WO2022048605A1 - Heterocyclic compound, preparation method therefor, intermediate, composition, and applications - Google Patents

Heterocyclic compound, preparation method therefor, intermediate, composition, and applications Download PDF

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WO2022048605A1
WO2022048605A1 PCT/CN2021/116287 CN2021116287W WO2022048605A1 WO 2022048605 A1 WO2022048605 A1 WO 2022048605A1 CN 2021116287 W CN2021116287 W CN 2021116287W WO 2022048605 A1 WO2022048605 A1 WO 2022048605A1
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ring
formula
independently
alkyl
hydrogen
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PCT/CN2021/116287
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Chinese (zh)
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WO2022048605A8 (en
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张继跃
杨光
李文龙
邓斌
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南昌奥瑞药业有限公司
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    • 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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a heterocyclic compound, its preparation method, intermediate and application.
  • Prostate cancer is a common male malignant tumor, and its incidence worldwide is second only to lung cancer, ranking second in all male malignant tumors.
  • the incidence of prostate cancer in China is increasing year by year, and it is expected that by 2020, prostate cancer will become the third leading cause of cancer deaths among men in my country.
  • androgen deprivation therapy (ADT) is the main treatment for early-stage prostate cancer, including surgical castration and medical castration.
  • ADT cannot cure prostate cancer.
  • CRPC castration-resistant prostate cancer
  • the proliferation or mutation of the androgen receptor (AR) can make it sensitive to lower levels of androgens in serum, which is the main reason for the deterioration of prostate cancer.
  • the representative drugs of androgen receptor inhibitors for the treatment of CRPC include abiraterone, enzalutamide, etc.
  • 15-25% of patients do not respond to second-generation hormonal therapy such as abiraterone and enzalutamide, and most patients who do respond eventually develop severe drug resistance, leading to poor prognosis.
  • UPS The ubiquitin-proteasome system
  • UPS The ubiquitin-proteasome system
  • Ub The ubiquitin-proteasome system
  • E1 ubiquitin
  • E2 ubiquitin-conjugating enzyme
  • E3 ubiquitin-protein ligase
  • 26S proteasome The ubiquitin-activating enzyme system is responsible for activating ubiquitin and binding it to the protein to be degraded to form a polyubiquitin chain of the target protein, that is, ubiquitination.
  • the proteasome system recognizes and degrades ubiquitinated proteins.
  • Protein proteolysis-targeting chimeras is a hybrid bifunctional small molecule compound, including a small molecule compound that can bind to the target protein, linking groups at its appropriate position, and then Linked with a small molecule compound capable of binding to E3 ubiquitin ligase.
  • PROTACs form a target protein-PROTACs-E3 ternary polymer by bringing the target protein and intracellular E3 closer, and add ubiquitinated protein tag to the target protein through E3 ubiquitin ligase, and utilize ubiquitin-proteasome.
  • the ubiquitin-proteasome system specifically degrades target proteins.
  • Arvinus disclosed a class of degraders targeting androgen receptors (US 2018/0099940 A1), the representative drug ARV-110, which is currently in clinical phase I for the treatment of CRPC. Phase I data also demonstrated that ARV-110 was safe and effective in patients with metastatic castration-resistant prostate cancer (mCRPC).
  • mCRPC metastatic castration-resistant prostate cancer
  • the technical problem to be solved by the present invention is to provide a heterocyclic compound, its preparation method, intermediate and application in order to overcome the defect of few types of degradation agents targeting androgen receptor in the prior art.
  • the heterocyclic compounds of the present invention have better inhibitory activity on AR-dependent LNCap cells, which can be used for the treatment of prostate cancer.
  • the present invention mainly solves the above technical problems through the following technical solutions.
  • the present invention provides a compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its prodrug,
  • R 2 is hydrogen or
  • D is O, NR 6-1 or CR 6-2 R 6-3 ;
  • Ring W is a C 6 -C 10 aromatic ring, a C 6 -C 10 aromatic ring substituted by one or more R 8-1 (when there are multiple R 8-1 , R 8-1 is the same or different), 5- 10-membered heteroaromatic ring, or 5-10-membered heteroaromatic ring substituted by one or more R 8-2 (when R 8-2 is more than one, R 8-2 is the same or different); the 5-10
  • the heteroatom in the membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 8-2 substituted 5
  • the heteroatoms in the 5-10-membered heteroaromatic ring described in the -10-membered heteroaromatic ring are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4;
  • Ring Z is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
  • Ring Y is C 3 -C 10 alicyclic, C 3 -C 10 alicyclic substituted by one or more R 9-1 , 3-10 membered heteroalicyclic, or 3- alicyclic substituted by one or more R 9-2 10-membered heteroalicyclic ring; the heteroatoms in the 3-10-membered heteroalicyclic ring are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3; the described The heteroatoms in the 3-10-membered heteroalicyclic ring in the 3-10-membered heteroalicyclic ring substituted by one or more R 9-2 are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3;
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 4 alkyl
  • R 2-1 is C 1 -C 4 alkyl
  • R 6-1 is hydrogen or C 1 -C 4 alkyl
  • R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 11-1 and R 11-2 are independently hydrogen, halogen or C 1 -C 4 alkyl;
  • R 8-1 and R 8-2 are independently halogen or C 1 -C 4 alkyl
  • R 9-1 and R 9-2 are independently halogen, hydroxy or C 1 -C 4 alkyl.
  • the halogen eg R 1 , C 1 -C 4 alkyl substituted by one or more halogens, R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 8-1 , R 8-2 , R 9-1 , R 9-2 , R 11-1 , R 11-2 etc. halogen
  • R 1 , C 1 -C 4 alkyl substituted by one or more halogens, R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 8-1 , R 8-2 , R 9-1 , R 9-2 , R 11-1 , R 11-2 etc. halogen independently is fluorine, chlorine, bromine or iodine, such as fluorine, chlorine or bromine.
  • the C 1 -C 4 alkyl (R 1 , one or more halogen-substituted C 1 -C 4 alkyl, R 1-1 , R 1-2 , R 2-1 , R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 8-1 , R 8-2 , R 9-1 , R C 1 -C 4 alkyl in 9-2 , R 11-1 , R 11-2 , etc.) is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl, eg methyl.
  • the C 1 -C 4 alkoxy group (eg R 1 , one or more halogen-substituted C 1 -C 4 alkoxy groups C 1 -C 4 alkoxy in radicals etc.) is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert- Butoxy.
  • the C 6 -C 10 aryl group is a benzene ring or a naphthalene ring, preferably a benzene ring.
  • the C 6 -C 10 aryl group is a benzene ring or a naphthalene ring, such as benzene ring.
  • the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring; the 5-10-membered heteroaromatic ring And the heteroatom in the 5-6 membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1 or 2.
  • the 5-6 membered heteroaromatic ring is preferably a pyridazine ring, a pyridine ring, a pyrimidine ring or a pyrazine ring.
  • the pyridazine ring is preferably The pyridine ring is preferably The pyrimidine ring is preferably Described pyrazine ring is preferably
  • the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring;
  • the heteroatom in the 5-10-membered heteroaromatic ring and the 5-6-membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1 or 2.
  • the 5-6 membered heteroaromatic ring is preferably a pyridazine ring or a pyridine ring.
  • the pyridazine ring is preferably The pyridine ring is preferably
  • the number of the R 8-2 is one.
  • the C 6 -C 10 aromatic ring is a benzene ring or a naphthalene ring, such as a benzene ring.
  • the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring; the 5-10-membered heteroaromatic ring and the heteroatom in the 5-6 membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1.
  • Described 5-10 yuan heteroaromatic ring is preferably pyridine ring, more preferably
  • the C 3 -C 10 alicyclic ring is a C 4 -C 7 alicyclic ring, preferably a butane ring, a pentane ring, a hexyl ring , heptyl or spiro[3,3]heptyl.
  • the C 3 -C 10 alicyclic ring may be a single ring or a spiro ring, such as a single ring.
  • the C 4 -C 10 alicyclic is a C 4 -C 6 alicyclic, Preferably it is butane, pentane or hexyl.
  • the C 3 -C 10 alicyclic ring in the one or more R 9-1 substituted C 3 -C 10 alicyclic rings may be monocyclic or spirocyclic, such as monocyclic.
  • the number of the R 9-1 is 1, 2 or 4.
  • the 3-10 membered heteroalicyclic ring is a 5-6 membered heteroalicyclic ring; the 3-10 membered heteroalicyclic ring and the heteroatom in the 5-6 membered heteroalicyclic ring is preferably N, and the number of heteroatoms is preferably 1.
  • the 3-10-membered heteroalicyclic ring is preferably a tetrahydropyrrole ring or a piperidine ring. Described tetrahydropyrrole ring is preferably Described piperidine ring is preferably The 3-10 membered heteroalicyclic ring may be a single ring or a spiro ring.
  • the 3-10-membered heteroalicyclic ring is a 5-6-membered heteroalicyclic ring;
  • the heteroatom in the 3-10-membered heteroalicyclic ring and the 5-6-membered heteroalicyclic ring is preferably N, and the number of heteroatoms is preferably 1.
  • the 3-10-membered heteroalicyclic ring is preferably a tetrahydropyrrole ring or a piperidine ring.
  • Described tetrahydropyrrole ring is preferably Described piperidine ring is preferably
  • the 3-10-membered heteroalicyclic ring in the one or more R 9-2 substituted 3-10-membered heteroalicyclic rings can be a monocyclic ring or a spirocyclic ring.
  • the number of the R 9-2 is one.
  • R 3-1 and R 3-2 are independently hydrogen, halogen, hydroxy or C 1-4 alkyl
  • A is N or CR 4-1 ;
  • B is N or CR 4-2 ;
  • C is N or CR 4-3 ;
  • E is N or CR 4-4 ;
  • F is N or CR 4-5 ;
  • G is independently NR 5-1 or CR 5-2 R 5-3 ;
  • L is independently NR 10-1 or CR 10-2 R 10-3 ;
  • R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R 5-2 , R 5-3 , R 10-2 , R 10-3 are independently hydrogen, halogen or C 1 -C 4 alkyl;
  • R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl
  • n and n are independently 0, 1, 2 or 3;
  • n1, m2, n1, and n2 are independently 0, 1, 2, or 3, and m1 and n1 are not both 0, and m2 and n2 are not both 0.
  • the halogen eg R 3-1 , R 3-2 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R 4-1 , 5-2 , R 5-3 , R 10-2 , R 10-3 , etc. halogen
  • R 3-1 , R 3-2 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R 4-1 , 5-2 , R 5-3 , R 10-2 , R 10-3 , etc. halogen are independently fluorine, chlorine, bromine or iodine.
  • the C 1 -C 4 alkyl group (R 3-1 , R 3-2 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-1 C 1 -C 4 alkyl in 4-5 , R 5-1 , R 5-2 , R 5-3 , R 10-2 , R 10-3 , etc.) is independently methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 1 is halogen or one or more halogen substituted C 1 -C 4 alkyl, eg halogen.
  • R2 is hydrogen .
  • R 3-1 and R 3-2 are independently hydrogen, hydroxy or C 1-4 alkyl.
  • B is CR 4-2 .
  • C is CR 4-3 .
  • ring W is a C6 - C10 aromatic ring, a 5-10 membered heteroaromatic ring, or a 5-10 membered heteroaromatic ring substituted with one or more R8-2 , such as C6 -C 10 aromatic rings.
  • R 4-1 is hydrogen
  • R 4-2 is hydrogen
  • R 4-3 is hydrogen
  • R 4-4 is hydrogen
  • R 5-2 and R 5-3 are hydrogen.
  • R 6-1 is hydrogen
  • R 6-2 and R 6-3 are hydrogen.
  • R 7-1 and R 7-2 are hydrogen.
  • R 8-2 is independently halogen.
  • R 9-2 is independently C 1 -C 4 alkyl.
  • R 10-2 and R 10-3 are independently hydrogen or C 1 -C 4 alkyl.
  • R 11-1 and R 11-2 are hydrogen.
  • m is 0, 1 or 2.
  • n 0, 1 or 2.
  • the one or more halogen-substituted C 1 -C 4 alkyl groups are trifluoromethyl groups.
  • D is O or NH, eg O.
  • R2 is hydrogen .
  • ring W is
  • n1, m2, n1 and n2 are one.
  • R 1 is halogen or C 1 -C 4 alkyl substituted with one or more halogens
  • R 2 is hydrogen
  • R 3-1 and R 3-2 are independently hydrogen, hydroxyl or C 1-4 alkyl
  • A is N or CH
  • B is CH
  • D is O, NH or CH 2 ;
  • E is N or CH
  • F is N or CR 4-5 ;
  • G is independently NR 5-1 or CH 2 ;
  • L is independently NR 10-1 or CR 10-2 R 10-3 ;
  • Ring W is a C 6 -C 10 aromatic ring, a 5-10-membered heteroaromatic ring, or a 5-10-membered heteroaromatic ring substituted by one or more R 8-2 ;
  • the atom is selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 8-2 substituted 5-10-membered heteroaromatic rings
  • the heteroatom in the 5-10-membered heteroaromatic ring described in is selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatom is 1, 2, 3 or 4;
  • R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl
  • R 8-2 is independently halogen
  • R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl
  • R 10-2 and R 10-3 are independently hydrogen or C 1 -C 4 alkyl
  • n and n are independently 0, 1, 2, or 3;
  • n1, m2, n1, and n2 are independently 0, 1, 2, or 3, and m1 and n1 are not both 0, and m2 and n2 are not both 0.
  • R 1 is halogen
  • R 2 is hydrogen
  • R 3-1 and R 3-2 are independently hydrogen
  • A is N or CH
  • B is CH
  • D is O, NH or CH 2 ;
  • E is N or CH
  • F is N or CR 4-5 ;
  • G is independently NR 5-1 or CH 2 ;
  • L is independently NR 10-1 or CH 2 ;
  • Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
  • R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl
  • R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl
  • n 0 or 1
  • n 1 or 2.
  • R 1 is halogen
  • R 2 is hydrogen
  • R 3-1 and R 3-2 are independently hydrogen
  • A is N or CH
  • B is CH
  • D is O, NH or CH 2 ;
  • E is CH
  • F is N or CR 4-5 ;
  • G is independently NR 5-1 or CH 2 ;
  • L is independently NR 10-1 or CH 2 ;
  • Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
  • R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl
  • R 5-1 and R 10-1 are independently C 1 -C 4 alkyl
  • n 0 or 1
  • n 1 or 2.
  • R 1 is chlorine
  • R 2 is hydrogen
  • R 3-1 and R 3-2 are independently hydrogen
  • A is CH
  • B is CH
  • E is CH
  • G is independently CH 2 ;
  • L is independently CH 2 ;
  • Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
  • R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl
  • R 5-1 and R 10-1 are independently C 1 -C 4 alkyl
  • n 0 or 1
  • n 2;
  • the compound shown in formula I is the compound shown in formula Ia or Ib:
  • D is O or NH
  • D is attached to a carbon atom on ring Y, The a terminal in the middle is connected to the carbon atom on the ring Y;
  • Ring Z, ring Y, ring W, K, M, N, R 1 and R 2 are as defined above;
  • (straight dashed key) and (Straight solid line bond) represents that the connecting group connected to it is located on both sides of the plane of the ring Y; in formula Ib, (straight dashed key) and (Straight dashed bond) indicates that the link to which it is attached is on the same side of the Y plane of the ring.
  • the compound shown in formula I is the compound shown in formula Ic:
  • ring Y is pentane ring or hexyl ring; ring Z, K, M, R 1 and R 2 are as defined above;
  • R 1 is halogen (eg fluorine, chlorine or bromine);
  • R 2 is H
  • the compound shown in the formula I is the compound shown in the formula Id:
  • R 1 is halogen (eg chlorine);
  • R 2 is H
  • Ring Z is a C 6 -C 10 aromatic ring (eg, a benzene ring);
  • the compound shown in formula I is any of the following compounds:
  • the compound shown in formula I is any of the following compounds,
  • the present invention also provides a method for preparing the compound shown in the formula I, which is any of the following methods:
  • the first method includes the following steps: in a solvent, under the action of a base and a condensing agent, the compound shown in formula IV and the compound shown in formula V are subjected to the condensation reaction shown below,
  • the second method comprises the following steps: in a solvent, the compound shown in formula VI is subjected to the deprotection reaction shown below under the action of an acid,
  • the third method includes the following steps: in a solvent, the compound shown in formula VII and the compound shown in formula VIII are subjected to the addition reaction shown below,
  • the solvent can be a conventional solvent for this type of reaction in the field, and the present invention is particularly preferably an amide solvent, more preferably N,N-dimethylformamide.
  • the molar concentration of the compound shown in formula IV in the solvent can be the conventional molar concentration of this type of reaction in the field, and the present invention is particularly preferably 0.0001-0.1 mol/L, More preferably, it is 0.004 to 0.01 mol/L (for example, 0.008 mol/L).
  • the base can be a conventional base for this type of reaction in the art, preferably an organic amine, more preferably N,N-diisopropylethylamine.
  • the molar ratio of the base to the compound represented by the formula IV can be the conventional molar ratio of this type of reaction.
  • the molar ratio is particularly preferably 0.8:1 to 3:1, more preferably 0.9:1 to 1.3:1 (eg 1:1).
  • the described condensing agent can be a conventional condensing agent for this type of reaction in the field, and the present invention is particularly preferably 2-(7-azabenzotriazole)-N,N,N', N'-tetramethylurea hexafluorophosphate.
  • the molar ratio of the condensing agent to the compound represented by the formula IV can be the conventional molar ratio of this type of reaction, which is particularly preferably 1:1 to 3:1 in the present invention, and further It is preferably 1:1 to 1.5:1 (for example, 1.2:1).
  • the molar ratio of the compound represented by the formula V to the compound represented by the formula IV can be the conventional molar ratio of this type of reaction, and the present invention is particularly preferably 0.8:1 ⁇ 3:1, more preferably 0.9:1 to 1.3:1 (for example, 1:1).
  • the reaction temperature of the condensation reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
  • the reaction progress can be monitored by conventional monitoring methods (such as TLC, HPLC or NMR) in the art, generally to monitor the compound shown in the formula V or the compound shown in the formula IV.
  • the disappearance of the indicated compound is the end point of the reaction.
  • the reaction time of the condensation reaction is preferably 1 to 3 hours (for example, 2 hours).
  • a post-processing step may be further included.
  • the post-processing steps may include concentration and purification.
  • the purification method can be preparative TLC.
  • the eluent used in the preparation of TLC can be dichloromethane and methanol (the volume ratio is preferably 15:1).
  • the solvent can be a conventional solvent for this type of reaction in the field, and the present invention is particularly preferably an ether solvent, more preferably dioxane.
  • the molar concentration of the compound represented by formula VI in the solvent can be the conventional molar concentration of this type of reaction in the field, and the present invention is particularly preferably 0.0001-0.1 mol/L , more preferably 0.002 to 0.004 mol/L (for example, 0.0028 mol/L).
  • the acid can be a conventional acid for this type of reaction in the art, preferably an inorganic acid, more preferably hydrochloric acid.
  • the reaction temperature of the deprotection reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
  • the progress of the reaction can be monitored by conventional monitoring methods in the art (eg TLC, HPLC or NMR), and the end point of the reaction is generally to monitor the disappearance of the compound represented by formula VI.
  • the reaction time of the deprotection reaction is preferably 1 to 3 hours (for example, 2 hours).
  • a post-processing step may be further included.
  • the post-processing steps may include concentration.
  • the solvent can be a conventional solvent for this type of reaction in the field, and the present invention is particularly preferably an amide solvent, more preferably N,N-dimethylformamide.
  • the molar ratio of the compound represented by the formula VII to the compound represented by the formula VIII can be the conventional molar ratio of this type of reaction, and the present invention is particularly preferably 0.8:1 -3:1, more preferably 0.9:1 - 1.3:1 (for example, 1:1).
  • the reaction temperature of the addition reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
  • reaction progress can be monitored by conventional monitoring methods (such as TLC, HPLC or NMR) in the art, generally to monitor the compound shown in the formula VII or the compound shown in the formula VII.
  • the disappearance of the compound represented by VIII was the end point of the reaction.
  • the reaction time of the addition reaction is preferably 1 to 3 hours (for example, 2 hours).
  • a post-processing step may be further included.
  • the post-processing steps may include concentration and purification.
  • the present invention also provides a compound of formula IV or a stereoisomer thereof,
  • the compound shown in formula IV is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the stereoisomer of the compound represented by formula IV is
  • the present invention also provides a compound of formula VI or a stereoisomer thereof,
  • the compound shown in formula VI is the compound shown in formula VI-a or VI-b:
  • Ring Z, ring Y', D, K, M, ring W, R 1 and R 2 are as defined above;
  • (straight dashed key) and (Straight solid line bond) represents that the connecting group connected to it is located on both sides of the Y plane of the ring; in formula VI-b, (straight dashed key) and (Straight dashed bond) indicates that the link to which it is attached is on the same side of the Y plane of the ring.
  • the compound represented by the formula VI is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the stereoisomer of the compound represented by formula VI is
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, Its metabolites or prodrugs thereof, and pharmaceutically acceptable excipients.
  • the present invention also provides a compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its precursor
  • the invention relates to the application of the medicine, or the pharmaceutical composition, in the preparation of an androgen receptor degrading agent.
  • the present invention also provides a compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its precursor
  • the invention relates to the application of the medicine, or the pharmaceutical composition, in the preparation of a medicine for treating androgen receptor-related diseases.
  • the androgen receptor-related disease is prostate cancer, preferably metastatic castration-resistant prostate cancer.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • the aryl group represents the linking arylene group.
  • plural refers to 2, 3, 4, 5 or 6.
  • substituents or hetero atoms may be the same or different.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound of the present invention with a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • stereoisomers includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomer and (L)-isomer.
  • tautomer refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also referred to as proton tautomers
  • proton tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-enamine isomerization.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • solvate refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvent molecules in solvates can exist in ordered or non-ordered arrangements.
  • the solvent includes, but is not limited to, water, methanol, ethanol, and the like.
  • alicyclic refers to a saturated cyclic structure consisting of carbon atoms.
  • heteroalicyclic refers to a saturated cyclic structure composed of carbon atoms and heteroatoms, wherein the heteroatoms are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3 .
  • the room temperature in the present invention is 10-30°C.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that the heterocyclic compound of the present invention has better inhibitory activity on AR-dependent LNCap cells, and has less toxicity to AR-independent PC-3 cells.
  • Step 1 Dissolve 5-fluorobenzofuran-1,3-dione (5.0 g, 30.1 mmol, 1 eq) in acetic acid (50 mL), add 3-aminopiperazine-2,6-dione (4.2 g, 33.1 mmol, 1.1 eq) and potassium acetate (5.9 g, 60.2 mmol, 2 eq) and the resulting mixture was stirred at 90°C overnight. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, water (50 mL) was added, a solid was precipitated, suction filtered, the filter cake was washed with water, and dried to obtain 8.05 g of a gray solid.
  • Step 2 Dissolve the product obtained in Step 1 (3.0g, 10.9mmol, 1eq) in DMSO (50mL), add N-Boc piperazine (3.0g, 16.3mmol, 1.5eq) and DIEA (2.8g, 21.7mmole) respectively , 2eq), and the resulting mixture was stirred at 130°C for 3h. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, water (50 mL) was added, a solid was precipitated, suction filtration, the filter cake was washed with water, and dried to obtain a yellow solid 3.63g. ESI MS m/z 343[M+H] + .
  • Step 4 Dissolve the product obtained in Step 3 (2g, 28.8mmol, 1eq) in tert-butanol (50mL), add Boc anhydride (7.6g, 34.6mmol, 1.2eq), triethylamine (4.4g, 43.2mmol) respectively , 1.2 eq) and DMAP (352 mg, 2.9 mmol, 0.1 eq), and the resulting mixture was stirred at room temperature overnight.
  • Boc anhydride 7.6g, 34.6mmol, 1.2eq
  • triethylamine 4.4g, 43.2mmol
  • DMAP 352 mg, 2.9 mmol, 0.1 eq
  • Step 6 Dissolve the product obtained in step 5 (265 mg, 0.77 mmol, 1 eq) in dichloromethane (20 mL), add the product obtained in step 2 (237 mg, 0.77 mmol, 1 eq), stir at room temperature for half an hour, add acetic acid borohydride Sodium (328 mg, 1.55 mmol, 2 eq) and the resulting mixture was stirred at room temperature for 3.5 h.
  • Step 8 The trans product (100 mg, 0.34 mmol, 1 eq) obtained in Step 7 was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
  • Step 7 of Example 1 respectively obtain a trans-intermediate with a large Rf value and a cis-type intermediate with a small Rf value, and the trans-intermediate according to the synthetic method of Example 1, finally obtain a yellow solid product 3a 11mg .
  • Example 3 The cis intermediate in Example 3 was obtained according to the synthetic method of Example 1 to obtain 12 mg of yellow solid product 3b. ESI MS m/z 780[M+H] + .
  • Step 1 Dissolve 2-chloro-5-fluorobenzonitrile (500mg, 3.21mmol, 1eq) and methyl trans-4-aminocyclohexanecarboxylate (505mg, 3.21mmol, 1eq) in dioxane (20mL) ), triethylamine (650 mg, 6.43 mmol, 2 eq) was added, and the mixture was stirred at 120°C overnight. After the reaction was detected by TLC, dioxane was removed under reduced pressure, the residue was dissolved in methanol (20 mL), 10% aqueous NaOH solution (20 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
  • Step 1 Dissolve 2-chloro-5-bromomethylbenzonitrile (500mg, 2.17mmol, 1eq), methyl piperidine-4-carboxylate (372mg, 2.6mmol, 1.2eq) in anhydrous acetonitrile (20mL) To the solution, potassium carbonate (450 mg, 3.25 mmol, 1.5 eq) was added, followed by stirring at room temperature. After the reaction was detected by TLC, acetonitrile was removed under reduced pressure, the residue was dissolved in methanol (20 mL), 10% aqueous NaOH solution (20 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
  • Step 2 The product obtained in step 1 (100 mg, 0.26 mmol, 1 eq) was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
  • Step 4 Dissolve the product obtained in Step 3 (15 mg, 0.017 mmol, 1 eq) in dioxane (5 mL), slowly drop HCl in dioxane solution (4 M, 1 mL), and stir at room temperature for 2 h. After the reaction was detected by TLC, the solvent was removed under reduced pressure to obtain 16 mg of yellow solid product 6.
  • Step 1 The product obtained in Step 1 of Example 7 (100 mg, 0.26 mmol, 1 eq) was dissolved in dioxane (10 mL), slowly added dropwise to a solution of HCl in dioxane (5 mL), and stirred at room temperature for 2 h. After the reaction was detected by TLC, the solvent was removed under reduced pressure to obtain 73 mg of yellow solid product. ESI MS m/z 281[M+H] + .
  • Step 2 The product obtained in step 1 (73mg, 0.26mmol, 1eq) was dissolved in anhydrous acetonitrile (20mL), potassium carbonate (72mg, 0.52mmol, 2eq) and methyl iodide (44mg, 0.31mmol, 1.2eq) were added respectively. Then, stir at room temperature. After the reaction was detected by TLC, acetonitrile was removed under reduced pressure, diluted with ethyl acetate (50 mL), washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to obtain 65 mg of the product. ESI MS m/z 295[M+H] + .
  • Step 3 The product obtained in Step 2 (65 mg, 0.22 mmol, 1 eq) was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
  • Example 9 14 mg of yellow solid product 9 was obtained according to the synthetic method of Example 8. ESI MS m/z 780[M+H] + .
  • Step 1 Dissolve N-Boc piperidine methanol (776mg, 3.86mmol, 1.2eq) in anhydrous THF, add sodium hydrogen (193mg, 4.82mmol, 60%, 1.5eq) at 0°C, stir under nitrogen for 30min After that, 2-chloro-5-fluorobenzonitrile (500 mg, 3.21 mmol, 1 eq) was added, and the mixture was stirred at room temperature for 4 h.
