained.
将中间体2-甲基-2-(3-(1-((3-(噻吩-3-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸甲酯(280mg，0.56mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(94mg，2.2mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体115mg，收率46％。The intermediate methyl 2-methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoate (280 mg, 0.56 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (94 mg, 2.2 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (dichloromethane/methanol = 100:2-100:3) to give 115 mg of a white solid with a yield of 46%.
1H NMR(400MHz，DMSO-d6)δ13.04(s，1H)，8.12-8.02(m，2H)，7.98(s，1H)，7.66(dtd，J＝6.4，5.1，2.1Hz，4H)，7.16(t，J＝7.9Hz，1H)，6.83(d，J＝7.7Hz，1H)，6.71(d，J＝1.9Hz，1H)，6.64(dd，J＝8.1，2.0Hz，1H)，3.91-3.54(m，2H)，2.79-2.66(m，1H)，2.40-2.28(m，2H)，1.77(dd，J＝8.4，4.9Hz，2H)，1.67-1.51(m，1H)，1.51-1.36(m，7H)。 1 H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.12-8.02 (m, 2H), 7.98 (s, 1H), 7.66 (dtd, J=6.4, 5.1, 2.1 Hz, 4H) , 7.16 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 7.7 Hz, 1H), 6.71 (d, J = 1 .9 Hz, 1H), 6.64 (dd, J = 8.1, 2.0 Hz, 1H), 3.91-3.54 (m, 2H), 2.79-2.66 (m, 1H), 2.40-2.28 (m, 2H), 1.77 (dd , J = 8.4, 4.9 Hz, 2H), 1.67-1.51 (m, 1H), 1.51-1.36 (m, 7H).
实施例15Embodiment 15
2-(3-(1-([1，1′-联苯基]-3-基磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-15的制备Preparation of 2-(3-(1-([1,1′-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-15
Figure PCTCN2023071067-appb-000065
Figure PCTCN2023071067-appb-000065
参照实施例11得到中间体2-(3-(1-([1，1′-联苯基]-3-基磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Referring to Example 11, the intermediate 2-(3-(1-([1,1′-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid methyl ester was obtained.
将中间体2-(3-(1-([1，1′-联苯基]-3-基磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(420mg，0.85mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(178mg，4.2mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体101mg，收率24％。The intermediate methyl 2-(3-(1-([1,1′-biphenylyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (420 mg, 0.85 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (178 mg, 4.2 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column (dichloromethane/methanol = 100:2-100:3) to give 101 mg of a white solid with a yield of 24%.
1H NMR(600MHz，DMSO-d6)δ13.06(s，1H)，8.02(d，J＝6.7Hz，1H)，7.93(s，1H)，7.74(dd，J＝12.2，7.7Hz，4H)，7.56-7.46(m，2H)，7.44(t，J＝7.2Hz，1H)，7.17(t，J＝7.8Hz，1H)，6.85(d，J＝7.4Hz，1H)，6.70(d，J＝32.4Hz，1H)，6.65(d，J＝7.9Hz，1H)，3.80-3.56(m，2H)，2.74(t，J＝11.0Hz，1H)，2.48(d，J＝37.5Hz，1H)，2.39(t，J＝9.0Hz，1H)，1.82-1.40(m，10H)。 1 H NMR (600 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.02 (d, J = 6.7 Hz, 1H), 7.93 (s, 1H), 7.74 (dd, J = 12.2, 7.7 Hz, 4H ), 7.56-7.46 (m, 2H), 7.44 (t, J = 7.2 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.70 (d, J = 32.4 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 3.80-3.56 (m, 2H), 2.74 (t, J = 11.0 Hz, 1H), 2.48 (d, J = 37.5 Hz, 1H), 2.39 (t, J = 9.0 Hz, 1H), 1.82-1.40 (m, 10H).
实施例16Example 16
2-(3-(1-((3-环己基苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-16的制备Preparation of 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-16
Figure PCTCN2023071067-appb-000066
Figure PCTCN2023071067-appb-000066
参照实施例11得到中间体2-(3-(1-((3-环己基苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Referring to Example 11, the intermediate 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid methyl ester was obtained.
将中间体2-(3-(1-((3-环己基苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(190mg，0.38mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(71mg，1.7mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体110mg，收率30％。The intermediate methyl 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (190 mg, 0.38 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (71 mg, 1.7 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column (dichloromethane/methanol = 100:2-100:3) to give 110 mg of a white solid with a yield of 30%.
1H NMR(600MHz，DMSO-d6)δ7.10(t，J＝7.9Hz，1H)，6.76(d，J＝7.6Hz，1H)，6.69-6.52(m，2H)，3.58(dd，J＝31.0，9.9Hz，2H)，2.71-2.48(m，2H)，2.25-2.13(m，2H)，1.77-1.57(m，7H)，1.55-1.18(m，13H)。 1 H NMR (600 MHz, DMSO-d6) δ 7.10 (t, J=7.9 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.69-6.52 (m, 2H), 3.58 (dd, J=31.0, 9.9 Hz, 2H), 2.71-2.48 (m, 2H), 2.25-2.13 (m, 2H), 1.77-1.57 (m, 7H), 1.55-1.18 (m, 13H).
实施例17 Embodiment 17
2-甲基-2-(3-(1-((3-(噻吩-2-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸，化合物II-17的制备Preparation of 2-methyl-2-(3-(1-((3-(thiophen-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoic acid, compound II-17
Figure PCTCN2023071067-appb-000067
Figure PCTCN2023071067-appb-000067
参照实施例11得到中间体2-甲基-2-(3-(1-((3-(噻吩-2-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸甲酯Referring to Example 11, the intermediate methyl 2-methyl-2-(3-(1-((3-(thiophen-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoate was obtained.
将中间体2-甲基-2-(3-(1-((3-(噻吩-2-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸甲酯(190mg，0.38mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(71mg，1.7mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体110mg，收率30％。The intermediate methyl 2-methyl-2-(3-(1-((3-(thiophen-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoate (190 mg, 0.38 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (71 mg, 1.7 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column (dichloromethane/methanol = 100:2-100:3) to give 110 mg of a white solid with a yield of 30%.
1H NMR(600MHz，DMSO-d6)δ8.00(d，J＝5.9Hz，1H)，7.90(s，1H)，7.72-7.63(m，4H)，7.23-7.14(m，2H)，6.85(d，J＝7.6Hz，1H)，6.72(s，1H)，6.65(d，J＝8.1Hz，1H)，3.70(dd，J＝36.0，10.2Hz，2H)，2.73(dd，J＝15.3，7.3Hz，1H)，2.44-2.26(m，2H)，1.77(dd，J＝17.2，7.0Hz，2H)，1.67-1.40(m，8H)。 1 H NMR (600 MHz, DMSO-d6) δ 8.00 (d, J = 5.9 Hz, 1H), 7.90 (s, 1H), 7.72-7.63 (m, 4H), 7.23-7.14 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 6.65 (d, J = 8.1 Hz, 1H), 3.70 (dd, J = 36.0, 10.2 Hz, 2H), 2.73 (dd, J = 15.3, 7.3 Hz, 1H), 2.44-2.26 (m, 2H), 1.77 (dd, J = 17.2, 7.0 Hz, 2H), 1.67-1.40 (m, 8H).
实施例18 Embodiment 18
2-(3-(1-((3-(苯并[b]噻吩-6-基)苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-18的制备Preparation of 2-(3-(1-((3-(benzo[b]thiophen-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-18
Figure PCTCN2023071067-appb-000068
Figure PCTCN2023071067-appb-000068
参照实施例11得到中间体2-(3-(1-((3-(苯并[b]噻吩-6-基)苯基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯Referring to Example 11, the intermediate 2-(3-(1-((3-(benzo[b]thiophen-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester was obtained.
将中间体2-(3-(1-((3-(苯并[b]噻吩-6-基)苯基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯(310mg，0.57mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(119mg，2.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体123mg，收率24％。The intermediate methyl 2-(3-(1-((3-(benzo[b]thiophen-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-propanoate (310 mg, 0.57 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (119 mg, 2.8 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column (dichloromethane/methanol=100:2-100:3) to give 123 mg of a white solid with a yield of 24%.
1H NMR(400MHz，MeOD)δ8.18(s，1H)，8.08-7.88(m，3H)，7.82-7.56(m，4H)，7.40(d，J＝5.4Hz，1H)，7.21-7.12(m，1H)，6.83(d，J＝7.7Hz，1H)，6.79-6.68(m，2H)，3.83(d，J＝11.3Hz，2H)，2.87-2.63(m，1H)，2.49-2.21(m，2H)，1.92-1.45(m，10H)。 1 H NMR (400 MHz, MeOD) δ 8.18 (s, 1H), 8.08-7.88 (m, 3H), 7.82-7.56 (m, 4H), 7.40 (d, J=5.4 Hz, 1H), 7.21-7.12 (m, 1H), 6.83 (d, J=7.7 Hz, 1H), 6.79-6.68 (m, 2H), 3.83 (d, J=11.3 Hz, 2H), 2.87-2.63 (m, 1H), 2.49-2.21 (m, 2H), 1.92-1.45 (m, 10H).
实施例19Embodiment 19
2-(3-(1-((3′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-19的制备Preparation of 2-(3-(1-((3′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-19
Figure PCTCN2023071067-appb-000069
Figure PCTCN2023071067-appb-000069
参照实施例11得到中间体2-(3-(1-((3′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Referring to Example 11, the intermediate 2-(3-(1-((3′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid methyl ester was obtained.
将中间体2-(3-(1-((3′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(400mg，0.75mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(57mg，3.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体201mg，收率56％。The intermediate methyl 2-(3-(1-((3′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (400 mg, 0.75 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (57 mg, 3.8 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (dichloromethane/methanol = 100:2-100:3) to give 201 mg of a white solid with a yield of 56%.
1H NMR(400MHz，DMSO-d6)δ8.05-7.93(m，1H)，7.89(s，1H)，7.79-7.65(m，2H)，7.55-7.47(m，2H)，7.41(t，J＝7.6Hz，1H)，7.30(d，J＝7.6Hz，1H)，7.10(t，J＝7.8Hz，1H)，6.76(t，J＝12.2Hz，1H)，6.67(dd，J＝13.5，5.3Hz，2H)，3.68(dt，J＝19.9，11.1Hz，2H)，2.97(hept，J＝6.8Hz，1H)，2.71(dd，J＝15.2，7.3Hz，1H)，2.35(t，J＝11.2Hz，2H)，1.74(s，2H)，1.63-1.49(m，1H)，1.50-1.35(m，7H)，1.23(d，J＝6.9Hz，6H)。 1 H NMR (400 MHz, DMSO-d6) δ 8.05-7.93 (m, 1H), 7.89 (s, 1H), 7.79-7.65 (m, 2H), 7.55-7.47 (m, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.76 (t, J = 12.2 Hz, 1H), 6.67 (dd, J = 13 .5, 5.3 Hz, 2H), 3.68 (dt, J = 19.9, 11.1 Hz, 2H), 2.97 (hept, J = 6.8 Hz, 1H), 2.71 (dd, J = 15.2, 7.3 Hz, 1H), 2.35 (t, J = 11.2 Hz, 2H), 1.74 (s, 2H), 1.63-1.49 (m, 1H), 1.50-1.35 (m, 7H), 1.23 (d, J = 6.9 Hz, 6H).
实施例20 Embodiment 20
2-(3-(1-((4′-(叔丁基)-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-20的制备Preparation of 2-(3-(1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-20
Figure PCTCN2023071067-appb-000070
Figure PCTCN2023071067-appb-000070
参照实施例11得到中间体2-(3-(1-((4′-(叔丁基)-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯Referring to Example 11, the intermediate 2-(3-(1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester was obtained.
将中间体2-(3-(1-((4′-(叔丁基)-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯(300mg，0.55mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(115mg，2.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体121mg，收率46％。The intermediate 2-(3-(1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester (300 mg, 0.55 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (115 mg, 2.8 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (dichloromethane/methanol = 100:2-100:3) to give 121 mg of a white solid with a yield of 46%.
1H NMR(400MHz，DMSO-d6)δ8.06-7.94(m，1H)，7.89(s，1H)，7.76-7.67(m，2H)，7.69-7.60(m，2H)，7.51(d，J＝8.5Hz，2H)，7.15(t，J＝7.9Hz，1H)，6.83(d，J＝7.7Hz，1H)，6.68(d，J＝15.1Hz，1H)，6.64(dd，J＝8.1，2.1Hz，1H)，3.77-3.66(m，2H)，2.71(dt，J＝22.4，7.4Hz，1H)，2.41-2.26(m，2H)，1.76(dd，J＝8.3，4.9Hz，2H)，1.58(dt，J＝13.2，7.9Hz，1H)，1.49-1.38(m，7H)，1.30(d，J＝6.4Hz，9H)。 1 H NMR (400 MHz, DMSO-d6) δ 8.06-7.94 (m, 1H), 7.89 (s, 1H), 7.76-7.67 (m, 2H), 7.69-7.60 (m, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.15 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 7.7 Hz, 1H), 6.68 (d, J = 15.1 Hz, 1H), 6.64 (dd, J = 8.1, 2.1 Hz, 1H), 3.77-3.66 (m, 2H), 2.71 (dt, J = 22.4, 7.4 Hz, 1H), 2.41-2.26 (m, 2H), 1.76 (dd, J = 2 =8.3, 4.9 Hz, 2H), 1.58 (dt, J =13.2, 7.9 Hz, 1H), 1.49-1.38 (m, 7H), 1.30 (d, J =6.4 Hz, 9H).
实施例21 Embodiment 21
2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-21的制备Preparation of 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-21
Figure PCTCN2023071067-appb-000071
Figure PCTCN2023071067-appb-000071
步骤a：2-(3-(1-(3-溴苯基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯，化合物17的制备Step a: Preparation of methyl 2-(3-(1-(3-bromophenyl)piperidin-3-yl)phenoxy)-2-methylpropanoate, compound 17
将化合物6(1g，3.6mmol)和化合物16(1g，4.3mmol)溶解于甲苯(50mL)中，分别加入醋 酸钯(20mg，0.07mmol)、4，5-双(二苯基膦)-9，9-二甲基氧杂蒽(80mg，0.14mmol)和碳酸铯(1.63g，5mmol)，在氮气保护下，80℃反应过夜，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶2-100∶3)得到白色固体101mg，收率24％。Compound 6 (1 g, 3.6 mmol) and compound 16 (1 g, 4.3 mmol) were dissolved in toluene (50 mL), and palladium acetate (20 mg, 0.07 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (80 mg, 0.14 mmol) and cesium carbonate (1.63 g, 5 mmol) were added respectively. Under nitrogen protection, the mixture was reacted at 80°C overnight, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (dichloromethane/methanol=100:2-100:3) to obtain 101 mg of a white solid with a yield of 24%.
步骤b：参照实施例1得到2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-基)哌啶-3-基)苯氧基)-2-丙酸甲酯Step b: Refer to Example 1 to obtain methyl 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-propionate
步骤c：2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-21的制备Step c: Preparation of 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-21
将中间体2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-基)哌啶-3-基)苯氧基)-2-丙酸甲酯(160g，0.35mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(73mg，1.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，烘干得到白色固体120mg，收率77％。The intermediate 2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester (160 g, 0.35 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (73 mg, 1.8 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution. The mixture was filtered and dried to obtain 120 mg of a white solid with a yield of 77%.
1H NMR(400MHz，MeOD)δ7.31(d，J＝12.6Hz，1H)，7.29-7.21(m，2H)，7.22-7.10(m，3H)，7.05(d，J＝7.6Hz，1H)，6.95(dd，J＝11.0，5.0Hz，2H)，6.86(s，1H)，6.75(dd，J＝8.1，2.2Hz，1H)，3.73(t，J＝13.4Hz，2H)，2.95-2.69(m，3H)，2.28(d，J＝12.1Hz，6H)，2.07-1.77(m，3H)，1.73-1.43(m，7H)。 1 H NMR (400 MHz, MeOD) δ 7.31 (d, J=12.6 Hz, 1H), 7.29-7.21 (m, 2H), 7.22-7.10 (m, 3H), 7.05 (d, J=7.6 Hz, 1H), 6.95 (dd, J=11.0, 5.0 Hz, 2H), 6.86 (s, 1H), 6.75 (dd, J=8.1, 2.2 Hz, 1H), 3.73 (t, J=13.4 Hz, 2H), 2.95-2.69 (m, 3H), 2.28 (d, J=12.1 Hz, 6H), 2.07-1.77 (m, 3H), 1.73-1.43 (m, 7H).
实施例22Embodiment 22
2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)甲基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-22的制备Preparation of 2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-22
Figure PCTCN2023071067-appb-000072
Figure PCTCN2023071067-appb-000072
步骤a：2-(3-(1-(3-溴苄基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯，化合物21的制备Step a: Preparation of methyl 2-(3-(1-(3-bromobenzyl)piperidin-3-yl)phenoxy)-2-methylpropanoate, compound 21
将化合物6(1g，3.6mmol)和20(666mg，3.6mmol)溶解于1，2-二氯甲烷(50mL)溶液中，室温搅拌2h，然后加入三氟乙酰基硼氢化钠(1.5g，7.2mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1)，得无色油状物310mg，收率19％。Compound 6 (1 g, 3.6 mmol) and 20 (666 mg, 3.6 mmol) were dissolved in 1,2-dichloromethane (50 mL) solution, stirred at room temperature for 2 h, then sodium trifluoroacetylborohydride (1.5 g, 7.2 mmol) was added, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1) to give 310 mg of a colorless oil, with a yield of 19%.
步骤b：参照实施例1得到2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)甲基)哌啶-3-基)苯氧基)-2-丙酸甲酯Step b: Refer to Example 1 to obtain methyl 2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-propionate
步骤c：2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)甲基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-22的制备Step c: Preparation of 2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-22
将中间体2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)甲基)哌啶-3-基)苯氧基)-2-丙酸甲酯(300g，0.69mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(145mg，3.5mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，烘干得到白色固体18mg，收率6％。The intermediate 2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester (300 g, 0.69 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (145 mg, 3.5 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution. The mixture was filtered and dried to obtain 18 mg of a white solid with a yield of 6%.
1H NMR(400MHz，MeOD)δ7.77(d，J＝16.8Hz，1H)，7.72(d，J＝7.6Hz，1H)，7.67-7.43(m，4H)，7.36(dd，J＝18.8，8.5Hz，1H)，7.16(t，J＝8.2Hz，1H)，6.79(d，J＝7.5Hz，3H)，4.35(q，J＝13.0Hz，2H)，3.45(t，J＝13.0Hz，2H)，3.10-2.90(m，3H)，1.92-1.77(m，1H)，1.71(dd，J＝25.2，11.1Hz，1H)，1.53(d，J＝4.1Hz，6H)。 1 H NMR (400 MHz, MeOD) δ 7.77 (d, J=16.8 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.67-7.43 (m, 4H), 7.36 (dd, J=18.8, 8.5 Hz, 1H), 7.16 (t, J=8.2 Hz, 1H), 6.79 (d, J=7.5 Hz, 3H), 4.35 (q, J=13.0 Hz, 2H), 3.45 (t, J=13.0 Hz, 2H), 3.10-2.90 (m, 3H), 1.92-1.77 (m, 1H), 1.71 (dd, J=25.2, 11.1 Hz, 1H), 1.53 (d, J=4.1 Hz, 6H).
实施例23Embodiment 23
(3S)-3-((5-(3-(3-((2-羧基丙烷-2-基)氧基)苯基)哌啶-1-羰基)-3′，4′-二氟-[1，1′-联苯]-2-基)氧基)吡咯烷-1-氯化铵，化合物II-23的制备Preparation of (3S)-3-((5-(3-(3-((2-carboxypropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-3′,4′-difluoro-[1,1′-biphenyl]-2-yl)oxy)pyrrolidine-1-ammonium chloride, compound II-23
Figure PCTCN2023071067-appb-000073
Figure PCTCN2023071067-appb-000073
步骤a；(S)-3-(2-溴-4-(甲氧羰基)苯氧基)吡咯烷-1-羧酸叔丁酯，化合物26的制备Step a: Preparation of (S)-3-(2-bromo-4-(methoxycarbonyl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester, compound 26
将化合物24(1g，4.33mmol)、化合物25(811mg，4.3mmol)和三苯基磷(1.4mmol，5.2mmol)溶解于甲苯(50mL)溶液中，在氮气保护下，0℃加入偶氮二甲酸二异丙酯(1.0g，5.2mmol)，逐渐转至室温反应5h，加入10％的氢氧化钠溶液，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-7∶1)，得无色油状物1.7mg，收率94％。Compound 24 (1 g, 4.33 mmol), compound 25 (811 mg, 4.3 mmol) and triphenylphosphine (1.4 mmol, 5.2 mmol) were dissolved in toluene (50 mL) solution. Under nitrogen protection, diisopropyl azodicarboxylate (1.0 g, 5.2 mmol) was added at 0°C, and the temperature was gradually increased to room temperature for 5 h. A 10% sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-7:1) to obtain 1.7 mg of a colorless oil with a yield of 94%.
步骤b：参照实施例1得到(S)-3-((3′，4′-二氟-5-(甲氧基羰基)-[1，1′-联苯]-2-基)氧基)吡咯烷-1-羧酸叔丁酯Step b: Refer to Example 1 to obtain (S)-3-((3′,4′-difluoro-5-(methoxycarbonyl)-[1,1′-biphenyl]-2-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester
步骤c：参照实施例1得到(S)-6-((1-(叔丁氧基羰基)吡咯烷-3-基)氧基)-3′，4′-二氟-[1，1′-联苯]-3-羧酸Step c: Refer to Example 1 to obtain (S)-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-3′,4′-difluoro-[1,1′-biphenyl]-3-carboxylic acid
步骤d：参照实施例1得到叔丁基(3S)-3-((3′，4′-二氟-5-(3-(3-((1-甲氧基-2-甲基-1-氧丙烷-2-基)氧基)苯基)哌啶-1-羰基)-[1，1′-联苯基]-2-基)氧基)吡咯烷-1-羧酸盐Step d: Refer to Example 1 to obtain tert-butyl (3S)-3-((3′,4′-difluoro-5-(3-(3-((1-methoxy-2-methyl-1-oxopropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)oxy)pyrrolidine-1-carboxylate
步骤e：参照实施例1得到2-(3-(1-(6-(((S)-1-(叔丁氧基羰基)吡咯烷-3-基)氧基)-3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸Step e: Referring to Example 1, 2-(3-(1-(6-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid was obtained.
步骤f：(3S)-3-((5-(3-(3-((2-羧基丙烷-2-基)氧基)苯基)哌啶-1-羰基)-3′，4′-二氟-[1，1′- 联苯]-2-基)氧基)吡咯烷-1-氯化铵，化合物II-23的制备Step f: Preparation of (3S)-3-((5-(3-(3-((2-carboxypropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-3′,4′-difluoro-[1,1′-biphenyl]-2-yl)oxy)pyrrolidine-1-ammonium chloride, compound II-23
将中间体2-(3-(1-(6-(((S)-1-(叔丁氧基羰基)吡咯烷-3-基)氧基)-3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸(100mg，0.15mmol)溶解于4M盐酸二氧六环溶液(15mL)，室温反应2h，蒸干反应液，得到白色固体77mg，收率85％。The intermediate 2-(3-(1-(6-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid (100 mg, 0.15 mmol) was dissolved in 4M hydrochloric acid and dioxane solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to obtain 77 mg of a white solid with a yield of 85%.
1H NMR(400MHz，MeOD)δ7.31(d，J＝12.6Hz，1H)，7.29-7.21(m，2H)，7.22-7.10(m，3H)，7.05(d，J＝7.6Hz，1H)，6.95(dd，J＝11.0，5.0Hz，2H)，6.86(s，1H)，6.75(dd，J＝8.1，2.2Hz，1H)，3.73(t，J＝13.4Hz，2H)，2.95-2.69(m，3H)，2.28(d，J＝12.1Hz，6H)，2.07-1.77(m，3H)，1.73-1.43(m，7H)。 1 H NMR (400 MHz, MeOD) δ 7.31 (d, J=12.6 Hz, 1H), 7.29-7.21 (m, 2H), 7.22-7.10 (m, 3H), 7.05 (d, J=7.6 Hz, 1H), 6.95 (dd, J=11.0, 5.0 Hz, 2H), 6.86 (s, 1H), 6.75 (dd, J=8.1, 2.2 Hz, 1H), 3.73 (t, J=13.4 Hz, 2H), 2.95-2.69 (m, 3H), 2.28 (d, J=12.1 Hz, 6H), 2.07-1.77 (m, 3H), 1.73-1.43 (m, 7H).
实施例24Embodiment 24
(3S)-3-(4-(3-(3-((2-羧基丙烷-2-基)氧基)苯基)哌啶-1-羰基)-2-环己基苯氧基)吡咯烷-1-氯化铵，化合物II-24的制备Preparation of (3S)-3-(4-(3-(3-((2-carboxypropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-cyclohexylphenoxy)pyrrolidine-1-ammonium chloride, compound II-24
Figure PCTCN2023071067-appb-000074
Figure PCTCN2023071067-appb-000074
参照实施例23得到中间体2-(3-(1-(4-(((S)-1-(叔丁氧基羰基)吡咯烷-3-基)氧基)-3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸Referring to Example 23, the intermediate 2-(3-(1-(4-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid was obtained.
将中间体2-(3-(1-(4-(((S)-1-(叔丁氧基羰基)吡咯烷-3-基)氧基)-3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸(125mg，0.20mmol)溶解于4M盐酸二氧六环溶液(15mL)，室温反应2h，蒸干反应液，得到白色固体85mg，收率74％。The intermediate 2-(3-(1-(4-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid (125 mg, 0.20 mmol) was dissolved in 4M hydrochloric acid and dioxane solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to obtain 85 mg of a white solid with a yield of 74%.
1H NMR(400MHz，MeOD)δ7.38-7.07(m，3H)，7.04-6.89(m，1H)，6.89-6.60(m，2H)，5.24(s，1H)，4.63(s，1H)，3.82-3.42(m，5H)，3.26-2.66(m，4H)，2.29-2.26(m，2H)，2.10-2.00(m，1H)，1.94-1.66(m，7H)，1.57-1.19(m，11H)。 1 H NMR (400 MHz, MeOD) δ 7.38-7.07 (m, 3H), 7.04-6.89 (m, 1H), 6.89-6.60 (m, 2H), 5.24 (s, 1H), 4.63 (s, 1H), 3.82-3.42 (m, 5H), 3.26-2.66 (m, 4H), 2.29-2.26 (m, 2H), 2.10-2.00 (m, 1H), 1.94-1.66 (m, 7H), 1.57-1.19 (m, 11H).
实施例25Embodiment 25
4-(2-(3-(1-((3′，4′-二甲基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-氯化铵，化合物II-25的制备Preparation of 4-(2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-ammonium chloride, compound II-25
Figure PCTCN2023071067-appb-000075
Figure PCTCN2023071067-appb-000075
步骤a：参照实施例1得到叔丁基4-(2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-羧酸酯Step a: Refer to Example 1 to obtain tert-butyl 4-(2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-carboxylate
步骤b：将中间体叔丁基4-(2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-羧酸酯(230mg，0.34mmol)溶解于4M盐酸二氧六环溶液(15mL)，室温反应2h，蒸干反应液，得到白色固体130mg，收率63％。Step b: Dissolve the intermediate tert-butyl 4-(2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-carboxylate (230 mg, 0.34 mmol) in 4M hydrochloric acid dioxane solution (15 mL), react at room temperature for 2 h, evaporate the reaction solution to give 130 mg of a white solid, with a yield of 63%.
1H NMR(400MHz，DMSO-d6)δ9.42(s，2H)，7.97(dd，J＝5.5，2.9Hz，1H)，7.88(s，1H)，7.75-7.63(m，2H)，7.49(s，1H)，7.43(d，J＝5.7Hz，1H)，7.32-7.18(m，2H)，6.89(d，J＝7.5Hz，1H)，6.64(dd，J＝11.6，3.4Hz，2H)，3.95(s，1H)，3.73-3.64(m，4H)，3.54-3.45(m，1H)，2.93(s，2H)，2.72(dd，J＝28.2，16.9Hz，3H)，2.41-2.20(m，8H)，1.74(t，J＝18.9Hz，2H)，1.62-1.39(m，8H)。 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 2H), 7.97 (dd, J=5.5, 2.9 Hz, 1H), 7.88 (s, 1H), 7.75-7.63 (m, 2H), 7.49 (s, 1H), 7.43 (d, J = 5.7 Hz, 1H), 7.32-7.18 (m, 2H), 6.89 (d, J = 7.5 Hz, 1H), 6.64 ( dd, J = 11.6, 3.4 Hz, 2H), 3.95 (s, 1H), 3.73-3.64 (m, 4H), 3.54-3.45 (m, 1H), 2.93 (s, 2H), 2.72 (dd, J = 28.2, 16.9 Hz, 3H), 2.41-2.20 (m, 8H), 1.74 (t, J=18.9 Hz, 2H), 1.62-1.39 (m, 8H).
实施例26Embodiment 26
4-(2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-氯化铵，化合物II-26的制备Preparation of 4-(2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-ammonium chloride, compound II-26
Figure PCTCN2023071067-appb-000076
Figure PCTCN2023071067-appb-000076
参照实施例25得到中间体4-(2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-羧酸叔丁酯Referring to Example 25, the intermediate 4-(2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-carboxylic acid tert-butyl ester was obtained.
将中间体叔丁基4-(2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-羧酸叔丁酯(120mg，0.19mmol)溶解于4M盐酸二氧六环溶液(15mL)，室温反应2h，蒸干反应液，得到白色固体60mg，收率57％。The intermediate tert-butyl 4-(2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-carboxylate (120 mg, 0.19 mmol) was dissolved in 4M hydrochloric acid dioxane solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to obtain 60 mg of a white solid with a yield of 57%.
1H NMR(400MHz，MeOD)δ7.31(d，J＝12.6Hz，1H)，7.29-7.21(m，2H)，7.22-7.10(m，3H)，7.05(d，J＝7.6Hz，1H)，6.95(dd，J＝11.0，5.0Hz，2H)，6.86(s，1H)，6.75(dd，J＝8.1，2.2Hz，1H)，3.73(t，J＝13.4Hz，2H)，2.95-2.69(m，3H)，2.28(d，J＝12.1Hz，6H)，2.07-1.77(m，3H)，1.73-1.43 (m，7H)。 1 H NMR (400 MHz, MeOD) δ 7.31 (d, J=12.6 Hz, 1H), 7.29-7.21 (m, 2H), 7.22-7.10 (m, 3H), 7.05 (d, J=7.6 Hz, 1H), 6.95 (dd, J=11.0, 5.0 Hz, 2H), 6.86 (s, 1H), 6.75 (dd, J=8.1, 2.2 Hz, 1H), 3.73 (t, J=13.4 Hz, 2H), 2.95-2.69 (m, 3H), 2.28 (d, J=12.1 Hz, 6H), 2.07-1.77 (m, 3H), 1.73-1.43 (m, 7H).
实施例27Embodiment 27
2-(3-(1-((3′4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基-N-(苯磺酰基))丙酰胺，化合物II-27的制备Preparation of 2-(3-(1-((3'4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(phenylsulfonyl))propanamide, compound II-27
Figure PCTCN2023071067-appb-000077
Figure PCTCN2023071067-appb-000077
步骤a：将化合物II-11(200mg，0.39mmol)和化合物34(61mg，0.39mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(113mg，0.59mmol)和4-二甲氨基吡啶(95mg，0.78mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体50mg，收率20％。Step a: Dissolve compound II-11 (200 mg, 0.39 mmol) and compound 34 (61 mg, 0.39 mmol) in dichloromethane (15 mL) solution, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.59 mmol) and 4-dimethylaminopyridine (95 mg, 0.78 mmol) respectively, stir at room temperature overnight, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 50 mg of a white solid, with a yield of 20%.
1H NMR(400MHz，DMSO-d6)δ12.17(d，J＝147.9Hz，1H)，7.89(dd，J＝27.4，21.5Hz，4H)，7.76-7.36(m，7H)，7.24(d，J＝7.8Hz，1H)，7.03(t，J＝7.8Hz，1H)，6.84(d，J＝7.3Hz，1H)，6.62(s，1H)，6.45(d，J＝7.9Hz，1H)，3.68(dd，J＝34.6，10.2Hz，2H)，2.61(t，J＝8Hz，1H)，2.42-2.18(m，8H)，1.78-1.56(m，3H)，1.49-1.28(m，7H)。 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J = 147.9 Hz, 1H), 7.89 (dd, J = 27.4, 21.5 Hz, 4H), 7.76-7.36 (m, 7H), 7.24 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.3 Hz, 1H), 6.62 (s, 1H), 6.45 (d, J = 7.9 Hz, 1H), 3.68 (dd, J = 34.6, 10.2 Hz, 2H), 2.61 (t, J = 8 Hz, 1H), 2.42-2.18 (m, 8H), 1.78-1.56 (m, 3H), 1.49-1.28 (m, 7H).
