WO2024067783A1 - Phosphorus-containing compound, and preparation method therefor and pharmaceutical use thereof - Google Patents

Phosphorus-containing compound, and preparation method therefor and pharmaceutical use thereof Download PDF

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WO2024067783A1
WO2024067783A1 PCT/CN2023/122463 CN2023122463W WO2024067783A1 WO 2024067783 A1 WO2024067783 A1 WO 2024067783A1 CN 2023122463 W CN2023122463 W CN 2023122463W WO 2024067783 A1 WO2024067783 A1 WO 2024067783A1
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compound
mmol
alkyl
added
reaction
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PCT/CN2023/122463
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Chinese (zh)
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邓刚
黄火明
彭建彪
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上海济煜医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • 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
    • C07D207/12—Oxygen or sulfur atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and in particular, relates to a phosphorus-containing compound and a preparation method and medical application thereof.
  • Prostate cancer is an androgen-dependent tumor. Androgens can stimulate the growth and disease progression of prostate cancer cells through androgen receptors (AR).
  • Endocrine therapy is one of the conventional treatment methods.
  • the standard of care for advanced PCa is mainly androgen deprivation therapy (ADT), such as surgical castration (bilateral orchiectomy) or medical castration (such as injection of Noradrena).
  • ADT therapy has a significant effect in the early stages of treatment, but as the disease progresses, AR mutates, and the mutated AR is more sensitive to low levels of androgens, driving the disease to castration-resistant prostate cancer (CRPC).
  • CRPC castration-resistant prostate cancer
  • Almost all patients with advanced prostate cancer will eventually progress to CRPC after receiving endocrine therapy.
  • up to 30% of prostate cancer patients will develop metastatic castration-resistant prostate cancer (mCRPC) within 10 years of initial treatment.
  • AR-Vs Compared with normal full-length AR, AR-Vs is a truncated AR. These splice variants lack LBD during the formation process, which results in the inability of androgens to bind to AR-Vs. However, since AR-Vs retain the N-terminal domain and DNA-binding domain (DBD), they can still bind to genomic DNA and regulate the expression of downstream target genes, showing androgen-independent structural activity, which is one of the important mechanisms of ADT resistance and CRPC disease progression.
  • DBD DNA-binding domain
  • inhibitors targeting AR receptor NTD with good physicochemical properties and drugability which inhibit the transcriptional function of androgen receptor AR by regulating the N-terminal domain of AR and block the conduction pathway of androgen receptor, is a new research direction for the treatment of prostate cancer.
  • Inhibitors targeting AR-NTD will bring about deep and extensive AR inhibition by acting on the N-terminal domain of AR receptor. It has important clinical value for the treatment of AR-driven cancer diseases such as prostate cancer, especially the treatment of androgen-independent resistant prostate cancer.
  • the present invention provides a compound represented by formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from H, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl , C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • R 1 and R 2 are linked together to form a 4-8 membered ring, and the 4-8 membered ring is optionally substituted by 1, 2 or 3 R;
  • R 3 , R 4 , and R 5 are each independently selected from H, CN, F, Cl, Br, OH, NH 2 , C 1-6 alkyl, C 1-6 alkyl-O—, C 1-6 alkyl-S—, C 1-6 alkyl-NH—, C 2-6 alkenyl-O—, C 2-6 alkenyl-S—, C 2-6 alkenyl-NH—, C 3-6 cycloalkyl-O—, C 3-6 cycloalkyl-S—, C 3-6 cycloalkyl-NH—, 4-6 membered heterocycloalkyl-O—, 4-6 membered heterocycloalkyl-S— or 4-6 membered heterocycloalkyl-NH—; the C 1-6 alkyl, C 1-6 alkyl-O—, C 1-6 alkyl-S—, C 1-6 alkyl-NH—, C 2-6 alkenyl-O—, C 2-6 alkenyl-S—, C 2-6 alken
  • R 6 and R 7 are each independently selected from H, CN, F, Cl, Br, OH, NH 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
  • n and n are independently selected from 0, 1, 2 or 3;
  • Y is selected from O or S
  • L 1 is selected from a single bond, NH, O, CH 2 , CH 2 CH 2 or OCH 2 , wherein CH 2 , CH 2 CH 2 and OCH 2 are optionally substituted with 1 or 2 R;
  • L 2 and L 3 are each independently selected from -(CR 8 R 9 )x-, -O-, -S-, -C( ⁇ O)-, -S( ⁇ O)-, -S( ⁇ O) 2 -, -NR 10 -, -OR 11 - or a 5-10 membered heterocycloalkyl group;
  • L 4 is selected from -(CR 8 R 9 )x-, -O-, -S-, -C( ⁇ O)-, -S( ⁇ O)-, -S( ⁇ O) 2 -, -NR 10 -, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
  • R 8 and R 9 are each independently selected from H, CN, F, Cl, Br, OH, NH 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
  • R 8 and R 9 are linked together to form a C 4-8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C 4-8 cycloalkyl and 4-8 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
  • R 10 is selected from H or C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • R 11 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • Ring A is selected from phenyl or 5-10 membered heteroaryl
  • Ring B and Ring C are each independently selected from phenyl, 5-10 membered heteroaryl, benzo C 5-6 cycloalkyl, benzo 5-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C 5-6 cycloalkyl or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;
  • heteroaryl, heteroalkyl or heterocycloalkyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C( ⁇ O), C( ⁇ O)O, C( ⁇ O)NH, S( ⁇ O), S( ⁇ O) 2 , S( ⁇ O) 2 NH and N;
  • the above R is independently selected from H, halogen, OH, NH 2 , CN, ⁇ O, C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C( ⁇ O)—, C 1-3 alkyl-S( ⁇ O) 2 -, C 1-3 alkyl-C( ⁇ O)O—, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 alkylamino, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C( ⁇ O)—, C 1-3 alkyl-C( ⁇ O)O—, C 1-3 alkoxy, C 1-3 alkylthio and C 1-3 alkylamino are optionally substituted by 1, 2 or 3 R′, and the remaining variables are as defined herein.
  • the above R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, ⁇ O, CH3 , CH2F , CHF2 , CF3 ,
  • the remaining variables are as defined in the present invention.
  • R 1 and R 2 are independently selected from C 1-3 alkyl or C 1-3 alkenyl, and the C 1-3 alkyl and C 1-3 alkenyl are optionally substituted by 1, 2 or 3 R, and the remaining variables are as defined in the present invention.
  • R 1 and R 2 are independently selected from Me, The remaining variables are as defined in the present invention.
  • the above R1 and R2 are connected together to form a ring Said It is optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined herein.
  • the above R1 and R2 are connected together to form a ring
  • the remaining variables are as defined in the present invention.
  • R 3 , R 4 , and R 5 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-S-, C 1-3 alkyl-NH-, C 3-6 cycloalkyl-O-, C 3-6 cycloalkyl-S-, C 3-6 cycloalkyl-NH- or oxirane-O-; the C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-S-, C 1-3 alkyl-NH-, C 2-3 alkenyl-O-, C 2-3 alkenyl-S-, C 2-3 alkenyl-NH-, C 3-6 cycloalkyl-O-, C 3-6 cycloalkyl-S-, C 3-6 -cycloalkyl-NH- and oxirane-O- are optionally substituted with 1, 2
  • R 3 , R 4 , and R 5 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, Me, The Me, It is optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined herein.
  • R 3 , R 4 , and R 5 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, Me, The remaining variables are as defined in the present invention.
  • R 8 and R 9 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , Me or The remaining variables are as defined in the present invention.
  • R 10 is selected from H, Me, The remaining variables are as defined in the present invention.
  • the remaining variables are as defined in the present invention.
  • the remaining variables are as defined in the present invention.
  • the ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, oxazolyl and pyridazinyl, and the remaining variables are as defined in the present invention.
  • the ring B is selected from phenyl, benzocyclopentyl, and benzocyclohexyl, and the remaining variables are as defined in the present invention.
  • the ring C is selected from phenyl, benzocyclopentyl, benzocyclohexyl, 1H-indazolyl, 2H-indazolyl and 1H-benzo[d]imidazole, and the remaining variables are as defined in the present invention.
  • the structural unit Selected from The remaining variables are as defined in the present invention.
  • the present invention also provides the following compounds, their optical isomers and pharmaceutically acceptable salts thereof, which are selected from:
  • the present invention also proposes the use of the aforementioned compound, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a disease associated with androgen receptor (AR) activity or expression.
  • AR androgen receptor
  • the above-mentioned androgen receptor (AR) activity or expression-related diseases are selected from prostate cancer, ovarian cancer, breast cancer, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, renal cell carcinoma, melanoma, mantle cell lymphoma, glioblastoma, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy and age-related macular degeneration.
  • AR androgen receptor
  • the phrase "at least one" used when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements.
  • This definition also allows that there may be optionally elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or 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 a solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as 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, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and 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 basic and acidic functional groups, and
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are prepared by reacting with a stoichiometric amount of an appropriate base or acid.
  • “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, formulation aid or carrier commonly used with therapeutic agents in the art, which together constitute a “pharmaceutical composition” for administration to a subject.
  • a pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration used and is compatible with the other ingredients of the formulation.
  • the pharmaceutically acceptable carrier is suitable for the formulation used.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.
  • a hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent.
  • C1-6 alkylcarbonyl- refers to a C1-6 alkyl group that is attached to the rest of the molecule via a carbonyl group.
  • the "-" may be omitted.
  • substituted or “substituted by" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • substituent which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • optionally substituted or “optionally substituted by" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of chemical practicability.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with 1 or 2 or 3 R's, and each occurrence of R' has an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • substituents When the listed substituents do not specify through which atom they are bonded to the substituted group, such substituents may be bonded through any atom thereof.
  • a pyridyl substituent may be bonded to the substituted group through any carbon atom on the pyridine ring.
  • linking group L is -CH 2 O-, in which case -CH 2 O- can connect phenyl and cyclopentyl in the same direction as the reading order from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • halogen denotes fluorine, chlorine, bromine, iodine.
  • the number of atoms in a ring is generally defined as the ring member number, for example, "3-6 membered ring” refers to a “ring” having 3-6 atoms arranged around it.
  • C 1-6 alkyl is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or The price is more (such as ).
  • Examples of C 1-6 alkyl include, but are not limited to, CH 3 , wait.
  • C 1-4 alkyl is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 , C 3-4 and C 2-3 alkyl groups, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or polyvalent (such as divalent ).
  • Examples of C 1-4 alkyl groups include, but are not limited to, CH 3 , wait.
  • C2-6 alkenyl is used to represent a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group.
  • the C2-6 alkenyl group includes C2-4 , C2-3 , C4 , C3 and C2 alkenyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C2-6 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.
  • C 2-3 alkenyl is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group.
  • the C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group can be monovalent, divalent or polyvalent. Examples of C 2-3 alkenyl groups include but are not limited to wait.
  • C 2-6 alkynyl is used to represent a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent.
  • the C 2-6 alkynyl group includes C 2-3 , C 2-4 , C 2-5, C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , C 5-6 , C 6 , C 5 , C 4 , C 3 and C 2 alkynyl groups. Examples of C 2-6 alkynyl groups include, but are not limited to wait.
  • C 2-3 alkynyl is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent.
  • the C 2-3 alkynyl group includes C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl groups include, but are not limited to wait.
  • heteroalkyl by itself or in combination with another term refers to a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group.
  • the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized.
  • the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-3 heteroalkyl.
  • heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the term "alkoxy" is a customary expression to refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc.
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyl and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkoxy, etc.
  • Examples of C 1-3 alkoxy include But it is not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 1-6 alkylamino refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amino group.
  • the C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2, C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino groups, etc.
  • C 1-6 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )(CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 , and the like.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylamino groups, etc.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , etc.
  • C 1-6 alkylthio refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through a sulfur atom.
  • the C 1-6 alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylthio, etc.
  • Examples of C 1-6 alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH(CH 3 ) 2 , and the like.
  • C 1-3 alkylthio refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylthio groups, etc.
  • Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH(CH 3 ) 2 , etc.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • heteroatoms may occupy the position at which the heterocyclyl is connected to the rest of the molecule.
  • the 3-10 membered heterocyclic group includes 3-8 membered, 3-7 membered, 3-6 membered, 3-5 membered, 3-4 membered, 4-5 membered, 4-6 membered, 4-7 membered, 4-8 membered, 4-9 membered, 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 5-10 membered, 6-7 membered, 6-8 membered, 6-9 membered, 6-10 membered, 7-8 membered, 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heterocyclic groups, etc.
  • 3-9 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl,
  • the term "5-6 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings.
  • heteroatoms may occupy the position where the heterocyclyl is connected to the rest of the molecule.
  • the 5-6 membered heterocyclyl includes 5-membered and 6-membered heterocyclyls, etc.
  • 5-6 membered heterocyclyls include, but are not limited to, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazin
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” are used interchangeably.
  • the term “5-6 membered heteroaryl” refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and
  • C 6-10 aryl by itself or in combination with other terms , respectively, means a monocyclic or bicyclic aromatic ring system having six to ten carbon atoms.
  • Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph”), naphthyl.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 5 to 8 membered ring.
  • Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.
  • Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9, C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 .
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring and 6-10-membered ring, etc.
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
  • the solvent used in the present invention is commercially available.
  • the compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration, or a cis-Cis-configuration, or a trans-Trans-configuration.
  • the chiral centers of some compounds disclosed in the present invention are marked as *R, *S, R*, S*, *Cis-, or *Trans-, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been separated or chirally resolved and the chiral center is a chiral center of a single configuration, the compound is a single-configuration enantiomer monomer, or a single-configuration diastereoisomer monomer, or a diastereoisomer mixture with a single configuration of the chiral center (for example: the configuration of other chiral centers has not been resolved), or a single-configuration monomer (for example, a single cis-configuration monomer, or a single trans-configuration monomer).
  • the compounds can be identified based on their corresponding nuclear magnetic resonance ( 1 H-NMR, 31 P-NMR) The peak shape in the spectrum or the corresponding retention time (RT or Rt) under the corresponding chromatographic column conditions (such as chromatographic column model, chromatographic column filling material, chromatographic column size, mobile phase, etc.) is confirmed.
  • Mass spectra were recorded using an Agilent 1260 (ESI) or Shimadzu LC-MS-2020 (ESI) or Agilent 6215 (ESI) mass spectrometer; reversed-phase preparative HPLC separations were performed using an Agilent 1290 UV-guided fully automated purification system ( Prep C18 OBDTM 21.2*250mm 10 ⁇ m column) or Gilson GX281 UV-guided automatic purification system ( Prep C18 OBDTM 19*250mm 10 ⁇ m column) or Waters QDa-guided fully automated purification system ( Prep C18 OBD 29*250mm 10 ⁇ m column).
  • CD 3 OD represents deuterated methanol
  • DMSO-d6 represents deuterated dimethyl sulfoxide
  • Chloroform-d or CDCl 3 represents deuterated chloroform
  • AcOH represents acetic acid
  • AlCl 3 represents aluminum chloride
  • Aq represents aqueous solution
  • N 2 represents nitrogen
  • Ar represents argon
  • B 2 Pin 2 represents diboronic acid pinacol ester
  • BBr 3 represents boron tribromide
  • BH 3 represents borane
  • (Boc) 2 O represents di-tert-butyl dicarbonate
  • Et 3 SiH represents triethylsilane
  • HATU represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
  • HOBt represents 1-hydroxybenzotriazole
  • K 2 CO 3 represents potassium carbonate
  • KOAc represents potassium acetate
  • TFA trifluoroacetic acid
  • FA formic acid
  • TMSCN trimethylsilyl cyanide
  • H 2 O represents water
  • HCl hydrogen chloride gas
  • reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10Prep-C18 250x21.2 mm; column temperature: 25 ° C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 5 (190 mg, yield 27%).
  • reaction solution was filtered and dried to obtain a crude product, which was purified by preparative separation (preparation method: chromatographic column: Agilent 10Prep-C18 250x21.2 mm; column temperature: 25 ° C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 7 (70 mg, yield 20%).
  • reaction solution was filtered to obtain a crude product, which was purified by preparative separation (preparation method: chromatographic column: Agilent 10Prep-C18 250x21.2 mm; column temperature: 25 ° C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 8 (3 mg, yield 6%).
  • compound 1-3 (1.8 g, 4.8 mmol), methylboric acid (574 g, 9.6 mmol), potassium carbonate (1.33 g, 9.6 mmol), Pd(dppf)Cl 2 (348 mg, 0.48 mmol), 1,4-dioxane (20 mL) and water (4 mL) were added to a 100 mL three-necked flask and reacted at 100°C for 16 hours. After the reaction, 60 mL of water was added, and the reaction system was extracted with EtOAc (30 mL ⁇ 3).
  • the crude compound 13-3 (4.1 g, 23.3 mmol) was dissolved in dichloromethane (100 mL), and NBS (4.56 g, 25.6 mmol) was added thereto. After the addition, the system was stirred at room temperature for 16 h. Water (10 mL) was added to the system to quench the reaction, and then extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • LCMS monitored the reaction until the reaction was complete, and ethanol (100 mL) was added dropwise to quench the reaction.
  • the reaction system was quenched with saturated sodium bicarbonate (10 mL), the organic phase was separated, dried and concentrated to obtain a crude product, and the crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent10Prep-C18250 ⁇ 21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain 110 mg of the title compound 28, with a yield of 40%.
  • the crude product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250 ⁇ 21.2 mm; column temperature: 25°C; gradient: 35%-95% acetonitrile in 20 min; flow rate: 30 mL/min) to obtain 10 mg of the title compound 31, with a yield of 9%.
  • the reaction solution was filtered, and the filtrate was evaporated to dryness under reduced pressure.
  • the crude product was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x 21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/ L NH4HCO3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 10 mg of the title compound 33, with a yield of 18%.
  • the crude product was purified by high-performance preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 35.
  • the crude product was purified by high-efficiency preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25 ° C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 36.
  • the crude compound 38-5 (150 mg, 0.29 mmol) and dimethylphosphine oxide (223 mg, 2.9 mmol) were dissolved in acetonitrile (5 mL), and potassium carbonate (120 mg, 0.87 mmol) was added thereto. After the addition, the system was stirred at 80°C for 8 h. Saturated ammonium chloride solution (10 mL) was added to the system to quench, and ethyl acetate (50 mL) was extracted three times. The organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product was purified by high-efficiency preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% 10 mM/L NH 4 HCO 3 )-acetonitrile; the mobile phase acetonitrile ratio was 40%-40% in 12 minutes with gradient elution; flow rate was 30 mL/min) to obtain the title compound 38.
  • the crude product was subjected to high-efficiency preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% 10 mM/L NH 4 HCO 3 )-acetonitrile; the mobile phase acetonitrile ratio was 45%-65% at 12
  • the title compound 39 was purified by gradient elution within 10 minutes; flow rate 30 mL/min, LC-MS (ESI): m/z 573.2 [M+H] + .
  • Compound 39 (38.55 mg, 0.067 mmol) was chirally separated by SFC (preparation method: chromatographic column: ChiralPak AD, 250 ⁇ 30 mm ID, 10 ⁇ m; column temperature: 38°C; mobile phase: A is CO 2 , B is ethanol (containing 0.1% ammonia water); mobile phase B ratio 30% in 8 min; flow rate 150 mL/min) to obtain 11.11 mg of the title compound 39A (chiral column retention time of 11.11 min) and 17.34 mg of compound 39B (chiral column retention time of 7.60 min).
  • Compound 39A LC-MS (ESI): 573.2 [M+H] + .
  • the crude product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250 ⁇ 21.2 mm; column temperature: 25°C; gradient: 10%-95% acetonitrile in 20 minutes; flow rate: 30 mL/min) to obtain 5 mg of the title compound 43A (yield 2%) and 10 mg of the title compound 43B (yield 4%).
  • Compound 43A (HPLC analysis method: chromatographic column: Agilent ZORBAX Extend-C18 4.6*150mm, 3.5 ⁇ m; column temperature: 30°C; mobile phase: water (0.1mL/1L trifluoroacetic acid)-acetonitrile (0.4mL/4L trifluoroacetic acid); acetonitrile: 5%-95% 8min, 95% 7min; flow rate: 1mL/min, retention time Rt: 7.685min).
  • Compound 43B (HPLC analysis method: chromatographic column: Agilent ZORBAX Extend-C18 4.6*150mm, 3.5 ⁇ m; column temperature: 30°C; mobile phase: water (0.1mL/1L trifluoroacetic acid)-acetonitrile (0.4mL/4L trifluoroacetic acid); acetonitrile: 5%-95% 8min, 95% 7min; flow rate: 1mL/min, retention time Rt: 7.816min).
  • the crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250 ⁇ 21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile elution over 30 minutes; flow rate: 30 mL/min) to give the title compound 44 (3 mg) in a yield of 6%.
  • the crude filtrate was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 18 mg of the title compound with a yield of 28%.
  • reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 45 mg of the title compound 47, with a yield of 33%.
  • the compound 2-iodoaniline (1 g, 4.57 mmol) was dissolved in DMF (5 mL), and dimethylphosphine oxide (356 mg, 4.57 mmol), DIEA (1.77 g, 13.70 mmol), Pd 2 (dba) 3 (418 mg, 0.456 mmol) and Xantphos (264 mg, 0.456 mmol) were added in sequence.
  • the reaction system was replaced with nitrogen three times and stirred in a microwave at 120° C. for 2 hours. After the reaction, the insoluble solid was filtered off, water (50 mL) was added to the filtrate, and the mixture was extracted twice with dichloromethane (30 mL).
  • reaction solution was filtered, and the filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250 ⁇ 21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain 20 mg of the title compound, with a yield of 14%.
  • reaction liquid was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent10Prep-C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 10 mg of the title compound, with a yield of 7%.
  • the crude compound 53-3 (580 mg) was dissolved in anhydrous methanol (10 mL), and DIPEA (516 mg, 4 mmol) was added. After stirring at 0°C for 5 minutes, the compound 2,4-dichloropyrimidine (325 mg, 2.2 mmol) was added, and the temperature was raised to 25°C for reaction for 1 hour. After the reaction was completed, a saturated ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (30 mL) was added for extraction.
  • the crude compound 54-3 (180 mg) was dissolved in anhydrous methanol (10 mL), and DIPEA (516 mg, 4 mmol) was added. After stirring at 0°C for 5 minutes, the compound 2,4-dichloropyrimidine (300 mg, 2.0 mmol) was added, and the temperature was raised to 25°C for reaction for 1 hour. After the reaction was completed, a saturated ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (30 mL) was added to extract twice.
  • reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25° C.; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 35%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 4.67 mg of the title compound 54, with a yield of 4.29%.
  • the reaction solution was filtered, and the filtrate was evaporated to dryness under reduced pressure.
  • the crude product was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x 21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/ L NH4HCO3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 35 mg of the title compound 55, with a yield of 27%.
  • the crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250 ⁇ 21.2 mm; column temperature: 25°C; gradient: 20%-90% acetonitrile in 40 min; flow rate: 30 mL/min) to obtain 12 mg of the title compound 59.
  • the dosing solution was prepared on the day of the experiment. Weigh 2 mg of the compound and dissolve it in dosage form A: 3% DMSO + 1.5% Tween80 + 95.5% Saline to prepare an intravenous solution with a concentration of 0.1 mg/mL; weigh 2 mg of the compound and dissolve it in dosage form B: 3% DMSO + 1.5% Tween80 +95.5% Saline to obtain a 0.5 mg/mL oral administration solution; weigh 3 mg of the compound and dissolve it with dosage form C: 5% DMSO + 5% NMP + 10% Solutol + 80% PEG400 to obtain a 3.0 mg/mL oral administration solution.
  • mice Take healthy male six ICR mice, weighing 25-30g, were divided into two groups (intravenous and oral groups), three mice in each group, and administered once. After 3 days of adaptive feeding, the mice were fasted overnight (10-12h) before the experiment, and were allowed to drink water freely during the experiment. They resumed eating 4h after administration. Timing began after intravenous and oral administration, and blood was collected through the orbital venous plexus at the planned time points (IV&PO 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h). 30 ⁇ L of whole blood was collected at each point into a 1.5mL EP tube containing sodium heparin.
  • the collected whole blood was placed on a vortexer and shaken twice to mix, placed on wet ice, centrifuged at 8000rpm for 5min at 4°C within 1h, and the supernatant plasma was stored in a -80°C refrigerator until processed and analyzed.
  • the dosing solution was prepared on the day of administration. Weigh 2 mg of the compound and dissolve it in 3% DMSO + 1.5% Tween80 + 95.5% Saline to prepare an intravenous dosing solution with a concentration of 0.1 mg/mL; weigh 6 mg of the compound and dissolve it in 3% DMSO + 1.5% Tween80 + 95.5% Saline to obtain a 0.5 mg/mL oral dosing solution.
  • the collected whole blood was placed on a vortexer and shaken twice to mix, placed on wet ice, centrifuged at 8000rpm for 5min at 4°C within 1h, and the supernatant plasma was stored in a -80°C refrigerator until processed and analyzed.
  • Human prostate cancer cell line LNCaP was purchased from ATCC, the cell culture medium was RPMI-1640 + 10% FBS, and cultured in a 37°C, 100% relative humidity, 5% CO2 incubator.
  • the IC50 curve was fitted and the IC50 value was calculated using the software Graphpad Prism 8 and the calculation formula XY-analysis/Nonlinear regression (curve fit)/Dose response-Inhibition/log (inhibitor) vs. normalized response-Variable slope.

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Abstract

Provided are a compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and use of the compound as an androgen receptor (AR) inhibitor.

Description

含磷类化合物及其制备方法和医药应用Phosphorus-containing compounds and preparation methods and medical applications thereof
本发明主张如下优先权：The present invention claims the following priority:
1)申请号CN 202211194169.6，申请日2022年09月28日；1) Application number CN 202211194169.6, application date September 28, 2022;
2)申请号CN 202211506143.0，申请日2022年11月28日；2) Application number CN 202211506143.0, application date November 28, 2022;
3)申请号CN 202310287532.7，申请日2023年03月21日；3) Application number CN 202310287532.7, application date March 21, 2023;
4)申请号CN 202310862597.X，申请日2023年07月13日；4) Application number CN 202310862597.X, application date July 13, 2023;
5)申请号CN 202311208427.6，申请日2023年09月18日。5) Application number CN 202311208427.6, application date September 18, 2023.
技术领域Technical Field
本发明属于药物化学领域，具体地，本发明涉及一种含磷类化合物及其制备方法和医药应用。The present invention belongs to the field of pharmaceutical chemistry, and in particular, relates to a phosphorus-containing compound and a preparation method and medical application thereof.
背景技术Background technique
前列腺癌是一种雄激素依赖的肿瘤，雄激素可以雄激素受体(AR)进而刺激前列腺癌细胞的生长和疾病进展。内分泌治疗是常规的治疗手段之一，例如晚期PCa的治疗标准主要为雄激素剥夺疗法(ADT),如采用手术去势(双侧睾丸切除)或药物去势(如注射诺雷得)。ADT疗法在治疗的初期具有显著的效果，但是随着疾病的进展，AR发生突变，突变的AR对于低水平的雄激素更加敏感，从而驱使疾病进展为去势抵抗前列腺癌(CRPC)。几乎所有的晚期前列腺癌患者在接受内分泌治疗后，都会最终进展为CRPC。此外，高达30％的前列腺癌患者会在初步治疗的10年内转变为转移性去势抵抗前列腺癌(mCRPC)。Prostate cancer is an androgen-dependent tumor. Androgens can stimulate the growth and disease progression of prostate cancer cells through androgen receptors (AR). Endocrine therapy is one of the conventional treatment methods. For example, the standard of care for advanced PCa is mainly androgen deprivation therapy (ADT), such as surgical castration (bilateral orchiectomy) or medical castration (such as injection of Noradrena). ADT therapy has a significant effect in the early stages of treatment, but as the disease progresses, AR mutates, and the mutated AR is more sensitive to low levels of androgens, driving the disease to castration-resistant prostate cancer (CRPC). Almost all patients with advanced prostate cancer will eventually progress to CRPC after receiving endocrine therapy. In addition, up to 30% of prostate cancer patients will develop metastatic castration-resistant prostate cancer (mCRPC) within 10 years of initial treatment.