  • Step 1 Mix 5,6-dichloropyridin-3-ol (500mg, 3.05mmol, 1eq), methyl(1R,3R)-3-ethanesulfonyloxy)cyclopentane-1-carboxylate (792mg , 3.35mmol, 1.1eq) was dissolved in DMF (20mL), potassium carbonate (506mg, 3.66mmol, 1.2eq) was added, and stirred at 90°C.
  • Step 2 Dissolve the product obtained in step 1 (50mg, 0.17mmol, 1eq) in anhydrous DMF (10mL), add zinc cyanide (12mg, 0.10mmol, 0.6eq) and tetrakistriphenylphosphine palladium (20mg, 0.02 mmol, 0.1 eq), stirred at 120 °C for 2 h under nitrogen.
  • Step 3 The product obtained in Step 2 (25 mg, 0.086 mmol, 1 eq) was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
  • Step 1 Dissolve 4-fluoronitrobenzene (500mg, 3.54mmol, 1eq), piperidine-4-methanol (490mg, 4.25mmol, 1.2eq) in dioxane (20mL), add DIEA (696uL, 4.25 mmol, 1.2 eq) and stirred at 120°C overnight. After the reaction was detected by TLC, water (50 mL) was added to dilute, and ethyl acetate (50 mL) was used for extraction. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 250 mg of product by column chromatography. ESI MS m/z 237[M+H] + .
  • Step 3 Dissolve the product obtained in Step 2 (180 mg, 0.77 mmol, 1 eq) in dichloromethane (20 mL), add the product of Step 2 in Example 1 (237 mg, 0.77 mmol, 1 eq), and stir at room temperature for half an hour, Sodium borohydride acetate (328 mg, 1.55 mmol, 2 eq) was added and the resulting mixture was stirred at room temperature for 3.5 h.
  • Step 4 Dissolve the product obtained in Step 3 (160mg, 0.29mmol, 1eq) in a mixed solvent of methanol and saturated ammonium chloride solution (1:1, 20mL), add iron powder (80mg, 1.43mmol, 1eq), After stirring at 80 degrees for half an hour, dichloromethane (50 mL) was added for extraction, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to obtain 152 mg of crude product.
  • ESI MS m/z 531[M+H] + .
  • Example 18 Prepared with Example 18 As starting material, following the procedure of Example 17, 10 mg of yellow solid 18 was obtained, ESI MS m/z 779 [M+H] + .
  • Example 14 Using methyl 1-methyl-3-hydroxycyclopentanecarboxylate as a raw material, according to the operation of Example 14, a trans intermediate with a large Rf value and a cis intermediate with a small Rf value were obtained, and the trans intermediate was carried out. In the next step, 10 mg of trans product 19 was finally obtained, ESI MS m/z 794 [M+H] + .
  • Example 14 Using methyl 1-fluoro-3-hydroxycyclopentanecarboxylate as a raw material, according to the operation of Example 14, a trans intermediate with a large Rf value and a cis intermediate with a small Rf value were obtained, and the trans intermediate was subjected to the following steps. In one step, 20 8 mg of trans-yellow solid was finally obtained, ESI MS m/z 798 [M+H] + .
  • Step 1 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolinone-5-yl)piperazine-1-tert-butyl carbonate Ester (1g, 2.26mmol, 1eq) was dissolved in acetic acid, zinc powder (1.48g, 22.6mmol, 10eq) was added, stirred at 60°C for 1h, cooled, suction filtered, the filtrate was concentrated, diluted with 20mL of water, saturated sodium bicarbonate The pH was adjusted to neutral, extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a mixture of 470 mg, ESI MS m/z 445 [M+H] + .
  • Step 2 The product obtained in Step 1 (470mg, 1.06mmol, 1eq) was dissolved in dichloromethane, and trifluoroacetic acid (923mg, 9.52mmol, 9eq) and triethylsilane (737mg, 22.6mmol, 6eq) were added dropwise respectively. , after stirring at room temperature for 2 h, the reaction solution was concentrated, prepared and separated to obtain 210 mg of the 3 -position substituted product.
  • Step 3 Dissolve the above products (1eq) in THF respectively, add (6-(4-formylpiperidin-1-yl)pyridazin-3-yl)carbamic acid tert-butyl ester (1eq) and stir at room temperature for 30min.
  • Step 4 Substitute (1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexane-1-carboxylic acid (30mg, 0.107mmol, 1eq), the 3- and 2-position obtained in step 3
  • the product 56mg, 0.107mmol, 1eq
  • DIEA 20mg, 0.132mmol, 1.2eq
  • HATU 51mg, 0.132mmol, 1.2eq
  • reaction was quenched with saturated aqueous ammonium chloride solution, extracted with EA, the organic phases were combined, water was removed with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 100 mg of product, ESI MS m/z 324 [M+H] + .
  • PC-3 cells procell, Cat. No. CL-0185.
  • LNCaP cells Wuhan Proceeds Life Science and Technology.
  • NC negative control
  • PC positive control
  • NC negative control
  • PC positive control
  • 158 is the molecule whose compound number is 158 in US 2018/0099940 A1, and the structure is as follows,
  • Mass spectrometry conditions LC-MS/MS was used for determination, the ion source was APIC source, positive ionization mode was used for detection, and the scanning mode was selective reaction monitoring (MRM).
  • MRM selective reaction monitoring
  • mice Male, weighing 180-220g, fasted for 12h, and given the sample solution by oral administration at a dose of 5mg/kg [the vehicle is PEG300:Solutol HS 15:pH 4.65 acetate buffer(10:10:80)], Before administration, blank blood was taken, and about 100 ⁇ L of venous blood was collected at different time points after administration, placed in a test tube with heparin, centrifuged, and about 50 ⁇ L of plasma was collected and stored at -20°C for testing. The blood collection time points were: 18min, 30min, 60min, 120min, 240min, 360min, 480min, 1440min. Take 50 ⁇ L of rat plasma sample, centrifuge at 5500 rpm for 18 minutes, and take 10 ⁇ L for LC-MS/MS determination. The plasma concentration was calculated by the established standard curve.
  • PK parameter 2a 158 PO AUC(0-t)(nM.h) 2075 ⁇ 582 6782 ⁇ 735 Cmax(nM) 250 ⁇ 85 453 ⁇ 43 Tmax(h) 2.0 ⁇ 0.0 4.0 ⁇ 0.0 T 1/2 (h) 5.2 ⁇ 1.0 17.9 ⁇ 6.5

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Abstract

Provided are a compound as represented by formula I, a stereoisomer of same, a tautomer of same, a solvate of same, a pharmaceutically acceptable salt of same, a metabolic product of same, or a prodrug of same. The compound has improved inhibitory activity with respect to AR-dependent LNCap cells and has reduced toxicity with respect to AR-independent PC-3 cells. <img file="dest_path_image002.jpg" he="140.76" img-content="drawing" img-format="jpg" inline="yes" orientation="portrait" wi="160.87"/>

Description

一种杂环化合物、其制备方法、中间体、组合物以及应用A kind of heterocyclic compound, its preparation method, intermediate, composition and application
本申请要求申请日为2020年9月4日的中国专利申请2020109214641的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2020109214641 with a filing date of September 4, 2020. This application cites the full text of the above Chinese patent application.
技术领域technical field
本发明涉及药物化学领域，具体涉及一种杂环化合物、其制备方法、中间体以及应用。The invention relates to the field of medicinal chemistry, in particular to a heterocyclic compound, its preparation method, intermediate and application.
背景技术Background technique
前列腺癌是一种常见的男性恶性肿瘤，在全球范围内的发病率仅次于肺癌，排在所有男性恶性肿瘤第二位。中国前列腺癌发病率逐年递增，预计到2020年前列腺癌将成为我国男性癌症死亡第三大疾病。目前，雄激素去势治疗(ADT)是早期前列腺癌主要治疗方法，包括手术去势法和药物去势法。但ADT不能治愈前列腺癌，经过14-30个月的中位治疗时间后，几乎所有患者都会逐渐发展为去势抵抗性前列腺癌(CRPC)，患者对ADT不再敏感，中位生存期小于20个月。在前列腺癌组织中，雄激素受体(AR)的增殖或突变能使其对血清中较低含量的雄激素敏感，是前列腺癌恶化的主要原因。目前，治疗CRPC的雄激素受体抑制剂代表药物有阿比特龙、恩杂鲁胺等。然而，15-25％的患者对阿比特龙和恩杂鲁胺等第二代激素治疗没有反应，大多数产生反应性的患者最终会产生严重的耐药性，导致预后不良。Prostate cancer is a common male malignant tumor, and its incidence worldwide is second only to lung cancer, ranking second in all male malignant tumors. The incidence of prostate cancer in China is increasing year by year, and it is expected that by 2020, prostate cancer will become the third leading cause of cancer deaths among men in my country. Currently, androgen deprivation therapy (ADT) is the main treatment for early-stage prostate cancer, including surgical castration and medical castration. However, ADT cannot cure prostate cancer. After a median treatment time of 14-30 months, almost all patients will gradually develop castration-resistant prostate cancer (CRPC). Patients are no longer sensitive to ADT, and the median survival time is less than 20 months. In prostate cancer tissue, the proliferation or mutation of the androgen receptor (AR) can make it sensitive to lower levels of androgens in serum, which is the main reason for the deterioration of prostate cancer. At present, the representative drugs of androgen receptor inhibitors for the treatment of CRPC include abiraterone, enzalutamide, etc. However, 15-25% of patients do not respond to second-generation hormonal therapy such as abiraterone and enzalutamide, and most patients who do respond eventually develop severe drug resistance, leading to poor prognosis.
泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)是细胞中蛋白降解的主要途径，参与细胞中80％以上的蛋白质的降解。UPS由泛素(Ub)、泛素活化酶(E1)、泛素结合酶(E2)、泛素-蛋白质连接酶(E3)、26S蛋白酶体及其目标蛋白组成。泛素活化酶系统负责活化泛素，并将其结合到待降解的蛋白上，形成靶蛋白多聚泛素链，即泛素化。蛋白酶体系统可以识别已泛素化的蛋白并将其降解。蛋白水解靶向嵌合分子(protein proteolysis-targeting chimeras,PROTACs)是一种杂合双功能小分子化合物，包括一个能够与目标靶蛋白结合的小分子化合物，在其合适位置上连接基团，再与一个能够与E3泛素连接酶结合的小分子化合物连接。PROTACs通过将目标靶蛋白和细胞内的E3拉近，形成靶蛋白-PROTACs-E3三元聚合体，通过E3泛素连接酶给目标靶蛋白加上泛素化蛋白标签，利用泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)特异性地降解靶蛋白。The ubiquitin-proteasome system (UPS) is the main pathway of protein degradation in cells and is involved in the degradation of more than 80% of proteins in cells. UPS consists of ubiquitin (Ub), ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), ubiquitin-protein ligase (E3), 26S proteasome and its target proteins. The ubiquitin-activating enzyme system is responsible for activating ubiquitin and binding it to the protein to be degraded to form a polyubiquitin chain of the target protein, that is, ubiquitination. The proteasome system recognizes and degrades ubiquitinated proteins. Protein proteolysis-targeting chimeras (PROTACs) is a hybrid bifunctional small molecule compound, including a small molecule compound that can bind to the target protein, linking groups at its appropriate position, and then Linked with a small molecule compound capable of binding to E3 ubiquitin ligase. PROTACs form a target protein-PROTACs-E3 ternary polymer by bringing the target protein and intracellular E3 closer, and add ubiquitinated protein tag to the target protein through E3 ubiquitin ligase, and utilize ubiquitin-proteasome. The ubiquitin-proteasome system (UPS) specifically degrades target proteins.
2018年，Arvinus公司披露了一类靶向雄激素受体的降解剂(US 2018/0099940 A1)，其代表药物ARV-110，目前处于临床I期用于治疗CRPC。临床I期数据结果也表明，ARV-110在转移性去势抵抗前列腺癌(mCRPC)患者身上安全且有效。In 2018, Arvinus disclosed a class of degraders targeting androgen receptors (US 2018/0099940 A1), the representative drug ARV-110, which is currently in clinical phase I for the treatment of CRPC. Phase I data also demonstrated that ARV-110 was safe and effective in patients with metastatic castration-resistant prostate cancer (mCRPC).
发明内容SUMMARY OF THE INVENTION
本发明所要解决的技术问题是为了克服现有技术中靶向雄激素受体的降解剂种类少的缺陷，而提供一种杂环化合物、其制备方法、中间体以及应用。本发明的杂环化合物对AR依赖的LNCap细胞 有较好的抑制活性，其可用于治疗前列腺癌。The technical problem to be solved by the present invention is to provide a heterocyclic compound, its preparation method, intermediate and application in order to overcome the defect of few types of degradation agents targeting androgen receptor in the prior art. The heterocyclic compounds of the present invention have better inhibitory activity on AR-dependent LNCap cells, which can be used for the treatment of prostate cancer.
本发明主要是通过以下技术方案解决上述技术问题的。The present invention mainly solves the above technical problems through the following technical solutions.
本发明提供一种如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，The present invention provides a compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its prodrug,
Figure PCTCN2021116287-appb-000001
Figure PCTCN2021116287-appb-000001
其中，R 1为氢、卤素、羟基、C 1-C 4烷基、一个或多个卤素取代的C 1-C 4烷基(当卤素为多个时，所述的卤素相同或不同)、C 1-C 4烷氧基、一个或多个卤素取代的C 1-C 4烷氧基(当卤素为多个时，所述的卤素相同或不同)、C 1-C 4烷基-C(＝O)-、C 1-C 4烷基-S-或-NR 1-1R 1-2； Wherein, R 1 is hydrogen, halogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by one or more halogens (when there are multiple halogens, the halogens are the same or different), C 1 -C 4 alkoxy, C 1 -C 4 alkoxy substituted with one or more halogens (when there are multiple halogens, the halogens are the same or different), C 1 -C 4 alkyl-C (=O)-, C 1 -C 4 alkyl-S- or -NR 1-1 R 1-2 ;
R 2为氢或
Figure PCTCN2021116287-appb-000002
R 2 is hydrogen or
Figure PCTCN2021116287-appb-000002
D为O、NR 6-1或CR 6-2R 6-3； D is O, NR 6-1 or CR 6-2 R 6-3 ;
K为-C(＝O)-或CR 7-1R 7-2； K is -C(=O)- or CR 7-1 R 7-2 ;
M为-C(＝O)-或CR 11-1R 11-2； M is -C(=O)- or CR 11-1 R 11-2 ;
环W为C 6-C 10芳环、一个或多个R 8-1取代的C 6-C 10芳环(当R 8-1为多个时，R 8-1相同或不同)、5-10元杂芳环、或一个或多个R 8-2取代的5-10元杂芳环(当R 8-2为多个时，R 8-2相同或不同)；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4；所述的一个或多个R 8-2取代的5-10元杂芳环中所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring, a C 6 -C 10 aromatic ring substituted by one or more R 8-1 (when there are multiple R 8-1 , R 8-1 is the same or different), 5- 10-membered heteroaromatic ring, or 5-10-membered heteroaromatic ring substituted by one or more R 8-2 (when R 8-2 is more than one, R 8-2 is the same or different); the 5-10 The heteroatom in the membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 8-2 substituted 5 The heteroatoms in the 5-10-membered heteroaromatic ring described in the -10-membered heteroaromatic ring are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4;
环Z为C 6-C 10芳环或5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring Z is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
环Y为C 3-C 10脂环、一个或多个R 9-1取代的C 3-C 10脂环、3-10元杂脂环、或一个或多个R 9-2取代的3-10元杂脂环；所述的3-10元杂脂环中的杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2或3；所述的一个或多个R 9-2取代的3-10元杂脂环中的3-10元杂脂环中的杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2或3； Ring Y is C 3 -C 10 alicyclic, C 3 -C 10 alicyclic substituted by one or more R 9-1 , 3-10 membered heteroalicyclic, or 3- alicyclic substituted by one or more R 9-2 10-membered heteroalicyclic ring; the heteroatoms in the 3-10-membered heteroalicyclic ring are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3; the described The heteroatoms in the 3-10-membered heteroalicyclic ring in the 3-10-membered heteroalicyclic ring substituted by one or more R 9-2 are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3;
R 1-1和R 1-2独立地为氢或C 1-C 4烷基； R 1-1 and R 1-2 are independently hydrogen or C 1 -C 4 alkyl;
R 2-1为C 1-C 4烷基； R 2-1 is C 1 -C 4 alkyl;
R 6-1为氢或C 1-C 4烷基； R 6-1 is hydrogen or C 1 -C 4 alkyl;
R 6-2、R 6-3、R 7-1、R 7-2、R 11-1和R 11-2独立地为氢、卤素或C 1-C 4烷基； R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 11-1 and R 11-2 are independently hydrogen, halogen or C 1 -C 4 alkyl;
R 8-1和R 8-2独立地为卤素或C 1-C 4烷基； R 8-1 and R 8-2 are independently halogen or C 1 -C 4 alkyl;
R 9-1和R 9-2独立地为卤素、羟基或C 1-C 4烷基。 R 9-1 and R 9-2 are independently halogen, hydroxy or C 1 -C 4 alkyl.
在本发明一实施方案中，所述的如式I所示的化合物中，所述的卤素(例如R 1、一个或多个卤素取代的C 1-C 4烷基、R 6-2、R 6-3、R 7-1、R 7-2、R 8-1、R 8-2、R 9-1、R 9-2、R 11-1、R 11-2等中的卤素)独立地为氟、氯、溴或碘，例如氟、氯或溴。 In one embodiment of the present invention, in the compound represented by formula I, the halogen (eg R 1 , C 1 -C 4 alkyl substituted by one or more halogens, R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 8-1 , R 8-2 , R 9-1 , R 9-2 , R 11-1 , R 11-2 etc. halogen) independently is fluorine, chlorine, bromine or iodine, such as fluorine, chlorine or bromine.
在本发明一实施方案中，所述的如式I所示的化合物中，所述的C 1-C 4烷基(R 1、一个或多个卤素取代的C 1-C 4烷基、R 1-1、R 1-2、R 2-1、R 6-2、R 6-3、R 7-1、R 7-2、R 8-1、R 8-2、R 9-1、R 9-2、R 11-1、R 11-2等中的C 1-C 4烷基)独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例甲基。 In an embodiment of the present invention, in the compound shown in formula I, the C 1 -C 4 alkyl (R 1 , one or more halogen-substituted C 1 -C 4 alkyl, R 1-1 , R 1-2 , R 2-1 , R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 8-1 , R 8-2 , R 9-1 , R C 1 -C 4 alkyl in 9-2 , R 11-1 , R 11-2 , etc.) is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl, eg methyl.
在本发明一实施方案中，所述的如式I所示的化合物中，所述的C 1-C 4烷氧基(例如R 1、一个或多个卤素取代的C 1-C 4烷氧基等中的C 1-C 4烷氧基)独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。 In one embodiment of the present invention, in the compound represented by formula I, the C 1 -C 4 alkoxy group (eg R 1 , one or more halogen-substituted C 1 -C 4 alkoxy groups C 1 -C 4 alkoxy in radicals etc.) is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert- Butoxy.
在本发明一实施方案中，当环W为C 6-C 10芳环时，所述的C 6-C 10芳基为苯环或萘环，优选为苯环。 In an embodiment of the present invention, when ring W is a C 6 -C 10 aromatic ring, the C 6 -C 10 aryl group is a benzene ring or a naphthalene ring, preferably a benzene ring.
在本发明一实施方案中，当环W为一个或多个R 8-1取代的C 6-C 10芳环时，所述的C 6-C 10芳基为苯环或萘环，例如苯环。 In one embodiment of the present invention, when ring W is one or more C 6 -C 10 aromatic rings substituted by R 8-1 , the C 6 -C 10 aryl group is a benzene ring or a naphthalene ring, such as benzene ring.
在本发明一实施方案中，当环W为5-10元杂芳环时，所述的5-10元杂芳环为5-6元杂芳环；所述的5-10元杂芳环和所述的5-6元杂芳环中的杂原子优选为N，杂原子个数优选为1或2。所述的5-6元杂芳环优选为哒嗪环、吡啶环、嘧啶环或吡嗪环。所述的哒嗪环优选为
Figure PCTCN2021116287-appb-000003
所述的吡啶环优选为
Figure PCTCN2021116287-appb-000004
所述的嘧啶环优选为
Figure PCTCN2021116287-appb-000005
所述的吡嗪环优选为
Figure PCTCN2021116287-appb-000006
In one embodiment of the present invention, when ring W is a 5-10-membered heteroaromatic ring, the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring; the 5-10-membered heteroaromatic ring And the heteroatom in the 5-6 membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1 or 2. The 5-6 membered heteroaromatic ring is preferably a pyridazine ring, a pyridine ring, a pyrimidine ring or a pyrazine ring. The pyridazine ring is preferably
Figure PCTCN2021116287-appb-000003
The pyridine ring is preferably
Figure PCTCN2021116287-appb-000004
The pyrimidine ring is preferably
Figure PCTCN2021116287-appb-000005
Described pyrazine ring is preferably
Figure PCTCN2021116287-appb-000006
在本发明一实施方案中，当环W为一个或多个R 8-2取代的5-10元杂芳环时，所述的5-10元杂芳环为5-6元杂芳环；所述的5-10元杂芳环和所述的5-6元杂芳环中的杂原子优选为N，杂原子个数优选为1或2。所述的5-6元杂芳环优选为哒嗪环或吡啶环。所述的哒嗪环优选为
Figure PCTCN2021116287-appb-000007
所述的吡啶环优选为
Figure PCTCN2021116287-appb-000008
In one embodiment of the present invention, when ring W is a 5-10-membered heteroaromatic ring substituted by one or more R 8-2 , the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring; The heteroatom in the 5-10-membered heteroaromatic ring and the 5-6-membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1 or 2. The 5-6 membered heteroaromatic ring is preferably a pyridazine ring or a pyridine ring. The pyridazine ring is preferably
Figure PCTCN2021116287-appb-000007
The pyridine ring is preferably
Figure PCTCN2021116287-appb-000008
在本发明一实施方案中，所述的R 8-2的个数为1个。 In an embodiment of the present invention, the number of the R 8-2 is one.
在本发明一实施方案中，当环Z为C 6-C 10芳环时，所述的C 6-C 10芳环为苯环或萘环，例如苯环。 In one embodiment of the present invention, when ring Z is a C 6 -C 10 aromatic ring, the C 6 -C 10 aromatic ring is a benzene ring or a naphthalene ring, such as a benzene ring.
在本发明一实施方案中，当环Z为5-10元杂芳环时，所述的5-10元杂芳环为5-6元杂芳环；所述的5-10元杂芳环和5-6元杂芳环中的杂原子优选为N，杂原子个数优选为1。所述的5-10元杂芳环优选为吡啶环，进一步优选为
Figure PCTCN2021116287-appb-000009
In an embodiment of the present invention, when ring Z is a 5-10-membered heteroaromatic ring, the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring; the 5-10-membered heteroaromatic ring and the heteroatom in the 5-6 membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1. Described 5-10 yuan heteroaromatic ring is preferably pyridine ring, more preferably
Figure PCTCN2021116287-appb-000009
在本发明一实施方案中，当环Y为C 3-C 10脂环时，所述的C 3-C 10脂环为C 4-C 7脂环，优选为丁环、戊环、己环、庚环或螺[3,3]庚环。所述的C 3-C 10脂环可为单环或螺环，例如单环。 In an embodiment of the present invention, when ring Y is a C 3 -C 10 alicyclic ring, the C 3 -C 10 alicyclic ring is a C 4 -C 7 alicyclic ring, preferably a butane ring, a pentane ring, a hexyl ring , heptyl or spiro[3,3]heptyl. The C 3 -C 10 alicyclic ring may be a single ring or a spiro ring, such as a single ring.
在本发明一实施方案中，当环Y为一个或多个R 9-1取代的C 3-C 10脂环时，所述的C 4-C 10脂环为C 4-C 6脂环，优选为丁环、戊环或己环。所述的一个或多个R 9-1取代的C 3-C 10脂环中的C 3-C 10脂环可为单环或螺环，例如单环。 In one embodiment of the present invention, when ring Y is a C 3 -C 10 alicyclic substituted by one or more R 9-1 , the C 4 -C 10 alicyclic is a C 4 -C 6 alicyclic, Preferably it is butane, pentane or hexyl. The C 3 -C 10 alicyclic ring in the one or more R 9-1 substituted C 3 -C 10 alicyclic rings may be monocyclic or spirocyclic, such as monocyclic.
在本发明一实施方案中，所述的R 9-1的个数为1、2或4个。 In an embodiment of the present invention, the number of the R 9-1 is 1, 2 or 4.
在本发明一实施方案中，当环Y为3-10元杂脂环时，所述的3-10元杂脂环为5-6元杂脂环；所述的3-10元杂脂环和5-6元杂脂环中的杂原子优选为N，杂原子个数优选为1。所述的3-10元杂脂环优选为四氢吡咯环或哌啶环。所述的四氢吡咯环优选为
Figure PCTCN2021116287-appb-000010
所述的哌啶环优选为
Figure PCTCN2021116287-appb-000011
所述的3-10元杂脂环可为单环或螺环。 In one embodiment of the present invention, when ring Y is a 3-10 membered heteroalicyclic ring, the 3-10 membered heteroalicyclic ring is a 5-6 membered heteroalicyclic ring; the 3-10 membered heteroalicyclic ring and the heteroatom in the 5-6 membered heteroalicyclic ring is preferably N, and the number of heteroatoms is preferably 1. The 3-10-membered heteroalicyclic ring is preferably a tetrahydropyrrole ring or a piperidine ring. Described tetrahydropyrrole ring is preferably
Figure PCTCN2021116287-appb-000010
Described piperidine ring is preferably
Figure PCTCN2021116287-appb-000011
The 3-10 membered heteroalicyclic ring may be a single ring or a spiro ring.
在本发明一实施方案中，当环Y为一个或多个R 9-2取代的3-10元杂脂环时，所述的3-10元杂脂环为5-6元杂脂环；所述的3-10元杂脂环和5-6元杂脂环中的杂原子优选为N，杂原子个数优选为1。所述的3-10元杂脂环优选为四氢吡咯环或哌啶环。所述的四氢吡咯环优选为
Figure PCTCN2021116287-appb-000012
所述的哌啶环优选为
Figure PCTCN2021116287-appb-000013
所述的一个或多个R 9-2取代的3-10元杂脂环中的3-10元杂脂环可为单环或螺环。 In one embodiment of the present invention, when ring Y is a 3-10-membered heteroalicyclic ring substituted with one or more R 9-2 , the 3-10-membered heteroalicyclic ring is a 5-6-membered heteroalicyclic ring; The heteroatom in the 3-10-membered heteroalicyclic ring and the 5-6-membered heteroalicyclic ring is preferably N, and the number of heteroatoms is preferably 1. The 3-10-membered heteroalicyclic ring is preferably a tetrahydropyrrole ring or a piperidine ring. Described tetrahydropyrrole ring is preferably
Figure PCTCN2021116287-appb-000012
Described piperidine ring is preferably
Figure PCTCN2021116287-appb-000013
The 3-10-membered heteroalicyclic ring in the one or more R 9-2 substituted 3-10-membered heteroalicyclic rings can be a monocyclic ring or a spirocyclic ring.
在本发明一实施方案中，所述的R 9-2的个数为1个。 In an embodiment of the present invention, the number of the R 9-2 is one.