实施例28Embodiment 28
2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基-N-(苯磺酰基)丙酰胺，化合物II-28的制备Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(phenylsulfonyl)propionamide, compound II-28
Figure PCTCN2023071067-appb-000078
Figure PCTCN2023071067-appb-000078
将II-13(50mg，0.09mmol)和化合物34(14mg，0.09mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(27mg，0.14mmol)和4-二甲氨基吡啶(22mg，0.18mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体30mg，收率22％。II-13 (50 mg, 0.09 mmol) and compound 34 (14 mg, 0.09 mmol) were dissolved in dichloromethane (15 mL) solution, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (27 mg, 0.14 mmol) and 4-dimethylaminopyridine (22 mg, 0.18 mmol) were added respectively. The mixture was stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 30 mg of a white solid, with a yield of 22%.
1H NMR(400MHz，DMSO-d6)δ12.35(s，1H)，8.02-7.93(m，1H)，7.90-7.66(m，5H)，7.59(dd，J＝31.4，19.7Hz，5H)，7.36(d，J＝8.2Hz，2H)，6.99(t，J＝7.8Hz，1H)，6.79(d，J＝6.4Hz，1H)，6.59(s，1H)，6.43(dd，J＝8.1，2.0Hz，1H)，3.67(dd，J＝39.1，11.3Hz，2H)，3.01-2.83(m，1H)，2.67-2.53(m，1H)，2.41-2.26(m，2H)，1.80-1.16(m，18H)。 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.02-7.93 (m, 1H), 7.90-7.66 (m, 5H), 7.59 (dd, J=31.4, 19.7 Hz, 5H) , 7.36 (d, J = 8.2 Hz, 2H), 6.99 (t, J = 7.8 Hz, 1H), 6.79 (d, J =6.4 Hz, 1H), 6.59 (s, 1H), 6.43 (dd, J = 8.1, 2.0 Hz, 1H), 3.67 (dd, J = 39.1, 11.3 Hz, 2H), 3.01-2.83 (m, 1H) , 2.67-2.53 (m, 1H), 2.41-2.26 (m, 2H), 1.80-1.16 (m, 18H).
实施例29Embodiment 29
2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-N-(苯磺酰基)丙酰胺，化合物II-29的制备Preparation of 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(phenylsulfonyl)propionamide, compound II-29
Figure PCTCN2023071067-appb-000079
Figure PCTCN2023071067-appb-000079
将II-2(580mg，1.2mmol)和化合物34(171mg，1.1mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(347mg，1.8mmol)和4-二甲氨基吡啶(296mg，2.4mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体177mg，收率25％。 1H NMR(400MHz，MeOD)δ8.01(dd，J＝22.3，7.5Hz，2H)，7.65(ddd，J＝23.3，21.5，7.5Hz，7H)，7.53-7.26(m，3H)，7.14-6.42(m，4H)，4.69(dd，J＝21.5，13.1Hz，1H)，3.74(dd，J＝38.0，12.6Hz，1H)，3.23-3.06(m，1H)，2.99-2.78(m，1H)，2.80-2.57(m，1H)，2.08-1.55(m，4H)，1.49-1.31(m，6H)。 II-2 (580 mg, 1.2 mmol) and compound 34 (171 mg, 1.1 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.8 mmol) and 4-dimethylaminopyridine (296 mg, 2.4 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 177 mg of a white solid, with a yield of 25%. 1 H NMR (400 MHz, MeOD) δ 8.01 (dd, J=22.3, 7.5 Hz, 2H), 7.65 (ddd, J=23.3, 21.5, 7.5 Hz, 7H), 7.53-7.26 (m, 3H), 7.14-6.42 (m, 4H), 4.69 (dd, J=21.5, 13.1 Hz, 1H), 3.74 (dd, J=38.0, 12.6 Hz, 1H), 3.23-3.06 (m, 1H), 2.99-2.78 (m, 1H), 2.80-2.57 (m, 1H), 2.08-1.55 (m, 4H), 1.49-1.31 (m, 6H).
实施例30 2-(3-(1-((3，4-二甲基苄基)氨基甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物I-1的制备Example 30 Preparation of 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound I-1
Figure PCTCN2023071067-appb-000080
Figure PCTCN2023071067-appb-000080
参照实施例1得到中间体2-(3-(1-((3，4-二甲基苄基)氨基甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Referring to Example 1, the intermediate 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid methyl ester was obtained.
将中间体2-(3-(1-((3，4-二甲基苄基)氨基甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(700mg，1.6mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(335mg，8.0mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝3∶1-2∶1)得到白色固体280mg，收率40％。The intermediate methyl 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (700 mg, 1.6 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (335 mg, 8.0 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column (petroleum ether/ethyl acetate = 3:1-2:1) to give 280 mg of a white solid with a yield of 40%.
1H NMR(400MHz，DMSO-d 6)δ13.05(s，1H)，7.19(t，J＝7.9Hz，1H)，7.08-6.97(m，3H)，6.96(d，J＝7.6Hz，1H)，6.88(d，J＝7.7Hz，1H)，6.74(s，1H)，6.64(dd，J＝8.1，2.1Hz，1H)，4.13(t，J＝16.4Hz，2H)，4.05(d，J＝4.4Hz，1H)，2.75-2.61(m，2H)，2.18(d，J＝5.9Hz，6H)，1.87(d，J＝11.7Hz，1H)，1.77-1.51(m，2H)，1.54-1.38(m，7H)。 1 H NMR (400 MHz, DMSO-d 6 )δ13.05(s, 1H), 7.19(t, J＝7.9 Hz, 1H), 7.08-6.97(m, 3H), 6.96(d, J＝7.6 Hz, 1H), 6.88(d, J＝7.7 Hz, 1H), 6.74(s, 1H), 6.64(dd, J＝8.1, 2.1 Hz, 1H), 4.13(t, J＝16.4 Hz, 2H), 4.05(d, J＝4.4 Hz, 1H), 2.75-2.61(m, 2H), 2.18(d, J＝5.9 Hz, 6H), 1.87(d, J＝11.7 Hz, 1H), 1.77-1.51(m, 2H), 1.54-1.38(m, 7H).
实施例31 2-(3-(1-(3-(3，4-二甲基苯基)丙基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物I-2的制备Example 31 Preparation of 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound I-2
Figure PCTCN2023071067-appb-000081
Figure PCTCN2023071067-appb-000081
参照实施例1得到中间体2-(3-(1-(3-(3，4-二甲基苯基)丙基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯。将中间体2-(3-(1-(3-(3，4-二甲基苯基)丙基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(625mg，1.5mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(310mg，7.4mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(二氯甲烷/甲醇＝100∶5-100∶10)得到白色固体270mg，收率45％。The intermediate 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid methyl ester was obtained by referring to Example 1. The intermediate 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid methyl ester (625 mg, 1.5 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (310 mg, 7.4 mmol), stirring at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (dichloromethane/methanol=100:5-100:10) to obtain 270 mg of a white solid with a yield of 45%.
1H NMR(600MHz，DMSO-d 6)δ7.12(t，J＝7.9Hz，1H)，7.00(d，J＝7.6Hz，1H)，6.94(s，1H)，6.88(d，J＝7.1Hz，1H)，6.75(t，J＝9.6Hz，1H)，6.72(s，1H)，6.64(dd，J＝8.2，2.2Hz，1H)，3.05(t，J＝11.5Hz，2H)，2.76(dd，J＝15.7，7.5Hz，1H)，2.50-2.42(m，4H)，2.30-2.09(m，8H)，1.80-1.67(m，4H)，1.58-1.40(m，8H)。 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.12 (t, J=7.9 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.94 (s, 1H), 6.88 (d, J=7.1 Hz, 1H), 6.75 (t, J=9.6 Hz, 1H), 6.72 (s, 1H), 6.64 (dd, J=8.2, 2.2 Hz, 1H), 3.05 (t, J=11.5 Hz, 2H), 2.76 (dd, J=15.7, 7.5 Hz, 1H), 2.50-2.42 (m, 4H), 2.30-2.09 (m, 8H), 1.80-1.67 (m, 4H), 1.58-1.40 (m, 8H).
实施例32 2-(3-(1-(2-(4-异丙基苯基)乙酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-30的制备Example 32 Preparation of 2-(3-(1-(2-(4-isopropylphenyl)acetyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-30
Figure PCTCN2023071067-appb-000082
Figure PCTCN2023071067-appb-000082
参照实施例1得到中间体2-(3-(1-2-(4-异丙基苯基乙酰基)哌啶-3-基苯氧基)-2-甲基丙酸甲酯Refer to Example 1 to obtain the intermediate 2-(3-(1-2-(4-isopropylphenylacetyl)piperidin-3-ylphenoxy)-2-methylpropionic acid methyl ester
将中间体2-(3-(1-2-(4-异丙基苯基乙酰基)哌啶-3-基苯氧基)-2-甲基丙酸甲酯(360mg，0.82mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(172mg，4.1mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体130mg，收率51％。The intermediate methyl 2-(3-(1-2-(4-isopropylphenylacetyl)piperidin-3-ylphenoxy)-2-methylpropanoate (360 mg, 0.82 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (172 mg, 4.1 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column (petroleum ether/ethyl acetate = 5:1-3:1) to give 130 mg of a white solid with a yield of 51%.
1H NMR(400MHz，CD 3OD)δ7.06-7.24(m，5H)，6.70-6.89(m，2H)，6.50-6.54(m，1H)，4.54-4.63(m，1H)，3.87-4.02(m，1H)，3.66-3.81(m，2H)，2.84-3.09(m，2H)，2.52-2.70(m，1H)，1.99-2.12(m，1H)，1.63-1.93(m，3H)，1.53-1.54(m，7H)，1.22-1.28(m，6H). 13C NMR(100MHz，CD 3OD)δ178.75，178.51，172.18，171.98，157.14，157.09，148.87，148.70，145.77，145.31，133.87，133.80，130.18，129.96，129.65，129.54，128.04，127.77，124.94，121.84，119.55，119.30，118.58，118.22，80.35，80.25，54.38，47.96，44.47，43.64，43.57，41.85，41.26，35.07，35.00，32.60，32.33，26.86，26.29，25.79-25.90(m)，24.56，24.52，24.45. 1 H NMR(400MHz，CD 3 OD)δ7.06-7.24(m，5H)，6.70-6.89(m，2H)，6.50-6.54(m，1H)，4.54-4.63(m，1H)，3.87-4.02(m，1H)，3.66-3.81(m，2H)，2.84-3.09(m，2H)，2.52-2.70(m，1H)，1.99-2.12(m，1H)，1.63-1.93(m，3H)，1.53-1.54(m，7H)，1.22-1.28(m，6H). 13 C NMR(100MHz，CD 3 OD)δ178.75,178.51,172.18,171.98,157.14,157.09,148.87,148.70,145.77,145.31,133.87,133.80,130.18,129.96,129.65,129.54,128.04,127.77,124.94,121.84,119 .55, 119.30, 118.58, 118.22, 80.35, 80.25, 54.38, 47.96, 44.47, 43.64, 43.57, 41.85, 41.26, 35.07, 35.00, 32.60, 32.33, 26.86, 26.29, 25.79-25.90 (m), 24.56, 24.52, 24.45.
实施例33 3-(3-(3-(4-异丙基苯基丙烯酰基)哌啶-3-基苯氧基)-2-甲基丙酸，化合物II-31的制备Example 33 Preparation of 3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy)-2-methylpropanoic acid, compound II-31
Figure PCTCN2023071067-appb-000083
Figure PCTCN2023071067-appb-000083
参照实施例1得到中间体3-(3-(3-(4-异丙基苯基丙烯酰基)哌啶-3-基苯氧基-2-甲基丙酸甲酯Referring to Example 1, the intermediate 3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy-2-methylpropionic acid methyl ester was obtained.
将中间体3-(3-(3-(4-异丙基苯基丙烯酰基)哌啶-3-基苯氧基-2-甲基丙酸甲酯(318mg，0.75mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(157mg，3.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体60mg，收率23％。The intermediate 3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy-2-methylpropionic acid methyl ester (318 mg, 0.75 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by addition of lithium hydroxide (157 mg, 3.8 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to give 60 mg of a white solid with a yield of 23%.
1H NMR(600MHz，CD 3OD)δ7.49-7.58(m，3H)，7.18-7.27(m，3H)，7.04-7.13(m，1H)，6.92(d，1H，J＝7.8Hz)，6.85(s，1H)，6.77(d，1H，J＝7.8Hz)，4.65(t，1H，J＝12.0Hz)，4.21-4.30(m，1H)，3.16-3.24(m，1H)，2.87-2.93(m，1H)，2.62-2.80(m，1H)，2.00-2.01(m，2H)，1.84-1.90(m，1H)，1.73-1.77(m，1H)，1.52-1.62(m，7H)，1.22-1.25(m，6H). 13C NMR(150MHz，CD 3OD)δ177.93，167.82，167.81，157.11，152.29，145.94，145.67，144.23，134.18，134.10，130.33，130.24，129.17，127.97，122.04，119.40，118.62，117.44，117.27，80.17，53.68，50.20，47.58，45.01，44.05，43.91，35.27，33.09，32.88，30.76，27.59，26.36，25.79，24.23. 1 H NMR (600 MHz, CD 3 OD) δ 7.49-7.58 (m, 3H), 7.18-7.27 (m, 3H), 7.04-7.13 (m, 1H), 6.92 (d, 1H, J=7.8 Hz) , 6.85 (s, 1H), 6.77 (d, 1H, J = 7.8 Hz), 4.65 (t, 1H, J = 12.0 Hz), 4.21-4.30 (m , 1H), 3.16-3.24 (m, 1H), 2.87-2.93 (m, 1H), 2.62-2.80 (m, 1H), 2.00-2.01 (m, 2H), 1.84-1.90 (m, 1H), 1.73 -1.77 (m, 1H), 1.52-1.62 (m, 7H), 1.22-1.25 (m, 6H). 13 C NMR (150 MHz, CD 3 OD) δ 177.93, 167.82, 167.81, 157.11, 152.29, 145.94, 145.67, 144.23, 134.18, 134.10, 130.33, 130.24, 129.17, 127.97, 122.04, 119.40, 118.62, 117.44, 117.27, 80.17, 53.68, 50.20, 47.58, 45.01, 44.05, 43.91, 35.27, 33.09, 32.88, 30.76, 27.59, 26.36, 25.79, 24.23.
实施例34 2-(3-(1-(4-异丙基苯甲酰基)哌啶-3-基苯氧基)-2-甲基丙酸，化合物II-32的制备Example 34 Preparation of 2-(3-(1-(4-isopropylbenzoyl)piperidin-3-ylphenoxy)-2-methylpropanoic acid, compound II-32
Figure PCTCN2023071067-appb-000084
Figure PCTCN2023071067-appb-000084
参照实施例1得到中间体2-(3-(1-(4-异丙基苯甲酰基)哌啶-3-基苯氧基)-2-甲基丙酸甲酯Refer to Example 1 to obtain the intermediate 2-(3-(1-(4-isopropylbenzoyl)piperidin-3-ylphenoxy)-2-methylpropionic acid methyl ester
将中间体将2-(3-(1-(4-异丙基苯甲酰基)哌啶-3-基苯氧基)-2-甲基丙酸甲酯(410mg，0.96mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(157mg，4.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体75mg，收率19％。The intermediate methyl 2-(3-(1-(4-isopropylbenzoyl)piperidin-3-ylphenoxy)-2-methylpropanoate (410 mg, 0.96 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (157 mg, 4.8 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to give 75 mg of a white solid with a yield of 19%.
1H NMR(600MHz，CD 3OD)δ7.33-7.35(m，4H)，7.12-7.21(m，1H)，6.88-6.96(m，1H)，6.70-6.78(m，2H)，4.66(s，1H)，3.77(t，1H，J＝13.8Hz)，3.06-3.13(m，1H)，2.73-2.94(m，3H)，2.01-2.04(m，1H)，1.51-1.90(m，9H)，1.24-1.30(m，6H). 13C NMR(150MHz，CD 3OD)δ178.13，178.03，172.64，157.14，152.33， 145.84，145.26，134.59，134.49，130.27，128.06，127.96，127.70，121.98，121.64，119.38，118.62，80.19，55.78，49.92，44.86，43.77，35.28，32.76，32.61，27.26，26.32，26.32，26.01，25.82，25.54，24.25. 1 H NMR (600 MHz, CD 3 OD) δ7.33-7.35 (m, 4H), 7.12-7.21 (m, 1H), 6.88-6.96 (m, 1H), 6.70-6.78 (m, 2H), 4.66 (s, 1H), 3.77 (t, 1H, J=13.8 Hz), 3.06-3.13 (m, 1H), 2.73-2.94 (m, 3H), 2.01-2.04 (m, 1H), 1.51-1.90 (m, 9H), 1.24-1.30 (m, 6H). 13 C NMR (150 MHz, CD 3 OD) δ178.13, 178.03, 172.64, 157.14, 152.33, 145.84, 145.26, 134.59, 134.49, 130.27, 128.06, 127.96, 127.70, 121.98, 121.64, 119.38, 118.62, 80.19, 55.78, 49.92, 44.86, 43.77, 35.28, 32.76, 32.61, 27.26, 26.32, 26.32, 26.01, 25.82, 25.54, 24.25.
实施例35 2-(3-(1-(4-异丙基苄基)氨甲酰基哌啶-3-基苯氧基)-2-甲基丙酸，化合物II-33的制备Example 35 Preparation of 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropanoic acid, compound II-33
Figure PCTCN2023071067-appb-000085
Figure PCTCN2023071067-appb-000085
参照实施例1得到中间体2-(3-(1-(4-异丙基苄基)氨甲酰基哌啶-3-基苯氧基)-2-甲基丙酸甲酯Referring to Example 1, the intermediate 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropionic acid methyl ester was obtained.
将中间体2-(3-(1-(4-异丙基苄基)氨甲酰基哌啶-3-基苯氧基)-2-甲基丙酸甲酯(400mg，0.88mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(185mg，4.4mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体113mg，收率31％。The intermediate methyl 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropanoate (400 mg, 0.88 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (185 mg, 4.4 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to obtain 113 mg of a white solid with a yield of 31%.
1H NMR(600MHz，DMSO-d 6)δ13.10(s，1H)，7.15-7.20(m，5H)，7.06(t，1H，J＝6.0Hz)，6.87(d，1H，J＝7.2Hz)，6.75(s，1H)，6.65(dd，1H，J 1＝1.8Hz，J 2＝7.8Hz)，4.19(d，2H，J＝6.0Hz)，4.03-4.06(m，2H)，2.82-2.87(m，1H)，2.65-2.72(m，2H)，2.51-2.56(m，1H)，1.87-1.89(m，1H)，1.66-1.68(m，1H)，1.47-1.59(m，8H)，1.18(d，6H，J＝7.2Hz). 13C NMR(150MHz，DMSO-d 6)δ175.18，157.23，155.42，146.48，145.23，138.59，128.97，127.09，125.95，120.29，117.37，115.71，78.23，50.14，43.74，43.32，41.97，33.13，31.56，25.13，25.07，23.99. 1 H NMR (600 MHz, DMSO-d 6 ) δ 13.10 (s, 1H), 7.15-7.20 (m, 5H), 7.06 (t, 1H, J=6.0 Hz), 6.87 (d, 1H, J=7.2 Hz), 6.75 (s, 1H), 6.65 (dd, 1H, J 1 =1.8 Hz, J 2 =7.8 Hz), 4.19 (d, 2H, J = 6.0 Hz), 4.03-4.06 (m, 2H), 2.82-2.87 (m, 1H), 2.65-2.72 (m, 2H), 2.51-2.56 (m, 1H), 1.87-1.89 (m, 1H), 1.66-1.68 (m, 1H), 1.47-1.59 (m, 8H), 1.18 (d, 6H, J = 7.2 Hz). 13 C NMR (150 MHz, DMSO-d 6 )δ175.18, 157.23, 155.42, 146.48, 145.23, 138.59, 128.97, 127.09, 125.95, 120.29, 117.37, 115.71, 78.23, 50.14, 43.74, 43.32, 41.97, 33.13, 31.56, 25.13, 25.07, 23.99.
实施例36 2-(3-1-联苯)-4-羰基哌啶-3-苯氧基)-2-甲基丙酸，化合物II-34的制备Example 36 Preparation of 2-(3-(1-biphenyl)-4-carbonylpiperidin-3-phenoxy)-2-methylpropionic acid, compound II-34
Figure PCTCN2023071067-appb-000086
Figure PCTCN2023071067-appb-000086
参照实施例1得到中间体2-(3-1-联苯)-4-羰基哌啶-3-苯氧基-2-甲基丙酸甲酯Refer to Example 1 to obtain the intermediate 2-(3-1-biphenyl)-4-carbonylpiperidin-3-phenoxy-2-methylpropionic acid methyl ester
将中间体2-(3-(1-(4-异丙基苄基)氨甲酰基哌啶-3-基苯氧基)-2-甲基丙酸甲酯(350mg，0.76mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(159mg，3.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体177mg，收率53％。The intermediate methyl 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropanoate (350 mg, 0.76 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (159 mg, 3.8 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified using a silica gel column (petroleum ether/ethyl acetate = 5:1-3:1) to give 177 mg of a white solid with a yield of 53%.
1H NMR(400MHz，CD 3OD)δ7.63-7.70(m，4H)，7.36-7.50(m，5H)，7.11-7.21(m，1H)，6.88-6.96(m，1H)，6.70-6.78(m，2H)，4.67(d，1H，J＝10.0Hz)，3.78(t，1H，J＝10.8Hz)，3.08-3.17(m，1H)，2.75-2.90(m，2H)，1.99-2.04(m，1H)，1.47-1.91(m，9H). 13C NMR(100MHz，CD 3OD)δ178.14，178.01，172.27，157.10，145.81，145.20，144.07，141.29，135.83，130.30，130.00，128.94，128.52，128.42，128.20，128.07，122.01，121.66，119.40，119.23，118.62，80.20，55.84，49.92，44.84，43.76，32.74，32.51，30.77，30.72，27.25，26.30，25.98，25.82，25.50. 1 H NMR(400MHz，CD 3 OD)δ7.63-7.70(m，4H)，7.36-7.50(m，5H)，7.11-7.21(m，1H)，6.88-6.96(m，1H)，6.70-6.78(m，2H)，4.67(d，1H，J＝10.0Hz)，3.78(t，1H，J＝10.8Hz)，3.08-3.17(m，1H)，2.75-2.90(m，2H)，1.99-2.04(m，1H)，1.47-1.91(m，9H). 13 C NMR(100MHz，CD 3 OD)δ178.14, 178.01, 172.27, 157.10, 145.81, 145.20, 144.07, 141.29, 135.83, 130.30, 130.00, 128.94, 128.52, 128.42, 128.20, 128.07, 122.01, 121.66, 119.40, 119.23, 118.62, 80.20, 55.84, 49.92, 44.84, 43.76, 32.74, 32.51, 30.77, 30.72, 27.25, 26.30, 25.98, 25.82, 25.50.
实施例37 2-(3-1-3′-异丙基联苯)-3-磺酰基哌啶-3-基苯氧基)-2-甲基丙酸，化合物II-35的制备Example 37 Preparation of 2-(3-(1-3′-isopropylbiphenyl)-3-sulfonylpiperidin-3-ylphenoxy)-2-methylpropanoic acid, compound II-35
Figure PCTCN2023071067-appb-000087
Figure PCTCN2023071067-appb-000087
参照实施例11得到中间体2-(3-1-(3′-异丙基联苯)-3-磺酰基哌啶-3-基苯氧基-2-甲基丙酸甲酯Referring to Example 11, the intermediate 2-(3-1-(3′-isopropylbiphenyl)-3-sulfonylpiperidin-3-ylphenoxy-2-methylpropionic acid methyl ester was obtained.
将中间体2-(3-1-(3′-异丙基联苯)-3-磺酰基哌啶-3-基苯氧基-2-甲基丙酸甲酯(400mg，0.76mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(157mg，3.8mmol)，室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体288mg，收率61％。The intermediate 2-(3-1-(3′-isopropylbiphenyl)-3-sulfonylpiperidin-3-ylphenoxy-2-methylpropionic acid methyl ester (400 mg, 0.76 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), followed by the addition of lithium hydroxide (157 mg, 3.8 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to obtain 288 mg of a white solid with a yield of 61%.
1H NMR(400MHz，DMSO-d 6)δ7.98-8.01(m，1H)，7.90(s，1H)，7.70-7.73(m，2H)，7.49-7.53(m，2H)，7.41(t，1H，J＝7.6Hz)，7.30(d，1H，J＝7.6Hz)，7.11(t，1H，J＝7.6Hz)，6.78(d，1H，J＝7.6Hz)，6.66-6.70(m，2H)，3.66-3.74(m，2H)，2.92-3.02(m，1H)，2.69-2.74(m，1H)，2.33-2.38(m，2H)，1.74-1.76(m，2H)，1.38-1.60(m，8H)，1.23(d，6H，J＝6.4Hz). 13C NMR(100MHz，DMSO-d 6)δ175.99，155.82，149.40，143.82，141.66，138.54，136.59，131.47，130.16，129.19，128.87，126.21，125.16，125.01，124.60，119.66，117.54，116.02，78.80，51.88，45.94，41.47，33.48，29.82，25.41，25.25，24.50，23.84. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.98-8.01 (m, 1H), 7.90 (s, 1H), 7.70-7.73 (m, 2H), 7.49-7.53 (m, 2H), 7.41 (t , 1H, J = 7.6 Hz), 7.30 (d, 1H, J = 7.6 Hz), 7.11 (t, 1H, J = 7.6 Hz), 6.78 (d, 1H, J = 7.6 Hz) z), 6.66-6.70 (m, 2H), 3.66-3.74 (m, 2H), 2.92-3.02 (m, 1H), 2.69-2.74 (m, 1H), 2.33-2.38 (m, 2H), 1.74- 1.76 (m, 2H), 1.38-1.60 (m, 8H), 1.23 (d, 6H, J = 6.4 Hz). 13 C NMR (100 MHz, DMSO-d 6 ) δ 175.99, 155.82, 149.40, 143.82, 141.66, 138.54, 136.59, 131.47, 130.16, 129.19, 128.87, 126.21, 125.16, 125.01, 124.60, 119.66, 117.54, 116.02, 78.80 , 51.88, 45.94, 41.47, 33.48, 29.82, 25.41, 25.25, 24.50, 23.84.
实施例38 2-(3-1-叔丁基)-3-磺酰基-3-磺酰基哌啶-3-基苯氧基)-2-甲基丙酸，化合物II-36的制备Example 38 Preparation of 2-(3-(1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidin-3-ylphenoxy)-2-methylpropanoic acid, compound II-36
Figure PCTCN2023071067-appb-000088
Figure PCTCN2023071067-appb-000088
参照实施例11得到中间体2-(3-1-叔丁基)-3-磺酰基-3-磺酰基哌啶-2-甲基丙酸甲酯Refer to Example 11 to obtain the intermediate 2-(3-1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidin-2-methylpropionic acid methyl ester
将中间体2-(3-1-叔丁基)-3-磺酰基-3-磺酰基哌啶-2-甲基丙酸甲酯(300mg，0.55mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(115mg，2.75mmol)，室温搅拌16 h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体120mg，收率48％。The intermediate methyl 2-(3-1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidine-2-methylpropanoate (300 mg, 0.55 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (115 mg, 2.75 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to obtain 120 mg of a white solid with a yield of 48%.
1H NMR(400MHz，DMSO-d 6)δ7.97-8.00(m，1H)，7.89(s，1H)，7.72(d，2H，J＝5.2Hz)，7.64(d，2H，J＝8.4Hz)，7.52(d，2H，J＝8.8Hz)，7.16(t，1H，J＝8.0Hz)，6.83(d，1H，J＝7.6Hz)，6.70(s，1H)，6.64(dd，1H，J 1＝2.0Hz，J 2＝8.0Hz)，3.65-3.73(m，2H)，2.70-2.75(m，1H)，2.32-2.39(m，2H)，1.75-1.78(m，2H)，1.41-1.63(m，8H)，1.31(s，9H). 13C NMR(100MHz，DMSO-d 6)δ175.15，155.51，150.91，144.09，141.22，136.60，135.60，131.14，130.21，129.15，126.70，126.05，125.99，124.79，120.24，117.50，115.99，78.33，51.83，45.98，41.44，34.34，31.05，29.83，25.24，24.97，24.48. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.97-8.00 (m, 1H), 7.89 (s, 1H), 7.72 (d, 2H, J=5.2 Hz), 7.64 (d, 2H, J=8.4 Hz), 7.52 (d, 2H, J=8.8 Hz), 7.16 (t, 1H, J=8.0 Hz), 6.83 (d, 1H, J=7.6 Hz), 6.70 (s, 1H), 6.64 (dd, 1H, J 1 =2.0 Hz, J 2 =8.0 Hz), 3.65-3.73 (m, 2H), 2.70-2.75 (m, 1H), 2.32-2.39 (m, 2H), 1.75-1.78 (m, 2H), 1.41-1.63 (m, 8H), 1.31 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 )δ175.15, 155.51, 150.91, 144.09, 141.22, 136.60, 135.60, 131.14, 130.21, 129.15, 126.70, 126.05, 125.99, 124.79, 120.24, 117.50, 115.99, 78.33, 51.83, 45.98, 41.44, 34.34, 31.05, 29.83, 25.24, 24.97, 24.48.
实施例39 N-((4-氰基苯基)磺酰基)-2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰)哌啶-3-基(苯氧基)-2-甲基丙酰胺，化合物II-37的制备Example 39 Preparation of N-((4-cyanophenyl)sulfonyl)-2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methylpropanamide, Compound II-37
Figure PCTCN2023071067-appb-000089
Figure PCTCN2023071067-appb-000089
将II-13(100mg，0.19mmol)和化合物34的衍生物(34mg，0.17mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(55mg，0.28mmol)和4-二甲氨基吡啶(46mg，0.38mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体72mg，收率65％。II-13 (100 mg, 0.19 mmol) and a derivative of compound 34 (34 mg, 0.17 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (55 mg, 0.28 mmol) and 4-dimethylaminopyridine (46 mg, 0.38 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 72 mg of a white solid, with a yield of 65%.
1H NMR(400MHz，CD 3OD)δ8.05(t，2H，J＝4.8Hz)，7.91(t，1H，J＝1.2Hz)，7.83-7.88(m，3H)，7.60-7.70(m，2H)，7.52(d，2H，J＝8.4Hz)，7.29(d，2H，J＝8.4Hz)，6.98(t，1H，J＝8.0Hz)，6.75(d，1H J＝7.6Hz)，6.62(s，1H)，6.49(dd，1H，J 1＝2.0Hz，J 2＝8.0Hz)，3.73-3.80(m，2H)，2.86-2.92(m，6.9Hz，1H)，2.60-2.66(m，1H)，2.28-2.38(m，2H)，1.74-1.80(m，2H)，1.60-1.69(m，1H)，1.33-1.42(m，7H)，1.22(d，6H，J＝7.2Hz). 13C NMR(100MHz，CD 3OD)δ177.48，156.42，150.37，145.80，145.45，143.49，138.17，137.81，133.72，132.29，130.98，130.32，129.83，128.24，128.07，127.11，126.45，122.16，119.03，118.50，118.31，117.45，81.59，53.57，47.54，43.31，34.98，31.50，26.04，25.09，24.36. 1 H NMR (400 MHz, CD 3 OD) δ 8.05 (t, 2H, J = 4.8 Hz), 7.91 (t, 1H, J = 1.2 Hz), 7.83-7.88 (m, 3H), 7.60-7.70 (m, 2H), 7.52 (d, 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.4 Hz), 6.98 (t, 1H, J = 8.0 Hz), 6.75 (d, 1H, J = 7.6 Hz), 6.62 (s, 1H), 6.49 (dd, 1H, J 1 = 2.0 Hz, J 2 =8.0 Hz), 3.73-3.80 (m, 2H), 2.86-2.92 (m, 6.9 Hz, 1H), 2.60-2.66 (m, 1H), 2.28-2.38 (m, 2H), 1.74-1.80 (m, 2H), 1.60-1.69 (m, 1H), 1.33-1.42 (m, 7H), 1.22 (d, 6H, J=7.2 Hz). 13 C NMR (100 MHz, CD 3 OD)δ177.48,156.42,150.37,145.80,145.45,143.49,138.17,137.81,133.72,132.29,130.98,130.32,129.83,128.24,128.07,127.11,126.45,122.16,119.03,118.50,118.31,117.45,81.59,53.57,47.54,43.31,34.98,31.50,26.04,25.09,24.36.