目前已有多款用于治疗mCRPC的口服药物，例如恩杂鲁胺、阿帕鲁胺和达洛鲁胺等，它们主要通过与雄激素受体的配体结合域(AR-LBD)结合，从而阻断AR与DNA的相互作用并进而发挥药效。但用这些药物治疗2—3年后，患者易于发生耐药。缺失LBD区域的雄激素受体变体(AR-Vs)的出现及LBD区域突变，是两个重要的耐药机制。There are currently a number of oral drugs for the treatment of mCRPC, such as enzalutamide, apalutamide, and darolutamide, which mainly bind to the ligand binding domain (AR-LBD) of the androgen receptor, thereby blocking the interaction between AR and DNA and exerting their efficacy. However, after 2-3 years of treatment with these drugs, patients are prone to drug resistance. The emergence of androgen receptor variants (AR-Vs) lacking the LBD region and mutations in the LBD region are two important mechanisms of drug resistance.
与正常全长AR相比较，AR-Vs是一种截短型的AR，这些剪切变异体在形成过程中缺失了LBD，这导致了雄激素无法与AR-Vs结合。但是，由于AR-Vs保留了N-端域和DNA结合域(DNA-binding domain，DBD)，故仍能与基因组DNA结合，调控下游靶基因的表达，呈现出雄激素非依赖性的结构性活性，这是ADT抵抗和CRPC疾病进展的重要机制之一。Compared with normal full-length AR, AR-Vs is a truncated AR. These splice variants lack LBD during the formation process, which results in the inability of androgens to bind to AR-Vs. However, since AR-Vs retain the N-terminal domain and DNA-binding domain (DBD), they can still bind to genomic DNA and regulate the expression of downstream target genes, showing androgen-independent structural activity, which is one of the important mechanisms of ADT resistance and CRPC disease progression.
研发具有良好理化性质及成药性的靶向AR受体NTD的抑制剂，通过调控AR的N-端域以抑制雄激素受体AR的转录功能，并阻断雄激素受体的传导通路，是前列腺癌治疗研究新方向。靶向AR-NTD的抑制剂，通过作用于AR受体N-端域，将带来深入和广泛的AR抑制作用。对前列腺癌等AR驱动的癌症疾病治疗，特别是雄激素非依赖性耐药的前列腺癌治疗，有重要的临床价值。The development of inhibitors targeting AR receptor NTD with good physicochemical properties and drugability, which inhibit the transcriptional function of androgen receptor AR by regulating the N-terminal domain of AR and block the conduction pathway of androgen receptor, is a new research direction for the treatment of prostate cancer. Inhibitors targeting AR-NTD will bring about deep and extensive AR inhibition by acting on the N-terminal domain of AR receptor. It has important clinical value for the treatment of AR-driven cancer diseases such as prostate cancer, especially the treatment of androgen-independent resistant prostate cancer.
发明内容Summary of the invention
在本发明的一方面，本发明提出了式(Ⅰ)所示化合物、其光学异构体及其药效上可接受的盐，
In one aspect of the present invention, the present invention provides a compound represented by formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof,
其中，in,
R1、R2分别独立地选自H、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C3-6环烯基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C3- 6环烯基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代； R 1 and R 2 are each independently selected from H, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl , C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
或者，R1与R2连接在一起，形成一个4-8元环，所述4-8元环任选被1、2或3个R取代；Alternatively, R 1 and R 2 are linked together to form a 4-8 membered ring, and the 4-8 membered ring is optionally substituted by 1, 2 or 3 R;
R3、R4、R5分别独立地选自H、CN、F、Cl、Br、OH、NH2、CNC1-6烷基、C1-6烷基-O-、C1-6烷基-S-、C1- 6烷基-NH-、C2-6烯基-O-、C2-6烯基-S-、C2-6烯基-NH-、C3-6环烷基-O-、C3-6环烷基-S-、C3-6环烷基-NH-、4-6元杂环烷基-O-、4-6元杂环烷基-S-或4-6元杂环烷基-NH-，所述C1-6烷基、C1-6烷基-O-、C1-6烷基-S-、C1-6烷基-NH-、C2-6烯基-O-、C2-6烯基-S-、C2-6烯基-NH-、C3-6环烷基-O-、C3-6环烷基-S-、C3-6环烷基-NH-、4-6元杂环烷基-O-、4-6元杂环烷基-S-和4-6元杂环烷基-NH-任选被1、2或3个R取代；R 3 , R 4 , and R 5 are each independently selected from H, CN, F, Cl, Br, OH, NH 2 , C 1-6 alkyl, C 1-6 alkyl-O—, C 1-6 alkyl-S—, C 1-6 alkyl-NH—, C 2-6 alkenyl-O—, C 2-6 alkenyl-S—, C 2-6 alkenyl-NH—, C 3-6 cycloalkyl-O—, C 3-6 cycloalkyl-S—, C 3-6 cycloalkyl-NH—, 4-6 membered heterocycloalkyl-O—, 4-6 membered heterocycloalkyl-S— or 4-6 membered heterocycloalkyl-NH—; the C 1-6 alkyl, C 1-6 alkyl-O—, C 1-6 alkyl-S—, C 1-6 alkyl-NH—, C 2-6 alkenyl-O—, C 2-6 alkenyl-S—, C 2-6 alkenyl-NH—, C C 3-6 cycloalkyl-O—, C 3-6 cycloalkyl-S—, C 3-6 cycloalkyl-NH—, 4-6 membered heterocycloalkyl-O—, 4-6 membered heterocycloalkyl-S— and 4-6 membered heterocycloalkyl-NH— are optionally substituted with 1, 2 or 3 R;
R6、R7分别独立地选自H、CN、F、Cl、Br、OH、NH2、C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代；R 6 and R 7 are each independently selected from H, CN, F, Cl, Br, OH, NH 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
m、n分别独立地选自0、1、2或3；m and n are independently selected from 0, 1, 2 or 3;
Y选自O或S；Y is selected from O or S;
L1选自单键、NH、O、CH2、CH2CH2或OCH2，所述CH2、CH2CH2和OCH2任选被1或2个R取代；L 1 is selected from a single bond, NH, O, CH 2 , CH 2 CH 2 or OCH 2 , wherein CH 2 , CH 2 CH 2 and OCH 2 are optionally substituted with 1 or 2 R;
L2、L3分别独立地选自-(CR8R9)x-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-NR10-、-OR11-或5-10元杂环烷基；L 2 and L 3 are each independently selected from -(CR 8 R 9 )x-, -O-, -S-, -C(═O)-, -S(═O)-, -S(═O) 2 -, -NR 10 -, -OR 11 - or a 5-10 membered heterocycloalkyl group;
L4选自-(CR8R9)x-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-NR10-、C3-6环烷基或3-6元杂环烷基，所述C3- 6环烷基和3-6元杂环烷基任选被1、2或3个R取代；L 4 is selected from -(CR 8 R 9 )x-, -O-, -S-, -C(═O)-, -S(═O)-, -S(═O) 2 -, -NR 10 -, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
R8、R9分别独立地选自H、CN、F、Cl、Br、OH、NH2、C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代；R 8 and R 9 are each independently selected from H, CN, F, Cl, Br, OH, NH 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
或者R8与R9连接在一起，形成一个C4-8环烷基或4-8元杂环烷基，所述C4-8环烷基和4-8元杂环烷基任选被1、2或3个R取代；Or R 8 and R 9 are linked together to form a C 4-8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C 4-8 cycloalkyl and 4-8 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
R10选自H或C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1- 6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代；R11选自C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代；x选自0、1、2或3；R 10 is selected from H or C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; R 11 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; x is selected from 0, 1, 2 or 3;
环A选自苯基或5-10元杂芳基；Ring A is selected from phenyl or 5-10 membered heteroaryl;
环B、环C分别独立地选自苯基、5-10元杂芳基、苯并C5-6环烷基、苯并5-7元杂环烷基、5-6元杂芳基并C5-6环烷基或5-6元杂芳基并5-6元杂环烷基；Ring B and Ring C are each independently selected from phenyl, 5-10 membered heteroaryl, benzo C 5-6 cycloalkyl, benzo 5-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C 5-6 cycloalkyl or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;
R分别独立地选自H、卤素、＝O、OH、NH2、CN、C1-6烷基、C1-6杂烷基、C3-6环烷基或3-6元杂环烷基，所述C1-6烷基、-C1-6烷基-OH、C3-6杂烷基、C3-6环烷基、C3-6杂环烷基、C1-6烷基-C(＝O)-、C1- 6烷基-C(＝O)O-、C1-6烷基-O-C(＝O)-、C1-6烷基-C(＝O)NH-、C1-6烷基-NH-C(＝O)-、C1-6烷基-S(＝O)2-、C1-6烷基-S(＝O)2NH-、C1-6烷基-NHS(＝O)2-、C1-6烷氧基、C1-6烷硫基和C1-6烷氨基任选被1、2或3个R’取代；R’选自F、Cl、Br、I、OH、NH2、CN、CH3、CH2F、CHF2和CF3；R is independently selected from H, halogen, =O, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, -C 1-6 alkyl-OH, C 3-6 heteroalkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 1-6 alkyl-C(=O)-, C 1-6 alkyl -C(=O)O-, C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-C(=O)NH-, C 1-6 alkyl-NH-C(=O)-, C 1-6 alkyl-S(=O) 2- , C 1-6 alkyl-S(=O)2NH-, C 1-6 alkyl-NHS(=O) 2- , C 1-6 alkoxy, C 1-6 alkylthio and C 1-6 alkylamino are optionally substituted by 1 , 2 or 3 R';R' is selected from F, Cl, Br, I, OH, NH 2. CN CH 3 , CH 2 F, CHF 2 and CF 3 ;
上述杂芳基、杂烷基或杂环烷基包含1、2或3个独立选自O、NH、S、C(＝O)、C(＝O)O、C(＝O)NH、S(＝O)、S(＝O)2、S(＝O)2NH和N的杂原子或杂原子团；The above heteroaryl, heteroalkyl or heterocycloalkyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(═O), C(═O)O, C(═O)NH, S(═O), S(═O) 2 , S(═O) 2 NH and N;
且式(I)化合物不选自：
And the compound of formula (I) is not selected from:
本发明的一些方案中，上述R分别独立地选自H、卤素、OH、NH2、CN、＝O、C1-3烷基、C3-6环烷基、C1-3烷基-C(＝O)-、C1-3烷基-S(＝O)2-、C1-3烷基-C(＝O)O-、C1-3烷氧基、C1-3烷硫基或C1-3烷氨基，所述C1-3烷基、C3-6环烷基、C1-3烷基-C(＝O)-、C1-3烷基-C(＝O)O-、C1-3烷氧基、C1-3烷硫基和C1-3烷氨基任选被1、2或3个R’取代，其余变量如本发明所定义。In some embodiments of the present invention, the above R is independently selected from H, halogen, OH, NH 2 , CN, ═O, C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C(═O)—, C 1-3 alkyl-S(═O) 2 -, C 1-3 alkyl-C(═O)O—, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 alkylamino, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C(═O)—, C 1-3 alkyl-C(═O)O—, C 1-3 alkoxy, C 1-3 alkylthio and C 1-3 alkylamino are optionally substituted by 1, 2 or 3 R′, and the remaining variables are as defined herein.
本发明的一些方案中，上述R分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、＝O、 CH3、CH2F、CHF2、CF3、 其余变量如本发明所定义。In some embodiments of the present invention, the above R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, ═O, CH3 , CH2F , CHF2 , CF3 , The remaining variables are as defined in the present invention.
本发明的一些方案中，上述R1、R2分别独立地选自C1-3烷基或C1-3烯基，所述C1-3烷基和C1-3烯基任选被1、2或3个R取代，其余变量如本发明所定义。In some embodiments of the present invention, R 1 and R 2 are independently selected from C 1-3 alkyl or C 1-3 alkenyl, and the C 1-3 alkyl and C 1-3 alkenyl are optionally substituted by 1, 2 or 3 R, and the remaining variables are as defined in the present invention.
本发明的一些方案中，上述R1、R2分别独立地选自Me、其余变量如本发明所定义。In some embodiments of the present invention, the above R 1 and R 2 are independently selected from Me, The remaining variables are as defined in the present invention.
本发明的一些方案中，上述R1与R2连接在一起，形成环所述任选被1、2或3个R取代，其余变量如本发明所定义。In some embodiments of the present invention, the above R1 and R2 are connected together to form a ring Said It is optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined herein.
本发明的一些方案中，上述R1与R2连接在一起，形成环 其余变量如本发明所定义。In some embodiments of the present invention, the above R1 and R2 are connected together to form a ring The remaining variables are as defined in the present invention.
本发明的一些方案中，上述R3、R4、R5分别独立地选自H、CN、F、Cl、Br、OH、NH2、CN、C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、C3-6环烷基-O-、C3-6环烷基-S-、C3-6环烷基-NH-或氧杂环丙烷基-O-，所述C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、C2-3烯基-O-、C2-3烯基-S-、C2-3烯基-NH-、C3-6环烷基-O-、C3-6环烷基-S-、C3-6环烷基-NH-和氧杂环丙烷基-O-任选被1、2或3个R取代，其余变量如本发明所定义。In some embodiments of the present invention, the above R 3 , R 4 , and R 5 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-S-, C 1-3 alkyl-NH-, C 3-6 cycloalkyl-O-, C 3-6 cycloalkyl-S-, C 3-6 cycloalkyl-NH- or oxirane-O-; the C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-S-, C 1-3 alkyl-NH-, C 2-3 alkenyl-O-, C 2-3 alkenyl-S-, C 2-3 alkenyl-NH-, C 3-6 cycloalkyl-O-, C 3-6 cycloalkyl-S-, C 3-6 -cycloalkyl-NH- and oxirane-O- are optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined herein.
本发明的一些方案中，上述R3、R4、R5分别独立地选自H、CN、F、Cl、Br、OH、NH2、CN、Me、所述Me、 任选被1、2或3个R取代，其余变量如本发明所定义。In some embodiments of the present invention, R 3 , R 4 , and R 5 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, Me, The Me, It is optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined herein.
本发明的一些方案中，上述R3、R4、R5分别独立地选自H、CN、F、Cl、Br、OH、NH2、CN、Me、 其余变量如本发明所定义。In some embodiments of the present invention, R 3 , R 4 , and R 5 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, Me, The remaining variables are as defined in the present invention.
本发明的一些方案中，上述R8、R9分别独立地选自H、CN、F、Cl、Br、OH、NH2、Me或其余变量如本发明所定义。In some embodiments of the present invention, R 8 and R 9 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , Me or The remaining variables are as defined in the present invention.
本发明的一些方案中，上述R10选自H、Me、其余变量如本发明所定义。In some embodiments of the present invention, the above R 10 is selected from H, Me, The remaining variables are as defined in the present invention.
本发明的一些方案中，上述L2、L3分别独立地选自单键、-CH2-、-CH(CH3)-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-NH-、 其余变量如本发明所定义。In some embodiments of the present invention, L 2 and L 3 are independently selected from a single bond, -CH 2 -, -CH(CH 3 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) 2 -, -NH-, The remaining variables are as defined in the present invention.
本发明的一些方案中，上述L4选自-CH2-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-NH-、 其余变量如本发明所定义。In some embodiments of the present invention, the above L 4 is selected from -CH 2 -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) 2 -, -NH-, The remaining variables are as defined in the present invention.
本发明的一些方案中，上述环A选自苯基、吡啶基、嘧啶基、吡嗪基、噻唑基、噻吩基、恶唑基和哒嗪基，其余变量如本发明所定义。In some embodiments of the present invention, the ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, oxazolyl and pyridazinyl, and the remaining variables are as defined in the present invention.
本发明的一些方案中，上述结构单元选自 In some embodiments of the present invention, the structural unit Selected from
本发明的一些方案中，上述环B选自苯基、苯并环戊烷基、苯并环己烷基，其余变量如本发明所定义。In some embodiments of the present invention, the ring B is selected from phenyl, benzocyclopentyl, and benzocyclohexyl, and the remaining variables are as defined in the present invention.
本发明的一些方案中，上述结构单元选自 In some embodiments of the present invention, the structural unit Selected from
本发明的一些方案中，上述环C选自苯基、苯并环戊烷基、苯并环己烷基、1H-吲唑基、2H-吲唑基和1H-苯并[d]咪唑，其余变量如本发明所定义。In some embodiments of the present invention, the ring C is selected from phenyl, benzocyclopentyl, benzocyclohexyl, 1H-indazolyl, 2H-indazolyl and 1H-benzo[d]imidazole, and the remaining variables are as defined in the present invention.
本发明的一些方案中，上述结构单元选自 其余变量如本发明所定义。In some embodiments of the present invention, the structural unit Selected from The remaining variables are as defined in the present invention.
本发明还提供了下式化合物、其光学异构体及其药效上可接受的盐，其选自：


The present invention also provides the following compounds, their optical isomers and pharmaceutically acceptable salts thereof, which are selected from:


在本发明的再一方面，本发明还提出了前面所述化合物、其光学异构体或其药学上可接受的盐在制备治疗与雄激素受体(AR)活性或表达量相关疾病的药物中的用途。In another aspect of the present invention, the present invention also proposes the use of the aforementioned compound, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a disease associated with androgen receptor (AR) activity or expression.
本发明的一些方案中，上述雄激素受体(AR)活性或表达量相关疾病，其选自前列腺癌、卵巢癌、乳腺癌、膀胱癌、胰腺癌、子宫内膜癌、肝细胞癌、肾细胞癌、黑色素瘤、套细胞淋巴瘤、胶质母细胞瘤、唾液腺癌、脱发、痤疮、多毛症、卵巢囊肿、多囊卵巢疾病、性早熟、脊髓和延髓肌肉萎缩和年龄相关性黄斑病变。In some embodiments of the present invention, the above-mentioned androgen receptor (AR) activity or expression-related diseases are selected from prostate cancer, ovarian cancer, breast cancer, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, renal cell carcinoma, melanoma, mantle cell lymphoma, glioblastoma, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy and age-related macular degeneration.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.
如本发明中，采用的短语“至少一个”在提及一个或多个要素的列表时应理解为意指至少一个选自所述要素列表中的任一个或多个要素的要素，但不必包括所述要素列表内具体列出的每一个要素中的至少一者，并且不排除所述要素列表中的要素的任何组合。这个定义还允许，可以任选地存在除短语“至少一个”指代的所述要素列表内具体确定的要素以外的要素，不论与那些具体确定的要素相关还是不相关。As in the present invention, the phrase "at least one" used when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that there may be optionally elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基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、三氟乙酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as 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, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and 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 basic and acidic functional groups, and thus can be converted into any base or acid addition salt.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是:在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。 Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are prepared by reacting with a stoichiometric amount of an appropriate base or acid.
“药学上可接受的载体”是指此项技术中通常与治疗剂一起使用的无毒固体、半固体或液体填充剂、稀释剂、囊封材料、配制助剂或载体，其共同构成“药物组合物”以施用受试者。药学上可接受的载体在所用剂量和浓度下对接受者无毒且与配制物的其它成分相容。所述药学上可接受的载体适于所用配制物。"Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, formulation aid or carrier commonly used with therapeutic agents in the art, which together constitute a "pharmaceutical composition" for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration used and is compatible with the other ingredients of the formulation. The pharmaceutically acceptable carrier is suitable for the formulation used.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，可以选自 等。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，C1-6烷基羰基-指通过羰基与分子的其余部分连接的C1-6烷基。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如，卤素取代基，“-”可以被省略。A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, C1-6 alkylcarbonyl- refers to a C1-6 alkyl group that is attached to the rest of the molecule via a carbonyl group. However, when the point of attachment of a substituent is obvious to one skilled in the art, for example, a halogen substituent, the "-" may be omitted.
当基团价键上带有虚线时，例如在中，该虚线表示该基团与分子其它部分的连接点。When the group valence bond is marked with a dotted line When, for example, In the examples, the dashed line represents the point of attachment of the group to the rest of the molecule.
术语“被取代的”或“被…取代”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。术语“任选被取代的”或“任选被…取代”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" or "substituted by..." means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted by..." means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of chemical practicability.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被1、2或3个R’所取代，则所述基团可以任选地1个或2个或3个R’所取代，并且每种情况下的R’都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1, 2, or 3 R's, the group may be optionally substituted with 1 or 2 or 3 R's, and each occurrence of R' has an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如中L1代表单键时表示该结构实际上是 When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L 1 represents a single bond, it means that the structure is actually
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When the listed substituents do not specify through which atom they are bonded to the substituted group, such substituents may be bonded through any atom thereof. For example, a pyridyl substituent may be bonded to the substituted group through any carbon atom on the pyridine ring.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，中连接基团L为-CH2O-，此时-CH2O-既可以按与从左往右的读取顺序相同的方向连接苯基和环戊基构成也可以按照与从左往右的读取顺序相反的方向连接苯基和环戊基构成所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -CH 2 O-, in which case -CH 2 O- can connect phenyl and cyclopentyl in the same direction as the reading order from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
术语“卤素”表示氟、氯、溴、碘。The term "halogen" denotes fluorine, chlorine, bromine, iodine.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“3-6元环”是指环绕排列3-6个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, "3-6 membered ring" refers to a "ring" having 3-6 atoms arranged around it.
除非另有规定，术语“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C6和C5烷基等；其可以是一价(如CH3)、二价(-CH2-)或 者多价(如次)。C1-6烷基的实例包括但不限于CH3、 等。Unless otherwise specified, the term "C 1-6 alkyl" is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or The price is more (such as ). Examples of C 1-6 alkyl include, but are not limited to, CH 3 , wait.
除非另有规定，术语“C1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C1-4烷基包括C1-2、C1-3、C3-4和C2-3烷基等；其可以是一价(如CH3)、二价(-CH2-)或者多价(如次)。C1-4烷基的实例包括但不限于CH3、等。Unless otherwise specified, the term "C 1-4 alkyl" is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 alkyl group includes C 1-2 , C 1-3 , C 3-4 and C 2-3 alkyl groups, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or polyvalent (such as divalent ). Examples of C 1-4 alkyl groups include, but are not limited to, CH 3 , wait.
除非另有规定，“C2-6烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至6个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C2-6烯基包括C2-4、C2-3、C4、C3和C2烯基等；其可以是一价、二价或者多价。C2-6烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁间二烯基、戊间二烯基、己间二烯基等。Unless otherwise specified, " C2-6 alkenyl" is used to represent a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. The C2-6 alkenyl group includes C2-4 , C2-3 , C4 , C3 and C2 alkenyl, etc.; it may be monovalent, divalent or polyvalent. Examples of C2-6 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.
除非另有规定，“C2-3烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至3个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C2-3烯基包括C3和C2烯基；所述C2-3烯基可以是一价、二价或者多价。C2-3烯基的实例包括但不限于等。Unless otherwise specified, "C 2-3 alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group. The C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group can be monovalent, divalent or polyvalent. Examples of C 2-3 alkenyl groups include but are not limited to wait.
除非另有规定，“C2-6炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至6个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。其可以是一价、二价或者多价。所述C2-6炔基包括C2-3、C2-4、C2-5、C3-4、C3-5、C3-6、C4-5、C4-6、C5-6、C6、C5、C4、C3和C2炔基。C2-6炔基的实例包括但不限于等。Unless otherwise specified, "C 2-6 alkynyl" is used to represent a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-6 alkynyl group includes C 2-3 , C 2-4 , C 2-5, C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , C 5-6 , C 6 , C 5 , C 4 , C 3 and C 2 alkynyl groups. Examples of C 2-6 alkynyl groups include, but are not limited to wait.
除非另有规定，“C2-3炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至3个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。其可以是一价、二价或者多价。所述C2-3炔基包括C3和C2炔基。C2-3炔基的实例包括但不限于等。Unless otherwise specified, "C 2-3 alkynyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-3 alkynyl group includes C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl groups include, but are not limited to wait.
术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C1-6杂烷基；在另一些实施方案中，所述杂烷基为C1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“烷氧基”属于惯用表达，是指通过一个氧原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2、-CH2-CH2-O-CH3、-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)(CH2CH3)、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH(CH3)2、-CH2-S-CH2-CH3、-CH2-CH2-S-CH3、-S(＝O)-CH3、-CH2-CH2-S(＝O)2-CH3、和至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。The term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) 2 -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) 2 N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-3 heteroalkyl. The heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the term "alkoxy" is a customary expression to refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom. Examples of heteroalkyl groups include, but are not limited to , -OCH3 , -OCH2CH3 , -OCH2CH2CH3 , -OCH( CH3 ) 2 , -CH2 - CH2 -O- CH3 , -NHCH3 , -N(CH3) 2 , -NHCH2CH3 , -N( CH3 )( CH2CH3 ), -CH2 - CH2- NH -CH3, -CH2 - CH2 -N( CH3 ) -CH3 , -SCH3 , -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2 , -CH2 - S - CH2 - CH3 , -CH2 - CH2 -S- CH3 , -S(=O) -CH3 , -CH2 - CH2 -S(=O) 2 -CH 3 , and up to two heteroatoms may be consecutive, for example -CH 2 -NH-OCH 3 .
除非另有规定，术语“C1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷氧基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4和C3烷氧基等。C1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。Unless otherwise specified, the term "C 1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom. The C 1-6 alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc. Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyl and the like.
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-3、C1-2、C2-3、C1、C2和C3烷氧基等。C1-3烷氧基的实例包括 但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C 1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkoxy, etc. Examples of C 1-3 alkoxy include But it is not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
除非另有规定，术语“C1-6烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷氨基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4、C3和C2烷氨基等。C1-6烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-N(CH2CH3)(CH2CH3)、-NHCH2CH2CH3、-NHCH(CH3)2、-NHCH2CH2CH2CH3等。Unless otherwise specified, the term "C 1-6 alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amino group. The C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2, C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino groups, etc. Examples of C 1-6 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )(CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 , and the like.
除非另有规定，术语“C1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氨基包括C1-3、C1-2、C2-3、C1、C2和C3烷氨基等。C1-3烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-NHCH2CH2CH3、-NHCH(CH3)2等。Unless otherwise specified, the term "C 1-3 alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group. The C 1-3 alkylamino group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylamino groups, etc. Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , etc.
除非另有规定，术语“C1-6烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷硫基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4、C3和C2烷硫基等。C1-6烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH(CH3)2等等。Unless otherwise specified, the term "C 1-6 alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through a sulfur atom. The C 1-6 alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylthio, etc. Examples of C 1-6 alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH(CH 3 ) 2 , and the like.
除非另有规定，术语“C1-3烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷硫基包括C1-3、C1-2、C2-3、C1、C2和C3烷硫基等。C1-3烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH(CH3)2等。Unless otherwise specified, the term "C 1-3 alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through a sulfur atom. The C 1-3 alkylthio group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylthio groups, etc. Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH(CH 3 ) 2 , etc.
