WO2022048605A1 - 一种杂环化合物、其制备方法、中间体、组合物以及应用 - Google Patents

一种杂环化合物、其制备方法、中间体、组合物以及应用 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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WO2022048605A8 (zh
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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

提供了一种如式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。该化合物对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。

Description

一种杂环化合物、其制备方法、中间体、组合物以及应用
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。
技术领域
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。
背景技术
***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***癌发病率逐年递增，预计到2020年***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***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***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***癌(CRPC)，患者对ADT不再敏感，中位生存期小于20个月。在***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***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。
泛素-蛋白酶体***(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***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***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***(ubiquitin-proteasome system,UPS)特异性地降解靶蛋白。
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***癌(mCRPC)患者身上安全且有效。
发明内容
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***癌。
本发明主要是通过以下技术方案解决上述技术问题的。
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，
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；
R 2为氢或
Figure PCTCN2021116287-appb-000002
D为O、NR 6-1或CR 6-2R 6-3；
K为-C(＝O)-或CR 7-1R 7-2；
M为-C(＝O)-或CR 11-1R 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；
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；
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；
R 1-1和R 1-2独立地为氢或C 1-C 4烷基；
R 2-1为C 1-C 4烷基；
R 6-1为氢或C 1-C 4烷基；
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 8-1和R 8-2独立地为卤素或C 1-C 4烷基；
R 9-1和R 9-2独立地为卤素、羟基或C 1-C 4烷基。
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。
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。
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。
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。
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。
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
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
在本发明一实施方案中，所述的R 8-2的个数为1个。
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。
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
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。
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。
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。
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。
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。
在本发明一实施方案中，所述的R 9-2的个数为1个。
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；
R 3-1和R 3-2独立地为氢、卤素、羟基或C 1-4烷基；
A为N或CR 4-1；
B为N或CR 4-2；
C为N或CR 4-3；
E为N或CR 4-4；
F为N或CR 4-5；
G独立地为NR 5-1或CR 5-2R 5-3；
L独立地为NR 10-1或CR 10-2R 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 5-1和R 10-1独立地为氢或C 1-C 4烷基；
m和n独立地为0、1、2或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。
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。
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。
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。
在本发明一实施方案中，R 2为氢。
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。
在本发明一实施方案中，B为CR 4-2。
在本发明一实施方案中，C为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。
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。
在本发明一实施方案中，R 4-1为氢。
在本发明一实施方案中，R 4-2为氢。
在本发明一实施方案中，R 4-3为氢。
在本发明一实施方案中，R 4-4为氢。
在本发明一实施方案中，R 5-2和R 5-3为氢。
在本发明一实施方案中，R 6-1为氢。
在本发明一实施方案中，R 6-2和R 6-3为氢。
在本发明一实施方案中，R 7-1和R 7-2为氢。
在本发明一实施方案中，R 8-2独立地为卤素。
在本发明一实施方案中，R 9-2独立地为C 1-C 4烷基。
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。
在本发明一实施方案中，R 11-1和R 11-2为氢。
在本发明一实施方案中，m为0、1或2。
在本发明一实施方案中，n为0、1或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。
在本发明一实施方案中，D为O或NH，例如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
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
在本发明一实施方案中，
Figure PCTCN2021116287-appb-000026
为
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
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
在本发明一实施方案中，R 2为氢。
在本发明一实施方案中，环W为
Figure PCTCN2021116287-appb-000038
在本发明一实施方案中，m1、m2、n1和n2为1。
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)-。
在本发明一实施方案中，其中，
R 1为卤素或一个或多个卤素取代的C 1-C 4烷基；
R 2为氢；
R 3-1和R 3-2独立地为氢、羟基或C 1-4烷基；
A为N或CH；
B为CH；
C为CH；
D为O、NH或CH 2；
E为N或CH；
F为N或CR 4-5；
G独立地为NR 5-1或CH 2；
L独立地为NR 10-1或CR 10-2R 10-3；
K为-C(＝O)-或CH 2；
M为-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；
R 4-5为氢、卤素或C 1-C 4烷基；
R 8-2独立地为卤素；
R 5-1和R 10-1独立地为氢或C 1-C 4烷基；
R 10-2、R 10-3独立地为氢或C 1-C 4烷基；
m和n独立地为0、1、2或3；和
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。
在本发明一实施方案中，其中，
R 1为卤素；
R 2为氢；
R 3-1和R 3-2独立地为氢；
A为N或CH；
B为CH；
C为CH；
D为O、NH或CH 2；
E为N或CH；
F为N或CR 4-5；
K为-C(＝O)-或CH 2；
M为-C(＝O)-；
G独立地为NR 5-1或CH 2；
L独立地为NR 10-1或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；
R 4-5为氢、卤素或C 1-C 4烷基；
R 5-1和R 10-1独立地为氢或C 1-C 4烷基；
m为0或1；和
n为1或2。
在本发明一实施方案中，其中，
R 1为卤素；
R 2为氢；
R 3-1和R 3-2独立地为氢；
A为N或CH；
B为CH；
C为CH；
D为O、NH或CH 2；
E为CH；
F为N或CR 4-5；
G独立地为NR 5-1或CH 2；
L独立地为NR 10-1或CH 2；
K为-C(＝O)-或CH 2；
M为-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；
R 4-5为氢、卤素或C 1-C 4烷基；
R 5-1和R 10-1独立地为C 1-C 4烷基；
m为0或1；和
n为1或2。
在本发明一实施方案中，其中，
R 1为氯；
R 2为氢；
R 3-1和R 3-2独立地为氢；
A为CH；
B为CH；
C为CH；
D为O；
E为CH；
F为CH；
G独立地为CH 2；
L独立地为CH 2；
K为-C(＝O)-和M为CH 2；或，K为CH 2和M为-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；
R 4-5为氢、卤素或C 1-C 4烷基；
R 5-1和R 10-1独立地为C 1-C 4烷基；
m为0或1；
n为2；
且当m为0时，环W为
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：
Figure PCTCN2021116287-appb-000040
其中，D为O或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；
环Z、环Y、环W、K、M、N、R 1和R 2的定义同前所述；
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。
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：
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；
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。
优选，所述的如式Ic所示的化合物中：
R 1为卤素(例如氟、氯或溴)；
R 2为H；
Figure PCTCN2021116287-appb-000049
为
Figure PCTCN2021116287-appb-000050