实施例40 N-苄基-2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基苯氧基)-2-甲基丙酰胺，化合物II-38的制备Example 40 Preparation of N-benzyl-2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropanamide, Compound II-38
Figure PCTCN2023071067-appb-000090
Figure PCTCN2023071067-appb-000090
将II-13(200mg，0.38mmol)和化合物34的衍生物(32mg，0.34mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(109mg，0.57mmol)和4-二甲氨基吡啶(93mg，0.76mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体151mg，收率65％。II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (32 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 151 mg of a white solid, with a yield of 65%.
1H NMR(400MHz，DMSO-d 6)δ8.62(t，1H，J＝6.0Hz)，7.97-8.00(m，1H)，7.89(s，1H)，7.68-7.73(m，2H)，7.63(d，2H，J＝8.4Hz)，7.36(d，2H，J＝8.4Hz)，7.12-7.25(m，6H)，6.88(d，1H，J＝7.6Hz)，6.69-6.73(m，2H)，4.26-4.28(m，2H)，3.63-3.74(m，2H)，2.90-2.97(m，1H)，2.67-2.72(m，1H)，2.28-2.38(m，2H)，1.69-1.77(m，2H)，1.42-1.63(m，8H)，1.22(d，6H，J＝7.2Hz). 13C NMR(100MHz，DMSO-d 6)δ173.47，154.87，148.67，143.91，141.30，139.54，136.56，135.96，131.11，130.15，129.08，128.07，127.18，127.11，126.92，126.59，125.96，124.74，120.96，118.72，117.97，80.07，51.79，45.93，42.24，41.36，33.11，29.71，25.13，24.97，24.44，23.75. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.62 (t, 1H, J=6.0 Hz), 7.97-8.00 (m, 1H), 7.89 (s, 1H), 7.68-7.73 (m, 2H), 7.63 (d, 2H, J = 8.4 Hz), 7.36 (d, 2H, J = 8.4 Hz), 7.12-7.25 (m, 6H), 6.88 (d, 1H, J = 7.6 Hz), 6.69- 6.73 (m, 2H), 4.26-4.28 (m, 2H), 3.63-3.74 (m, 2H), 2.90-2.97 (m, 1H), 2.67-2.72 (m, 1H), 2.28-2.38 (m, 2H ), 1.69-1.77 (m, 2H), 1.42-1.63 (m, 8H), 1.22 (d, 6H, J = 7.2 Hz). 13 C NMR (100 MHz, DMSO-d 6 ) δ 173.47, 154.87, 148.67, 143.91, 141.30, 139.54, 136.56, 135.96, 131.11, 130.15, 129.08, 128.07, 127.18, 127.11, 126.92, 126.59, 125.96, 124.74, 120.96 , 118.72, 117.97, 80.07, 51.79, 45.93, 42.24, 41.36, 33.11, 29.71, 25.13, 24.97, 24.44, 23.75.
实施例41 2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基(苯氧基)-2-甲基-N-((4-(三氟甲基)苯基)磺酰)丙酰胺，化合物II-39的制备Example 41 Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)propionamide, Compound II-39
Figure PCTCN2023071067-appb-000091
Figure PCTCN2023071067-appb-000091
将II-13(200mg，0.38mmol)和化合物34的衍生物(76mg，0.34mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(109mg，0.57mmol)和4-二甲氨基吡啶(93mg，0.76mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体65mg，收率59％。II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (76 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 65 mg of a white solid, with a yield of 59%.
1H NMR(600MHz，CD 3OD)δ8.08(d，2H，J＝8.4Hz)，7.92(t，1H，J＝1.8Hz)，7.87-7.88(m，1H)，7.79(d，2H，J＝8.4Hz)，7.69-7.71(m，1H)，7.64(t，1H，J＝7.8Hz)，7.54(d，2H，J＝8.4Hz)，7.31(d，2H，J＝7.8Hz)，6.95(t，1H，J＝7.8Hz)，6.75(d，1H，J＝7.8Hz)，6.66(s，1H)，6.47(dd，1H，J 1＝2.4Hz，J 2＝8.4Hz)，3.75-3.81(m，2H)，2.85-2.98(m，1H)，2.65-2.70(m，1H)，2.31-2.39(m，2H)，1.78-1.82(m，2H)，1.63-1.69(m，1H)，1.39-1.43(m，7H)，1.24(d，6H，J＝6.6Hz). 13C NMR(150MHz，CD 3OD)δ156.77，150.41，146.49，145.36，143.59，138.26，137.92，132.31，130.98，130.13，129.70，128.24，128.08，127.11，126.67，126.64，125.88，124.08，121.77，119.01，118.08，81.72，53.67，47.57，43.39，35.03，31.52，26.05，25.39，25.36，24.34. 1 H NMR (600 MHz, CD 3 OD) δ 8.08 (d, 2H, J = 8.4 Hz), 7.92 (t, 1H, J = 1.8 Hz), 7.87-7.88 (m, 1H), 7.79 (d, 2H, J = 8.4 Hz), 7.69-7.71 (m, 1H), 7.64 (t, 1H, J = 7.8 Hz), 7.54 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J = 7.8 Hz), 6.95 (t, 1H, J = 7.8 Hz), 6.75 (d, 1H, J = 7.8 Hz), 6.66 (s, 1H), 6.47 (dd, 1H, J 1 = 2.4 Hz, J 2 =8.4 Hz), 3.75-3.81 (m, 2H), 2.85-2.98 (m, 1H), 2.65-2.70 (m, 1H), 2.31-2.39 (m, 2H), 1.78-1.82 (m, 2H), 1.63-1.69 (m, 1H), 1.39-1.43 (m, 7H), 1.24 (d, 6H, J=6.6 Hz). 13 C NMR (150 MHz, CD 3 OD)δ156.77,150.41,146.49,145.36,143.59,138.26,137.92,132.31,130.98,130.13,129.70,128.24,128.08,127.11,126.67,126.64,125.88,124.08,121.77,119.01,118.08,81.72,53.67,47.57,43.39,35.03,31.52,26.05,25.39,25.36,24.34.
实施例42 2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基(苯氧基)-2-甲基-N-((3-(三氟甲基)苯基)磺酰)丙酰胺，化合物II-40的制备Example 42 Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-((3-(trifluoromethyl)phenyl)sulfonyl)propionamide, Compound II-40
Figure PCTCN2023071067-appb-000092
Figure PCTCN2023071067-appb-000092
将II-13(200mg，0.38mmol)和化合物34的衍生物(76mg，0.34mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(109mg，0.57mmol)和4-二甲氨基吡啶(93mg，0.76mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体95mg，收率62％。II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (76 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 95 mg of a white solid, with a yield of 62%.
1H NMR(600MHz，DMSO-d 6)δ12.62(s，1H)，8.08-8.10(m，2H)，7.98(d，2H，J＝3.0Hz)，7.89(s，1H)，7.78-7.80(m，1H)，7.71-7.72(m，2H)，7.62(d，2H，J＝7.8Hz)，7.35(d，2H，J＝7.8Hz)，6.96(t，1H，J＝7.8Hz)，6.78(d，1H，J＝6.6Hz)，6.60(s，1H)，6.40(d，1H，J＝7.8Hz)，3.64-3.73(m，2H)，2.90-2.95(m，1H)，2.63-2.66(m，1H)，2.31-2.37(m，2H)，1.68-1.77(m，2H)，1.56-1.58(m，1H)，1.33-1.43(m，7H)，1.21(d，6H，J＝6.6Hz). 13C NMR(150MHz，DMSO-d 6)δ175.16，155.12，148.64，143.92，141.28，136.59，136.00，131.19，131.09，130.16，128.76，127.09，126.94，126.01，124.77，123.84，120.19，117.74，116.05，80.13，51.75，45.94，41.39，33.11，29.76，24.61，24.48，23.74. 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.62 (s, 1H), 8.08-8.10 (m, 2H), 7.98 (d, 2H, J=3.0 Hz), 7.89 (s, 1H), 7.78- 7.80 (m, 1H), 7.71-7.72 (m, 2H), 7.62 (d, 2H, J = 7.8 Hz), 7.35 (d, 2H, J = 7.8 Hz), 6.96 (t, 1H, J = 7.8 Hz ), 6.78 (d, 1H, J = 6.6 Hz), 6.60 (s, 1H), 6.40 (d, 1H, J = 7.8 Hz), 3.64-3.73 (m, 2H), 2.90-2.95 (m, 1H), 2.63-2.66 (m, 1H), 2.31 -2.37 (m, 2H), 1.68-1.77 (m, 2H), 1.56-1.58 (m, 1H), 1.33-1.43 (m, 7H), 1.21 (d, 6H, J = 6.6 Hz). 13 C NMR (150 MHz, DMSO-d 6 ) δ 175.16, 155.12, 148.64, 143.92, 141.28, 136.59, 136.00, 131.19, 131.09, 130.16, 128.76, 127.09, 126.94, 126.01, 124.77, 123.84, 120.19, 117.74, 116.05 , 80.13, 51.75, 45.94, 41.39, 33.11, 29.76, 24.61, 24.48, 23.74.
实施例43 2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基(苯氧基)-N-((4-甲氧基苯基)磺酰)-2-甲基丙酰胺，化合物II-41的制备Example 43 Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-N-((4-methoxyphenyl)sulfonyl)-2-methylpropanamide, Compound II-41
Figure PCTCN2023071067-appb-000093
Figure PCTCN2023071067-appb-000093
将II-13(205mg，0.39mmol)和化合物34的衍生物(71mg，0.35mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(111mg，0.58mmol)和4-二甲氨基吡啶(95mg，0.78mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体82mg，收率61％。II-13 (205 mg, 0.39 mmol) and a derivative of compound 34 (71 mg, 0.35 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (111 mg, 0.58 mmol) and 4-dimethylaminopyridine (95 mg, 0.78 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 82 mg of a white solid, with a yield of 61%.
1H NMR(600MHz，DMSO-d 6)δ12.18(s，1H)，7.98-8.00(m，1H)，7.89(s，1H)，7.81(d，2H，J＝9.0Hz)，7.71(d，2H，J＝4.8Hz)，7.63(d，2H，J＝8.4Hz)，7.36(d，2H，J＝8.4Hz)，7.12(d，2H，J＝9.0Hz)，7.06(t，1H，J＝7.8Hz)，6.88(d，1H，J＝7.2Hz)，6.65(s，1H)，6.45(dd，1H，J 1＝2.4Hz，J 2＝8.4Hz)，3.86(s，3H)，3.64-3.73(m，2H)，2.91-2.95(m，1H)，2.64-2.69(m，1H)，2.32-2.38(m，2H)，1.69-1.78(m，2H)，1.57-1.59(m，1H)，1.32-1.42(m，7H)，1.22(d，6H，J＝7.2Hz). 13C NMR(150MHz，DMSO-d 6)δ173.06，163.05，154.54， 148.67，144.14，141.30，136.56，135.99，131.11，130.18，129.99，129.16，127.11，126.94，125.99，124.77，121.19，118.35，116.97，114.11，79.94，55.76，51.71，45.95，41.33，33.11，29.73，24.43，23.94，23.75. 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.18 (s, 1H), 7.98-8.00 (m, 1H), 7.89 (s, 1H), 7.81 (d, 2H, J=9.0 Hz), 7.71 (d, 2H, J=4.8 Hz), 7.63 (d, 2H, J=8.4 Hz), 7.36 (d, 2H, J=8.4 Hz), 7.12 (d, 2H, J=9.0 Hz), 7.06 (t, 1H, J=7.8 Hz), 6.88 (d, 1H, J=7.2 Hz), 6.65 (s, 1H), 6.45 (dd, 1H, J 1 =2.4 Hz, J 2 =8.4 Hz), 3.86 (s, 3H), 3.64-3.73 (m, 2H), 2.91-2.95 (m, 1H), 2.64-2.69 (m, 1H), 2.32-2.38 (m, 2H), 1.69-1.78 (m, 2H), 1.57-1.59 (m, 1H), 1.32-1.42 (m, 7H), 1.22 (d, 6H, J=7.2 Hz). 13 C NMR (150 MHz, DMSO-d 6 ) δ 173.06, 163.05, 154.54, 148.67, 144.14, 141.30, 136.56, 135.99, 131.11, 130.18, 129.99, 129.16, 127.11, 126.94, 125.99, 124.77, 121.19, 118.35, 116.97, 114.11, 79.94, 55.76, 51.71, 45.95, 41.33, 33.11, 29.73, 24.43, 23.94, 23.75.
实施例44 2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基苯氧基)-2-甲基-N-((4-硝基苯基)磺酰)丙酰胺，化合物II-42的制备Example 44 Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methyl-N-((4-nitrophenyl)sulfonyl)propionamide, Compound II-42
Figure PCTCN2023071067-appb-000094
Figure PCTCN2023071067-appb-000094
将II-13(200mg，0.38mmol)和化合物34的衍生物(69mg，0.34mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(109mg，0.57mmol)和4-二甲氨基吡啶(93mg，0.76mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体82mg，收率61％。II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (69 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 82 mg of a white solid, with a yield of 61%.
1H NMR(600MHz，DMSO-d 6)δ12.73(s，1H)，8.30(d，2H，J＝8.4Hz)，7.97-8.02(m，3H)，7.89(s，1H)，7.71(d，2H，J＝4.8Hz)，7.62(d，2H，J＝8.4Hz)，7.35(d，2H，J＝7.8Hz)，6.98(t，1H，J＝7.8Hz)，6.75(d，1H，J＝6.6Hz)，6.62(s，1H)，6.43(d，1H，J＝8.4Hz)，3.63-3.73(m，2H)，2.90-2.95(m，1H)，2.62-2.66(m，1H)，2.31-2.37(m，2H)，1.68-1.76(m，2H)，1.55-1.57(m，1H)，1.34-1.46(m，7H)，1.22(d，6H，J＝7.2Hz). 13C NMR(150MHz，DMSO-d 6)δ155.42，148.91，148.63，143.77，141.27，136.60，136.00，131.09，130.18，128.76，128.63，127.10，126.94，126.01，124.75，123.58，117.46，116.03，80.23，51.83，45.94，41.44，33.11，29.72，24.92，24.49，23.76，23.75. 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.73 (s, 1H), 8.30 (d, 2H, J=8.4 Hz), 7.97-8.02 (m, 3H), 7.89 (s, 1H), 7.71 ( d, 2H, J = 4.8 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 7.8 Hz), 6.98 (t, 1H, J = 7.8 Hz), 6.75 (d, 1H, J = 6.6 Hz), 6.6 2 (s, 1H), 6.43 (d, 1H, J = 8.4 Hz), 3.63-3.73 (m, 2H), 2.90-2.95 (m, 1H), 2.62-2.66 (m, 1H), 2.31-2.37 ( m, 2H), 1.68-1.76 (m, 2H), 1.55-1.57 (m, 1H), 1.34-1.46 (m, 7H), 1.22 (d, 6H, J = 7.2 Hz). 13 C NMR (150 MHz, DMSO-d 6 ) δ 155.42, 148.91, 148.63, 143.77, 141.27, 136.60, 136.00, 131.09, 130.18, 128.76, 128.63, 127.10, 126.94, 126.01, 124.75, 123.58, 117.46, 116.03, 80.23 , 51.83, 45.94, 41.44, 33.11, 29.72, 24.92, 24.49, 23.76, 23.75.
实施例45 N-((4-氟苯基)磺酰基)-2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰)哌啶-3-基苯氧基)-2-甲基丙酰胺，化合物II-43的制备Example 45 Preparation of N-((4-fluorophenyl)sulfonyl)-2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropanamide, Compound II-43
Figure PCTCN2023071067-appb-000095
Figure PCTCN2023071067-appb-000095
将II-13(190mg，0.36mmol)和化合物34的衍生物(56mg，0.32mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(103mg，0.54mmol)和4-二甲氨基吡啶(88mg，0.72mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体79mg，收率65％。II-13 (190 mg, 0.36 mmol) and a derivative of compound 34 (56 mg, 0.32 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) and 4-dimethylaminopyridine (88 mg, 0.72 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 79 mg of a white solid, with a yield of 65%.
1H NMR(600MHz，CD 3OD)δ7.99-8.01(m，2H)，7.92(s，1H)，7.88(d，1H，J＝7.8Hz)，7.70(d，1H，J＝7.8Hz)，7.64(t，1H，J＝7.8Hz)，7.54(d，2H，J＝7.8Hz)，7.31(d，2H，J＝7.8Hz)，7.25(t，2H，J＝8.4Hz)，7.01(t，1H，J＝7.8Hz)，6.80(d，1H，J＝7.2Hz)，6.61(s，1H)，6.49(dd，1H，J 1＝1.8Hz，J 2＝7.8Hz)，3.75-3.81(m，2H)，2.89-2.94(m，1H)，2.63-2.67(m，1H)，2.29-2.38(m，2H)，1.76-1.81(m，2H)，1.63-1.70(m，1H)，1.35-1.39(m，7H)，1.25(d，6H，J＝7.2Hz). 13C NMR(150MHz，CD 3OD)δ176.05，166.88，156.31，150.43，145.59，143.61，138.27，137.93，137.18，132.42，132.35，132.32，130.98，130.41，128.25，128.10，127.13，126.50，122.44，119.10，118.50，117.01，116.86，81.48，53.59，47.56，43.36，35.05，31.56，26.04，24.89，24.86，24.35. 1 H NMR (600 MHz, CD 3 OD) δ 7.99-8.01 (m, 2H), 7.92 (s, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.70 (d, 1H, J=7.8 Hz), 7.64 (t, 1H, J=7.8 Hz), 7.54 (d, 2H, J=7.8 Hz), 7.31 (d, 2H, J=7.8 Hz), 7.25 (t, 2H, J=8.4 Hz), 7.01 (t, 1H, J=7.8 Hz), 6.80 (d, 1H, J=7.2 Hz), 6.61 (s, 1H), 6.49 (dd, 1H, J 1 =1.8 Hz, J 2 =7.8 Hz), 3.75-3.81 (m, 2H), 2.89-2.94 (m, 1H), 2.63-2.67 (m, 1H), 2.29-2.38 (m, 2H), 1.76-1.81 (m, 2H), 1.63-1.70 (m, 1H), 1.35-1.39 (m, 7H), 1.25 (d, 6H, J=7.2 Hz). 13 C NMR (150 MHz, CD 3 OD)δ176.05,166.88,156.31,150.43,145.59,143.61,138.27,137.93,137.18,132.42,132.35,132.32,130.98,130.41,128.25,128.10,127.13,126.50,122.44,119.10,118.50,117.01,116.86,81.48,53.59,47.56,43.36,35.05,31.56,26.04,24.89,24.86,24.35.
实施例46 N-((3-氟苯基)磺酰基)-2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰)哌啶-3-基苯氧基)-2-甲基丙酰胺，化合物II-44的制备Example 46 Preparation of N-((3-fluorophenyl)sulfonyl)-2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropanamide, Compound II-44
Figure PCTCN2023071067-appb-000096
Figure PCTCN2023071067-appb-000096
将II-13(190mg，0.36mmol)和化合物34的衍生物(56mg，0.32mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(103mg，0.54mmol)和4-二甲氨基吡啶(88mg，0.72mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体75mg，收率63％。II-13 (190 mg, 0.36 mmol) and a derivative of compound 34 (56 mg, 0.32 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) and 4-dimethylaminopyridine (88 mg, 0.72 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 75 mg of a white solid, with a yield of 63%.
1H NMR(600MHz，CD 3OD)δ7.92(t，1H，J＝1.8Hz)，7.87-7.88(m，1H)，7.75-7.76(m，1H)，7.69-7.71(m，1H)，7.63-7.66(m，2H)，7.53-7.58(m，3H)，7.39-7.42(m，1H)，7.31(d，2H，J＝7.8Hz)，7.00(t，1H，J＝8.4Hz)，6.79(d，1H，J＝7.8Hz)，6.61(s，1H)，6.49(dd，1H，J 1＝1.8Hz，J 2＝7.8Hz)，3.74-3.81(m，2H)，2.89-2.94(m，1H)，2.64-2.65(m，1H)，2.30-2.38(m，2H)，1.77-1.82(m，2H)，1.64-1.69(m，1H)，1.35-1.40(m，7H)，1.25(d，6H，J＝7.2Hz). 13C NMR(150MHz，CD 3OD)δ163.34，156.35，150.42，145.59，143.63，143.26，138.26，137.93，132.32，132.04，131.98，130.97，130.39，128.24，128.09，127.11，126.52，125.11，122.34，121.61，121.48，119.05，118.32，116.41，116.25，81.50，53.55，47.57，43.37，35.05，31.64，26.07，24.97，24.89，24.35. 1 H NMR (600 MHz, CD 3 OD) δ 7.92 (t, 1H, J = 1.8 Hz), 7.87-7.88 (m, 1H), 7.75-7.76 (m, 1H), 7.69-7.71 (m, 1H), 7.63-7.66 (m, 2H), 7.53-7.58 (m, 3H), 7.39-7.42 (m, 1H), 7.31 (d, 2H, J = 7.8 Hz), 7.00 (t, 1H, J = 8.4 Hz), 6.79 (d, 1H, J = 7.8 Hz), 6.61 (s, 1H), 6.49 (dd, 1H, J 1 = 1.8 Hz, J 2 =7.8 Hz), 3.74-3.81 (m, 2H), 2.89-2.94 (m, 1H), 2.64-2.65 (m, 1H), 2.30-2.38 (m, 2H), 1.77-1.82 (m, 2H), 1.64-1.69 (m, 1H), 1.35-1.40 (m, 7H), 1.25 (d, 6H, J=7.2 Hz). 13 C NMR (150 MHz, CD 3 OD)δ163.34,156.35,150.42,145.59,143.63,143.26,138.26,137.93,132.32,132.04,131.98,130.97,130.39,128.24,128.09,127.11,126.52,125.11,122.34,121.61,121.48,119.05,118.32,116.41,116.25,81.50,53.55,47.57,43.37,35.05,31.64,26.07,24.97,24.89,24.35.
实施例47 2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基苯氧基)-2-甲基-N-((3-硝基苯基)磺酰)丙酰胺，化合物II-45的制备Example 47 Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methyl-N-((3-nitrophenyl)sulfonyl)propionamide, Compound II-45
Figure PCTCN2023071067-appb-000097
Figure PCTCN2023071067-appb-000097
将II-13(195mg，0.37mmol)和化合物34的衍生物(67mg，0.33mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(105mg，0.55mmol)和4-二甲氨基吡啶(90mg，0.74mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体82mg，收率66％。II-13 (195 mg, 0.37 mmol) and a derivative of compound 34 (67 mg, 0.33 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and 4-dimethylaminopyridine (90 mg, 0.74 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 82 mg of a white solid, with a yield of 66%.
1H NMR(600MHz，CD 3OD)δ8.65(t，1H，J＝1.8Hz)，8.39-8.40(m，1H)，8.25(d，1H，J＝7.8Hz)，7.92(s，1H)，7.88(d，1H，J＝7.8Hz)，7.70-7.75(m，2H)，7.65(t，1H，J＝7.2Hz)，7.54(d，2H，J＝7.8Hz)，7.30(d，2H，J＝7.8Hz)，6.89(t，1H，J＝8.4Hz)，6.68(d，1H，J＝7.2Hz)，6.62(s，1H)，6.43(dd，1H，J 1＝1.8Hz，J 2＝7.8Hz)，3.74-3.81(m，2H)，2.88-2.93(m，1H)，2.59-2.64(m，1H)，2.29-2.37(m，2H)，1.76-1.81(m，2H)，1.62-1.68(m，1H)，1.36-1.44(m，7H)，1.24(d，6H，J＝6.9Hz). 13C NMR(150MHz，CD 3OD)δ179.82，156.93，150.38，149.16，145.31，145.02，143.60，138.25，137.92，134.57，132.30，131.10，130.96，130.01，128.21，128.08，127.72，127.12，126.52，123.95，121.38，118.82，117.65，81.73，53.63，47.57，43.45，35.03，31.59，26.11，25.54，24.33. 1 H NMR (600 MHz, CD 3 OD) δ 8.65 (t, 1H, J = 1.8 Hz), 8.39-8.40 (m, 1H), 8.25 (d, 1H, J = 7.8 Hz), 7.92 (s, 1H), 7.88 (d, 1H, J = 7.8 Hz), 7.70-7.75 (m, 2H), 7.65 (t, 1H, J = 7.2 Hz), 7.54 (d, 2H, J = 7.8 Hz), 7.30 (d, 2H, J = 7.8 Hz), 6.89 (t, 1H, J = 8.4 Hz), 6.68 (d, 1H, J = 7.2 Hz), 6.62 (s, 1H), 6.43 (dd, 1H, J 1 = 1.8 Hz, J 2 =7.8 Hz), 3.74-3.81 (m, 2H), 2.88-2.93 (m, 1H), 2.59-2.64 (m, 1H), 2.29-2.37 (m, 2H), 1.76-1.81 (m, 2H), 1.62-1.68 (m, 1H), 1.36-1.44 (m, 7H), 1.24 (d, 6H, J=6.9 Hz). 13 C NMR (150 MHz, CD 3 OD)δ179.82,156.93,150.38,149.16,145.31,145.02,143.60,138.25,137.92,134.57,132.30,131.10,130.96,130.01,128.21,128.08,127.72,127.12,126.52,123.95,121.38,118.82,117.65,81.73,53.63,47.57,43.45,35.03,31.59,26.11,25.54,24.33.
实施例48 N-((3-氰基苯基)磺酰基)-2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰)哌啶-3-基苯氧基)-2-甲基丙酰胺，化合物II-46的制备Example 48 Preparation of N-((3-cyanophenyl)sulfonyl)-2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropanamide, Compound II-46
Figure PCTCN2023071067-appb-000098
Figure PCTCN2023071067-appb-000098
将II-13(208mg，0.42mmol)和化合物34的衍生物(70mg，0.38mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(121mg，0.63mmol)和4-二甲氨基吡啶(103mg，0.84mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体75mg，收率67％。II-13 (208 mg, 0.42 mmol) and a derivative of compound 34 (70 mg, 0.38 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 75 mg of a white solid, with a yield of 67%.
1H NMR(600MHz，CD 3OD)δ8.18-8.19(m，2H)，7.97(d，1H，J＝7.8Hz)，7.93(s，1H)，7.87-7.88(m，1H)，7.69-7.72(m，2H)，7.64(t，1H，J＝7.8Hz)，7.54(d，2H，J＝8.4Hz)，7.30(d，2H，J＝8.4Hz)，6.97(t，1H，J＝7.8Hz)，6.77(d，1H，J＝7.8Hz)，6.62(s，1H)，6.45(dd，1H，J 1＝1.8Hz，J 2＝7.8Hz)，3.75-3.81(m，2H)， 2.88-2.93(m，1H)，2.62-2.64(m，1H)，2.31-2.37(m，2H)，1.78-1.82(m，2H)，1.64-1.70(m，1H)，1.36-1.41(m，7H)，1.24(d，6H，J＝7.2Hz). 13C NMR(150MHz，CD 3OD)δ177.40，156.48，150.40，145.55，143.59，143.09，138.23，137.90，137.46，133.35，132.84，132.31，131.15，130.96，130.31，128.24，128.10，127.13，126.52，122.11，118.94，118.37，117.92，114.08，81.52，53.55，47.58，43.39，35.03，31.65，26.09，25.10，25.05，24.35. 1 H NMR (600 MHz, CD 3 OD) δ 8.18-8.19 (m, 2H), 7.97 (d, 1H, J=7.8 Hz), 7.93 (s, 1H), 7.87-7.88 (m, 1H), 7.69-7.72 (m, 2H), 7.64 (t, 1H, J=7.8 Hz), 7.54 (d, 2H, J=8.4 Hz), 7.30 (d, 2H, J=8.4 Hz), 6.97 (t, 1H, J=7.8 Hz), 6.77 (d, 1H, J=7.8 Hz), 6.62 (s, 1H), 6.45 (dd, 1H, J 1 =1.8 Hz, J 2 =7.8 Hz), 3.75-3.81 (m, 2H), 2.88-2.93 (m, 1H), 2.62-2.64 (m, 1H), 2.31-2.37 (m, 2H), 1.78-1.82 (m, 2H), 1.64-1.70 (m, 1H), 1.36-1.41 (m, 7H), 1.24 (d, 6H, J=7.2 Hz). 13 C NMR (150 MHz, CD 3 OD)δ177.40,156.48,150.40,145.55,143.59,143.09,138.23,137.90,137.46,133.35,132.84,132.31,131.15,130.96,130.31,128.24,128.10,127.13,126.52,122.11,118.94,118.37,117.92,114.08,81.52,53.55,47.58,43.39,35.03,31.65,26.09,25.10,25.05,24.35.
实施例49 2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基苯氧基)-2-甲基-N-(噻吩-2-基磺酰)丙酰胺，化合物II-47的制备Example 49 Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methyl-N-(thiophen-2-ylsulfonyl)propionamide, Compound II-47
Figure PCTCN2023071067-appb-000099
Figure PCTCN2023071067-appb-000099
将II-13(200mg，0.40mmol)和化合物34的衍生物(58mg，0.36mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(115mg，0.60mmol)和4-二甲氨基吡啶(121mg，0.80mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体69mg，收率63％。II-13 (200 mg, 0.40 mmol) and a derivative of compound 34 (58 mg, 0.36 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol) and 4-dimethylaminopyridine (121 mg, 0.80 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 69 mg of a white solid, with a yield of 63%.
1H NMR(600MHz，CD 3OD)δ7.92(s，1H)，7.88(d，1H，J＝7.8Hz)，7.84(d，1H，J＝4.2Hz)，7.78(d，1H，J＝3.0Hz)，7.68-7.71(m，1H)，7.65(t，1H，J＝7.2Hz)，7.54(d，2H，J＝8.4Hz)，7.32(d，2H，J＝8.4Hz)，7.13(t，1H，J＝4.8Hz)，7.03(t，1H，J＝7.8Hz)，6.78(d，1H，J＝7.8Hz)，6.52-6.55(m，2H)，3.74-3.81(m，2H)，2.90-2.94(m，1H)，2.58-2.62(m，1H)，2.27-2.37(m，2H)，1.75-1.81(m，2H)，1.62-1.68(m，1H)，1.39-1.44(m，6H)，1.25(d，6H，J＝6.6Hz). 13C NMR(150MHz，CD 3OD)δ176.17，156.31，150.44，145.56，143.62，141.16，138.22，137.92，135.50，135.01，132.34，131.01，130.49，128.27，128.24，128.10，127.12，126.50，122.35，118.99，118.71，81.47，53.55，48.86，48.71，48.57，47.56，43.40，35.06，31.66，26.07，25.05，24.73，24.36. 1 H NMR (600 MHz, CD 3 OD) δ 7.92 (s, 1H), 7.88 (d, 1H, J = 7.8 Hz), 7.84 (d, 1H, J = 4.2 Hz), 7.78 (d, 1H, J = =3.0 Hz), 7.68-7.71 (m, 1H), 7.65 (t, 1H, J = 7.2 Hz), 7.54 (d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J = 8.4 Hz), 7.13 (t, 1H, J = 4.8 Hz), 7.03 (t, 1H, J＝7.8 Hz), 6.78 (d, 1H, J＝7.8 Hz), 6.52-6.55 (m, 2H), 3.74-3.81 (m, 2H), 2.90-2.94 (m, 1H), 2.58-2.62 (m , 1H), 2.27-2.37 (m, 2H), 1.75-1.81 (m, 2H), 1.62-1.68 (m, 1H), 1.39-1.44 (m, 6H), 1.25 (d, 6H, J = 6.6 Hz ). 13 C NMR (150 MHz, CD 3 OD) δ 176.17, 156.31, 150.44, 145.56, 143.62, 141.16, 138.22, 137.92, 135.50, 135.01, 132.34, 131.01, 130.49, 128.27, 128.24, 128.10, 127.12, 126.50, 122.35, 118.99, 118.71, 81.47, 53.55, 48.86, 48.71, 48.57, 47.56, 43.40, 35.06, 31.66, 26.07, 25.05, 24.73, 24.36.
实施例50 2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基苯氧基)-2-甲基-N-((4-(三氟甲氧基)苯基)磺酰)丙酰胺，化合物II-48的制备Example 50 Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methyl-N-((4-(trifluoromethoxy)phenyl)sulfonyl)propionamide, Compound II-48
Figure PCTCN2023071067-appb-000100
Figure PCTCN2023071067-appb-000100
将II-13(200mg，0.38mmol)和化合物34的衍生物(82mg，0.34mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(109mg，0.57mmol)和4-二甲氨基吡啶(93mg，0.76mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体58mg，收率56％。II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (82 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 58 mg of a white solid, with a yield of 56%.