在本发明一实施方案中，
Figure PCTCN2021116287-appb-000014
为
Figure PCTCN2021116287-appb-000015
为
Figure PCTCN2021116287-appb-000016
Figure PCTCN2021116287-appb-000017
其中E与D相连； In one embodiment of the present invention,
Figure PCTCN2021116287-appb-000014
for
Figure PCTCN2021116287-appb-000015
for
Figure PCTCN2021116287-appb-000016
Figure PCTCN2021116287-appb-000017
where E is connected to D;
R 3-1和R 3-2独立地为氢、卤素、羟基或C 1-4烷基； R 3-1 and R 3-2 are independently hydrogen, halogen, hydroxy or C 1-4 alkyl;
A为N或CR 4-1； A is N or CR 4-1 ;
B为N或CR 4-2； B is N or CR 4-2 ;
C为N或CR 4-3； C is N or CR 4-3 ;
E为N或CR 4-4； E is N or CR 4-4 ;
F为N或CR 4-5； F is N or CR 4-5 ;
G独立地为NR 5-1或CR 5-2R 5-3； G is independently NR 5-1 or CR 5-2 R 5-3 ;
L独立地为NR 10-1或CR 10-2R 10-3； L is independently NR 10-1 or CR 10-2 R 10-3 ;
R 4-1、R 4-2、R 4-3、R 4-4、R 4-5、R 5-2、R 5-3、R 10-2、R 10-3独立地为氢、卤素或C 1-C 4烷基； R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R 5-2 , R 5-3 , R 10-2 , R 10-3 are independently hydrogen, halogen or C 1 -C 4 alkyl;
R 5-1和R 10-1独立地为氢或C 1-C 4烷基； R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl;
m和n独立地为0、1、2或3；m and n are independently 0, 1, 2 or 3;
m1、m2、n1和n2独立地为0、1、2或3，且m1和n1不同时为0，m2和n2不同时为0。m1, m2, n1, and n2 are independently 0, 1, 2, or 3, and m1 and n1 are not both 0, and m2 and n2 are not both 0.
在本发明一实施方案中，所述的卤素(例如R 3-1、R 3-2、R 4-1、R 4-2、R 4-3、R 4-4、R 4-5、R 5-2、R 5-3、R 10-2、R 10-3等中的卤素)独立地为氟、氯、溴或碘。 In one embodiment of the present invention, the halogen (eg R 3-1 , R 3-2 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R 4-1 , 5-2 , R 5-3 , R 10-2 , R 10-3 , etc. halogen) are independently fluorine, chlorine, bromine or iodine.
在本发明一实施方案中，所述的C 1-C 4烷基(R 3-1、R 3-2、R 4-1、R 4-2、R 4-3、R 4-4、R 4-5、R 5-1、R 5-2、R 5-3、R 10-2、R 10-3、等中的C 1-C 4烷基)独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In one embodiment of the present invention, the C 1 -C 4 alkyl group (R 3-1 , R 3-2 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-1 C 1 -C 4 alkyl in 4-5 , R 5-1 , R 5-2 , R 5-3 , R 10-2 , R 10-3 , etc.) is independently methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在本发明一实施方案中，R 1为卤素或一个或多个卤素取代的C 1-C 4烷基，例如卤素。 In one embodiment of the invention, R 1 is halogen or one or more halogen substituted C 1 -C 4 alkyl, eg halogen.
在本发明一实施方案中，R 2为氢。 In one embodiment of the present invention, R2 is hydrogen .
在本发明一实施方案中，R 3-1和R 3-2独立地为氢、羟基或C 1-4烷基。 In one embodiment of the present invention, R 3-1 and R 3-2 are independently hydrogen, hydroxy or C 1-4 alkyl.
在本发明一实施方案中，B为CR 4-2。 In one embodiment of the invention, B is CR 4-2 .
在本发明一实施方案中，C为CR 4-3。 In one embodiment of the invention, C is CR 4-3 .
在本发明一实施方案中，K为-C(＝O)-和M为-C(＝O)-；或，K为CR 7-1R 7-2和M为-C(＝O)-；或，K为-C(＝O)-和M为CR 11-1R 11-2。 In one embodiment of the present invention, K is -C(=O)- and M is -C(=O)-; or, K is CR 7-1 R 7-2 and M is -C(=O)- ; or, K is -C(=O)- and M is CR 11-1 R 11-2 .
在本发明一实施方案中，环W为C 6-C 10芳环、5-10元杂芳环或一个或多个R 8-2取代的5-10元杂芳环，例如C 6-C 10芳环。 In one embodiment of the present invention, ring W is a C6 - C10 aromatic ring, a 5-10 membered heteroaromatic ring, or a 5-10 membered heteroaromatic ring substituted with one or more R8-2 , such as C6 -C 10 aromatic rings.
在本发明一实施方案中，R 4-1为氢。 In one embodiment of the present invention, R 4-1 is hydrogen.
在本发明一实施方案中，R 4-2为氢。 In one embodiment of the present invention, R 4-2 is hydrogen.
在本发明一实施方案中，R 4-3为氢。 In one embodiment of the present invention, R 4-3 is hydrogen.
在本发明一实施方案中，R 4-4为氢。 In one embodiment of the present invention, R 4-4 is hydrogen.
在本发明一实施方案中，R 5-2和R 5-3为氢。 In one embodiment of the present invention, R 5-2 and R 5-3 are hydrogen.
在本发明一实施方案中，R 6-1为氢。 In one embodiment of the present invention, R 6-1 is hydrogen.
在本发明一实施方案中，R 6-2和R 6-3为氢。 In one embodiment of the present invention, R 6-2 and R 6-3 are hydrogen.
在本发明一实施方案中，R 7-1和R 7-2为氢。 In one embodiment of the present invention, R 7-1 and R 7-2 are hydrogen.
在本发明一实施方案中，R 8-2独立地为卤素。 In one embodiment of the present invention, R 8-2 is independently halogen.
在本发明一实施方案中，R 9-2独立地为C 1-C 4烷基。 In one embodiment of the invention, R 9-2 is independently C 1 -C 4 alkyl.
在本发明一实施方案中，R 10-2和R 10-3独立地为氢或C 1-C 4烷基。 In one embodiment of the present invention, R 10-2 and R 10-3 are independently hydrogen or C 1 -C 4 alkyl.
在本发明一实施方案中，R 11-1和R 11-2为氢。 In one embodiment of the present invention, R 11-1 and R 11-2 are hydrogen.
在本发明一实施方案中，m为0、1或2。In one embodiment of the present invention, m is 0, 1 or 2.
在本发明一实施方案中，n为0、1或2。In one embodiment of the present invention, n is 0, 1 or 2.
在本发明一实施方案中，所述的一个或多个卤素取代的C 1-C 4烷基为三氟甲基。 In one embodiment of the present invention, the one or more halogen-substituted C 1 -C 4 alkyl groups are trifluoromethyl groups.
在本发明一实施方案中，D为O或NH，例如O。In one embodiment of the invention D is O or NH, eg O.
在本发明一实施方案中，
Figure PCTCN2021116287-appb-000018
为
Figure PCTCN2021116287-appb-000019
Figure PCTCN2021116287-appb-000020
例如
Figure PCTCN2021116287-appb-000021
In one embodiment of the present invention,
Figure PCTCN2021116287-appb-000018
for
Figure PCTCN2021116287-appb-000019
Figure PCTCN2021116287-appb-000020
E.g
Figure PCTCN2021116287-appb-000021
在本发明一实施方案中，
Figure PCTCN2021116287-appb-000022
为
Figure PCTCN2021116287-appb-000023
Figure PCTCN2021116287-appb-000024
例如
Figure PCTCN2021116287-appb-000025
In one embodiment of the present invention,
Figure PCTCN2021116287-appb-000022
for
Figure PCTCN2021116287-appb-000023
Figure PCTCN2021116287-appb-000024
E.g
Figure PCTCN2021116287-appb-000025
在本发明一实施方案中，
Figure PCTCN2021116287-appb-000026
为
Figure PCTCN2021116287-appb-000027
In one embodiment of the present invention,
Figure PCTCN2021116287-appb-000026
for
Figure PCTCN2021116287-appb-000027
在本发明一实施方案中，
Figure PCTCN2021116287-appb-000028
为
Figure PCTCN2021116287-appb-000029
Figure PCTCN2021116287-appb-000030
Figure PCTCN2021116287-appb-000031
例如
Figure PCTCN2021116287-appb-000032
In one embodiment of the present invention,
Figure PCTCN2021116287-appb-000028
for
Figure PCTCN2021116287-appb-000029
Figure PCTCN2021116287-appb-000030
Figure PCTCN2021116287-appb-000031
E.g
Figure PCTCN2021116287-appb-000032
在本发明一实施方案中，
Figure PCTCN2021116287-appb-000033
为
Figure PCTCN2021116287-appb-000034
Figure PCTCN2021116287-appb-000035
Figure PCTCN2021116287-appb-000036
例如
Figure PCTCN2021116287-appb-000037
In one embodiment of the present invention,
Figure PCTCN2021116287-appb-000033
for
Figure PCTCN2021116287-appb-000034
Figure PCTCN2021116287-appb-000035
Figure PCTCN2021116287-appb-000036
E.g
Figure PCTCN2021116287-appb-000037
在本发明一实施方案中，R 2为氢。 In one embodiment of the present invention, R2 is hydrogen .
在本发明一实施方案中，环W为
Figure PCTCN2021116287-appb-000038
In one embodiment of the present invention, ring W is
Figure PCTCN2021116287-appb-000038
在本发明一实施方案中，m1、m2、n1和n2为1。In one embodiment of the present invention, m1, m2, n1 and n2 are one.
在本发明一实施方案中，K为-C(＝O)-和M为CR 11-1R 11-2；或，K为CR 7-1R 7-2和M为-C(＝O)-。 In one embodiment of the invention, K is -C(=O)- and M is CR 11-1 R 11-2 ; or, K is CR 7-1 R 7-2 and M is -C(=O) -.
在本发明一实施方案中，其中，In one embodiment of the present invention, wherein,
R 1为卤素或一个或多个卤素取代的C 1-C 4烷基； R 1 is halogen or C 1 -C 4 alkyl substituted with one or more halogens;
R 2为氢； R 2 is hydrogen;
R 3-1和R 3-2独立地为氢、羟基或C 1-4烷基； R 3-1 and R 3-2 are independently hydrogen, hydroxyl or C 1-4 alkyl;
A为N或CH；A is N or CH;
B为CH；B is CH;
C为CH；C is CH;
D为O、NH或CH 2； D is O, NH or CH 2 ;
E为N或CH；E is N or CH;
F为N或CR 4-5； F is N or CR 4-5 ;
G独立地为NR 5-1或CH 2； G is independently NR 5-1 or CH 2 ;
L独立地为NR 10-1或CR 10-2R 10-3； L is independently NR 10-1 or CR 10-2 R 10-3 ;
K为-C(＝O)-或CH 2； K is -C(=O)- or CH 2 ;
M为-C(＝O)-；M is -C(=O)-;
环W为C 6-C 10芳环、5-10元杂芳环、或一个或多个R 8-2取代的5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4；所述的一个或多个R 8-2取代的5-10元杂芳环中所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring, a 5-10-membered heteroaromatic ring, or a 5-10-membered heteroaromatic ring substituted by one or more R 8-2 ; The atom is selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 8-2 substituted 5-10-membered heteroaromatic rings The heteroatom in the 5-10-membered heteroaromatic ring described in is selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatom is 1, 2, 3 or 4;
R 4-5为氢、卤素或C 1-C 4烷基； R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl;
R 8-2独立地为卤素； R 8-2 is independently halogen;
R 5-1和R 10-1独立地为氢或C 1-C 4烷基； R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl;
R 10-2、R 10-3独立地为氢或C 1-C 4烷基； R 10-2 and R 10-3 are independently hydrogen or C 1 -C 4 alkyl;
m和n独立地为0、1、2或3；和m and n are independently 0, 1, 2, or 3; and
m1、m2、n1和n2独立地为0、1、2或3，且m1和n1不同时为0，m2和n2不同时为0。m1, m2, n1, and n2 are independently 0, 1, 2, or 3, and m1 and n1 are not both 0, and m2 and n2 are not both 0.
在本发明一实施方案中，其中，In one embodiment of the present invention, wherein,
R 1为卤素； R 1 is halogen;
R 2为氢； R 2 is hydrogen;
R 3-1和R 3-2独立地为氢； R 3-1 and R 3-2 are independently hydrogen;
A为N或CH；A is N or CH;
B为CH；B is CH;
C为CH；C is CH;
D为O、NH或CH 2； D is O, NH or CH 2 ;
E为N或CH；E is N or CH;
F为N或CR 4-5； F is N or CR 4-5 ;
K为-C(＝O)-或CH 2； K is -C(=O)- or CH 2 ;
M为-C(＝O)-；M is -C(=O)-;
G独立地为NR 5-1或CH 2； G is independently NR 5-1 or CH 2 ;
L独立地为NR 10-1或CH 2； L is independently NR 10-1 or CH 2 ;
环W为C 6-C 10芳环或5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
R 4-5为氢、卤素或C 1-C 4烷基； R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl;
R 5-1和R 10-1独立地为氢或C 1-C 4烷基； R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl;
m为0或1；和m is 0 or 1; and
n为1或2。n is 1 or 2.
在本发明一实施方案中，其中，In one embodiment of the present invention, wherein,
R 1为卤素； R 1 is halogen;
R 2为氢； R 2 is hydrogen;
R 3-1和R 3-2独立地为氢； R 3-1 and R 3-2 are independently hydrogen;
A为N或CH；A is N or CH;
B为CH；B is CH;
C为CH；C is CH;
D为O、NH或CH 2； D is O, NH or CH 2 ;
E为CH；E is CH;
F为N或CR 4-5； F is N or CR 4-5 ;
G独立地为NR 5-1或CH 2； G is independently NR 5-1 or CH 2 ;
L独立地为NR 10-1或CH 2； L is independently NR 10-1 or CH 2 ;
K为-C(＝O)-或CH 2； K is -C(=O)- or CH 2 ;
M为-C(＝O)-；M is -C(=O)-;
环W为C 6-C 10芳环或5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
R 4-5为氢、卤素或C 1-C 4烷基； R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl;
R 5-1和R 10-1独立地为C 1-C 4烷基； R 5-1 and R 10-1 are independently C 1 -C 4 alkyl;
m为0或1；和m is 0 or 1; and
n为1或2。n is 1 or 2.
在本发明一实施方案中，其中，In one embodiment of the present invention, wherein,
R 1为氯； R 1 is chlorine;
R 2为氢； R 2 is hydrogen;
R 3-1和R 3-2独立地为氢； R 3-1 and R 3-2 are independently hydrogen;
A为CH；A is CH;
B为CH；B is CH;
C为CH；C is CH;
D为O；D is O;
E为CH；E is CH;
F为CH；F is CH;
G独立地为CH 2； G is independently CH 2 ;
L独立地为CH 2； L is independently CH 2 ;
K为-C(＝O)-和M为CH 2；或，K为CH 2和M为-C(＝O)-； K is -C(=O)- and M is CH2 ; or, K is CH2 and M is -C(=O)-;
环W为C 6-C 10芳环或5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
R 4-5为氢、卤素或C 1-C 4烷基； R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl;
R 5-1和R 10-1独立地为C 1-C 4烷基； R 5-1 and R 10-1 are independently C 1 -C 4 alkyl;
m为0或1；m is 0 or 1;
n为2；n is 2;
且当m为0时，环W为
Figure PCTCN2021116287-appb-000039
And when m is 0, the ring W is
Figure PCTCN2021116287-appb-000039
在本发明一实施方案中，所述的如式I所示的化合物为如式Ia或Ib所示的化合物：In one embodiment of the present invention, the compound shown in formula I is the compound shown in formula Ia or Ib:
Figure PCTCN2021116287-appb-000040
Figure PCTCN2021116287-appb-000040
其中，D为O或NH；Wherein, D is O or NH;
D与环Y上的碳原子连接，
Figure PCTCN2021116287-appb-000041
中a端与环Y上的碳原子连接； D is attached to a carbon atom on ring Y,
Figure PCTCN2021116287-appb-000041
The a terminal in the middle is connected to the carbon atom on the ring Y;
环Z、环Y、环W、K、M、N、R 1和R 2的定义同前所述； Ring Z, ring Y, ring W, K, M, N, R 1 and R 2 are as defined above;
式Ia中，
Figure PCTCN2021116287-appb-000042
(直形虚线键)和
Figure PCTCN2021116287-appb-000043
(直形实线键)表示的与其连接的接团位于环Y平面的两侧；式Ib中，
Figure PCTCN2021116287-appb-000044
(直形虚线键)和
Figure PCTCN2021116287-appb-000045
(直形虚线键)表示的与其连接的接团位于环Y平面的同侧。 In formula Ia,
Figure PCTCN2021116287-appb-000042
(straight dashed key) and
Figure PCTCN2021116287-appb-000043
(Straight solid line bond) represents that the connecting group connected to it is located on both sides of the plane of the ring Y; in formula Ib,
Figure PCTCN2021116287-appb-000044
(straight dashed key) and
Figure PCTCN2021116287-appb-000045
(Straight dashed bond) indicates that the link to which it is attached is on the same side of the Y plane of the ring.
在本发明一实施方案中，所述的如式I所示的化合物为如式Ic所示的化合物：In one embodiment of the present invention, the compound shown in formula I is the compound shown in formula Ic:
Figure PCTCN2021116287-appb-000046
Figure PCTCN2021116287-appb-000046
其中，环Y为戊环或己环；环Z、K、M、R 1和R 2的定义同前所述； Wherein, ring Y is pentane ring or hexyl ring; ring Z, K, M, R 1 and R 2 are as defined above;
式Ic中，
Figure PCTCN2021116287-appb-000047
(直形虚线键)和
Figure PCTCN2021116287-appb-000048
(直形实线键)表示的与其连接的接团位于环Y平面的两侧。 In formula Ic,
Figure PCTCN2021116287-appb-000047
(straight dashed key) and
Figure PCTCN2021116287-appb-000048
(Straight solid bond) indicates that the link to which it is attached is located on either side of the Y plane of the ring.
优选，所述的如式Ic所示的化合物中：Preferably, in the compound shown in the formula Ic:
R 1为卤素(例如氟、氯或溴)； R 1 is halogen (eg fluorine, chlorine or bromine);
R 2为H； R 2 is H;
Figure PCTCN2021116287-appb-000049
为
Figure PCTCN2021116287-appb-000050
(例如
Figure PCTCN2021116287-appb-000051
Figure PCTCN2021116287-appb-000052
Figure PCTCN2021116287-appb-000049
for
Figure PCTCN2021116287-appb-000050
(E.g
Figure PCTCN2021116287-appb-000051
Figure PCTCN2021116287-appb-000052
在本发明一实施方案中，所述的如式I所示的化合物为如式Id所示的化合物：In one embodiment of the present invention, the compound shown in the formula I is the compound shown in the formula Id:
Figure PCTCN2021116287-appb-000053
Figure PCTCN2021116287-appb-000053
其中，环Z、K、M、R 1和R 2的定义同前所述。 Wherein, the definitions of ring Z, K, M, R 1 and R 2 are as described above.
优选，所述的如式Id所示的化合物中，Preferably, in the compound shown in the formula Id,
R 1为卤素(例如氯)； R 1 is halogen (eg chlorine);
R 2为H； R 2 is H;
环Z为C 6-C 10芳环(例如苯环)； Ring Z is a C 6 -C 10 aromatic ring (eg, a benzene ring);
Figure PCTCN2021116287-appb-000054
为
Figure PCTCN2021116287-appb-000055
Figure PCTCN2021116287-appb-000054
for
Figure PCTCN2021116287-appb-000055
在本发明一实施方案中，所述的如式I所示的化合物为如下任一所示的化合物：In one embodiment of the present invention, the compound shown in formula I is any of the following compounds:
Figure PCTCN2021116287-appb-000056
Figure PCTCN2021116287-appb-000056
Figure PCTCN2021116287-appb-000057
Figure PCTCN2021116287-appb-000057
Figure PCTCN2021116287-appb-000058
Figure PCTCN2021116287-appb-000058
Figure PCTCN2021116287-appb-000059
Figure PCTCN2021116287-appb-000059
Figure PCTCN2021116287-appb-000060
Figure PCTCN2021116287-appb-000060
Figure PCTCN2021116287-appb-000061
Figure PCTCN2021116287-appb-000061
Figure PCTCN2021116287-appb-000062
Figure PCTCN2021116287-appb-000062
在本发明一实施方案中，所述的如式I所示的化合物为如下任一所示的化合物，In an embodiment of the present invention, the compound shown in formula I is any of the following compounds,
Figure PCTCN2021116287-appb-000063
Figure PCTCN2021116287-appb-000063
Figure PCTCN2021116287-appb-000064
Figure PCTCN2021116287-appb-000064
Figure PCTCN2021116287-appb-000065
Figure PCTCN2021116287-appb-000065
Figure PCTCN2021116287-appb-000066
Figure PCTCN2021116287-appb-000066
Figure PCTCN2021116287-appb-000067
Figure PCTCN2021116287-appb-000067
Figure PCTCN2021116287-appb-000068
Figure PCTCN2021116287-appb-000068
Figure PCTCN2021116287-appb-000069
Figure PCTCN2021116287-appb-000069
Figure PCTCN2021116287-appb-000070
Figure PCTCN2021116287-appb-000070
Figure PCTCN2021116287-appb-000071
Figure PCTCN2021116287-appb-000071
本发明还提供了一种所述的如式I所示的化合物的制备方法，其为以下任一方法：The present invention also provides a method for preparing the compound shown in the formula I, which is any of the following methods:
方法一包括以下步骤：溶剂中，在碱和缩合剂的作用下，将如式IV所示的化合物和如式V所示的化合物进行如下所示的缩合反应即可，The first method includes the following steps: in a solvent, under the action of a base and a condensing agent, the compound shown in formula IV and the compound shown in formula V are subjected to the condensation reaction shown below,
Figure PCTCN2021116287-appb-000072
Figure PCTCN2021116287-appb-000072
其中，环Z、环Y、D、K、M、环W、R 1和R 2的定义同前所述； Wherein, the definitions of ring Z, ring Y, D, K, M, ring W, R 1 and R 2 are as described above;
方法二包括以下步骤：溶剂中，在酸的作用下将如式VI所示的化合物进行如下所示的脱保护反应即可，The second method comprises the following steps: in a solvent, the compound shown in formula VI is subjected to the deprotection reaction shown below under the action of an acid,
Figure PCTCN2021116287-appb-000073
Figure PCTCN2021116287-appb-000073
其中，
Figure PCTCN2021116287-appb-000074
为
Figure PCTCN2021116287-appb-000075
为
Figure PCTCN2021116287-appb-000076
E与D相连；环Z、D、E、F、K、M、环W、L、R 1、R 2、R 3-1、R 3-2和n同前所述； in,
Figure PCTCN2021116287-appb-000074
for
Figure PCTCN2021116287-appb-000075
for
Figure PCTCN2021116287-appb-000076
E is connected to D; ring Z, D, E, F, K, M, ring W, L, R 1 , R 2 , R 3-1 , R 3-2 and n are as previously described;
方法三包括如下步骤：在溶剂中，将如式VII所示的化合物和如式VIII所示的化合物进行如下所示的加成反应即可，The third method includes the following steps: in a solvent, the compound shown in formula VII and the compound shown in formula VIII are subjected to the addition reaction shown below,
Figure PCTCN2021116287-appb-000077
Figure PCTCN2021116287-appb-000077
其中，
Figure PCTCN2021116287-appb-000078
为
Figure PCTCN2021116287-appb-000079
为
Figure PCTCN2021116287-appb-000080
E与D相连；环Z、D、E、G、K、M、环W、L、R 1、R 2、R 3-1、R 3-2、m和n同前所述。 in,
Figure PCTCN2021116287-appb-000078
for
Figure PCTCN2021116287-appb-000079
for
Figure PCTCN2021116287-appb-000080
E is linked to D; rings Z, D, E, G, K, M, rings W, L, R 1 , R 2 , R 3-1 , R 3-2 , m and n are as previously described.
所述的缩合反应中，所述的溶剂可为本领域该类反应常规的溶剂，本发明特别优选为酰胺类溶剂，进一步优选为N,N-二甲基甲酰胺。In the condensation reaction, the solvent can be a conventional solvent for this type of reaction in the field, and the present invention is particularly preferably an amide solvent, more preferably N,N-dimethylformamide.
所述的缩合反应中，所述的如式IV所示的化合物在所述的溶剂中的摩尔浓度可为本领域该类反应常规的摩尔浓度，本发明特别优选为0.0001～0.1mol/L，进一步优选为0.004～0.01mol/L(例如0.008mol/L)。In the condensation reaction, the molar concentration of the compound shown in formula IV in the solvent can be the conventional molar concentration of this type of reaction in the field, and the present invention is particularly preferably 0.0001-0.1 mol/L, More preferably, it is 0.004 to 0.01 mol/L (for example, 0.008 mol/L).
所述的缩合反应中，所述的碱可为本领域该类反应常规的碱，优选为有机胺，进一步优选为N,N-二异丙基乙胺。In the condensation reaction, the base can be a conventional base for this type of reaction in the art, preferably an organic amine, more preferably N,N-diisopropylethylamine.
所述的缩合反应中，所述的碱与所述的如式IV所示的化合物的摩尔比可为该类反应常规的摩尔比，本发明特别优选为0.8:1～3:1，进一步优选为0.9:1～1.3:1(例如1:1)。In the condensation reaction, the molar ratio of the base to the compound represented by the formula IV can be the conventional molar ratio of this type of reaction. In the present invention, the molar ratio is particularly preferably 0.8:1 to 3:1, more preferably 0.9:1 to 1.3:1 (eg 1:1).
所述的缩合反应中，所述的缩合剂可为本领域该类反应常规的缩合剂，本发明特别优选为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐。In the described condensation reaction, the described condensing agent can be a conventional condensing agent for this type of reaction in the field, and the present invention is particularly preferably 2-(7-azabenzotriazole)-N,N,N', N'-tetramethylurea hexafluorophosphate.
所述的缩合反应中，所述的缩合剂与所述的如式IV所示的化合物的摩尔比可为该类反应常规的摩尔比，本发明特别优选为1:1～3:1，进一步优选为1:1～1.5:1(例如1.2:1)。In the condensation reaction, the molar ratio of the condensing agent to the compound represented by the formula IV can be the conventional molar ratio of this type of reaction, which is particularly preferably 1:1 to 3:1 in the present invention, and further It is preferably 1:1 to 1.5:1 (for example, 1.2:1).
所述的缩合反应中，所述的如式V所示的化合物与所述的如式IV所示的化合物的摩尔比可为该类反应常规的摩尔比，本发明特别优选为0.8:1～3:1，进一步优选为0.9:1～1.3:1(例如1:1)。In the condensation reaction, the molar ratio of the compound represented by the formula V to the compound represented by the formula IV can be the conventional molar ratio of this type of reaction, and the present invention is particularly preferably 0.8:1～ 3:1, more preferably 0.9:1 to 1.3:1 (for example, 1:1).
所述的缩合反应中，所述缩合反应的反应温度可为本领域该类反应常规的反应温度，本发明特别优选为室温。In the condensation reaction, the reaction temperature of the condensation reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
所述的缩合反应中，反应进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以监测到所述的如式V所示的化合物或所述的如式IV所示的化合物消失为反应终点。 所述缩合反应的反应时间优选为1～3小时(例如2小时)。In the described condensation reaction, the reaction progress can be monitored by conventional monitoring methods (such as TLC, HPLC or NMR) in the art, generally to monitor the compound shown in the formula V or the compound shown in the formula IV. The disappearance of the indicated compound is the end point of the reaction. The reaction time of the condensation reaction is preferably 1 to 3 hours (for example, 2 hours).
所述的缩合反应中，所述的缩合反应结束后还可进一步包括后处理步骤。所述的后处理步骤可包括浓缩和纯化。所述的纯化的方式可为制备TLC。所述的制备TLC所使用的洗脱剂可为二氯甲烷和甲醇(体积比优选为15:1)。In the condensation reaction, after the condensation reaction is completed, a post-processing step may be further included. The post-processing steps may include concentration and purification. The purification method can be preparative TLC. The eluent used in the preparation of TLC can be dichloromethane and methanol (the volume ratio is preferably 15:1).
所述的脱保护反应中，所述的溶剂可为本领域该类反应常规的溶剂，本发明特别优选为醚类溶剂，进一步优选为二氧六环。In the deprotection reaction, the solvent can be a conventional solvent for this type of reaction in the field, and the present invention is particularly preferably an ether solvent, more preferably dioxane.