除非另有规定，“C3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C3-6环烷基包括C3-5、C4-5和C5-6环烷基等；其可以是一价、二价或者多价。C3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。Unless otherwise specified, "C 3-6 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
除非另有规定，术语“3-10元杂环基”本身或者与其他术语联合分别表示由3至10个环原子组成的饱和或部分不饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫原子可独立任选被氧化(即C＝O、NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-10元杂环基”而言，杂原子可以占据杂环基与分子其余部分的连接位置。所述3-10元杂环基包括3-8元、3-7元、3-6元、3-5元、3-4元、4-5元、4-6元、4-7元、4-8元、4-9元、5-6元、5-7元、5-8元、5-9元、5-10元、6-7元、6-8元、6-9元、6-10元、7-8元、3元、4元、5元、6元、7元、8元、9元、10杂环基等。3-9元杂环基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、1,3-二氧戊烷、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。Unless otherwise specified, the term "3-10 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur atoms are independently optionally oxidized (i.e., C=O, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-10 membered heterocyclyl", heteroatoms may occupy the position at which the heterocyclyl is connected to the rest of the molecule. The 3-10 membered heterocyclic group includes 3-8 membered, 3-7 membered, 3-6 membered, 3-5 membered, 3-4 membered, 4-5 membered, 4-6 membered, 4-7 membered, 4-8 membered, 4-9 membered, 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 5-10 membered, 6-7 membered, 6-8 membered, 6-9 membered, 6-10 membered, 7-8 membered, 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heterocyclic groups, etc. Examples of 3-9 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.
除非另有规定，术语“5-6元杂环基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和或部分不饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-6元杂环基”而言，杂原子可以占据杂环基与分子其余部分的连接位置。所述5-6元杂环基包括5元和6元杂环基等。5-6元杂环基的实例包括但不限于1,3-二氧戊烷、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "5-6 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "5-6 membered heterocyclyl", heteroatoms may occupy the position where the heterocyclyl is connected to the rest of the molecule. The 5-6 membered heterocyclyl includes 5-membered and 6-membered heterocyclyls, etc. Examples of 5-6 membered heterocyclyls include, but are not limited to, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably. The term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定，术语“C6-10芳基”本身或者与其他术语联合分别表示具有六至十个碳原子的单环或双环芳族环系统。非限制性例示性芳基包括苯基(缩写为“Ph”)、萘基。Unless otherwise specified, the term "C 6-10 aryl" by itself or in combination with other terms , respectively, means a monocyclic or bicyclic aromatic ring system having six to ten carbon atoms. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl.
除非另有规定，术语“环烯基”是指不完全饱和的并且可以以呈单环、桥环或螺环存在的非芳族碳环。除非另有指示，该碳环通常为5至8元环。环烯基的非限制性实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基等。Unless otherwise specified, the term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 5 to 8 membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.
除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12，也包括n至n+m中的任何一个范围，例如C1-12包括C1-3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、5-10元环、6-7元环、6-8元环、6-9元环和6-10元环等。Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9, C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 . 9-12 , etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring and 6-10-membered ring, etc.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.
本发明所公开化合物可能有一个或多个手性中心，每个手性中心各自独立的具有R构型或者S构型，或者顺式Cis-构型，或者反式Trans-构型。本发明所公开部分化合物手性中心标记为*R，*S，R*，S*，*Cis-，或者*Trans-，表示该化合物该手性中心绝对构型未经鉴定，但是该化合物已经过分离或手性拆分且该手性中心为单一构型的手性中心，该化合物为单一构型对映异构体单体，或单一构型的非对映异构体单体，或该手性中心构型单一的非对映异构体混合物(例如:其它手性中心构型未被拆分)，或单一构型单体(例如，单一顺式构型单体，或者单一反式构型单体)。当本发明所公开化合物手性中心其绝对构型(R构型，S构型，Cis-构型，或者Trans-构型)未经鉴定时，该类化合物可根据其在相应核磁共振(1H-NMR,31P-NMR) 谱图中峰型，或相应色谱柱条件下(例如色谱柱型号，色谱柱填充物，色谱柱尺寸，流动相等)所对应保留时间(RT或Rt)予以确认。The compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration, or a cis-Cis-configuration, or a trans-Trans-configuration. The chiral centers of some compounds disclosed in the present invention are marked as *R, *S, R*, S*, *Cis-, or *Trans-, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been separated or chirally resolved and the chiral center is a chiral center of a single configuration, the compound is a single-configuration enantiomer monomer, or a single-configuration diastereoisomer monomer, or a diastereoisomer mixture with a single configuration of the chiral center (for example: the configuration of other chiral centers has not been resolved), or a single-configuration monomer (for example, a single cis-configuration monomer, or a single trans-configuration monomer). When the absolute configuration (R configuration, S configuration, Cis-configuration, or Trans-configuration) of the chiral center of the compounds disclosed in the present invention is not identified, the compounds can be identified based on their corresponding nuclear magnetic resonance ( 1 H-NMR, 31 P-NMR) The peak shape in the spectrum or the corresponding retention time (RT or Rt) under the corresponding chromatographic column conditions (such as chromatographic column model, chromatographic column filling material, chromatographic column size, mobile phase, etc.) is confirmed.
在下述实施例中更具体地解释本发明。然而，应当理解，这些实施例是为了举例说明本发明，而并不是以任何方式限制本发明的范围。下列实施例中如未注明具体条件的实验方法，通常按照这类反应的常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。除非另外说明，否则液体的比为体积比。The present invention is explained in more detail in the following examples. However, it should be understood that these examples are for illustrating the present invention and are not intended to limit the scope of the present invention in any way. The experimental methods in the following examples, if no specific conditions are specified, are usually based on the conventional conditions of this type of reaction, or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts. Unless otherwise stated, the ratio of liquid is volume ratio.
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
具体实施方式Detailed ways
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请,其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。The present application is described in detail below by way of examples, but this does not mean that there are any adverse limitations to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.
所有实施例中，1H NMR，13C NMR、19F NMR和31P NMR谱图使用Bruker Ascend 400mHz核磁共振仪记录，使用Topspin软件处理谱图，氘代溶剂作为内部氘锁。其中13C NMR、19F NMR和31P NMR对1H去耦。根据明确的化学位移/耦合模式，或根据2D Cosy，HMBC，HSQC或NOESY实验进行分配。峰的多重性定义为:s单重峰、d双重峰、t三重峰、q四重峰、m多重峰、br宽峰、br.s宽单重峰；耦合常数(J)精确到0.1Hz。质谱是用Agilent 1260(ESI)型或Shimadzu LC-MS-2020(ESI型)或Agilent 6215(ESI)型质谱仪记录的；反相制备型HPLC分离是用Agilent 1290紫外引导的全自动纯化系统(Prep C18 OBDTM 21.2*250mm 10μm柱)或用Gilson GX281紫外引导的全自动纯化系统(Prep C18 OBDTM 19*250mm 10μm柱)或Waters QDa引导的全自动纯化系统(Prep C18 OBD 29*250mm 10μm柱)进行的。除非另外指定，分离用SepaFlash预装正相硅胶柱(国药集团化学试剂有限公司)，TLC分析板(烟台江友硅胶开发有限公司，型号:HSGF254，规格:2.5×5cm)，洗脱液的配比均为体积比。In all examples, 1 H NMR, 13 C NMR, 19 F NMR and 31 P NMR spectra were recorded using a Bruker Ascend 400 MHz NMR instrument, and the spectra were processed using Topspin software, with deuterated solvents as internal deuterium locks. 13 C NMR, 19 F NMR and 31 P NMR were decoupled from 1 H. Assignments were made based on clear chemical shift/coupling patterns, or based on 2D Cosy, HMBC, HSQC or NOESY experiments. Peak multiplicity was defined as: s singlet, d doublet, t triplet, q quartet, m multiplet, br broad, br.s broad singlet; coupling constants (J) were accurate to 0.1 Hz. Mass spectra were recorded using an Agilent 1260 (ESI) or Shimadzu LC-MS-2020 (ESI) or Agilent 6215 (ESI) mass spectrometer; reversed-phase preparative HPLC separations were performed using an Agilent 1290 UV-guided fully automated purification system ( Prep C18 OBDTM 21.2*250mm 10μm column) or Gilson GX281 UV-guided automatic purification system ( Prep C18 OBDTM 19*250mm 10μm column) or Waters QDa-guided fully automated purification system ( Prep C18 OBD 29*250mm 10μm column). Unless otherwise specified, separation was performed using SepaFlash pre-packed normal phase silica gel column (Sinopharm Chemical Reagent Co., Ltd.), TLC analysis plate (Yantai Jiangyou Silica Gel Development Co., Ltd., model: HSGF254, specification: 2.5×5cm), and the ratio of eluent was volume ratio.
其中，化学式或英文字母缩写代表的试剂中文名称如下：Among them, the Chinese names of the reagents represented by chemical formulas or English abbreviations are as follows:
CD3OD代表氘代甲醇；DMSO-d6代表氘代二甲亚砜；Chloroform-d或CDCl3代表氘代氯仿；AcOH代表醋酸；AlCl3代表三氯化铝；Aq代表水溶液；N2代表氮气；Ar代表氩气；B2Pin2代表联硼酸频那醇酯；BBr3代表三溴化硼；BH3代表硼烷；(Boc)2O代表二碳酸二叔丁酯；Et3SiH代表三乙基硅烷；HATU代表1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐；HOBt代表1-羟基苯并三唑；K2CO3代表碳酸钾；KOAc代表醋酸钾；MeONa代表甲醇钠；LDA代表二异丙基氨基锂；LiHMDS代表双(三甲基硅基)胺基锂；LiOH代表氢氧化锂；m-CPBA代表间氯过氧苯甲酸；Na2CO3代表碳酸钠；NaBH4代表硼氢化钠；NaCl代表氯化钠；NaHCO3代表碳酸氢钠；NaOH代表氢氧化钠；Na2SO4代表硫酸钠；NBS代表N-溴代丁二酰亚胺；NCS代表N-氯代丁二酰亚胺；NIS代表N-碘代丁二酰亚胺；n-BuLi代表正丁基锂；NH4Cl代表氯化铵；NMP代表N-甲基-2-吡咯烷酮；PBr3代表三溴化磷；Pd(dppf)Cl2或PdCl2(dppf)代表1,1’-双(二苯基膦基)二茂铁二氯化钯；Pd2(dba)3代表三(二亚苄基丙酮)二钯(0)；Pd(OAc)2代表醋酸钯；conc.代表浓；(COCl)2代表草酰氯；Cs2CO3代表碳酸铯；CuCl代表氯化亚铜；CuI代表碘化亚铜；DCM代表二氯甲烷；Dioxane或1,4-dioxane代表1,4-二氧六环；MeCN,ACN或CH3CN代表乙腈；MeOH或methanol代表甲醇；EtOH或ethanol代表乙醇；DEA代表二乙胺；DIPEA或DIEA代表N,N-二异丙基乙胺；DIAD代表偶氮二甲酸二异丙酯；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；DMAP代表4-二甲氨基吡啶；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲基亚砜；EA或EtOAc代表乙酸乙酯；PE代表石油醚；THF代表四氢呋喃；Toluene或tol.代表甲苯；SOCl2代表二氯亚砜；TFA代表三氟乙酸；FA代表甲酸；TMSCN代表三甲基硅氰；H2O代表水；HCl代表氯化氢气体；HCl aq.代表盐酸水溶液；℃代表摄氏度；rt或RT代表室温；h代表小时；min代表分钟；g代表克；mg代表毫克；mL代表毫升；mmol代 表毫摩尔；M代表摩尔；cm代表厘米；mm代表毫米；μm代表微米；nm代表纳米；mL/min代表毫升每分钟；Hz代表赫兹；MHz代表兆赫兹；bar代表压力单位巴；psi代表压力单位磅每平方英寸；N2代表氮气；HPLC代表高效液相色谱法；I.D.代表内径；LCMS或LC-MS代表液相色谱法-质谱法联用；m/z代表质荷比；ESI代表电喷雾电离；CO2代表二氧化碳；TLC代表薄层色谱法；UV代表紫外；IV代表静脉注射；PO代表口服；rpm代表转每分钟；ATCC代表美国菌种保藏中心(American type culture collection)。CD 3 OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; Chloroform-d or CDCl 3 represents deuterated chloroform; AcOH represents acetic acid; AlCl 3 represents aluminum chloride; Aq represents aqueous solution; N 2 represents nitrogen; Ar represents argon; B 2 Pin 2 represents diboronic acid pinacol ester; BBr 3 represents boron tribromide; BH 3 represents borane; (Boc) 2 O represents di-tert-butyl dicarbonate; Et 3 SiH represents triethylsilane; HATU represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HOBt represents 1-hydroxybenzotriazole; K 2 CO 3 represents potassium carbonate; KOAc represents potassium acetate; MeONa represents sodium methoxide; LDA represents lithium diisopropylamide; LiHMDS represents lithium bis(trimethylsilyl)amide; LiOH represents lithium hydroxide; m-CPBA represents m-chloroperbenzoic acid; Na 2 CO 3 represents sodium carbonate; NaBH 4 represents sodium borohydride; NaCl represents sodium chloride; NaHCO 3 represents sodium bicarbonate; NaOH represents sodium hydroxide; Na 2 SO 4 represents sodium sulfate; NBS represents N-bromosuccinimide; NCS represents N-chlorosuccinimide; NIS represents N-iodosuccinimide; n-BuLi represents n-butyllithium; NH 4 Cl represents ammonium chloride; NMP represents N-methyl-2-pyrrolidone; PBr 3 represents phosphorus tribromide; Pd(dppf)Cl 2 or PdCl 2 (dppf) represents 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; Pd 2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium(0); Pd(OAc) 2 represents palladium acetate; conc. represents concentrated; (COCl) 2 represents oxalyl chloride; Cs 2 CO 3 represents cesium carbonate; CuCl represents cuprous chloride; CuI represents cuprous iodide; DCM represents dichloromethane; Dioxane or 1,4-dioxane represents 1,4-dioxane; MeCN, ACN or CH 3 CN represents acetonitrile; MeOH or methanol represents methanol; EtOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N,N-diisopropylethylamine; DIAD represents diisopropyl azodicarboxylate; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc represents ethyl acetate; PE represents petroleum ether; THF represents tetrahydrofuran; Toluene or tol. represents toluene; SOCl 2 represents dichlorothionyl; TFA represents trifluoroacetic acid; FA represents formic acid; TMSCN represents trimethylsilyl cyanide; H 2 O represents water; HCl represents hydrogen chloride gas; HCl aq. represents aqueous hydrochloric acid; ℃ represents degrees Celsius; rt or RT represents room temperature; h represents hours; min represents minutes; g represents grams; mg represents milligrams; mL represents milliliters; mmol represents stands for millimolar; M stands for molar; cm stands for centimeter; mm stands for millimeter; μm stands for micrometer; nm stands for nanometer; mL/min stands for milliliter per minute; Hz stands for hertz; MHz stands for megahertz; bar stands for bar; psi stands for pounds per square inch; N2 stands for nitrogen; HPLC stands for high performance liquid chromatography; ID stands for inner diameter; LCMS or LC-MS stands for liquid chromatography-mass spectrometry; m/z stands for mass-to-charge ratio; ESI stands for electrospray ionization; CO2 stands for carbon dioxide; TLC stands for thin layer chromatography; UV stands for ultraviolet; IV stands for intravenous; PO stands for oral; rpm stands for revolutions per minute; ATCC stands for American type culture collection.
实施例1：化合物1的制备
Example 1: Preparation of Compound 1
化合物1-2的制备Preparation of compound 1-2
将化合物1-1(120.0g，643.1mmol)溶于MeCN(1.2L)中，冰水浴降温至0℃，加入对甲苯磺酸一水合物(122.2g，643.1mmol)并在该温度下搅拌30分钟；随后加入NIS(173.6g，771.1mmol)，加毕，撤去冰水浴，反应体系在室温下搅拌16h。反应体系中加入亚硫酸钠淬灭反应，加水(3L)，乙酸乙酯萃取(2L×2)，饱和食盐水(2L×3)洗涤有机相，无水硫酸钠干燥，浓缩有机相并经正相硅胶层析柱(EA/PE＝0-30％)纯化得到标题化合物1-2(168.0g，白色固体，收率84％)。Compound 1-1 (120.0 g, 643.1 mmol) was dissolved in MeCN (1.2 L), cooled to 0°C in an ice-water bath, p-toluenesulfonic acid monohydrate (122.2 g, 643.1 mmol) was added and stirred at this temperature for 30 minutes; NIS (173.6 g, 771.1 mmol) was then added, and the ice-water bath was removed after the addition, and the reaction system was stirred at room temperature for 16 h. Sodium sulfite was added to the reaction system to quench the reaction, water (3 L) was added, ethyl acetate was extracted (2 L × 2), the organic phase was washed with saturated brine (2 L × 3), dried over anhydrous sodium sulfate, the organic phase was concentrated and purified by normal phase silica gel chromatography (EA/PE = 0-30%) to obtain the title compound 1-2 (168.0 g, white solid, yield 84%).
化合物1-3的制备Preparation of Compound 1-3
将化合物1-2(163.0g，0.52mol)溶于DMF(800mL)中，依次加入碳酸铯(338.9g,1.04mol)、化合物1-溴-2-氯乙烷(149.1g，1.04mol)和H2O(12mL)，升温至65℃反应16h。反应结束，过滤，滤液中加入水(3L),乙酸乙酯萃取(2L×2)，饱和食盐水(2L×3)洗涤有机相，无水硫酸钠干燥，浓缩有机相并经正相硅胶层析柱(EA/PE＝0-30％)纯化得到标题化合物1-3(136.9g，白色固体，收率70％)。Compound 1-2 (163.0 g, 0.52 mol) was dissolved in DMF (800 mL), and cesium carbonate (338.9 g, 1.04 mol), compound 1-bromo-2-chloroethane (149.1 g, 1.04 mol) and H 2 O (12 mL) were added in sequence, and the temperature was raised to 65°C for reaction for 16 h. After the reaction was completed, the mixture was filtered, and water (3 L) was added to the filtrate, and the mixture was extracted with ethyl acetate (2 L × 2). The organic phase was washed with saturated brine (2 L × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by normal phase silica gel chromatography (EA/PE = 0-30%) to obtain the title compound 1-3 (136.9 g, white solid, yield 70%).
化合物1-4的制备Preparation of Compound 1-4
将化合1-3(168.0g，448.0mmol)溶于DMF(1L)，加入CuCN(100.3g，1120.0mmol)和CuI(73.1g，385.4mmol)并升温至140℃反应4小时。TLC(PE/EA＝5/1，产物Rf≈0.5)监测反应结束，薄层硅藻土过滤，乙酸乙酯淋洗滤饼。收集滤液并加入水(4L)，乙酸乙酯萃取(3L×2)，有机相用饱和盐水洗涤(2L×3)、无水硫酸钠干燥，浓缩有机相并经正相硅胶层析柱(EA/PE＝0-20％)纯化得到标题化合物1-4(66.7g，白色固体，收率54％)。1H NMR(400MHz,CDCl3)δ8.46(d,J＝5.1Hz,1H),6.93(d,J＝5.0Hz,1H),5.32(s,2H),2.51(s,3H),2.05(s,2H)。Compound 1-3 (168.0 g, 448.0 mmol) was dissolved in DMF (1 L), CuCN (100.3 g, 1120.0 mmol) and CuI (73.1 g, 385.4 mmol) were added and the temperature was raised to 140°C for 4 hours. The reaction was monitored by TLC (PE/EA=5/1, product Rf≈0.5), filtered through a thin layer of diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was collected and added with water (4 L), extracted with ethyl acetate (3 L×2), the organic phase was washed with saturated brine (2 L×3), dried over anhydrous sodium sulfate, the organic phase was concentrated and purified by normal phase silica gel chromatography (EA/PE=0-20%) to obtain the title compound 1-4 (66.7 g, white solid, yield 54%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (d, J=5.1 Hz, 1H), 6.93 (d, J=5.0 Hz, 1H), 5.32 (s, 2H), 2.51 (s, 3H), 2.05 (s, 2H).
化合物1-5的制备Preparation of Compound 1-5
将化合物1-4(5g,18mmol)加入三口瓶中，氮气置换三次，加入无水四氢呋喃(20mL)，并在-10℃下滴加甲基溴化镁(3.0M，18mL，54mmol)。反应体系在0℃下搅拌反应2小时，反应结束。在冰浴下向反应体系缓慢加入饱和氯化铵水溶液(50mL)，EtOAc(50mL×3)萃取。有机相合并，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥并浓缩有机相得粗产品，硅胶柱层析(EtOAc/PE＝0-20％)分离纯化得到标题化合物1-5(3g，浅黄色液体，收率60％)。1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝2.2Hz,1H),7.83(d, J＝2.2Hz,1H),5.37(s,1H),4.43(t,J＝4.0Hz,2H),3.97(t,J＝4.0Hz,2H),1.43(s,6H)。Compound 1-4 (5 g, 18 mmol) was added to a three-necked flask, replaced with nitrogen three times, anhydrous tetrahydrofuran (20 mL) was added, and methylmagnesium bromide (3.0 M, 18 mL, 54 mmol) was added dropwise at -10°C. The reaction system was stirred at 0°C for 2 hours, and the reaction was completed. Saturated aqueous ammonium chloride solution (50 mL) was slowly added to the reaction system under an ice bath, and extracted with EtOAc (50 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried with anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (EtOAc/PE＝0-20%) to obtain the title compound 1-5 (3 g, light yellow liquid, yield 60%). 1 H NMR (400 MHz, DMSO-d6) δ7.90 (d, J＝2.2 Hz, 1H), 7.83 (d, J＝2.2 Hz, 1H), 5.37(s, 1H), 4.43(t, J＝4.0 Hz, 2H), 3.97(t, J＝4.0 Hz, 2H), 1.43(s, 6H).
化合物1-6的制备Preparation of Compound 1-6
将化合物1-5(3g,10.9mmol)加入三口瓶中，依次加入无水THF(30mL)、苯酚(3g，32.8mmol)，在0℃下加入三氟化硼乙醚溶液(9.71g，32.8mmol)。反应体系在0℃下搅拌反应3小时。反应结束后，缓慢加入冰水(20mL)淬灭反应，EtOAc(30mL×3)萃取，合并有机相，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥、浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物1-6(2.3g，浅黄色液体，收率57％)。1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),7.61(d,J＝2.2Hz,1H),7.54(d,J＝2.2Hz,1H),7.04(d,J＝8.6Hz,2H),6.69(d,J＝8.6Hz,2H),4.41(t,J＝4.0Hz,2H),3.95(t,J＝4.0Hz 2H),1.60(s,6H)。Compound 1-5 (3 g, 10.9 mmol) was added to a three-necked flask, followed by anhydrous THF (30 mL) and phenol (3 g, 32.8 mmol), and then a boron trifluoride ether solution (9.71 g, 32.8 mmol) was added at 0°C. The reaction system was stirred at 0°C for 3 hours. After the reaction was completed, ice water (20 mL) was slowly added to quench the reaction, and EtOAc (30 mL × 3) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-20%) to obtain the title compound 1-6 (2.3 g, light yellow liquid, yield 57%). 1 H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.04 (d, J=8.6 Hz, 2H), 6.69 (d, J=8.6 Hz, 2H), 4.41 (t, J=4.0 Hz, 2H), 3.95 (t, J=4.0 Hz 2H), 1.60 (s, 6H).
化合物1-7的制备Preparation of Compound 1-7
将化合物1-6(1.5g，4.3mmol)加入单口瓶中，依次加入DMF(5mL)、无水碳酸钾(1.2g，8.6mmol)和2-氯-4-(氯甲基)嘧啶(700mg，4.3mmol)，反应体系搅拌1小时。待反应结束后，反应体系中加水(10mL)淬灭反应，EtOAc(20mL×3)萃取，合并有机相，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥、浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到标题化合物1-7(1.8g，白色固体，收率88％)。LC-MS(ESI):m/z 476.0[M+H]+。Compound 1-6 (1.5 g, 4.3 mmol) was added to a single-mouth bottle, and DMF (5 mL), anhydrous potassium carbonate (1.2 g, 8.6 mmol) and 2-chloro-4-(chloromethyl)pyrimidine (700 mg, 4.3 mmol) were added in sequence, and the reaction system was stirred for 1 hour. After the reaction was completed, water (10 mL) was added to the reaction system to quench the reaction, and EtOAc (20 mL × 3) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-30%) to obtain the title compound 1-7 (1.8 g, white solid, yield 88%). LC-MS (ESI): m/z 476.0 [M+H] + .
化合物1的制备Preparation of compound 1
将化合物1-7(300mg，0.63mmol)溶解于DMF(5.0mL)中，依次加入二甲基氧化膦(245mg，3.2mmol)、三乙胺(191mg，1.9mmol)、三(二亚苄基丙酮)二钯(115mg，0.13mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(73mg，0.13mmol)。反应体系用氮气置换三次，在120℃下微波搅拌反应2小时。反应结束后，滤除不溶性固体，滤液加水(10mL)，二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥、浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物1(45mg，收率14％)。LC-MS(ESI):m/z 518.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝5.1Hz,1H),7.71(dd,J＝5.2,3.2Hz,1H),7.64(d,J＝2.3Hz,1H),7.57(d,J＝2.3Hz,1H),7.20(d,J＝8.9Hz,2H),7.00(d,J＝8.9Hz,2H),5.28(s,2H),4.52–4.34(m,2H),4.05–3.86(m,2H),1.76(d,J＝13.7Hz,6H),1.63(s,6H)；31P NMR(162MHz,DMSO-d6)δ34.00(s,1P)。Compound 1-7 (300 mg, 0.63 mmol) was dissolved in DMF (5.0 mL), and dimethylphosphine oxide (245 mg, 3.2 mmol), triethylamine (191 mg, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (115 mg, 0.13 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (73 mg, 0.13 mmol) were added in sequence. The reaction system was replaced with nitrogen three times, and the reaction was stirred in a microwave at 120° C. for 2 hours. After the reaction, the insoluble solid was filtered off, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 1 (45 mg, yield 14%). LC-MS (ESI): m/z 518.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ8.99 (d, J=5.1 Hz, 1H), 7.71 (dd, J=5.2, 3.2 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.20 (d, J=8.9 Hz, 2H), 7.00 (d, J=8.9 Hz, 2H), 5.28 (s, 2H), 4.52–4.34 (m, 2H), 4.05–3.86 (m, 2H), 1.76 (d, J=13.7 Hz, 6H), 1.63 (s, 6H); 31 P NMR (162 MHz, DMSO-d6) δ34.00 (s, 1P).
实施例2：化合物2的制备
Example 2: Preparation of Compound 2
化合物2-1的制备Preparation of compound 2-1
将化合物1-5(1g，3.65mmol)和化合物2-碘苯酚(1.61g，7.3mmol)溶于无水二氯甲烷(20mL)中，0℃下缓慢滴加三氟化硼乙醚溶液(48％，1.93mL，7.3mmol)，滴毕，室温反应2小时。LCMS跟踪反应至完全后加水淬灭，反应体系用DCM(50mL×2)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到标题化合物2-1(180mg)，收率10％。LC-MS(ESI):m/z 474.4[M-H]-。 Compound 1-5 (1 g, 3.65 mmol) and compound 2-iodophenol (1.61 g, 7.3 mmol) were dissolved in anhydrous dichloromethane (20 mL), and a boron trifluoride ether solution (48%, 1.93 mL, 7.3 mmol) was slowly added dropwise at 0°C. After the addition, the mixture was reacted at room temperature for 2 hours. LCMS was used to track the reaction until it was complete and then water was added to quench the reaction. The reaction system was extracted with DCM (50 mL × 2), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-30%) to obtain the title compound 2-1 (180 mg) with a yield of 10%. LC-MS (ESI): m/z 474.4 [MH] - .