(例如
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：
Figure PCTCN2021116287-appb-000053
其中，环Z、K、M、R 1和R 2的定义同前所述。
优选，所述的如式Id所示的化合物中，
R 1为卤素(例如氯)；
R 2为H；
环Z为C 6-C 10芳环(例如苯环)；
Figure PCTCN2021116287-appb-000054
为
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：
Figure PCTCN2021116287-appb-000056
Figure PCTCN2021116287-appb-000057
Figure PCTCN2021116287-appb-000058
Figure PCTCN2021116287-appb-000059
Figure PCTCN2021116287-appb-000060
Figure PCTCN2021116287-appb-000061
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，
Figure PCTCN2021116287-appb-000063
Figure PCTCN2021116287-appb-000064
Figure PCTCN2021116287-appb-000065
Figure PCTCN2021116287-appb-000066
Figure PCTCN2021116287-appb-000067
Figure PCTCN2021116287-appb-000068
Figure PCTCN2021116287-appb-000069
Figure PCTCN2021116287-appb-000070
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：
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，
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；
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，
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；
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，
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。
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。
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)。
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。
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)。
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。
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)。
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)。
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。
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)。
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)。
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。
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)。
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。
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。
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)。
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。
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。
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)。
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。
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)。
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。
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，
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
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
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
Figure PCTCN2021116287-appb-000085
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，
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。
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：
Figure PCTCN2021116287-appb-000088
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；
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。
在本发明一实施方案中，所述的如式VI所示的化合物为
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
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。
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。
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。
在本发明一实施方案中，所述的与雄激素受体相关疾病为***癌，优选为转移性去势抵抗前列 腺癌。
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。
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。
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。
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。
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。
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。
术语“脂环”是指由碳原子组成的饱和环状结构。
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。
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。
本发明所述的室温为10-30℃。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的杂环化合物对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。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
参考例1
合成路线
Figure PCTCN2021116287-appb-000100
实施例1
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。
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] +。
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] +。
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] +。
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] +。
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] +。
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)。
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] +。
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)。
实施例2
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] +。
实施例3
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)。
实施例4
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] +。
实施例5
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] -。
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)。
实施例6
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] -。
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)。
实施例7
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] +。
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] -。
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] +。
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)。
实施例8
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] +。
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] +。
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] -。
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)。
实施例9
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)。
实施例10
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)。
实施例11
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，***洗，干燥得白色固体450mg。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)。
实施例12
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] +。
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] +。
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] +。
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)。
实施例13
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)。
实施例14
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] +。
实施例15
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] +。
实施例16
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] +.