所述的脱保护反应中，所述的如式VI所示的化合物在所述的溶剂中的摩尔浓度可为本领域该类反应常规的摩尔浓度，本发明特别优选为0.0001～0.1mol/L，进一步优选为0.002～0.004mol/L(例如0.0028mol/L)。In the deprotection reaction, the molar concentration of the compound represented by formula VI in the solvent can be the conventional molar concentration of this type of reaction in the field, and the present invention is particularly preferably 0.0001-0.1 mol/L , more preferably 0.002 to 0.004 mol/L (for example, 0.0028 mol/L).
所述的脱保护反应中，所述的酸可为本领域该类反应常规的酸，优选为无机酸，进一步优选为盐酸。In the deprotection reaction, the acid can be a conventional acid for this type of reaction in the art, preferably an inorganic acid, more preferably hydrochloric acid.
所述的脱保护反应中，所述脱保护反应的反应温度可为本领域该类反应常规的反应温度，本发明特别优选为室温。In the deprotection reaction, the reaction temperature of the deprotection reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
所述的脱保护反应中，反应进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以监测到所述的如式VI所示的化合物消失为反应终点。所述脱保护反应的反应时间优选为1～3小时(例如2小时)。In the deprotection reaction, the progress of the reaction can be monitored by conventional monitoring methods in the art (eg TLC, HPLC or NMR), and the end point of the reaction is generally to monitor the disappearance of the compound represented by formula VI. The reaction time of the deprotection reaction is preferably 1 to 3 hours (for example, 2 hours).
所述的脱保护反应中，所述的脱保护反应结束后还可进一步包括后处理步骤。所述的后处理步骤可包括浓缩。In the deprotection reaction, after the deprotection reaction is completed, a post-processing step may be further included. The post-processing steps may include concentration.
所述的加成反应中，所述的溶剂可为本领域该类反应常规的溶剂，本发明特别优选为酰胺类溶剂，进一步优选为N,N-二甲基甲酰胺。In the addition reaction, the solvent can be a conventional solvent for this type of reaction in the field, and the present invention is particularly preferably an amide solvent, more preferably N,N-dimethylformamide.
所述的加成反应中，所述的如式VII所示的化合物与所述的如式VIII所示的化合物的摩尔比可为该类反应常规的摩尔比，本发明特别优选为0.8:1～3:1，进一步优选为0.9:1～1.3:1(例如1:1)。In the addition reaction, the molar ratio of the compound represented by the formula VII to the compound represented by the formula VIII can be the conventional molar ratio of this type of reaction, and the present invention is particularly preferably 0.8:1 -3:1, more preferably 0.9:1 - 1.3:1 (for example, 1:1).
所述的加成反应中，所述加成反应的反应温度可为本领域该类反应常规的反应温度，本发明特别优选为室温。In the addition reaction, the reaction temperature of the addition reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
所述的加成反应中，反应进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以监测到所述的如式VII所示的化合物或所述的如式VIII所示的化合物消失为反应终点。所述加成反应的反应时间优选为1～3小时(例如2小时)。In the described addition reaction, the reaction progress can be monitored by conventional monitoring methods (such as TLC, HPLC or NMR) in the art, generally to monitor the compound shown in the formula VII or the compound shown in the formula VII. The disappearance of the compound represented by VIII was the end point of the reaction. The reaction time of the addition reaction is preferably 1 to 3 hours (for example, 2 hours).
所述的加成反应中，所述的加成反应结束后还可进一步包括后处理步骤。所述的后处理步骤可包括浓缩和纯化。In the addition reaction, after the addition reaction is completed, a post-processing step may be further included. The post-processing steps may include concentration and purification.
本发明还提供了一种如式IV所示的化合物或其立体异构体，The present invention also provides a compound of formula IV or a stereoisomer thereof,
Figure PCTCN2021116287-appb-000081
Figure PCTCN2021116287-appb-000081
其中，环Z、环Y、D和R 1的定义同前所述；且如式IV所示的化合物不为
Figure PCTCN2021116287-appb-000082
Wherein, the definitions of ring Z, ring Y, D and R 1 are the same as above; and the compound represented by formula IV is not
Figure PCTCN2021116287-appb-000082
在本发明一实施方案中，所述的如式IV所示的化合物为
Figure PCTCN2021116287-appb-000083
Figure PCTCN2021116287-appb-000084
In one embodiment of the present invention, the compound shown in formula IV is
Figure PCTCN2021116287-appb-000083
Figure PCTCN2021116287-appb-000084
在本发明一实施方案中，所述的如式IV所示的化合物的立体异构体为In one embodiment of the present invention, the stereoisomer of the compound represented by formula IV is
Figure PCTCN2021116287-appb-000085
Figure PCTCN2021116287-appb-000085
Figure PCTCN2021116287-appb-000086
Figure PCTCN2021116287-appb-000086
本发明还提供了如式VI所示的化合物或其立体异构体，The present invention also provides a compound of formula VI or a stereoisomer thereof,
Figure PCTCN2021116287-appb-000087
Figure PCTCN2021116287-appb-000087
其中，环Z、环Y’、D、K、M、环W、R 1和R 2的定义同前所述。 Wherein, the definitions of ring Z, ring Y', D, K, M, ring W, R 1 and R 2 are as described above.
在本发明一实施方案中，所述的如式VI所示的化合物为如式VI-a或VI-b所示的化合物：In one embodiment of the present invention, the compound shown in formula VI is the compound shown in formula VI-a or VI-b:
Figure PCTCN2021116287-appb-000088
Figure PCTCN2021116287-appb-000088
Figure PCTCN2021116287-appb-000089
Figure PCTCN2021116287-appb-000089
环Z、环Y’、D、K、M、环W、R 1和R 2的定义同前所述； Ring Z, ring Y', D, K, M, ring W, R 1 and R 2 are as defined above;
式VI-a中，
Figure PCTCN2021116287-appb-000090
(直形虚线键)和
Figure PCTCN2021116287-appb-000091
(直形实线键)表示的与其连接的接团位于环Y平面的两侧；式VI-b中，
Figure PCTCN2021116287-appb-000092
(直形虚线键)和
Figure PCTCN2021116287-appb-000093
(直形虚线键)表示的与其连接的接团位于环Y平面的同侧。 In formula VI-a,
Figure PCTCN2021116287-appb-000090
(straight dashed key) and
Figure PCTCN2021116287-appb-000091
(Straight solid line bond) represents that the connecting group connected to it is located on both sides of the Y plane of the ring; in formula VI-b,
Figure PCTCN2021116287-appb-000092
(straight dashed key) and
Figure PCTCN2021116287-appb-000093
(Straight dashed bond) indicates that the link to which it is attached is on the same side of the Y plane of the ring.
在本发明一实施方案中，所述的如式VI所示的化合物为In one embodiment of the present invention, the compound represented by the formula VI is
Figure PCTCN2021116287-appb-000094
Figure PCTCN2021116287-appb-000094
在本发明一实施方案中，所述的如式VI所示的化合物的立体异构体为In one embodiment of the present invention, the stereoisomer of the compound represented by formula VI is
Figure PCTCN2021116287-appb-000095
Figure PCTCN2021116287-appb-000095
本发明还提供了一种药物组合物，其包括所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，以及药学上可接受的辅料。The present invention also provides a pharmaceutical composition comprising the compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, Its metabolites or prodrugs thereof, and pharmaceutically acceptable excipients.
本发明还提供了一种所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药、或所述的药物组合物在制备雄激素受体降解剂中的应用。The present invention also provides a compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its precursor The invention relates to the application of the medicine, or the pharmaceutical composition, in the preparation of an androgen receptor degrading agent.
本发明还提供了一种所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药、或所述的药物组合物在制备治疗与雄激素受体相关疾病的药物中的应用。The present invention also provides a compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its precursor The invention relates to the application of the medicine, or the pharmaceutical composition, in the preparation of a medicine for treating androgen receptor-related diseases.
在本发明一实施方案中，所述的与雄激素受体相关疾病为前列腺癌，优选为转移性去势抵抗前列 腺癌。In one embodiment of the present invention, the androgen receptor-related disease is prostate cancer, preferably metastatic castration-resistant prostate cancer.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。再例如，在一些具体的结构中，当芳基为连接基团时，则该芳基基团代表连接的亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group. As another example, in some specific structures, when an aryl group is a linking group, then the aryl group represents the linking arylene group.
术语“多个”是指2个、3个、4个、5个或6个。当为多个时，取代基或者杂原子的种类可以相同或者不同。The term "plurality" refers to 2, 3, 4, 5 or 6. When there are more than one, the kinds of substituents or hetero atoms may be the same or different.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound of the present invention with a relatively non-toxic acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
术语“立体异构体”包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体和(L)-异构体。The term "stereoisomers" includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomer and (L)-isomer.
术语“互变异构体”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(也称质子转移互变异构体)包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The term "tautomer" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also referred to as proton tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-enamine isomerization. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. Solvent molecules in solvates can exist in ordered or non-ordered arrangements. The solvent includes, but is not limited to, water, methanol, ethanol, and the like.
术语“脂环”是指由碳原子组成的饱和环状结构。The term "alicyclic" refers to a saturated cyclic structure consisting of carbon atoms.
术语“杂脂环”是指由碳原子和杂原子组成的饱和环状结构，其中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2或3。The term "heteroalicyclic" refers to a saturated cyclic structure composed of carbon atoms and heteroatoms, wherein the heteroatoms are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3 .
除非另有说明，用楔形实线键
Figure PCTCN2021116287-appb-000096
和楔形虚线键
Figure PCTCN2021116287-appb-000097
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021116287-appb-000098
和直形虚线键
Figure PCTCN2021116287-appb-000099
表示立体中心的相对构型。 Use solid wedge keys unless otherwise specified
Figure PCTCN2021116287-appb-000096
and wedge-dotted keys
Figure PCTCN2021116287-appb-000097
Indicate the absolute configuration of a stereocenter, using a straight solid key
Figure PCTCN2021116287-appb-000098
and straight dashed keys
Figure PCTCN2021116287-appb-000099
Represents the relative configuration of the stereocenter.
本发明所述的室温为10-30℃。The room temperature in the present invention is 10-30°C.
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。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples 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 all commercially available.
本发明的积极进步效果在于：本发明的杂环化合物对AR依赖的LNCap细胞有较好的抑制活性，并对不依赖AR的PC-3细胞有较小的毒性。The positive improvement effect of the present invention is that the heterocyclic compound of the present invention has better inhibitory activity on AR-dependent LNCap cells, and has less toxicity to AR-independent PC-3 cells.
具体实施方式detailed description
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 described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
参考例1Reference Example 1
合成路线synthetic route
Figure PCTCN2021116287-appb-000100
Figure PCTCN2021116287-appb-000100
实施例1Example 1
Figure PCTCN2021116287-appb-000101
Figure PCTCN2021116287-appb-000101
步骤一：将5-氟苯并呋喃-1,3-二酮(5.0g，30.1mmol，1eq)溶于醋酸(50mL)中，分别加入3-氨基哌嗪-2,6-二酮(4.2g，33.1mmol，1.1eq)及醋酸钾(5.9g，60.2mmol，2eq)，所得混合物在90℃搅拌过夜。TLC检测反应结束后，将反应液冷却至室温，加入水(50mL)，有固体析出，抽滤，滤饼水洗，干燥，得灰色固体8.05g。Step 1: Dissolve 5-fluorobenzofuran-1,3-dione (5.0 g, 30.1 mmol, 1 eq) in acetic acid (50 mL), add 3-aminopiperazine-2,6-dione (4.2 g, 33.1 mmol, 1.1 eq) and potassium acetate (5.9 g, 60.2 mmol, 2 eq) and the resulting mixture was stirred at 90°C overnight. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, water (50 mL) was added, a solid was precipitated, suction filtered, the filter cake was washed with water, and dried to obtain 8.05 g of a gray solid.
步骤二：将步骤一所得产物(3.0g，10.9mmol，1eq)溶于DMSO(50mL)中，分别加入N-Boc哌嗪(3.0g，16.3mmol，1.5eq)及DIEA(2.8g，21.7mmol，2eq)，所得混合物于130℃下搅拌3h。TLC检测反应结束后，将反应液冷却至室温，加入水(50mL)，有固体析出，抽滤，滤饼水洗，干燥，得黄色固体3.63g.ESI MS m/z 343[M+H] +。 Step 2: Dissolve the product obtained in Step 1 (3.0g, 10.9mmol, 1eq) in DMSO (50mL), add N-Boc piperazine (3.0g, 16.3mmol, 1.5eq) and DIEA (2.8g, 21.7mmole) respectively , 2eq), and the resulting mixture was stirred at 130°C for 3h. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, water (50 mL) was added, a solid was precipitated, suction filtration, the filter cake was washed with water, and dried to obtain a yellow solid 3.63g. ESI MS m/z 343[M+H] + .
步骤三：将3-氨基-6-氯哒嗪(10g，77.2mmol，1eq)与4-羟甲基哌啶(9.9g，77.2mmol，1eq)混合于140℃下搅拌6h，TLC检测反应结束后，反应液浓缩后，柱层析(DCM/MeOH＝30:1-10:1)得产物10.7g，ESI MS m/z 223[M+H] +。 Step 3: Mix 3-amino-6-chloropyridazine (10 g, 77.2 mmol, 1 eq) with 4-hydroxymethylpiperidine (9.9 g, 77.2 mmol, 1 eq) and stir at 140°C for 6 h, TLC detects the end of the reaction After that, the reaction solution was concentrated and subjected to column chromatography (DCM/MeOH=30:1-10:1) to obtain 10.7 g of the product, ESI MS m/z 223 [M+H] + .
步骤四：将步骤三所得产物(2g，28.8mmol，1eq)溶于叔丁醇(50mL)中，分别加入Boc酸酐(7.6g，34.6mmol，1.2eq)、三乙胺(4.4g，43.2mmol，1.2eq)及DMAP(352mg，2.9mmol，0.1eq)，所得混合物室温搅拌过夜。TLC检测反应结束后，减压除去叔丁醇，加入乙酸乙酯(200mL)稀释，分别用水(200mL)洗，饱和食盐水(200mL)洗，无水硫酸钠干燥后浓缩，残余物柱层析(DCM/MeOH＝50:1)得白色固体产物8.5g。ESI MS m/z 309[M+H] +。 Step 4: Dissolve the product obtained in Step 3 (2g, 28.8mmol, 1eq) in tert-butanol (50mL), add Boc anhydride (7.6g, 34.6mmol, 1.2eq), triethylamine (4.4g, 43.2mmol) respectively , 1.2 eq) and DMAP (352 mg, 2.9 mmol, 0.1 eq), and the resulting mixture was stirred at room temperature overnight. After TLC detected the reaction, tert-butanol was removed under reduced pressure, diluted with ethyl acetate (200 mL), washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was subjected to column chromatography (DCM/MeOH=50:1) to obtain 8.5 g of white solid product. ESI MS m/z 309[M+H] + .
步骤五：将步骤四所得产物(3g，9.7mmol，1eq)溶于二氯甲烷(50mL)中，分别加入Dess-Martin(6.2g，14.6mmol，1.5eq)、碳酸氢钠(1.2g，14.6mmol，1.5eq)，所得混合物室温搅拌2h。TLC检测反应结束后，减压除去二氯甲烷，加入乙酸乙酯(200mL)稀释，分别用饱和碳酸氢钠水溶液(50mL)洗，饱和食盐水(200mL)洗，无水硫酸钠干燥后浓缩，残余物柱层析(PE/EA＝3:1)得产物520mg。ESI MS m/z 307[M+H] +。 Step 5: Dissolve the product obtained in Step 4 (3g, 9.7mmol, 1eq) in dichloromethane (50mL), add Dess-Martin (6.2g, 14.6mmol, 1.5eq), sodium bicarbonate (1.2g, 14.6g) respectively mmol, 1.5 eq) and the resulting mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, dichloromethane was removed under reduced pressure, ethyl acetate (200 mL) was added to dilute, washed with saturated aqueous sodium bicarbonate (50 mL), saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography (PE/EA=3:1) to obtain 520 mg of product. ESI MS m/z 307[M+H] + .
步骤六：将步骤五所得产物(265mg，0.77mmol，1eq)溶于二氯甲烷(20mL)中，加入步骤二所得产物(237mg，0.77mmol，1eq)，室温搅拌半小时后，加入醋酸硼氢化钠(328mg，1.55mmol，2eq)，所得混合物室温搅拌3.5h。TLC检测反应结束后，滴入饱和氯化铵水溶液淬灭，加入二氯甲烷(50mL)稀释，分别用饱和碳酸氢钠水溶液(50mL)洗，饱和食盐水(200mL)洗，无水硫酸钠干燥后浓缩，残余物柱层析(PE/EA＝1:1)得产物240mg。将该产物溶于二氧六环(10mL)中，滴入HCl的二氧六环溶液(4M,10mL)，室温搅拌过夜。TLC检测反应结束后，减压浓缩得黄色固体230mg。ESI MS m/z 533[M+H] +。 Step 6: Dissolve the product obtained in step 5 (265 mg, 0.77 mmol, 1 eq) in dichloromethane (20 mL), add the product obtained in step 2 (237 mg, 0.77 mmol, 1 eq), stir at room temperature for half an hour, add acetic acid borohydride Sodium (328 mg, 1.55 mmol, 2 eq) and the resulting mixture was stirred at room temperature for 3.5 h. After the reaction was detected by TLC, saturated aqueous ammonium chloride was added dropwise to quench, dichloromethane (50 mL) was added to dilute, washed with saturated aqueous sodium bicarbonate (50 mL), saturated brine (200 mL), and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to column chromatography (PE/EA=1:1) to obtain 240 mg of the product. The product was dissolved in dioxane (10 mL), and a solution of HCl in dioxane (4M, 10 mL) was added dropwise and stirred at room temperature overnight. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 230 mg of yellow solid. ESI MS m/z 533[M+H] + .
步骤七：将3-氰基-4-氯苯酚(500mg，3.26mmol，1eq)、4-羟基环己烷甲酸甲酯(3.9mmol，1.2eq)、三苯基膦(1.02g，3.91mmol，1.2eq)溶于THF(20mL)中，氮气条件下于0℃搅拌0.5h， 加入DBAD(900mg，3.91mmol，1.2eq)，室温搅拌4h。TLC检测反应结束后，减压浓缩后柱层析(PE/EA＝20:1)分别得到反式产物ESI MS m/z 294[M+H] +， 1H NMR(400MHz,Chloroform-d)δ7.48(d,J＝8.7Hz,1H),6.91(d,J＝2.4Hz,1H),6.76(dd,J＝8.7,2.4Hz,1H),4.21(ddd,J＝13.6,9.8,3.8Hz,1H),3.63(s,2H),2.31(ddd,J＝14.4,7.2,3.6Hz,1H),2.19–1.96(m,4H),1.45–1.30(m,4H)及顺式产物，ESI MS m/z 294[M+H] +， 1H NMR(400MHz,Chloroform-d)δ7.48(d,J＝8.7Hz,1H),6.93(d,J＝2.5Hz,1H),6.78(dd,J＝8.7,2.4Hz,1H),4.47(d,J＝2.6Hz,1H),3.63(s,3H),2.37(ddd,J＝9.9,8.9,3.9Hz,1H),1.96–1.77(m,4H),1.78–1.55(m,4H)。 Step 7: Combine 3-cyano-4-chlorophenol (500mg, 3.26mmol, 1eq), methyl 4-hydroxycyclohexanecarboxylate (3.9mmol, 1.2eq), triphenylphosphine (1.02g, 3.91mmol, 1.2eq) was dissolved in THF (20mL), stirred at 0°C for 0.5h under nitrogen, added DBAD (900mg, 3.91mmol, 1.2eq), and stirred at room temperature for 4h. After the reaction was detected by TLC, the trans products were obtained by column chromatography (PE/EA=20:1) after concentration under reduced pressure. ESI MS m/z 294[M+H] + , 1 H NMR (400MHz, Chloroform-d) δ7.48(d,J＝8.7Hz,1H),6.91(d,J＝2.4Hz,1H),6.76(dd,J＝8.7,2.4Hz,1H),4.21(ddd,J＝13.6,9.8, 3.8Hz, 1H), 3.63 (s, 2H), 2.31 (ddd, J=14.4, 7.2, 3.6Hz, 1H), 2.19–1.96 (m, 4H), 1.45–1.30 (m, 4H) and cis products , ESI MS m/z 294[M+H] + , 1 H NMR(400MHz, Chloroform-d)δ7.48(d,J=8.7Hz,1H),6.93(d,J=2.5Hz,1H), 6.78(dd,J＝8.7,2.4Hz,1H),4.47(d,J＝2.6Hz,1H),3.63(s,3H),2.37(ddd,J＝9.9,8.9,3.9Hz,1H),1.96 –1.77(m,4H),1.78–1.55(m,4H).
步骤八：将步骤七所得反式产物(100mg，0.34mmol，1eq)溶于甲醇(5mL)中，滴入10％NaOH水溶液(5mL)，室温搅拌2h。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL)洗，水层用1M盐酸调pH至4，加入乙酸乙酯(50mL)稀释，水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩得产物75mg。ESI MS m/z 280[M+H] +。 Step 8: The trans product (100 mg, 0.34 mmol, 1 eq) obtained in Step 7 was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, water (50 mL) was added to dilute, washed with ethyl acetate (50 mL), the pH of the aqueous layer was adjusted to 4 with 1M hydrochloric acid, diluted with ethyl acetate (50 mL), washed with water (50 mL), and saturated brine ( 50 mL) was washed, dried over anhydrous sodium sulfate, and concentrated to obtain 75 mg of the product. ESI MS m/z 280[M+H] + .
步骤九：将步骤八所得产物(11mg，0.04mmol，1eq)、1(20mg，0.04mmol，1eq)溶于DMF(5mL)中，分别加入DIEA(18mg，0.12mmol，1eq)及HATU(18mg，0.05mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化得黄色固体产物2a 15mg。ESI MS m/z 794[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.07(s,1H),10.57(s,1H),7.99(t,J＝12.9Hz,1H),7.85(d,J＝8.8Hz,1H),7.68(d,J＝8.5Hz,1H),7.39(d,J＝2.4Hz,1H),7.37–7.29(m,2H),7.26(d,J＝8.7Hz,1H),7.13(dd,J＝8.8,2.4Hz,1H),5.12–5.00(m,1H),4.65–4.48(m,1H),4.25(d,J＝12.7Hz,2H),3.45(s,3H),2.93–2.80(m,4H),2.65–2.52(m,4H),2.27–2.09(m,4H),1.96–1.54(m,15H)。 Step 9: Dissolve the products obtained in Step 8 (11 mg, 0.04 mmol, 1 eq) and 1 (20 mg, 0.04 mmol, 1 eq) in DMF (5 mL), add DIEA (18 mg, 0.12 mmol, 1 eq) and HATU (18 mg, 0.05mmol, 1.2eq), stirred at room temperature for 2h. After the reaction was detected by TLC, DMF was removed under reduced pressure, and 15 mg of yellow solid product 2a was obtained by pre-TLC (DCM/MeOH=15:1) purification. ESI MS m/z 794[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.07(s, 1H), 10.57(s, 1H), 7.99(t, J=12.9Hz, 1H), 7.85(d, J=8.8Hz, 1H) ,7.68(d,J＝8.5Hz,1H),7.39(d,J＝2.4Hz,1H),7.37–7.29(m,2H),7.26(d,J＝8.7Hz,1H),7.13(dd, J=8.8, 2.4Hz, 1H), 5.12–5.00 (m, 1H), 4.65–4.48 (m, 1H), 4.25 (d, J=12.7Hz, 2H), 3.45 (s, 3H), 2.93–2.80 (m, 4H), 2.65–2.52 (m, 4H), 2.27–2.09 (m, 4H), 1.96–1.54 (m, 15H).
实施例2Example 2
Figure PCTCN2021116287-appb-000102
Figure PCTCN2021116287-appb-000102
以实施例1步骤七的顺式产物为原料，按照实施例1的合成方法得到黄色固体产物2b 10mg。ESI MS m/z 794[M+H] +。 Using the cis product of step 7 of Example 1 as a raw material, 10 mg of yellow solid product 2b was obtained according to the synthesis method of Example 1. ESI MS m/z 794[M+H] + .
实施例3Example 3
Figure PCTCN2021116287-appb-000103
Figure PCTCN2021116287-appb-000103
按照实施例1步骤七的合成方法，分别得到Rf值大的反式中间体及Rf值小的顺式中间体，将反式中间体按照实施例1的合成方法，最终得到黄色固体产物3a 11mg。ESI MS m/z 780[M+H] +。 1H NMR(400MHz,Chloroform-d)δ8.14(s,1H),8.05(s,1H),7.65-7.54(m,2H),7.40(s,1H),7.19(s,1H),7.11–6.86(m,3H),6.70(s,1H),4.44(s,1H),3.71(s,1H),3.68–3.63(m,1H),3.53–3.48(m,1H),3.39–3.33(m,2H),3.23–3.17(m,2H),3.14(s,1H),2.88–2.83(m,2H),2.73(s,1H),2.62(s,1H),2.56(t,J＝1.5Hz,3H),2.47(s,1H),2.35–2.24(m,3H),2.04(d,J＝5.8Hz,2H),1.90(s,1H),1.79–1.69(m,3H),1.64(s,1H),1.58–1.53(m,2H),1.35(s,1H)。 According to the synthetic method of Step 7 of Example 1, respectively obtain a trans-intermediate with a large Rf value and a cis-type intermediate with a small Rf value, and the trans-intermediate according to the synthetic method of Example 1, finally obtain a yellow solid product 3a 11mg . ESI MS m/z 780[M+H] + . 1 H NMR(400MHz, Chloroform-d)δ8.14(s,1H),8.05(s,1H),7.65-7.54(m,2H),7.40(s,1H),7.19(s,1H),7.11 –6.86(m,3H),6.70(s,1H),4.44(s,1H),3.71(s,1H),3.68–3.63(m,1H),3.53–3.48(m,1H),3.39–3.33 (m, 2H), 3.23–3.17 (m, 2H), 3.14 (s, 1H), 2.88–2.83 (m, 2H), 2.73 (s, 1H), 2.62 (s, 1H), 2.56 (t, J =1.5Hz,3H),2.47(s,1H),2.35-2.24(m,3H),2.04(d,J=5.8Hz,2H),1.90(s,1H),1.79-1.69(m,3H) , 1.64(s, 1H), 1.58–1.53(m, 2H), 1.35(s, 1H).
实施例4Example 4
Figure PCTCN2021116287-appb-000104
Figure PCTCN2021116287-appb-000104
将实施例3中的顺式中间体，按照实施例1的合成方法得到黄色固体产物3b 12mg。ESI MS m/z 780[M+H] +。 The cis intermediate in Example 3 was obtained according to the synthetic method of Example 1 to obtain 12 mg of yellow solid product 3b. ESI MS m/z 780[M+H] + .
实施例5Example 5
Figure PCTCN2021116287-appb-000105
Figure PCTCN2021116287-appb-000105
步骤一：将2-氯-5-氟苯甲腈(500mg，3.21mmol，1eq)、反-4-氨基环己烷甲酸甲酯(505mg，3.21mmol，1eq)溶于二氧六环(20mL)中，加入三乙胺(650mg，6.43mmol，2eq)后，120℃搅拌过夜。TLC检测反应结束后，减压除去二氧六环，残余物溶于甲醇(20mL)中，滴入10％NaOH水溶液(20mL)，室温搅拌2h。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL) 洗，水层用1M盐酸调pH至4，加入乙酸乙酯(50mL)稀释，水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩得产物20mg。ESI MS m/z 278[M-H] -。 Step 1: Dissolve 2-chloro-5-fluorobenzonitrile (500mg, 3.21mmol, 1eq) and methyl trans-4-aminocyclohexanecarboxylate (505mg, 3.21mmol, 1eq) in dioxane (20mL) ), triethylamine (650 mg, 6.43 mmol, 2 eq) was added, and the mixture was stirred at 120°C overnight. After the reaction was detected by TLC, dioxane was removed under reduced pressure, the residue was dissolved in methanol (20 mL), 10% aqueous NaOH solution (20 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, water (50 mL) was added to dilute, washed with ethyl acetate (50 mL), the pH of the aqueous layer was adjusted to 4 with 1M hydrochloric acid, diluted with ethyl acetate (50 mL), washed with water (50 mL), and saturated brine ( 50 mL) was washed, dried over anhydrous sodium sulfate, and concentrated to obtain 20 mg of the product. ESI MS m/z 278 [MH] - .