化合物2-2的制备Preparation of compound 2-2
将化合物2-1(170mg，0.36mmol)和氰化亚铜(128mg，1.43mmol)溶于DMF(5mL)中，氮气置换三次后微波120℃反应2小时。LCMS跟踪反应至完全后，加水，用EtOAc(50mL×2)萃取，合并有机相，干燥浓缩得到标题化合物2-2的粗品130mg，直接用于下一步。LC-MS(ESI):m/z 373.0[M-H]-。Compound 2-1 (170 mg, 0.36 mmol) and cuprous cyanide (128 mg, 1.43 mmol) were dissolved in DMF (5 mL), replaced with nitrogen three times, and then microwaved at 120°C for 2 hours. After the reaction was complete as tracked by LCMS, water was added, and the mixture was extracted with EtOAc (50 mL×2). The organic phases were combined, dried, and concentrated to obtain 130 mg of the crude product of the title compound 2-2, which was used directly in the next step. LC-MS (ESI): m/z 373.0 [MH] - .
化合物2-3的制备Preparation of compound 2-3
将化合物2-2(130mg，0.35mmol)、化合物(2-氯嘧啶-4-基)甲醇(100mg，0.69mmol)和三苯基膦(273mg，1mmol)溶于无水四氢呋喃(8mL)中，室温下缓慢滴加偶氮二甲酸二乙酯(181mg，1mmol)，滴毕50℃反应4小时。LCMS跟踪反应至完全后，加水，反应体系用EtOAc(50mL×2)萃取，合并有机相，干燥浓缩得到标题化合物2-3的粗品150mg，直接用于下一步。LC-MS(ESI):m/z 501.0[M+H]+。Compound 2-2 (130 mg, 0.35 mmol), compound (2-chloropyrimidin-4-yl)methanol (100 mg, 0.69 mmol) and triphenylphosphine (273 mg, 1 mmol) were dissolved in anhydrous tetrahydrofuran (8 mL), and diethyl azodicarboxylate (181 mg, 1 mmol) was slowly added dropwise at room temperature, and the mixture was reacted at 50°C for 4 hours. After the reaction was completed by LCMS tracking, water was added, and the reaction system was extracted with EtOAc (50 mL×2), and the organic phases were combined, dried and concentrated to obtain 150 mg of a crude product of the title compound 2-3, which was directly used in the next step. LC-MS (ESI): m/z 501.0 [M+H] + .
化合物2的制备Preparation of compound 2
将化合物2-3(150mg，0.3mmol)溶解于DMF(8.0mL)中，依次加入二甲基氧化膦(70mg，0.9mmol)、三乙胺(91mg，0.9mmol)、Pd2(dba)3(27mg，0.03mmol)和Xantphos(35mg，0.06mmol)。用氮气置换三次后微波100℃下反应2小时。LCMS跟踪反应至完全后反应液过滤，滤液粗品经制备分离纯化(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)得到标题化合物2(25mg，收率15％)。LC-MS(ESI):m/z 543.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.05(d,J＝5.2Hz,1H),7.76–7.69(m,2H),7.70–7.62(m,2H),7.49(dd,J＝9.0,2.6Hz,1H),7.25(d,J＝9.0Hz,1H),5.49(s,2H),4.42(t,J＝6.2Hz,2H),3.96(t,J＝6.2Hz,2H),1.73(d,J＝13.6Hz,6H),1.66(s,6H).31P NMR(162MHz,DMSO-d6)δ34.01(s,1P)。Compound 2-3 (150 mg, 0.3 mmol) was dissolved in DMF (8.0 mL), and dimethylphosphine oxide (70 mg, 0.9 mmol), triethylamine (91 mg, 0.9 mmol), Pd 2 (dba) 3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. After nitrogen replacement three times, the mixture was reacted at 100°C in a microwave oven for 2 hours. After the reaction was completed by LCMS tracking, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 2 (25 mg, yield 15%). LC-MS (ESI): m/z 543.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.05 (d, J=5.2 Hz, 1H), 7.76–7.69 (m, 2H), 7.70–7.62 (m, 2H), 7.49 (dd, J=9.0, 2.6 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 5.49 (s, 2H), 4.42 (t, J=6.2 Hz, 2H), 3.96 (t, J=6.2 Hz, 2H), 1.73 (d, J=13.6 Hz, 6H), 1.66 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ34.01 (s, 1P).
实施例3：化合物3的制备
Example 3: Preparation of Compound 3
化合物3-1的制备Preparation of compound 3-1
将化合物1-5(300mg，1.1mmol)加入三口瓶中，再加入5,6,7,8-四氢-1-萘酚(486mg，3.3mmol)、无水二氯甲烷(10mL)，氮气置换三次后，在0℃冷却温度下逐滴加入三氟化硼乙醚溶液(48％，620mg，2.2mmol)。反应体系在0℃下搅拌反应2小时。反应结束后，加水淬灭反应，用二氯甲烷(50mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物3-1(200mg)，收率45％。1H NMR(400MHz,Chloroform-d)δ7.48(d,J＝2.4Hz,1H),7.33(d,J＝2.3Hz,1H),7.19(d,J＝8.0Hz,1H),6.74(d,J＝8.0Hz,1H),4.40(t,J＝6.3Hz,2H),3.87(t,J＝6.3Hz,2H),2.77(t,J＝6.2Hz,2H),2.44(t,J＝6.3Hz,2H),1.90–1.81(m,2H),1.76(dq,J＝5.2,3.0,2.2Hz,2H),1.65(s,6H)。Compound 1-5 (300 mg, 1.1 mmol) was added to a three-necked flask, and then 5,6,7,8-tetrahydro-1-naphthol (486 mg, 3.3 mmol) and anhydrous dichloromethane (10 mL) were added. After nitrogen replacement three times, a boron trifluoride ether solution (48%, 620 mg, 2.2 mmol) was added dropwise at a cooling temperature of 0°C. The reaction system was stirred at 0°C for 2 hours. After the reaction was completed, water was added to quench the reaction, and dichloromethane (50 mL × 3) was used for extraction. The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-20%) to obtain the title compound 3-1 (200 mg) with a yield of 45%. 1 H NMR (400 MHz, Chloroform-d) δ7.48 (d, J=2.4 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 4.40 (t, J=6.3 Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 2.77 (t, J=6.2 Hz, 2H), 2.44 (t, J=6.3 Hz, 2H), 1.90–1.81 (m, 2H), 1.76 (dq, J=5.2, 3.0, 2.2 Hz, 2H), 1.65 (s, 6H).
化合物3-2的制备Preparation of compound 3-2
将化合物3-1(200mg，0.5mmol)加入三口瓶中，依次加入无水DCM(10mL)，(2-甲硫基嘧啶-4-基)甲醇(155mg，1.0mmol)，三苯基膦(260mg，1.0mmol)，用氮气替换三次，在0℃下加入偶氮二甲酸二异丙酯(200mg，1.0mmol)。反应在25℃下搅拌反应16小时。反应结束后，加水(30mL)，用EtOAc(30mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物3-2(100mg)，收率38％。LC-MS(ESI):542.3[M+H]+。 Compound 3-1 (200 mg, 0.5 mmol) was added to a three-necked flask, followed by anhydrous DCM (10 mL), (2-methylthiopyrimidin-4-yl)methanol (155 mg, 1.0 mmol), triphenylphosphine (260 mg, 1.0 mmol), replaced with nitrogen three times, and diisopropyl azodicarboxylate (200 mg, 1.0 mmol) was added at 0°C. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-20%) to obtain the title compound 3-2 (100 mg) with a yield of 38%. LC-MS (ESI): 542.3 [M+H] + .
化合物3-3的制备Preparation of compound 3-3
将化合物3-2(100mg，0.2mmol)加入单口瓶中，再加入THF(5mL)。往锥形瓶中加入5mL水，加入过氧单磺酸钾(427g，1.2mmol)，缓慢滴入单口瓶中，室温搅拌反应16小时。反应结束后，加水(30mL)淬灭反应，用DCM(20mL×3)萃取，合并有机相，干燥浓缩得粗品标题化合物3-3(110mg)，收率93％。LC-MS(ESI):574.3[M+H]+。Compound 3-2 (100 mg, 0.2 mmol) was added to a single-mouth bottle, and THF (5 mL) was added. 5 mL of water was added to the conical flask, potassium peroxymonosulfonate (427 g, 1.2 mmol) was added, and the mixture was slowly dripped into the single-mouth bottle, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, water (30 mL) was added to quench the reaction, and DCM (20 mL × 3) was used for extraction. The organic phases were combined, dried and concentrated to obtain the crude title compound 3-3 (110 mg), with a yield of 93%. LC-MS (ESI): 574.3 [M+H] + .
化合物3的制备Preparation of compound 3
将化合物3-3(100mg，0.18mmol)溶解于乙腈(2.0mL)中，依次加入二甲基氧化膦(68mg，0.9mmol)、碳酸钾(73mg，0.54mmol)，反应体系在80℃下搅拌反应3小时。反应结束后，反应体系过滤后加水(30mL)，用二氯甲烷(20mL×3)萃取，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物3(2.2mg，收率2.2％)。LC-MS(ESI):m/z 572.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.01(d,J＝5.2Hz,1H),7.62(dd,J＝5.1,3.1Hz,1H),7.45(s,2H),7.35(d,J＝8.1Hz,1H),6.99(d,J＝8.1Hz,1H),4.23(t,J＝5.9Hz,2H),3.90(t,J＝5.9Hz,2H),3.85(s,2H),2.76(t,J＝6.4Hz,2H),2.67(q,J＝1.9Hz,2H),1.75(d,J＝13.6Hz,6H),1.71(m,2H),1.65(s,6H),1.62(m,2H).31P NMR(162MHz,DMSO-d6)δ33.85(s,1P)。Compound 3-3 (100 mg, 0.18 mmol) was dissolved in acetonitrile (2.0 mL), and dimethylphosphine oxide (68 mg, 0.9 mmol) and potassium carbonate (73 mg, 0.54 mmol) were added in sequence, and the reaction system was stirred at 80°C for 3 hours. After the reaction was completed, the reaction system was filtered and water (30 mL) was added, and extracted with dichloromethane (20 mL×3), and the organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 3 (2.2 mg, yield 2.2%). LC-MS (ESI): m/z 572.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.01 (d, J=5.2 Hz, 1H), 7.62 (dd, J=5.1, 3.1 Hz, 1H), 7.45 (s, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 4.23 (t, J=5.9 Hz, 2H), 3.90 (t, J=5.9 Hz, 2H), 3.85 (s, 2H), 2.76 (t, J=6.4 Hz, 2H), 2.67 (q, J=1.9 Hz, 2H), 1.75 (d, J=13.6 Hz, 6H), 1.71 (m, 2H), 1.65 (s, 6H), 1.62 (m, 2H). 31 P NMR (162 MHz, DMSO-d6) δ 33.85 (s, 1P).
实施例4：化合物4的制备
Example 4: Preparation of Compound 4
化合物4-1的制备Preparation of compound 4-1
将化合物1-5(300mg，1.1mmol)加入三口瓶中，再加入4-茚醇(440mg，3.3mmol)和无水二氯甲烷(10mL)，氮气置换三次后，在0℃冷却温度下逐滴加入三氟化硼乙醚溶液(48％，620mg，2.2mmol)。反应体系在0℃下搅拌反应2小时。反应结束后，加水(50mL)，用二氯甲烷(50mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物4-1(200mg)，收率45％。1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.51(d,J＝2.3Hz,1H),7.44(d,J＝2.3Hz,1H),7.11(d,J＝8.3Hz,1H),6.62(d,J＝8.3Hz,1H),4.43(t,J＝5.0Hz,2H),3.96(t,J＝5.0Hz,2H),2.61(t,J＝7.3Hz,2H),2.10(t,J＝7.3Hz,2H),1.76–1.66(m,2H),1.56(s,6H)。Compound 1-5 (300 mg, 1.1 mmol) was added to a three-necked flask, and then 4-indanol (440 mg, 3.3 mmol) and anhydrous dichloromethane (10 mL) were added. After nitrogen replacement three times, a boron trifluoride ether solution (48%, 620 mg, 2.2 mmol) was added dropwise at a cooling temperature of 0°C. The reaction system was stirred at 0°C for 2 hours. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-20%) to obtain the title compound 4-1 (200 mg) with a yield of 45%. 1 H NMR (400 MHz, DMSO-d6) δ9.14 (s, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 4.43 (t, J = 5.0 Hz, 2H), 3.96 (t, J = 5.0 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 2.10 (t, J = 7.3 Hz, 2H), 1.76–1.66 (m, 2H), 1.56 (s, 6H).
化合物4-2的制备Preparation of compound 4-2
将化合物4-1(200mg，0.5mmol)加入三口瓶中，依次加入无水DCM(10mL)，(2-甲硫基嘧啶-4-基)甲醇(155mg，1.0mmol)，三苯基膦(270mg，1.0mmol)，用氮气替换三次，在0℃下加入偶氮二甲酸二异丙酯(208mg，1.0mmol)。反应在25℃下搅拌反应16小时。反应结束后，加水(40mL)，用EtOAc(30mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物4-2(100mg)，收率36％。LC-MS(ESI):528.0[M+H]+。Compound 4-1 (200 mg, 0.5 mmol) was added to a three-necked flask, followed by anhydrous DCM (10 mL), (2-methylthiopyrimidin-4-yl)methanol (155 mg, 1.0 mmol), triphenylphosphine (270 mg, 1.0 mmol), replaced with nitrogen three times, and diisopropyl azodicarboxylate (208 mg, 1.0 mmol) was added at 0°C. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, water (40 mL) was added, and the mixture was extracted with EtOAc (30 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-20%) to obtain the title compound 4-2 (100 mg) with a yield of 36%. LC-MS (ESI): 528.0 [M+H] + .
化合物4-3的制备Preparation of compound 4-3
将化合物4-2(100mg，0.19mmol)加入单口瓶中，再加入THF(5mL)。往锥形瓶中加入5mL水，加入过氧单磺酸钾(394mg，1.2mmol)，搅拌溶解后，所得溶液缓慢滴入单口瓶中，滴加完毕，室温搅拌反应16小时。反应结束后，在冰浴下向反应体系缓慢加入硫代硫酸钠水溶液(20mL)，用DCM(20mL×3) 萃取，合并有机相，干燥浓缩得粗品标题化合物4-3(100mg)，收率94％。LC-MS(ESI):560.5[M+H]+。Compound 4-2 (100 mg, 0.19 mmol) was added to a single-mouth bottle, and then THF (5 mL) was added. 5 mL of water was added to a conical flask, and potassium peroxymonosulfonate (394 mg, 1.2 mmol) was added. After stirring and dissolving, the resulting solution was slowly dripped into the single-mouth bottle. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After the reaction was completed, sodium thiosulfate aqueous solution (20 mL) was slowly added to the reaction system under an ice bath, and DCM (20 mL × 3) was used. After extraction, the organic phases were combined, dried and concentrated to obtain the crude title compound 4-3 (100 mg) with a yield of 94%. LC-MS (ESI): 560.5 [M+H] + .
化合物4的制备Preparation of compound 4
将化合物4-3(100mg，0.18mmol)溶解于乙腈(2.0mL)中，依次加入二甲基氧化膦(68mg，0.9mmol)、碳酸钾(73mg，0.54mmol)。反应体系在80℃下搅拌反应3小时。反应结束后，反应体系过滤，滤液加水(20mL)，用二氯甲烷(20mL×3)萃取，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物4(34mg，收率63％)。LC-MS(ESI):m/z 558.4[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.00(d,J＝5.2Hz,1H),7.72(dd,J＝5.2,3.1Hz,1H),7.53(d,J＝2.3Hz,1H),7.46(d,J＝2.3Hz,1H),7.27(d,J＝8.6Hz,1H),6.85(d,J＝8.5Hz,1H),5.32(s,2H),4.54–4.37(t,J＝5.8Hz,2H),3.96(t,J＝5.8Hz,2H),2.80(t,J＝7.3Hz,2H),2.16(q,J＝7.4Hz,2H),1.77(d,J＝13.6Hz,6H),1.77(m,2H),1.59(s,6H).31P NMR(162MHz,DMSO-d6)δ34.01(s,1P)。Compound 4-3 (100 mg, 0.18 mmol) was dissolved in acetonitrile (2.0 mL), and dimethylphosphine oxide (68 mg, 0.9 mmol) and potassium carbonate (73 mg, 0.54 mmol) were added in sequence. The reaction system was stirred at 80 ° C for 3 hours. After the reaction was completed, the reaction system was filtered, the filtrate was added with water (20 mL), extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried and concentrated to obtain a crude product, and the crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25 ° C; gradient: 45%-65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain the title compound 4 (34 mg, yield 63%). LC-MS (ESI): m/z 558.4 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.00 (d, J = 5.2 Hz, 1H), 7.72 (dd, J = 5.2, 3.1 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 5.32 (s, 2H), 4.54–4.37 (t, J = 5.8 Hz, 2H), 3.96 (t, J = 5.8 Hz, 2H), 2.80 (t, J = 7.3 Hz, 2H) , 2.16 (q, J = 7.4 Hz, 2H), 1.77 (d, J = 13.6 Hz, 6H), 1.77 (m, 2H), 1.59 (s, 6H). NMR (162 MHz, DMSO-d6) δ 34.01 (s, 1P).
实施例5：化合物5的制备
Example 5: Preparation of Compound 5
化合物5-2的制备Preparation of compound 5-2
封管中加入化合物5-1(2g，15.56mmol)，NCS(2.08g，15.56mmol)和AIBN(0.255g,1.56mmol)，溶于乙腈(20mL)，80℃反应过夜。加水(50mL)，用乙酸乙酯(20mL×3)萃取，干燥浓缩得粗品，该粗品以正相硅胶柱(biotage，硅胶柱，20g，UV254，乙酸乙酯/石油醚＝0～100％)纯化得标题产物5-2(0.8g，收率31％)。LC-MS(ESI):m/z 162.9[M+H]+。Compound 5-1 (2 g, 15.56 mmol), NCS (2.08 g, 15.56 mmol) and AIBN (0.255 g, 1.56 mmol) were added to the sealed tube, dissolved in acetonitrile (20 mL), and reacted at 80°C overnight. Water (50 mL) was added, extracted with ethyl acetate (20 mL × 3), dried and concentrated to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate/petroleum ether = 0-100%) to obtain the title product 5-2 (0.8 g, yield 31%). LC-MS (ESI): m/z 162.9 [M+H] + .
化合物5-3的制备Preparation of compound 5-3
反应瓶中加入化合物5-2(0.8g，4.91mmol)及DCM(5mL)，加入TEA(0.5g，4.91mmol)和乙酸(0.294g，2.91mmol)，55℃反应过夜。加水(50mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，干燥浓缩得粗品，该粗品以正相硅胶柱(biotage，硅胶柱，20g，UV254，乙酸乙酯/石油醚＝0～100％)纯化得标题产物5-3(0.5g，收率54％)。LC-MS(ESI):m/z 187.0[M+H]+。Compound 5-2 (0.8 g, 4.91 mmol) and DCM (5 mL) were added to the reaction flask, followed by TEA (0.5 g, 4.91 mmol) and acetic acid (0.294 g, 2.91 mmol), and the mixture was reacted at 55°C overnight. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate/petroleum ether = 0-100%) to obtain the title product 5-3 (0.5 g, yield 54%). LC-MS (ESI): m/z 187.0 [M+H] + .
化合物5-4的制备Preparation of compound 5-4
将化合物5-3(500mg，2.68mmol)溶解于DMF溶液(1mL)中，加入化合物二甲基氧化膦(209mg，2.68mmol)和DIPEA(209mg，2.68mmol)。反应体系160℃封管搅拌1小时。待反应体系冷却后，过滤，滤液加入适量水冻干，得到粗品标题化合物5-4(0.5g)，收率81％，直接用于下一步反应。LC-MS(ESI):m/z 229.4[M+H]+。Compound 5-3 (500 mg, 2.68 mmol) was dissolved in DMF solution (1 mL), and dimethylphosphine oxide (209 mg, 2.68 mmol) and DIPEA (209 mg, 2.68 mmol) were added. The reaction system was sealed and stirred at 160°C for 1 hour. After the reaction system was cooled, it was filtered, and the filtrate was added with appropriate amount of water and freeze-dried to obtain the crude title compound 5-4 (0.5 g) with a yield of 81%, which was directly used for the next step reaction. LC-MS (ESI): m/z 229.4 [M+H] + .
化合物5-5的制备Preparation of compound 5-5
反应瓶中加入化合物5-4(0.5g，2.19mmol)及甲醇(3mL)，加入TEA(0.443g，4.38mmol)，55℃反应过夜。加水(50mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，干燥浓缩得粗品，该粗品以正相硅胶柱(biotage，硅胶柱，20g，UV254，二氯甲烷/甲醇＝0～100％)纯化得标题产物5-5(0.25g，收率62％)。LC-MS(ESI):m/z 187.2[M+H]+。Compound 5-4 (0.5 g, 2.19 mmol) and methanol (3 mL) were added to the reaction flask, and TEA (0.443 g, 4.38 mmol) was added, and the mixture was reacted at 55°C overnight. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, dichloromethane/methanol=0-100%) to obtain the title product 5-5 (0.25 g, yield 62%). LC-MS (ESI): m/z 187.2 [M+H] + .
化合物5的制备 Preparation of compound 5
将化合物5-5(250mg，1.34mmol)，化合物1-6(470mg，1.34mmol)和三丁基膦(815mg，4.03mmol)分别加入三口瓶中，加入二氯甲烷(10mL)做溶剂，氮气保护，冰水浴下加入N,N,N',N'-四甲基偶氮二甲酰胺(694mg，4.03mmol)，反应体系在室温下搅拌反应16小时。反应液过滤，滤液粗品经制备分离纯化(制备方法:色谱柱:Agilent 10Prep-C18 250x21.2mm；柱温:25℃；流动相:水(0.1％TFA)-乙腈；流动相乙腈比例50％-70％在12分钟内梯度洗脱；流速30mL/min)得到标题化合物5(190mg，收率27％)。LC-MS(ESI):m/z 518.0[M+H]+.1H NMR(400MHz,Chloroform-d)δ9.00(t,J＝4.8Hz,1H),8.00(t,J＝5.1Hz,1H),7.42(d,J＝2.3Hz,1H),7.32(d,J＝2.3Hz,1H),7.13–7.03(m,2H),6.95–6.89(m,2H),5.36(s,2H),4.42(t,J＝6.2Hz,2H),3.88(t,J＝6.2Hz,2H),1.73(d,J＝13.6Hz,6H),1.63(s,6H).31P NMR(162MHz,Chloroform-d)36.12(s,1P)。Compound 5-5 (250 mg, 1.34 mmol), compound 1-6 (470 mg, 1.34 mmol) and tributylphosphine (815 mg, 4.03 mmol) were added to a three-necked flask, dichloromethane (10 mL) was added as solvent, nitrogen was protected, N, N, N', N'-tetramethylazodicarbonamide (694 mg, 4.03 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10Prep-C18 250x21.2 mm; column temperature: 25 ° C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 5 (190 mg, yield 27%). LC-MS (ESI): m/z 518.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ9.00 (t, J=4.8 Hz, 1H), 8.00 (t, J=5.1 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.13–7.03 (m, 2H), 6.95–6.89 (m, 2H), 5.36 (s, 2H), 4.42 (t, J=6.2 Hz, 2H), 3.88 (t, J=6.2 Hz, 2H), 1.73 (d, J=13.6 Hz, 6H), 1.63 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) 36.12 (s, 1P).
实施例6：化合物6的制备
Example 6: Preparation of Compound 6
化合物6的制备Preparation of compound 6
将化合物1(50mg，0.09mmol)溶解于甲苯(2.0mL)中，加入五硫化二磷(86mg，0.4mmol)。反应体系在100℃下搅拌反应16小时。反应结束后，反应体系过滤，滤液加水，用二氯甲烷(20mL×3)萃取，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物6(4mg，收率7％)。LC-MS(ESI):m/z 534.5[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.97(d,J＝5.2Hz,1H),7.69(t,J＝4.5Hz,1H),7.63(d,J＝2.3Hz,1H),7.57(d,J＝2.3Hz,1H),7.20(d,J＝8.7Hz,2H),7.01(d,J＝8.7Hz,2H),5.27(s,2H),4.41(t,J＝5.1Hz,2H),3.95(t,J＝5.1Hz,2H),2.05(d,J＝14.0Hz,6H),1.63(s,6H).31P NMR(162MHz,DMSO-d6)δ36.63(s,1P)。Compound 1 (50 mg, 0.09 mmol) was dissolved in toluene (2.0 mL), and phosphorus pentasulfide (86 mg, 0.4 mmol) was added. The reaction system was stirred at 100 ° C for 16 hours. After the reaction was completed, the reaction system was filtered, the filtrate was added with water, extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried and concentrated to obtain a crude product, and the crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25 ° C; gradient: 45%-65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain the title compound 6 (4 mg, yield 7%). LC-MS (ESI): m/z 534.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.97 (d, J=5.2 Hz, 1H), 7.69 (t, J=4.5 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 5.27 (s, 2H), 4.41 (t, J=5.1 Hz, 2H), 3.95 (t, J=5.1 Hz, 2H), 2.05 (d, J=14.0 Hz, 6H), 1.63 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ36.63 (s, 1P).
实施例7：化合物7的制备
Example 7: Preparation of Compound 7
化合物7-2的制备Preparation of compound 7-2
将化合物7-1(140mg，0.968mmol)溶解于DMSO溶液(1mL)中，加入化合物二甲基氧化膦(78mg，1.94mmol)和DIPEA(376mg，2.91mmol)。反应体系150℃封管搅拌1小时。待反应体系冷却后，过滤，滤液加入适量水冻干，残留物通过正相硅胶柱(MeOH/DCM＝0-5％)分离纯化得到标题化合物7-2(120mg，收率66％)，为白色固体。LC-MS(ESI):m/z 187.0[M+H]+。Compound 7-1 (140 mg, 0.968 mmol) was dissolved in DMSO solution (1 mL), and dimethylphosphine oxide (78 mg, 1.94 mmol) and DIPEA (376 mg, 2.91 mmol) were added. The reaction system was sealed and stirred at 150°C for 1 hour. After the reaction system was cooled, it was filtered, and the filtrate was freeze-dried by adding an appropriate amount of water. The residue was separated and purified by a normal phase silica gel column (MeOH/DCM=0-5%) to obtain the title compound 7-2 (120 mg, yield 66%) as a white solid. LC-MS (ESI): m/z 187.0 [M+H] + .
化合物7的制备Preparation of compound 7
将化合物7-2(120mg，0.645mmol)，化合物1-6(226mg，0.645mmol)和三正丁基磷(391mg，1.93mmol)分别加入三口瓶中，加入二氯甲烷(10mL)做溶剂，氮气保护，冰水浴下加入N,N,N',N'-四甲基偶氮二甲酰胺(333mg，1.93mmol)，反应体系在室温下搅拌反应16小时。反应液过滤，旋干得到粗品，经制备分离纯化(制备方法：色谱柱:Agilent 10Prep-C18 250x21.2mm；柱温:25℃；流动相:水(0.1％TFA)-乙腈；流动相乙腈比例50％-70％在12分钟内梯度洗脱；流速30mL/min)得到标题化合物7(70mg，收率20％)。LC-MS(ESI):m/z 518.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ9.22(s,1H),8.98(d,J＝3.2Hz,1H),7.45(d,J＝2.4Hz,1H),7.33(d,J＝2.4Hz,1H),7.14(d,J＝8.8Hz,2H),6.95(d,J＝8.8Hz,2H),5.27(s,2H),4.43(t,J＝6.2Hz,2H),3.88(t,J＝6.2Hz,2H),1.83(d,J＝13.6Hz,6H),1.66(s,6H).31P NMR(162MHz, Chloroform-d)δ35.95(s,1P)。Compound 7-2 (120 mg, 0.645 mmol), compound 1-6 (226 mg, 0.645 mmol) and tri-n-butylphosphine (391 mg, 1.93 mmol) were added to a three-necked flask, dichloromethane (10 mL) was added as solvent, nitrogen was protected, N, N, N', N'-tetramethylazodicarbonamide (333 mg, 1.93 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered and dried to obtain a crude product, which was purified by preparative separation (preparation method: chromatographic column: Agilent 10Prep-C18 250x21.2 mm; column temperature: 25 ° C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 7 (70 mg, yield 20%). LC-MS (ESI): m/z 518.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ9.22 (s, 1H), 8.98 (d, J = 3.2 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.27 (s, 2H), 4.43 (t, J = 6.2 Hz, 2H), 3.88 (t, J = 6.2 Hz, 2H), 1.83 (d, J = 13.6 Hz, 6H), 1.66 (s, 6H). 31 P NMR (162 MHz, Chloroform-d)δ35.95(s,1P).