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] +。
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] +。
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] +。
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] +。
实施例17
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] +。
实施例18
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] +。
实施例19
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] +。
实施例20
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] +。
实施例21
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] +。
实施例22
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] +。
实施例23
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] +。
实施例24
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] +。
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。
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。
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] +。
实施例25
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] +。
实施例26
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] +。
实施例27
Figure PCTCN2021116287-appb-000134
步骤一：
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] +。
步骤二：
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] +。
步骤三：
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] +。
实施例28
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] +
效果实施例1
实验方法
PC-3细胞：procell，货号CL-0185。LNCaP细胞：武汉普诺赛生命科技。
1.PC-3细胞抗增殖活性
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。
2.LNCap细胞抗增殖活性
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。
表1.本发明化合物对LNCap细胞及PC-3细胞的抑制活性
化合物 LNCap(IC50，μM) PC-3(IC50，μM)
2a 0.052 >10
2b 1.12 >10
3a 0.052 >10
3b 1.20 >10
4 0.525 >10
7 0.980 >10
9 1.12 >10
10 2.54 >10
11 0.352 >10
12 0.588 >10
13 0.120 >10
14 0.098 >10
15 0.251 >10
16 0.363 >10
17 0.174 >10
18 0.525 >10
19 0.088 >10
20 0.078 >10
21 0.251 >10
22 0.173 >10
23a 0.006 >10
23b 0.030 >10
24a 0.009 >10
24b 0.045 >10
26 79.4 >10
27 612.4 >10
158 0.065 >10
158为US 2018/0099940 A1中化合物编号为158的分子，结构如下所示，
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。
效果实施例2
1.药代动力学实验方法
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。
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)。
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。
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。
2.药代动力学实验结果
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
PK参数 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
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。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (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，
    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；
    R 2为氢或
    Figure PCTCN2021116287-appb-100002
    D为O、NR 6-1或CR 6-2R 6-3；
    K为-C(＝O)-或CR 7-1R 7-2；
    M为-C(＝O)-或CR 11-1R 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；
    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；
    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；
    R 1-1和R 1-2独立地为氢或C 1-C 4烷基；
    R 2-1为C 1-C 4烷基；
    R 6-1为氢或C 1-C 4烷基；
    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 8-1和R 8-2独立地为卤素或C 1-C 4烷基；
    R 9-1和R 9-2独立地为卤素、羟基或C 1-C 4烷基。
  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，
    所述的卤素独立地为氟、氯、溴或碘，例如氟、氯或溴；
    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；
    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；
    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；
    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；
    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
    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
    和/或，所述的R 8-2的个数为1个；
    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；
    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
    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；
    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；
    和/或，所述的R 9-1的个数为1、2或4个；
    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；
    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；
    和/或，所述的R 9-2的个数为1个。
  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，
    Figure PCTCN2021116287-appb-100014
    为
    Figure PCTCN2021116287-appb-100015
    为
    Figure PCTCN2021116287-appb-100016
    其中E与D相连；
    R 3-1和R 3-2独立地为氢、卤素、羟基或C 1-4烷基；
    A为N或CR 4-1；
    B为N或CR 4-2；
    C为N或CR 4-3；
    E为N或CR 4-4；
    F为N或CR 4-5；
    G独立地为NR 5-1或CR 5-2R 5-3；
    L独立地为NR 10-1或CR 10-2R 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 5-1和R 10-1独立地为氢或C 1-C 4烷基；
    m和n独立地为0、1、2或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。
  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，
    所述的卤素独立地为氟、氯、溴或碘；
    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。
  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，
    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；
    和/或，R 2为氢；
    和/或，R 3-1和R 3-2独立地为氢、羟基或C 1-4烷基；
    和/或，B为CR 4-2；
    和/或，C为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；
    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；
    和/或，R 4-1为氢；
    和/或，R 4-2为氢；
    和/或，R 4-3为氢；
    和/或，R 4-4为氢；
    和/或，R 5-2和R 5-3为氢；
    和/或，R 6-1为氢；
    和/或，R 6-2和R 6-3为氢；
    和/或，R 7-1和R 7-2为氢；
    和/或，R 8-2独立地为卤素；
    和/或，R 9-2独立地为C 1-C 4烷基；
    和/或，R 10-2和R 10-3独立地为氢或C 1-C 4烷基；
    和/或，R 11-1和R 11-2为氢；
    和/或，m为0、1或2；