步骤二：将步骤一所得产物(11mg，0.04mmol，1eq)、1(20mg，0.04mmol，1eq)溶于DMF(5mL)中，分别加入DIEA(18mg，0.12mmol，1eq)及HATU(18mg，0.05mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化得黄色固体产物4 5mg。ESI MS m/z 793[M+H] +。 1H NMR(400MHz,Chloroform-d)δ8.18(s,1H),7.97(s,1H),7.64(s,1H),7.46(d,J＝16.8Hz,2H),7.03(d,J＝13.3Hz,2H),6.94(s,1H),6.74(s,1H),6.41(s,1H),4.44(s,1H),3.80(s,1H),3.69–3.64(m,2H),3.53–3.48(m,2H),3.36–3.30(m,2H),3.26–3.21(m,2H),2.76(t,J＝0.9Hz,3H),2.70–2.53(m,5H),2.50(s,1H),2.35–2.21(m,2H),2.20–2.11(m,4H),2.01–1.90(m,2H),1.87–1.78(m,2H),1.76–1.54(m,5H),-0.78(s,1H)。 Step 2: Dissolve the products obtained in step 1 (11mg, 0.04mmol, 1eq) and 1 (20mg, 0.04mmol, 1eq) in DMF (5mL), add DIEA (18mg, 0.12mmol, 1eq) and HATU (18mg, 0.05mmol, 1.2eq), stirred at room temperature for 2h. After the reaction was detected by TLC, DMF was removed under reduced pressure, and purified by pre-TLC (DCM/MeOH=15:1) to obtain 45 mg of yellow solid product. ESI MS m/z 793[M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.18(s, 1H), 7.97(s, 1H), 7.64(s, 1H), 7.46(d, J=16.8Hz, 2H), 7.03(d, J = 13.3Hz, 2H), 6.94(s, 1H), 6.74(s, 1H), 6.41(s, 1H), 4.44(s, 1H), 3.80(s, 1H), 3.69–3.64(m, 2H) ,3.53–3.48(m,2H),3.36–3.30(m,2H),3.26–3.21(m,2H),2.76(t,J=0.9Hz,3H),2.70–2.53(m,5H),2.50 (s, 1H), 2.35–2.21 (m, 2H), 2.20–2.11 (m, 4H), 2.01–1.90 (m, 2H), 1.87–1.78 (m, 2H), 1.76–1.54 (m, 5H) ,-0.78(s,1H).
实施例6Example 6
Figure PCTCN2021116287-appb-000106
Figure PCTCN2021116287-appb-000106
步骤一：将2-氯-5-溴甲基苯甲腈(500mg，2.17mmol，1eq)，哌啶-4-甲酸甲酯(372mg，2.6mmol，1.2eq)溶于无水乙腈(20mL)中，加入碳酸钾(450mg，3.25mmol，1.5eq)后，室温搅拌。TLC检测反应结束后，减压除去乙腈，残余物溶于甲醇(20mL)中，滴入10％NaOH水溶液(20mL)，室温搅拌2h。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL)洗，水层用1M盐酸调pH至4，加入乙酸乙酯(50mL)稀释，水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩得产物620mg。ESI MS m/z 279[M-H] -。 Step 1: Dissolve 2-chloro-5-bromomethylbenzonitrile (500mg, 2.17mmol, 1eq), methyl piperidine-4-carboxylate (372mg, 2.6mmol, 1.2eq) in anhydrous acetonitrile (20mL) To the solution, potassium carbonate (450 mg, 3.25 mmol, 1.5 eq) was added, followed by stirring at room temperature. After the reaction was detected by TLC, acetonitrile was removed under reduced pressure, the residue was dissolved in methanol (20 mL), 10% aqueous NaOH solution (20 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, water (50 mL) was added to dilute, washed with ethyl acetate (50 mL), the pH of the aqueous layer was adjusted to 4 with 1M hydrochloric acid, diluted with ethyl acetate (50 mL), washed with water (50 mL), and saturated brine ( 50 mL) was washed, dried over anhydrous sodium sulfate, and concentrated to obtain 620 mg of the product. ESI MS m/z 279 [MH] - .
步骤二：将步骤一所得产物(11mg，0.04mmol，1eq)、1(20mg，0.04mmol，1eq)溶于DMF(5mL)中，分别加入DIEA(18mg，0.12mmol，1eq)及HATU(18mg，0.05mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化得黄色固体产物5 8mg。ESI MS m/z 793[M+H] +。 1H NMR(400MHz,Chloroform-d)δ8.24(s,1H),7.81(s,1H),7.64–7.50(m,3H),7.27(d,J＝29.0Hz,2H),6.98(s,1H),6.86(s,1H),4.44(s,1H),4.04(s,1H),3.73–3.68(m,2H),3.63–3.58(m,2H),3.58–3.53(m,2H),3.40–3.34(m,2H),3.25–3.19(m,2H),2.94–2.89(m,2H),2.80(d,J＝19.5Hz,2H),2.75–2.70(m,2H),2.65(t,J＝8.1Hz,3H),2.57(s,1H),2.43(t,J＝4.8Hz,2H),2.33–2.23(m,3H),1.79–1.74(m,1H),1.68–1.63(m,2H),1.43(s,1H),1.33–1.28(m,2H)。 Step 2: Dissolve the products obtained in step 1 (11mg, 0.04mmol, 1eq) and 1 (20mg, 0.04mmol, 1eq) in DMF (5mL), add DIEA (18mg, 0.12mmol, 1eq) and HATU (18mg, 0.05mmol, 1.2eq), stirred at room temperature for 2h. After the reaction was detected by TLC, DMF was removed under reduced pressure, and purified by pre-TLC (DCM/MeOH=15:1) to obtain 58 mg of yellow solid product. ESI MS m/z 793[M+H] + . 1 H NMR(400MHz, Chloroform-d)δ8.24(s,1H),7.81(s,1H),7.64-7.50(m,3H),7.27(d,J=29.0Hz,2H),6.98(s ,1H),6.86(s,1H),4.44(s,1H),4.04(s,1H),3.73–3.68(m,2H),3.63–3.58(m,2H),3.58–3.53(m,2H) ), 3.40–3.34 (m, 2H), 3.25–3.19 (m, 2H), 2.94–2.89 (m, 2H), 2.80 (d, J=19.5Hz, 2H), 2.75–2.70 (m, 2H), 2.65(t,J=8.1Hz,3H),2.57(s,1H),2.43(t,J=4.8Hz,2H),2.33-2.23(m,3H),1.79-1.74(m,1H),1.68 –1.63(m, 2H), 1.43(s, 1H), 1.33 – 1.28(m, 2H).
实施例7Example 7
Figure PCTCN2021116287-appb-000107
Figure PCTCN2021116287-appb-000107
步骤一：将3-氰基-4-氯苯酚(500mg，3.26mmol，1eq)、N-Boc-顺式-4-羟基-L-脯氨酸甲酯(958mg，3.91mmol，1.2eq)、三苯基膦(1.02g，3.91mmol，1.2eq)溶于THF(20mL)中，氮气条件下于0℃搅拌0.5h，加入DBAD(900mg，3.91mmol，1.2eq)，室温搅拌4h。TLC检测反应结束后，减压浓缩后柱层析(PE/EA＝20:1)得到无色油状625mg。ESI MS m/z 381[M+H] +。 Step 1: Combine 3-cyano-4-chlorophenol (500mg, 3.26mmol, 1eq), N-Boc-cis-4-hydroxy-L-proline methyl ester (958mg, 3.91mmol, 1.2eq), Triphenylphosphine (1.02 g, 3.91 mmol, 1.2 eq) was dissolved in THF (20 mL), stirred at 0°C for 0.5 h under nitrogen, added DBAD (900 mg, 3.91 mmol, 1.2 eq), and stirred at room temperature for 4 h. After the reaction was detected by TLC, 625 mg of colorless oil was obtained by column chromatography (PE/EA=20:1) after concentration under reduced pressure. ESI MS m/z 381[M+H] + .
步骤二：将步骤一所得产物(100mg，0.26mmol，1eq)溶于甲醇(5mL)中，滴入10％NaOH水溶液(5mL)，室温搅拌2h。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL)洗，水层用1M盐酸调pH至4，加入乙酸乙酯(50mL)稀释，水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩得产物72mg。ESI MS m/z 365[M-H] -。 Step 2: The product obtained in step 1 (100 mg, 0.26 mmol, 1 eq) was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, water (50 mL) was added to dilute, washed with ethyl acetate (50 mL), the pH of the aqueous layer was adjusted to 4 with 1M hydrochloric acid, diluted with ethyl acetate (50 mL), washed with water (50 mL), and saturated brine ( 50 mL) was washed, dried over anhydrous sodium sulfate, and concentrated to obtain 72 mg of the product. ESI MS m/z 365 [MH] - .
步骤三：将步骤二所得产物(14mg，0.04mmol，1eq)、1(20mg，0.04mmol，1eq)溶于DMF(5mL)中，分别加入DIEA(18mg，0.12mmol，1eq)及HATU(18mg，0.05mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化得黄色固体产物15mg。ESI MS m/z 881[M+H] +。 Step 3: Dissolve the products obtained in step 2 (14mg, 0.04mmol, 1eq) and 1 (20mg, 0.04mmol, 1eq) in DMF (5mL), add DIEA (18mg, 0.12mmol, 1eq) and HATU (18mg, 0.05mmol, 1.2eq), stirred at room temperature for 2h. After the reaction was detected by TLC, DMF was removed under reduced pressure and purified by pre-TLC (DCM/MeOH=15:1) to obtain 15 mg of yellow solid product. ESI MS m/z 881[M+H] + .
步骤四：将步骤三所得产物(15mg，0.017mmol，1eq)溶于二氧六环(5mL)中，缓慢滴入HCl的二氧六环溶液(4M,1mL)，室温搅拌2h。TLC检测反应结束后，减压除去溶剂，得黄色固体产物6 16mg。ESI MS m/z 781[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.24(s,1H),7.86(s,1H),7.51(d,J＝15.2Hz,2H),7.29(s,1H),7.14(s,1H),7.04(d,J＝3.8Hz,2H),5.00(s,1H),4.44(s,1H),3.81(d,J＝18.2Hz,2H),3.62–3.57(m,2H),3.39–3.31(m,4H),3.31–2.92(m,4H),3.00(s,1H),3.00(s,1H),2.77(t,J＝1.2Hz,3H),2.64(t,J＝8.2Hz,3H),2.56(s,1H),2.46(s,1H),2.39(s,1H),2.31–2.25(m,2H),2.21(s,1H),2.11(s,1H),1.69–1.64(m,1H),1.43–1.38(m,2H)。 Step 4: Dissolve the product obtained in Step 3 (15 mg, 0.017 mmol, 1 eq) in dioxane (5 mL), slowly drop HCl in dioxane solution (4 M, 1 mL), and stir at room temperature for 2 h. After the reaction was detected by TLC, the solvent was removed under reduced pressure to obtain 16 mg of yellow solid product 6. ESI MS m/z 781[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.24(s, 1H), 7.86(s, 1H), 7.51(d, J=15.2Hz, 2H), 7.29(s, 1H), 7.14(s, 1H), 7.04(d, J＝3.8Hz, 2H), 5.00(s, 1H), 4.44(s, 1H), 3.81(d, J＝18.2Hz, 2H), 3.62–3.57(m, 2H), 3.39-3.31(m, 4H), 3.31-2.92(m, 4H), 3.00(s, 1H), 3.00(s, 1H), 2.77(t, J=1.2Hz, 3H), 2.64(t, J= 8.2Hz, 3H), 2.56(s, 1H), 2.46(s, 1H), 2.39(s, 1H), 2.31–2.25(m, 2H), 2.21(s, 1H), 2.11(s, 1H), 1.69–1.64 (m, 1H), 1.43–1.38 (m, 2H).
实施例8Example 8
Figure PCTCN2021116287-appb-000108
Figure PCTCN2021116287-appb-000108
步骤一：将实施例7步骤一所得产物(100mg，0.26mmol，1eq)溶于二氧六环(10mL)中，缓慢滴入HCl的二氧六环溶液(5mL)，室温搅拌2h。TLC检测反应结束后，减压除去溶剂，得黄色固体产物73mg。ESI MS m/z 281[M+H] +。 Step 1: The product obtained in Step 1 of Example 7 (100 mg, 0.26 mmol, 1 eq) was dissolved in dioxane (10 mL), slowly added dropwise to a solution of HCl in dioxane (5 mL), and stirred at room temperature for 2 h. After the reaction was detected by TLC, the solvent was removed under reduced pressure to obtain 73 mg of yellow solid product. ESI MS m/z 281[M+H] + .
步骤二：将步骤一所得产物(73mg，0.26mmol，1eq)溶于无水乙腈(20mL)中，分别加入碳酸钾(72mg，0.52mmol，2eq)及碘甲烷(44mg，0.31mmol，1.2eq)后，室温搅拌。TLC检测反应结束后，减压除去乙腈，加入乙酸乙酯(50mL)稀释，水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩得产物65mg。ESI MS m/z 295[M+H] +。 Step 2: The product obtained in step 1 (73mg, 0.26mmol, 1eq) was dissolved in anhydrous acetonitrile (20mL), potassium carbonate (72mg, 0.52mmol, 2eq) and methyl iodide (44mg, 0.31mmol, 1.2eq) were added respectively. Then, stir at room temperature. After the reaction was detected by TLC, acetonitrile was removed under reduced pressure, diluted with ethyl acetate (50 mL), washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to obtain 65 mg of the product. ESI MS m/z 295[M+H] + .
步骤三：将步骤二所得产物(65mg，0.22mmol，1eq)溶于甲醇(5mL)中，滴入10％NaOH水溶液(5mL)，室温搅拌2h。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL)洗，水层用1M盐酸调pH至4，加入乙酸乙酯(50mL)稀释，水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩得产物白色固体52mg。ESI MS m/z 279[M-H] -。 Step 3: The product obtained in Step 2 (65 mg, 0.22 mmol, 1 eq) was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, water (50 mL) was added to dilute, washed with ethyl acetate (50 mL), the pH of the aqueous layer was adjusted to 4 with 1M hydrochloric acid, diluted with ethyl acetate (50 mL), washed with water (50 mL), and saturated brine ( 50 mL) was washed, dried over anhydrous sodium sulfate, and concentrated to obtain 52 mg of the product as a white solid. ESI MS m/z 279 [MH] - .
步骤四：将步骤三所得产物(11mg，0.04mmol，1eq)、1(20mg，0.04mmol，1eq)溶于DMF(5mL)中，分别加入DIEA(18mg，0.12mmol，1eq)及HATU(18mg，0.05mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化得黄色固体产物32 13mg。ESI MS m/z 795[M+H] +。 1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝9.4Hz,2H),7.66(s,1H),7.55(s,2H),7.38(s,1H),7.14(s,1H),7.04(t,J＝6.4Hz,3H),6.41(s,1H),4.44(s,1H),3.79(s,1H),3.67–3.62(m,2H),3.55–3.45(m,4H),3.29(s,1H),3.20–3.13(m,2H),3.02(s,1H),2.94(s,1H),2.87–2.82(m,2H),2.69(s,1H),2.62–2.52(m,4H),2.44(s,1H),2.35(s,1H),2.32–2.24(m,2H),2.07(s,1H),2.03–1.98(m,3H),1.79–1.69(m,2H),1.65–1.56(m,3H)。 Step 4: Dissolve the products obtained in Step 3 (11mg, 0.04mmol, 1eq) and 1 (20mg, 0.04mmol, 1eq) in DMF (5mL), add DIEA (18mg, 0.12mmol, 1eq) and HATU (18mg, 0.05mmol, 1.2eq), stirred at room temperature for 2h. After the reaction was detected by TLC, DMF was removed under reduced pressure, and 13 mg of yellow solid product 32 was obtained by pre-TLC (DCM/MeOH=15:1) purification. ESI MS m/z 795[M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.01(d, J=9.4Hz, 2H), 7.66(s, 1H), 7.55(s, 2H), 7.38(s, 1H), 7.14(s, 1H) ), 7.04(t, J＝6.4Hz, 3H), 6.41(s, 1H), 4.44(s, 1H), 3.79(s, 1H), 3.67–3.62(m, 2H), 3.55–3.45(m, 4H), 3.29(s, 1H), 3.20–3.13(m, 2H), 3.02(s, 1H), 2.94(s, 1H), 2.87–2.82(m, 2H), 2.69(s, 1H), 2.62 – 2.52(m, 4H), 2.44(s, 1H), 2.35(s, 1H), 2.32 – 2.24(m, 2H), 2.07(s, 1H), 2.03 – 1.98(m, 3H), 1.79 – 1.69 (m, 2H), 1.65–1.56 (m, 3H).
实施例9Example 9
Figure PCTCN2021116287-appb-000109
Figure PCTCN2021116287-appb-000109
以
Figure PCTCN2021116287-appb-000110
为起始原料，按照实施例7的合成方法得到黄色固体产物8 15mg。ESI MS m/z 780[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),7.95(s,1H),7.65-7.59(m,2H),7.42 (s,1H),7.15–7.02(m,3H),6.94(s,1H),4.44(s,1H),3.79(s,1H),3.64(t,J＝6.9Hz,3H),3.41–3.35(m,2H),3.27–3.17(m,4H),3.02–2.89(m,4H),2.80(s,1H),2.56–2.44(m,5H),2.34(d,J＝1.9Hz,2H),2.31–2.24(m,2H),2.11(s,1H),1.87(s,1H),1.66–1.55(m,2H),1.40–1.30(m,2H)。 by
Figure PCTCN2021116287-appb-000110
As the starting material, 15 mg of yellow solid product 8 was obtained according to the synthetic method of Example 7. ESI MS m/z 780[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.56(s,1H),7.95(s,1H),7.65-7.59(m,2H),7.42(s,1H),7.15-7.02(m,3H) ), 6.94(s, 1H), 4.44(s, 1H), 3.79(s, 1H), 3.64(t, J=6.9Hz, 3H), 3.41–3.35(m, 2H), 3.27–3.17(m, 4H), 3.02–2.89 (m, 4H), 2.80 (s, 1H), 2.56–2.44 (m, 5H), 2.34 (d, J=1.9Hz, 2H), 2.31–2.24 (m, 2H), 2.11 (s, 1H), 1.87 (s, 1H), 1.66–1.55 (m, 2H), 1.40–1.30 (m, 2H).
实施例10Example 10
Figure PCTCN2021116287-appb-000111
Figure PCTCN2021116287-appb-000111
以实施例9中合成的
Figure PCTCN2021116287-appb-000112
为起始原料，按照实施例8的合成方法得到黄色固体产物9 14mg。ESI MS m/z 780[M+H] +。 1H NMR(400MHz,Chloroform-d)δ8.34(s,1H),8.12(s,1H),7.59(d,J＝35.6Hz,2H),7.35(s,1H),7.14(s,1H),7.07(s,1H),6.99(d,J＝14.3Hz,2H),6.46(s,1H),4.44(s,1H),3.79(s,1H),3.65–3.60(m,2H),3.51–3.46(m,2H),3.40–3.33(m,2H),3.29(s,1H),3.31–3.08(m,4H),2.87(t,J＝22.7Hz,3H),2.69(s,1H),2.61(s,1H),2.58–2.42(m,5H),2.33–2.23(m,5H),2.05(s,1H),1.74–1.69(m,1H),1.48–1.43(m,1H),1.35(s,1H)。 Synthesized in Example 9
Figure PCTCN2021116287-appb-000112
As the starting material, 14 mg of yellow solid product 9 was obtained according to the synthetic method of Example 8. ESI MS m/z 780[M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.34(s, 1H), 8.12(s, 1H), 7.59(d, J=35.6Hz, 2H), 7.35(s, 1H), 7.14(s, 1H) ), 7.07(s, 1H), 6.99(d, J=14.3Hz, 2H), 6.46(s, 1H), 4.44(s, 1H), 3.79(s, 1H), 3.65–3.60(m, 2H) ,3.51–3.46(m,2H),3.40–3.33(m,2H),3.29(s,1H),3.31–3.08(m,4H),2.87(t,J=22.7Hz,3H),2.69(s ,1H),2.61(s,1H),2.58–2.42(m,5H),2.33–2.23(m,5H),2.05(s,1H),1.74–1.69(m,1H),1.48–1.43(m , 1H), 1.35(s, 1H).
实施例11Example 11
Figure PCTCN2021116287-appb-000113
Figure PCTCN2021116287-appb-000113
步骤一：将N-Boc哌啶甲醇(776mg，3.86mmol，1.2eq)溶于无水THF中，0℃条件下加入钠氢(193mg，4.82mmol，60％，1.5eq)，氮气条件搅拌30min后，加入2-氯-5-氟苯甲腈(500mg，3.21mmol，1eq)、室温搅拌4h。TLC检测反应结束后，加入水淬灭反应，减压除去THF，加入乙酸乙酯(100mL)稀释，水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩，残余物经柱层析(PE/EA 10:1)得产物520mg。将以上产物溶于20mL二氧六环中，滴入HCl的二氧六环溶液(4M,10mL)，室温搅拌过夜，抽滤，滤饼二氧六环洗，乙醚洗，干燥得白色固体450mg。ESI MS m/z 237[M+H] +。 Step 1: Dissolve N-Boc piperidine methanol (776mg, 3.86mmol, 1.2eq) in anhydrous THF, add sodium hydrogen (193mg, 4.82mmol, 60%, 1.5eq) at 0°C, stir under nitrogen for 30min After that, 2-chloro-5-fluorobenzonitrile (500 mg, 3.21 mmol, 1 eq) was added, and the mixture was stirred at room temperature for 4 h. After the reaction was detected by TLC, water was added to quench the reaction, THF was removed under reduced pressure, ethyl acetate (100 mL) was added to dilute, washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The product was obtained by column chromatography (PE/EA 10:1), 520 mg. The above product was dissolved in 20 mL of dioxane, HCl in dioxane solution (4M, 10 mL) was added dropwise, stirred at room temperature overnight, suction filtered, the filter cake was washed with dioxane, washed with ether, and dried to obtain 450 mg of white solid . ESI MS m/z 237[M+H] + .
步骤二：将1(10.2mg，0.04mmol，1eq)溶于DMF(5mL)中，分别加入三光气(3.3mg，0.013mmol，0.3eq)及三乙胺(3.8mg，0.04mmol，1eq)，室温搅拌1h后，加入步骤一所得产物(20mg，0.04mmol，1eq)，继续搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化得黄色固体产物10 2mg。ESI MS m/z 795[M+H] +。 1H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.88(s,1H),7.59(s,1H),7.46(d,J＝11.6Hz,2H),7.14(s,1H),6.98(s,1H),6.92(s,1H),6.86(s,1H),5.86(s,1H),4.44(s,1H),3.89(s,1H),3.71–3.66(m,2H),3.64–3.59(m,2H),3.52–3.47(m, 2H),3.41–3.35(m,4H),3.18–3.13(m,2H),3.09(s,1H),2.82–2.77(m,2H),2.70–2.48(m,5H),2.33–2.25(m,4H),2.10–2.05(m,2H),1.66–1.61(m,2H),1.42–1.36(m,3H)。 Step 2: Dissolve 1 (10.2mg, 0.04mmol, 1eq) in DMF (5mL), add triphosgene (3.3mg, 0.013mmol, 0.3eq) and triethylamine (3.8mg, 0.04mmol, 1eq) respectively, After stirring at room temperature for 1 h, the product obtained in step 1 (20 mg, 0.04 mmol, 1 eq) was added, and stirring was continued for 2 h. After the reaction was detected by TLC, DMF was removed under reduced pressure, and purified by pre-TLC (DCM/MeOH=15:1) to obtain 10 2 mg of yellow solid product. ESI MS m/z 795[M+H] + . 1 H NMR(400MHz, Chloroform-d)δ8.04(s,1H),7.88(s,1H),7.59(s,1H),7.46(d,J=11.6Hz,2H),7.14(s,1H) ), 6.98(s, 1H), 6.92(s, 1H), 6.86(s, 1H), 5.86(s, 1H), 4.44(s, 1H), 3.89(s, 1H), 3.71–3.66(m, 2H), 3.64–3.59 (m, 2H), 3.52–3.47 (m, 2H), 3.41–3.35 (m, 4H), 3.18–3.13 (m, 2H), 3.09 (s, 1H), 2.82–2.77 ( m, 2H), 2.70–2.48 (m, 5H), 2.33–2.25 (m, 4H), 2.10–2.05 (m, 2H), 1.66–1.61 (m, 2H), 1.42–1.36 (m, 3H).
实施例12Example 12
Figure PCTCN2021116287-appb-000114
Figure PCTCN2021116287-appb-000114
步骤一：将5,6-二氯吡啶-3-醇(500mg，3.05mmol，1eq)、methyl(1R,3R)-3-乙磺酰氧基)环戊烷-1-甲酸甲酯(792mg，3.35mmol，1.1eq)溶于DMF(20mL)中，加入碳酸钾(506mg，3.66mmol，1.2eq)，90℃搅拌。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL)萃取三次，有机层浓缩，饱和食盐水洗，无水硫酸钠干燥，减压浓缩后柱层析(PE/EA＝20:1)得到反式构型产物325mg。ESI MS m/z 290[M+H] +。 Step 1: Mix 5,6-dichloropyridin-3-ol (500mg, 3.05mmol, 1eq), methyl(1R,3R)-3-ethanesulfonyloxy)cyclopentane-1-carboxylate (792mg , 3.35mmol, 1.1eq) was dissolved in DMF (20mL), potassium carbonate (506mg, 3.66mmol, 1.2eq) was added, and stirred at 90°C. After the reaction was detected by TLC, water (50 mL) was added for dilution, ethyl acetate (50 mL) was added for extraction three times, the organic layer was concentrated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure by column chromatography (PE/EA=20: 1) 325 mg of trans-configuration product was obtained. ESI MS m/z 290[M+H] + .
步骤二：将步骤一所得产物(50mg，0.17mmol，1eq)溶于无水DMF(10mL)中，分别加入氰化锌(12mg，0.10mmol，0.6eq)及四三苯基膦钯(20mg，0.02mmol，0.1eq)，氮气条件下120℃搅拌2h。TLC检测反应结束后，加入水(20mL)稀释，乙酸乙酯(20mL)萃取三次，有机层浓缩，饱和食盐水洗，无水硫酸钠干燥，减压浓缩后柱层析(PE/EA＝20:1)得到产物25mg。ESI MS m/z 281[M+H] +。 Step 2: Dissolve the product obtained in step 1 (50mg, 0.17mmol, 1eq) in anhydrous DMF (10mL), add zinc cyanide (12mg, 0.10mmol, 0.6eq) and tetrakistriphenylphosphine palladium (20mg, 0.02 mmol, 0.1 eq), stirred at 120 °C for 2 h under nitrogen. After the reaction was detected by TLC, water (20 mL) was added for dilution, ethyl acetate (20 mL) was added for extraction three times, the organic layer was concentrated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure by column chromatography (PE/EA=20: 1) 25 mg of product was obtained. ESI MS m/z 281[M+H] + .
步骤三：将步骤二所得产物(25mg，0.086mmol，1eq)溶于甲醇(5mL)中，滴入10％NaOH水溶液(5mL)，室温搅拌2h。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL)洗，水层用1M盐酸调pH至4，加入乙酸乙酯(50mL)稀释，水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩得产物18mg。ESI MS m/z 267[M+H] +。 Step 3: The product obtained in Step 2 (25 mg, 0.086 mmol, 1 eq) was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, water (50 mL) was added to dilute, washed with ethyl acetate (50 mL), the pH of the aqueous layer was adjusted to 4 with 1M hydrochloric acid, diluted with ethyl acetate (50 mL), washed with water (50 mL), and saturated brine ( 50 mL) was washed, dried over anhydrous sodium sulfate, and concentrated to obtain 18 mg of the product. ESI MS m/z 267[M+H] + .