实施例8：化合物8的制备
Example 8: Preparation of Compound 8
化合物8-2的制备Preparation of compound 8-2
将化合物8-1(100mg，5.36mmol)溶解于DMSO溶液(1mL)中，加入化合物二甲基膦(692mg，5.36mmol)和DIPEA(376mg，5.36mmol)。反应体系150℃封管搅拌1小时。待反应体系冷却后，过滤，滤液加入适量水冻干，残留物通过正相硅胶柱(MeOH/DCM＝0-5％)分离纯化得到标题化合物8-2(0.4g，收率32％)。LC-MS(ESI):m/z 229.0[M+H]+。Compound 8-1 (100 mg, 5.36 mmol) was dissolved in DMSO solution (1 mL), and dimethylphosphine (692 mg, 5.36 mmol) and DIPEA (376 mg, 5.36 mmol) were added. The reaction system was sealed and stirred at 150°C for 1 hour. After the reaction system was cooled, it was filtered, and the filtrate was freeze-dried by adding an appropriate amount of water. The residue was separated and purified by a normal phase silica gel column (MeOH/DCM=0-5%) to obtain the title compound 8-2 (0.4 g, yield 32%). LC-MS (ESI): m/z 229.0 [M+H] + .
化合物8-3的制备Preparation of compound 8-3
将化合物8-2(400mg，1.75mmol)溶解于THF溶液(3mL)中，加入化合物硼氢化钠(66mg，1.75mmol)。反应体系20℃搅拌1小时。待反应体系冷却后过滤，滤液加入适量水冻干，残留物通过正相硅胶柱(MeOH/DCM＝0-5％)分离纯化得到标题化合物8-3(0.04g，收率12％)。LC-MS(ESI):m/z 187.2[M+H]+。Compound 8-2 (400 mg, 1.75 mmol) was dissolved in THF solution (3 mL), and sodium borohydride (66 mg, 1.75 mmol) was added. The reaction system was stirred at 20°C for 1 hour. After the reaction system was cooled, it was filtered, and the filtrate was freeze-dried by adding an appropriate amount of water. The residue was separated and purified by a normal phase silica gel column (MeOH/DCM=0-5%) to obtain the title compound 8-3 (0.04 g, yield 12%). LC-MS (ESI): m/z 187.2 [M+H] + .
化合物8的制备Preparation of compound 8
将化合物8-3(40mg，0.215mmol)，化合物1-6(75mg，0.215mmol)和三正丁基磷(43mg，0.214mmol)分别加入三口瓶中，加入二氯甲烷(2mL)做溶剂，氮气保护，冰水浴下加入N,N,N',N'-四甲基偶氮二甲酰胺(37mg，0.215mmol)，反应体系在室温下搅拌反应16小时。反应液过滤得到粗品，粗品经制备分离纯化(制备方法:色谱柱:Agilent 10Prep-C18 250x21.2mm；柱温:25℃；流动相:水(0.1％TFA)-乙腈；流动相乙腈比例50％-70％在12分钟内梯度洗脱；流速30mL/min)得到标题化合物8(3mg，收率6％)。LC-MS(ESI):m/z 518.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.41(d,J＝5.7Hz,1H),7.45(d,J＝2.4Hz,1H),7.34(d,J＝2.4Hz,1H),7.13(d,J＝8.9Hz,2H),6.95(d,J＝8.9Hz,2H),5.21(s,2H),4.43(t,J＝6.2Hz,2H),3.88(t,J＝6.2Hz,2H),1.82(d,J＝13.7Hz,6H),1.66(s,6H).31P NMR(162MHz,Chloroform-d)δ36.42(s,1P)。 Compound 8-3 (40 mg, 0.215 mmol), compound 1-6 (75 mg, 0.215 mmol) and tri-n-butylphosphine (43 mg, 0.214 mmol) were added to a three-necked flask, dichloromethane (2 mL) was added as solvent, nitrogen was protected, N, N, N', N'-tetramethylazodicarbonamide (37 mg, 0.215 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered to obtain a crude product, which was purified by preparative separation (preparation method: chromatographic column: Agilent 10Prep-C18 250x21.2 mm; column temperature: 25 ° C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 8 (3 mg, yield 6%). LC-MS (ESI): m/z 518.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ9.29 (s, 1H), 8.41 (d, J=5.7 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.13 (d, J=8.9 Hz, 2H), 6.95 (d, J=8.9 Hz, 2H), 5.21 (s, 2H), 4.43 (t, J=6.2 Hz, 2H), 3.88 (t, J=6.2 Hz, 2H), 1.82 (d, J=13.7 Hz, 6H), 1.66 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ36.42 (s, 1P).
实施例9：化合物9的制备
Example 9: Preparation of Compound 9
化合物9-2的制备Preparation of compound 9-2
将化合物9-1(8g，49.01mmol)溶于二氯甲烷(100mL)。在-70℃下，滴加乙烯基溴化镁(1.0M，98mL，98.20mmol)，自然升到室温反应2小时。加入乙醇(100mL)淬灭反应体系，用乙酸乙酯(200mL×3)萃取，合并有机相，干燥浓缩得粗产品，该粗品用正相硅胶柱(biotage，硅胶柱20g，UV254，甲醇/二氯甲烷＝0～10％)纯化得标题产物9-2(8g，收率83％)。1H NMR(400MHz,Chloroform-d)δ6.36–6.06(m,6H),4.04(m,2H),1.30(t,J＝7.0Hz,3H)。Compound 9-1 (8 g, 49.01 mmol) was dissolved in dichloromethane (100 mL). Vinylmagnesium bromide (1.0 M, 98 mL, 98.20 mmol) was added dropwise at -70 °C, and the mixture was naturally warmed to room temperature for 2 hours. Ethanol (100 mL) was added to quench the reaction system, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column 20 g, UV254, methanol/dichloromethane = 0-10%) to obtain the title product 9-2 (8 g, yield 83%). 1 H NMR (400 MHz, Chloroform-d) δ 6.36–6.06 (m, 6H), 4.04 (m, 2H), 1.30 (t, J = 7.0 Hz, 3H).
化合物9-3的制备Preparation of compound 9-3
化合物9-2(2g，13.69mmol)，2,4-二甲氧基苯甲胺(2.29g，13.69mmol)溶于乙醇(30mL)中，反应液在100℃搅拌1小时。旋干得到粗品，该粗品以正相硅胶柱(biotage，硅胶柱20g，UV254，甲醇/二氯甲烷＝0～10％)得标题化合物9-3(1.4g，收率32％)。1H NMR(400MHz,Chloroform-d)δ7.22(d,J＝8.2Hz,1H),6.48(dd,J＝8.2,2.4Hz,1H),6.45(d,J＝2.4Hz,1H),4.10–4.03(m,2H),3.80(d,J＝7.0Hz,6H),3.59(s,2H),3.11–2.96(m,2H),2.78-2.66(m,2H),2.02–1.93(m,2H),1.91–1.77(m,2H),1.34(t,J＝7.0Hz,3H).31P NMR(162MHz,Chloroform-d)δ45.70(s,1P)。Compound 9-2 (2 g, 13.69 mmol) and 2,4-dimethoxybenzylamine (2.29 g, 13.69 mmol) were dissolved in ethanol (30 mL), and the reaction solution was stirred at 100 ° C for 1 hour. The crude product was spin-dried and the crude product was subjected to normal phase silica gel column (biotage, silica gel column 20 g, UV254, methanol/dichloromethane = 0-10%) to obtain the title compound 9-3 (1.4 g, yield 32%). 1 H NMR (400 MHz, Chloroform-d) δ7.22 (d, J=8.2 Hz, 1H), 6.48 (dd, J=8.2, 2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 4.10–4.03 (m, 2H), 3.80 (d, J=7.0 Hz, 6H), 3.59 (s, 2H), 3.11–2.96 (m, 2H), 2.78-2.66 (m, 2H), 2.02–1.93 (m, 2H), 1.91–1.77 (m, 2H), 1.34 (t, J=7.0 Hz, 3H). 31 P NMR (162 MHz, Chloroform-d) δ45.70 (s, 1P).
化合物9-4和9-5的制备Preparation of compounds 9-4 and 9-5
三口瓶中加入化合物9-3(0.45g，1.44mmol)，抽换氮气，加入THF(5mL)。在-78℃下，滴加氢化铝锂四氢呋喃溶液(1M，1.44mL)，滴加完毕反应30min。反应体系用十水硫酸钠固体(100mg)淬灭，过滤，滤液合并，干燥浓缩得到粗标题产物9-4和9-5(0.27g，收率74％)的混合物。LC-MS(ESI):m/z253.8[M+H]+,269.8[M+H]+。Compound 9-3 (0.45 g, 1.44 mmol) was added to a three-necked flask, nitrogen was replaced, and THF (5 mL) was added. At -78 ° C, lithium aluminum hydride tetrahydrofuran solution (1M, 1.44 mL) was added dropwise, and the reaction was continued for 30 minutes after the addition was completed. The reaction system was quenched with sodium sulfate decahydrate solid (100 mg), filtered, and the filtrates were combined, dried and concentrated to obtain a mixture of crude title products 9-4 and 9-5 (0.27 g, yield 74%). LC-MS (ESI): m/z 253.8 [M+H] + , 269.8 [M+H] + .
化合物9-6的制备Preparation of compound 9-6
将上述化合物9-4和9-5(0.270g，大约1.07mmol)的混合物，及30％双氧水(0.2mL)，DCM(5mL)分别加入三口瓶中，在室温下反应1小时。反应结束后浓缩，该粗品以正相硅胶柱(biotage，硅胶柱40g，UV254，甲醇/二氯甲烷＝0～10％)纯化得到标题化合物9-6(0.160g，收率55％)。LC-MS(ESI):m/z269.8[M+H]+。A mixture of the above compounds 9-4 and 9-5 (0.270 g, about 1.07 mmol), 30% hydrogen peroxide (0.2 mL), and DCM (5 mL) were added to a three-necked flask and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated and the crude product was purified by a normal phase silica gel column (biotage, silica gel column 40 g, UV254, methanol/dichloromethane = 0-10%) to obtain the title compound 9-6 (0.160 g, yield 55%). LC-MS (ESI): m/z 269.8 [M+H] + .
化合物9-7的制备Preparation of compound 9-7
将化合物9-6(0.270g，1mmol)溶解于DMF溶液(2mL)中，加入化合物(2-氯嘧啶-4-基)甲醇(145mg，1mmol)，DIPEA(389mg，3.01mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(58mg，0.1mmol)，Pd2(dba)3(92mg，0.1mmol)。反应体系150℃封管搅拌1小时。待反应体系冷却后，过滤，滤液加入适量水冻干，残留物通过正相硅胶柱(MeOH/DCM＝0-10％)分离纯化得到标题化合物9-7(0.15g，收率39％)。LC-MS (ESI):m/z 377.8[M+H]+。Compound 9-6 (0.270 g, 1 mmol) was dissolved in DMF solution (2 mL), and compound (2-chloropyrimidin-4-yl)methanol (145 mg, 1 mmol), DIPEA (389 mg, 3.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (58 mg, 0.1 mmol), and Pd 2 (dba) 3 (92 mg, 0.1 mmol) were added. The reaction system was sealed and stirred at 150°C for 1 hour. After the reaction system was cooled, it was filtered, and the filtrate was freeze-dried by adding an appropriate amount of water. The residue was separated and purified by normal phase silica gel column (MeOH/DCM=0-10%) to obtain the title compound 9-7 (0.15 g, yield 39%). LC-MS (ESI): m/z 377.8 [M+H] + .
化合物9-8的制备Preparation of compound 9-8
将化合物9-7(150mg，0.397mmol)溶于TFA(2mL)，反应液在25℃搅拌1小时后,浓缩得到残留物。向残留物加入甲醇(2mL)，然后加入三乙胺(40mg，0.397mmol)和二碳酸二叔丁酯(87mg，0.397mmol)，反应液在25℃搅拌1小时后。TLC点板显示反应结束。反应液倒入水(50mL)中，二氯甲烷(50mL×3)萃取，有机相旋干，得到粗品。该粗品以正相硅胶柱(biotage，硅胶柱25g，UV254，乙酸乙酯/石油醚＝0～100％)纯化得到标题化合物9-8(0.120g，收率92％)。LC-MS(ESI):m/z 327.8[M+H]+。Compound 9-7 (150 mg, 0.397 mmol) was dissolved in TFA (2 mL), and the reaction solution was stirred at 25 ° C for 1 hour and concentrated to obtain a residue. Methanol (2 mL) was added to the residue, followed by triethylamine (40 mg, 0.397 mmol) and di-tert-butyl dicarbonate (87 mg, 0.397 mmol), and the reaction solution was stirred at 25 ° C for 1 hour. TLC spot plate showed that the reaction was complete. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL × 3), and the organic phase was dried to obtain a crude product. The crude product was purified by a normal phase silica gel column (biotage, silica gel column 25 g, UV254, ethyl acetate/petroleum ether = 0-100%) to obtain the title compound 9-8 (0.120 g, yield 92%). LC-MS (ESI): m/z 327.8 [M+H] + .
化合物9-9的制备Preparation of compound 9-9
将化合物9-8(130mg，0.344mmol)，化合物1-6(120mg，0.344mmol)和三丁基磷(139mg，0.689mmol)分别加入三口瓶中，加入二氯甲烷(2mL)做溶剂，氮气保护，冰水浴下加入N,N,N',N'-四甲基氮杂二甲酰胺(118mg，0.689mmol)，反应体系在室温下搅拌反应16小时。反应液过滤，滤液粗品经正相硅胶柱(biotage，硅胶柱25g，UV254，MeOH/DCM＝0-10％)纯化得到标题化合物9-9(0.2g，收率88％)，LC-MS(ESI):m/z 659.0[M+H]+。Compound 9-8 (130 mg, 0.344 mmol), compound 1-6 (120 mg, 0.344 mmol) and tributylphosphine (139 mg, 0.689 mmol) were added to a three-necked flask, dichloromethane (2 mL) was added as solvent, nitrogen was protected, N, N, N', N'-tetramethyl azadicarbonamide (118 mg, 0.689 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by normal phase silica gel column (biotage, silica gel column 25 g, UV254, MeOH/DCM=0-10%) to obtain the title compound 9-9 (0.2 g, yield 88%), LC-MS (ESI): m/z 659.0 [M+H] + .
化合物9的制备Preparation of compound 9
将化合物9-9(200mg，0.303mmol)溶于DCM(3mL)中，加入TFA(1mL)，反应体系室温反应1小时后。反应液旋干得到粗品(180mg)，该粗品(30mg)制备分离(制备方法：流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Agilent 10Prep-C18 250×21.2mm；柱温:25℃；梯度:55％-75％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物9(5mg，收率12％)。LC-MS(ESI):m/z 559.0[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.91(d,J＝5.2Hz,1H),7.70(dd,J＝5.1,3.2Hz,1H),7.45(d,J＝2.3Hz,1H),7.31(d,J＝2.3Hz,1H),7.13(d,J＝8.6Hz,2H),6.91(d,J＝8.6Hz,2H),5.24(s,2H),4.43(t,J＝6.1Hz,2H),3.88(t,J＝6.1Hz,2H),3.53–3.37(m,2H),3.04–2.88(m,2H),2.74-2.67(m,2H),2.29–2.14(m,2H),1.65(s,6H).31P NMR(162MHz,Chloroform-d)δ30.19(s,1P)。Compound 9-9 (200 mg, 0.303 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and the reaction system was reacted at room temperature for 1 hour. The reaction solution was spin-dried to obtain a crude product (180 mg), and the crude product (30 mg) was prepared and separated (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain the title compound 9 (5 mg, yield 12%). LC-MS (ESI): m/z 559.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.91 (d, J = 5.2 Hz, 1H), 7.70 (dd, J = 5.1, 3.2 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 5.24 (s, 2H), 4.43 (t, J = 6.1 Hz, 2H), 3.88 (t, J = 6.1 Hz, 2H), 3.53–3.37 (m, 2H), 3.04–2.88 (m, 2H), 2.74-2.67 (m, 2H), 2.29–2.14 (m, 2H), 1.65 (s, 6H ). NMR (162 MHz, Chloroform-d) δ 30.19 (s, 1P).
实施例10：化合物10的制备
Example 10: Preparation of Compound 10
化合物10-2的制备Preparation of compound 10-2
将化合物1-6(350mg，1mmol)，化合物10-1(352mg,3mmol)，三苯基膦(789mg，3mmol)，DIAD(606mg，3mmol)和无水四氢呋喃(10mL)加入单口瓶中，氮气置换三次，反应在50℃下搅拌反应2小时。反应结束后，将反应液降至室温，向反应体系加入饱和氯化钠水溶液(30mL)，用EtOAc(50mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到标题化合物10-2(230mg)，收率48％。LC-MS(ESI):476.2[M+H]+。Compound 1-6 (350 mg, 1 mmol), compound 10-1 (352 mg, 3 mmol), triphenylphosphine (789 mg, 3 mmol), DIAD (606 mg, 3 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a single-mouth bottle, replaced with nitrogen three times, and stirred at 50°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, saturated sodium chloride aqueous solution (30 mL) was added to the reaction system, extracted with EtOAc (50 mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, and separated and purified by a normal phase silica gel column (EtOAc/PE=0-30%) to obtain the title compound 10-2 (230 mg), with a yield of 48%. LC-MS (ESI): 476.2 [M+H] + .
化合物10的制备Preparation of compound 10
将化合物10-2(230mg，0.48mmol)溶解于N,N-二甲基甲酰胺(3.0mL)中，依次加入二甲基氧化膦(2mg，1.45mmol)，三乙胺(146mg，1.45mmol)，三(二亚苄基丙酮)二钯(46mg,0.05mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(30mg，0.05mmol)。用氮气替换三次，反应体系在120℃下微波搅拌反应2小时。反应结束后，反应体系过滤后用二氯甲烷(20mL×3)萃取，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物10(3.86mg，收率1.5％)。LC-MS(ESI):m/z 518.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.81–8.83(m,2H),7.65(d,J＝2.3Hz,1H),7.59(d,J＝2.3Hz,1H),7.17(d,J＝8.8Hz,2H),6.96(d,J＝8.8Hz,2H),5.62(s,2H),4.45–4.37 (m,2H),3.99–3.91(m,2H),1.76(d,J＝13.7Hz,6H),1.63(s,6H).31P NMR(162MHz,DMSO-d6)δ39.24(s,1P)。Compound 10-2 (230 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (3.0 mL), and dimethylphosphine oxide (2 mg, 1.45 mmol), triethylamine (146 mg, 1.45 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (30 mg, 0.05 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction, the reaction system was filtered and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 10 (3.86 mg, yield 1.5%). LC-MS (ESI): m/z 518.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.81–8.83 (m, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.62 (s, 2H), 4.45–4.37 (m, 2H), 3.99–3.91 (m, 2H), 1.76 (d, J＝13.7 Hz, 6H), 1.63 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 39.24 (s, 1P).
实施例11：化合物11的制备
Example 11: Preparation of Compound 11
化合物11-1的制备Preparation of compound 11-1
氮气保护下，将化合物对羟基苯甲酸甲酯(3.0g，19.72mmol)和二异丙胺盐酸盐(542.8mg，3.94mmol)溶解于甲苯(30mL)中。于0℃下，缓慢加入1,3-二氯-5,5-二甲基海因(7.77g，9.44mmol)，0℃下搅拌5小时。反应结束后，加入饱和亚硫酸钠水溶液(30mL)淬灭反应，反应体系用EtOAc(100mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-5％)分离纯化得到标题化合物11-1(1.5g)，收率34％。LC-MS(ESI):m/z 221.2[M+H]+。Under nitrogen protection, the compound methyl p-hydroxybenzoate (3.0 g, 19.72 mmol) and diisopropylamine hydrochloride (542.8 mg, 3.94 mmol) were dissolved in toluene (30 mL). At 0°C, 1,3-dichloro-5,5-dimethylhydantoin (7.77 g, 9.44 mmol) was slowly added and stirred at 0°C for 5 hours. After the reaction was completed, a saturated aqueous sodium sulfite solution (30 mL) was added to quench the reaction, and the reaction system was extracted with EtOAc (100 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-5%) to obtain the title compound 11-1 (1.5 g) with a yield of 34%. LC-MS (ESI): m/z 221.2[M+H] + .
化合物11-2的制备Preparation of compound 11-2
将化合物11-1(1.3g，5.88mmol)，1-溴-2-氯乙烷(1.69g，11.76mmol)，碳酸铯(3.83g，11.76mmol)，DMF(13mL)加入100mL封管中，120℃下反应16小时。反应结束后加水60mL，反应体系用EtOAc(30mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-10％)分离纯化得到标题化合物11-2(0.4g)，收率24％。LC-MS(ESI):m/z 283.1[M+H]+。Compound 11-1 (1.3 g, 5.88 mmol), 1-bromo-2-chloroethane (1.69 g, 11.76 mmol), cesium carbonate (3.83 g, 11.76 mmol), and DMF (13 mL) were added to a 100 mL sealed tube and reacted at 120° C. for 16 hours. After the reaction, 60 mL of water was added, and the reaction system was extracted with EtOAc (30 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-10%) to obtain the title compound 11-2 (0.4 g) with a yield of 24%. LC-MS (ESI): m/z 283.1[M+H] + .
化合物11-3的制备Preparation of compound 11-3
将化合物11-2(400mg，1.41mmol)加入三口瓶中，氮气置换三次。在三口瓶中加入无水四氢呋喃(5mL)，并在0℃冷却温度下，缓滴加甲基溴化镁四氢呋喃溶液(3.0M，1.88mL，4.65mmol)。反应体系在0℃下搅拌反应60分钟后，向反应体系中加入饱和氯化铵溶液(5mL)淬灭，用EtOAc(5mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-10％)分离纯化得到标题化合物11-3(280mg)，收率70％。LC-MS(ESI):m/z 264.8[M-H2O+H]+。Compound 11-2 (400 mg, 1.41 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous tetrahydrofuran (5 mL) was added to the three-necked flask, and methyl magnesium bromide tetrahydrofuran solution (3.0 M, 1.88 mL, 4.65 mmol) was slowly added dropwise at a cooling temperature of 0°C. After the reaction system was stirred at 0°C for 60 minutes, a saturated ammonium chloride solution (5 mL) was added to the reaction system to quench, and extracted with EtOAc (5 mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, and separated and purified by a normal phase silica gel column (EtOAc/PE=0-10%) to obtain the title compound 11-3 (280 mg), with a yield of 70%. LC-MS (ESI): m/z 264.8 [MH 2 O+H] + .
化合物11-4的制备Preparation of compound 11-4
将化合物11-3(280mg，0.98mmol)和苯酚(185mg，1.97mmol)溶解于二氯甲烷(3mL)中，降温至0℃后，滴加三氟化硼乙醚溶液(48％，387mg，1.97mmol)，缓慢升温至室温并搅拌1小时。反应体系中加入水(5mL)淬灭，用EtOAc(5mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物11-4(180mg)，收率50％。LC-MS(ESI):m/z 357.0[M-H]-。Compound 11-3 (280 mg, 0.98 mmol) and phenol (185 mg, 1.97 mmol) were dissolved in dichloromethane (3 mL), cooled to 0 ° C, and then a solution of boron trifluoride in ether (48%, 387 mg, 1.97 mmol) was added dropwise, and the temperature was slowly raised to room temperature and stirred for 1 hour. Water (5 mL) was added to the reaction system to quench, and the mixture was extracted with EtOAc (5 mL × 3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-20%) to obtain the title compound 11-4 (180 mg) with a yield of 50%. LC-MS (ESI): m/z 357.0 [MH] - .
化合物11-5的制备Preparation of compound 11-5
将化合物11-4(180mg，0.5mmol)，三苯基膦(393mg，1.5mmol)，化合物(2-(甲硫基)嘧啶-4-基)甲醇(117mg，0.75mmol)溶解于四氢呋喃(2mL)中，氮气保护下降温至0℃后，滴加DIAD(303mg， 1.5mmol)，缓慢升温至室温并搅拌16小时。反应体系中加入水(5mL)淬灭，用EtOAc(5mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物11-5(160mg)，收率64％。LC-MS(ESI):m/z 497.0[M+H]+。Compound 11-4 (180 mg, 0.5 mmol), triphenylphosphine (393 mg, 1.5 mmol), and compound (2-(methylthio)pyrimidin-4-yl)methanol (117 mg, 0.75 mmol) were dissolved in tetrahydrofuran (2 mL), cooled to 0° C. under nitrogen protection, and DIAD (303 mg, 1.5mmol), slowly warmed to room temperature and stirred for 16 hours. Water (5mL) was added to the reaction system to quench, extracted with EtOAc (5mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-20%) to obtain the title compound 11-5 (160mg), with a yield of 64%. LC-MS (ESI): m/z 497.0[M+H] + .
化合物11-6的制备Preparation of compound 11-6
将化合物11-5(160mg，0.5mmol)溶解于四氢呋喃(2mL)加入过氧单磺酸钾(445mg，1.29mmol)水(2mL)溶液，室温下搅拌16小时。反应完成后加水(5mL)，用EtOAc(15mL×3)萃取，合并有机相，干燥浓缩得标题化合物11-6(120mg)，收率70％。LC-MS(ESI):m/z 529.2[M+H]+。Compound 11-5 (160 mg, 0.5 mmol) was dissolved in tetrahydrofuran (2 mL) and potassium peroxymonosulfonate (445 mg, 1.29 mmol) in water (2 mL) was added, and stirred at room temperature for 16 hours. After the reaction was completed, water (5 mL) was added, and the mixture was extracted with EtOAc (15 mL×3). The organic phases were combined, dried, and concentrated to obtain the title compound 11-6 (120 mg) with a yield of 70%. LC-MS (ESI): m/z 529.2 [M+H] + .
化合物11的制备Preparation of compound 11
将化合物11-6(120mg，0.22mmol)，碳酸钾(93mg，0.68mmol)，二甲基氧化膦(53mg，0.68mmol)和乙腈(2mL)加入封管中，于80℃搅拌16小时。反应体系中加入水(5mL)淬灭，用EtOAc(5mL×3)萃取，合并有机相，干燥浓缩得粗产品，粗品经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Agilent 10Prep-C18 250×21.2mm；柱温:25℃；梯度:55％-75％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物11(40mg，收率33％)。LC-MS(ESI):m/z 527.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝5.2Hz,1H),7.79–7.65(m,1H),7.25(s,2H),7.23–7.17(m,2H),7.03–6.95(m,2H),5.28(s,2H),4.30–4.16(m,2H),3.98–3.90(m,2H),1.75(d,J＝13.7Hz,6H),1.61(s,6H).31P NMR(162MHz,DMSO-d6)δ33.97(s,1P)。Compound 11-6 (120 mg, 0.22 mmol), potassium carbonate (93 mg, 0.68 mmol), dimethylphosphine oxide (53 mg, 0.68 mmol) and acetonitrile (2 mL) were added to a sealed tube and stirred at 80°C for 16 hours. Water (5 mL) was added to the reaction system to quench, and the mixture was extracted with EtOAc (5 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 11 (40 mg, yield 33%). LC-MS (ESI): m/z 527.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.99 (d, J＝5.2 Hz, 1H), 7.79–7.65 (m, 1H), 7.25 (s, 2H), 7.23–7.17 (m, 2H), 7.03–6.95 (m, 2H), 5.28 (s, 2H), 4.30–4.16 (m, 2H), 3.98–3.90 (m, 2H), 1.75 (d, J＝13.7 Hz, 6H), 1.61 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ33.97 (s, 1P).