    和/或，n为0、1或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，
    D为O或NH，例如O；
    和/或，R 2为氢；
    和/或，
    Figure PCTCN2021116287-appb-100017
    为
    Figure PCTCN2021116287-appb-100018
    例如
    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
    和/或，
    Figure PCTCN2021116287-appb-100024
    为
    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
  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：
    方案一：
    R 1为卤素或一个或多个卤素取代的C 1-C 4烷基；
    R 2为氢；
    R 3-1和R 3-2独立地为氢、羟基或C 1-4烷基；
    A为N或CH；
    B为CH；
    C为CH；
    D为O、NH或CH 2；
    E为N或CH；
    F为N或CR 4-5；
    G独立地为NR 5-1或CH 2；
    L独立地为NR 10-1或CR 10-2R 10-3；
    K为-C(＝O)-或CH 2；
    M为-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；
    R 4-5为氢、卤素或C 1-C 4烷基；
    R 8-2独立地为卤素；
    R 5-1和R 10-1独立地为氢或C 1-C 4烷基；
    R 10-2、R 10-3独立地为氢或C 1-C 4烷基；
    m和n独立地为0、1、2或3；和
    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；
    方案二：
    R 1为卤素；
    R 2为氢；
    R 3-1和R 3-2独立地为氢；
    A为N或CH；
    B为CH；
    C为CH；
    D为O、NH或CH 2；
    E为N或CH；
    F为N或CR 4-5；
    K为-C(＝O)-或CH 2；
    M为-C(＝O)-；
    G独立地为NR 5-1或CH 2；
    L独立地为NR 10-1或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；
    R 4-5为氢、卤素或C 1-C 4烷基；
    R 5-1和R 10-1独立地为氢或C 1-C 4烷基；
    m为0或1；和
    n为1或2；
    方案三：
    R 1为卤素；
    R 2为氢；
    R 3-1和R 3-2独立地为氢；
    A为N或CH；
    B为CH；
    C为CH；
    D为O、NH或CH 2；
    E为CH；
    F为N或CR 4-5；
    G独立地为NR 5-1或CH 2；
    L独立地为NR 10-1或CH 2；
    K为-C(＝O)-或CH 2；
    M为-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；
    R 4-5为氢、卤素或C 1-C 4烷基；
    R 5-1和R 10-1独立地为C 1-C 4烷基；
    m为0或1；和
    n为1或2；
    方案四：
    R 1为氯；
    R 2为氢；
    R 3-1和R 3-2独立地为氢；
    A为CH；
    B为CH；
    C为CH；
    D为O；
    E为CH；
    F为CH；
    G独立地为CH 2；
    L独立地为CH 2；
    K为-C(＝O)-和M为CH 2；或K为CH 2和M为-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；
    R 4-5为氢、卤素或C 1-C 4烷基；
    R 5-1和R 10-1独立地为C 1-C 4烷基；
    m为0或1；
    n为2；
    且当m为0时，环W为
    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：
    方案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：
    Figure PCTCN2021116287-appb-100032
    其中，D为O或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；
    方案b：
    所述的如式I所示的化合物为如式Ic所示的化合物：
    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；
    优选，所述的如式Ic所示的化合物中：
    R 1为卤素；
    R 2为H；
    Figure PCTCN2021116287-appb-100034
    为
    Figure PCTCN2021116287-appb-100035
    方案c：
    所述的如式I所示的化合物为如式Id所示的化合物：
    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；
    优选，所述的如式Id所示的化合物中，
    R 1为卤素；
    R 2为H；
    环Z为C 6-C 10芳环；
    Figure PCTCN2021116287-appb-100037
    为
    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：
    Figure PCTCN2021116287-appb-100039
    Figure PCTCN2021116287-appb-100040
    Figure PCTCN2021116287-appb-100041
    Figure PCTCN2021116287-appb-100042
    Figure PCTCN2021116287-appb-100043
    Figure PCTCN2021116287-appb-100044
    Figure PCTCN2021116287-appb-100045
    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，
    Figure PCTCN2021116287-appb-100047
    Figure PCTCN2021116287-appb-100048
    Figure PCTCN2021116287-appb-100049
    Figure PCTCN2021116287-appb-100050
    Figure PCTCN2021116287-appb-100051
    Figure PCTCN2021116287-appb-100052
    Figure PCTCN2021116287-appb-100053
    Figure PCTCN2021116287-appb-100054
    Figure PCTCN2021116287-appb-100055
    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：
    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，
    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；
    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，
    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；
    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，
    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。
  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，
    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；
    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；
    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；
    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；
    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；
    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；
    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；
    和/或，所述缩合反应的反应温度为室温；
    和/或，所述缩合反应的反应时间优选为1～3小时；
    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；
    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；
    和/或，所述的脱保护反应中，所述的酸为无机酸，优选为盐酸；
    和/或，所述脱保护反应的反应温度为室温；
    和/或，所述脱保护反应的反应时间为1～3小时；
    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；
    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；
    和/或，所述加成反应的反应温度为室温；
    和/或，所述加成反应的反应时间优选为1～3小时。
  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，
    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：
    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
  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，
    所述的如式IV所示的化合物为
    Figure PCTCN2021116287-appb-100070
    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
    Figure PCTCN2021116287-appb-100074
    所述的如式VI所示的化合物为
    Figure PCTCN2021116287-appb-100075
    所述的如式VI所示的化合物的立体异构体为
    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。
  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；
    所述的与雄激素受体相关疾病优选为***癌，进一步优选为转移性去势抵抗***癌。
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