1H NMR(600MHz，CD 3OD)δ8.00(d，2H，J＝9.0Hz，)，7.92(s，1H)，7.88(d，1H，J＝7.8Hz)，7.70(d，1H，J＝7.8Hz)，7.64(t，1H，J＝7.2Hz)，7.55(d，2H，J＝7.8Hz)，7.36(d，2H，J＝8.4Hz)，7.32(d，2H，J＝8.4Hz)，6.95(t，1H，J＝7.8Hz)，6.73(d，1H，J＝7.2Hz)，6.65(s，1H)，6.47(dd，1H，J 1＝1.8Hz，J 2＝8.4Hz)，3.76-3.81(m，2H)，2.90-2.94(m，1H)，2.64-2.68(m，1H)，2.30-2.39(m，2H)，1.78-1.82(m，2H)，1.63-1.69(m，1H)，1.39-1.44(m，7H)，1.25(d，6H，J＝7.2Hz). 13C NMR(150MHz，CD 3OD)δ179.96，156.97，152.83，150.41，145.27，143.61，142.02，138.32，137.95，132.30，131.19，130.96，130.04，128.24，128.09，127.10，126.49，122.57，121.52，120.87，119.02，118.06，81.82，53.71，47.56，43.45，35.05，31.54，26.08，25.61，25.56，24.34. 1 H NMR (600 MHz, CD 3 OD) δ 8.00 (d, 2H, J = 9.0 Hz), 7.92 (s, 1H), 7.88 (d, 1H, J = 7.8 Hz), 7.70 (d, 1H, J = 7.8 Hz), 7.64 (t, 1H, J = 7.2 Hz), 7.55 (d, 2H, J = 7.8 Hz), 7.36 (d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J = 8.4 Hz), 6.95 (t, 1H, J = 7.8 Hz), 6.73 (d, 1H, J = 7.2 Hz), 6.65 (s, 1H), 6.47 (dd, 1H, J 1 = 1.8 Hz, J 2 =8.4 Hz), 3.76-3.81 (m, 2H), 2.90-2.94 (m, 1H), 2.64-2.68 (m, 1H), 2.30-2.39 (m, 2H), 1.78-1.82 (m, 2H), 1.63-1.69 (m, 1H), 1.39-1.44 (m, 7H), 1.25 (d, 6H, J=7.2 Hz). 13 C NMR (150 MHz, CD 3 OD)δ179.96,156.97,152.83,150.41,145.27,143.61,142.02,138.32,137.95,132.30,131.19,130.96,130.04,128.24,128.09,127.10,126.49,122.57,121.52,120.87,119.02,118.06,81.82,53.71,47.56,43.45,35.05,31.54,26.08,25.61,25.56,24.34.
实施例51 N-((4-乙酰氨基苯基)磺酰基)-2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰)哌啶-3-基(苯氧基)-2-甲基丙酰胺，化合物II-49的制备Example 51 Preparation of N-((4-acetylaminophenyl)sulfonyl)-2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methylpropanamide, Compound II-49
Figure PCTCN2023071067-appb-000101
Figure PCTCN2023071067-appb-000101
将II-13(200mg，0.38mmol)和化合物34的衍生物(72mg，0.34mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(109mg，0.57mmol)和4-二甲氨基吡啶(93mg，0.76mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体75mg，收率68％。II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (72 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 75 mg of a white solid, with a yield of 68%.
1H NMR(600MHz，CD 3OD)δ7.92(s，1H)，7.87(d，3H，J＝9.0Hz)，7.75(d，2H，J＝8.4Hz)，7.69(d，1H，J＝7.8Hz)，7.64(t，1H，J＝7.8Hz)，7.53(d，2H，J＝7.8Hz)，7.30(d，2H，J＝8.4Hz)，7.01(t，1H，J＝7.8Hz)，6.79(d，1H，J＝7.2Hz)，6.57(s，1H)，6.48(d，1H，J＝7.8Hz)，3.72-3.79(m，2H)，2.89-2.93(m，1H)，2.59-2.63(m，1H)，2.27-2.37(m，2H)，2.17(s，3H)，1.74-1.79(m，2H)，1.61-1.67(m，1H)，1.33-1.38(m，7H)，1.24(d，6H，J＝7.2Hz). 13C NMR(150MHz，CD 3OD)δ175.44，172.01，156.20，150.41，145.61，145.05，143.62，138.18，137.91，134.53，132.33，130.98，130.56，130.51，128.24，128.10，127.13，126.52，122.54，119.97，119.04，118.61，81.43，53.52，47.58，43.25，35.04，31.62，26.01，24.85，24.72，24.36，24.16. 1 H NMR (600 MHz, CD 3 OD) δ 7.92 (s, 1H), 7.87 (d, 3H, J = 9.0 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.69 (d, 1H, J =7.8 Hz), 7.64 (t, 1H, J = 7.8 Hz), 7.53 (d, 2H, J = 7.8 Hz), 7.30 (d, 2H, J = 8.4 Hz), 7.01 (t, 1H, J = 7.8 Hz), 6.79 (d, 1H, J = 7.2 Hz), 6. 57 (s, 1H), 6.48 (d, 1H, J = 7.8 Hz), 3.72-3.79 (m, 2H), 2.89-2.93 (m, 1H), 2.59-2.63 (m, 1H), 2.27-2.37 ( m, 2H), 2.17 (s, 3H), 1.74-1.79 (m, 2H), 1.61-1.67 (m, 1H), 1.33-1.38 (m, 7H), 1.24 (d, 6H, J = 7.2 Hz) . 13 C NMR (150 MHz, CD 3 OD) δ 175.44, 172.01, 156.20, 150.41, 145.61, 145.05, 143.62, 138.18, 137.91, 134.53, 132.33, 130.98, 130.56, 130.51, 128.24, 128.10, 127.13, 126.52, 122.54, 119.97, 119.04, 118.61, 81.43, 53.52, 47.58, 43.25, 35.04, 31.62, 26.01, 24.85, 24.72, 24.36, 24.16.
实施例52 2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基(苯氧基)-2-甲基-N-(萘-2-基磺酰)丙酰胺，化合物II-50的制备Example 52 Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-(naphthalene-2-ylsulfonyl)propionamide, Compound II-50
Figure PCTCN2023071067-appb-000102
Figure PCTCN2023071067-appb-000102
将II-13(200mg，0.38mmol)和化合物34的衍生物(70mg，0.34mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(109mg，0.57mmol)和4-二甲氨基吡啶(93mg，0.76mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体78mg，收率69％。II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (70 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 78 mg of a white solid, with a yield of 69%.
1H NMR(600MHz，CD 3OD)δ8.54(s，1H)，7.97(t，3H，J＝9.0Hz)，7.87-7.92(m，3H)，7.60-7.70(m，4H)，7.55(d，2H，J＝8.4Hz)，7.30(d，2H，J＝7.8Hz)，6.84(t，1H，J＝8.4Hz)，6.70(d，1H，J＝7.8Hz)，6.52(s，1H)，6.46(dd，1H，J 1＝1.8Hz，J 2＝7.8Hz)，3.70-3.74(m，2H)，2.88-2.92(m，1H)，2.46-2.50(m，1H)，2.22-2.26(m，2H)，1.60-1.66(m，2H)，1.34-1.51(m，8H)，1.23(d，6H，J＝6.6Hz). 13C NMR(150MHz，CD 3OD)δ156.35，150.46，145.49，143.65，138.23，137.96，136.61，133.26，132.34，131.06，131.00，130.53，130.37，130.34，130.08，129.11，128.72，128.27，128.11，127.14，126.52，124.00，122.30，118.71，118.54，81.48，53.51，47.50，43.19，35.06，31.52，25.93，25.14，24.67，24.34. 1 H NMR (600 MHz, CD 3 OD) δ 8.54 (s, 1H), 7.97 (t, 3H, J = 9.0 Hz), 7.87-7.92 (m, 3H), 7.60-7.70 (m, 4H), 7.55 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 7.8 Hz), 6.84 (t, 1H, J = 8.4 Hz), 6.70 (d, 1H, J = 7.8 Hz), 6.52 (s, 1H), 6.46 (dd, 1H, J 1 = 1.8 Hz, J 2 =7.8 Hz), 3.70-3.74 (m, 2H), 2.88-2.92 (m, 1H), 2.46-2.50 (m, 1H), 2.22-2.26 (m, 2H), 1.60-1.66 (m, 2H), 1.34-1.51 (m, 8H), 1.23 (d, 6H, J=6.6 Hz). 13 C NMR (150 MHz, CD 3 OD)δ156.35,150.46,145.49,143.65,138.23,137.96,136.61,133.26,132.34,131.06,131.00,130.53,130.37,130.34,130.08,129.11,128.72,128.27,128.11,127.14,126.52,124.00,122.30,118.71,118.54,81.48,53.51,47.50,43.19,35.06,31.52,25.93,25.14,24.67,24.34.
实施例53 2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基(苯氧基)-N-((3-甲氧基苯基)磺酰)-2-甲基丙酰胺，化合物II-51的制备Example 53 Preparation of 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-N-((3-methoxyphenyl)sulfonyl)-2-methylpropanamide, Compound II-51
Figure PCTCN2023071067-appb-000103
Figure PCTCN2023071067-appb-000103
将II-13(200mg，0.38mmol)和化合物34的衍生物(68mg，0.34mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(109mg，0.57mmol)和4-二甲氨基吡啶(93mg，0.76mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体81mg，收率70％。II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (68 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 81 mg of a white solid, with a yield of 70%.
1H NMR(600MHz，CD 3OD)δ7.92(s，1H)，7.87(d，1H，J＝7.2Hz)，7.70(d，1H，J＝7.8Hz)，7.64(t，1H，J＝7.8Hz)，7.50-7.54(m，3H)，7.41-7.46(m，2H)，7.31(d，2H，J＝7.8Hz)，7.18-7.20(m，1H)，6.98(t，1H，J＝7.8Hz)，6.78(d，1H，J＝7.8Hz)，6.58(s，1H)，6.45(dd，1H，J 1＝1.8Hz，J 2＝7.8Hz)，3.74-3.80(m，5H)，2.89-2.93(m，1H)，2.60-2.64(m，1H)，2.28-2.37(m，2H)，1.74-1.80(m，2H)，1.62-1.68(m，1H)，1.32- 1.44(m，7H)，1.24(d，6H，J＝6.6Hz). 13C NMR(150MHz，CD 3OD)δ175.91，161.03，156.30，150.44，145.58，143.62，142.00，138.26，137.92，132.32，131.02，130.99，130.42，128.26，128.10，127.12，126.51，122.32，121.14，120.80，119.02，118.37，114.04，81.45，56.16，53.54，47.56，43.29，35.05，31.61，26.05，24.94，24.81，24.36. 1 H NMR (600 MHz, CD 3 OD) δ 7.92 (s, 1H), 7.87 (d, 1H, J = 7.2 Hz), 7.70 (d, 1H, J = 7.8 Hz), 7.64 (t, 1H, J = 7.8 Hz), 7.50-7.54 (m, 3H), 7.41-7.46 (m, 2H), 7.31 (d, 2H, J = 7.8 Hz), 7.18-7.20 (m, 1H), 6.98 (t, 1H, J = 7.8 Hz), 6.78 (d, 1H, J = 7.8 Hz), 6.58 (s, 1H), 6.45 (dd, 1H, J 1 = 1.8 Hz, J 2 =7.8 Hz), 3.74-3.80 (m, 5H), 2.89-2.93 (m, 1H), 2.60-2.64 (m, 1H), 2.28-2.37 (m, 2H), 1.74-1.80 (m, 2H), 1.62-1.68 (m, 1H), 1.32- 1.44 (m, 7H), 1.24 (d, 6H, J = 6.6 Hz). 13 C NMR (150 MHz, CD 3 OD)δ175.91, 161.03, 156.30, 150.44, 145.58, 143.62, 142.00, 138.26, 137.92, 132.32, 131.02, 130.99, 130.42, 128.26, 128.10, 127.12, 126.51, 122.32, 121.14, 120.80, 119.02, 118.37, 114.04, 81.45, 56.16, 53.54, 47.56, 43.29, 35.05, 31.61, 26.05, 24.94, 24.81, 24.36.
实施例54 N-((2-氯-4-(三氟甲基)苯基)磺酰基)-2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰)哌啶-3-基苯氧基)-2-甲基丙酰胺，化合物II-52的制备Example 54 Preparation of N-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropanamide, Compound II-52
Figure PCTCN2023071067-appb-000104
Figure PCTCN2023071067-appb-000104
将II-13(200mg，0.38mmol)和化合物34的衍生物(88mg，0.34mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(109mg，0.57mmol)和4-二甲氨基吡啶(93mg，0.76mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体67mg，收率60％。II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (88 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added respectively, stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 67 mg of a white solid, with a yield of 60%.
1H NMR(600MHz，CD 3OD)δ8.28(d，1H，J＝8.4Hz)，7.93(s，1H)，7.88(d，1H，J＝7.8Hz)，7.80(s，1H)，7.63-7.72(m，3H)，7.55(d，2H，J＝8.4Hz)，7.31(d，2H，J＝8.4Hz)，7.03(t，1H，J＝7.8Hz)，6.77(d，1H，J＝7.2Hz)，6.70(s，1H)，6.63(dd，1H，J 1＝1.8Hz，J 2＝7.8Hz)，3.79-3.83(m，2H)，2.89-2.94(m，1H)，2.70-7.74(m，1H)，2.34-2.41(m，2H)，1.81-1.83(m，2H)，1.64-1.71(m，1H)，1.43-1.45(m，7H)，1.24(d，6H，J＝7.2Hz). 13C NMR(150MHz，CD 3OD)δ156.98，150.40，145.34，143.59，138.32，137.94，135.79，134.26，133.88，132.29，130.98，130.16，129.32，128.24，128.10，127.15，126.49，125.13，124.70，123.33，121.74，118.77，118.39，81.70，53.70，47.59，43.56，35.04，31.62，26.14，25.56，25.48，24.33. 1 H NMR (600 MHz, CD 3 OD) δ 8.28 (d, 1H, J = 8.4 Hz), 7.93 (s, 1H), 7.88 (d, 1H, J = 7.8 Hz), 7.80 (s, 1H), 7.63-7.72 (m, 3H), 7.55 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J = 8.4 Hz), 7.03 (t, 1H, J = 7.8 Hz), 6.77 (d, 1H, J = 7.2 Hz), 6.70 (s, 1H), 6.63 (dd, 1H, J 1 = 1.8 Hz, J 2 =7.8 Hz), 3.79-3.83 (m, 2H), 2.89-2.94 (m, 1H), 2.70-7.74 (m, 1H), 2.34-2.41 (m, 2H), 1.81-1.83 (m, 2H), 1.64-1.71 (m, 1H), 1.43-1.45 (m, 7H), 1.24 (d, 6H, J = 7.2 Hz). 13 C NMR (150 MHz, CD 3 OD)δ156.98,150.40,145.34,143.59,138.32,137.94,135.79,134.26,133.88,132.29,130.98,130.16,129.32,128.24,128.10,127.15,126.49,125.13,124.70,123.33,121.74,118.77,118.39,81.70,53.70,47.59,43.56,35.04,31.62,26.14,25.56,25.48,24.33.
实施例55 2-(3-(1-(3-异丙基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸，化合物II-53的制备Example 55 Preparation of 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid, compound II-53
Figure PCTCN2023071067-appb-000105
Figure PCTCN2023071067-appb-000105
参照实施例1得到中间体2-(3-(1-(3-异丙基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯Refer to Example 1 to obtain the intermediate 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid methyl ester
将中间体将2-(3-(1-(3-异丙基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯(380mg，0.93mmol)溶解于四氢呋喃/甲醇/水(3∶1∶1，25mL)的溶液中，随后加入氢氧化锂(195mg，4.6mmol)， 室温搅拌16h，将反应液减压浓缩，使用适量1N盐酸溶液将反应液pH调至3-4，过滤，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)得到白色固体200mg，收率72％。The intermediate methyl 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate (380 mg, 0.93 mmol) was dissolved in a solution of tetrahydrofuran/methanol/water (3:1:1, 25 mL), and then lithium hydroxide (195 mg, 4.6 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 with an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column chromatography (petroleum ether/ethyl acetate=5:1-3:1) to obtain 200 mg of a white solid with a yield of 72%.
1H NMR(600MHz，CD 3OD)δ7.29-7.38(m，3H)，7.10-7.22(m，2H)，6.88-6.97(m，1H)，6.70-6.79(m，2H)，4.66-4.67(m，1H)，3.67-3.74(m，1H)，3.05-3.15(m，1H)，2.85-2.97(m，2H)，2.72-2.77(m，1H)，2.01-2.05(m，1H)，1.50-1.93(m，9H)，1.25-1.28(m，6H). 13C NMR(150MHz，CD 3OD)δ178.00，177.87，172.76，157.14，157.08，150.80，145.85，145.28，137.20，137.15，130.26，129.79，129.73，129.10，125.82，125.60，125.24，125.10，122.03，121.74，119.42，119.34，118.63，118.59，80.17，80.13，55.71，49.83，44.88，43.77，43.68，35.29，32.78，32.62，27.24，26.33，25.88，25.81，25.61，24.37，24.30. 1 H NMR(600MHz，CD 3 OD)δ7.29-7.38(m，3H)，7.10-7.22(m，2H)，6.88-6.97(m，1H)，6.70-6.79(m，2H)，4.66-4.67(m，1H)，3.67-3.74(m，1H)，3.05-3.15(m，1H)，2.85-2.97(m，2H)，2.72-2.77(m，1H)，2.01-2.05(m，1H)，1.50-1.93(m，9H)，1.25-1.28(m，6H). 13 C NMR(150MHz，CD 3 OD)δ178.00,177.87,172.76,157.14,157.08,150.80,145.85,145.28,137.20,137.15,130.26,129.79,129.73,129.10,125.82,125.60,125.24,125.10,122.03, 121.74, 119.42, 119.34, 118.63, 118.59, 80.17, 80.13, 55.71, 49.83, 44.88, 43.77, 43.68, 35.29, 32.78, 32.62, 27.24, 26.33, 25.88, 25.81, 25.61, 24.37, 24.30.
实施例56 2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-N-(噻吩-2-基磺酰基)丙酰胺，化合物II-54的制备Example 56 Preparation of 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(thiophen-2-ylsulfonyl)propionamide, Compound II-54
Figure PCTCN2023071067-appb-000106
Figure PCTCN2023071067-appb-000106
将II-2(200mg，0.42mmol)和化合物34衍生物(60mg，0.37mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(121mg，0.63mmol)和4-二甲氨基吡啶(103mg，0.84mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体177mg，收率82％。II-2 (200 mg, 0.42 mmol) and compound 34 derivative (60 mg, 0.37 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 177 mg of a white solid, with a yield of 82%.
1H NMR(400MHz，CD 3OD)δ7.77-7.82(m，2H)，7.54-7.71(m，4H)，7.27-7.44(m，3H)，6.48-7.15(m，5H)，4.63-4.70(m，1H)，3.66-3.77(m，1H)，3.08-3.18(m，1H)，2.65-2.87(m，2H)，1.72-2.00(m，4H)，1.36-1.46(m，6H). 13C NMR(100MHz，CD 3OD)δ176.73，171.91，156.43，152.80，150.44，145.94，145.28，141.70，140.76，138.77，138.04，137.86，135.15，135.04，134.62，134.50，130.48，130.42，129.40，128.11，127.14，127.03，126.30，124.54-124.64(m)，122.34，121.88，118.65-119.04(m)，118.53，117.09，116.91，81.54，81.47，55.62，44.84，43.64，32.59-32.80(m)，27.21，26.27，25.42，25.02，24.49. 1 H NMR (400 MHz, CD 3 OD) δ 7.77-7.82 (m, 2H), 7.54-7.71 (m, 4H), 7.27-7.44 (m, 3H), 6.48-7.15 (m, 5H), 4.63-4.70 (m, 1H), 3.66-3.77 (m, 1H), 3.08-3.18 (m, 1H), 2.65-2.87 (m, 2H), 1.72-2.00 (m, 4H), 1.36-1.46 (m, 6H). 13 C NMR (100 MHz, CD 3 OD) δ 7.77-7.82 (m, 2H), 7.54-7.71 (m, 4H), 7.27-7.44 (m, 3H), 6.48-7.15 (m, 5H), 4.63-4.70 (m, 1H), 3.66-3.77 (m, 1H), 3.08-3.18 (m, 1H), 2.65-2.87 (m, 2H), 1.72-2.00 (m, 4H), 1.36-1.46 (m, 6H) . OD)δ176.73,171.91,156.43,152.80,150.44,145.94,145.28,141.70,140.76,138.77,138.04,137.86,135.15,135.04,134.62,134.50,130.48,130.42,129.40,128.11,127.14,127 .03, 126.30, 124.54-124.64 (m), 122.34, 121.88, 118.65-119.04 (m), 118.53, 117.09, 116.91, 81.54, 81.47, 55.62, 44.84, 43.64, 32.59-32.80 (m), 27.21, 26.27, 25.42, 25.02, 24.49.
实施例57 2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-N-((4-(三氟甲基)苯基)磺酰基)丙酰胺，化合物II-55的制备Example 57 Preparation of 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)propionamide, Compound II-55
Figure PCTCN2023071067-appb-000107
Figure PCTCN2023071067-appb-000107
将II-2(200mg，0.42mmol)和化合物34衍生物(83mg，0.37mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(121mg，0.63mmol)和4-二甲氨基吡啶(103mg，0.84mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体217mg，收率90％。II-2 (200 mg, 0.42 mmol) and compound 34 derivative (83 mg, 0.37 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 217 mg of a white solid, with a yield of 90%.
1H NMR(400MHz，CD 3OD)δ8.11-8.20(m，2H)，7.84-7.91(m，2H)，7.64-7.71(m，2H)，7.25-7.43(m，5H)，6.84-7.07(m，2H)，6.64-6.76(m，1H)，6.42-6.51(m，1H)，4.65-4.72(m，1H)，3.70-3.78(m，1H)，3.12-3.15(m，1H)，2.85-2.91(m，1H)，2.71-2.74(m，1H)，1.61-1.99(m，4H)，1.34-1.44(m，6H). 13C NMR(100MHz，CD 3OD)δ175.84，175.78，171.96，156.21，152.81，150.36，146.13，145.53，144.43，140.76，138.77，138.01，137.91，136.37，136.04，135.71，135.39，130.45，130.42，130.17，129.40，128.84，127.10，126.32，126.28，126.14，124.51-124.61(m)，123.43，122.67，122.25，119.38，118.88，118.72，118.20，117.10，116.91，81.48，81.37，55.59，44.79，43.72，32.66，27.17，26.23，24.97，24.84，24.70，24.38. 1 H NMR (400 MHz, CD 3 OD) δ 8.11-8.20 (m, 2H), 7.84-7.91 (m, 2H), 7.64-7.71 (m, 2H), 7.25-7.43 (m, 5H), 6.84-7.07 (m, 2H), 6.64-6.76 (m, 1H), 6.42-6.51 (m, 1H), 4.65-4.72 (m, 1H), 3.70-3.78 (m, 1H), 3.12-3.15 (m, 1H), 2.85-2.91 (m, 1H), 2.71-2.74 (m, 1H), 1.61-1.99 (m, 4H), 1.34-1.44 (m, 6H). 13 C NMR (100 MHz, CD 3 OD) δ 175.84, 175.78, 171.96, 156.21, 152.81, 150.36, 146.13, 145.53, 144.43, 140.76, 138.77, 138.01, 137.91, 136.37, 136.04, 135.71, 135.39, 130.45, 130.42, 130.17, 129.40, 128.84, 127.10, 126. 32, 126.28, 126.14, 124.51-124.61 (m), 123.43, 122.67, 122.25, 119.38, 118.88, 118.72, 118.20, 117.10, 116.91, 81.48, 81.37, 55.59, 44.79, 43.72, 32.66, 27.17, 26.23, 24.97, 24.84, 24.70, 24.38.
实施例58 2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-N-(萘-2-基磺酰基)丙酰胺，化合物II-56的制备Example 58 Preparation of 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(naphthalene-2-ylsulfonyl)propionamide, Compound II-56
Figure PCTCN2023071067-appb-000108
Figure PCTCN2023071067-appb-000108
将II-2(200mg，0.42mmol)和化合物34衍生物(77mg，0.37mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(121mg，0.63mmol)和4-二甲氨基吡啶(103mg，0.84mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体201mg，收率86％。II-2 (200 mg, 0.42 mmol) and compound 34 derivative (77 mg, 0.37 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 201 mg of a white solid, with a yield of 86%.
1H NMR(400MHz，CD 3OD)δ8.56-8.61(m，1H)，7.86-7.99(m，4H)，7.45-7.68(m，6H)，7.24-7.40(m，3H)，6.73-6.90(m，2H)，6.40-6.65(m，2H)，4.59-4.63(m，1H)，3.59-3.69(m，1H)，2.96-3.00(m，1H)，2.72-2.78(m，1H)，2.48-2.60(m，1H)，1.56-1.82(m，4H)，1.26-1.41(m，6H). 13C NMR(100MHz，CD 3OD)δ175.59，175.44，171.82，156.19，150.33，145.92，145.26，140.73，138.73，137.97，137.81，137.41，136.66，133.21， 131.27，130.54，130.45，130.14，130.09，129.38，129.03，128.79，127.16，126.93，126.33，126.23，124.51-124.60(m)，123.97，122.58，122.03，118.89，118.72，118.44，117.08，116.90，81.42，81.32，55.64，44.62，43.63，43.44，32.52，32.30，27.09，26.17，25.22，24.85，24.74，24.21. 1 H NMR(400MHz，CD 3 OD)δ8.56-8.61(m，1H)，7.86-7.99(m，4H)，7.45-7.68(m，6H)，7.24-7.40(m，3H)，6.73-6.90(m，2H)，6.40-6.65(m，2H)，4.59-4.63(m，1H)，3.59-3.69(m，1H)，2.96-3.00(m，1H)，2.72-2.78(m，1H)，2.48-2.60(m，1H)，1.56-1.82(m，4H)，1.26-1.41(m，6H). 13 C NMR(100MHz，CD 3 OD)δ175.59,175.44,171.82,156.19,150.33,145.92,145.26,140.73,138.73,137.97,137.81,137.41,136.66,133.21, 131.27, 130.54, 130.45, 130.14, 130.09, 129.38, 129.03, 128.79, 127.16, 126.93, 126.33, 126.23, 124.51-124.60 (m), 123.97, 122.58, 122.03, 118.89, 118.72, 118.44, 117.08, 116.90, 81.42, 81.32, 55.64, 44.62, 43.63, 43.44, 32.52, 32.30, 27.09, 26.17, 25.22, 24.85, 24.74, 24.21.
实施例59 1-(2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-4-酮，化合物II-57的制备Example 59 Preparation of 1-(2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazin-4-one, Compound II-57
Figure PCTCN2023071067-appb-000109
Figure PCTCN2023071067-appb-000109
化合物II-2(200mg，0.42mmol)溶解于二氯甲烷(25mL)溶液中，分别加入4-哌啶酮(316mg，1.4mmol)、2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(836g，1.2mmol)和三乙胺(364mg，3.6mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-6∶1))得到白色固体112mg，收率75％。Compound II-2 (200 mg, 0.42 mmol) was dissolved in dichloromethane (25 mL) solution, and 4-piperidone (316 mg, 1.4 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (836 g, 1.2 mmol) and triethylamine (364 mg, 3.6 mmol) were added respectively. The mixture was stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-6:1) to obtain 112 mg of a white solid with a yield of 75%.
1H NMR(600MHz，CD 3OD)δ7.66-7.71(m，2H)，7.53-7.56(m，2H)，7.42-7.43(m，2H)，7.33-7.34(m，1H)，7.09-7.25(m，1H)，6.73-6.96(m，2H)，6.62-6.68(m，1H)，4.64-4.69(m，1H)，3.59-3.91(m，5H)，3.14-3.19(m，1H)，2.85-2.92(m，1H)，2.78-2.80(m，1H)，2.25-2.41(m，1H)，1.75-2.02(m，4H)，1.55-1.73(m，9H). 13C NMR(150MHz，CD 3OD)δ208.59，208.37，173.97，173.77，173.35，173.16，171.93，157.12，152.42，150.78，145.66-146.43(m)，140.75，138.80，137.92-138.06(m)，130.85，130.70，130.50，130.45，129.42，127.14，127.10，126.33，126.23，124.56-124.62(m)，121.24-121.69(m)，118.90，118.78，117.10，116.98，116.26-116.85(m)，96.13，96.02，81.82，81.72，55.64，55.55，49.85，49.42，44.86-45.10(m)，44.26，44.18，43.75，41.93，41.84，41.66，41.56，41.19，41.12，38.87，36.77，36.52，36.13，32.86，32.77，27.20，26.25-26.58(m). 1 H NMR (600 MHz, CD 3 OD) δ 7.66-7.71 (m, 2H), 7.53-7.56 (m, 2H), 7.42-7.43 (m, 2H), 7.33-7.34 (m, 1H), 7.09-7.25 (m, 1H), 6.73-6.96 (m, 2H), 6.62-6.68 (m, 1H), 4.64-4.69 (m, 1H), 3.59-3.91 (m, 5H), 3.14-3.19 (m, 1H), 2.85-2.92 (m, 1H), 2.78-2.80 (m, 1H), 2.25-2.41 (m, 1H), 1.75-2.02 (m, 4H), 1.55-1.73 (m, 9H). 13 C NMR (150 MHz, CD 3 OD) δ 208.59, 208.37, 173.97, 173.77, 173.35, 173.16, 171.93, 157.12, 152.42, 150.78, 145.66-146.43 (m), 140.75, 138.80, 137.92-138.06 (m), 130.85, 130.70, 130.50, 130.45, 129.42, 127.14, 127.10, 126.33, 126.23, 124.56-124.62 (m), 121.24-121.69 (m), 118.90, 118.78, 117.10, 116.98, 116.26-116.85 (m), 96.13, 96.02, 81.82, 81.72, 55.64, 55.55, 49.85, 49.42, 44.86-45.10 (m), 44.26, 44.18, 43.75, 41.93, 41.84, 41.66, 41.56, 41.19, 41.12, 38.87, 36.77, 36.52, 36.13, 32.86, 32.77, 27.20, 26.25-26.58 (m).
实施例60 4-(2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-氯化铵，化合物II-58的制备Example 60 Preparation of 4-(2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-ammonium chloride, Compound II-58
Figure PCTCN2023071067-appb-000110
Figure PCTCN2023071067-appb-000110
参照实施例25得到中间体2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-1-(哌嗪-1-基)丙-1-酮Referring to Example 25, the intermediate 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-1-(piperazin-1-yl)propan-1-one was obtained.
将中间体2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-1-(哌嗪-1-基)丙-1-酮(225mg，0.41mmol)溶解于4M盐酸二氧六环溶液(15mL)，室温反应2h，蒸干反应液， 得到白色固体75mg，收率61％。The intermediate 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-1-(piperazin-1-yl)propan-1-one (225 mg, 0.41 mmol) was dissolved in 4M hydrochloric acid and dioxane solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to obtain 75 mg of a white solid with a yield of 61%.
1H NMR(600MHz，CD 3OD)δ7.57-7.73(m，4H)，7.27-7.46(m，4H)，7.00-7.15(m，1H)，6.65-6.84(m，2H)，4.65-4.67(m，1H)，3.60-4.18(m，5H)，2.73-3.23(m，7H)，1.94-2.06(m，1H)，1.76-1.80(m，2H)，1.57-1.66(m，6H). 13C NMR(150MHz，CD 3OD)δ173.64，173.50，172.01，171.89，156.71，156.64，152.41，150.77，146.64，146.07，140.77，138.79，137.96，130.98，130.51，129.46，127.15，127.07，126.30，126.22，124.58-124.64(m)，121.89，121.77，118.94，118.82，117.07，117.02，116.95，116.33，116.17，81.84，55.61，49.90，49.43，49.29，43.80-44.72(m)，40.81，32.72，27.19，26.46，26.25. 1 H NMR (600 MHz, CD 3 OD) δ 7.57-7.73 (m, 4H), 7.27-7.46 (m, 4H), 7.00-7.15 (m, 1H), 6.65-6.84 (m, 2H), 4.65-4.67 (m, 1H), 3.60-4.18 (m, 5H), 2.73-3.23 (m, 7H), 1.94-2.06 (m, 1H), 1.76-1.80 (m, 2H), 1.57-1.66 (m, 6H). 13 C NMR (150 MHz, CD 3 OD) δ 7.57-7.73 (m, 4H), 7.27-7.46 (m, 4H), 7.00-7.15 (m, 1H), 6.65-6.84 (m, 2H), 4.65-4.67 (m, 1H), 3.60-4.18 (m, 5H), 2.73-3.23 (m, 7H), 1.94-2.06 (m, 1H), 1.76-1.80 (m, 2H), 1.57-1.66 (m, 6H) . OD)δ173.64,173.50,172.01,171.89,156.71,156.64,152.41,150.77,146.64,146.07,140.77,138.79,137.96,130.98,130.51,129.46,127.15,127.07,126.30,126.22,124.5 8-124.64(m), 121.89, 121.77, 118.94, 118.82, 117.07, 117.02, 116.95, 116.33, 116.17, 81.84, 55.61, 49.90, 49.43, 49.29, 43.80-44.72(m), 40.81, 32.72, 27.19, 26.46, 26.25.