实施例12：化合物12的制备
Example 12: Preparation of Compound 12
化合物12-1的制备Preparation of compound 12-1
氮气保护下，将化合物1-3(1.8g，4.8mmol)，甲基硼酸(574g，9.6mmol)，碳酸钾(1.33g，9.6mmol)，Pd(dppf)Cl2(348mg，0.48mmol)，1,4-二氧六环(20mL)和水(4mL)加入100mL三口瓶中，100℃下反应16小时。反应结束后加水60mL，反应体系用EtOAc(30mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-10％)分离纯化得到标题化合物12-1(0.6g)，收率47％。LC-MS(ESI):m/z 263.0[M+H]+。Under nitrogen protection, compound 1-3 (1.8 g, 4.8 mmol), methylboric acid (574 g, 9.6 mmol), potassium carbonate (1.33 g, 9.6 mmol), Pd(dppf)Cl 2 (348 mg, 0.48 mmol), 1,4-dioxane (20 mL) and water (4 mL) were added to a 100 mL three-necked flask and reacted at 100°C for 16 hours. After the reaction, 60 mL of water was added, and the reaction system was extracted with EtOAc (30 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-10%) to obtain the title compound 12-1 (0.6 g) with a yield of 47%. LC-MS (ESI): m/z 263.0 [M+H] + .
化合物12-2的制备Preparation of compound 12-2
将化合物12-1(600mg，2.28mmol)加入三口瓶中，氮气置换三次。在三口瓶中加入无水四氢呋喃(5mL)，并在0℃冷却温度下缓滴加甲基溴化镁四氢呋喃溶液(3M，3.04mL，9.12mmol)。反应体系在0℃ 下搅拌反应60分钟后，反应体系中加入饱和氯化铵溶液(5mL)淬灭，用EtOAc(5mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-10％)分离纯化得到标题化合物12-2(340mg)，收率70％。LC-MS(ESI):m/z 263.0[M+H]+。Compound 12-1 (600 mg, 2.28 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous tetrahydrofuran (5 mL) was added to the three-necked flask and methylmagnesium bromide tetrahydrofuran solution (3 M, 3.04 mL, 9.12 mmol) was slowly added dropwise at 0°C. The reaction system was heated to 0°C. After stirring for 60 minutes, the reaction system was quenched by adding saturated ammonium chloride solution (5 mL), extracted with EtOAc (5 mL×3), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-10%) to obtain the title compound 12-2 (340 mg) with a yield of 70%. LC-MS (ESI): m/z 263.0 [M+H] + .
化合物12-3的制备Preparation of compound 12-3
将化合物12-2(340mg，1.29mmol)和苯酚(243mg，2.58mmol)溶解于二氯甲烷(5mL)中，降温至0℃后，滴加三氟化硼乙醚溶液(48％，2.58mmol)，缓慢升温至室温并搅拌1小时。反应体系中加入水(5mL)淬灭，用EtOAc(15mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物12-3(300mg)，收率68％。LC-MS(ESI):m/z 337.0[M-H]-。Compound 12-2 (340 mg, 1.29 mmol) and phenol (243 mg, 2.58 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 ° C, and then boron trifluoride ether solution (48%, 2.58 mmol) was added dropwise, and the temperature was slowly raised to room temperature and stirred for 1 hour. Water (5 mL) was added to the reaction system to quench, and extracted with EtOAc (15 mL × 3), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-20%) to obtain the title compound 12-3 (300 mg), with a yield of 68%. LC-MS (ESI): m/z 337.0 [MH] - .
化合物12-4的制备Preparation of compound 12-4
将化合物12-3(300mg，0.88mmol)，三苯基膦(463mg，1.77mmol)，化合物(2-(甲硫基)嘧啶-4-基)甲醇(207mg，1.33mmol)溶解于四氢呋喃(3mL)中，氮气保护下降温至0℃后，滴加DIAD(357mg，1.77mmol)，缓慢升温至室温并搅拌16小时。反应体系中加入水(5mL)淬灭，用EtOAc(5mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物12-4(180mg)，收率42％。LC-MS(ESI):m/z 477.0[M+H]+。Compound 12-3 (300 mg, 0.88 mmol), triphenylphosphine (463 mg, 1.77 mmol), and compound (2-(methylthio)pyrimidin-4-yl)methanol (207 mg, 1.33 mmol) were dissolved in tetrahydrofuran (3 mL), cooled to 0°C under nitrogen protection, and DIAD (357 mg, 1.77 mmol) was added dropwise, and the temperature was slowly raised to room temperature and stirred for 16 hours. Water (5 mL) was added to the reaction system to quench, and extracted with EtOAc (5 mL×3), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-20%) to obtain the title compound 12-4 (180 mg) with a yield of 42%. LC-MS (ESI): m/z 477.0[M+H] + .
化合物12-5的制备Preparation of compound 12-5
将化合物12-4(180mg，0.38mmol)溶解于四氢呋喃(2mL)加入过氧单磺酸钾(522mg，1.51mmol)的水(2mL)溶液，室温下搅拌16小时。反应完成后加水(5mL)，用EtOAc(5mL×3)萃取，合并有机相，干燥浓缩得标题化合物12-5(100mg)，收率52％。LC-MS(ESI):m/z 509.0[M+H]+。Compound 12-4 (180 mg, 0.38 mmol) was dissolved in tetrahydrofuran (2 mL) and potassium peroxymonosulfonate (522 mg, 1.51 mmol) in water (2 mL) was added and stirred at room temperature for 16 hours. After the reaction was completed, water (5 mL) was added and extracted with EtOAc (5 mL×3). The organic phases were combined, dried and concentrated to obtain the title compound 12-5 (100 mg) with a yield of 52%. LC-MS (ESI): m/z 509.0 [M+H] + .
化合物12的制备Preparation of compound 12
将化合物12-5(100mg，0.20mmol)，碳酸钾(81mg，0.59mmol)，二甲基氧化膦(46mg，0.59mmol)和乙腈(2mL)加入封管中，于80℃搅拌16小时。反应体系中加入水(5mL)淬灭，用EtOAc(5mL×3)萃取，合并有机相，干燥浓缩得粗产品，粗品经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Agilent 10Prep-C18 250×21.2mm；柱温:25℃；梯度:50％-80％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物12(45mg，收率45％)。LC-MS(ESI):m/z 507.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝5.2Hz,1H),7.73–7.67(m,1H),7.21–7.12(m,2H),7.04(s,2H),7.01–6.93(m,2H),5.27(s,2H),4.17–4.05(m,2H),3.99–3.84(m,2H),2.25(s,3H),1.75(d,J＝13.7Hz,6H),1.59(s,6H).31P NMR(162MHz,DMSO-d6)δ33.97(s,1P)。 Compound 12-5 (100 mg, 0.20 mmol), potassium carbonate (81 mg, 0.59 mmol), dimethylphosphine oxide (46 mg, 0.59 mmol) and acetonitrile (2 mL) were added to a sealed tube and stirred at 80°C for 16 hours. Water (5 mL) was added to the reaction system to quench, and the mixture was extracted with EtOAc (5 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 50%-80% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 12 (45 mg, yield 45%). LC-MS (ESI): m/z 507.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.99 (d, J＝5.2 Hz, 1H), 7.73–7.67 (m, 1H), 7.21–7.12 (m, 2H), 7.04 (s, 2H), 7.01–6.93 (m, 2H), 5.27 (s, 2H), 4.17–4.05 (m, 2H), 3.99–3.84 (m, 2H), 2.25 (s, 3H), 1.75 (d, J＝13.7 Hz, 6H), 1.59 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ33.97 (s, 1P).
实施例13：化合物13的制备
Example 13: Preparation of Compound 13
化合物13-2的制备Preparation of compound 13-2
将化合物13-1(5g，37.3mmol)，乙酰氯(5.85g，74.6mmol)溶于二氯甲烷(100mL)，向其中加入三氯化铝(14.9g，111.9mmol)。加毕，将体系于室温搅拌16h。向体系中加冰水(10mL)淬灭反应后，用二氯甲烷萃取(50mL x 3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，经无水硫酸钠干燥，过滤，滤液浓缩得标题化合物13-2粗品，未经纯化直接用于下一步反应。LC-MS(ESI):218.6[M+H]+。Compound 13-1 (5 g, 37.3 mmol) and acetyl chloride (5.85 g, 74.6 mmol) were dissolved in dichloromethane (100 mL), and aluminum chloride (14.9 g, 111.9 mmol) was added thereto. After the addition, the system was stirred at room temperature for 16 h. Ice water (10 mL) was added to the system to quench the reaction, and then extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of the title compound 13-2, which was directly used in the next step without purification. LC-MS (ESI): 218.6 [M+H] + .
化合物13-3的制备Preparation of compound 13-3
将粗品化合物13-2(5.3g，24.3mmol)溶于甲醇(50mL)及水(50mL)的混合溶剂中，向其中加入氢氧化锂(2.91g，121mmol)。加毕，将体系于室温搅拌2h。向体系中加入稀盐酸将溶液调至pH＝5，用乙酸乙酯萃取(50mL x 3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，无水硫酸钠干燥，过滤，滤液浓缩得标题化合物13-3粗品，未经纯化直接用于下一步反应。LC-MS(ESI):176.6[M+H]+。The crude compound 13-2 (5.3 g, 24.3 mmol) was dissolved in a mixed solvent of methanol (50 mL) and water (50 mL), and lithium hydroxide (2.91 g, 121 mmol) was added thereto. After the addition, the system was stirred at room temperature for 2 h. Dilute hydrochloric acid was added to the system to adjust the solution to pH = 5, and extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude title compound 13-3, which was directly used in the next step without purification. LC-MS (ESI): 176.6 [M+H] + .
化合物13-4的制备Preparation of compound 13-4
将粗品化合物13-3(4.1g，23.3mmol)溶于二氯甲烷(100mL)，向其中加入NBS(4.56g，25.6mmol)。加毕，将体系于室温搅拌16h。向体系中加水(10mL)淬灭反应后，用二氯甲烷萃取(50mL x 3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～25％)得标题化合物13-4。LC-MS(ESI):254.6[M+H]+。The crude compound 13-3 (4.1 g, 23.3 mmol) was dissolved in dichloromethane (100 mL), and NBS (4.56 g, 25.6 mmol) was added thereto. After the addition, the system was stirred at room temperature for 16 h. Water (10 mL) was added to the system to quench the reaction, and then extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-25%) to obtain the title compound 13-4. LC-MS (ESI): 254.6 [M+H] + .
化合物13-5的制备Preparation of compound 13-5
将化合物13-4(5.1g，20.0mmol)，1-溴-2-氯乙烷(5.7g，40.0mmol)溶于DMF(50mL)中，向其中加入碳酸铯(19.5g，60.0mmol)。加毕，将体系于70℃搅拌16h。向体系中加水(50mL)稀释后，用乙酸乙酯萃取(50mL x 3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～25％)得标题化合物13-5。LC-MS(ESI):316.6[M+H]+。Compound 13-4 (5.1 g, 20.0 mmol) and 1-bromo-2-chloroethane (5.7 g, 40.0 mmol) were dissolved in DMF (50 mL), and cesium carbonate (19.5 g, 60.0 mmol) was added thereto. After the addition, the system was stirred at 70°C for 16 h. After dilution with water (50 mL), the system was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-25%) to obtain the title compound 13-5. LC-MS (ESI): 316.6 [M+H] + .
化合物13-6的制备Preparation of compound 13-6
将化合物13-5(2g，6.3mmol)，氰化锌(1.5g，12.6mmol)溶于DMF(20mL)中，向其中加入四三苯基膦钯(0.7g，0.6mmol)。加毕，将体系于微波反应仪中120℃搅拌2h。将体系过滤，向体系中加水(50mL)稀释后，用乙酸乙酯萃取(50mL x 3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，经 无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～25％)得标题化合物13-6。LC-MS(ESI):264.0[M+H]+。Compound 13-5 (2 g, 6.3 mmol) and zinc cyanide (1.5 g, 12.6 mmol) were dissolved in DMF (20 mL), and tetrakistriphenylphosphine palladium (0.7 g, 0.6 mmol) was added thereto. After the addition, the system was stirred at 120°C for 2 h in a microwave reactor. The system was filtered, diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), and then purified by Drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-25%) to obtain the title compound 13-6. LC-MS (ESI): 264.0 [M+H] + .
化合物13-7的制备Preparation of compound 13-7
将化合物13-6(1g，3.8mmol)溶于四氢呋喃(50mL)中，在-78℃条件下，向其中加入甲基溴化镁(1.0M,3.8mL)。加毕，将体系于室温搅拌2h。向体系中加饱和氯化铵溶液(10mL)，淬灭反应后，用乙酸乙酯萃取(50mL x 3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～25％)得标题化合物13-7。Compound 13-6 (1 g, 3.8 mmol) was dissolved in tetrahydrofuran (50 mL), and methylmagnesium bromide (1.0 M, 3.8 mL) was added thereto at -78 °C. After the addition, the system was stirred at room temperature for 2 h. Saturated ammonium chloride solution (10 mL) was added to the system, the reaction was quenched, and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-25%) to obtain the title compound 13-7.
化合物13-8的制备Preparation of compound 13-8
将化合物13-7(700mg，2.5mmol)，苯酚(282mg，3.0mmol)溶于二氯甲烷(50mL)中，在0℃条件下，向其中加入三氟化硼乙醚(48％，1.42mL)。加毕，将体系于室温搅拌2h。向体系中加水(10mL)淬灭反应后，用乙酸乙酯萃取(50mL x 3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～25％)得标题化合物13-8。LC-MS(ESI):355.8[M+H]+。Compound 13-7 (700 mg, 2.5 mmol) and phenol (282 mg, 3.0 mmol) were dissolved in dichloromethane (50 mL). Boron trifluoride etherate (48%, 1.42 mL) was added thereto at 0°C. After the addition, the system was stirred at room temperature for 2 h. Water (10 mL) was added to the system to quench the reaction, and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-25%) to obtain the title compound 13-8. LC-MS (ESI): 355.8 [M+H] + .
化合物13-9的制备Preparation of compound 13-9
将化合物13-8(230mg，0.65mmol)，化合物(2-(甲硫基)嘧啶-4-基)甲磺酸甲酯(302mg，1.3mmol)溶于DMF(10mL)中，向其中加入碳酸铯(635mg，1.95mmol)。加毕，将体系于80℃搅拌2h。向体系中加水(10mL)稀释后，用乙酸乙酯萃取(50mL x 3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～35％)得标题化合物13-9。LC-MS(ESI):493.8[M+H]+。Compound 13-8 (230 mg, 0.65 mmol) and compound (2-(methylthio)pyrimidin-4-yl)methanesulfonic acid methyl ester (302 mg, 1.3 mmol) were dissolved in DMF (10 mL), and cesium carbonate (635 mg, 1.95 mmol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After dilution with water (10 mL), the system was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-35%) to obtain the title compound 13-9. LC-MS (ESI): 493.8 [M+H] + .
化合物13-10的制备Preparation of Compound 13-10
将化合物13-9(250mg，0.51mmol)溶于二氯甲烷(10mL)中，加入间氯过氧苯甲酸(175mg，1.02mmol)。加毕，将体系于室温搅拌2h。向体系中加水(10mL)稀释后，用乙酸乙酯萃取(50mL x 3)，合并有机相，用饱和碳酸氢钠洗涤(50mL x 3)后，经无水硫酸钠干燥，过滤，滤液浓缩得标题化合物13-10粗品，未经纯化直接用于下一步反应。LC-MS(ESI):525.8[M+H]+。Compound 13-9 (250 mg, 0.51 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (175 mg, 1.02 mmol) was added. After the addition, the system was stirred at room temperature for 2 h. After dilution with water (10 mL), the system was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated sodium bicarbonate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of the title compound 13-10, which was directly used in the next step without purification. LC-MS (ESI): 525.8 [M+H] + .
化合物13的制备Preparation of compound 13
将粗品化合物13-10(130mg，0.25mmol)和二甲基氧化膦(192mg，2.5mmol)溶于乙腈(3mL)中，向其中碳酸钾(102mg，0.74mmol)。加毕，将体系于80℃搅拌8h。向体系中加水(10mL)稀释后，乙酸乙酯萃取(50mL x 3)，合并有机相，用饱和碳酸氢钠洗涤(50mL x 3)，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经高效制备液相(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(0.1％FA)-乙腈；流动相乙腈比例50％-70％在12分钟内梯度洗脱；流速30mL/min)纯化得标题化合物13。LC-MS(ESI):523.8[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.87(s,1H),7.68(s,1H),7.55(s,1H),7.11–7.03(m,2H),6.93–6.82(m,2H),5.23(s,2H),4.42(t,J＝5.8Hz,2H),3.83(t,J＝5.8Hz,2H),2.84(t,J＝7.4Hz,2H),2.20(t,J＝7.4Hz,2H),1.90(d,J＝13.5Hz,6H),1.84–1.80(m,2H),1.62(s,6H).31P NMR(162MHz,Chloroform-d)δ35.17(s,1P)。 The crude compound 13-10 (130 mg, 0.25 mmol) and dimethylphosphine oxide (192 mg, 2.5 mmol) were dissolved in acetonitrile (3 mL), and potassium carbonate (102 mg, 0.74 mmol) was added thereto. After the addition, the system was stirred at 80°C for 8 h. After dilution with water (10 mL), the system was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated sodium bicarbonate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 13. LC-MS (ESI): 523.8 [M + H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.11–7.03 (m, 2H), 6.93–6.82 (m, 2H), 5.23 (s, 2H), 4.42 (t, J = 5.8 Hz, 2H), 3.83 (t, J = 5.8 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.4 Hz, 2H), 1.90 (d, J = 13.5 Hz, 6H), 1.84–1.80 (m, 2H), 1.62 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ 35.17 (s, 1P).
实施例14：化合物14的制备
Example 14: Preparation of Compound 14
化合物14-2的制备Preparation of compound 14-2
将化合物14-1(900mg，4.09mmol)溶于四氢呋喃(30mL)，在0℃条件下，向其中加入二异丁基氢化铝(1.0M，8.18mL)。加毕，将体系于室温搅拌16h。向体系中加水(1mL)然后加入氢氧化钠水溶液(15％，1.5mL)淬灭反应后，用无水硫酸钠干燥，过滤，滤液浓缩得标题化合物14-2粗品，未经纯化直接用于下一步反应。LC-MS(ESI):178.8[M+H]+。Compound 14-1 (900 mg, 4.09 mmol) was dissolved in tetrahydrofuran (30 mL), and diisobutylaluminum hydride (1.0 M, 8.18 mL) was added thereto at 0°C. After the addition, the system was stirred at room temperature for 16 h. Water (1 mL) was added to the system, and then an aqueous sodium hydroxide solution (15%, 1.5 mL) was added to quench the reaction, and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of the title compound 14-2, which was directly used in the next step without purification. LC-MS (ESI): 178.8 [M+H] + .
化合物14-3的制备Preparation of compound 14-3
将化合物14-2(230mg，1.29mmol)和甲磺酰氯(295mg，2.58mmol)溶于二氯甲烷(20mL)，在0℃条件下，向其中加入三乙胺(392mg，3.88mmol)。加毕，将体系于室温搅拌2h。向体系中加水(10mL)淬灭反应后，用二氯甲烷萃取(50mL x 3)。有机相合并，用饱和食盐水洗涤(50mL x 3)后，经无水硫酸钠干燥，过滤，滤液浓缩得标题化合物14-3，未经纯化直接用于下一步反应。LC-MS(ESI):256.8[M+H]+。Compound 14-2 (230 mg, 1.29 mmol) and methanesulfonyl chloride (295 mg, 2.58 mmol) were dissolved in dichloromethane (20 mL). Triethylamine (392 mg, 3.88 mmol) was added thereto at 0°C. After the addition, the system was stirred at room temperature for 2 h. Water (10 mL) was added to the system to quench the reaction, and then extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound 14-3, which was directly used in the next step without purification. LC-MS (ESI): 256.8 [M+H] + .
化合物14-4的制备Preparation of compound 14-4
将化合物14-3(200mg，0.78mmol)和化合物1-6(200mg，0.57mmol)溶于DMF(20mL)，向其中加入碳酸铯(555mg，1.71mmol)。加毕，将体系于80℃搅拌2h。向体系中加水(10mL)稀释后，用乙酸乙酯萃取(50mL x 3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～30％)得标题化合物14-4。LC-MS(ESI):508.6[M+H]+。Compound 14-3 (200 mg, 0.78 mmol) and compound 1-6 (200 mg, 0.57 mmol) were dissolved in DMF (20 mL), and cesium carbonate (555 mg, 1.71 mmol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After dilution with water (10 mL), the system was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate/petroleum ether (v/v) = 0-30%) to obtain the title compound 14-4. LC-MS (ESI): 508.6 [M+H] + .
化合物14的制备Preparation of compound 14
将化合物14-4(200mg，0.39mmol)，二甲基氧化膦(304mg，3.9mmol)，Xantphos(45mg，0.078mmol)和三乙胺(393mg，3.9mmol)溶于DMF(20mL)，向其中加入Pd2(dba)3(35.7mg，0.039mmol)。加毕，将体系于微波反应仪中120℃搅拌2h。向体系中加水(10mL)稀释后，用乙酸乙酯萃取(50mL x3)，合并有机相，用饱和食盐水洗涤(50mL x 3)后，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经高效制备液相(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(0.1％FA)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)纯化得标题化合物14。LC-MS(ESI):507.0[M+H]+.1H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.42(d,J＝2.4Hz,1H),7.32(d,J＝2.4Hz,1H),7.10(d,J＝8.7Hz,2H),7.02(d,J＝8.7Hz,2H),5.45(s,2H),4.42(t,J＝6.2Hz,2H),3.87(t,J＝6.2Hz,2H),1.75(d,J＝13.8Hz,6H),1.63(s,6H).31P NMR(162MHz,Chloroform-d)δ31.49(s,1P)。 Compound 14-4 (200 mg, 0.39 mmol), dimethylphosphine oxide (304 mg, 3.9 mmol), Xantphos (45 mg, 0.078 mmol) and triethylamine (393 mg, 3.9 mmol) were dissolved in DMF (20 mL), and Pd 2 (dba) 3 (35.7 mg, 0.039 mmol) was added thereto. After the addition, the system was stirred at 120° C. for 2 h in a microwave reactor. Water (10 mL) was added to the system for dilution, and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 14. LC-MS (ESI): 507.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ7.97 (s, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.10 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 5.45 (s, 2H), 4.42 (t, J=6.2 Hz, 2H), 3.87 (t, J=6.2 Hz, 2H), 1.75 (d, J=13.8 Hz, 6H), 1.63 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ31.49 (s, 1P).
实施例15：化合物15的制备
Example 15: Preparation of Compound 15
化合物15-2的制备Preparation of compound 15-2
将化合物15-1(1g，4.57mmol)溶于无水二氯甲烷(20mL)中，氮气保护-60℃下缓慢滴加二异丁基氢化铝(1.0M，6.85mL，6.85mmol)，滴毕室温反应2小时。TLC跟踪反应至完全后加水淬灭，反应体系用DCM(50mL×2)萃取，合并有机相，干燥浓缩得到标题化合物15-2的粗品330mg，直接用于下一步反应。1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),5.28(t,J＝5.7Hz,1H),4.34(dd,J＝5.7,1.2Hz,2H)。Compound 15-1 (1 g, 4.57 mmol) was dissolved in anhydrous dichloromethane (20 mL), and diisobutylaluminum hydride (1.0 M, 6.85 mL, 6.85 mmol) was slowly added dropwise at -60 °C under nitrogen protection. The reaction was allowed to react at room temperature for 2 hours. TLC was used to track the reaction until it was complete, and water was added to quench the reaction system. The reaction system was extracted with DCM (50 mL × 2), and the organic phases were combined, dried and concentrated to obtain 330 mg of the crude product of the title compound 15-2, which was directly used in the next step. 1 H NMR (400 MHz, DMSO-d6) δ8.09 (s, 1H), 5.28 (t, J = 5.7 Hz, 1H), 4.34 (dd, J = 5.7, 1.2 Hz, 2H).
化合物15-3的制备Preparation of compound 15-3
将化合物15-2(320mg，1.81mmol)溶于二氯甲烷(10mL)中，0℃下滴加三乙胺(0.38mL，2.71mmol)，反应10分钟后再加入甲磺酰氯(249mg，2.17mmol)，室温反应4小时。LCMS跟踪反应至完全后反应体系用DCM(50mL×2)萃取，合并有机相，干燥浓缩得到标题化合物15-3(320mg)的粗品，直接用于下一步反应。1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),5.17(s,2H),3.24(s,3H)。Compound 15-2 (320 mg, 1.81 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.38 mL, 2.71 mmol) was added dropwise at 0°C, and methanesulfonyl chloride (249 mg, 2.17 mmol) was added after 10 minutes of reaction, and the reaction was continued at room temperature for 4 hours. After the reaction was completed by LCMS tracking, the reaction system was extracted with DCM (50 mL×2), and the organic phases were combined, dried and concentrated to obtain the crude product of the title compound 15-3 (320 mg), which was directly used in the next step. 1 H NMR (400 MHz, DMSO-d6) δ8.44 (s, 1H), 5.17 (s, 2H), 3.24 (s, 3H).
化合物15-4的制备Preparation of compound 15-4
将化合物15-3(320mg，0.92mmol)溶于DMF(5mL)中，搅拌下加入碳酸铯(598mg，1.83mmol)，反应5分钟后再加入化合物1-6(304mg，1.19mmol)，80℃下反应4小时。LCMS跟踪反应至完全后将反应液倒入冰水中，EtOAc(50mL×2)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到标题化合物15-4(210mg)，收率45％。LC-MS(ESI):m/z 508.6[M+H]+。Compound 15-3 (320 mg, 0.92 mmol) was dissolved in DMF (5 mL), and cesium carbonate (598 mg, 1.83 mmol) was added under stirring. After reacting for 5 minutes, compound 1-6 (304 mg, 1.19 mmol) was added, and the mixture was reacted at 80°C for 4 hours. After the reaction was completed by LCMS tracking, the reaction solution was poured into ice water, extracted with EtOAc (50 mL×2), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-30%) to obtain the title compound 15-4 (210 mg), with a yield of 45%. LC-MS (ESI): m/z 508.6 [M+H] + .
化合物15的制备Preparation of compound 15
将化合物15-4(210mg，0.41mmol)溶解于N,N-二甲基甲酰胺(3.0mL)中，依次加入二甲基氧化膦(97mg，1.24mmol)、三乙胺(125mg，1.24mmol)、三(二亚苄基丙酮)二钯(38mg，0.04mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(48mg，0.08mmol)。用氮气置换三次后微波100℃下反应2小时。LCMS跟踪反应至反应完全，将反应液过滤，滤液粗品经制备分离纯化(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)得到标题化合物15(35mg，收率17％)。LC-MS(ESI):m/z 507.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.63(d,J＝2.2Hz,1H),7.57(d,J＝2.2Hz,1H),7.18(d,J＝8.9Hz,2H),6.97(d,J＝8.9Hz,2H),5.04(s,2H),4.45–4.36(m,2H),4.01–3.88(m,2H),1.84(d,J＝14.4Hz,6H),1.63(s,6H).31P NMR(162MHz,DMSO-d6)δ25.57(s,1P)。 Compound 15-4 (210 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (3.0 mL), and dimethylphosphine oxide (97 mg, 1.24 mmol), triethylamine (125 mg, 1.24 mmol), tris(dibenzylideneacetone)dipalladium (38 mg, 0.04 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (48 mg, 0.08 mmol) were added in sequence. After replacing with nitrogen three times, the mixture was reacted at 100°C in a microwave oven for 2 hours. The reaction was followed by LCMS until the reaction was complete, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 15 (35 mg, yield 17%). LC-MS (ESI): m/z 507.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.47 (s, 1H), 7.63 (d, J＝2.2 Hz, 1H), 7.57 (d, J＝2.2 Hz, 1H), 7.18 (d, J＝8.9 Hz, 2H), 6.97 (d, J＝8.9 Hz, 2H), 5.04 (s, 2H), 4.45–4.36 (m, 2H), 4.01–3.88 (m, 2H), 1.84 (d, J＝14.4 Hz, 6H), 1.63 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ25.57 (s, 1P).