步骤四：将步骤三所得产物(11mg，0.04mmol，1eq)、1(20mg，0.04mmol，1eq)溶于DMF(5mL)中，分别加入DIEA(18mg，0.12mmol，1eq)及HATU(18mg，0.05mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化得黄色固体产物11 8mg。ESI MS m/z 781[M+H] +。 1H NMR(400MHz,Chloroform-d)δ8.78(s,1H),8.32(s,1H),8.03(s,1H),7.97(s,1H),7.70(s,1H),7.46(s,1H),7.08(s,1H),7.02(s,1H),4.44(s,1H),3.69(dd,J＝13.6,2.4Hz,4H),3.55–3.50(m,2H),3.37–3.31(m,2H),3.28–3.22(m,2H),2.88–2.83(m,2H),2.74(s,1H),2.63(s,1H),2.60–2.55(m,3H),2.51(s,1H),2.40(s,1H),2.34(s,1H),2.30–2.18(m,2H),2.04(s,1H),1.92(d,J＝10.8Hz,2H),1.77(s,1H),1.72–1.62(m,3H),1.51(s,1H),1.44–1.39(m,2H)。 Step 4: Dissolve the products obtained in Step 3 (11mg, 0.04mmol, 1eq) and 1 (20mg, 0.04mmol, 1eq) in DMF (5mL), add DIEA (18mg, 0.12mmol, 1eq) and HATU (18mg, 0.05mmol, 1.2eq), stirred at room temperature for 2h. After the reaction was detected by TLC, DMF was removed under reduced pressure, and purified by pre-TLC (DCM/MeOH=15:1) to obtain 118 mg of yellow solid product. ESI MS m/z 781[M+H] + . 1 H NMR (400MHz, Chloroform-d)δ8.78(s,1H), 8.32(s,1H), 8.03(s,1H), 7.97(s,1H), 7.70(s,1H), 7.46(s ,1H),7.08(s,1H),7.02(s,1H),4.44(s,1H),3.69(dd,J=13.6,2.4Hz,4H),3.55–3.50(m,2H),3.37– 3.31 (m, 2H), 3.28–3.22 (m, 2H), 2.88–2.83 (m, 2H), 2.74 (s, 1H), 2.63 (s, 1H), 2.60–2.55 (m, 3H), 2.51 ( s, 1H), 2.40(s, 1H), 2.34(s, 1H), 2.30–2.18(m, 2H), 2.04(s, 1H), 1.92(d, J=10.8Hz, 2H), 1.77(s , 1H), 1.72–1.62 (m, 3H), 1.51 (s, 1H), 1.44–1.39 (m, 2H).
实施例13Example 13
Figure PCTCN2021116287-appb-000115
Figure PCTCN2021116287-appb-000115
按照实施例12的操作得到黄色固体12 12mg，ESI MS m/z 795[M+H] +。 1H NMR(400MHz,Chloroform-d)δ8.78(s,1H),8.34(s,1H),8.17(s,1H),7.93(s,1H),7.63(s,1H),7.44(s,1H),7.03(d,J＝16.8Hz,2H),6.42(s,1H),4.57(s,1H),4.44(s,1H),3.73–3.68(m,2H),3.56–3.51(m,2H),3.35–3.29(m,2H),3.26–3.18(m,2H),2.76(t,J＝0.9Hz,3H),2.71–2.54(m,6H),2.54–2.46(m,2H),2.34–2.22(m,2H),2.22–2.11(m,2H),2.02–1.95(m,4H),1.87–1.78(m,2H),1.69–1.57(m,3H)。 Following the procedure of Example 12, 12 mg of yellow solid 12 was obtained, ESI MS m/z 795 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.78(s,1H), 8.34(s,1H), 8.17(s,1H), 7.93(s,1H), 7.63(s,1H), 7.44(s ,1H),7.03(d,J＝16.8Hz,2H),6.42(s,1H),4.57(s,1H),4.44(s,1H),3.73–3.68(m,2H),3.56–3.51( m, 2H), 3.35–3.29 (m, 2H), 3.26–3.18 (m, 2H), 2.76 (t, J=0.9Hz, 3H), 2.71–2.54 (m, 6H), 2.54–2.46 (m, 2H), 2.34–2.22 (m, 2H), 2.22–2.11 (m, 2H), 2.02–1.95 (m, 4H), 1.87–1.78 (m, 2H), 1.69–1.57 (m, 3H).
实施例14Example 14
Figure PCTCN2021116287-appb-000116
Figure PCTCN2021116287-appb-000116
0度下，将
Figure PCTCN2021116287-appb-000117
(221mg，1.30mmol，1eq)溶于无水DMF(20mL)中，加入60％的钠氢(62mg，4.25mmol，1.2eq)后，搅拌30min。分批加入3-氯-4-氰基苯酚(200mg，1.30mmol，1eq)，室温搅拌2h。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL)萃取，有机层用饱和食盐水(50mL)洗，无水硫酸钠干燥，浓缩后柱层析分别得到反式ESI MS m/z 308[M+H] +, 1H NMR(400MHz,Chloroform-d)δ7.54(d,J＝8.7Hz,1H),6.97(d,J＝2.4Hz,1H),6.82(dd,J＝8.7,2.4Hz,1H),4.27(ddd,J＝13.6,9.8,3.8Hz,1H),4.20(q,J＝8.0Hz,1H),2.28(s,2H),1.98-1.97(m,2H),1.70–1.60(m,2H),1.31–1.21(m,8H)及顺式产物ESI MS m/z 308[M+H] +, 1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝8.7Hz,1H),6.99(d,J＝2.4Hz,1H),6.83(dd,J＝8.7,2.4Hz,1H),4.48-4.49(m,1H),4.17(q J＝8.0Hz,1H),1.99-1.96(m,2H),1.85-1.84(m,2H),1.76–1.65(m,2H),1.64–1.59(m,2H),1.29–1.22(m,6H)。以反式产物为原料，按照实施例1的操作，得到黄色固体13 12mg，ESI MS m/z 808[M+H] +。 0 degrees, the
Figure PCTCN2021116287-appb-000117
(221 mg, 1.30 mmol, 1 eq) was dissolved in anhydrous DMF (20 mL), added with 60% sodium hydrogen (62 mg, 4.25 mmol, 1.2 eq), and stirred for 30 min. 3-Chloro-4-cyanophenol (200 mg, 1.30 mmol, 1 eq) was added in portions and stirred at room temperature for 2 h. After the reaction was detected by TLC, water (50 mL) was added to dilute, and ethyl acetate (50 mL) was used for extraction. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain trans ESI MS m by column chromatography. /z 308[M+H] + , 1 H NMR(400MHz, Chloroform-d)δ7.54(d,J=8.7Hz,1H),6.97(d,J=2.4Hz,1H),6.82(dd, J=8.7,2.4Hz,1H),4.27(ddd,J=13.6,9.8,3.8Hz,1H),4.20(q,J=8.0Hz,1H),2.28(s,2H),1.98-1.97(m , 2H), 1.70–1.60(m, 2H), 1.31–1.21(m, 8H) and the cis product ESI MS m/z 308[M+H] + , 1 H NMR (400MHz, Chloroform-d)δ7. 55(d,J＝8.7Hz,1H),6.99(d,J＝2.4Hz,1H),6.83(dd,J＝8.7,2.4Hz,1H),4.48-4.49(m,1H),4.17(q J=8.0Hz, 1H), 1.99-1.96(m, 2H), 1.85-1.84(m, 2H), 1.76-1.65(m, 2H), 1.64-1.59(m, 2H), 1.29-1.22(m, 6H). Using the trans product as the raw material, according to the operation in Example 1, 12 mg of yellow solid 13 was obtained, ESI MS m/z 808 [M+H] + .
实施例15Example 15
Figure PCTCN2021116287-appb-000118
Figure PCTCN2021116287-appb-000118
0度下，将
Figure PCTCN2021116287-appb-000119
(244mg，1.30mmol，1eq)溶于无水DMF(20mL)中，加入60％的钠氢(62mg，4.25mmol，1.2eq)后，搅拌30min。分批加入3-氯-4-氰基苯酚(200mg，1.30mmol，1eq)，室温搅拌2h。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL)萃取，有机层用饱和食盐水(50mL)洗，无水硫酸钠干燥，浓缩后柱层析得到Rf值大的反式中间体52mg及Rf值小的顺式中间体26mg，按照实施例14的操作，得到终产物黄色固体14，ESI MS m/z 812[M+H] +。 0 degrees, the
Figure PCTCN2021116287-appb-000119
(244 mg, 1.30 mmol, 1 eq) was dissolved in anhydrous DMF (20 mL), 60% sodium hydrogen (62 mg, 4.25 mmol, 1.2 eq) was added, and the mixture was stirred for 30 min. 3-Chloro-4-cyanophenol (200 mg, 1.30 mmol, 1 eq) was added in portions and stirred at room temperature for 2 h. After the reaction was detected by TLC, water (50 mL) was added to dilute, and ethyl acetate (50 mL) was used for extraction. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain a trans-form with a large Rf value. 52 mg of the intermediate and 26 mg of the cis-intermediate with a small Rf value, according to the operation of Example 14, the final product of yellow solid 14 was obtained, ESI MS m/z 812 [M+H] + .
实施例16Example 16
Figure PCTCN2021116287-appb-000120
Figure PCTCN2021116287-appb-000120
步骤一：将4-氟硝基苯(500mg，3.54mmol，1eq)、哌啶-4-甲醇(490mg，4.25mmol，1.2eq)溶于二氧六环(20mL)中，加入DIEA(696uL，4.25mmol，1.2eq)后，120℃搅拌过夜。TLC检测反应结束后，加入水(50mL)稀释，乙酸乙酯(50mL)萃取，有机层用饱和食盐水(50mL)洗，无水硫酸钠干燥，浓缩后柱层析得产物250mg。ESI MS m/z 237[M+H] +. Step 1: Dissolve 4-fluoronitrobenzene (500mg, 3.54mmol, 1eq), piperidine-4-methanol (490mg, 4.25mmol, 1.2eq) in dioxane (20mL), add DIEA (696uL, 4.25 mmol, 1.2 eq) and stirred at 120°C overnight. After the reaction was detected by TLC, water (50 mL) was added to dilute, and ethyl acetate (50 mL) was used for extraction. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 250 mg of product by column chromatography. ESI MS m/z 237[M+H] + .
步骤二：将步骤一所得产物(250mg，1.06mmol，1eq)溶于二氯甲烷(50mL)中，加入Dess-Martin(540g，14.6mmol，1.2eq)，所得混合物室温搅拌2h。TLC检测反应结束后，减压除去二氯甲烷，加入乙酸乙酯(200mL)稀释，分别用饱和碳酸氢钠水溶液(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩，残余物柱层析(PE/EA＝3:1)得产物180mg.ESI MS m/z 235[M+H] +。 Step 2: The product obtained in Step 1 (250 mg, 1.06 mmol, 1 eq) was dissolved in dichloromethane (50 mL), Dess-Martin (540 g, 14.6 mmol, 1.2 eq) was added, and the resulting mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, dichloromethane was removed under reduced pressure, diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated. Column chromatography (PE/EA=3:1) of the residue gave the product 180 mg. ESI MS m/z 235 [M+H] + .
步骤三：将步骤二所得产物(180mg，0.77mmol，1eq)溶于二氯甲烷(20mL)中，加入实施 例一中步骤二的产物(237mg，0.77mmol，1eq)，室温搅拌半小时后，加入醋酸硼氢化钠(328mg，1.55mmol，2eq)，所得混合物室温搅拌3.5h。TLC检测反应结束后，滴入饱和氯化铵水溶液淬灭，加入二氯甲烷(50mL)稀释，分别用饱和碳酸氢钠水溶液(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩，残余物柱层析得产物160mg.ESI MS m/z 561[M+H] +。 Step 3: Dissolve the product obtained in Step 2 (180 mg, 0.77 mmol, 1 eq) in dichloromethane (20 mL), add the product of Step 2 in Example 1 (237 mg, 0.77 mmol, 1 eq), and stir at room temperature for half an hour, Sodium borohydride acetate (328 mg, 1.55 mmol, 2 eq) was added and the resulting mixture was stirred at room temperature for 3.5 h. After the reaction was detected by TLC, saturated aqueous ammonium chloride solution was added dropwise to quench, dichloromethane (50 mL) was added to dilute, washed with saturated aqueous sodium bicarbonate solution (50 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After concentrating, the residue was subjected to column chromatography to obtain the product 160 mg. ESI MS m/z 561 [M+H] + .
步骤四：将步骤三所得产物(160mg，0.29mmol，1eq)溶于甲醇与饱和氯化铵溶液的混合溶剂中(1:1,20mL)中，加入铁粉(80mg，1.43mmol，1eq)，80度搅拌半小时后，加入二氯甲烷(50mL)萃取，饱和食盐水(200mL)洗，无水硫酸钠干燥后浓缩，得粗品152mg.ESI MS m/z 531[M+H] +。 Step 4: Dissolve the product obtained in Step 3 (160mg, 0.29mmol, 1eq) in a mixed solvent of methanol and saturated ammonium chloride solution (1:1, 20mL), add iron powder (80mg, 1.43mmol, 1eq), After stirring at 80 degrees for half an hour, dichloromethane (50 mL) was added for extraction, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to obtain 152 mg of crude product. ESI MS m/z 531[M+H] + .
步骤五：将(1R,4R)-4-(3-氯-4-氰基苯氧基)环己烷-1-甲酸(11mg，0.038mmol，1eq)、步骤四所得产物(20mg，0.038mmol，1eq)溶于DMF(5mL)中，分别加入DIEA(6.8mg，0.046mmol，1.2eq)及HATU(17mg，0.046mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化得黄色固体产物15 13mg。ESI MS m/z 792[M+H] +。 Step 5: Combine (1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexane-1-carboxylic acid (11mg, 0.038mmol, 1eq), the product obtained in step 4 (20mg, 0.038mmol) , 1eq) was dissolved in DMF (5mL), DIEA (6.8mg, 0.046mmol, 1.2eq) and HATU (17mg, 0.046mmol, 1.2eq) were added, and the mixture was stirred at room temperature for 2h. After the reaction was detected by TLC, DMF was removed under reduced pressure, and purified by pre-TLC (DCM/MeOH=15:1) to obtain 13 mg of yellow solid product 15. ESI MS m/z 792[M+H] + .
实施例17Example 17
Figure PCTCN2021116287-appb-000121
Figure PCTCN2021116287-appb-000121
将(1R,3R)-3-(3-氯-4-氰基苯氧基)环戊烷-1-羧酸(10mg，0.038mmol，1eq)、实施例16步骤四所得产物(20mg，0.038mmol，1eq)溶于DMF(5mL)中，分别加入DIEA(6.8mg，0.046mmol，1.2eq)及HATU(17mg，0.046mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化得黄色固体产物16 15mg。ESI MS m/z 778[M+H] +。 (1R,3R)-3-(3-chloro-4-cyanophenoxy)cyclopentane-1-carboxylic acid (10 mg, 0.038 mmol, 1 eq), the product obtained in step 4 of Example 16 (20 mg, 0.038 mmol, 1 eq) was dissolved in DMF (5 mL), DIEA (6.8 mg, 0.046 mmol, 1.2 eq) and HATU (17 mg, 0.046 mmol, 1.2 eq) were added, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, DMF was removed under reduced pressure, and 15 mg of yellow solid product 16 was obtained by pre-TLC (DCM/MeOH=15:1) purification. ESI MS m/z 778[M+H] + .
实施例18Example 18
Figure PCTCN2021116287-appb-000122
Figure PCTCN2021116287-appb-000122
以2-氟-5-硝基吡啶为原料，按照实施例16的操作，得到黄色固体17 10mg，ESI MS m/z 793[M+H] +。 Using 2-fluoro-5-nitropyridine as a raw material, according to the operation of Example 16, 10 mg of yellow solid 17 was obtained, ESI MS m/z 793 [M+H] + .
实施例19Example 19
Figure PCTCN2021116287-appb-000123
Figure PCTCN2021116287-appb-000123
以实施例18制备得到的
Figure PCTCN2021116287-appb-000124
为起始原料，按照实施例17的操作，得到黄色固体18 10mg，ESI MS m/z 779[M+H] +。 Prepared with Example 18
Figure PCTCN2021116287-appb-000124
As starting material, following the procedure of Example 17, 10 mg of yellow solid 18 was obtained, ESI MS m/z 779 [M+H] + .
实施例20Example 20
Figure PCTCN2021116287-appb-000125
Figure PCTCN2021116287-appb-000125
以1-甲基-3-羟基环戊烷甲酸甲酯为原料，按照实施例14的操作，得到Rf值大的反式中间体及Rf值小的顺式中间体，将反式中间体进行下一步，最终得到反式产物19 10mg，ESI MS m/z 794[M+H] +。 Using methyl 1-methyl-3-hydroxycyclopentanecarboxylate as a raw material, according to the operation of Example 14, a trans intermediate with a large Rf value and a cis intermediate with a small Rf value were obtained, and the trans intermediate was carried out. In the next step, 10 mg of trans product 19 was finally obtained, ESI MS m/z 794 [M+H] + .
实施例21Example 21
Figure PCTCN2021116287-appb-000126
Figure PCTCN2021116287-appb-000126
以1-氟-3-羟基环戊烷甲酸甲酯为原料，按照实施例14的操作，得到Rf值大的反式中间体及Rf值小的顺式中间体，将反式中间体进行下一步，最终得到反式黄色固体20 8mg，ESI MS m/z 798[M+H] +。 Using methyl 1-fluoro-3-hydroxycyclopentanecarboxylate as a raw material, according to the operation of Example 14, a trans intermediate with a large Rf value and a cis intermediate with a small Rf value were obtained, and the trans intermediate was subjected to the following steps. In one step, 20 8 mg of trans-yellow solid was finally obtained, ESI MS m/z 798 [M+H] + .
实施例22Example 22
Figure PCTCN2021116287-appb-000127
Figure PCTCN2021116287-appb-000127
以2-硝基-5-氟吡啶为原料，按照实施例16的操作，得到黄色固体21 8mg，ESI MS m/z 793[M+H] +。 Using 2-nitro-5-fluoropyridine as a raw material, following the operation in Example 16, 21 8 mg of yellow solid was obtained, ESI MS m/z 793 [M+H] + .
实施例23Example 23
Figure PCTCN2021116287-appb-000128
Figure PCTCN2021116287-appb-000128
以实施例22合成的
Figure PCTCN2021116287-appb-000129
为起始原料，按照实施例17的操作，得到黄色固体22 10mg，ESI MS m/z 779[M+H] +。 Synthesized with Example 22
Figure PCTCN2021116287-appb-000129
As starting material, following the procedure of Example 17, 10 mg of yellow solid 22 was obtained, ESI MS m/z 779 [M+H] + .
实施例24Example 24
Figure PCTCN2021116287-appb-000130
Figure PCTCN2021116287-appb-000130
步骤一：将4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉酮-5-基)哌嗪-1-碳酸叔丁酯(1g，2.26mmol，1eq)溶于乙酸中，加入锌粉(1.48g，22.6mmol，10eq)，60℃搅拌1h后，冷却，抽滤，滤液浓缩，加入20mL水稀释，饱和碳酸氢钠调pH至中性后，用乙酸乙酯(50mL)萃取，饱和食盐水(50mL)洗，无水硫酸钠干燥后浓缩得混合物470mg，ESI MS m/z 445[M+H] +。 Step 1: 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolinone-5-yl)piperazine-1-tert-butyl carbonate Ester (1g, 2.26mmol, 1eq) was dissolved in acetic acid, zinc powder (1.48g, 22.6mmol, 10eq) was added, stirred at 60°C for 1h, cooled, suction filtered, the filtrate was concentrated, diluted with 20mL of water, saturated sodium bicarbonate The pH was adjusted to neutral, extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a mixture of 470 mg, ESI MS m/z 445 [M+H] + .
步骤二：将步骤一所得产物(470mg，1.06mmol，1eq)溶于二氯甲烷中，分别滴入三氟乙酸(923mg，9.52mmol，9eq)及三乙基硅烷(737mg，22.6mmol，6eq)，室温搅拌2h后，将反应液浓缩，制备分离，分别得到210mg 3位取代产物 1H NMR(400MHz,DMSO-d 6)δ10.95(s,1H),8.81(s,2H),7.59(d,J＝8.4Hz,1H),7.15(d,J＝4.7Hz,1H),7.13(dd,J＝8.5,2.1Hz,1H),5.06(dd,J＝13.3,5.1Hz,1H),4.36(d,J＝17.1Hz,1H),4.23(d,J＝17.0Hz,1H),3.53–3.45(m,4H),3.25(s,4H),2.99–2.83(m,1H),2.59(d,J＝17.2Hz,1H),2.38(ddd,J＝25.8,13.1,4.2Hz,1H),2.04–1.92(m,1H)及90mg 2位取代的中间体1H NMR(400MHz,DMSO-d 6)δ10.97(s,1H),8.70(s,2H),7.49(d,J＝8.4Hz,1H),7.31(dd,J＝8.4,2.4Hz,1H),7.27(d,J＝2.2Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.36(d,J＝17.0Hz,1H),4.23(d,J＝16.8Hz,1H),3.47–3.38(m,4H),3.26(s,4H),3.00–2.81(m,1H),2.70–2.55(m,1H),2.47–2.29(m,1H),2.08–1.88(m,1H).色谱柱：waters BEH C18液相色谱柱(250×20mm,5μm)，流动相A为 水(千分之一三氟乙酸)，B为乙腈，15％-30％B梯度洗脱，流速：1mL/min，3位取代产物保留时间为16.3min，2位取代产物保留时间为17.2min。 Step 2: The product obtained in Step 1 (470mg, 1.06mmol, 1eq) was dissolved in dichloromethane, and trifluoroacetic acid (923mg, 9.52mmol, 9eq) and triethylsilane (737mg, 22.6mmol, 6eq) were added dropwise respectively. , after stirring at room temperature for 2 h, the reaction solution was concentrated, prepared and separated to obtain 210 mg of the 3 -position substituted product. d, J=8.4Hz, 1H), 7.15 (d, J=4.7Hz, 1H), 7.13 (dd, J=8.5, 2.1Hz, 1H), 5.06 (dd, J=13.3, 5.1Hz, 1H), 4.36(d,J=17.1Hz,1H),4.23(d,J=17.0Hz,1H),3.53–3.45(m,4H),3.25(s,4H),2.99–2.83(m,1H),2.59 (d, J=17.2Hz, 1H), 2.38 (ddd, J=25.8, 13.1, 4.2Hz, 1H), 2.04–1.92 (m, 1H) and 90mg 2-substituted intermediate 1H NMR (400MHz, DMSO- d 6 )δ10.97(s,1H),8.70(s,2H),7.49(d,J=8.4Hz,1H),7.31(dd,J=8.4,2.4Hz,1H),7.27(d,J =2.2Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.36(d,J=17.0Hz,1H),4.23(d,J=16.8Hz,1H),3.47–3.38(m ,4H),3.26(s,4H),3.00–2.81(m,1H),2.70–2.55(m,1H),2.47–2.29(m,1H),2.08–1.88(m,1H).Column: waters BEH C18 liquid chromatography column (250×20mm, 5μm), mobile phase A is water (1/1000 trifluoroacetic acid), B is acetonitrile, 15%-30% B gradient elution, flow rate: 1mL/min, The retention time of the 3-substituted product was 16.3 min, and the retention time of the 2-substituted product was 17.2 min.
步骤三：将以上产物分别(1eq)溶于THF中，加入(6-(4-甲酰基哌啶-1-基)哒嗪-3-基)氨基甲酸叔丁酯(1eq)室温搅拌30min后，加入醋酸硼氢化钠(1.1eq)，室温搅拌过夜，TLC检测反应结束后，滴入饱和氯化铵水溶液淬灭，加入二氯甲烷(50mL)稀释，分别用饱和碳酸氢钠水溶液(50mL)洗，饱和食盐水(200mL)洗，无水硫酸钠干燥后浓缩，残余物柱层析(PE/EA＝1:1)分别得到3位取代产物及2位取代产物。将产物分别溶于二氧六环(10mL)中，滴入HCl的二氧六环溶液(4M,10mL)，室温搅拌过夜。TLC检测反应结束后，减压浓缩分别得180mg 3位取代产物及90mg 2位取代产物。Step 3: Dissolve the above products (1eq) in THF respectively, add (6-(4-formylpiperidin-1-yl)pyridazin-3-yl)carbamic acid tert-butyl ester (1eq) and stir at room temperature for 30min. , add sodium borohydride acetate (1.1eq), stir overnight at room temperature, after TLC detection of the reaction, add dropwise saturated ammonium chloride aqueous solution to quench, add dichloromethane (50mL) to dilute, respectively use saturated sodium bicarbonate aqueous solution (50mL) Washed, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated, the residue was subjected to column chromatography (PE/EA=1:1) to obtain the 3-substituted product and the 2-substituted product, respectively. The products were respectively dissolved in dioxane (10 mL), and a solution of HCl in dioxane (4M, 10 mL) was added dropwise, and the mixture was stirred at room temperature overnight. After TLC detected the reaction, concentrated under reduced pressure to obtain 180 mg of the 3-substituted product and 90 mg of the 2-substituted product, respectively.
步骤四：将(1R,4R)-4-(3-氯-4-氰基苯氧基)环己烷-1-甲酸(30mg，0.107mmol，1eq)、步骤三所得3位及2位取代产物(56mg，0.107mmol，1eq)溶于DMF(10mL)中，分别加入DIEA(20mg，0.132mmol，1.2eq)及HATU(51mg，0.132mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化分别得到23a，ESI MS m/z 780[M+H] +及23b，ESI MS m/z 780[M+H] +。 Step 4: Substitute (1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexane-1-carboxylic acid (30mg, 0.107mmol, 1eq), the 3- and 2-position obtained in step 3 The product (56mg, 0.107mmol, 1eq) was dissolved in DMF (10mL), DIEA (20mg, 0.132mmol, 1.2eq) and HATU (51mg, 0.132mmol, 1.2eq) were added respectively, and the mixture was stirred at room temperature for 2h. After the reaction was detected by TLC, DMF was removed under reduced pressure and purified by pre-TLC (DCM/MeOH=15:1) to obtain 23a, ESI MS m/z 780[M+H] + and 23b, ESI MS m/z 780[ M+H] + .
实施例25Example 25
Figure PCTCN2021116287-appb-000131
Figure PCTCN2021116287-appb-000131
将(1R,3R)-3-(3-氯-4-氰基苯氧基)环戊烷-1-羧酸(15mg，0.056mmol，1eq)、实施例24步骤三所得3位及2位取代产物(30mg，0.056mmol，1eq)溶于DMF(10mL)中，分别加入DIEA(10mg，0.66mmol，1.2eq)及HATU(26mg，0.066mmol，1.2eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝15:1)纯化分别得到24a，ESI MS m/z 766[M+H] +及24b，ESI MS m/z 766[M+H] +。 Combine (1R,3R)-3-(3-chloro-4-cyanophenoxy)cyclopentane-1-carboxylic acid (15 mg, 0.056 mmol, 1 eq), the 3-position and 2-position obtained in step 3 of Example 24 The substituted product (30 mg, 0.056 mmol, 1 eq) was dissolved in DMF (10 mL), DIEA (10 mg, 0.66 mmol, 1.2 eq) and HATU (26 mg, 0.066 mmol, 1.2 eq) were added, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, DMF was removed under reduced pressure and purified by pre-TLC (DCM/MeOH=15:1) to obtain 24a, ESI MS m/z 766[M+H] + and 24b, ESI MS m/z 766[ M+H] + .