实施例61 1-(2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-4-氯化铵，化合物II-59的制备Example 61 Preparation of 1-(2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-4-ammonium chloride, Compound II-59
Figure PCTCN2023071067-appb-000111
Figure PCTCN2023071067-appb-000111
参照实施例25得到中间体1-(4-氨基哌啶-1-基)-2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙烷-1-酮Referring to Example 25, the intermediate 1-(4-aminopiperidin-1-yl)-2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropane-1-one was obtained.
将中间体1-(4-氨基哌啶-1-基)-2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙烷-1-酮(150mg，0.27mmol)溶解于4M盐酸二氧六环溶液(15mL)，室温反应2h，蒸干反应液，得到白色固体61mg，收率53％。The intermediate 1-(4-aminopiperidin-1-yl)-2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropane-1-one (150 mg, 0.27 mmol) was dissolved in 4M hydrochloric acid dioxane solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to obtain 61 mg of white solid with a yield of 53%.
1H NMR(600MHz，CD 3OD)δ7.57-7.73(m，4H)，7.23-7.44(m，4H)，6.97-7.12(m，1H)，6.61-6.83(m，2H)，4.58-4.78(m，2H)，3.71-3.79(m，1H)，2.64-3.23(m，6H)，1.93-2.05(m，3H)，1.34-1.87(m，11H)，1.19-1.24(m，1H). 13C NMR(150MHz，CD 3OD)δ173.71，173.56，171.88，156.91，156.81，152.42，150.78，146.31，145.75，140.78，140.69，138.79，137.95，130.79，130.52，129.46，127.16，126.30，124.58-124.65(m)，121.75，121.59，118.94，118.82，117.37，117.07，116.95，116.78，116.37，81.79，55.63，50.08，49.83，44.67-44.93(m)，43.78，42.55，42.45，32.87，32.63，32.52，31.46，30.87，27.20，26.61，26.39，26.20. 1 H NMR (600 MHz, CD 3 OD) δ 7.57-7.73 (m, 4H), 7.23-7.44 (m, 4H), 6.97-7.12 (m, 1H), 6.61-6.83 (m, 2H), 4.58-4.78 (m, 2H), 3.71-3.79 (m, 1H), 2.64-3.23 (m, 6H), 1.93-2.05 (m, 3H), 1.34-1.87 (m, 11H), 1.19-1.24 (m, 1H). 13 C NMR (150 MHz, CD 3 OD) δ 7.57-7.73 (m, 4H), 7.23-7.44 (m, 4H), 6.97-7.12 (m, 1H), 6.61-6.83 (m, 2H), 4.58-4.78 (m, 2H), 3.71-3.79 (m, 1H), 2.64-3.23 (m, 6H), 1.93-2.05 (m, 3H), 1.34-1.87 (m, 11H), 1.19-1.24 (m, 1H) . OD)δ173.71,173.56,171.88,156.91,156.81,152.42,150.78,146.31,145.75,140.78,140.69,138.79,137.95,130.79,130.52,129.46,127.16,126.30,124.58-124.65(m),121.75,121.59 , 118.94, 118.82, 117.37, 117.07, 116.95, 116.78, 116.37, 81.79, 55.63, 50.08, 49.83, 44.67-44.93 (m), 43.78, 42.55, 42.45, 32.87, 32.63, 32.52, 31.46, 30.87, 27.20, 26.61, 26.39, 26.20.
实施例62 2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-1-吗啉丙-1-酮，化合物II-60的制备Example 62 Preparation of 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-1-morpholinopropan-1-one, Compound II-60
Figure PCTCN2023071067-appb-000112
Figure PCTCN2023071067-appb-000112
化合物II-2(200mg，0.42mmol)溶解于二氯甲烷(25mL)溶液中，分别加入吗啉(40mg，0.46mmol)、2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(239g，0.63mmol)和N，N-二异丙基乙 胺(108mg，0.84mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-6∶1))得到白色固体108mg，收率65％。Compound II-2 (200 mg, 0.42 mmol) was dissolved in dichloromethane (25 mL) solution, and morpholine (40 mg, 0.46 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (239 g, 0.63 mmol) and N,N-diisopropylethylamine (108 mg, 0.84 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-6:1) to give 108 mg of a white solid with a yield of 65%.
1H NMR(400MHz，CD 3OD)δ7.53-7.71(m，4H)，7.32-7.44(m，3H)，6.81-7.26(m，2H)，6.61-6.77(m，2H)，4.68-4.70(m，1H)，3.36-3.87(m，7H)，2.80-3.21(m，5H)，1.92-2.04(m，3H)，1.56-1.75(m，7H). 1 H NMR (400 MHz, CD 3 OD) δ 7.53-7.71 (m, 4H), 7.32-7.44 (m, 3H), 6.81-7.26 (m, 2H), 6.61-6.77 (m, 2H), 4.68-4.70 (m, 1H), 3.36-3.87 (m, 7H), 2.80-3.21 (m, 5H), 1.92-2.04 (m, 3H), 1.56-1.75 (m, 7H).
13C NMR(100MHz，CD 3OD)δ173.46，173.25，171.95，171.90，156.85，152.83，150.38，146.32，145.82，140.74，138.79，138.02，130.77，130.47，129.41，127.14，126.33，126.23，124.53-124.63(m)，121.59，121.31，118.93，118.76，117.12，116.94，116.68，116.36，81.72，67.35-67.73(m)，55.59，49.87，48.17，44.89，44.67，44.58，43.80，43.72，32.93，32.85，27.20，26.44，26.36，26.25. 13 C NMR (100 MHz, CD 3 OD) δ 173.46, 173.25, 171.95, 171.90, 156.85, 152.83, 150.38, 146.32, 145.82, 140.74, 138.79, 138.02, 130.77, 130.47, 129.41, 127.14, 126.33, 126.23, 124.53- 124.63(m), 121.59, 121.31, 118.93, 118.76, 117.12, 116.94, 116.68, 116.36, 81.72, 67.35-67.73 (m), 55.59, 49.87, 48.17, 44.89, 44.67, 44.58, 43.80, 43.72, 32.93, 32.85, 27.20, 26.44, 26.36, 26.25 .
实施例63 4-(2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酰胺)哌啶-1-氯化铵，化合物II-61的制备Example 63 Preparation of 4-(2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionamide)piperidin-1-ammonium chloride, Compound II-61
Figure PCTCN2023071067-appb-000113
Figure PCTCN2023071067-appb-000113
参照实施例25得到中间体2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-N-(哌啶-4-基)丙酰胺Referring to Example 25, the intermediate 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(piperidin-4-yl)propionamide was obtained.
将中间体2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-N-(哌啶-4-基)丙酰胺(240mg，0.43mmol)溶解于4M盐酸二氧六环溶液(15mL)，室温反应2h，蒸干反应液，得到白色固体72mg，收率57％。The intermediate 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(piperidin-4-yl)propanamide (240 mg, 0.43 mmol) was dissolved in 4M hydrochloric acid dioxane solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to obtain 72 mg of white solid with a yield of 57%.
1H NMR(400MHz，CD 3OD)δ7.56-7.73(m，4H)，7.24-7.44(m，4H)，7.01-7.14(m，1H)，6.72-6.89(m，2H)，4.66-4.74(m，1H)，4.01-4.04(m，1H)，3.65-3.79(m，1H)，3.36-3.39(m，2H)，2.77-3.23(m，5H)，1.80-2.06(m，8H)，1.40-1.68(m，6H). 13C NMR(100MHz，CD 3OD)δ176.77，176.65，171.96，171.91，156.34，156.18，152.82，150.34，145.84，145.40，140.75，138.75，138.02，130.50，130.36，129.42，127.13，126.68，126.16，124.55-124.65(m)，122.33，120.48，120.17，119.65，117.08，116.90，81.47，64.38，64.27，55.64，49.91，45.84，45.77，44.76，44.34，43.81，32.66，29.21，27.20，26.25，26.00，25.66，25.26. 1 H NMR (400 MHz, CD 3 OD) δ 7.56-7.73 (m, 4H), 7.24-7.44 (m, 4H), 7.01-7.14 (m, 1H), 6.72-6.89 (m, 2H), 4.66-4.74 (m, 1H), 4.01-4.04 (m, 1H), 3.65-3.79 (m, 1H), 3.36-3.39 (m, 2H), 2.77-3.23 (m, 5H), 1.80-2.06 (m, 8H), 1.40-1.68 (m, 6H). 13 C NMR (100 MHz, CD 3 OD) δ 7.56-7.73 (m, 4H), 7.24-7.44 (m, 4H), 7.01-7.14 (m, 1H), 6.72-6.89 (m, 2H), 4.66-4.74 (m, 1H), 4.01-4.04 (m, 1H), 3.65-3.79 (m, 1H), 3.36-3.39 (m, 2H), 2.77-3.23 (m, 5H), 1.80-2.06 (m, 8H), 1.40-1.68 (m, 6H ) . OD)δ176.77, 176.65, 171.96, 171.91, 156.34, 156.18, 152.82, 150.34, 145.84, 145.40, 140.75, 138.75, 138.02, 130.50, 130.36, 129.42, 127.13, 126.68, 126.16, 124.55-124.6 5(m), 122.33, 120.48, 120.17, 119.65, 117.08, 116.90, 81.47, 64.38, 64.27, 55.64, 49.91, 45.84, 45.77, 44.76, 44.34, 43.81, 32.66, 29.21, 27.20, 26.25, 26.00, 25.66, 25.26.
实施例64 2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-N-((4-羟基苯基)磺酰基)-2-甲基丙酰胺，化合物II-62的制备Example 64 Preparation of 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-N-((4-hydroxyphenyl)sulfonyl)-2-methylpropanamide, Compound II-62
Figure PCTCN2023071067-appb-000114
Figure PCTCN2023071067-appb-000114
将II-2(200mg，0.42mmol)和化合物34衍生物(64mg，0.37mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(121mg，0.63mmol)和4-二甲氨基吡啶(103mg，0.84mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体80mg，收率32％。II-2 (200 mg, 0.42 mmol) and compound 34 derivative (64 mg, 0.37 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 80 mg of a white solid, with a yield of 32%.
1H NMR(400MHz，CD 3OD)δ7.88-7.96(m，2H)，7.62-7.70(m，2H)，7.26-7.58(m，6H)，7.00-7.20(m，3H)，6.74-6.92(m，2H)，4.65-4.68(m，1H)，3.69-3.75(m，1H)，3.10-3.15(m，1H)，2.75-2.85(m，2H)，1.88-2.00(m，2H)，1.57-1.75(m，8H). 13C NMR(100MHz，CD 3OD)δ173.76，173.57，171.98，171.92，157.01，154.59，152.80，150.34，146.17，145.67，142.88，140.72，138.76，137.98，137.84，130.66，130.45，129.41，128.97，128.92，127.14，127.00，126.31，126.42，124.53-124.63(m)，123.11，123.03，122.43，122.18，119.25，119.17，118.90，118.72，118.52，118.19，117.09，116.91，80.53，55.63，49.83，44.73，43.71，32.70，27.15，26.19，25.94，25.82，25.68. 1 H NMR (400 MHz, CD 3 OD) δ 7.88-7.96 (m, 2H), 7.62-7.70 (m, 2H), 7.26-7.58 (m, 6H), 7.00-7.20 (m, 3H), 6.74-6.92 (m, 2H), 4.65-4.68 (m, 1H), 3.69-3.75 (m, 1H), 3.10-3.15 (m, 1H), 2.75-2.85 (m, 2H), 1.88-2.00 (m, 2H), 1.57-1.75 (m, 8H). 13 C NMR (100 MHz, CD 3 OD) δ 7.88-7.96 (m, 2H), 7.62-7.70 (m, 2H), 7.26-7.58 (m, 6H), 7.00-7.20 (m, 3H), 6.74-6.92 (m, 2H), 4.65-4.68 (m, 1H), 3.69-3.75 (m, 1H), 3.10-3.15 (m, 1H), 2.75-2.85 (m, 2H), 1.88-2.00 (m, 2H), 1.57-1.75 (m, 8H ) . OD)δ173.76,173.57,171.98,171.92,157.01,154.59,152.80,150.34,146.17,145.67,142.88,140.72,138.76,137.98,137.84,130.66,130.45,129.41,128.97,128.92,127.14,127.00,126.31,126. 42, 124.53-124.63 (m), 123.11, 123.03, 122.43, 122.18, 119.25, 119.17, 118.90, 118.72, 118.52, 118.19, 117.09, 116.91, 80.53, 55.63, 49.83, 44.73, 43.71, 32.70, 27.15, 26.19, 25.94, 25.82, 25.68.
实施例65 2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-1-(4-羟基哌啶-1-基)-2-甲基丙-1-酮，化合物II-63的制备Example 65 Preparation of 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-1-(4-hydroxypiperidin-1-yl)-2-methylpropan-1-one, Compound II-63
Figure PCTCN2023071067-appb-000115
Figure PCTCN2023071067-appb-000115
将II-57(88mg，0.15mmol)的化合物溶解于甲醇(10mL)中，缓慢加入硼氢化钠(11mg，0.30mmol)，室温反应过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝5∶1-3∶1)，得白色固体55mg，收率75％。The compound II-57 (88 mg, 0.15 mmol) was dissolved in methanol (10 mL), and sodium borohydride (11 mg, 0.30 mmol) was slowly added. The reaction was allowed to react at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to obtain 55 mg of a white solid, with a yield of 75%.
1H NMR(400MHz，CD 3OD)δ7.66-7.72(m，2H)，7.54-7.57(m，2H)，7.31-7.44(m，3H)，7.08-7.24(m，1H)，6.81-6.95(m，1H)，6.61-6.74(m，2H)，4.67-4.70(m，1H)，3.34-4.31(m，5H)，2.78-3.18(m，4H)，1.92-2.05(m，1H)，1.39-1.94(m，13H). 13C NMR(100MHz，CD 3OD)δ173.40，173.22，171.94，157.09，152.84，150.38，146.18，145.63，140.76，138.82，138.05，137.94，130.68，130.47，129.42，127.14，126.31，124.54，124.64，124.54-124.64(m)，121.55，121.31，118.93，118.76，117.13，116.95，116.34-116.79(m)，81.72，67.46，55.62，49.88，44.86，44.22，43.80，41.92，35.28，35.28，35.18，32.84，27.22，26.56，26.45，26.26. 1 H NMR (400 MHz, CD 3 OD) δ 7.66-7.72 (m, 2H), 7.54-7.57 (m, 2H), 7.31-7.44 (m, 3H), 7.08-7.24 (m, 1H), 6.81-6.95 (m, 1H), 6.61-6.74 (m, 2H), 4.67-4.70 (m, 1H), 3.34-4.31 (m, 5H), 2.78-3.18 (m, 4H), 1.92-2.05 (m, 1H), 1.39-1.94 (m, 13H). 13 C NMR (100 MHz, CD 3 OD) δ 7.66-7.72 (m, 2H), 7.54-7.57 (m, 2H), 7.31-7.44 (m, 3H), 7.08-7.24 (m, 1H), 6.81-6.95 (m, 1H), 6.61-6.74 (m, 2H), 4.67-4.70 (m, 1H), 3.34-4.31 (m, 5H), 2.78-3.18 (m, 4H), 1.92-2.05 (m, 1H), 1.39-1.94 (m, 13H ) . OD)δ173.40,173.22,171.94,157.09,152.84,150.38,146.18,145.63,140.76,138.82,138.05,137.94,130.68,130.47,129.42,127.14,126.31,124.54,124.64,124.54-124.64 (m), 121.55, 121.31, 118.93, 118.76, 117.13, 116.95, 116.34-116.79 (m), 81.72, 67.46, 55.62, 49.88, 44.86, 44.22, 43.80, 41.92, 35.28, 35.28, 35.18, 32.84, 27.22, 26.56, 26.45, 26.26.
实施例66 (S)-2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基(苯氧基)-2-甲基-N-((4-(三氟甲基)苯基)磺酰)丙酰胺，化合物II-64的制备Example 66 Preparation of (S)-2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)propionamide, Compound II-64
Figure PCTCN2023071067-appb-000116
Figure PCTCN2023071067-appb-000116
将(S)-II-13(219mg，0.42mmol)和化合物34的衍生物(85mg，0.38mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(121mg，0.63mmol)和4-二甲氨基吡啶(103mg，0.84mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体150mg，收率65％。(S)-II-13 (219 mg, 0.42 mmol) and a derivative of compound 34 (85 mg, 0.38 mmol) were dissolved in dichloromethane (15 mL) solution, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added respectively. The mixture was stirred at room temperature overnight, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 150 mg of a white solid, with a yield of 65%.
1H NMR(400MHz，CD 3OD)δ8.12(d，2H，J＝8.0Hz)，7.92(s，1H)，7.73-7.85(m，3H)，7.60-7.70(m，2H)，7.53(d，2H，J＝8.0Hz)，7.29(d，2H，J＝8.0Hz)，6.97(t，1H，J＝7.6Hz)，6.80(d，1H，J＝7.6Hz)，6.68(s，1H)，6.46(d，1H，J＝7.6Hz)，3.75-3.80(m，2H)，2.86-2.93(m，1H)，2.66-2.72(m，1H)，2.30-2.39(m，2H)，1.77-1.80(m，2H)，1.60-1.66(m，1H)，1.33-1.38(m，7H)，1.22(d，6H，J＝6.8Hz). 13C NMR(100MHz，CD 3OD)δ175.68，156.13，150.40，145.70，144.33，143.56，138.22，137.88，135.85，132.29，130.97，130.40，130.16，128.24，128.08，127.12，127.08，126.48，126.12，123.41，122.66，119.23，118.25，81.43，53.55，47.56，43.29，35.01，31.54，26.00，24.72，24.70，24.34. 1 H NMR (400 MHz, CD 3 OD) δ 8.12 (d, 2H, J = 8.0 Hz), 7.92 (s, 1H), 7.73-7.85 (m, 3H), 7.60-7.70 (m, 2H), 7.53 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 6.97 (t, 1H, J = 7.6 Hz), 6.80 (d, 1H, J = 7.6 Hz), 6.68 (s , 1H ), 6.46 (d, 1H, J = 7.6 Hz), 3.75-3.80 (m, 2H), 2.86-2.93 (m, 1H), 2.66-2.72 (m, 1H), 2.30-2.39 (m, 2H), 1.77-1.80 (m, 2H), 1.60-1.66 (m, 1H), 1.33-1.38 (m, 7H), 1.22 (d, 6H, J = 6.8 Hz). 13 C NMR (100 MHz, CD 3 OD) δ 175.68, 156.13, 150.40, 145.70, 144.33, 143.56, 138.22, 137.88, 135.85, 132.29, 130.97, 130.40, 130.16, 128.24, 128.08, 127.12, 127.08, 126.48, 126.12, 123.41, 122.66, 119.23, 118.25, 81.43, 53.55, 47.56, 43.29, 35.01, 31.54, 26.00, 24.72, 24.70, 24.34.
实施例67 (1R，4R)-5-(2-(3-(3-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)-2，5-二氮杂二环[2.2.1]庚-2-氯化铵，化合物II-65的制备Example 67 Preparation of (1R, 4R)-5-(2-(3-(3', 4'-difluoro-[1, 1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)-2,5-diazabicyclo[2.2.1]heptane-2-ammonium chloride, compound II-65
Figure PCTCN2023071067-appb-000117
Figure PCTCN2023071067-appb-000117
参照实施例25得到中间体1-((1R，4R)-2，5-二氮杂二环[2.2.1]庚烷-2-基)-2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙烷-1-酮Referring to Example 25, the intermediate 1-((1R, 4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-(3-(1-(3′, 4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropane-1-one was obtained.
将中间体1-((1R，4R)-2，5-二氮杂二环[2.2.1]庚烷-2-基)-2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙烷-1-酮(200mg，0.36mmol)溶解于4M盐酸二氧六环溶液(15mL)，室温反应2h，蒸干反应液，得到白色固体84mg，收率55％。The intermediate 1-((1R, 4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-(3-(1-(3′, 4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropane-1-one (200 mg, 0.36 mmol) was dissolved in 4M hydrochloric acid dioxane solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to obtain 84 mg of a white solid with a yield of 55%.
1H NMR(600MHz，CD 3OD)δ7.66-7.73(m，2H)，7.57-7.60(m，2H)，7.43-7.46(m，2H)，7.34-7.38(m，1H)，7.15-7.28(m，1H)，6.64-6.86(m，3H)，5.33-5.44(m，1H)，4.60-4.70(m，1H)，4.35-4.43(m，1H)，3.50-3.77(m，3H)，3.19-3.23(m，2H)，2.69-2.93(m，3H)，1.78-2.05(m，5H)，1.56-1.64(m，6H). 13C NMR(150 MHz，CD 3OD)δ173.37，172.03，156.62，152.60，152.23，150.97，150.59，146.70，140.79，138.80，137.94，130.96，130.53，129.46，127.11，126.27，124.60，122.04，118.94，118.92，117.54，117.07，116.95，116.52，81.62，81.35，59.97，58.29，57.87，56.78，55.57，52.74，50.88，49.84，44.79，43.66，37.43，35.03，32.64，27.18，26.49，26.22，25.33，25.15，24.03. 1 H NMR (600 MHz, CD 3 OD) δ 7.66-7.73 (m, 2H), 7.57-7.60 (m, 2H), 7.43-7.46 (m, 2H), 7.34-7.38 (m, 1H), 7.15-7.28 (m, 1H), 6.64-6.86 (m, 3H), 5.33-5.44 (m, 1H), 4.60-4.70 (m, 1H), 4.35-4.43 (m, 1H), 3.50-3.77 (m, 3H), 3.19-3.23 (m, 2H), 2.69-2.93 (m, 3H), 1.78-2.05 (m, 5H), 1.56-1.64 (m, 6H). 13 C NMR (150 MHz, CD 3 OD) δ 173.37, 172.03, 156.62, 152.60, 152.23, 150.97, 150.59, 146.70, 140.79, 138.80, 137.94, 130.96, 130.53, 129.46, 127.11, 126.27, 124.60, 122.04, 118.94, 118.92, 117.5 4, 117.07, 116.95, 116.52, 81.62, 81.35, 59.97, 58.29, 57.87, 56.78, 55.57, 52.74, 50.88, 49.84, 44.79, 43.66, 37.43, 35.03, 32.64, 27.18, 26.49, 26.22, 25.33, 25.15, 24.03.
实施例68 (1S，4S)-5-(2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)-2，5-二氮杂二环[2.2.1]庚烷-2-氯化铵，化合物II-66的制备Example 68 Preparation of (1S, 4S)-5-(2-(3-(1-(3′, 4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)-2,5-diazabicyclo[2.2.1]heptane-2-ammonium chloride, compound II-66
Figure PCTCN2023071067-appb-000118
Figure PCTCN2023071067-appb-000118
参照实施例25得到中间体1-((1S，4S)-2，5-二氮杂二环[2.2.1]庚烷-2-基)-2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙-1-酮Referring to Example 25, the intermediate 1-((1S, 4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-(3-(1-(3′, 4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropan-1-one was obtained.
将中间体1-((1S，4S)-2，5-二氮杂二环[2.2.1]庚烷-2-基)-2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙-1-酮(200mg，0.36mmol)溶解于4M盐酸二氧六环溶液(15mL)，室温反应2h，蒸干反应液，得到白色固体92mg，收率56％。The intermediate 1-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropan-1-one (200 mg, 0.36 mmol) was dissolved in 4M hydrochloric acid and dioxane solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to obtain 92 mg of a white solid with a yield of 56%.
1H NMR(600MHz，CD 3OD)δ7.66-7.72(m，2H)，7.44-7.57(m，4H)，7.35-7.38(m，1H)，7.15-7.28(m，1H)，6.64-6.85(m，3H)，5.33-5.44(m，1H)，4.65-4.68(m，1H)，4.34-4.43(m，1H)，3.41-3.73(m，4H)，2.71-3.21(m，5H)，1.80-2.05(m，5H)，1.53-1.64(m，6H). 13C NMR(150MHz，CD 3OD)δ173.38，172.05，156.62，152.58，152.29，150.98，150.64，140.81，138.81，137.94，130.97，130.53，129.47，127.11，126.27，124.62，122.02，118.94，118.82，117.53，117.017，116.95，116.57，81.63，81.36，59.96，58.30，57.86，56.79，55.58，52.73，50.87，49.77，44.81，43.77，37.41，34.95，32.64，27.18，26.38，26.22，25.33，25.13，23.98. 1 H NMR(600MHz，CD 3 OD)δ7.66-7.72(m，2H)，7.44-7.57(m，4H)，7.35-7.38(m，1H)，7.15-7.28(m，1H)，6.64-6.85(m，3H)，5.33-5.44(m，1H)，4.65-4.68(m，1H)，4.34-4.43(m，1H)，3.41-3.73(m，4H)，2.71-3.21(m，5H)，1.80-2.05(m，5H)，1.53-1.64(m，6H). 13 C NMR(150MHz，CD 3 OD)δ173.38,172.05,156.62,152.58,152.29,150.98,150.64,140.81,138.81,137.94,130.97,130.53,129.47,127.11,126.27,124.62,122.02,118.94,118.82,117.53,11 7.017, 116.95, 116.57, 81.63, 81.36, 59.96, 58.30, 57.86, 56.79, 55.58, 52.73, 50.87, 49.77, 44.81, 43.77, 37.41, 34.95, 32.64, 27.18, 26.38, 26.22, 25.33, 25.13, 23.98.
实施例69 (R)-2-(3-(1-((4′-异丙基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基(苯氧基)-2-甲基-N-((4-(三氟甲基)苯基)磺酰)丙酰胺，化合物II-67的制备Example 69 Preparation of (R)-2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)propionamide, Compound II-67
Figure PCTCN2023071067-appb-000119
Figure PCTCN2023071067-appb-000119
将(R)-II-13(270mg，0.51mmol)和化合物34的衍生物(105mg，0.47mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(146mg，0.76mmol)和4-二甲氨基吡啶(124mg，1.0mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体120mg，收率58％。(R)-II-13 (270 mg, 0.51 mmol) and a derivative of compound 34 (105 mg, 0.47 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (146 mg, 0.76 mmol) and 4-dimethylaminopyridine (124 mg, 1.0 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give 120 mg of a white solid, with a yield of 58%.
1H NMR(400MHz，CD 3OD)δ8.13(d，2H，J＝8.4Hz)，7.93(t，1H，J＝2.4Hz)，7.83-7.89(m，3H)，7.69-7.72(m，1H)，7.62-7.66(m，1H)，7.53-7.56(m，2H)，7.30(d，2H，J＝8.4Hz)，6.98(t，1H，J＝8.0Hz)，6.80(d，1H，J＝7.6Hz)，6.68(t，1H，J＝2.0Hz)，6.45-6.48(m，1H)，3.75-3.81(m，2H)，2.88-2.94(m，1H)，2.66-2.73(m，1H)，2.31-2.41(m，2H)，1.79-1.82(m，2H)，1.62-1.71(m，1H)，1.37-1.40(m，7H)，1.24(d，6H，J＝7.2Hz). 13C NMR(100MHz，CD 3OD)δ176.14，156.26，150.43，145.68，144.65，143.60，138.26，137.93，135.89，135.56，132.31，130.98，130.37，130.11，128.25，128.10，127.14，127.03，126.50，122.56，119.16，118.24，81.47，53.60，43.34，35.04，31.56，26.03，24.80，24.34. 1 H NMR (400 MHz, CD 3 OD) δ 8.13 (d, 2H, J = 8.4 Hz), 7.93 (t, 1H, J = 2.4 Hz), 7.83-7.89 (m, 3H), 7.69-7.72 (m , 1H), 7.62-7.66 (m, 1H), 7.53-7.56 (m, 2H), 7.30 (d, 2H, J = 8.4 Hz), 6.98 (t, 1H, J = 8.0 Hz), 6.80 (d, 1H, J = 7.6 Hz), 6 .68 (t, 1H, J = 2.0 Hz), 6.45-6.48 (m, 1H), 3.75-3.81 (m, 2H), 2.88-2.94 (m, 1H), 2.66-2.73 (m, 1H), 2.31 -2.41 (m, 2H), 1.79-1.82 (m, 2H), 1.62-1.71 (m, 1H), 1.37-1.40 (m, 7H), 1.24 (d, 6H, J = 7.2 Hz). 13 C NMR (100 MHz, CD 3 OD) δ 176.14, 156.26, 150.43, 145.68, 144.65, 143.60, 138.26, 137.93, 135.89, 135.56, 132.31, 130.98, 130.37, 130.11, 128.25, 128.10, 127.14, 127.03, 126.50, 122.56, 119.16, 118.24, 81.47, 53.60, 43.34, 35.04, 31.56, 26.03, 24.80, 24.34.
实施例70 2-(3-(1-(3′，4′-二氟-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-N-((4-甲氧基苯基)磺酰基)-2-甲基丙酰胺，化合物II-68的制备Example 70 Preparation of 2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-N-((4-methoxyphenyl)sulfonyl)-2-methylpropanamide, Compound II-68
Figure PCTCN2023071067-appb-000120
Figure PCTCN2023071067-appb-000120
将II-2(207mg，0.43mmol)和化合物34的衍生物(77mg，0.39mmol)溶解于二氯甲烷(15mL)溶液，分别加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(243mg，0.64mmol)和4-二甲氨基吡啶(111mg，0.86mmol)，室温搅拌过夜，使用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品，使用硅胶色谱柱纯化(石油醚/乙酸乙酯＝10∶1-5∶1)，得白色固体72mg，收率42％。II-2 (207 mg, 0.43 mmol) and a derivative of compound 34 (77 mg, 0.39 mmol) were dissolved in dichloromethane (15 mL) solution, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (243 mg, 0.64 mmol) and 4-dimethylaminopyridine (111 mg, 0.86 mmol) were added respectively, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain 72 mg of a white solid, with a yield of 42%.
1H NMR(400MHz，CD 3OD)δ7.88-7.96(m，2H)，7.51-7.71(m，4H)，7.28-7.48(m，3H)，6.45-7.10(m，6H)，4.62-4.85(m，1H)，3.85(s，3H)，3.65-3.77(m，1H)，3.04-3.16(m，1H)，2.78-2.88(m，1H)，2.61-2.68(m，1H)，1.68-1.95(m，4H)，1.31-1.43(m，6H). 13C NMR(100MHz，CD 3OD)δ176.05，171.90，165.07，156.34，152.92，152.68，150.21，145.94，145.26，140.74，138.76，137.94，132.36，131.61，130.46，129.39，127.19，126.99，126.34，124.53-124.63(m)，122.46，121.91，119.08，118.91，118.74，118.65，117.10，116.91，114.94，81.52，81.38，56.32，55.67，44.82，43.71，43.58，32.70，32.50，31.80，30.71，27.18，26.22，25.42，25.05，24.86，24.32. 1 H NMR(400MHz，CD 3 OD)δ7.88-7.96(m，2H)，7.51-7.71(m，4H)，7.28-7.48(m，3H)，6.45-7.10(m，6H)，4.62-4.85(m，1H)，3.85(s，3H)，3.65-3.77(m，1H)，3.04-3.16(m，1H)，2.78-2.88(m，1H)，2.61-2.68(m，1H)，1.68-1.95(m，4H)，1.31-1.43(m，6H). 13 C NMR(100MHz，CD 3 OD)δ176.05,171.90,165.07,156.34,152.92,152.68,150.21,145.94,145.26,140.74,138.76,137.94,132.36,131.61,130.46,129.39,127.19,126.99,126.34,124.53-124.63 (m),122.4 6, 121.91, 119.08, 118.91, 118.74, 118.65, 117.10, 116.91, 114.94, 81.52, 81.38, 56.32, 55.67, 44.82, 43.71, 43.58, 32.70, 32.50, 31.80, 30.71, 27.18, 26.22, 25.42, 25.05, 24.86, 24.32.
实施例71 β-catenin/BCL蛋白-蛋白亲和力实验Example 71 β-catenin/BCL protein-protein affinity experiment
荧光偏振实验在
Figure PCTCN2023071067-appb-000121
黑色96孔板中进行，并使用Biotek Synergy H1(BioTek)进行检测。在实验中，终浓度为1μM的β-catenin(1-781)被加入到缓冲液中(25mM HEPES pH 7.4，100mM NaCl，0.01％Triton-X100，0.1％BSA)，并加入浓度梯度稀释的抑制剂，摇床上室温孵育1h。后加入终浓度为20nM的BCL9-FAM(Tracer)，体系中DMSO的浓度为10％(V/V)，终体积为200ul，锡箔纸包裹，摇床上室温孵育1h。 Fluorescence polarization experiments
Figure PCTCN2023071067-appb-000121
The assay was performed in a black 96-well plate and detected using a Biotek Synergy H1 (BioTek). In the experiment, β-catenin (1-781) was added to a buffer (25mM HEPES pH 7.4, 100mM NaCl, 0.01% Triton-X100, 0.1% BSA) at a final concentration of 1μM, and inhibitors were added in gradient dilutions and incubated on a shaker at room temperature for 1h. BCL9-FAM (Tracer) was then added at a final concentration of 20nM, the concentration of DMSO in the system was 10% (V/V), the final volume was 200ul, wrapped in tin foil, and incubated on a shaker at room temperature for 1h.