实施例16：化合物16的制备
Example 16: Preparation of Compound 16
化合物16-1的制备Preparation of compound 16-1
将化合物1-6(500mg，1.42mmol)溶解于THF溶液(10mL)中，加入化合物(6-溴吡啶-3-基)甲醇(320mg，1.7mmol)和三苯基膦(558mg，2.13mmol)。冷却至0℃，缓慢滴加偶氮二甲酸二乙酯(494mg，2.84mmol)，室温反应16小时，反应结束后，粗品经制备分离纯化(分离方法，PE：EA＝10：1-2：1)得到标题化合物16-1(300mg，收率40.6％)。LC-MS(ESI):519.0[M+H]+。Dissolve compound 1-6 (500 mg, 1.42 mmol) in THF solution (10 mL), add compound (6-bromopyridin-3-yl)methanol (320 mg, 1.7 mmol) and triphenylphosphine (558 mg, 2.13 mmol). Cool to 0°C, slowly drop diethyl azodicarboxylate (494 mg, 2.84 mmol), react at room temperature for 16 hours, after the reaction is completed, the crude product is purified by preparative separation (separation method, PE: EA = 10: 1-2: 1) to obtain the title compound 16-1 (300 mg, yield 40.6%). LC-MS (ESI): 519.0 [M+H] + .
化合物16的制备Preparation of compound 16
将化合物16-1(250mg，0.48mmol)溶解于DMF溶液(5mL)中，加入化合物二甲基氧化膦(187mg，2.4mmol)，三乙胺(250mg，0.48mmol)，Pd2(dba)3(18.3mg，0.02mmol)，Xantphos(23.1mg，0.04mmol)，120℃下微波反应16小时，反应结束后，滤液粗品经制备分离纯化(制备方法：流动相：A:0.1％甲酸水溶液；B:乙腈；色谱柱：Agilent 10Prep-C18 250×21.2mm；柱温：25℃；梯度：55％-75％乙腈在12分钟内梯度洗脱；流速：30mL/min)得到标题化合物16(12mg，4.8％)。LC-MS(ESI):517.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.76(d,J＝5.0Hz,1H),8.02(d,J＝5.4Hz,1H),7.63(d,J＝2.3Hz,1H),7.58(m,1H),7.57(d,J＝2.3Hz,1H),7.20(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),5.25(s,2H),4,41(t,J＝5.2Hz,2H),3.95(d,J＝5.2Hz,2H),1.65(d,J＝14.4Hz,6H),1.64(s,6H).31P NMR(162MHz,DMSO-d6)δ34.22。Compound 16-1 (250 mg, 0.48 mmol) was dissolved in DMF solution (5 mL), and dimethylphosphine oxide (187 mg, 2.4 mmol), triethylamine (250 mg, 0.48 mmol), Pd 2 (dba) 3 (18.3 mg, 0.02 mmol), and Xantphos (23.1 mg, 0.04 mmol) were added. The mixture was subjected to microwave reaction at 120°C for 16 hours. After the reaction, the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 16 (12 mg, 4.8%). LC-MS (ESI): 517.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.76 (d, J=5.0 Hz, 1H), 8.02 (d, J=5.4 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.58 (m, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.20 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 5.25 (s, 2H), 4,41 (t, J=5.2 Hz, 2H), 3.95 (d, J=5.2 Hz, 2H), 1.65 (d, J=14.4 Hz, 6H), 1.64 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ34.22.
实施例17：化合物17的制备
Example 17: Preparation of Compound 17
化合物17-1的制备Preparation of compound 17-1
将化合物1-6(500mg，1.42mmol)溶解于THF溶液(10mL)中，加入化合物(2-碘苯基)甲醇(398mg，1.7mmol)和三苯基膦(558mg，2.13mmol)。冷却至0℃，缓慢滴加偶氮二甲酸二乙酯(494mg，2.84mmol)，室温反应16小时，反应结束后，粗品经制备分离纯化(分离方法，PE：EA＝10：1-2：1)得到标题化合物17-1(280mg，收率34.8％)。1H NMR(400MHz,DMSO-d6)δ7.82(t,J＝1.7Hz,1H),7.69(dt,J＝7.9,1.4Hz,1H),7.63(d,J＝2.4Hz,1H),7.56(d,J＝2.4Hz,1H),7.46(d,J＝7.7Hz,1H),7.21(d,J＝7.8Hz,1H),7.17(d,J＝8.8Hz,2H),6.94(d,J＝8.8Hz,2H),5.05(s,2H),4.41(t,J＝5.2HZ,2H),3.95(t,J＝5.2HZ,2H),1.63(s,6H)。Dissolve compound 1-6 (500 mg, 1.42 mmol) in THF solution (10 mL), add compound (2-iodophenyl)methanol (398 mg, 1.7 mmol) and triphenylphosphine (558 mg, 2.13 mmol). Cool to 0°C, slowly drop diethyl azodicarboxylate (494 mg, 2.84 mmol), react at room temperature for 16 hours, and after the reaction, the crude product is purified by preparative separation (separation method, PE: EA = 10: 1-2: 1) to obtain the title compound 17-1 (280 mg, yield 34.8%). 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (t, J = 1.7 Hz, 1H), 7.69 (dt, J = 7.9, 1.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.05 (s, 2H), 4.41 (t, J = 5.2 HZ, 2H), 3.95 (t, J = 5.2 HZ, 2H), 1.63 (s, 6H).
化合物17的制备Preparation of compound 17
将化合物17-1(280mg，0.49mmol)溶解于DMF溶液(5mL)中，加入化合物二甲基氧化膦(187mg，2.4mmol)，三乙胺(250mg，0.48mmol)，Pd2(dba)3(18.3mg，0.02mmol)，Xantphos(23.1mg，0.04mmol)，120℃下微波反应16小时，反应结束后，滤液粗品经制备分离纯化(制备方法：流动相：A:0.1％甲酸水溶液；B:乙腈；色谱柱：Agilent 10Prep-C18 250×21.2mm；柱温：25℃；梯度：55％-75％乙腈在12分钟内梯度洗脱；流速：30mL/min)得到标题化合物17(12mg，4.7％)。LC-MS(ESI):516.5[M+H]+. 1H NMR(400MHz,DMSO-d6)δ7.78–7.80(m,2H),7.64(d,J＝2.4Hz,1H),7.58(t,J＝2.0Hz,1H),7.47(dd,J＝4.9,2.3Hz,2H),7.18(d,J＝8.9Hz,2H),6.95(d,J＝8.9Hz,2H),5.52(s,2H),4.41(t,J＝5.0Hz,2H),3.95(t,J＝5.0Hz,2H),1.74(d,J＝13.3Hz,6H),1.63(s,6H).31P NMR(162MHz,DMSO-d6)δ36.37。Compound 17-1 (280 mg, 0.49 mmol) was dissolved in DMF solution (5 mL), and dimethylphosphine oxide (187 mg, 2.4 mmol), triethylamine (250 mg, 0.48 mmol), Pd 2 (dba) 3 (18.3 mg, 0.02 mmol), and Xantphos (23.1 mg, 0.04 mmol) were added. The mixture was subjected to microwave reaction at 120°C for 16 hours. After the reaction, the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 17 (12 mg, 4.7%). LC-MS (ESI): 516.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ7.78–7.80 (m, 2H), 7.64 (d, J=2.4 Hz, 1H), 7.58 (t, J=2.0 Hz, 1H), 7.47 (dd, J=4.9, 2.3 Hz, 2H), 7.18 (d, J=8.9 Hz, 2H), 6.95 (d, J=8.9 Hz, 2H), 5.52 (s, 2H), 4.41 (t, J=5.0 Hz, 2H), 3.95 (t, J=5.0 Hz, 2H), 1.74 (d, J=13.3 Hz, 6H), 1.63 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ36.37.
实施例18：化合物18的制备
Example 18: Preparation of Compound 18
化合物18的制备Preparation of compound 18
将化合物9(140mg，约0.75mmol，粗品)溶解在MeOH(3.0mL)中，并加入多聚甲醛(68mg，0.75mmol)，室温下搅拌1小时后，随后加入氰基硼氢化钠(47mg，0.75mmol)。反应体系在室温下搅拌1小时。反应结束后，反应液过滤，滤液粗品经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Agilent 10Prep-C18 250×21.2mm；柱温:25℃；梯度:55％-75％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物18(5mg，收率8％)。LC-MS(ESI):m/z 573.0[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.89(d,J＝5.2Hz,1H),7.69(t,J＝4.2Hz,1H),7.44(d,J＝2.4Hz,1H),7.31(d,J＝2.4Hz,1H),7.12(d,J＝8.8Hz,2H),6.90(d,J＝8.8Hz,2H),5.23(s,2H),4.42(t,J＝6.2Hz,2H),3.87(t,J＝6.2Hz,2H),3.17-2.99(m,2H),2.76-2.58(m,4H),2.45–2.27(m,5H),1.64(s,6H).31P NMR(162MHz,Chloroform-d)δ29.02(s,1P)。Compound 9 (140 mg, about 0.75 mmol, crude product) was dissolved in MeOH (3.0 mL), and paraformaldehyde (68 mg, 0.75 mmol) was added. After stirring at room temperature for 1 hour, sodium cyanoborohydride (47 mg, 0.75 mmol) was subsequently added. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 18 (5 mg, yield 8%). LC-MS (ESI): m/z 573.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.89 (d, J = 5.2 Hz, 1H), 7.69 (t, J = 4.2 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 4.42 (t, J = 6.2 Hz, 2H), 3.87 (t, J = 6.2 Hz, 2H), 3.17-2.99 (m, 2H), 2.76-2.58 (m, 4H), 2.45-2.27 (m, 5H), 1.64 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ 29.02 (s, 1P).
实施例19：化合物19的制备
Example 19: Preparation of Compound 19
化合物19-2的制备Preparation of compound 19-2
将化合物1-6(350mg，1mmol)，19-1(580mg，3mmol)，三苯基膦(789mg，3mmol)，DIAD(606mg，3mmol)和无水四氢呋喃(10mL)加入单口瓶中，氮气置换三次，反应在50℃下搅拌反应2小时。反应结束后，将反应液降至室温后向反应体系加入饱和氯化钠水溶液(30mL)，用EtOAc(50mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到标题化合物19-2(250mg)，收率51％。LC-MS(ESI):525.2[M+H]+。Compound 1-6 (350 mg, 1 mmol), 19-1 (580 mg, 3 mmol), triphenylphosphine (789 mg, 3 mmol), DIAD (606 mg, 3 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a single-mouth bottle, replaced with nitrogen three times, and stirred at 50°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature and a saturated sodium chloride aqueous solution (30 mL) was added to the reaction system, extracted with EtOAc (50 mL×3), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-30%) to obtain the title compound 19-2 (250 mg) with a yield of 51%. LC-MS (ESI): 525.2 [M+H] + .
化合物19的制备Preparation of compound 19
将化合物19-2(250mg，0.48mmol)溶解于N,N-二甲基甲酰胺(3.0mL)中，依次加入二甲基氧化膦(114mg，1.45mmol)、三乙胺(146mg，1.45mmol)、三(二亚苄基丙酮)二钯(46mg，0.05mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(30mg，0.05mmol)。用氮气替换三次，反应体系在120℃下微波搅拌反应2小时。反应结束后，反应体系过滤后用二氯甲烷(20mL×3)萃取，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物19(18.25mg，收率7.3％)。LC-MS(ESI):m/z 523.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),7.63(d,J＝2.4Hz,1H),7.56(d,J＝2.4Hz,1H),7.19(d,J＝8.4Hz,2H),6.97(d,J＝8.3Hz,2H),5.76(s,2H),4.41(t,J＝5.1Hz,2H),3.95(t,J＝5.1Hz,2H),1.71(d,J＝13.7Hz,6H),1.62(s,6H).31P NMR(162MHz,DMSO-d6)δ33.66(s,1P)。 Compound 19-2 (250 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (3.0 mL), and dimethylphosphine oxide (114 mg, 1.45 mmol), triethylamine (146 mg, 1.45 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (30 mg, 0.05 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction, the reaction system was filtered and extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25 ° C; gradient: 45%-65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain the title compound 19 (18.25 mg, yield 7.3%). LC-MS (ESI): m/z 523.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.21 (s, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.3 Hz, 2H), 5.76 (s, 2H), 4.41 (t, J=5.1 Hz, 2H), 3.95 (t, J=5.1 Hz, 2H), 1.71 (d, J=13.7 Hz, 6H), 1.62 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ33.66 (s, 1P).
实施例20：化合物20的制备
Example 20: Preparation of Compound 20
化合物20-2的制备Preparation of compound 20-2
将化合物20-1(350mg，1.8mmol)，二氯甲烷(5mL)加入单口瓶中，搅拌下加入戴斯-马丁氧化剂(955mg，2.7mmol)，反应在室温下搅拌反应2小时。反应结束后，将反应液过滤，滤饼用二氯甲烷(10mL)淋洗。向滤液中加入饱和氯化钠水溶液(15mL)清洗，用二氯甲烷(10mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-10％)分离纯化得到标题化合物20-2(300mg)，收率86％。LC-MS(ESI):191.8[M+H]+。Compound 20-1 (350 mg, 1.8 mmol) and dichloromethane (5 mL) were added to a single-mouth bottle, and Dess-Martin periodinane (955 mg, 2.7 mmol) was added under stirring. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered and the filter cake was rinsed with dichloromethane (10 mL). Saturated sodium chloride aqueous solution (15 mL) was added to the filtrate for washing, and it was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-10%) to obtain the title compound 20-2 (300 mg) with a yield of 86%. LC-MS (ESI): 191.8 [M+H] + .
化合物20-3的制备Preparation of Compound 20-3
将化合物20-2(300mg，1.56mmol)，和无水四氢呋喃(6mL)加入三口瓶中，氮气置换三次，反应在-20℃下搅拌反应0.5小时后滴加甲基溴化镁(3.0M,0.65mL)，反应在-20℃下搅拌反应2小时。反应结束后，向反应体系加入饱和氯化铵水溶液(10mL)，用EtOAc(10mL×3)萃取合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到标题化合物20-3(260mg)，收率80％。LC-MS(ESI):208.0[M+H]+。Compound 20-2 (300 mg, 1.56 mmol) and anhydrous tetrahydrofuran (6 mL) were added to a three-necked flask, and the atmosphere was replaced with nitrogen three times. The reaction was stirred at -20°C for 0.5 hours, and then methylmagnesium bromide (3.0 M, 0.65 mL) was added dropwise. The reaction was stirred at -20°C for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride (10 mL) was added to the reaction system, and the organic phases were extracted and combined with EtOAc (10 mL × 3), dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-30%) to obtain the title compound 20-3 (260 mg), with a yield of 80%. LC-MS (ESI): 208.0 [M + H] + .
化合物20-4的制备Preparation of Compound 20-4
将化合物20-3(260mg，1.25mmol)，三乙胺(253mg，2.5mmol)，和无水二氯甲烷(5mL)加入三口瓶中，氮气置换三次，反应在0℃下滴加甲基磺酰氯(178mg，1.56mmol)，室温搅拌反应2小时。反应结束后，向反应体系加入饱和氯化钠水溶液(10mL)，用二氯甲烷(15mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-25％)分离纯化得到标题化合物20-4(310mg)，收率87％。Compound 20-3 (260 mg, 1.25 mmol), triethylamine (253 mg, 2.5 mmol), and anhydrous dichloromethane (5 mL) were added to a three-necked flask, and the atmosphere was replaced with nitrogen three times. Methanesulfonyl chloride (178 mg, 1.56 mmol) was added dropwise at 0°C, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, a saturated sodium chloride aqueous solution (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-25%) to obtain the title compound 20-4 (310 mg) with a yield of 87%.
化合物20-5的制备Preparation of Compound 20-5
将化合物20-4(100mg，0.48mmol)，化合物1-6(168mg，0.48mmol)，碳酸铯(319mg，0.96mmol)和N,N-二甲基甲酰胺(3.0mL)加单口瓶中，氮气置换三次，反应在80℃下搅拌反应2小时。反应结束后冷却至室温，向反应体系加入饱和氯化钠水溶液(10mL)，用EtOAc(15mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-35％)分离纯化得到标题化合物20-5(192mg)，收率74％。LC-MS(ESI):538.8[M+H]+。Compound 20-4 (100 mg, 0.48 mmol), compound 1-6 (168 mg, 0.48 mmol), cesium carbonate (319 mg, 0.96 mmol) and N,N-dimethylformamide (3.0 mL) were added to a single-mouth bottle, replaced with nitrogen three times, and stirred at 80°C for 2 hours. After the reaction was completed, it was cooled to room temperature, and a saturated sodium chloride aqueous solution (10 mL) was added to the reaction system, and extracted with EtOAc (15 mL×3), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-35%) to obtain the title compound 20-5 (192 mg), with a yield of 74%. LC-MS (ESI): 538.8 [M+H] + .
化合物20的制备Preparation of compound 20
将化合物20-5(192mg，0.355mmol)溶解于N,N-二甲基甲酰胺(2mL)中，依次加入二甲基氧化膦(138mg，1.77mmol)、三乙胺(90mg，0.887mmol)、三(二亚苄基丙酮)二钯(46mg，0.05mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(30mg，0.05mmol)。用氮气替换三次，反应体系在120℃下微波搅拌反应2小时。反应结束后，反应体系过滤后用二氯甲烷(20mL×3)萃取，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250 ×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物20(18.25mg，收率7.3％)。LC-MS(ESI):m/z 537.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.61(d,J＝2.4Hz,1H),7.54(d,J＝2.3Hz,1H),7.13(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),6.66(q,J＝6.2Hz,1H),4.40(t,J＝5.1Hz,2H),3.95(t,J＝5.1Hz,2H),1.70(dd,J＝13.8,4.9Hz,6H),1.65(d,J＝6.3Hz,3H),1.59(s,6H).31P NMR(162MHz,DMSO-d6)δ34.21(s,1P)。Compound 20-5 (192 mg, 0.355 mmol) was dissolved in N,N-dimethylformamide (2 mL), and dimethylphosphine oxide (138 mg, 1.77 mmol), triethylamine (90 mg, 0.887 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg, 0.05 mmol) were added in sequence. The gas was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the reaction system was filtered and extracted with dichloromethane (20 mL×3), the organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to give the title compound 20 (18.25 mg, yield 7.3%). LC-MS (ESI): m/z 537.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.14 (s, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.66 (q, J=6.2 Hz, 1H), 4.40 (t, J=5.1 Hz, 2H), 3.95 (t, J=5.1 Hz, 2H), 1.70 (dd, J=13.8, 4.9 Hz, 6H), 1.65 (d, J=6.3 Hz, 3H), 1.59 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ34.21 (s, 1P).
实施例21：化合物21的制备
Example 21: Preparation of Compound 21
化合物21-2的制备Preparation of compound 21-2
氮气保护下，将化合物21-1(13.0g，76.47mmol)和NCS(12.2g，91.76mmol)溶解于乙腈(100mL)中。于室温下搅拌12小时。反应结束后，加入饱和氯化钠溶液(15mL)，反应体系用EtOAc(100mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到标题化合物21-2(10.2g)，产率65％。LC-MS(ESI):m/z 202.8[M-H]-。Under nitrogen protection, compound 21-1 (13.0 g, 76.47 mmol) and NCS (12.2 g, 91.76 mmol) were dissolved in acetonitrile (100 mL). The mixture was stirred at room temperature for 12 hours. After the reaction, saturated sodium chloride solution (15 mL) was added, and the reaction system was extracted with EtOAc (100 mL × 3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-50%) to obtain the title compound 21-2 (10.2 g) with a yield of 65%. LC-MS (ESI): m/z 202.8 [MH] - .
化合物21-3的制备Preparation of compound 21-3
在化合物21-2(12.2g，59.81mmol)，1-溴-2-氯乙烷(17.1g，119.61mmol)，碳酸铯(39.1g，119.61mmol)中加入DMF(150mL)，120℃下反应16小时。反应结束后加入水(300mL)，反应体系用EtOAc(100mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到标题化合物21-3(3.3g)，产率25％。LC-MS(ESI):m/z 267.0[M+H]+。DMF (150 mL) was added to compound 21-2 (12.2 g, 59.81 mmol), 1-bromo-2-chloroethane (17.1 g, 119.61 mmol), and cesium carbonate (39.1 g, 119.61 mmol), and the mixture was reacted at 120°C for 16 hours. After the reaction, water (300 mL) was added, and the reaction system was extracted with EtOAc (100 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-50%) to obtain the title compound 21-3 (3.3 g) with a yield of 25%. LC-MS (ESI): m/z 267.0 [M+H] + .
化合物21-4的制备Preparation of compound 21-4
将化合物21-3(3.3g，12.42mmol)加入三口瓶中，氮气置换三次。在三口瓶中加入无水四氢呋喃(50mL)，并在0℃冷却温度下逐滴滴加甲基溴化镁四氢呋喃溶液(3M，12.4mL，37.26mmol)。反应体系在0℃下搅拌反应60分钟后，反应体系中加入饱和氯化铵溶液(50mL)淬灭，用EtOAc(50mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到标题化合物21-4(2.1g)，产率64％。LC-MS(ESI):m/z 249.2[M-H2O+H]+。Compound 21-3 (3.3 g, 12.42 mmol) was added to a three-necked flask and replaced with nitrogen three times. Anhydrous tetrahydrofuran (50 mL) was added to the three-necked flask, and methyl magnesium bromide tetrahydrofuran solution (3M, 12.4 mL, 37.26 mmol) was added dropwise at a cooling temperature of 0°C. After the reaction system was stirred at 0°C for 60 minutes, a saturated ammonium chloride solution (50 mL) was added to the reaction system for quenching, and the reaction system was extracted with EtOAc (50 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-50%) to obtain the title compound 21-4 (2.1 g) with a yield of 64%. LC-MS (ESI): m/z 249.2 [MH 2 O+H] + .
化合物21-5的制备Preparation of compound 21-5
将化合物21-4(600mg，2.24mmol)和苯酚(633mg，6.75mmol)溶解于二氯甲烷(10mL)中，降温至0℃后，滴加三氟化硼乙醚溶液(48％，1.33g，6.75mmol)，缓慢升温至室温并搅拌1小时。反应体系中加入水(10mL)淬灭，用EtOAc(5mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到标题化合物21-5(400mg)，产率52％。LC-MS(ESI):m/z 341.0[M-H]-。Compound 21-4 (600 mg, 2.24 mmol) and phenol (633 mg, 6.75 mmol) were dissolved in dichloromethane (10 mL). After cooling to 0°C, a boron trifluoride ether solution (48%, 1.33 g, 6.75 mmol) was added dropwise, and the temperature was slowly raised to room temperature and stirred for 1 hour. Water (10 mL) was added to the reaction system to quench, and the mixture was extracted with EtOAc (5 mL × 3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE = 0-50%) to obtain the title compound 21-5 (400 mg) with a yield of 52%. LC-MS (ESI): m/z 341.0 [MH] - .
化合物21-6的制备Preparation of Compound 21-6
将化合物21-5(400mg，1.16mmol)，(2-氯嘧啶-4-基)甲醇(501mg，3.48mmol)，三苯基膦(1.25g， 3.48mmol)，DIAD(702mg，3.48mmol)和无水四氢呋喃(15mL)加入单口瓶中，氮气置换三次，反应在50℃下搅拌反应2小时。反应结束后，将反应液降至室温后向反应体系加入饱和氯化钠水溶液(30mL)，用EtOAc(50mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到标题化合物21-6(200mg)，产率37％。LC-MS(ESI):468.9[M+H]+。Compound 21-5 (400 mg, 1.16 mmol), (2-chloropyrimidin-4-yl)methanol (501 mg, 3.48 mmol), triphenylphosphine (1.25 g, 3.48mmol), DIAD (702mg, 3.48mmol) and anhydrous tetrahydrofuran (15mL) were added to a single-mouth bottle, and nitrogen was replaced three times. The reaction was stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and a saturated sodium chloride aqueous solution (30mL) was added to the reaction system, and extracted with EtOAc (50mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE＝0-50%) to obtain the title compound 21-6 (200mg), with a yield of 37%. LC-MS (ESI): 468.9[M+H] + .
化合物21的制备Preparation of compound 21
将化合物21-6(200mg，0.45mmol)溶解于N,N-二甲基甲酰胺(3mL)中，依次加入二甲基氧化膦(105mg，1.35mmol)、三乙胺(136mg，1.35mmol)、三(二亚苄基丙酮)二钯(46mg，0.05mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(30mg，0.05mmol)。用氮气替换三次，反应体系在120℃下微波搅拌反应2小时。反应结束后，反应体系过滤后用二氯甲烷(20mL×3)萃取，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到标题化合物21(17.56mg，产率8.1％)。LC-MS(ESI):m/z 511.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝5.2Hz,1H),7.71(dd,J＝5.2,3.2Hz,1H),7.19(d,J＝8.8Hz,2H),7.10(dd,J＝12.5,2.3Hz,1H),7.07(dd,J＝3.7,2.1Hz,1H),6.99(d,J＝8.8Hz,2H),5.28(s,2H),4.29(t,J＝5.6Hz,2H),3.89(t,J＝5.6Hz,2H),1.75(d,J＝13.7Hz,6H),1.60(s,6H).31P NMR(162MHz,DMSO-d6)δ33.99(s,1P).19F NMR(377MHz,DMSO-d6)δ-127.02(s,1F)。Compound 21-6 (200 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (3 mL), and dimethylphosphine oxide (105 mg, 1.35 mmol), triethylamine (136 mg, 1.35 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (30 mg, 0.05 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction, the reaction system was filtered and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain the title compound 21 (17.56 mg, yield 8.1%). LC-MS (ESI): m/z 511.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ8.99 (d, J=5.2 Hz, 1H), 7.71 (dd, J=5.2, 3.2 Hz, 1H), 7.19 (d, J=8.8 Hz, 2H), 7.10 (dd, J=12.5, 2.3 Hz, 1H), 7.07 (dd, J=3.7, 2.1 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 5.28 (s, 2H), 4.29 (t, J=5.6 Hz, 2H), 3.89 (t, J=5.6 Hz, 2H), 1.75 (d, J=13.7 Hz, 6H), 1.60 (s, 6H). 31 P NMR (162 MHz, DMSO-d 6 )δ33.99(s,1P). 19 F NMR (377MHz, DMSO-d6)δ-127.02(s,1F).