实施例26Example 26
Figure PCTCN2021116287-appb-000132
Figure PCTCN2021116287-appb-000132
以
Figure PCTCN2021116287-appb-000133
为原料，按照实施例25的操作，得到25a和25b,ESI MS m/z 794[M+H] +。 by
Figure PCTCN2021116287-appb-000133
As starting materials, following the procedure of Example 25, 25a and 25b were obtained, ESI MS m/z 794 [M+H] + .
实施例27Example 27
Figure PCTCN2021116287-appb-000134
Figure PCTCN2021116287-appb-000134
步骤一：step one:
将反式-4-羟基环己烷羧酸(300mg，2.081mmol，1eq)、三苯基氯甲烷(637mg，2.289mmol，1.1eq)溶于THF(3mL)中，加入DBU(380mg，2.497mmol，1.2eq)，N2置换空气三次，回流搅拌6h。TLC检测反应结束后，减压除去THF，硅胶柱层析纯化得到产物402mg，ESI MS m/z 387[M+H] +。 Trans-4-hydroxycyclohexanecarboxylic acid (300 mg, 2.081 mmol, 1 eq), triphenylchloromethane (637 mg, 2.289 mmol, 1.1 eq) were dissolved in THF (3 mL), DBU (380 mg, 2.497 mmol) was added , 1.2eq), N2 replaced the air three times, refluxed and stirred for 6h. After the reaction was detected by TLC, THF was removed under reduced pressure, and the product was purified by silica gel column chromatography to obtain 402 mg of product, ESI MS m/z 387 [M+H] + .
步骤二：Step 2:
在0℃下，将步骤一产物(200mg，0.517mmol，1eq)的DMF(1mL)溶液滴加入NaH(22.8mg，0.569mmol，1.1eq)的DMF(1mL)悬浮液中，搅拌反应30min，随即，滴加2-溴-4-二氟苯腈(103mg，0.517mmol，1eq)的DMF(1mL)溶液，室温搅拌反应2h。反应结束后，使用饱和氯化铵水溶液淬灭反应，EA萃取，合并有机相，无水硫酸钠除水，减压除去溶剂，得到产物100mg，ESI MS m/z 324[M+H] +。 At 0°C, a solution of the product of step 1 (200 mg, 0.517 mmol, 1 eq) in DMF (1 mL) was added dropwise to a suspension of NaH (22.8 mg, 0.569 mmol, 1.1 eq) in DMF (1 mL), and the reaction was stirred for 30 min. , 2-bromo-4-difluorobenzonitrile (103 mg, 0.517 mmol, 1 eq) in DMF (1 mL) solution was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with EA, the organic phases were combined, water was removed with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 100 mg of product, ESI MS m/z 324 [M+H] + .
步骤三：Step 3:
将步骤二所得产物(6.59mg，0.020mmol，1eq)、实施例24步骤三所得3位及2位取代产物(16.9mg，0.024mmol，1.2eq)溶于DMF(1mL)中，分别加入DIEA(13mg，0.101mmol，5eq)及HATU(8mg，0.020mmol，1eq)，室温搅拌2h。TLC检测反应结束后，减压除去DMF，pre-TLC(DCM/MeOH＝12:1)纯化分别得到26(15.1mg)，ESI MS m/z 824[M+H] +。 The product obtained in step 2 (6.59 mg, 0.020 mmol, 1 eq) and the 3- and 2-substituted products obtained in step 3 of Example 24 (16.9 mg, 0.024 mmol, 1.2 eq) were dissolved in DMF (1 mL), and DIEA ( 13mg, 0.101mmol, 5eq) and HATU (8mg, 0.020mmol, 1eq), stirred at room temperature for 2h. After the reaction was detected by TLC, DMF was removed under reduced pressure, and purified by pre-TLC (DCM/MeOH=12:1) to obtain 26 (15.1 mg), respectively, ESI MS m/z 824 [M+H] + .
实施例28Example 28
Figure PCTCN2021116287-appb-000135
Figure PCTCN2021116287-appb-000135
以2,4-二氟苯腈为原料，按照实施例27的方法得到产物27(16.7mg)，ESI MS m/z 764[M+H] + Using 2,4-difluorobenzonitrile as raw material, following the method of Example 27 to obtain product 27 (16.7 mg), ESI MS m/z 764 [M+H] +
效果实施例1Effect Example 1
实验方法experimental method
PC-3细胞：procell，货号CL-0185。LNCaP细胞：武汉普诺赛生命科技。PC-3 cells: procell, Cat. No. CL-0185. LNCaP cells: Wuhan Proceeds Life Science and Technology.
1.PC-3细胞抗增殖活性1. Antiproliferative activity of PC-3 cells
将PC-3细胞消化、计数、制成浓度为2.2×10 4个/ml的细胞悬液，96孔板中每孔加入160μL细胞悬液(每孔3500个细胞)；96孔板置于37℃，5％CO 2培养箱中培养24小时；用完全培养基稀释药物至所需浓度，每孔加入40μL相应的含药培养基；96孔板置于37℃，5％CO 2培养箱中培养4d；最后用CCK-8法检测细胞活性，根据公式细胞活力＝((NC-空白组)-(化合物组-空白组))/((NC-空白组)-(PC-空白组))*100％计算细胞抗增殖活性。NC(negative control)为DMSO组和PC(positive control)为100％致死率的药物。 PC-3 cells were digested, counted, and made into a cell suspension with a concentration of 2.2×10 4 cells/ml, and 160 μL of cell suspension was added to each well of a 96-well plate (3500 cells per well); the 96-well plate was placed in 37 Incubate for 24 hours in a 5% CO2 incubator at °C; dilute the drug to the desired concentration with complete medium, and add 40 μL of the corresponding drug-containing medium to each well; place the 96-well plate in a 37 °C, 5% CO2 incubator Culture for 4 days; finally, the cell viability was detected by CCK-8 method, according to the formula cell viability=((NC-blank group)-(compound group-blank group))/((NC-blank group)-(PC-blank group)) *100% calculated cell antiproliferative activity. NC (negative control) was the DMSO group and PC (positive control) was the drug with 100% lethality.
2.LNCap细胞抗增殖活性2. Antiproliferative activity of LNCap cells
将LNCap细胞消化、计数，制成浓度为3.13×10 4个/ml的细胞悬液，取足量体积细胞悬液，加DCC培养基稀释细胞密度至5000细胞/160uL，混匀。取160uL细胞悬液于96孔板中，加入PC组，然后加入适量的R1881,每孔加入160ul细胞悬液，37℃培养箱培养2d。用完全培养基稀释药物至所需浓度，每孔加入40μL相应的含药培养基；96孔板置于37℃，5％CO 2培养箱中培养4d；最后用CCK-8法检测细胞活性，根据公式细胞活力＝((NC-空白组)-(化合物组-空白组))/((NC-空白组)-(PC-空白组))*100％，计算细胞抗增殖活性。NC(negative control)为未加R1881(美曲勃龙)的对照组和PC(positive control)为R1881的对照组。 Digest and count LNCap cells to prepare a cell suspension with a concentration of 3.13×10 4 cells/ml, take a sufficient volume of cell suspension, add DCC medium to dilute the cell density to 5000 cells/160uL, and mix well. Take 160uL of cell suspension into a 96-well plate, add PC group, then add an appropriate amount of R1881, add 160ul of cell suspension to each well, and culture in a 37°C incubator for 2 days. Dilute the drug to the desired concentration with complete medium, and add 40 μL of the corresponding drug-containing medium to each well; place the 96-well plate in a 37°C, 5% CO 2 incubator for 4 days; finally detect the cell viability by the CCK-8 method. According to the formula cell viability=((NC-blank group)-(compound group-blank group))/((NC-blank group)-(PC-blank group))*100%, the anti-proliferative activity of cells was calculated. NC (negative control) is a control group without R1881 (metabolone) and PC (positive control) is a control group with R1881.
表1.本发明化合物对LNCap细胞及PC-3细胞的抑制活性Table 1. Inhibitory activity of the compounds of the present invention on LNCap cells and PC-3 cells
化合物compound LNCap(IC50，μM)LNCap(IC50, μM) PC-3(IC50，μM)PC-3 (IC50, μM)
2a2a 0.0520.052 >10>10
2b2b 1.121.12 >10>10
3a3a 0.0520.052 >10>10
3b3b 1.201.20 >10>10
44 0.5250.525 >10>10
77 0.9800.980 >10>10
99 1.121.12 >10>10
1010 2.542.54 >10>10
1111 0.3520.352 >10>10
1212 0.5880.588 >10>10
1313 0.1200.120 >10>10
1414 0.0980.098 >10>10
1515 0.2510.251 >10>10
1616 0.3630.363 >10>10
1717 0.1740.174 >10>10
1818 0.5250.525 >10>10
1919 0.0880.088 >10>10
2020 0.0780.078 >10>10
21twenty one 0.2510.251 >10>10
22twenty two 0.1730.173 >10>10
23a23a 0.0060.006 >10>10
23b23b 0.0300.030 >10>10
24a24a 0.0090.009 >10>10
24b24b 0.0450.045 >10>10
2626 79.479.4 >10>10
2727 612.4612.4 >10>10
158158 0.0650.065 >10>10
158为US 2018/0099940 A1中化合物编号为158的分子，结构如下所示，158 is the molecule whose compound number is 158 in US 2018/0099940 A1, and the structure is as follows,
Figure PCTCN2021116287-appb-000136
Figure PCTCN2021116287-appb-000136
本发明大部分化合物在LNCap细胞上显示了纳摩尔级别的活性，且对PC-3细胞增殖影响较小。Most of the compounds of the present invention show nanomolar activity on LNCap cells, and have little effect on PC-3 cell proliferation.
效果实施例2Effect Example 2
1.药代动力学实验方法1. Pharmacokinetic experimental method
色谱条件：色谱柱：Waters XBridge C18液相色谱柱(50×2.1mm,5μm)，柱温：40℃；流动相A为水(0.1％甲酸)，流动相B为乙腈(0.1％甲酸)，洗脱剂：90％B。流速为1mL/min。Chromatographic conditions: Column: Waters XBridge C18 liquid chromatography column (50×2.1mm, 5μm), column temperature: 40°C; mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile (0.1% formic acid), Eluent: 90% B. The flow rate was 1 mL/min.
质谱条件：用LC-MS/MS进行测定，离子源为APIC源，使用正离子化方式检测，扫描方式为选择性反应监测(MRM)。Mass spectrometry conditions: LC-MS/MS was used for determination, the ion source was APIC source, positive ionization mode was used for detection, and the scanning mode was selective reaction monitoring (MRM).
标准曲线的建立：精密称取待测样品1mg，加入1mL DMSO配制成1mg/mL的标准溶液，以甲醇为稀释剂，逐级稀释至不同浓度(2,5,10,20,50,100,200,500,1000,2000,5000ng/mL)，取上清液1μL进行LC-MS/MS测定，建立标准曲线。Establishment of the standard curve: Precisely weigh 1 mg of the sample to be tested, add 1 mL of DMSO to prepare a 1 mg/mL standard solution, and use methanol as the diluent to dilute to different concentrations (2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000ng/mL), take 1 μL of the supernatant for LC-MS/MS determination, and establish a standard curve.
选取小鼠9只，雄性，体重180-220g，禁食12h，按5mg/kg剂量[溶媒为PEG300:Solutol HS 15:pH 4.65 acetate buffer(10:10:80)]口服给药给予样品溶液，给药前取空白血，分别于给药后不同时间点取静脉血约100μL，置加有肝素的试管中，离心，取血浆约50μL，-20℃保存供测试。采血时间点为：18min、30min、60min、120min、240min、360min、480min、1440min。取大鼠血浆样品50μL，5500rpm离心18分钟，取10μL进行LC-MS/MS测定。通过建立的标准曲线计算血药浓度。Select 9 mice, male, weighing 180-220g, fasted for 12h, and given the sample solution by oral administration at a dose of 5mg/kg [the vehicle is PEG300:Solutol HS 15:pH 4.65 acetate buffer(10:10:80)], Before administration, blank blood was taken, and about 100 μL of venous blood was collected at different time points after administration, placed in a test tube with heparin, centrifuged, and about 50 μL of plasma was collected and stored at -20°C for testing. The blood collection time points were: 18min, 30min, 60min, 120min, 240min, 360min, 480min, 1440min. Take 50 μL of rat plasma sample, centrifuge at 5500 rpm for 18 minutes, and take 10 μL for LC-MS/MS determination. The plasma concentration was calculated by the established standard curve.
2.药代动力学实验结果2. Pharmacokinetic experiment results
表2.本发明化合物2a与阳性药158口服给药(5mg/kg)的药代动力学参数Table 2. Pharmacokinetic parameters of compound 2a of the present invention and positive drug 158 administered orally (5mg/kg)
PK参数PK parameter 2a2a 158158
PO AUC(0-t)(nM.h)PO AUC(0-t)(nM.h) 2075±5822075±582 6782±7356782±735
Cmax(nM)Cmax(nM) 250±85250±85 453±43453±43
Tmax(h)Tmax(h) 2.0±0.02.0±0.0 4.0±0.04.0±0.0
T 1/2(h) T 1/2 (h) 5.2±1.05.2±1.0 17.9±6.517.9±6.5
结论：158的半衰期为17.9h，存在蓄积的现象。本发明化合物2a具有更为合理的药代动力学性质，相比于158，半衰期更短，药物蓄积可能性低。Conclusion: The half-life of 158 is 17.9h, and there is accumulation phenomenon. Compound 2a of the present invention has more reasonable pharmacokinetic properties. Compared with 158, the half-life is shorter and the possibility of drug accumulation is low.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims (15)

  1. 一种如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，A compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its prodrug,
    Figure PCTCN2021116287-appb-100001
    Figure PCTCN2021116287-appb-100001
    其中，R 1为氢、卤素、羟基、C 1-C 4烷基、一个或多个卤素取代的C 1-C 4烷基、C 1-C 4烷氧基、一个或多个卤素取代的C 1-C 4烷氧基、C 1-C 4烷基-C(＝O)-、C 1-C 4烷基-S-或-NR 1-1R 1-2； wherein, R 1 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more halogens, C 1 -C 4 alkoxy, and C 1 -C 4 alkoxy substituted with one or more halogens C 1 -C 4 alkoxy, C 1 -C 4 alkyl-C(=O)-, C 1 -C 4 alkyl-S- or -NR 1-1 R 1-2 ;
    R 2为氢或
    Figure PCTCN2021116287-appb-100002
    R 2 is hydrogen or
    Figure PCTCN2021116287-appb-100002
    D为O、NR 6-1或CR 6-2R 6-3； D is O, NR 6-1 or CR 6-2 R 6-3 ;
    K为-C(＝O)-或CR 7-1R 7-2； K is -C(=O)- or CR 7-1 R 7-2 ;
    M为-C(＝O)-或CR 11-1R 11-2； M is -C(=O)- or CR 11-1 R 11-2 ;
    环W为C 6-C 10芳环、一个或多个R 8-1取代的C 6-C 10芳环、5-10元杂芳环、或一个或多个R 8-2取代的5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4；所述的一个或多个R 8-2取代的5-10元杂芳环中所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring, a C 6 -C 10 aromatic ring substituted by one or more R 8-1 , a 5-10-membered heteroaromatic ring, or a 5-aromatic ring substituted by one or more R 8-2 10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the One or more R 8-2 substituted 5-10-membered heteroaromatic ring in the 5-10-membered heteroaromatic ring described in the heteroatom is selected from one or more of nitrogen, oxygen and sulfur, the heteroatom The number is 1, 2, 3 or 4;
    环Z为C 6-C 10芳环或5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring Z is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
    环Y为C 3-C 10脂环、一个或多个R 9-1取代的C 3-C 10脂环、3-10元杂脂环、或一个或多个R 9-2取代的3-10元杂脂环；所述的3-10元杂脂环中的杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2或3；所述的一个或多个R 9-2取代的3-10元杂脂环中的3-10元杂脂环中的杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2或3； Ring Y is C 3 -C 10 alicyclic, C 3 -C 10 alicyclic substituted by one or more R 9-1 , 3-10 membered heteroalicyclic, or 3- alicyclic substituted by one or more R 9-2 10-membered heteroalicyclic ring; the heteroatoms in the 3-10-membered heteroalicyclic ring are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3; the described The heteroatoms in the 3-10-membered heteroalicyclic ring in the 3-10-membered heteroalicyclic ring substituted by one or more R 9-2 are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3;
    R 1-1和R 1-2独立地为氢或C 1-C 4烷基； R 1-1 and R 1-2 are independently hydrogen or C 1 -C 4 alkyl;
    R 2-1为C 1-C 4烷基； R 2-1 is C 1 -C 4 alkyl;
    R 6-1为氢或C 1-C 4烷基； R 6-1 is hydrogen or C 1 -C 4 alkyl;
    R 6-2、R 6-3、R 7-1、R 7-2、R 11-1和R 11-2独立地为氢、卤素或C 1-C 4烷基； R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 11-1 and R 11-2 are independently hydrogen, halogen or C 1 -C 4 alkyl;
    R 8-1和R 8-2独立地为卤素或C 1-C 4烷基； R 8-1 and R 8-2 are independently halogen or C 1 -C 4 alkyl;
    R 9-1和R 9-2独立地为卤素、羟基或C 1-C 4烷基。 R 9-1 and R 9-2 are independently halogen, hydroxy or C 1 -C 4 alkyl.
  2. 如权利要求1所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，其特征在于，The compound represented by formula I according to claim 1, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its prodrug, its is characterized by,
    所述的卤素独立地为氟、氯、溴或碘，例如氟、氯或溴；Said halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine, chlorine or bromine;
    和/或，所述的C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例甲基； And/or, the C 1 -C 4 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl ;
    和/或，所述的C 1-C 4烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； And/or, the C 1 -C 4 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    和/或，当环W为C 6-C 10芳环时，所述的C 6-C 10芳基为苯环或萘环，优选为苯环； And/or, when ring W is a C 6 -C 10 aromatic ring, the C 6 -C 10 aryl group is a benzene ring or a naphthalene ring, preferably a benzene ring;
    和/或，当环W为一个或多个R 8-1取代的C 6-C 10芳环时，所述的C 6-C 10芳基为苯环或萘环，例如苯环； And/or, when ring W is one or more C 6 -C 10 aromatic rings substituted by R 8-1 , the C 6 -C 10 aryl group is a benzene ring or a naphthalene ring, such as a benzene ring;
    和/或，当环W为5-10元杂芳环时，所述的5-10元杂芳环为5-6元杂芳环；所述的5-10元杂芳环和所述的5-6元杂芳环中的杂原子优选为N，杂原子个数优选为1或2；所述的5-6元杂芳环优选为哒嗪环、吡啶环、嘧啶环或吡嗪环；所述的哒嗪环优选为
    Figure PCTCN2021116287-appb-100003
    所述的吡啶环优选为
    Figure PCTCN2021116287-appb-100004
    所述的嘧啶环优选为
    Figure PCTCN2021116287-appb-100005
    所述的吡嗪环优选为
    Figure PCTCN2021116287-appb-100006
    And/or, when ring W is a 5-10 membered heteroaromatic ring, the 5-10 membered heteroaromatic ring is a 5-6 membered heteroaromatic ring; the 5-10 membered heteroaromatic ring and the described 5-10 membered heteroaromatic ring are The heteroatom in the 5-6 membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1 or 2; the 5-6 membered heteroaromatic ring is preferably a pyridazine ring, a pyridine ring, a pyrimidine ring or a pyrazine ring ; the pyridazine ring is preferably
    Figure PCTCN2021116287-appb-100003
    The pyridine ring is preferably
    Figure PCTCN2021116287-appb-100004
    The pyrimidine ring is preferably
    Figure PCTCN2021116287-appb-100005
    Described pyrazine ring is preferably
    Figure PCTCN2021116287-appb-100006
    和/或，当环W为一个或多个R 8-2取代的5-10元杂芳环时，所述的5-10元杂芳环为5-6元杂芳环；所述的5-10元杂芳环和所述的5-6元杂芳环中的杂原子优选为N，杂原子个数优选为1或2；所述的5-6元杂芳环优选为哒嗪环或吡啶环；所述的哒嗪环优选为
    Figure PCTCN2021116287-appb-100007
    所述的吡啶环优选为
    Figure PCTCN2021116287-appb-100008
    And/or, when ring W is a 5-10-membered heteroaromatic ring substituted by one or more R 8-2 , the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring; The heteroatom in the -10-membered heteroaromatic ring and the 5-6-membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1 or 2; the 5-6-membered heteroaromatic ring is preferably a pyridazine ring or pyridine ring; the pyridazine ring is preferably
    Figure PCTCN2021116287-appb-100007
    The pyridine ring is preferably
    Figure PCTCN2021116287-appb-100008
    和/或，所述的R 8-2的个数为1个； And/or, the number of described R 8-2 is 1;
    和/或，当环Z为C 6-C 10芳环时，所述的C 6-C 10芳环为苯环或萘环，例如苯环； And/or, when ring Z is a C 6 -C 10 aromatic ring, the C 6 -C 10 aromatic ring is a benzene ring or a naphthalene ring, such as a benzene ring;
    和/或，当环Z为5-10元杂芳环时，所述的5-10元杂芳环为5-6元杂芳环；所述的5-10元杂芳环和5-6元杂芳环中的杂原子优选为N，杂原子个数优选为1；所述的5-10元杂芳环优选为吡啶环，进一步优选为
    Figure PCTCN2021116287-appb-100009
    And/or, when ring Z is a 5-10-membered heteroaromatic ring, the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring; the 5-10-membered heteroaromatic ring and the 5-6 The heteroatom in the membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1; the 5-10 membered heteroaromatic ring is preferably a pyridine ring, more preferably
    Figure PCTCN2021116287-appb-100009
    和/或，当环Y为C 3-C 10脂环时，所述的C 3-C 10脂环为C 4-C 7脂环，优选为丁环、戊环、己环、庚环或螺[3,3]庚环；所述的C 3-C 10脂环可为单环或螺环，例如单环； And/or, when ring Y is a C 3 -C 10 alicyclic ring, the C 3 -C 10 alicyclic ring is a C 4 -C 7 alicyclic ring, preferably a butane ring, a pentane ring, a hexyl ring, a heptyl ring or Spiro[3,3]heptyl; the C 3 -C 10 alicyclic ring can be monocyclic or spiro, such as monocyclic;
    和/或，当环Y为一个或多个R 9-1取代的C 3-C 10脂环时，所述的C 4-C 10脂环为C 4-C 6脂环，优选为丁环、戊环或己环；所述的一个或多个R 9-1取代的C 3-C 10脂环中的C 3-C 10脂环可为单环或螺环，例如单环； And/or, when ring Y is a C 3 -C 10 alicyclic ring substituted by one or more R 9-1 , the C 4 -C 10 alicyclic ring is a C 4 -C 6 alicyclic ring, preferably a butane ring , pentane ring or hexyl ring; the C 3 -C 10 alicyclic ring in the one or more R 9-1 substituted C 3 -C 10 alicyclic rings can be monocyclic or spirocyclic, such as monocyclic;
    和/或，所述的R 9-1的个数为1、2或4个； And/or, the number of the R 9-1 is 1, 2 or 4;
    和/或，当环Y为3-10元杂脂环时，所述的3-10元杂脂环为5-6元杂脂环；所述的3-10元杂脂环和5-6元杂脂环中的杂原子优选为N，杂原子个数优选为1；所述的3-10元杂脂环优选为四氢吡咯环或哌啶环；所述的四氢吡咯环优选为
    Figure PCTCN2021116287-appb-100010
    所述的哌啶环优选为
    Figure PCTCN2021116287-appb-100011
    所述的3-10元杂脂环可为单环或螺环；     And/or, when ring Y is a 3-10 membered heteroalicyclic ring, the 3-10 membered heteroalicyclic ring is a 5-6 membered heteroalicyclic ring; the 3-10 membered heteroalicyclic ring and the 5-6 membered heteroalicyclic ring The heteroatom in the membered heteroalicyclic ring is preferably N, and the number of heteroatoms is preferably 1; the 3-10-membered heteroalicyclic ring is preferably a tetrahydropyrrole ring or a piperidine ring; the tetrahydropyrrole ring is preferably a
    Figure PCTCN2021116287-appb-100010
    Described piperidine ring is preferably
    Figure PCTCN2021116287-appb-100011
    The 3-10-membered heteroalicyclic ring can be a single ring or a spiro ring;
    和/或，当环Y为一个或多个R 9-2取代的3-10元杂脂环时，所述的3-10元杂脂环为5-6元杂脂环；所述的3-10元杂脂环和5-6元杂脂环中的杂原子优选为N，杂原子个数优选为1；所述的3-10元杂脂环优选为四氢吡咯环或哌啶环；所述的四氢吡咯环优选为
    Figure PCTCN2021116287-appb-100012
    所述的哌啶环优选为
    Figure PCTCN2021116287-appb-100013
    所述的一个或多个R 9-2取代的3-10元杂脂环中的3-10元杂脂环可为单环或螺环；     And/or, when ring Y is a 3-10-membered heteroalicyclic ring substituted by one or more R 9-2 , the 3-10-membered heteroalicyclic ring is a 5-6-membered heteroalicyclic ring; the 3-10 membered heteroalicyclic ring; The heteroatom in the -10-membered heteroalicyclic ring and the 5-6-membered heteroalicyclic ring is preferably N, and the number of heteroatoms is preferably 1; the 3-10-membered heteroalicyclic ring is preferably a tetrahydropyrrole ring or a piperidine ring ; Described tetrahydropyrrole ring is preferably
    Figure PCTCN2021116287-appb-100012
    Described piperidine ring is preferably
    Figure PCTCN2021116287-appb-100013
    The 3-10-membered heteroalicyclic ring in the 3-10-membered heteroalicyclic ring substituted by one or more R 9-2 can be monocyclic or spirocyclic;
    和/或，所述的R 9-2的个数为1个。 And/or, the number of the R 9-2 is one.
  3. 如权利要求1或2所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，其特征在于，The compound represented by formula I as claimed in claim 1 or 2, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its prodrug , which is characterized by,
    Figure PCTCN2021116287-appb-100014
    为
    Figure PCTCN2021116287-appb-100015
    为
    Figure PCTCN2021116287-appb-100016
    其中E与D相连；
    Figure PCTCN2021116287-appb-100014
    for
    Figure PCTCN2021116287-appb-100015
    for
    Figure PCTCN2021116287-appb-100016
    where E is connected to D;
    R 3-1和R 3-2独立地为氢、卤素、羟基或C 1-4烷基； R 3-1 and R 3-2 are independently hydrogen, halogen, hydroxy or C 1-4 alkyl;
    A为N或CR 4-1； A is N or CR 4-1 ;
    B为N或CR 4-2； B is N or CR 4-2 ;
    C为N或CR 4-3； C is N or CR 4-3 ;
    E为N或CR 4-4； E is N or CR 4-4 ;
    F为N或CR 4-5； F is N or CR 4-5 ;
    G独立地为NR 5-1或CR 5-2R 5-3； G is independently NR 5-1 or CR 5-2 R 5-3 ;
    L独立地为NR 10-1或CR 10-2R 10-3； L is independently NR 10-1 or CR 10-2 R 10-3 ;
    R 4-1、R 4-2、R 4-3、R 4-4、R 4-5、R 5-2、R 5-3、R 10-2、R 10-3独立地为氢、卤素或C 1-C 4烷基； R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R 5-2 , R 5-3 , R 10-2 , R 10-3 are independently hydrogen, halogen or C 1 -C 4 alkyl;
    R 5-1和R 10-1独立地为氢或C 1-C 4烷基； R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl;
    m和n独立地为0、1、2或3；m and n are independently 0, 1, 2 or 3;
    m1、m2、n1和n2独立地为0、1、2或3，且m1和n1不同时为0，m2和n2不同时为0。m1, m2, n1, and n2 are independently 0, 1, 2, or 3, and m1 and n1 are not both 0, and m2 and n2 are not both 0.