最后使用485nM激发光和520发射光分别进行检测，抑制百分比的计算用下列等式：Finally, 485nM excitation light and 520 emission light were used for detection, and the inhibition percentage was calculated using the following equation:
％inhibition＝100[1-(mP-mP free)/(mP bound-mP free)] %inhibition＝100[1-(mP-mP free )/(mP bound -mP free )]
其中mP free是自由探针孔的信号(阳性对照)，mP bound是结合探针孔的信号(阴性对照)。 Where mP free is the signal of the free probe well (positive control), and mP bound is the signal of the bound probe well (negative control).
IC 50，即能够取代50％tracer所需的抑制剂浓度，使用GraphPad
Figure PCTCN2023071067-appb-000122
中的非线性拟合进行分析。结果如表1所示： IC 50 , the concentration of inhibitor required to displace 50% of the tracer, was calculated using GraphPad
Figure PCTCN2023071067-appb-000122
The nonlinear fitting in is analyzed. The results are shown in Table 1:
表1 β-catenin/BCL蛋白-蛋白亲和力实验结果Table 1 Results of β-catenin/BCL protein-protein affinity experiments
化合物Compound IC 50(μM) IC 50 (μM)
化合物cCompound c 3.133.13
II-2II-2 3.513.51
II-3II-3 4.844.84
II-4II-4 5.335.33
II-5II-5 5.235.23
II-6II-6 5.575.57
II-7II-7 8.48.4
II-8II-8 12.712.7
II-9II-9 3.093.09
II-10II-10 4.174.17
II-11II-11 4.634.63
II-13II-13 1.51.5
II-14II-14 3.33.3
II-15II-15 5.225.22
II-16II-16 2.562.56
II-17II-17 2.012.01
II-18II-18 4.114.11
II-19II-19 5.095.09
II-20II-20 3.453.45
II-21II-21 4.934.93
II-24II-24 4.174.17
II-25II-25 2.132.13
II-26II-26 5.35.3
II-27II-27 1.881.88
II-28II-28 0.760.76
II-29II-29 2.902.90
I-1I-1 6.686.68
I-2I-2 8.248.24
II-30II-30 3.193.19
II-31II-31 5.395.39
II-32II-32 3.853.85
II-33II-33 8.628.62
II-34II-34 5.675.67
II-35II-35 4.274.27
II-36II-36 3.143.14
II-37II-37 1.861.86
II-38II-38 3.763.76
II-39II-39 0.720.72
II-40II-40 2.472.47
II-41II-41 4.474.47
II-42II-42 0.940.94
II-43II-43 0.840.84
II-44II-44 1.051.05
II-45II-45 0.950.95
II-46II-46 1.271.27
II-47II-47 0.910.91
II-48II-48 1.001.00
II-49II-49 0.890.89
II-50II-50 0.790.79
II-51II-51 0.850.85
II-52II-52 1.181.18
II-53II-53 8.718.71
II-54II-54 7.297.29
II-55II-55 2.042.04
II-56II-56 2.132.13
II-57II-57 1.691.69
II-58II-58 0.560.56
II-59II-59 1.01.0
II-60II-60 1.831.83
II-61II-61 2.132.13
II-62II-62 ＞10>10
II-63II-63 0.820.82
II-64II-64 1.101.10
11-6511-65 2.132.13
11-6611-66 0.620.62
11-6711-67 0.650.65
11-6811-68 0.530.53
实验结果表明，本发明多数化合物对β-catenin/BCL9蛋白-蛋白显示较好靶向作用。与对照品化合物c(Anal Biochem,2015,469,43-53)相比，本发明所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂中的化合物II-9、II-13、II-16、II-17、II-25、II-27、II-28、II-29、II-37、II-39、II-40、II-42、II-43、II-44、II-45、II-46、II-47、II-48、II-49、II-50、II-51、II-52、II-55、II-56、II-57、II-58、II-59、II-60、II-61、II-63、II-64、II-65、II-66、II-67和II-68对β-catenin/BCL9蛋白-蛋白亲和活性更优。The experimental results show that most of the compounds of the present invention show good targeting effect on β-catenin/BCL9 protein-protein. Compared with the reference compound c (Anal Biochem, 2015, 469, 43-53), compounds II-9, II-13, II-16, II-17, II-25, II-27, II-28, II-29, II-37, II-39, II-40, II-42, II-43, II-44, II-45, II-46, II-47, II-48, II-49, II-50, II-51, II-52, II-55, II-56, II-57, II-58, II-59, II-60, II-61, II-63, II-64, II-65, II-66, II-67 and II-68 among the small molecule inhibitors of β-catenin/BCL9 protein-protein interaction described in the present invention have better affinity activity for β-catenin/BCL9 protein-protein.
实施例72抗肿瘤细胞增殖活性测试Example 72 Anti-tumor cell proliferation activity test
1)采用CCK-8法测定本发明部分化合物单浓度(10μM)条件下对人乳腺癌细胞MDA-MB-23l、人乳腺癌细胞MDA-MB-468、人结肠癌细胞HCT-116、人肝癌细胞株HepG2及MRC-5人正常胚肺成纤维细胞的抗增殖活性，选择化合物c为对照。具体结果如表2(单位为：Inh％in 10μM)：1) CCK-8 method was used to determine the anti-proliferative activity of some compounds of the present invention on human breast cancer cells MDA-MB-231, human breast cancer cells MDA-MB-468, human colon cancer cells HCT-116, human liver cancer cell line HepG2 and MRC-5 human normal embryonic lung fibroblasts under single concentration (10 μM) conditions, and compound c was selected as a control. The specific results are shown in Table 2 (unit: Inh% in 10 μM):
表2抗肿瘤细胞增殖活性Table 2 Anti-tumor cell proliferation activity
Figure PCTCN2023071067-appb-000123
Figure PCTCN2023071067-appb-000123
Figure PCTCN2023071067-appb-000124
Figure PCTCN2023071067-appb-000124
A：＞90％；B：80％～90％；C：70％～80％；D：50％～70％E：＜50％A: >90%; B: 80% to 90%; C: 70% to 80%; D: 50% to 70% E: <50%
从上表可见，阳性对照化合物c对细胞株基本无活性，提示其可能较难透过细胞膜。而本发明所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂对多种肿瘤细胞均显示体外抗肿瘤细胞增殖活性，其中对人乳腺癌细胞MDA-MB-468和人结肠癌细胞HCT-116抑制活性最优，提示本发明化合物可透过细胞膜作用相关靶点，且化合物对肿瘤细胞抑制存在一定选择性。As can be seen from the table above, the positive control compound c has little activity against the cell line, suggesting that it may be difficult to penetrate the cell membrane. The small molecule inhibitors interacting with the β-catenin/BCL9 protein of the present invention show in vitro anti-tumor cell proliferation activity against a variety of tumor cells, among which the inhibitory activity against human breast cancer cells MDA-MB-468 and human colon cancer cells HCT-116 is the best, suggesting that the compounds of the present invention can penetrate the cell membrane to act on related targets, and the compounds have a certain selectivity in inhibiting tumor cells.
同时，本发明化合物对MRC-5人正常胚肺成纤维细胞的抑制活性较弱，具有更低的毒副作用，揭示了本发明化合物在对于肿瘤细胞和正常细胞的抑制增殖方面具有更好的选择性，预示其作为抗肿瘤药物使用时，具有更低的毒副作用。At the same time, the compounds of the present invention have weaker inhibitory activity on MRC-5 human normal embryonic lung fibroblasts and have lower toxic side effects, revealing that the compounds of the present invention have better selectivity in inhibiting the proliferation of tumor cells and normal cells, indicating that when used as anti-tumor drugs, they have lower toxic side effects.
2)采用CCK-8法测定本发明部分化合物II-39单浓度(10μM)条件下对人结肠癌细胞HCT-116、人结肠癌细胞CT-26、人结肠癌细胞SW480、人肺癌细胞A549、人结肠腺癌细胞RKO及HEK293人正常细胞的抗增殖活性，选择化合物ICG-001为对照。具体结果如下表：2) CCK-8 method was used to determine the anti-proliferative activity of some compounds II-39 of the present invention at a single concentration (10 μM) on human colon cancer cells HCT-116, human colon cancer cells CT-26, human colon cancer cells SW480, human lung cancer cells A549, human colon adenocarcinoma cells RKO and HEK293 human normal cells, and compound ICG-001 was selected as a control. The specific results are shown in the following table:
Figure PCTCN2023071067-appb-000125
Figure PCTCN2023071067-appb-000125
从上表可知，化合物II-39表现出较好的抗结肠癌活性，尤其是针对CT-26细胞，显著的优于阳性对照药ICG-001，且II-39对正常细胞没有影响，表现出优异的细胞选择性。As can be seen from the above table, compound II-39 exhibits good anti-colon cancer activity, especially against CT-26 cells, which is significantly better than the positive control drug ICG-001. II-39 has no effect on normal cells, showing excellent cell selectivity.
实施例73 hERG钾通道影响实验Example 73 hERG potassium channel effect experiment
将稳转的HEK293细胞接种于玻片上，细胞密度低于50％，培养过夜。将实验用细胞转移到一个嵌于倒置显微镜平台的细胞浴槽中，灌流细胞外液，灌流速度为2.7ml/分钟。稳定5分钟细胞沉淀后即可开始实验。采用HEKA EPC-10膜片钳放大器和PATCHMASTER采集系统记录膜电流(HEKA Instruments Inc.，D-67466 Lambrecht，Pfalz，Germany)。所有实验均在室温(22-24℃)下完成。实验中使用P-97微电极拉制仪(Sutter Instrument Company，One Digital Drive，Novato，CA 94949)拉直电极(BF150-110-10)。电极内径为1-1.5mm，充满内液后的入水电阻为2-4MΩ。Stably transfected HEK293 cells were inoculated on glass slides with a cell density of less than 50% and cultured overnight. The experimental cells were transferred to a cell bath embedded in an inverted microscope platform and perfused with extracellular solution at a rate of 2.7 ml/min. The experiment can be started after the cells have settled for 5 minutes. The membrane current was recorded using a HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were performed at room temperature (22-24°C). The P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949) was used to straighten the electrode (BF150-110-10). The inner diameter of the electrode was 1-1.5 mm, and the water resistance after filling with internal solution was 2-4 MΩ.
hERG钾通道的电生理刺激方案，是首先将膜电压钳制在-80mV，给予细胞持续2s，+20mV电压刺激，激活hERG钾通道，再复极化至-50mV，持续5s，产生外向尾电流，刺激频率每15s一次。电流值为尾电流的峰值。The electrophysiological stimulation scheme for hERG potassium channels is to first clamp the membrane voltage at -80mV, give the cell a voltage stimulus of +20mV for 2s, activate the hERG potassium channels, and then repolarize to -50mV for 5s to generate an outward tail current. The stimulation frequency is once every 15s. The current value is the peak value of the tail current.
实验中采用全细胞记录模式记录通道电流。首先灌流细胞外液(大约每分钟2毫升)并持续记录，并等待电流稳定(5分钟内电流衰减(Run-Down)小于5％)，此时尾电流峰值即为对照电流值。接着 灌流含表3中待测药物的细胞外液并持续记录直到药物对hERG电流的抑制作用到达稳定状态，此时尾电流峰值即为加药后电流值。稳定状态的标准以最近的连续3个电流记录线是否重合来判断。达到稳定态势以后如果以细胞外液灌流冲洗后hERG电流回复或接近加药物之前的大小，则可以继续灌流测试其它浓度或药物。30μM Quinidine(奎尼丁)被用于实验中作为阳性对照以保证所使用的细胞反应正常，本研究通过测量对照组与药物处理组的电流最大值，计算处理组最大电流值所占对照组最大电流值的比率，评估待测化合物在测试浓度下对hERG钾离子通道的作用效果(Mean±SE)。实验数据使用PATCHMASTER V2X60(HEKA Instruments Inc.，D-67466 Lambrecht，Pfalz，Germany)采集，并采用Origin 8.5(OriginLab Corporation，Northampton，MA)软件以及Microsoft Excel进行分析和统计。The whole-cell recording mode was used to record the channel current in the experiment. First, the extracellular fluid (about 2 ml per minute) was perfused and recorded continuously, and the current was allowed to stabilize (the current decay (Run-Down) was less than 5% within 5 minutes). At this time, the peak value of the tail current was the control current value. Then, the extracellular fluid containing the drug to be tested in Table 3 was perfused and recorded continuously until the inhibitory effect of the drug on the hERG current reached a stable state. At this time, the peak value of the tail current was the current value after drug addition. The standard of the stable state is judged by whether the three most recent consecutive current recording lines overlap. After reaching a stable state, if the hERG current recovers or approaches the size before the addition of the drug after perfusion with extracellular fluid, other concentrations or drugs can be perfused and tested. 30μM Quinidine was used as a positive control in the experiment to ensure that the cells used responded normally. This study measured the maximum current of the control group and the drug-treated group, calculated the ratio of the maximum current value of the treatment group to the maximum current value of the control group, and evaluated the effect of the test compound on the hERG potassium channel at the test concentration (Mean±SE). The experimental data were collected using PATCHMASTER V2X60 (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany) and analyzed and statistically analyzed using Origin 8.5 (OriginLab Corporation, Northampton, MA) software and Microsoft Excel.
选择本发明部分化合物进行测试，结果如表3所示：Some compounds of the present invention were selected for testing, and the results are shown in Table 3:
表3各化合物对钾离子通道的活性影响Table 3 Effects of various compounds on the activity of potassium ion channels
化合物Compound hERG IC 50(μM) hERG IC 50 (μM)
II-2II-2 ＞10>10
II-13II-13 ＞10>10
II-14II-14 ＞10>10
II-25II-25 ＞10>10
II-27II-27 ＞10>10
II-28II-28 ＞10>10
II-39II-39 ＞10>10
实验结果显示，化合物II-2，II-13，II-14，II-25，II-27和II-28对hERG钾离子通道的抑制活性IC 50均大于10μM，提示本发明所述与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂潜在的心脏毒性较低。 The experimental results show that the inhibitory activity IC50 of compounds II-2, II-13, II-14, II-25, II-27 and II-28 on hERG potassium ion channels is greater than 10 μM, indicating that the small molecule inhibitors of the present invention that interact with β-catenin/BCL9 protein have low potential cardiac toxicity.
实施例75肝微粒体代谢稳定性Example 75 Metabolic stability of liver microsomes
以DMSO为溶剂制备浓度为10mM的表4和表5中的供试品和阳性对照品储备溶液。用70％乙腈将储备液稀释浓度至0.25mM。制备NADPH(还原型辅酶II)溶液，由6.5mM的NADP、16.5mm的葡萄糖-6-磷酸、3U/mL葡萄糖-6-磷酸脱氢酶组成。淬灭剂由乙腈、甲苯丁酰胺和丙醇组成(作为内标)。缓冲液为100mM磷酸钾缓冲液，内含3.3mM MgCl 2。将含0.5mg/mL肝微粒体蛋白和1μM供试品/阳性对照品的混合物置于缓冲液中孵育混匀。将每种孵育混合物的80μL等分试样加到400μL淬灭试剂中以沉淀蛋白质来制备初始样品，涡旋样品后加入20μL NADPH溶液的等分试样。将80μL NADPH溶液加至320μL的培养混合物中引发反应。将混合物在37℃水浴中温和摇动孵育。分别在0，10，30，90min时，取100μL混合物移至含400μL淬灭剂的96孔板中，离心(4000转，15min)后取80μL上清液加入预先放有160μL超纯水的96孔板中，用LC-MS/MS分析。 Prepare 10 mM stock solutions of the test articles and positive controls in Tables 4 and 5 using DMSO as solvent. Dilute the stock solutions to a concentration of 0.25 mM using 70% acetonitrile. Prepare NADPH (reduced coenzyme II) solution consisting of 6.5 mM NADP, 16.5 mM glucose-6-phosphate, and 3 U/mL glucose-6-phosphate dehydrogenase. Quencher consists of acetonitrile, toluene butanamide, and propanol (as internal standard). The buffer is 100 mM potassium phosphate buffer containing 3.3 mM MgCl 2. Incubate a mixture containing 0.5 mg/mL liver microsomal protein and 1 μM test article/positive control in the buffer. Prepare initial samples by adding 80 μL aliquots of each incubation mixture to 400 μL quenching reagent to precipitate proteins, and add 20 μL aliquots of NADPH solution after vortexing the samples. 80 μL of NADPH solution was added to 320 μL of the culture mixture to initiate the reaction. The mixture was gently shaken and incubated in a 37°C water bath. At 0, 10, 30, and 90 min, 100 μL of the mixture was transferred to a 96-well plate containing 400 μL of quencher, centrifuged (4000 rpm, 15 min), and 80 μL of the supernatant was added to a 96-well plate pre-filled with 160 μL of ultrapure water for analysis by LC-MS/MS.
根据以下公式计算T 1/2和CL int，其中斜率用残留化合物百分率和时间的自然对数测量，V/M等于1/蛋白质浓度。 T1 /2 and CLint were calculated according to the following formulas, where the slope is measured as the percent compound remaining and the natural logarithm of time, and V/M equals 1/protein concentration.
Figure PCTCN2023071067-appb-000126
Figure PCTCN2023071067-appb-000126
Figure PCTCN2023071067-appb-000127
Figure PCTCN2023071067-appb-000127
表4肝微粒体代谢的稳定性Table 4 Stability of liver microsomal metabolism
Figure PCTCN2023071067-appb-000128
Figure PCTCN2023071067-appb-000128
实验结果显示，化合物II-13、II-27和II-28肝微粒体代谢稳定。The experimental results showed that compounds II-13, II-27 and II-28 were stably metabolized in liver microsomes.
表5肝微粒体代谢的稳定性Table 5 Stability of liver microsome metabolism
Figure PCTCN2023071067-appb-000129
Figure PCTCN2023071067-appb-000129
化合物II-39肝微粒体代谢稳定Compound II-39 is stable in liver microsome metabolism
实施例76小鼠体内抗肿瘤实验Example 76 In vivo anti-tumor experiment in mice
1)体内实验一：化合物II-25和II-27体内抑瘤试验1) In vivo experiment 1: In vivo tumor inhibition test of compounds II-25 and II-27
动物实验操作步骤如下：The animal experiment operation steps are as follows:
1.培养CT26结肠癌细胞，待其达到对数期时，将其消化后800rpm离心5min，PBS重悬，细胞浓度为5×10 6cells/ml，并尽快接种于BALB/c小鼠右腹股沟皮下，每只小鼠注射100ul体积的细胞悬液。操作期间可将细胞悬液放置冰水浴中。 1. Cultivate CT26 colon cancer cells. When they reach the logarithmic phase, digest them and centrifuge them at 800rpm for 5 minutes. Resuspend them in PBS to a cell concentration of 5×10 6 cells/ml. Inoculate them subcutaneously in the right groin of BALB/c mice as soon as possible. Each mouse is injected with 100ul of cell suspension. The cell suspension can be placed in an ice water bath during the operation.
2.待肿瘤体积生长到30-50mm 3后，根据肿瘤体积将小鼠随机分组，开始记录肿瘤生长曲线。阳性对照化合物37(Journal of Medicinal Chemistry，2021，64，16，12109-12131)给药剂量为30mg/kg，每天给药一次；测试化合物II-25和II-27的给药剂量为30mg/kg，每天给药一次。每天测量肿瘤体积。肿瘤体积公式：V＝L*W*W*1/2。待肿瘤体积达到约1200mm 3后终止实验。 2. After the tumor volume grows to 30-50 mm 3 , the mice are randomly grouped according to the tumor volume, and the tumor growth curve is recorded. The positive control compound 37 (Journal of Medicinal Chemistry, 2021, 64, 16, 12109-12131) is administered at a dose of 30 mg/kg, once a day; the test compounds II-25 and II-27 are administered at a dose of 30 mg/kg, once a day. The tumor volume is measured every day. Tumor volume formula: V = L*W*W*1/2. The experiment is terminated when the tumor volume reaches approximately 1200 mm 3 .
实验结果如图1所示，采用结肠癌小鼠模型进行化合物体内药效测试，试验结果显示本发明的化合物II-25和II-27在给药5天后，可显著抑制小鼠体内肿瘤的生长，且优于阳性对照化合物37。在实验期间，化合物II-25和II-27组动物耐受，安全性良好。The experimental results are shown in Figure 1. The compound in vivo efficacy test was conducted using a colon cancer mouse model. The test results showed that compounds II-25 and II-27 of the present invention can significantly inhibit the growth of tumors in mice after 5 days of administration, and are superior to the positive control compound 37. During the experiment, the animals in the compound II-25 and II-27 groups were well tolerated and had good safety.
2)体内实验二：化合物II-39体内抑瘤试验2) In vivo experiment 2: In vivo tumor inhibition test of compound II-39
动物实验操作步骤如下：The animal experiment operation steps are as follows:
1.培养CT26结肠癌细胞，待其达到对数期时，将其消化后800rpm离心5min，PBS重悬，细胞浓度为5×10 6cells/ml，并尽快接种于BALB/c小鼠右腹股沟皮下，每只小鼠注射100ul体积的细胞悬液。操作期间可将细胞悬液放置冰水浴中。 1. Cultivate CT26 colon cancer cells. When they reach the logarithmic phase, digest them and centrifuge them at 800rpm for 5 minutes. Resuspend them in PBS to a cell concentration of 5×10 6 cells/ml. Inoculate them subcutaneously in the right groin of BALB/c mice as soon as possible. Each mouse is injected with 100ul of cell suspension. The cell suspension can be placed in an ice water bath during the operation.
2.待肿瘤体积生长到30-50mm 3后，根据肿瘤体积将小鼠随机分组，开始记录肿瘤生长曲线。PD-1抗体(Bio X Cell，BE0146-25MG，InVivoMAb anti-mouse PD-1，clone RMP1-14)给药剂量为10mg/kg，腹腔给药，一周给药两次；测试化合物II-39腹腔给药剂量为30mg/kg，每天给药一次。每天测量肿瘤体积。肿瘤体积公式：V＝L*W*W*1/2。待肿瘤体积达到约1200mm 3后终止实验。 2. After the tumor volume grows to 30-50 mm 3 , the mice are randomly divided into groups according to the tumor volume, and the tumor growth curve is recorded. The PD-1 antibody (Bio X Cell, BE0146-25MG, InVivoMAb anti-mouse PD-1, clone RMP1-14) is administered at a dose of 10 mg/kg, intraperitoneally, twice a week; the test compound II-39 is administered intraperitoneally at a dose of 30 mg/kg, once a day. The tumor volume is measured every day. Tumor volume formula: V = L*W*W*1/2. The experiment is terminated when the tumor volume reaches about 1200 mm 3 .
实验结果如图2和图3所示，体内实验结果表明，化合物II-39在30mg/kg的给药剂量下，可以很好的抑制结肠癌的生长，且与PD-1抗体联用后，肿瘤得到进一步的抑制，TGI＝1-(治疗组肿瘤体积/对照组肿瘤体积)×100％，达到81.1％。给药期间，化合物II-39给药组动物耐受，安全性良好，未观察到小鼠体重有明显减轻。The experimental results are shown in Figures 2 and 3. The in vivo experimental results show that compound II-39 can effectively inhibit the growth of colon cancer at a dose of 30 mg/kg, and after combined with PD-1 antibody, the tumor is further inhibited, TGI = 1-(tumor volume of the treatment group/tumor volume of the control group) × 100%, reaching 81.1%. During the administration period, the animals in the compound II-39 administration group were well tolerated and safe, and no significant weight loss of mice was observed.
实施例77药物组合物1Example 77 Pharmaceutical composition 1
将实施例25制备的化合物II-25与填充剂、崩解剂、润滑剂混合、制粒、压片，得到以化合物II-25为活性成分的药物组合物1。The compound II-25 prepared in Example 25 was mixed with a filler, a disintegrant, and a lubricant, granulated, and tableted to obtain a pharmaceutical composition 1 containing the compound II-25 as an active ingredient.
实施例78药物组合物2Example 78 Pharmaceutical composition 2
将实施例27制备的化合物II-27与溶剂、稳定剂混合、过滤、包装，得到以化合物II-27为活性成分的药物组合物2。The compound II-27 prepared in Example 27 is mixed with a solvent and a stabilizer, filtered, and packaged to obtain a pharmaceutical composition 2 containing the compound II-27 as an active ingredient.
实施例79药物组合物3Example 79 Pharmaceutical Composition 3
将实施例41制备的化合物II-39与填充剂、崩解剂、润滑剂混合、制粒、压片，得到以化合物II-39为活性成分的药物组合物3。The compound II-39 prepared in Example 41 was mixed with a filler, a disintegrant, and a lubricant, granulated, and tableted to obtain a pharmaceutical composition 3 containing the compound II-39 as an active ingredient.
实施例80药物组合物4Example 80 Pharmaceutical composition 4
将实施例2制备的化合物II-2、实施例13制备的化合物II-13与填充剂、崩解剂、润滑剂混合、制粒、压片，得到以化合物II-2和II-13为活性成分的药物组合物4。Compound II-2 prepared in Example 2 and compound II-13 prepared in Example 13 were mixed with a filler, a disintegrant, and a lubricant, granulated, and tableted to obtain a pharmaceutical composition 4 having compounds II-2 and II-13 as active ingredients.

Claims (15)

  1. [根据细则26改正 31.03.2023]
    一种式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药；
    Figure PCTCN2023071067-appb-100001

    其中，
    环A为饱和脂肪环基、芳环基或杂芳基；
    X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-CH(OH)-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-，其中各个n独立地为0、1、2、3或4；m为0、1或2；
    R 1和R 2相互独立地为氢、饱和或不饱和烷基、烷氧基、烷氧羰基、羟基、卤素、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代环烷基、取代或非取代芳基、-OR a、取代或非取代杂芳基或取代或非取的饱和或不饱和杂环；
    R a为4～6元杂环烷基；
    R 3为烷氧基、取代或非取代烷基、卤素、硝基、胺基、烷胺基、羧基、
    Figure PCTCN2023071067-appb-100002
    Figure PCTCN2023071067-appb-100003
    其中，R 4为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代烷胺基、取代或非取代胺基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环；
    结构通式如式(I)所示的化合物不为：
    Figure WO-DOC-FIGURE-3

    Figure WO-DOC-FIGURE-4
     [Corrected 31.03.2023 in accordance with Rule 26]
    A compound represented by formula (I), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;
    Figure PCTCN2023071067-appb-100001

    in,
    Ring A is a saturated aliphatic ring group, an aromatic ring group or a heteroaryl group;
    X is -C(=O)-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -, -CH(OH)-(CH 2 ) n -, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(=O)-(CH=CH) m -(CH 2 ) n -, or -(CH 2 ) n -, wherein each n is independently 0, 1, 2, 3 or 4; m is 0, 1 or 2;
    R1 and R2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, -ORa , substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring;
    Ra is a 4- to 6-membered heterocycloalkyl group;
    R3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
    Figure PCTCN2023071067-appb-100002
    Figure PCTCN2023071067-appb-100003
    wherein R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted amine, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring;
    The compound with the general structural formula (I) is not:
    Figure WO-DOC-FIGURE-3

    Figure WO-DOC-FIGURE-4
  2. 如权利要求1所述的式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药， 其特征在于所述式(I)所示化合物为式(I-1)所示化合物，The compound of formula (I) according to claim 1, or its isomer, or its pharmaceutically acceptable salt, ester or prodrug, characterized in that the compound of formula (I) is a compound of formula (I-1),
    Figure PCTCN2023071067-appb-100006
    Figure PCTCN2023071067-appb-100006
    其中，in,
    环A为饱和脂肪环、芳环或杂芳环；Ring A is a saturated aliphatic ring, an aromatic ring or a heteroaromatic ring;
    X为-C(＝O)-(CH 2)n-、-C(＝O)-NH-(CH 2)n-、-CH(OH)-(CH 2)n-、-SO 2-(CH 2)n-、-SO 2-NH-(CH 2)n-或-(CH 2)n-，其中n为0、1、2、3或4； X is -C(=O)-(CH 2 )n-, -C(=O)-NH-(CH 2 )n-, -CH(OH)-(CH 2 )n-, -SO 2 -(CH 2 )n-, -SO 2 -NH-(CH 2 )n-, or -(CH 2 )n-, wherein n is 0, 1, 2, 3, or 4;
    R 1、R 2相互独立地为氢、饱和或不饱和烷基、烷氧基、烷氧羰基、羟基、卤素、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代环烷基、取代或非取代芳基、取代或非取代杂芳基或取代或非取的饱和或不饱和杂环； R 1 and R 2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring;
    R 3为烷氧基、取代或非取代烷基、卤素、硝基、胺基、烷胺基、羧基、
    Figure PCTCN2023071067-appb-100007
    Figure PCTCN2023071067-appb-100008
    其中，R 4为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环；     R3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
    Figure PCTCN2023071067-appb-100007
    Figure PCTCN2023071067-appb-100008
    wherein R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring;
    优选地，所述式(I-1)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药为与β-catenin/BCL9蛋白蛋白相互作用的小分子抑制剂。Preferably, the compound represented by formula (I-1), or its isomer, or its pharmaceutically acceptable salt, ester or prodrug is a small molecule inhibitor that interacts with β-catenin/BCL9 protein.
  3. 如权利要求2所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药，其特征在于，所述式(I-1)所示的化合物为式(II)所示化合物，The compound of formula (I) according to claim 2, or its isomer, or its pharmaceutically acceptable salt, ester or prodrug, characterized in that the compound of formula (I-1) is a compound of formula (II),
    Figure PCTCN2023071067-appb-100009
    Figure PCTCN2023071067-appb-100009
    其中，in,
    X、R 1和R 2的定义如权利要求2所述； X, R1 and R2 are as defined in claim 2;
    R 4为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环。 R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring.
  4. 如权利要求3所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药，其特征在于，所述化合物满足如下一个或多个条件：The compound of formula (I) according to claim 3, or its isomer, or its pharmaceutically acceptable salt, ester or prodrug, characterized in that the compound satisfies one or more of the following conditions:
    (1)所述脂肪环或环烷基相互独立地为含有5个碳原子以上的环烷基；(1) The aliphatic ring or cycloalkyl group is independently a cycloalkyl group containing 5 or more carbon atoms;
    (2)所述芳基、芳环、芳杂基和杂芳环相互独立地为苯基、联苯基、萘基、蒽基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、吡咯基、吗啉基、哌啶基或哌嗪基、噻吩基、苯并噻吩基、吡唑基、苯并吡唑基、吲哚基、二氧戊环基、苯并[1，3]二氧戊环基、噁唑基、苯并噁唑基、呋喃基、苯并呋喃基、噻唑基或苯并噻唑基，其可任选被取代；(2) the aryl group, aromatic ring, aromatic hetero group and heteroaromatic ring are independently phenyl, biphenyl, naphthyl, anthracenyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, morpholinyl, piperidinyl or piperazinyl, thienyl, benzothienyl, pyrazolyl, benzopyrazolyl, indolyl, dioxolanyl, benzo[1,3]dioxolanyl, oxazolyl, benzoxazolyl, furanyl, benzofuranyl, thiazolyl or benzothiazolyl, which may be optionally substituted;
    (3)所述卤素或卤代中的卤素相互独立地为氟、氯或溴；(3) The halogen or halogen in the halogenated group is independently fluorine, chlorine or bromine;
    (4)所述烷基为含有1-6个碳原子的烷基；(4) The alkyl group is an alkyl group containing 1 to 6 carbon atoms;
    (5)所述杂环为含有至少1个O、N或S的五元环或六元环；(5) The heterocyclic ring is a five-membered ring or a six-membered ring containing at least one O, N or S;
    (6)所述药学上可接受的盐包括所述式(II)所示化合物与下列酸中的一种或多种形成的酸加成盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸和杏仁酸。(6) The pharmaceutically acceptable salts include acid addition salts formed between the compound represented by formula (II) and one or more of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid and mandelic acid.