  4. 如权利要求3所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，其特征在于，The compound represented by formula I as claimed in claim 3, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its prodrug, its is characterized by,
    所述的卤素独立地为氟、氯、溴或碘；The halogen is independently fluorine, chlorine, bromine or iodine;
    和/或，所述的C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 And/or, the C 1 -C 4 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  5. 如权利要求3或4所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，其特征在于，The compound represented by the formula I according to claim 3 or 4, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its prodrug , which is characterized by,
    R 1为卤素或一个或多个卤素取代的C 1-C 4烷基，例如卤素； R 1 is halogen or C 1 -C 4 alkyl substituted with one or more halogens, such as halogen;
    和/或，R 2为氢； and/or, R 2 is hydrogen;
    和/或，R 3-1和R 3-2独立地为氢、羟基或C 1-4烷基； and/or, R 3-1 and R 3-2 are independently hydrogen, hydroxyl or C 1-4 alkyl;
    和/或，B为CR 4-2； and/or, B is CR 4-2 ;
    和/或，C为CR 4-3； and/or, C is CR 4-3 ;
    和/或，K为-C(＝O)-和M为-C(＝O)-；或，K为CR 7-1R 7-2和M为-C(＝O)-；或，K为-C(＝O)-和M为CR 11-1R 11-2； and/or, K is -C(=O)- and M is -C(=O)-; or, K is CR 7-1 R 7-2 and M is -C(=O)-; or, K is -C(=O)- and M is CR 11-1 R 11-2 ;
    和/或，环W为C 6-C 10芳环、5-10元杂芳环或一个或多个R 8-2取代的5-10元杂芳环，例如C 6-C 10芳环； And/or, ring W is a C 6 -C 10 aromatic ring, a 5-10-membered heteroaromatic ring or a 5-10-membered heteroaromatic ring substituted by one or more R 8-2 , such as a C 6 -C 10 aromatic ring;
    和/或，R 4-1为氢； and/or, R 4-1 is hydrogen;
    和/或，R 4-2为氢； and/or, R 4-2 is hydrogen;
    和/或，R 4-3为氢； and/or, R 4-3 is hydrogen;
    和/或，R 4-4为氢； and/or, R 4-4 is hydrogen;
    和/或，R 5-2和R 5-3为氢； and/or, R 5-2 and R 5-3 are hydrogen;
    和/或，R 6-1为氢； and/or, R 6-1 is hydrogen;
    和/或，R 6-2和R 6-3为氢； and/or, R 6-2 and R 6-3 are hydrogen;
    和/或，R 7-1和R 7-2为氢； and/or, R 7-1 and R 7-2 are hydrogen;
    和/或，R 8-2独立地为卤素； and/or, R 8-2 is independently halogen;
    和/或，R 9-2独立地为C 1-C 4烷基； and/or, R 9-2 is independently C 1 -C 4 alkyl;
    和/或，R 10-2和R 10-3独立地为氢或C 1-C 4烷基； and/or, R 10-2 and R 10-3 are independently hydrogen or C 1 -C 4 alkyl;
    和/或，R 11-1和R 11-2为氢； and/or, R 11-1 and R 11-2 are hydrogen;
    和/或，m为0、1或2；and/or, m is 0, 1 or 2;
    和/或，n为0、1或2。And/or, n is 0, 1 or 2.
  6. 如权利要求1-5任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，其特征在于，The compound represented by formula I according to any one of claims 1-5, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or Its prodrug is characterized in that,
    D为O或NH，例如O；D is O or NH, such as O;
    和/或，R 2为氢； and/or, R 2 is hydrogen;
    和/或，
    Figure PCTCN2021116287-appb-100017
    为
    Figure PCTCN2021116287-appb-100018
    例如
    Figure PCTCN2021116287-appb-100019
    and / or,
    Figure PCTCN2021116287-appb-100017
    for
    Figure PCTCN2021116287-appb-100018
    E.g
    Figure PCTCN2021116287-appb-100019
    和/或，
    Figure PCTCN2021116287-appb-100020
    为
    Figure PCTCN2021116287-appb-100021
    Figure PCTCN2021116287-appb-100022
    例如
    Figure PCTCN2021116287-appb-100023
    and / or,
    Figure PCTCN2021116287-appb-100020
    for
    Figure PCTCN2021116287-appb-100021
    Figure PCTCN2021116287-appb-100022
    E.g
    Figure PCTCN2021116287-appb-100023
    和/或，
    Figure PCTCN2021116287-appb-100024
    为
    Figure PCTCN2021116287-appb-100025
    and / or,
    Figure PCTCN2021116287-appb-100024
    for
    Figure PCTCN2021116287-appb-100025
    和/或，
    Figure PCTCN2021116287-appb-100026
    为
    Figure PCTCN2021116287-appb-100027
    Figure PCTCN2021116287-appb-100028
    Figure PCTCN2021116287-appb-100029
    例如
    Figure PCTCN2021116287-appb-100030
    and / or,
    Figure PCTCN2021116287-appb-100026
    for
    Figure PCTCN2021116287-appb-100027
    Figure PCTCN2021116287-appb-100028
    Figure PCTCN2021116287-appb-100029
    E.g
    Figure PCTCN2021116287-appb-100030
  7. 如权利要求3-6任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，其特征在于，所述的化合物为如下任一方案：The compound represented by formula I according to any one of claims 3-6, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or Its prodrug is characterized in that, the described compound is any of the following schemes:
    方案一：Option One:
    R 1为卤素或一个或多个卤素取代的C 1-C 4烷基； R 1 is halogen or C 1 -C 4 alkyl substituted with one or more halogens;
    R 2为氢； R 2 is hydrogen;
    R 3-1和R 3-2独立地为氢、羟基或C 1-4烷基； R 3-1 and R 3-2 are independently hydrogen, hydroxyl or C 1-4 alkyl;
    A为N或CH；A is N or CH;
    B为CH；B is CH;
    C为CH；C is CH;
    D为O、NH或CH 2； D is O, NH or CH 2 ;
    E为N或CH；E is N or CH;
    F为N或CR 4-5； F is N or CR 4-5 ;
    G独立地为NR 5-1或CH 2； G is independently NR 5-1 or CH 2 ;
    L独立地为NR 10-1或CR 10-2R 10-3； L is independently NR 10-1 or CR 10-2 R 10-3 ;
    K为-C(＝O)-或CH 2； K is -C(=O)- or CH 2 ;
    M为-C(＝O)-；M is -C(=O)-;
    环W为C 6-C 10芳环、5-10元杂芳环、或一个或多个R 8-2取代的5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4；所述的一个或多个R 8-2取代的5-10元杂芳环中所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring, a 5-10-membered heteroaromatic ring, or a 5-10-membered heteroaromatic ring substituted by one or more R 8-2 ; The atom is selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 8-2 substituted 5-10-membered heteroaromatic rings The heteroatom in the 5-10-membered heteroaromatic ring described in is selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatom is 1, 2, 3 or 4;
    R 4-5为氢、卤素或C 1-C 4烷基； R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl;
    R 8-2独立地为卤素； R 8-2 is independently halogen;
    R 5-1和R 10-1独立地为氢或C 1-C 4烷基； R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl;
    R 10-2、R 10-3独立地为氢或C 1-C 4烷基； R 10-2 and R 10-3 are independently hydrogen or C 1 -C 4 alkyl;
    m和n独立地为0、1、2或3；和m and n are independently 0, 1, 2, or 3; and
    m1、m2、n1和n2独立地为0、1、2或3，且m1和n1不同时为0，m2和n2不同时为0；m1, m2, n1, and n2 are independently 0, 1, 2, or 3, and m1 and n1 are not both 0, and m2 and n2 are not both 0;
    方案二：Option II:
    R 1为卤素； R 1 is halogen;
    R 2为氢； R 2 is hydrogen;
    R 3-1和R 3-2独立地为氢； R 3-1 and R 3-2 are independently hydrogen;
    A为N或CH；A is N or CH;
    B为CH；B is CH;
    C为CH；C is CH;
    D为O、NH或CH 2； D is O, NH or CH 2 ;
    E为N或CH；E is N or CH;
    F为N或CR 4-5； F is N or CR 4-5 ;
    K为-C(＝O)-或CH 2； K is -C(=O)- or CH 2 ;
    M为-C(＝O)-；M is -C(=O)-;
    G独立地为NR 5-1或CH 2； G is independently NR 5-1 or CH 2 ;
    L独立地为NR 10-1或CH 2； L is independently NR 10-1 or CH 2 ;
    环W为C 6-C 10芳环或5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
    R 4-5为氢、卤素或C 1-C 4烷基； R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl;
    R 5-1和R 10-1独立地为氢或C 1-C 4烷基； R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl;
    m为0或1；和m is 0 or 1; and
    n为1或2；n is 1 or 2;
    方案三：third solution:
    R 1为卤素； R 1 is halogen;
    R 2为氢； R 2 is hydrogen;
    R 3-1和R 3-2独立地为氢； R 3-1 and R 3-2 are independently hydrogen;
    A为N或CH；A is N or CH;
    B为CH；B is CH;
    C为CH；C is CH;
    D为O、NH或CH 2； D is O, NH or CH 2 ;
    E为CH；E is CH;
    F为N或CR 4-5； F is N or CR 4-5 ;
    G独立地为NR 5-1或CH 2； G is independently NR 5-1 or CH 2 ;
    L独立地为NR 10-1或CH 2； L is independently NR 10-1 or CH 2 ;
    K为-C(＝O)-或CH 2； K is -C(=O)- or CH 2 ;
    M为-C(＝O)-；M is -C(=O)-;
    环W为C 6-C 10芳环或5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
    R 4-5为氢、卤素或C 1-C 4烷基； R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl;
    R 5-1和R 10-1独立地为C 1-C 4烷基； R 5-1 and R 10-1 are independently C 1 -C 4 alkyl;
    m为0或1；和m is 0 or 1; and
    n为1或2；n is 1 or 2;
    方案四：Option four:
    R 1为氯； R 1 is chlorine;
    R 2为氢； R 2 is hydrogen;
    R 3-1和R 3-2独立地为氢； R 3-1 and R 3-2 are independently hydrogen;
    A为CH；A is CH;
    B为CH；B is CH;
    C为CH；C is CH;
    D为O；D is O;
    E为CH；E is CH;
    F为CH；F is CH;
    G独立地为CH 2； G is independently CH 2 ;
    L独立地为CH 2； L is independently CH 2 ;
    K为-C(＝O)-和M为CH 2；或K为CH 2和M为-C(＝O)-； K is -C(=O)- and M is CH2 ; or K is CH2 and M is -C(=O)-;
    环W为C 6-C 10芳环或5-10元杂芳环；所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种，杂原子的个数为1、2、3或4； Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
    R 4-5为氢、卤素或C 1-C 4烷基； R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl;
    R 5-1和R 10-1独立地为C 1-C 4烷基； R 5-1 and R 10-1 are independently C 1 -C 4 alkyl;
    m为0或1；m is 0 or 1;
    n为2；n is 2;
    且当m为0时，环W为
    Figure PCTCN2021116287-appb-100031
    And when m is 0, the ring W is
    Figure PCTCN2021116287-appb-100031
  8. 如权利要求1-7任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，所述的化合物为如下任一方案：The compound represented by formula I according to any one of claims 1-7, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or Its prodrug, the compound is any of the following schemes:
    方案a：Option a:
    所述的如式I所示的化合物为如式Ia或Ib所示的化合物：The compound shown in the formula I is the compound shown in the formula Ia or Ib:
    Figure PCTCN2021116287-appb-100032
    Figure PCTCN2021116287-appb-100032
    其中，D为O或NH；Wherein, D is O or NH;
    环Z、环Y、环W、K、M、N、R 1和R 2的定义如权利要求1所述； Ring Z, Ring Y, Ring W, K, M, N, R 1 and R 2 are as defined in claim 1;
    方案b：Option b:
    所述的如式I所示的化合物为如式Ic所示的化合物：The compound shown in the formula I is the compound shown in the formula Ic:
    Figure PCTCN2021116287-appb-100033
    Figure PCTCN2021116287-appb-100033
    其中，环Y为戊环或己环；环Z、K、M、R 1和R 2的定义如权利要求1所述； Wherein, ring Y is pentane ring or hexyl ring; ring Z, K, M, R 1 and R 2 are as defined in claim 1;
    优选，所述的如式Ic所示的化合物中：Preferably, in the compound shown in the formula Ic:
    R 1为卤素； R 1 is halogen;
    R 2为H； R 2 is H;
    Figure PCTCN2021116287-appb-100034
    为
    Figure PCTCN2021116287-appb-100035
    Figure PCTCN2021116287-appb-100034
    for
    Figure PCTCN2021116287-appb-100035
    方案c：Option c:
    所述的如式I所示的化合物为如式Id所示的化合物：The compound shown in the formula I is the compound shown in the formula Id:
    Figure PCTCN2021116287-appb-100036
    Figure PCTCN2021116287-appb-100036
    其中，环Z、K、M、R 1和R 2的定义如权利要求1所述； Wherein, the definitions of ring Z, K, M, R 1 and R 2 are as described in claim 1;
    优选，所述的如式Id所示的化合物中，Preferably, in the compound shown in the formula Id,
    R 1为卤素； R 1 is halogen;
    R 2为H； R 2 is H;
    环Z为C 6-C 10芳环； Ring Z is a C 6 -C 10 aromatic ring;
    Figure PCTCN2021116287-appb-100037
    为
    Figure PCTCN2021116287-appb-100038
    Figure PCTCN2021116287-appb-100037
    for
    Figure PCTCN2021116287-appb-100038
  9. 如权利要求1-8任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，其特征在于，所述的如式I所示的化合物为如下任一所示的化合物：The compound represented by formula I according to any one of claims 1-8, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or Its prodrug is characterized in that the compound shown in the formula I is the compound shown in any of the following:
    Figure PCTCN2021116287-appb-100039
    Figure PCTCN2021116287-appb-100039
    Figure PCTCN2021116287-appb-100040
    Figure PCTCN2021116287-appb-100040
    Figure PCTCN2021116287-appb-100041
    Figure PCTCN2021116287-appb-100041
    Figure PCTCN2021116287-appb-100042
    Figure PCTCN2021116287-appb-100042
    Figure PCTCN2021116287-appb-100043
    Figure PCTCN2021116287-appb-100043
    Figure PCTCN2021116287-appb-100044
    Figure PCTCN2021116287-appb-100044
    Figure PCTCN2021116287-appb-100045
    Figure PCTCN2021116287-appb-100045
    Figure PCTCN2021116287-appb-100046
    Figure PCTCN2021116287-appb-100046
    优选，所述的如式I所示的化合物为如下任一所示的化合物，Preferably, the compound shown in formula I is any of the following compounds,
    Figure PCTCN2021116287-appb-100047
    Figure PCTCN2021116287-appb-100047
    Figure PCTCN2021116287-appb-100048
    Figure PCTCN2021116287-appb-100048
    Figure PCTCN2021116287-appb-100049
    Figure PCTCN2021116287-appb-100049
    Figure PCTCN2021116287-appb-100050
    Figure PCTCN2021116287-appb-100050
    Figure PCTCN2021116287-appb-100051
    Figure PCTCN2021116287-appb-100051
    Figure PCTCN2021116287-appb-100052
    Figure PCTCN2021116287-appb-100052
    Figure PCTCN2021116287-appb-100053
    Figure PCTCN2021116287-appb-100053
    Figure PCTCN2021116287-appb-100054
    Figure PCTCN2021116287-appb-100054
    Figure PCTCN2021116287-appb-100055
    Figure PCTCN2021116287-appb-100055
    Figure PCTCN2021116287-appb-100056
    Figure PCTCN2021116287-appb-100056
  10. 一种如权利要求1-9任一项所述的如式I所示化合物的制备方法，其特征在于，其为以下任一方法：A kind of preparation method of the compound shown in formula I as described in any one of claim 1-9, it is characterized in that, it is following any method:
    方法一包括以下步骤：溶剂中，在碱和缩合剂的作用下，将如式IV所示的化合物和如式V所示的化合物进行如下所示的缩合反应即可，The first method includes the following steps: in a solvent, under the action of a base and a condensing agent, the compound shown in formula IV and the compound shown in formula V are subjected to the condensation reaction shown below,
    Figure PCTCN2021116287-appb-100057
    Figure PCTCN2021116287-appb-100057
    其中，环Z、环Y、D、K、M、环W、R 1和R 2的定义同权利要求1～9任一项所述； Wherein, the definitions of ring Z, ring Y, D, K, M, ring W, R 1 and R 2 are the same as those described in any one of claims 1 to 9;
    方法二包括以下步骤：溶剂中，在酸的作用下将如式VI所示的化合物进行如下所示的脱保护反应即可，The second method comprises the following steps: in a solvent, the compound shown in formula VI is subjected to the deprotection reaction shown below under the action of an acid,
    Figure PCTCN2021116287-appb-100058
    Figure PCTCN2021116287-appb-100058
    其中，
    Figure PCTCN2021116287-appb-100059
    为
    Figure PCTCN2021116287-appb-100060
    为
    Figure PCTCN2021116287-appb-100061
    E与D相连；环Z、D、E、F、K、M、环W、L、R 1、R 2、R 3-1、R 3-2和n的定义同权利要求1～9任一项所述；     in,
    Figure PCTCN2021116287-appb-100059
    for
    Figure PCTCN2021116287-appb-100060
    for
    Figure PCTCN2021116287-appb-100061
    E is connected to D; ring Z, D, E, F, K, M, ring W, L, R 1 , R 2 , R 3-1 , R 3-2 and n are defined as any of claims 1 to 9 item;
    方法三包括如下步骤：在溶剂中，将如式VII所示的化合物和如式VIII所示的化合物进行如下所示的加成反应即可，Method 3 includes the following steps: in a solvent, the compound shown in formula VII and the compound shown in formula VIII are subjected to the addition reaction shown below,
    Figure PCTCN2021116287-appb-100062
    Figure PCTCN2021116287-appb-100062
    其中，
    Figure PCTCN2021116287-appb-100063
    为
    Figure PCTCN2021116287-appb-100064
    为
    Figure PCTCN2021116287-appb-100065
    E与D相连；环Z、D、E、G、K、M、环W、L、R 1、R 2、R 3-1、R 3-2、m和n的定义同权利要求1～9任一项所述。     in,
    Figure PCTCN2021116287-appb-100063
    for
    Figure PCTCN2021116287-appb-100064
    for
    Figure PCTCN2021116287-appb-100065
    E is connected to D; ring Z, D, E, G, K, M, ring W, L, R 1 , R 2 , R 3-1 , R 3-2 , m and n are defined as in claims 1 to 9 any of the above.
  11. 如权利要求10所述的如式I所示化合物的制备方法，其特征在于，The preparation method of compound shown in formula I as claimed in claim 10, is characterized in that,
    所述的缩合反应中，所述的溶剂为酰胺类溶剂，优选为N,N-二甲基甲酰胺；In the condensation reaction, the solvent is an amide solvent, preferably N,N-dimethylformamide;
    和/或，所述的缩合反应中，所述的如式IV所示的化合物在所述的溶剂中的摩尔浓度为0.0001～0.1mol/L，优选为0.004～0.01mol/L；And/or, in the condensation reaction, the molar concentration of the compound represented by formula IV in the solvent is 0.0001-0.1 mol/L, preferably 0.004-0.01 mol/L;
    和/或，所述的缩合反应中，所述的碱为有机胺，优选为N,N-二异丙基乙胺；And/or, in the described condensation reaction, the described base is an organic amine, preferably N,N-diisopropylethylamine;
    和/或，所述的缩合反应中，所述的碱与所述的如式IV所示的化合物的摩尔比为0.8:1～3:1，优选为0.9:1～1.3:1；And/or, in the condensation reaction, the molar ratio of the base to the compound represented by formula IV is 0.8:1-3:1, preferably 0.9:1-1.3:1;
    和/或，所述的缩合反应中，所述的缩合剂为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；And/or, in the condensation reaction, the condensing agent is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate;
    和/或，所述的缩合反应中，所述的缩合剂与所述的如式IV所示的化合物的摩尔比为1:1～3:1，优选为1:1～1.5:1；And/or, in the condensation reaction, the molar ratio of the condensing agent to the compound represented by formula IV is 1:1-3:1, preferably 1:1-1.5:1;
    和/或，所述的缩合反应中，所述的如式V所示的化合物与所述的如式IV所示的化合物的摩尔比为0.8:1～3:1，优选为0.9:1～1.3:1；And/or, in the condensation reaction, the molar ratio of the compound represented by formula V to the compound represented by formula IV is 0.8:1～3:1, preferably 0.9:1～ 1.3:1;
    和/或，所述缩合反应的反应温度为室温；And/or, the reaction temperature of described condensation reaction is room temperature;
    和/或，所述缩合反应的反应时间优选为1～3小时；And/or, the reaction time of the condensation reaction is preferably 1 to 3 hours;
    和/或，所述的脱保护反应中，所述的溶剂为醚类溶剂，优选为二氧六环；And/or, in the described deprotection reaction, the solvent is an ether solvent, preferably dioxane;
    和/或，所述的脱保护反应中，所述的如式VI所示的化合物在所述的溶剂中的摩尔浓度为0.0001～0.1mol/L，优选为0.002～0.004mol/L；And/or, in the deprotection reaction, the molar concentration of the compound represented by formula VI in the solvent is 0.0001-0.1 mol/L, preferably 0.002-0.004 mol/L;
    和/或，所述的脱保护反应中，所述的酸为无机酸，优选为盐酸；And/or, in the described deprotection reaction, the acid is an inorganic acid, preferably hydrochloric acid;
    和/或，所述脱保护反应的反应温度为室温；And/or, the reaction temperature of described deprotection reaction is room temperature;
    和/或，所述脱保护反应的反应时间为1～3小时；And/or, the reaction time of the deprotection reaction is 1 to 3 hours;
    和/或，所述的加成反应中，所述的溶剂为酰胺类溶剂，优选为N,N-二甲基甲酰胺；And/or, in the described addition reaction, the solvent is an amide solvent, preferably N,N-dimethylformamide;
    和/或，所述的加成反应中，所述的如式VII所示的化合物与所述的如式VIII所示的化合物的摩尔比为0.8:1～3:1，优选为0.9:1～1.3:1；And/or, in the addition reaction, the molar ratio of the compound represented by the formula VII to the compound represented by the formula VIII is 0.8:1 to 3:1, preferably 0.9:1 ~1.3:1;
    和/或，所述加成反应的反应温度为室温；And/or, the reaction temperature of described addition reaction is room temperature;
    和/或，所述加成反应的反应时间优选为1～3小时。And/or, the reaction time of the addition reaction is preferably 1 to 3 hours.
  12. 一种如式IV所示的化合物或其立体异构体、如式VI所示的化合物或其立体异构体，A compound as shown in formula IV or a stereoisomer thereof, a compound as shown in formula VI or a stereoisomer thereof,
    Figure PCTCN2021116287-appb-100066
    Figure PCTCN2021116287-appb-100066
    所述的如式VI所示的化合物优选为如式VI-a或VI-b所示的化合物：The compound shown in the formula VI is preferably the compound shown in the formula VI-a or VI-b:
    Figure PCTCN2021116287-appb-100067
    Figure PCTCN2021116287-appb-100067
    其中，环Z、环Y、D、M、K、M、环W、R 1和R 2的定义同权利要求1～9任一项所述；环Y’的定义同权利要求10任一项所述；所述且如式IV所示的化合物不为
    Figure PCTCN2021116287-appb-100068
    Figure PCTCN2021116287-appb-100069
    Wherein, the definitions of ring Z, ring Y, D, M, K, M, ring W, R 1 and R 2 are the same as those described in any one of claims 1 to 9; the definition of ring Y' is the same as that of any one of claims 10 described; described and the compound of formula IV is not
    Figure PCTCN2021116287-appb-100068
    Figure PCTCN2021116287-appb-100069
  13. 如权利要求12所述的如式IV所示的化合物或其立体异构体、如式VI所示的化合物或其立体异构体，其特征在于，The compound represented by formula IV or its stereoisomer, the compound represented by formula VI or its stereoisomer according to claim 12, is characterized in that,
    所述的如式IV所示的化合物为
    Figure PCTCN2021116287-appb-100070
    Described compound shown in formula IV is
    Figure PCTCN2021116287-appb-100070
    Figure PCTCN2021116287-appb-100071
    Figure PCTCN2021116287-appb-100071
    所述的如式IV所示的化合物的立体异构体为
    Figure PCTCN2021116287-appb-100072
    Figure PCTCN2021116287-appb-100073
    The described stereoisomer of the compound shown in formula IV is
    Figure PCTCN2021116287-appb-100072
    Figure PCTCN2021116287-appb-100073
    Figure PCTCN2021116287-appb-100074
    Figure PCTCN2021116287-appb-100074
    所述的如式VI所示的化合物为
    Figure PCTCN2021116287-appb-100075
    The described compound shown in formula VI is
    Figure PCTCN2021116287-appb-100075
    所述的如式VI所示的化合物的立体异构体为The stereoisomer of the compound shown in the formula VI is
    Figure PCTCN2021116287-appb-100076
    Figure PCTCN2021116287-appb-100076
  14. 一种药物组合物，其包括如权利要求1-9任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药，以及药学上可接受的辅料。A pharmaceutical composition, it comprises the compound shown in formula I as described in any one of claim 1-9, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable compound. Accepted salts, metabolites or prodrugs thereof, and pharmaceutically acceptable excipients.
  15. 一种如权利要求1-9任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药、或如权利要求14所述的药物组合物在制备雄激素受体降解剂或治疗与雄激素受体相关疾病的药物中的应用；A compound shown in the formula I as described in any one of claims 1-9, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolism Use of the product or its prodrug, or the pharmaceutical composition as claimed in claim 14, in the preparation of an androgen receptor degrading agent or a medicine for treating androgen receptor-related diseases;
    所述的与雄激素受体相关疾病优选为前列腺癌，进一步优选为转移性去势抵抗前列腺癌。The androgen receptor-related disease is preferably prostate cancer, more preferably metastatic castration-resistant prostate cancer.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11883393B2 (en) 2019-12-19 2024-01-30 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor
US12043612B2 (en) 2020-05-09 2024-07-23 Arvinas Operations, Inc. Methods of manufacturing a bifunctional compound, ultrapure forms of the bifunctional compound, and dosage forms comprising the same

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019199816A1 (en) * 2018-04-13 2019-10-17 Arvinas Operations, Inc. Cereblon ligands and bifunctional compounds comprising the same
CN110506039A (en) * 2016-10-11 2019-11-26 阿尔维纳斯股份有限公司 Compounds and methods for for androgen receptor targeting degradation
CN110612294A (en) * 2017-01-31 2019-12-24 阿尔维纳斯运营股份有限公司 Human cereblon ligand and bifunctional compound comprising same
WO2021061644A1 (en) * 2019-09-23 2021-04-01 Accutar Biotechnology Inc. Novel substituted quinoline-8-carbonitrile derivatives with androgen receptor degradation activity and uses thereof
WO2021081108A1 (en) * 2019-10-22 2021-04-29 Arvinas Operations, Inc. Methods of treating prostate cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110506039A (en) * 2016-10-11 2019-11-26 阿尔维纳斯股份有限公司 Compounds and methods for for androgen receptor targeting degradation
CN110612294A (en) * 2017-01-31 2019-12-24 阿尔维纳斯运营股份有限公司 Human cereblon ligand and bifunctional compound comprising same
WO2019199816A1 (en) * 2018-04-13 2019-10-17 Arvinas Operations, Inc. Cereblon ligands and bifunctional compounds comprising the same
WO2021061644A1 (en) * 2019-09-23 2021-04-01 Accutar Biotechnology Inc. Novel substituted quinoline-8-carbonitrile derivatives with androgen receptor degradation activity and uses thereof
WO2021081108A1 (en) * 2019-10-22 2021-04-29 Arvinas Operations, Inc. Methods of treating prostate cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ACS: "RN 2222114-60-3 etc.", STN REGISTRY, 2 May 2018 (2018-05-02) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11883393B2 (en) 2019-12-19 2024-01-30 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor
US12043612B2 (en) 2020-05-09 2024-07-23 Arvinas Operations, Inc. Methods of manufacturing a bifunctional compound, ultrapure forms of the bifunctional compound, and dosage forms comprising the same

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