  5. 如权利要求4所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药，其特征在于，所述化合物满足如下一个或多个条件：The compound of formula (I) according to claim 4, or its isomer, or its pharmaceutically acceptable salt, ester or prodrug, characterized in that the compound satisfies one or more of the following conditions:
    (1)所述式(I-1)所示化合物中，环A为饱和脂肪环、芳环或杂芳环，例如，环A为环己烷、苯、联苯、萘或喹啉；(1) In the compound represented by formula (I-1), ring A is a saturated aliphatic ring, an aromatic ring or a heteroaromatic ring, for example, ring A is cyclohexane, benzene, biphenyl, naphthalene or quinoline;
    (2)X为-C(＝O)-(CH 2)n-、-C(＝O)-NH-(CH 2)n-、-CH(OH)-(CH 2)n-、-SO 2-(CH 2)n-、-SO 2-NH-(CH 2)n-或-(CH 2)n-，其中n为0、1、2、3或4；例如，X为-C(＝O)-、-C(＝O)-(CH 2) 2-、-SO 2-、-CH 2-或-(CH 2) 3-，又如，无X； (2) X is -C(=O)-(CH 2 )n-, -C(=O)-NH-(CH 2 )n-, -CH(OH)-(CH 2 )n-, -SO 2 -(CH 2 )n-, -SO 2 -NH-(CH 2 )n-, or -(CH 2 )n-, wherein n is 0, 1, 2, 3, or 4; for example, X is -C(=O)-, -C(=O)-(CH 2 ) 2 -, -SO 2 -, -CH 2 -, or -(CH 2 ) 3 -; for example, there is no X;
    (3)R 1和R 2相互独立地为氢、饱和或不饱和烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代环烷基、取代或非取代芳基、取代或非取代杂芳基或取代或非取的饱和或不饱和杂环；R 1、R 2相同或不同；优选地，R 1、R 2独立地选自氢、卤素、C 1-C 4烷基、烷氧基、噻吩基、苯并噻吩基、吡唑基、卤代芳基和
    Figure PCTCN2023071067-appb-100010
    中的任意两种；例如，所述R 1、R 2为下表所示的组合：     (3) R1 and R2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxyl, halogen, nitro, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle; R1 and R2 are the same or different; preferably, R1 and R2 are independently selected from hydrogen, halogen, C1 - C4 alkyl, alkoxy, thienyl, benzothienyl, pyrazolyl, haloaryl, and
    Figure PCTCN2023071067-appb-100010
    Any two of; for example, R 1 and R 2 are the combinations shown in the following table:
    Figure PCTCN2023071067-appb-100011
    Figure PCTCN2023071067-appb-100011
    Figure PCTCN2023071067-appb-100012
    Figure PCTCN2023071067-appb-100012
    (4)R 3为烷氧基、取代或非取代烷基、卤素、硝基、胺基、烷胺基、羧基、
    Figure PCTCN2023071067-appb-100013
    Figure PCTCN2023071067-appb-100014
    (4) R 3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
    Figure PCTCN2023071067-appb-100013
    Figure PCTCN2023071067-appb-100014
    (5)R 4为氢、氨基、酰胺基、羧基、
    Figure PCTCN2023071067-appb-100015
    优选地，R 4为羟基、烷氧基、烷胺基或苯磺酰基；     (5) R4 is hydrogen, amino, amide, carboxyl,
    Figure PCTCN2023071067-appb-100015
    Preferably, R 4 is hydroxy, alkoxy, alkylamino or benzenesulfonyl;
    (6)R 5为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环；优选地，R 5为氢、烷基、哌嗪或苯磺酰基； (6) R 5 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle; preferably, R 5 is hydrogen, alkyl, piperazine, or benzenesulfonyl;
    (7)所述烷基为C 1-C 6的烷基。 (7) The alkyl group is a C 1 -C 6 alkyl group.
  6. 如权利要求1～5中至少一项所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药，其特征在于，所述式(I)所示化合物为式(III)所示化合物，The compound represented by formula (I) according to at least one of claims 1 to 5, or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof, characterized in that the compound represented by formula (I) is a compound represented by formula (III),
    Figure PCTCN2023071067-appb-100016
    Figure PCTCN2023071067-appb-100016
    其中，in,
    环A为饱和脂肪环基、芳环基或杂芳基，Ring A is a saturated aliphatic ring group, an aromatic ring group or a heteroaryl group,
    所述饱和脂肪环基为4～6元环烷基，The saturated aliphatic ring group is a 4- to 6-membered cycloalkyl group,
    所述芳环基为6～14元芳基，The aromatic ring group is a 6- to 14-membered aromatic group,
    所述杂芳基为5～12元杂芳基；The heteroaryl group is a 5- to 12-membered heteroaryl group;
    X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-CH(OH)-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-，其中各个n独立地为0、1、2、3或4；m为0、1或2； X is -C(=O)-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -, -CH(OH)-(CH 2 ) n -, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(=O)-(CH=CH) m -(CH 2 ) n -, or -(CH 2 ) n -, wherein each n is independently 0, 1, 2, 3 or 4; m is 0, 1 or 2;
    R 1和R 2相互独立地为氢、饱和或不饱和烷基、烷氧基、烷氧羰基、羟基、卤素、氨基、烷胺基、硝基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代环烷基、取代或非取代芳基、-OR a、取代或非取代杂芳基或取代或非取的饱和或不饱和杂环， R1 and R2 are independently hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, amino, alkylamino, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, -ORa , substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring,
    所述饱和或不饱和烷基为C 1-C 6烷基， The saturated or unsaturated alkyl group is a C 1 -C 6 alkyl group,
    所述烷氧基为C 1-C 6烷氧基， The alkoxy group is a C 1 -C 6 alkoxy group,
    所述烷氧羰基为C 1-C 6烷基-O-C(＝O)-， The alkoxycarbonyl group is a C 1 -C 6 alkyl-OC(=O)-,
    所述烷胺基为C 1-C 6烷基-NH-， The alkylamino group is a C 1 -C 6 alkyl-NH-,
    所述酰基为C 1-C 6烷基-C(＝O)-、C 1-C 6烷基-SO 2-或苯磺酰基， The acyl group is C 1 -C 6 alkyl-C(═O)-, C 1 -C 6 alkyl-SO 2 - or benzenesulfonyl,
    所述酰胺基为C 1-C 6烷基-C(＝O)NH-、C 1-C 6烷基-SO 2NH-或苯磺酰胺基， The amide group is C 1 -C 6 alkyl-C(=O)NH-, C 1 -C 6 alkyl-SO 2 NH- or benzenesulfonamide,
    所述卤代烷基为被一个或多个卤素取代的C 1-C 6烷基， The haloalkyl group is a C 1 -C 6 alkyl group substituted by one or more halogens,
    所述卤代烷氧基为被一个或多个卤素取代的C 1-C 6烷氧基， The haloalkoxy group is a C 1 -C 6 alkoxy group substituted by one or more halogens,
    所述卤代烷硫基为被一个或多个卤素取代的C 1-C 6烷硫基， The haloalkylthio group is a C 1 -C 6 alkylthio group substituted by one or more halogens.
    所述取代或非取代环烷基中环烷基为3～6元环烷基，The cycloalkyl group in the substituted or unsubstituted cycloalkyl group is a 3- to 6-membered cycloalkyl group,
    所述取代或非取代芳基中芳基为6～14元芳基，其中，取代芳基为被一个或多个R b取代的6～14元芳基， The aryl group in the substituted or unsubstituted aryl group is a 6- to 14-membered aryl group, wherein the substituted aryl group is a 6- to 14-membered aryl group substituted by one or more R b ,
    所述取代或非取代杂芳基中杂芳基为5～12元杂芳基，其中取代杂芳基为被一个或多个R f取代的5～12元杂芳基， The heteroaryl in the substituted or unsubstituted heteroaryl is a 5- to 12-membered heteroaryl, wherein the substituted heteroaryl is a 5- to 12-membered heteroaryl substituted by one or more R f ,
    所述取代或非取饱和或不饱和杂环中杂环为4～6元杂环烷基；The heterocyclic ring in the substituted or unsubstituted saturated or unsaturated heterocyclic ring is a 4-6 membered heterocycloalkyl group;
    R a为4～6元杂环烷基； Ra is a 4- to 6-membered heterocycloalkyl group;
    各个R b和R f独立地为卤素或C 1-C 6烷基； Each R b and R f is independently halogen or C 1 -C 6 alkyl;
    R 3为烷氧基、取代或非取代烷基、卤素、硝基、胺基、烷胺基、羧基、
    Figure PCTCN2023071067-appb-100017
    Figure PCTCN2023071067-appb-100018
     R3 is alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amine, alkylamino, carboxyl,
    Figure PCTCN2023071067-appb-100017
    Figure PCTCN2023071067-appb-100018
    所述烷氧基为C 1-C 6烷氧基， The alkoxy group is a C 1 -C 6 alkoxy group,
    所述取代或非取代烷基中烷基为C 1-C 6烷基， The alkyl group in the substituted or unsubstituted alkyl group is a C 1 -C 6 alkyl group,
    所述烷胺基为C 1-C 6烷基-NH-； The alkylamino group is C 1 -C 6 alkyl-NH-;
    R 4为氢、烷基、烷氧基、烷氧羰基、羟基、卤素、硝基、氨基、烷胺基、氰基、羧基、酰基、酰胺基、卤代烷基、卤代烷氧基、卤代烷硫基、取代或非取代烷胺基、取代或非取代胺基、取代或非取代磺酰氨基、取代或非取代芳基、取代或非取代杂芳基或取代或非取代的饱和或不饱和杂环， R4 is hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxy, halogen, nitro, amino, alkylamino, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocyclic ring,
    所述烷基为C 1-C 6烷基， The alkyl group is a C 1 -C 6 alkyl group,
    所述烷氧基为C 1-C 6烷氧基， The alkoxy group is a C 1 -C 6 alkoxy group,
    所述烷氧羰基为C 1-C 6烷基-O-C(＝O)-， The alkoxycarbonyl group is a C 1 -C 6 alkyl-OC(=O)-,
    所述烷胺基烷胺基为C 1-C 6烷基-NH-， The alkylamino group is C 1 -C 6 alkyl-NH-,
    所述酰基为C 1-C 6烷基-C(＝O)-、C 1-C 6烷基-SO 2-或苯磺酰基， The acyl group is C 1 -C 6 alkyl-C(═O)-, C 1 -C 6 alkyl-SO 2 - or benzenesulfonyl,
    所述酰胺基为C 1-C 6烷基-C(＝O)NH-、C 1-C 6烷基-SO 2NH-或苯磺酰胺基， The amide group is C 1 -C 6 alkyl-C(=O)NH-, C 1 -C 6 alkyl-SO 2 NH- or benzenesulfonamide,
    所述卤代烷基为被一个或多个卤素取代的C 1-C 6烷基， The haloalkyl group is a C 1 -C 6 alkyl group substituted by one or more halogens,
    所述卤代烷氧基为被一个或多个卤素取代的C 1-C 6烷氧基， The haloalkoxy group is a C 1 -C 6 alkoxy group substituted by one or more halogens,
    所述卤代烷硫基为被一个或多个卤素取代的C 1-C 6烷硫基， The haloalkylthio group is a C 1 -C 6 alkylthio group substituted by one or more halogens.
    所述取代或非取代烷胺基中烷胺基为-NH-(CH 2) k，其中，取代烷胺基为-NH-(CH 2) k-R d，k为1、2、3或4， The alkylamino group in the substituted or unsubstituted alkylamino group is -NH-(CH 2 ) k , wherein the substituted alkylamino group is -NH-(CH 2 ) k -R d , k is 1, 2, 3 or 4,
    所述取代的胺基为-NH-(CH 2) k-R d，k为0， The substituted amine group is -NH-(CH 2 ) k -R d , k is 0,
    所述取代的磺酰氨基为-NH-(SO 2)-R c， The substituted sulfonylamino group is -NH-(SO 2 )-R c ,
    所述取代或非取代芳基中芳基为6～14元芳基，The aryl group in the substituted or unsubstituted aryl group is a 6- to 14-membered aryl group,
    所述取代或非取代杂芳基中杂芳基为5～12元杂芳基，The heteroaryl group in the substituted or unsubstituted heteroaryl group is a 5- to 12-membered heteroaryl group,
    所述取代或非取代的饱和或不饱和杂环中杂环为4～10元杂环烷基，其中取代的饱和或不饱和杂环为被一个或多个R e取代的4～10元杂环烷基； The heterocycle in the substituted or unsubstituted saturated or unsaturated heterocycle is a 4-10-membered heterocycloalkyl, wherein the substituted saturated or unsaturated heterocycle is a 4-10-membered heterocycloalkyl substituted by one or more Re ;
    R c为氢、6～14元芳基、4～6元杂环烷基、5～12元杂芳基、被一个或多个R c-1取代的6～14元芳基或被一个或多个R c-2取代的5～12元杂芳基； R c is hydrogen, 6- to 14-membered aryl, 4- to 6-membered heterocycloalkyl, 5- to 12-membered heteroaryl, 6- to 14-membered aryl substituted by one or more R c-1 , or 5- to 12-membered heteroaryl substituted by one or more R c-2 ;
    R d为氢、6～14元芳基、5～12元杂芳基或4～6元杂环烷基； R d is hydrogen, 6- to 14-membered aryl, 5- to 12-membered heteroaryl, or 4- to 6-membered heterocycloalkyl;
    各个R c-1和R c-2独立地为羟基、氰基、C 1-C 6烷基、被一个或多个R c-1-1取代的C 1-C 6烷基、C 1-C 6烷氧基、硝基、卤素、被一个或多个R c-1-2取代的C 1-C 6烷氧基或-NHC(＝O)-R c-1-3； each of R c-1 and R c-2 is independently hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R c-1-1 , C 1 -C 6 alkoxy, nitro, halogen, C 1 -C 6 alkoxy substituted by one or more R c-1-2 , or -NHC(=O)-R c-1-3 ;
    各个R e独立地为氧代基(C＝O)、羟基或氨基； Each Re is independently oxo (C=O), hydroxyl or amino;
    各个R c-1-1和R c-1-2独立地为卤素； Each of R c-1-1 and R c-1-2 is independently halogen;
    R c-1-3为C 1-C 6烷基； R c-1-3 is C 1 -C 6 alkyl;
    各个5～12元杂芳基、4～6元杂环烷基和4～10元杂环烷基中杂原子选自N、O或S，杂原子数为1个、2个或3个；The heteroatom in each 5- to 12-membered heteroaryl, 4- to 6-membered heterocycloalkyl and 4- to 10-membered heterocycloalkyl is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3;
    优选地，所述式(I)所示化合物满足如下一个或多个条件：Preferably, the compound represented by formula (I) satisfies one or more of the following conditions:
    (1)所述异构体为式(I)所示化合物的对映异构体或非对映异构体；(1) The isomer is an enantiomer or a diastereomer of the compound represented by formula (I);
    (2)环A为6～14元芳基；(2) Ring A is a 6- to 14-membered aromatic group;
    (3)R 1和R 2各自独立地为氢、C 1-C 6烷基、5～12元杂芳基、3～6元环烷基、6～14元芳基、-OR a或被一个或多个R b取代的6～14元芳基，例如，R 1为5～12元杂芳基、3～6元环烷基、6～14元芳基或被一个或多个R b取代的6～14元芳基，又如，R 1和R 2各自独立地为氢、5～12元杂芳基、3～6元环烷基、6～14元芳基、-OR a或被一个或多个R b取代的6～14元芳基； (3) R1 and R2 are each independently hydrogen, C1 - C6 alkyl, 5-12 membered heteroaryl, 3-6 membered cycloalkyl, 6-14 membered aryl, -ORa , or 6-14 membered aryl substituted by one or more Rb , for example, R1 is 5-12 membered heteroaryl, 3-6 membered cycloalkyl, 6-14 membered aryl, or 6-14 membered aryl substituted by one or more Rb , for example, R1 and R2 are each independently hydrogen, 5-12 membered heteroaryl, 3-6 membered cycloalkyl, 6-14 membered aryl, -ORa , or 6-14 membered aryl substituted by one or more Rb ;
    (4)X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-，例如，X为-C(＝O)-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-；又如，X为-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-； (4) X is -C(＝O)-(CH 2 ) n -, -C(＝O)-NH-(CH 2 ) n -, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(＝O)-(CH＝CH) m- (CH 2 ) n -, or -(CH 2 ) n -. For example, X is -C(＝O)-, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(＝O)-(CH＝CH) m- (CH 2 ) n -, or -(CH 2 ) n -. In another example, X is -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(＝O)-(CH＝CH) m- (CH 2 ) n -, or -(CH 2 ) n -.
    (5)X为羰基，所述式(III)所示化合物不为：(5) X is a carbonyl group, and the compound represented by formula (III) is not:
    Figure PCTCN2023071067-appb-100019
    Figure PCTCN2023071067-appb-100019
    (6)各个n独立地为0、1、3；(6) each n is independently 0, 1, or 3;
    (7)各个m独立地为1；(7) Each m is independently 1;
    (8)R 3为
    Figure PCTCN2023071067-appb-100020
    例如
    Figure PCTCN2023071067-appb-100021
    (8) R 3 is
    Figure PCTCN2023071067-appb-100020
    For example
    Figure PCTCN2023071067-appb-100021
    (9)R 4为羟基、C 1-C 6烷基、4～10元杂环烷基、-NH-(SO 2)-R c、-NH-(CH 2) k-R d或被一个 或多个R e取代的4～10元杂环烷基，例如，R 4为羟基、4～10元杂环烷基、-NH-(SO 2)-R c或-NH-(CH 2) k-R d，又如R 4为羟基、4～10元杂环烷基、-NH-(SO 2)-R c、-NH-(CH 2) k-R d或被一个或多个R e取代的4～10元杂环烷基； (9) R4 is hydroxy, C1 - C6 alkyl, 4- to 10-membered heterocycloalkyl, -NH-( SO2 ) -Rc , -NH-( CH2 ) k - Rd, or 4- to 10-membered heterocycloalkyl substituted by one or more Re , for example, R4 is hydroxy, 4- to 10-membered heterocycloalkyl, -NH-( SO2 ) -Rc , or -NH-( CH2 ) k - Rd , for example, R4 is hydroxy, 4- to 10-membered heterocycloalkyl, -NH-( SO2 ) -Rc , -NH-( CH2 ) k - Rd , or 4- to 10-membered heterocycloalkyl substituted by one or more Re ;
    (10)k为0或1；(10) k is 0 or 1;
    (11)R c为6～14元芳基、被一个或多个R c-1取代的6～14元芳基或5～12元杂芳基； (11) R c is a 6- to 14-membered aryl group, a 6- to 14-membered aryl group substituted with one or more R c-1 groups, or a 5- to 12-membered heteroaryl group;
    (12)R d为6～14元芳基或4～6元杂环烷基，例如，R d为4～6元杂环烷基，又如R d为6～14元芳基； (12) R d is a 6- to 14-membered aryl group or a 4- to 6-membered heterocycloalkyl group, for example, R d is a 4- to 6-membered heterocycloalkyl group, and for example, R d is a 6- to 14-membered aryl group;
    (13)各个R c-1独立地为氰基、被一个或多个R c-1-1取代的C 1-C 6烷基、C 1-C 6烷氧基、硝基、卤素、被一个或多个R c-1-2取代的C 1-C 6烷氧基或-NHC(＝O)-R c-1-3，或者，各个R c- 1独立地为羟基、被一个或多个R c-1-1取代的C 1-C 6烷基或C 1-C 6烷氧基； (13) each R c-1 is independently cyano, C 1 -C 6 alkyl substituted by one or more R c-1-1 , C 1 -C 6 alkoxy, nitro, halogen, C 1 -C 6 alkoxy substituted by one or more R c-1-2 , or -NHC(=O)-R c-1-3 ; or each R c- 1 is independently hydroxy, C 1 -C 6 alkyl substituted by one or more R c-1-1 , or C 1 -C 6 alkoxy;
    (14)环A中，所述4～6元环烷基为环丙烷基、环丁烷基、环戊烷基或环己烷基；(14) In ring A, the 4- to 6-membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
    (15)环A中，所述6～14元芳基为苯基或萘基，例如苯基；(15) In ring A, the 6- to 14-membered aryl group is phenyl or naphthyl, for example, phenyl;
    (16)环A中，所述5～12元杂芳基中杂原子为N、S或O，杂原子数为1个或2个，优选为6元含氮杂芳基。(16) In ring A, the heteroatom in the 5- to 12-membered heteroaryl group is N, S or O, and the number of heteroatoms is 1 or 2, and is preferably a 6-membered nitrogen-containing heteroaryl group.
  7. 如权利要求6所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药，其特征在于，所述化合物满足如下一个或多个条件：The compound of formula (I) according to claim 6, or its isomer, or its pharmaceutically acceptable salt, ester or prodrug, characterized in that the compound satisfies one or more of the following conditions:
    (1)R 1和R 2中，所述C 1-C 6烷基、C 1-C 6烷基-O-C(＝O)-、C 1-C 6烷基-NH-、C 1-C 6烷基-C(＝O)-、C 1-C 6烷基-C(＝O)NH-和被一个或多个卤素取代的C 1-C 6烷基中C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如甲基或异丙基； (1) In R1 and R2 , the C1 - C6 alkyl, C1 - C6 alkyl-OC(＝O)-, C1 - C6 alkyl-NH-, C1 - C6 alkyl-C(＝O)-, C1- C6 alkyl-C(＝O)NH- and C1 - C6 alkyl substituted by one or more halogens, wherein the C1 - C6 alkyl is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example, methyl or isopropyl;
    (2)R 1和R 2中，所述C 1-C 6烷氧基和被一个或多个卤素取代的C 1-C 6烷氧基中C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基； (2) In R1 and R2 , the C1 - C6 alkoxy group and the C1 - C6 alkoxy group substituted by one or more halogens are methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy;
    (3)R 1和R 2中，所述卤素、被一个或多个卤素取代的C 1-C 6烷基、被一个或多个卤素取代的C 1-C 6烷氧基和被一个或多个卤素取代的C 1-C 6烷硫基中卤素为氟、氯、溴或碘； (3) In R1 and R2 , the halogen, C1 - C6 alkyl substituted by one or more halogens, C1 - C6 alkoxy substituted by one or more halogens, and C1 - C6 alkylthio substituted by one or more halogens is fluorine, chlorine, bromine or iodine;
    (4)R 1和R 2中，所述被一个或多个卤素取代的C 1-C 6烷硫基中C 1-C 6烷硫基为甲硫基、乙硫基、异丙硫基、正丙硫基、正丁硫基、仲丁硫基、叔丁硫基或异丁硫基； (4) In R1 and R2 , the C1 - C6 alkylthio group substituted by one or more halogens is methylthio, ethylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio, tert-butylthio or isobutylthio;
    (5)R 1和R 2中，所述3～6元环烷基为环丙烷基、环丁烷基、环戊烷基或环己烷基，例如环己烷基； (5) In R1 and R2 , the 3- to 6-membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclohexyl;
    (6)R 1和R 2中，所述6～14元芳基和被一个或多个R b取代的6～14元芳基中6～14元芳基为苯基或萘基，例如苯基； (6) In R1 and R2 , the 6- to 14-membered aryl group and the 6- to 14-membered aryl group substituted by one or more Rb is phenyl or naphthyl, for example, phenyl;
    (7)R 1和R 2中，所述5～12元杂芳基和被一个或多个R f取代的5～12元杂芳基中5～12元杂芳基为5～10元杂芳基，优选地，所述5～10元杂芳基中杂原子为N、O或S，杂原子数为1个或2个，例如噻吩基、吡唑或苯并噻吩基； (7) In R1 and R2 , the 5- to 12-membered heteroaryl group and the 5- to 12-membered heteroaryl group substituted by one or more Rf are 5- to 10-membered heteroaryl groups, preferably, the heteroatom in the 5- to 10-membered heteroaryl group is N, O or S, and the number of heteroatoms is 1 or 2, such as thienyl, pyrazole or benzothienyl;
    (8)R 1和R 2中，所述4～6元杂环烷基中杂原子为N、S或O，杂原子数为1个或2个， 优选为6元含氮杂环己基； (8) In R1 and R2 , the heteroatom in the 4- to 6-membered heterocycloalkyl group is N, S or O, and the number of heteroatoms is 1 or 2, and is preferably a 6-membered nitrogen-containing heterocyclohexyl group;
    (9)R a中，所述4～6元杂环烷基为5～6元杂环烷基，优选地，所述5～6元杂环烷基中杂原子为N、O或S，杂原子数为1个，例如氮杂环戊烷； (9) In R a , the 4- to 6-membered heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group, and preferably, the heteroatom in the 5- to 6-membered heterocycloalkyl group is N, O or S, and the number of heteroatoms is 1, such as azacyclopentane;
    (10)R b和R f中，所述卤素为氟、氯、溴或碘，例如为氟； (10) In R b and R f , the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine;
    (11)R b和R f中，所述C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如为甲基、异丙基或叔丁基； (11) In R b and R f , the C 1 -C 6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example, methyl, isopropyl or tert-butyl;
    (12)R 3中，所述C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基； (12) In R 3 , the C 1 -C 6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy;
    (13)R 3中，所述C 1-C 6烷基和C 1-C 6烷基-NH-中C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基； (13) In R 3 , the C 1 -C 6 alkyl group and the C 1 -C 6 alkyl-NH- group wherein the C 1 -C 6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl;
    (14)R 3中，所述卤素为氟、氯、溴或碘； (14) In R 3 , the halogen is fluorine, chlorine, bromine or iodine;
    (15)R 4中，所述C 1-C 6烷基、C 1-C 6烷基-O-C(＝O)-、C 1-C 6烷基-NH-、C 1-C 6烷基-C(＝O)-、C 1-C 6烷基-SO 2-、C 1-C 6烷基-C(＝O)NH-、C 1-C 6烷基-SO 2NH-和被一个或多个卤素取代的C 1-C 6烷基中C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如甲基； (15) In R4 , the C1 - C6 alkyl, C1 - C6 alkyl-OC(＝O)-, C1 - C6 alkyl-NH-, C1 - C6 alkyl-C(＝O)-, C1 - C6 alkyl- SO2- , C1 - C6 alkyl-C(＝O)NH-, C1 - C6 alkyl- SO2NH- and C1- C6 alkyl substituted by one or more halogens, wherein the C1 - C6 alkyl is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example, methyl;
    (16)R 4中，所述C 1-C 6烷氧基和被一个或多个卤素取代的C 1-C 6烷氧基中C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基； (16) In R 4 , the C 1 -C 6 alkoxy group and the C 1 -C 6 alkoxy group substituted by one or more halogens is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy;
    (17)R 4中，所述卤素、被一个或多个卤素取代的C 1-C 6烷基、被一个或多个卤素取代的C 1-C 6烷氧基和被一个或多个卤素取代的C 1-C 6烷硫基中卤素为氟、氯、溴或碘； (17) In R 4 , the halogen, C 1 -C 6 alkyl substituted by one or more halogens, C 1 -C 6 alkoxy substituted by one or more halogens, and C 1 -C 6 alkylthio substituted by one or more halogens is fluorine, chlorine, bromine or iodine;
    (18)R 4中，所述被一个或多个卤素取代的C 1-C 6烷硫基中C 1-C 6烷硫基为甲硫基、乙硫基、异丙硫基、正丙硫基、正丁硫基、仲丁硫基、叔丁硫基或异丁硫基； (18) In R 4 , the C 1 -C 6 alkylthio group substituted by one or more halogens is methylthio, ethylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio, tert-butylthio or isobutylthio;
    (19)R 4中，所述6～14元芳基中6～14元芳基为苯基或萘基； (19) In R 4 , the 6- to 14-membered aryl group is phenyl or naphthyl;
    (20)R 4中，所述5～12元杂芳基中5～12元杂芳基为5～10元杂芳基，优选地，所述5～10元杂芳基中杂原子为N、O或S，杂原子数为1个或2个； (20) In R 4 , the 5- to 12-membered heteroaryl group is a 5- to 10-membered heteroaryl group, and preferably, the heteroatom in the 5- to 10-membered heteroaryl group is N, O or S, and the number of heteroatoms is 1 or 2;
    (21)R 4中，所述4～10元杂环烷基和被一个或多个R e取代的4～10元杂环烷基中4～10元杂环烷基为4～7元杂环烷基，优选地，所述4～7元杂环烷基中杂原子为O或N，进一步优选地，所述4～7元杂环烷基中杂原子数为1个或2个，例如
    Figure PCTCN2023071067-appb-100022
    Figure PCTCN2023071067-appb-100023
    (21) In R4 , the 4- to 10-membered heterocycloalkyl group and the 4- to 10-membered heterocycloalkyl group substituted by one or more Re are 4- to 7-membered heterocycloalkyl groups. Preferably, the heteroatom in the 4- to 7-membered heterocycloalkyl group is O or N. More preferably, the number of heteroatoms in the 4- to 7-membered heterocycloalkyl group is 1 or 2, for example
    Figure PCTCN2023071067-appb-100022
    Figure PCTCN2023071067-appb-100023
    (22)R c中，所述6～14元芳基和被一个或多个R c-1取代的6～14元芳基中6～14元芳基为苯基或萘基，例如苯基或萘基； (22) In R c , the 6- to 14-membered aryl group and the 6- to 14-membered aryl group substituted by one or more R c-1 is phenyl or naphthyl, for example, phenyl or naphthyl;
    (23)R c中，所述4～6元杂环烷基为5～6元杂环烷基，优选地，所述5～6元杂环烷基中杂原子为N，进一步优选地，所述5～6元杂环烷基中杂原子数为1个； (23) In R c , the 4- to 6-membered heterocycloalkyl is a 5- to 6-membered heterocycloalkyl, preferably, the heteroatom in the 5- to 6-membered heterocycloalkyl is N, and more preferably, the number of heteroatoms in the 5- to 6-membered heterocycloalkyl is 1;
    (24)R c中，所述5～12元杂芳基和被一个或多个R c-2取代的5～12元杂芳基中5～12元杂 芳基为5～10元杂芳基，优选地，所述5～10元杂芳基中杂原子为S或O，进一步优选地，所述5～10元杂芳基中杂原子数为1个，例如，所述5～10元杂芳基为噻吩； (24) In R c , the 5- to 12-membered heteroaryl group and the 5- to 12-membered heteroaryl group substituted by one or more R c-2 are 5- to 10-membered heteroaryl groups, preferably, the heteroatom in the 5- to 10-membered heteroaryl group is S or O, and more preferably, the number of heteroatoms in the 5- to 10-membered heteroaryl group is 1, for example, the 5- to 10-membered heteroaryl group is thiophene;
    (25)R d中，所述6～14元芳基为苯基或萘基，例如苯基； (25) In R d , the 6- to 14-membered aryl group is phenyl or naphthyl, for example, phenyl;
    (26)R d中，所述5～12元杂芳基为5～6元杂芳基，优选地，所述5～6元杂芳基中杂原子为N、S或O，进一步优选地，所述5～6元杂芳基中杂原子数为1个； (26) In R d , the 5- to 12-membered heteroaryl group is a 5- to 6-membered heteroaryl group, preferably, the heteroatom in the 5- to 6-membered heteroaryl group is N, S or O, and more preferably, the number of heteroatoms in the 5- to 6-membered heteroaryl group is 1;
    (27)R d中，所述4～6元杂环烷基为5～6元杂环烷基，优选地，所述5～6元杂环烷基中杂原子为N，进一步优选地，所述5～6元杂环烷基中杂原子数为1个，例如氮杂环己烷； (27) In R d , the 4- to 6-membered heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group, preferably, the heteroatom in the 5- to 6-membered heterocycloalkyl group is N, and more preferably, the number of heteroatoms in the 5- to 6-membered heterocycloalkyl group is 1, such as azacyclohexane;
    (28)R c-1和R c-2中，所述C 1-C 6烷基和被一个或多个R c-1-1取代的C 1-C 6烷基中C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如甲基； (28) In R c-1 and R c-2 , the C 1 -C 6 alkyl group and the C 1 -C 6 alkyl group substituted by one or more R c-1-1s are methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example , methyl;
    (29)R c-1和R c-2中，所述C 1-C 6烷氧基和被一个或多个R c-1-2取代的C 1-C 6烷氧基中C 1-C 6烷氧基为氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基，例如甲氧基； (29) In R c-1 and R c-2 , the C 1 -C 6 alkoxy group and the C 1 -C 6 alkoxy group substituted by one or more R c-1-2 are oxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy, for example , methoxy;
    (30)R c-1和R c-2中，所述卤素为氟、氯、溴或碘，例如氟或氯； (30) In R c-1 and R c-2 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine;
    (31)R c-1-1和R c-1-2中，所述卤素为氟、氯、溴或碘，例如氟； (31) In R c-1-1 and R c-1-2 , the halogen is fluorine, chlorine, bromine or iodine, for example fluorine;
    (32)R c-1-3中，所述C 1-C 6烷基为甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基或异丁基，例如甲基。 (32) In R c-1-3 , the C 1 -C 6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example, methyl.
  8. 如权利要求7所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药，其特征在于，所述式(III)所示化合物为如下任一方案：The compound of formula (I) according to claim 7, or its isomer, or its pharmaceutically acceptable salt, ester or prodrug, characterized in that the compound of formula (III) is any of the following schemes:
    方案一：Option One:
    所述式(III)所示化合物为如式(III-1)所示化合物，The compound represented by formula (III) is a compound represented by formula (III-1),
    Figure PCTCN2023071067-appb-100024
    Figure PCTCN2023071067-appb-100024
    其中，R 1为5～12元杂芳基、3～6元环烷基、6～14元芳基或被一个或多个R b取代的6～14元芳基； Wherein, R 1 is a 5- to 12-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a 6- to 14-membered aryl group, or a 6- to 14-membered aryl group substituted by one or more R b ;
    各个R b独立地为卤素或C 1-C 6烷基； Each R b is independently halogen or C 1 -C 6 alkyl;
    R 4为羟基、4～10元杂环烷基、-NH-(SO 2)-R c或-NH-(CH 2) k-R d；k为0、1、2、3或4； R 4 is hydroxy, 4- to 10-membered heterocycloalkyl, -NH-(SO 2 )-R c or -NH-(CH 2 ) k -R d ; k is 0, 1, 2, 3 or 4;
    R c为6～14元芳基、被一个或多个R c-1取代的6～14元芳基或5～12元杂芳基； R c is a 6- to 14-membered aryl group, a 6- to 14-membered aryl group substituted by one or more R c-1 groups, or a 5- to 12-membered heteroaryl group;
    R d为6～14元芳基； R d is a 6- to 14-membered aromatic group;
    各个R c-1独立地为氰基、被一个或多个R c-1-1取代的C 1-C 6烷基、C 1-C 6烷氧基、硝基、卤素、被一个或多个R c-1-2取代的C 1-C 6烷氧基或-NHC(＝O)-R c-1-3； each R c-1 is independently cyano, C 1 -C 6 alkyl substituted by one or more R c-1-1 , C 1 -C 6 alkoxy, nitro, halogen, C 1 -C 6 alkoxy substituted by one or more R c-1-2 , or -NHC(═O)-R c-1-3 ;
    各个R c-1-1和R c-1-2独立地为卤素； Each of R c-1-1 and R c-1-2 is independently halogen;
    R c-1-3为C 1-C 6烷基； R c-1-3 is C 1 -C 6 alkyl;
    各个5～12元杂芳基和4～10元杂环烷基中杂原子选自N、O或S，杂原子数为1个、2个或3个；The heteroatom in each 5- to 12-membered heteroaryl and 4- to 10-membered heterocycloalkyl is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3;
    方案二：Option II:
    所述式(III)所示化合物为如式(III-2)所示化合物，The compound represented by formula (III) is a compound represented by formula (III-2),
    Figure PCTCN2023071067-appb-100025
    Figure PCTCN2023071067-appb-100025
    R 1和R 2各自独立地为氢、5～12元杂芳基、3～6元环烷基、6～14元芳基、-OR a或被一个或多个R b取代的6～14元芳基； R1 and R2 are each independently hydrogen, 5- to 12-membered heteroaryl, 3- to 6-membered cycloalkyl, 6- to 14-membered aryl, -ORa, or 6- to 14-membered aryl substituted with one or more Rb ;
    R a为4～6元杂环烷基； Ra is a 4- to 6-membered heterocycloalkyl group;
    各个R b独立地为卤素或C 1-C 6烷基； Each R b is independently halogen or C 1 -C 6 alkyl;
    R 4为羟基、4～10元杂环烷基、-NH-(SO 2)-R c、-NH-(CH 2) k-R d或被一个或多个R e取代的4～10元杂环烷基；k为0、1、2、3或4； R 4 is hydroxy, 4- to 10-membered heterocycloalkyl, -NH-(SO 2 )-R c , -NH-(CH 2 ) k -R d or 4- to 10-membered heterocycloalkyl substituted by one or more Re ; k is 0, 1, 2, 3 or 4;
    R c为6～14元芳基、被一个或多个R c-1取代的6～14元芳基或5～12元杂芳基； R c is a 6- to 14-membered aryl group, a 6- to 14-membered aryl group substituted by one or more R c-1 groups, or a 5- to 12-membered heteroaryl group;
    R d为4～6元杂环烷基； R d is a 4- to 6-membered heterocycloalkyl group;
    各个R c-1独立地为羟基、被一个或多个R c-1-1取代的C 1-C 6烷基或C 1-C 6烷氧基； Each R c-1 is independently hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy substituted with one or more R c-1-1 ;
    各个R e独立地为氧代基(C＝O)、羟基或氨基； Each Re is independently oxo (C=O), hydroxyl or amino;
    各个R c-1-1和R c-1-2独立地为卤素； Each of R c-1-1 and R c-1-2 is independently halogen;
    各个5～12元杂芳基、4～6元杂环烷基和4～10元杂环烷基中杂原子选自N、O或S，杂原子数为1个、2个或3个；The heteroatom in each 5- to 12-membered heteroaryl, 4- to 6-membered heterocycloalkyl and 4- to 10-membered heterocycloalkyl is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3;
    方案三：third solution:
    所述式(III)所示化合物中，In the compound represented by formula (III),
    R 1和R 2各自独立地为氢、C 1-C 6烷基、5～12元杂芳基、3～6元环烷基、6～14元芳基、-OR a或被一个或多个R b取代的6～14元芳基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, 5- to 12-membered heteroaryl, 3- to 6-membered cycloalkyl, 6- to 14-membered aryl, -OR a , or 6- to 14-membered aryl substituted with one or more R b ;
    R a为4～6元杂环烷基； Ra is a 4- to 6-membered heterocycloalkyl group;
    各个R b独立地为卤素或C 1-C 6烷基； Each R b is independently halogen or C 1 -C 6 alkyl;
    X为-C(＝O)-(CH 2) n-、-C(＝O)-NH-(CH 2) n-、-SO 2-(CH 2) n-、-SO 2-NH-(CH 2) n-、-C(＝O)-(CH＝CH) m-(CH 2) n-或-(CH 2) n-，其中各个n独立地为0、1、2、3或4；m为0、1或2； X is -C(=O)-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -, -SO 2 -(CH 2 ) n -, -SO 2 -NH-(CH 2 ) n -, -C(=O)-(CH=CH) m -(CH 2 ) n -, or -(CH 2 ) n -, wherein each n is independently 0, 1, 2, 3 or 4; m is 0, 1 or 2;
    R 4为羟基、C 1-C 6烷基、4～10元杂环烷基、-NH-(SO 2)-R c、-NH-(CH 2) k-R d或被一个或多个R e取代的4～10元杂环烷基；k为0、1、2、3或4； R 4 is hydroxy, C 1 -C 6 alkyl, 4- to 10-membered heterocycloalkyl, -NH-(SO 2 )-R c , -NH-(CH 2 ) k -R d or 4- to 10-membered heterocycloalkyl substituted by one or more Re ; k is 0, 1, 2, 3 or 4;
    R c为6～14元芳基、被一个或多个R c-1取代的6～14元芳基或5～12元杂芳基； R c is a 6- to 14-membered aryl group, a 6- to 14-membered aryl group substituted by one or more R c-1 groups, or a 5- to 12-membered heteroaryl group;
    R d为6～14元芳基或4～6元杂环烷基； R d is a 6- to 14-membered aryl group or a 4- to 6-membered heterocycloalkyl group;
    各个R c-1独立地为羟基、氰基、C 1-C 6烷基、被一个或多个R c-1-1取代的C 1-C 6烷基、C 1-C 6烷氧基、硝基、卤素、被一个或多个R c-1-2取代的C 1-C 6烷氧基或-NHC(＝O)-R c-1-3； Each R c-1 is independently hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R c-1-1 , C 1 -C 6 alkoxy, nitro, halogen, C 1 -C 6 alkoxy substituted by one or more R c-1-2 , or -NHC(=O)-R c-1-3 ;
    各个R e独立地为氧代基(C＝O)、羟基或氨基； Each Re is independently oxo (C=O), hydroxyl or amino;
    各个R c-1-1和R c-1-2独立地为卤素； Each of R c-1-1 and R c-1-2 is independently halogen;
    R c-1-3为C 1-C 6烷基； R c-1-3 is C 1 -C 6 alkyl;
    各个5～12元杂芳基、4～6元杂环烷基和4～10元杂环烷基中杂原子选自N、O或S，杂原子数为1个、2个或3个。In each of the 5- to 12-membered heteroaryl, 4- to 6-membered heterocycloalkyl and 4- to 10-membered heterocycloalkyl, the heteroatom is selected from N, O or S, and the number of the heteroatoms is 1, 2 or 3.
  9. 如权利要求8所述的式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药，其特征在于，所述化合物为满足如下一个或多个条件：The compound of formula (I) according to claim 8, or its isomer, or its pharmaceutically acceptable salt, ester or prodrug, characterized in that the compound satisfies one or more of the following conditions:
    (1)R a为4～6元杂环烷基，盐酸与所述4～6元杂环烷基中N原子结合得到所述式(III)所示化合物的盐酸盐； (1) Ra is a 4- to 6-membered heterocycloalkyl group, and hydrochloric acid combines with the nitrogen atom of the 4- to 6-membered heterocycloalkyl group to obtain the hydrochloride of the compound represented by formula (III);
    (2)R e为氨基，盐酸与氨基结合得到所述如式(III)所示化合物的盐酸盐； (2) R e is an amino group, and hydrochloric acid combines with the amino group to obtain the hydrochloride of the compound represented by formula (III);
    (3)所述式(III)所示化合物药学上可接受的盐优选为盐酸盐；(3) The pharmaceutically acceptable salt of the compound represented by formula (III) is preferably hydrochloride;
    (4)X为
    Figure PCTCN2023071067-appb-100026
    化学键、甲基、
    Figure PCTCN2023071067-appb-100027
    (4)X is
    Figure PCTCN2023071067-appb-100026
    Chemical bond, methyl,
    Figure PCTCN2023071067-appb-100027
    (5)R 1和R 2各自独立地为氢、甲基、
    Figure PCTCN2023071067-appb-100028
    Figure PCTCN2023071067-appb-100029
    (5) R1 and R2 are each independently hydrogen, methyl,
    Figure PCTCN2023071067-appb-100028
    Figure PCTCN2023071067-appb-100029
    (6)R 3为
    Figure PCTCN2023071067-appb-100030
    Figure PCTCN2023071067-appb-100031
    (6) R 3 is
    Figure PCTCN2023071067-appb-100030
    Figure PCTCN2023071067-appb-100031
    Figure PCTCN2023071067-appb-100032
    Figure PCTCN2023071067-appb-100032
    (7)R 4为
    Figure PCTCN2023071067-appb-100033
    Figure PCTCN2023071067-appb-100034
    (7) R 4 is
    Figure PCTCN2023071067-appb-100033
    Figure PCTCN2023071067-appb-100034
    优选地，所述如式(III)所示的化合物，或其药学上可接受的盐为如下任一化合物：Preferably, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is any of the following compounds:
    Figure PCTCN2023071067-appb-100035
    Figure PCTCN2023071067-appb-100035
    Figure PCTCN2023071067-appb-100036
    Figure PCTCN2023071067-appb-100036
    Figure PCTCN2023071067-appb-100037
    Figure PCTCN2023071067-appb-100037
    Figure PCTCN2023071067-appb-100038
    Figure PCTCN2023071067-appb-100038
    Figure PCTCN2023071067-appb-100039
    Figure PCTCN2023071067-appb-100039
    Figure PCTCN2023071067-appb-100040
    Figure PCTCN2023071067-appb-100040
    2-(3-(1-((3′，4′-二甲基苄基)氨基甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′,4′-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-(3-(3′，4′-二甲基苯基)丙基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3-(3′,4′-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-(3-(苯并[b]噻吩-6-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3-(Benzo[b]thiophen-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-甲基-2-(3-(1-(3-(噻吩-3-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸；2-Methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propanoic acid;
    2-甲基-2-(3-(1-(3-(噻吩-2-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸；2-Methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propanoic acid;
    2-(3-(1-(3-(1H-吡唑-4-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-(4′-异丙基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(4′-isopropyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-([1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-([1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-([1，1′-联苯基]-4-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-([1,1′-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-甲基-2-(3-(1-((3-(噻吩-3-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸；2-Methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoic acid;
    2-(3-(1-([1，1′-联苯基]-3-基磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-([1,1′-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-((3-环己基苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-甲基-2-(3-(1-((3-(噻吩-2-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸；2-Methyl-2-(3-(1-((3-(thiophen-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoic acid;
    2-(3-(1-((3-(苯并[b]噻吩-6-基)苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3-(Benzo[b]thiophen-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-((3′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-((4′-(叔丁基)-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)甲基)哌啶-3-基)苯氧基)-2-甲基丙酸；2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-methylpropanoic acid;
    (3S)-3-((5-(3-(3-((2-羧基丙烷-2-基)氧基)苯基)哌啶-1-羰基)-3′，4′-二氟-[1，1′-联苯]-2-基)氧基)吡咯烷-1-氯化铵；(3S)-3-((5-(3-(3-((2-carboxypropan-2-yl)oxy)phenyl)piperidine-1-carbonyl)-3′,4′-difluoro-[1,1′-biphenyl]-2-yl)oxy)pyrrolidine-1-ammonium chloride;
    (3S)-3-(4-(3-(3-((2-羧基丙烷-2-基)氧基)苯基)哌啶-1-羰基)-2-环己基苯氧基)吡咯烷-1-氯化铵；(3S)-3-(4-(3-(3-((2-carboxypropan-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-cyclohexylphenoxy)pyrrolidine-1-ammonium chloride;
    4-(2-(3-(1-((3′，4′-二甲基-[1，1′-联苯]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-氯化铵；4-(2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-ammonium chloride;
    4-(2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酰基)哌嗪-1-氯化铵；4-(2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoyl)piperazine-1-ammonium chloride;
    2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基-N-(苯磺酰基)丙酰胺；2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(phenylsulfonyl)propionamide;
    2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基-N-(苯磺酰基)丙酰胺；2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(phenylsulfonyl)propionamide;
    2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-甲基-N-(苯磺酰基)丙酰胺。2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(phenylsulfonyl)propionamide.
  10. 一种如权利要求1～9中至少一项所述如式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药的制备方法，其特征在于，所述制备方法选自如下方案：A method for preparing a compound of formula (I) according to at least one of claims 1 to 9, or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof, characterized in that the preparation method is selected from the following schemes:
    方案(1)：溶剂中，在催化剂作用下，将式(III-4)所示化合物进行如下所示水解反应，得到式(III-3)所示化合物Scheme (1): In a solvent, in the presence of a catalyst, the compound represented by formula (III-4) is subjected to a hydrolysis reaction as shown below to obtain a compound represented by formula (III-3)
    Figure PCTCN2023071067-appb-100041
    Figure PCTCN2023071067-appb-100041
    其中，环A、R 1、R 2、X和R 4如权利要求1～9中至少一项所述； wherein ring A, R 1 , R 2 , X and R 4 are as described in at least one of claims 1 to 9;
    方案(2)：溶剂中，在催化剂作用下，将式(III-3)所示化合物与NH 2-R g进行如下所示的酰胺化反应得到式(III-5)所示化合物； Scheme (2): In a solvent, in the presence of a catalyst, the compound represented by formula (III-3) is subjected to an amidation reaction with NH 2 —R g as shown below to obtain a compound represented by formula (III-5);
    Figure PCTCN2023071067-appb-100042
    Figure PCTCN2023071067-appb-100042
    其中，R g为-(CH 2) k-R d或-(SO 2)-R c； wherein Rg is -( CH2 ) k - Rd or -( SO2 ) -Rc ;
    环A、K、R 1、R 2、X、R d和R c如权利要求1～9中至少一项所述； Ring A, K, R 1 , R 2 , X, R d and R c are as described in at least one of claims 1 to 9;
    方案(3)：溶剂中，在催化剂作用下，将式(III-3)所示化合物与H-R 4进行如下所示的酰化反应得到式(III-6)所示化合物； Scheme (3): In a solvent, in the presence of a catalyst, the compound represented by formula (III-3) is subjected to an acylation reaction with HR 4 as shown below to obtain a compound represented by formula (III-6);
    Figure PCTCN2023071067-appb-100043
    Figure PCTCN2023071067-appb-100043
    其中，R 4为4～10元杂环烷基或被一个或多个R e取代的4～10元杂环烷基； Wherein, R 4 is a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered heterocycloalkyl group substituted by one or more Re ;
    环A、R 1、R 2、R e、X、4～10元杂环烷基如权利要求1～9中至少一项所述； Ring A, R 1 , R 2 , Re , X, and 4- to 10-membered heterocycloalkyl are as described in at least one of claims 1 to 9;
    方案(4)：Solution (4):
    将式(V)化合物与式(VI)化合物偶联反应，得到式(VII)中间体化合物；coupling the compound of formula (V) with the compound of formula (VI) to obtain an intermediate compound of formula (VII);
    所述偶联反应试剂选自三乙胺、二氯甲烷、HATU、DMF、钯碳和Xantphos中的一种或多种；The coupling reaction reagent is selected from one or more of triethylamine, dichloromethane, HATU, DMF, palladium carbon and Xantphos;
    Figure PCTCN2023071067-appb-100044
    Figure PCTCN2023071067-appb-100044
    其中，in,
    环A’选自环A或环A的前体化合物；Ring A' is selected from Ring A or a precursor compound of Ring A;
    Y选自X或X的前体基团；Y is selected from X or a precursor group of X;
    R 5选自R 3或R 3的前体基团，或被R 3或R 3的前体基团取代的卤素、羟基、羧基、氨基、酰基、酰胺基、烷氧基、烷胺基、巯基、磺酰基、烃基、芳基、杂芳基或杂环基； R 5 is selected from R 3 or a precursor group of R 3 , or a halogen, hydroxyl , carboxyl, amino, acyl, amide, alkoxy, alkylamino, mercapto, sulfonyl, hydrocarbon, aryl, heteroaryl or heterocyclic group substituted by R 3 or a precursor group of R 3;
    R 8为能与哌啶环中1-NH反应的基团； R 8 is a group that can react with 1-NH in the piperidine ring;
    R 6、R 7独立地选自R 6/R 7或R 6/R 7的前体基团，或被R 6/R 7或R 6/R 7的前体基取代的卤素、羟基、羧基、氨基、酰基、酰胺基、烷氧基、烷胺基、巯基、磺酰基、烃基、芳基、杂芳基或杂环基； R 6 and R 7 are independently selected from R 6 /R 7 or a precursor group of R 6 /R 7 , or a halogen, hydroxyl, carboxyl, amino, acyl, amide, alkoxy, alkylamino, mercapto, sulfonyl, hydrocarbon, aryl, heteroaryl or heterocyclic group substituted by R 6 /R 7 or a precursor group of R 6 /R 7 ;
    优选地，式(V)化合物的制备方法包括：Preferably, the preparation method of the compound of formula (V) comprises:
    5-吡啶硼酸与式(III)化合物进行第一反应，得到式(IV)化合物；5-pyridineboronic acid and the compound of formula (III) undergo a first reaction to obtain a compound of formula (IV);
    式(IV)化合物进行第二反应，得到式(V)化合物；The compound of formula (IV) undergoes a second reaction to obtain a compound of formula (V);
    所述第一反应的条件包括反应物在碱性条件下加热；The conditions of the first reaction include heating the reactants under alkaline conditions;
    所述第二反应为催化加氢反应，催化剂选自Pt、Pd或Ni类催化剂；The second reaction is a catalytic hydrogenation reaction, and the catalyst is selected from Pt, Pd or Ni catalysts;
    Figure PCTCN2023071067-appb-100045
    Figure PCTCN2023071067-appb-100045
    方案(5)：Solution (5):
    式(II)化合物的制备方法包括以下步骤：The preparation method of the compound of formula (II) comprises the following steps:
    将式(VIII)化合物与式(VI)化合物偶联反应，得到式(IX)中间体化合物；coupling the compound of formula (VIII) with the compound of formula (VI) to obtain an intermediate compound of formula (IX);
    所述偶联反应试剂选自三乙胺、二氯甲烷、HATU、DMF、钯碳和Xantphos中的一种或多种；The coupling reaction reagent is selected from one or more of triethylamine, dichloromethane, HATU, DMF, palladium carbon and Xantphos;
    Figure PCTCN2023071067-appb-100046
    Figure PCTCN2023071067-appb-100046
    其中，in,
    环A”选自取代或非取代的苯或其前体基团；Ring A" is selected from substituted or unsubstituted benzene or its precursor group;
    R 9选自R 4或R 4的前体基团，或可被R 4或R 4的前体基团取代的卤素、羟基、羧基、氨基、酰基、酰胺基、烷氧基、烷胺基、巯基、磺酰基、烃基、芳基、杂芳基或杂环基； R 9 is selected from R 4 or a precursor group of R 4 , or a halogen , hydroxyl , carboxyl, amino, acyl, amide, alkoxy, alkylamino, mercapto, sulfonyl, hydrocarbon, aryl, heteroaryl or heterocyclic group which may be substituted by R 4 or a precursor group of R 4;
    优选地，式(VIII)化合物的制备方法包括：Preferably, the preparation method of the compound of formula (VIII) comprises:
    5-吡啶硼酸与式(X)化合物进行第三反应，得到式(XI)化合物；5-pyridineboronic acid and the compound of formula (X) undergo a third reaction to obtain a compound of formula (XI);
    式(XI)化合物与2-溴异丁酸甲酯进行第四反应，得到式(XII)化合物；The compound of formula (XI) is subjected to a fourth reaction with methyl 2-bromoisobutyrate to obtain a compound of formula (XII);
    式(XII)化合物进行第五反应，得到式(VIII)化合物；The compound of formula (XII) is subjected to a fifth reaction to obtain a compound of formula (VIII);
    所述第三反应的条件包括反应物在碱性条件下加热；The conditions of the third reaction include heating the reactants under alkaline conditions;
    所述第四反应的条件包括反应物在碱性条件下加热；The conditions of the fourth reaction include heating the reactants under alkaline conditions;
    所述第五反应为催化加氢反应，催化剂选自Pt、Pd或Ni类催化剂；The fifth reaction is a catalytic hydrogenation reaction, and the catalyst is selected from Pt, Pd or Ni catalysts;
    Figure PCTCN2023071067-appb-100047
    Figure PCTCN2023071067-appb-100047
    其中，in,
    R 10选自与2-溴异丁酸甲酯发生取代反应的基团； R 10 is selected from a group that undergoes substitution reaction with methyl 2-bromoisobutyrate;
    R 9选自R 4或R 4的前体基团，或可被R 4或R 4的前体基团取代的卤素、羟基、羧基、氨基、酰基、酰胺基、烷氧基、烷胺基、巯基、磺酰基、烃基、芳基、杂芳基或杂环基； R 9 is selected from R 4 or a precursor group of R 4 , or a halogen , hydroxyl , carboxyl, amino, acyl, amide, alkoxy, alkylamino, mercapto, sulfonyl, hydrocarbon, aryl, heteroaryl or heterocyclic group which may be substituted by R 4 or a precursor group of R 4;
    优选地，所述制备方法满足如下一个或多个条件：Preferably, the preparation method meets one or more of the following conditions:
    (1)所述方案(1)中，所述溶剂为四氢呋喃、甲醇和水中一种或多种，优选为四氢呋喃/甲醇/水＝3∶1∶1的混合溶剂；(1) In the scheme (1), the solvent is one or more of tetrahydrofuran, methanol and water, preferably a mixed solvent of tetrahydrofuran/methanol/water = 3:1:1;
    (2)所述方案(1)中，所述催化剂为氢氧化锂；(2) In the scheme (1), the catalyst is lithium hydroxide;
    (3)所述方案(1)中，所述水解反应结束后加入布朗斯特酸，例如盐酸，所述布朗斯特酸加入后体系pH为3-4；(3) In the scheme (1), after the hydrolysis reaction is completed, a Bronsted acid, such as hydrochloric acid, is added, and the pH of the system is 3-4 after the Bronsted acid is added;
    (4)所述方案(1)中，所述式(III-3)所示化合物进一步在盐酸的二氧六环溶液发生成盐反应；(4) In the scheme (1), the compound represented by the formula (III-3) is further subjected to a salt-forming reaction in a dioxane solution of hydrochloric acid;
    (5)所述方案(2)中，所述溶剂为DCM；(5) In the scheme (2), the solvent is DCM;
    (6)所述方案(2)中，所述催化剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和/或4-二甲氨基吡啶；(6) In the scheme (2), the catalyst is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and/or 4-dimethylaminopyridine;
    (7)所述方案(3)中，所述溶剂为二氯甲烷和/或DMF；(7) In the scheme (3), the solvent is dichloromethane and/or DMF;
    (8)所述方案(3)中，所述催化剂为三乙胺和/或HATU；(8) In the scheme (3), the catalyst is triethylamine and/or HATU;
    (9)所述方案(3)中，所述式(III-6)所示化合物进一步在盐酸的二氧六环溶液发生成盐反应。(9) In the scheme (3), the compound represented by the formula (III-6) further undergoes a salt-forming reaction in a hydrochloric acid solution of dioxane.
  11. 式(III-4)所示化合物，The compound represented by formula (III-4),
    Figure PCTCN2023071067-appb-100048
    Figure PCTCN2023071067-appb-100048
    其中，R 4为C 1-C 6烷氧基，环A、X、R 1和R 2如权利要求1～9中至少一项所述。 Wherein, R 4 is C 1 -C 6 alkoxy, and ring A, X, R 1 and R 2 are as described in at least one of claims 1 to 9.
  12. 如权利要求11所述式(III-4)所示化合物，其特征在于，R 4中，所述C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基、叔丁氧基或异丁氧基，例如甲氧基； The compound of formula (III-4) according to claim 11, characterized in that, in R 4 , the C 1 -C 6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy, such as methoxy;
    优选地，所述式(III-4)所示化合物为如下任一化合物：Preferably, the compound represented by formula (III-4) is any of the following compounds:
    2-(3-(1-(3′，4′-二甲基-[1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
    2-(3-(1-(3′，4′-二氟-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-(3′,4′-difluoro-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
    2-(3-(1-(3-(苯并[b]噻吩-6-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(3-(benzo[b]thiophen-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-(3-(1-(3-环己基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-甲基-2-(3-(1-(3-(噻吩-3-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸甲酯；Methyl 2-methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propanoate;
    2-甲基-2-(3-(1-(3-(噻吩-2-基)苯甲酰基)哌啶-3-基)苯氧基)丙酸甲酯；Methyl 2-methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propanoate;
    2-(3-(1-(3-(1H-吡唑-4-基)苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-(3-(1-(4′-异丙基-[1，1′-联苯基]-3-羰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-(4′-isopropyl-[1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
    2-(3-(1-([1，1′-联苯]-3-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-([1,1′-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-(3-(1-([1，1′-联苯基]-4-羰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-([1,1′-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-(3-(1-((3′，4′-二甲基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
    2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
    2-(3-(1-((4′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-((4′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-甲基-2-(3-(1-((3-(噻吩-3-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸甲酯；2-methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoic acid methyl ester;
    2-(3-(1-([1，1′-联苯基]-3-基磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-([1,1′-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-(3-(1-((3-环己基苯基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-甲基-2-(3-(1-((3-(噻吩-2-基)苯基)磺酰基)哌啶-3-基)苯氧基)丙酸甲酯；Methyl 2-methyl-2-(3-(1-((3-(thiophen-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propanoate;
    2-(3-(1-((3-(苯并[b]噻吩-6-基)苯基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((3-(Benzo[b]thiophen-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
    2-(3-(1-((3′-异丙基-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-((3′-isopropyl-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-(3-(1-((4′-(叔丁基)-[1，1′-联苯基]-3-基)磺酰基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
    2-(3-(1-(3′，4′-二甲基-[1，1′-联苯基]-3-基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
    2-(3-(1-((3′，4′-二氟-[1，1′-联苯基]-3-基)甲基)哌啶-3-基)苯氧基)-2-丙酸甲酯；2-(3-(1-((3′,4′-difluoro-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;
    2-(3-(1-((3，4-二甲基苄基)氨基甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-(3-(1-(3-(3，4-二甲基苯基)丙基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropanoate;
    2-(3-(1-2-(4-异丙基苯基乙酰基)哌啶-3-基苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-2-(4-isopropylphenylacetyl)piperidin-3-ylphenoxy)-2-methylpropanoate;
    3-(3-(3-(4-异丙基苯基丙烯酰基)哌啶-3-基苯氧基-2-甲基丙酸甲酯；3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy-2-methylpropionic acid methyl ester;
    2-(3-(1-(4-异丙基苯甲酰基)哌啶-3-基苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(4-isopropylbenzoyl)piperidin-3-ylphenoxy)-2-methylpropanoate;
    2-(3-(1-(4-异丙基苄基)氨甲酰基哌啶-3-基苯氧基)-2-甲基丙酸甲酯；Methyl 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropanoate;
    2-(3-1-联苯)-4-羰基哌啶-3-苯氧基-2-甲基丙酸甲酯；2-(3-1-biphenyl)-4-carbonylpiperidinyl-3-phenoxy-2-methylpropionic acid methyl ester;
    2-(3-1-(3′-异丙基联苯)-3-磺酰基哌啶-3-基苯氧基-2-甲基丙酸甲酯；2-(3-1-(3′-isopropylbiphenyl)-3-sulfonylpiperidin-3-ylphenoxy-2-methylpropionic acid methyl ester;
    2-(3-1-叔丁基)-3-磺酰基-3-磺酰基哌啶-2-甲基丙酸甲酯；Methyl 2-(3-1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidin-2-methylpropanoate;
    2-(3-(1-(3-异丙基苯甲酰基)哌啶-3-基)苯氧基)-2-甲基丙酸甲酯。Methyl 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropanoate.
  13. 一种药物组合物，其特征在于，其为如下任一方案：A pharmaceutical composition, characterized in that it is any of the following solutions:
    方案a：Plan A:
    药物组合物a：包含治疗有效量的物质A和药用辅料；所述物质A为如权利要求1～9至少一项所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药；Pharmaceutical composition a: comprising a therapeutically effective amount of substance A and pharmaceutical excipients; the substance A is a compound represented by formula (I) according to at least one of claims 1 to 9, or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;
    方案b：Option B:
    药物组合物b：包含物质A和免疫检查点抑制剂，其中所述物质A为如权利要求1～9至少一项所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药；Pharmaceutical composition b: comprising substance A and an immune checkpoint inhibitor, wherein the substance A is a compound of formula (I) as described in at least one of claims 1 to 9, or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;
    方案c：Option c:
    药物组合物c：包括至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂；Pharmaceutical composition c: comprising at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients;
    所述活性组分包括权利要求2～4中至少一项所述式(I)所示化合物或权利要求10所述制备方法制备得到的式(I)所示化合物，及其异构体、药学上可接受的盐或酯中的任意一种或多种。The active component comprises the compound of formula (I) as described in at least one of claims 2 to 4 or the compound of formula (I) prepared by the preparation method described in claim 10, and any one or more of its isomers, pharmaceutically acceptable salts or esters.
  14. 一种物质A在制备药物中的应用，其特征在于，所述药物用于治疗和/或预防肿瘤，所述物质A为如式(I)所示化合物、其异构体、其药学上可接受的盐、酯或其前药；A use of a substance A in the preparation of a drug, characterized in that the drug is used to treat and/or prevent tumors, and the substance A is a compound as represented by formula (I), an isomer thereof, a pharmaceutically acceptable salt, ester or a prodrug thereof;
    Figure PCTCN2023071067-appb-100049
    Figure PCTCN2023071067-appb-100049
    其中，R 1、R 2、X和R 3如权利要求1～9中至少一项所述； wherein R 1 , R 2 , X and R 3 are as described in at least one of claims 1 to 9;
    优选地，所述肿瘤为乳腺癌、结肠癌、肝癌、多发性骨髓瘤、肉瘤、肺癌、前列腺癌、直肠癌、肾癌、胰腺癌、血癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、卵巢癌、外阴癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤或皮肤癌，进一步优选地，所述肿瘤为乳腺癌、结肠癌或肝癌；更进一步地，所述应用中，所述物质A为如权利要求6～9中至少一项所述式(III)所示化合物或其药学上可接受的盐。Preferably, the tumor is breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, blood cancer, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, gastrointestinal stromal tumor or skin cancer. Further preferably, the tumor is breast cancer, colon cancer or liver cancer. Furthermore, in the application, the substance A is a compound of formula (III) or a pharmaceutically acceptable salt thereof as described in at least one of claims 6 to 9.
  15. 权利要求1～9中至少一项所述式(I)所示化合物，或其异构体，或其药学上可接受的盐、酯或前药、权利要求10所述方法制备得到的式(I)所示化合物或权利要求13所述药物组合物在制备抗肿瘤药物中的应用，优选地，所述应用中，所述肿瘤包括乳腺癌、结肠癌、肝癌、肺癌、前列腺癌、直肠癌、肾癌、胰腺癌、血癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、卵巢癌、外阴癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤、皮肤癌。Use of the compound of formula (I) according to at least one of claims 1 to 9, or its isomer, or its pharmaceutically acceptable salt, ester or prodrug, the compound of formula (I) prepared by the method according to claim 10, or the pharmaceutical composition according to claim 13 in the preparation of anti-tumor drugs, preferably, in the application, the tumor includes breast cancer, colon cancer, liver cancer, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, blood cancer, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, gastrointestinal stromal tumor, skin cancer.
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