实施例22：化合物22的制备
Example 22: Preparation of Compound 22
化合物22-2的制备Preparation of compound 22-2
将化合物1-6(1.0g，2.84mmol)溶解于THF溶液(20mL)中，加入化合物(6-溴吡啶-2-基)甲醇(640mg，3.4mmol)和三苯基膦(1.11mg，4.26mmol)。冷却至0℃，缓慢滴加偶氮二甲酸二乙酯(988mg，5.68mmol)，室温反应16小时，反应结束后，粗品经制备分离纯化(分离方法，PE:EA＝10:1-2:1)得到标题化合物22-2(700mg，收率47.3％)。LC-MS(ESI):519.0[M+H]+。Compound 1-6 (1.0 g, 2.84 mmol) was dissolved in THF solution (20 mL), and compound (6-bromopyridin-2-yl)methanol (640 mg, 3.4 mmol) and triphenylphosphine (1.11 mg, 4.26 mmol) were added. The mixture was cooled to 0°C, and diethyl azodicarboxylate (988 mg, 5.68 mmol) was slowly added dropwise. The mixture was reacted at room temperature for 16 hours. After the reaction was completed, the crude product was purified by preparative separation (separation method, PE:EA=10:1-2:1) to obtain the title compound 22-2 (700 mg, yield 47.3%). LC-MS (ESI): 519.0 [M+H] + .
化合物22的制备Preparation of compound 22
将化合物22-2(650mg，1.25mmol)溶解于DMF溶液(10mL)中，加入化合物二甲基氧化膦(390mg，5mmol)，三乙胺(1.26g，12.5mmol)，Pd2(dba)3(36.6mg，0.04mmol)，Xantphos(46.2mg，0.08mmol)，120℃微波反应16小时，反应结束后，滤液粗品经制备分离纯化(制备方法：流动相：A:0.1％甲酸水溶液；B:乙腈；色谱柱：Agilent 10Prep-C18 250×21.2mm；柱温：25℃；梯度：55％-75％乙腈在12分钟内梯度洗脱；流速：30mL/min)，得到浓缩物再经制备TLC分离(DCM：MeOH＝15:1)得到标题化合物22(150mg，4.8％)。LC-MS(ESI):517.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.01(dd,J＝7.7,3.5Hz,1H)，7.89(t,J＝6.3Hz,1H),7.66(d,J＝7.7Hz,1H),7.63(d,J＝2.3Hz,1H),7.57(d,J＝2.4Hz,1H),7.18(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),5.23(s,2H),4.41(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz,2H),1.64(d,J＝13.6Hz,6H),1.63(s,6H).31P NMR(162MHz,DMSO-d6)δ33.81(s,1P)。 Compound 22-2 (650 mg, 1.25 mmol) was dissolved in DMF solution (10 mL), and dimethylphosphine oxide (390 mg, 5 mmol), triethylamine (1.26 g, 12.5 mmol), Pd 2 (dba) 3 (36.6 mg, 0.04 mmol), and Xantphos (46.2 mg, 0.08 mmol) were added. The mixture was subjected to microwave reaction at 120°C for 16 hours. After the reaction, the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min). The concentrate was separated by preparative TLC (DCM: MeOH = 15:1) to obtain the title compound 22 (150 mg, 4.8%). LC-MS (ESI): 517.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.01 (dd, J = 7.7, 3.5 Hz, 1H), 7.89 (t, J = 6.3 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 4.41 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 1.64 (d, J = 13.6 Hz, 6H), 1.63 (s, 6H). 31 P NMR (162 MHz, DMSO-d 6 ) δ 33.81 (s, 1P).
实施例23：化合物23的制备
Example 23: Preparation of Compound 23
化合物23-2的制备Preparation of compound 23-2
将化合物1-6溶解于THF溶液(10mL)中，加入化合物(3-碘苯基)甲醇(398mg，1.7mmol)和三苯基膦(558mg，2.13mmol)。冷却至0℃，缓慢滴加偶氮二甲酸二乙酯(494mg，2.84mmol)，室温反应16小时，反应结束后，粗品经制备分离纯化(分离方法，PE:EA＝10:1-2:1)得到标题化合物23-2(320mg，产率39.8％)。1H NMR(400MHz,DMSO-d6)δ7.82(s,1H),7.69(d,J＝7.9Hz,1H),7.63(d,J＝2.4Hz,1H),7.57(d,J＝2.4Hz,1H),7.46(d,J＝7.7Hz,1H),7.20(t,J＝7.8Hz,1H),7.17(d,J＝8.9Hz,2H),6.94(d,J＝8.9Hz,2H),5.05(s,2H),4.41(t,J＝4.0Hz,2H),3.95(t,J＝4.0Hz,2H),1.63(s,6H)。Compound 1-6 was dissolved in THF solution (10 mL), and compound (3-iodophenyl)methanol (398 mg, 1.7 mmol) and triphenylphosphine (558 mg, 2.13 mmol) were added. The mixture was cooled to 0°C, and diethyl azodicarboxylate (494 mg, 2.84 mmol) was slowly added dropwise. The mixture was reacted at room temperature for 16 hours. After the reaction was completed, the crude product was purified by preparative separation (separation method, PE:EA=10:1-2:1) to obtain the title compound 23-2 (320 mg, yield 39.8%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.82 (s, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.17 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.9 Hz, 2H), 5.05 (s, 2H), 4.41 (t, J=4.0 Hz, 2H), 3.95 (t, J=4.0 Hz, 2H), 1.63 (s, 6H).
化合物23的制备Preparation of compound 23
将化合物23-2(300mg，0.53mmol)溶解于DMF溶液(5mL)中，加入化合物二甲基氧化膦(187mg，2.4mmol)，三乙胺(250mg，0.48mmol)，Pd2(dba)3(18.3mg，0.02mmol)，Xantphos(23.1mg，0.04mmol)，120℃微波反应16小时，反应结束后，滤液粗品经制备分离纯化(制备方法：流动相：A:0.1％甲酸水溶液；B:乙腈；色谱柱：Agilent 10Prep-C18 250×21.2mm；柱温：25℃；梯度：55％-75％乙腈在12分钟内梯度洗脱；流速：30mL/min)，得到浓缩物再经制备TLC分离(DCM：MeOH＝15：1)得到标题化合物23(14mg，5.1％).LC-MS(ESI):516.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.85(d,J＝11.8Hz,1H),7.72(t,J＝9.3Hz,1H),7.63(d,J＝2.3Hz,1H),7.62(s,1H),7.57(d,J＝2.4Hz,1H),7.54(dt,J＝7.5,2.8Hz,1H),7.18(d,J＝8.8Hz,2H),6.97(d,J＝8.8Hz,2H),5.14(s,2H),4.41(t,J＝5.3Hz,2H),3.96(t,J＝5.4Hz,2H),1.65(d,J＝13.4Hz,6H),1.63(s,6H).31P NMR(162MHz,DMSO-d6)δ32.34(s,1P)。Compound 23-2 (300 mg, 0.53 mmol) was dissolved in DMF solution (5 mL), and dimethylphosphine oxide (187 mg, 2.4 mmol), triethylamine (250 mg, 0.48 mmol), Pd 2 (dba) 3 (18.3 mg, 0.02 mmol), and Xantphos (23.1 mg, 0.04 mmol) were added, and microwave reaction was performed at 120°C for 16 hours. After the reaction, the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min), the concentrate was separated by preparative TLC (DCM: MeOH = 15: 1) to give the title compound 23 (14 mg, 5.1%). LC-MS (ESI): 516.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.85(d, J＝11.8 Hz, 1H), 7.72(t, J＝9.3 Hz, 1H), 7.63(d, J＝2.3 Hz, 1H), 7.62(s, 1H), 7.57(d, J＝2.4 Hz, 1H), 7.54(dt, J＝7.5, 2.8 Hz, 1H), 7.18(d, J＝8.8 Hz, 2H), 6.97(d, J＝8.8 Hz, 2H), 5.14(s, 2H), 4.41(t, J＝5.3 Hz, 2H), 3.96(t, J＝5.4 Hz, 2H), 1.65(d, J＝13.4 Hz, 6H), 1.63(s, 6H). 31 P NMR (162 MHz, DMSO-d 6 )δ32.34(s, 1P).
实施例24：化合物24的制备
Example 24: Preparation of Compound 24
化合物24-2的制备Preparation of compound 24-2
往100mL单口瓶加化合物24-1(1.75g，6.86mmol)，DMF(25mL)，1-溴-2-氯乙烷(1.51g，10.51mmol，875.00μL)，K2CO3(2.87g，20.77mmol)，室温(25℃)搅拌21小时TLC(PE:EA＝3:1)监测，显示有少量原料剩余，有两个主斑点。LCMS显示无原料分子离子峰，主峰为目标产物分子离子峰。加水(100mL)，乙酸乙酯(80mL)萃取两次。有机相合并，水洗(100mL)两次，无水硫酸钠干燥，抽滤， 滤液减压蒸干，得浅黄色液体，柱层析纯化(PE:EA＝1:0～10:1～5:1～3:1)得1.03g标题化合物24-2。LC-MS(ESI):m/z 317.0[M+H]+.1H NMR(400MHz,CDCl3)δ8.43(d,J＝1.6Hz,1H),8.26(d,J＝1.6Hz,1H),8.17(s,1H),5.15(t,J＝6.8Hz,2H),3.96(t,J＝6.8Hz,2H),3.95(s,3H).Add compound 24-1 (1.75 g, 6.86 mmol), DMF (25 mL), 1-bromo-2-chloroethane (1.51 g, 10.51 mmol, 875.00 μL), K 2 CO 3 (2.87 g, 20.77 mmol) to a 100 mL single-mouth bottle and stir at room temperature (25°C) for 21 hours. TLC (PE:EA=3:1) monitoring shows that a small amount of raw materials remain and there are two main spots. LCMS shows that there is no molecular ion peak of the raw material, and the main peak is the molecular ion peak of the target product. Add water (100 mL) and extract twice with ethyl acetate (80 mL). Combine the organic phases, wash twice with water (100 mL), dry over anhydrous sodium sulfate, and filter. The filtrate was evaporated to dryness under reduced pressure to obtain a light yellow liquid, which was purified by column chromatography (PE:EA＝1:0～10:1～5:1～3:1) to obtain 1.03 g of the title compound 24-2. LC-MS (ESI): m/z 317.0 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δ8.43 (d, J＝1.6 Hz, 1H), 8.26 (d, J＝1.6 Hz, 1H), 8.17 (s, 1H), 5.15 (t, J＝6.8 Hz, 2H), 3.96 (t, J＝6.8 Hz, 2H), 3.95 (s, 3H).
化合物24-3的制备Preparation of compound 24-3
往100mL单口瓶加化合物24-2(0.95g，2.99mmol)，Zn(CN)2(703.00mg，5.99mmol)，Pd(PPh3)4(694mg，600.57μmol)，DMF(19mL)，氮气置换三次，于100℃搅拌18小时。LCMS监测显示原料反应完全。冷却至室温。向反应体系中加入饱和氯化铵溶液(60mL)淬灭，加乙酸乙酯(60mL)，垫硅藻土滤除不溶性物质，乙酸乙酯洗涤(40mL)。滤液合并，混合，静置、分层。水相乙酸乙酯萃取(50mL)。有机相合并，水洗(80mL*2)，无水硫酸钠干燥，抽滤，滤液减压蒸干，得1.5g类白色固体。用乙酸乙酯(5mL)和PE(5mL)结晶，得0.91g标题化合物24-3。LC-MS-ESI+:m/z[M+H]+264.1.Add compound 24-2 (0.95 g, 2.99 mmol), Zn(CN) 2 (703.00 mg, 5.99 mmol), Pd(PPh 3 ) 4 (694 mg, 600.57 μmol), DMF (19 mL) to a 100 mL single-mouth bottle, replace with nitrogen three times, and stir at 100 ° C for 18 hours. LCMS monitoring shows that the raw material reacts completely. Cool to room temperature. Add saturated ammonium chloride solution (60 mL) to the reaction system to quench, add ethyl acetate (60 mL), filter out insoluble matter with diatomaceous earth, and wash with ethyl acetate (40 mL). Combine the filtrates, mix, stand and separate. Extract the aqueous phase with ethyl acetate (50 mL). Combine the organic phases, wash with water (80 mL*2), dry with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain 1.5 g of off-white solid. Crystallize with ethyl acetate (5 mL) and PE (5 mL) to obtain 0.91 g of the title compound 24-3. LC-MS-ESI + :m/z[M+H] + 264.1.
化合物24-4的制备Preparation of compound 24-4
往伴有氮气球的100mL三口瓶加化合物24-3(0.91g，3.45mmol)，THF(10mL)，搅拌溶解，氮气置换三次。冷却至0℃，滴加CH3MgBr(3M，12.08mmol，4.03mL)。滴加完毕，保温搅拌4小时。TLC(PE:EA＝1:1)监测，显示反应完全。缓慢滴加饱和氯化铵溶液(50mL)淬灭反应，将THF减压蒸除，加水(30mL)，乙酸乙酯萃取(50mL+30mL)。有机相合并，水洗(20mL)，无水硫酸钠干燥，抽滤，滤液减压蒸干，得1g标题化合物24-4。未经纯化，直接用于下一步。Add compound 24-3 (0.91 g, 3.45 mmol) and THF (10 mL) to a 100 mL three-necked flask with a nitrogen balloon, stir to dissolve, and replace with nitrogen three times. Cool to 0°C, add CH 3 MgBr (3M, 12.08 mmol, 4.03 mL) dropwise. After the addition is complete, stir for 4 hours. TLC (PE:EA＝1:1) monitoring shows that the reaction is complete. Saturated ammonium chloride solution (50 mL) is slowly added dropwise to quench the reaction, THF is evaporated under reduced pressure, water (30 mL) is added, and ethyl acetate is extracted (50 mL+30 mL). The organic phases are combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain 1 g of the title compound 24-4. It is used directly in the next step without purification.
化合物24-5的合成Synthesis of compound 24-5
往100mL单口瓶中加化合物24-4(1g，3.79mmol)，苯酚(714mg，7.59mmol)和DCM(10mL)，冰水浴冷却，滴加BF3-Et2O(1.15g，8.10mmol，1mL)，缓慢升至室温搅拌过夜(16小时)。LCMS监测显示反应完全。向反应体系中加入饱和氯化铵溶液(40mL)淬灭，DCM萃取(50mL+25mL)。有机相合并，水洗(30mL)，减压浓缩，通过正相硅胶柱纯化(EA/PE＝0～20％)，得0.52g标题化合物24-5。LC-MS(ESI):m/z 340.0[M+H]+.1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.90(d,J＝1.6Hz,1H),7.57(d,J＝1.6Hz,1H),7.06～7.09(m,2H),6.75～6.75(m,2H),5.02(t,J＝6Hz,3H),4.01(t,J＝6Hz,3H),1.71(s,6H).Add compound 24-4 (1 g, 3.79 mmol), phenol (714 mg, 7.59 mmol) and DCM (10 mL) to a 100 mL single-mouth bottle, cool in an ice-water bath, dropwise add BF 3 -Et 2 O (1.15 g, 8.10 mmol, 1 mL), slowly warm to room temperature and stir overnight (16 hours). LCMS monitoring shows that the reaction is complete. Add saturated ammonium chloride solution (40 mL) to the reaction system for quenching, and extract with DCM (50 mL + 25 mL). Combine the organic phases, wash with water (30 mL), concentrate under reduced pressure, and purify by normal phase silica gel column (EA/PE = 0-20%) to obtain 0.52 g of the title compound 24-5. LC-MS (ESI): m/z 340.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ8.09 (s, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.06-7.09 (m, 2H), 6.75-6.75 (m, 2H), 5.02 (t, J=6 Hz, 3H), 4.01 (t, J=6 Hz, 3H), 1.71 (s, 6H).
化合物24-6的制备Preparation of Compound 24-6
往25mL单口瓶加化合物24-5(0.38g，1.12mmol)，2-甲硫基嘧啶-4-基甲醇(265mg，1.70mmol)，DCM(14.99mL)和TMAD(600mg，3.48mmol)，氮气保护，冷却至0℃，加Bu3P(696.60mg，3.44mmol，860μL)，缓慢升至室温(25℃)搅拌1小时。LCMS监测显示原料反应完全。向反应体系中加入饱和氯化铵溶液(50mL)淬灭，二氯甲烷萃取(50+30mL)。有机相合并，无水硫酸钠干燥，抽滤，滤液减压蒸干，得黄色液体。通过正相硅胶纯化(EA/PE＝10～20％)得0.53g标题化合物24-6。LC-MS(ESI):m/z 478.0[M+H]+.Add compound 24-5 (0.38 g, 1.12 mmol), 2-methylthiopyrimidin-4-ylmethanol (265 mg, 1.70 mmol), DCM (14.99 mL) and TMAD (600 mg, 3.48 mmol) to a 25 mL single-mouth bottle, protect with nitrogen, cool to 0 ° C, add Bu 3 P (696.60 mg, 3.44 mmol, 860 μL), slowly warm to room temperature (25 ° C) and stir for 1 hour. LCMS monitoring shows that the raw material reaction is complete. Add saturated ammonium chloride solution (50 mL) to the reaction system to quench, and extract with dichloromethane (50+30 mL). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain a yellow liquid. Purify by normal phase silica gel (EA/PE=10-20%) to obtain 0.53 g of the title compound 24-6. LC-MS (ESI): m/z 478.0 [M+H] + .
化合物24-7的制备Preparation of compound 24-7
往100mL单口瓶加化合物24-6(0.48g，1.00mmol)，DCM(10mL)，搅拌溶解，加m-CPBA(615mg，3.03mmol，85％纯度)，25℃下搅拌16小时。LCMS显示原料反应完全。向反应体系中加入碳酸钠溶液(50mL)淬灭反应，DCM萃取(50+30mL)。有机相合并，水洗(30mL)，减压蒸干，得浅黄色液体。通过正相硅胶柱纯化(EA/PE＝10～50％)得0.43g标题化合物24-7。LC-MS(ESI):m/z 510.0[M+H]+.Add compound 24-6 (0.48 g, 1.00 mmol) and DCM (10 mL) to a 100 mL single-mouth bottle, stir to dissolve, add m-CPBA (615 mg, 3.03 mmol, 85% purity), and stir at 25°C for 16 hours. LCMS shows that the raw material is completely reacted. Add sodium carbonate solution (50 mL) to the reaction system to quench the reaction, and extract with DCM (50+30 mL). The organic phases are combined, washed with water (30 mL), and evaporated to dryness under reduced pressure to obtain a light yellow liquid. Purify by normal phase silica gel column (EA/PE=10-50%) to obtain 0.43 g of the title compound 24-7. LC-MS (ESI): m/z 510.0 [M+H] + .
化合物24的合成Synthesis of compound 24
往50mL单口瓶加化合物24-7(0.38g，745.09μmol)，CH3CN(10mL)，K2CO3(824mg，5.96mmol)和二甲基氧化膦(471.20mg，6.04mmol)，升至80℃搅拌16小时。LCMS显示反应完全。向反应体系中加入饱和氯化铵溶液(80mL)淬灭，乙酸乙酯萃取(50mL*3)。有机相合并，减压蒸干，通过正相硅胶柱纯化(MeOH/EA＝0～10％)，得黄色液体。再通过制备液相纯化，得105mg标题化合物24。LC-MS(ESI):m/z 508.0[M+H]+.1H NMR(400MHz,CDCl3)δ8.89(d,J＝4.8Hz,1H),8.10(s,1H),7.92(d,J＝1.6Hz,1H),7.71(t,J＝4Hz,1H),7.54(d,J＝1.6Hz,1H),7.16(d,J＝8.4Hz,2H),6.90(d,J＝8.0Hz,2H),5.24(s,2H), 5.02(t,J＝6Hz,2H),4.01(t,J＝6Hz,2H),1.96(d,J＝14Hz,6H),1.73(s,6H).31P NMR(162MHz,CDCl3)δ39.27(s,1P).Compound 24-7 (0.38 g, 745.09 μmol), CH 3 CN (10 mL), K 2 CO 3 (824 mg, 5.96 mmol) and dimethylphosphine oxide (471.20 mg, 6.04 mmol) were added to a 50 mL single-mouth bottle, and the temperature was raised to 80°C and stirred for 16 hours. LCMS showed that the reaction was complete. Saturated ammonium chloride solution (80 mL) was added to the reaction system to quench, and ethyl acetate was extracted (50 mL*3). The organic phases were combined, evaporated to dryness under reduced pressure, and purified by normal phase silica gel column (MeOH/EA=0-10%) to obtain a yellow liquid. It was further purified by preparative liquid phase to obtain 105 mg of the title compound 24. LC-MS (ESI): m/z 508.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ8.89 (d, J=4.8 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.71 (t, J=4 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.0 Hz, 2H), 5.24 (s, 2H), 5.02 (t, J = 6 Hz, 2H), 4.01 (t, J = 6 Hz, 2H), 1.96 (d, J = 14 Hz, 6H), 1.73 (s, 6H). 31 P NMR (162 MHz, CDCl 3 ) δ 39.27 (s, 1P).
实施例25：化合物25的制备
Example 25: Preparation of Compound 25
化合物25-2的合成Synthesis of compound 25-2
往50mL单口瓶加化合物25-1(0.88g，2.77mmol)，Pd(PPh3)4(640mg，553.84μmol)，Zn(CN)2(651mg，5.54mmol)和DMF(18mL)，氮气置换三次，于100℃搅拌18小时，LCMS显示原料反应完全。冷却至室温。加水(80mL)和乙酸乙酯(60mL)，垫硅藻土滤除不溶性固体。滤饼乙酸乙酯(40mL)淋洗。滤液合并，混合、静置、分层。水相乙酸乙酯(40mL)萃取。有机相合并，水洗(80mL*2)，无水硫酸钠干燥，抽滤，滤液减压蒸干，得黄色固体。用乙酸乙酯/石油醚(10mL/5mL)结晶，得0.66g标题化合物25-2。LC-MS(ESI):m/z 264.2[M+H]+.Add compound 25-1 (0.88 g, 2.77 mmol), Pd(PPh 3 ) 4 (640 mg, 553.84 μmol), Zn(CN) 2 (651 mg, 5.54 mmol) and DMF (18 mL) to a 50 mL single-mouth bottle, replace with nitrogen three times, stir at 100 ° C for 18 hours, LCMS shows that the raw material is completely reacted. Cool to room temperature. Add water (80 mL) and ethyl acetate (60 mL), filter out insoluble solids through diatomaceous earth pad. Rinse the filter cake with ethyl acetate (40 mL). Combine the filtrates, mix, stand, and separate. Extract the aqueous phase with ethyl acetate (40 mL). Combine the organic phases, wash with water (80 mL*2), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain a yellow solid. Crystallize with ethyl acetate/petroleum ether (10 mL/5 mL) to obtain 0.66 g of the title compound 25-2. LC-MS (ESI): m/z 264.2 [M+H] + .
化合物25-3的合成Synthesis of compound 25-3
往100mL三口瓶加化合物25-2(0.66g，2.50mmol)，THF(10mL)，冷却至0℃，滴加CH3MgBr(3M，8.76mmol，2.92mL)，滴加完毕，保温搅拌1小时。TLC(PE:EA＝1:1)显示反应完全。将反应液缓慢倒入氯化铵的水溶液中(80mL)，乙酸乙酯萃取(60+40mL)。有机相合并，水洗(30mL)，无水硫酸钠干燥，抽滤，滤液减压蒸干，得0.86g黄色液体。未经纯化，直接用于下一步。Add compound 25-2 (0.66 g, 2.50 mmol) and THF (10 mL) to a 100 mL three-necked flask, cool to 0°C, add CH 3 MgBr (3M, 8.76 mmol, 2.92 mL) dropwise, and stir for 1 hour after the addition is complete. TLC (PE:EA=1:1) shows that the reaction is complete. Slowly pour the reaction solution into an aqueous solution of ammonium chloride (80 mL), and extract with ethyl acetate (60+40 mL). Combine the organic phases, wash with water (30 mL), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain 0.86 g of a yellow liquid. Use it directly in the next step without purification.
化合物25-4的合成Synthesis of compound 25-4
氮气氛围下，往100mL单口瓶加化合物25-3(0.86g，3.26mmol)，苯酚(614mg，6.52mmol)，DCM(12mL)，冷却至0℃，加BF3-Et2O(1.93g，6.52mmol，1.68mL，48％质量分数)，滴加完毕，保温搅拌2小时，LCMS显示反应完全。加饱和氯化铵水溶液(50mL)淬灭反应，DCM萃取(80+50mL)。有机相合并，水洗(50mL)，减压蒸干，得黄色液体。通过正相硅胶柱纯化(EA/PE＝10～30％)，得0.34g标题化合物25-4。LC-MS(ESI):m/z 340.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.86(d,J＝1.6Hz,1H),7.49(d,J＝2.0Hz,1H),7.07～7.09(m,2H),6.75～6.77(m,2H),4.77(t,J＝6Hz,2H),4.07(t,J＝6Hz,2H),1.69(s,6H).Under nitrogen atmosphere, add compound 25-3 (0.86 g, 3.26 mmol), phenol (614 mg, 6.52 mmol), DCM (12 mL) to a 100 mL single-mouth bottle, cool to 0°C, add BF 3 -Et 2 O (1.93 g, 6.52 mmol, 1.68 mL, 48% mass fraction), add dropwise, keep warm and stir for 2 hours, LCMS shows the reaction is complete. Add saturated aqueous ammonium chloride solution (50 mL) to quench the reaction, extract with DCM (80+50 mL). Combine the organic phases, wash with water (50 mL), and evaporate to dryness under reduced pressure to obtain a yellow liquid. Purify by normal phase silica gel column (EA/PE=10-30%) to obtain 0.34 g of the title compound 25-4. LC-MS (ESI): m/z 340.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ8.10 (s, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.07-7.09 (m, 2H), 6.75-6.77 (m, 2H), 4.77 (t, J=6 Hz, 2H), 4.07 (t, J=6 Hz, 2H), 1.69 (s, 6H).
化合物25-5的合成Synthesis of compound 25-5
往100mL单口瓶加化合物25-4(0.34g，1.00mmol)，化合物2-甲硫基嘧啶-4-基甲醇(235mg，1.50mmol)，TMAD(520mg，3.02mmol)和DCM(10mL)，冷却至0℃，加Bu3P(610mg，3.02mmol)，缓慢升至室温搅拌16小时。LCMS监测反应完全。加饱和氯化铵水溶液(50mL)淬灭反应，二氯甲烷萃取(50+30mL)。有机相合并，水洗(30mL)，减压蒸干，得黄色液体。通过正相硅胶柱纯化(EA/PE＝0～25％)得0.44g标题化合物25-5。LC-MS(ESI):m/z 478.0[M+H]+.Add compound 25-4 (0.34 g, 1.00 mmol), compound 2-methylthiopyrimidin-4-ylmethanol (235 mg, 1.50 mmol), TMAD (520 mg, 3.02 mmol) and DCM (10 mL) to a 100 mL single-mouth bottle, cool to 0°C, add Bu 3 P (610 mg, 3.02 mmol), slowly warm to room temperature and stir for 16 hours. LCMS monitoring reaction is complete. Add saturated aqueous ammonium chloride solution (50 mL) to quench the reaction, extract with dichloromethane (50+30 mL). Combine the organic phases, wash with water (30 mL), and evaporate to dryness under reduced pressure to obtain a yellow liquid. Purify by normal phase silica gel column (EA/PE=0-25%) to obtain 0.44 g of the title compound 25-5. LC-MS (ESI): m/z 478.0 [M+H] + .
化合物25-6的合成Synthesis of compound 25-6
往100mL单口瓶加化合物25-5(0.44g，920.49μmol)，DCM(10mL)，冰水浴冷却至0℃，加m- CPBA(561mg，2.76mmol，85％纯度)，缓慢升至室温搅拌20小时。TLC(PE:EA＝1:1)显示反应完全。加饱和氯化铵水溶液(50mL)淬灭反应，DCM萃取(50+30mL)。有机相合并，碳酸钠溶液洗涤(30mL)，减压蒸干，得浅黄色液体。通过正相硅胶柱纯化(EA/PE＝0～50％)，得0.44g标题化合物25-6。1H NMR(400MHz,CDCl3)δ8.93(d,J＝5.2Hz,1H),8.12(s,1H),7.90(d,J＝2Hz,1H),7.85(d,J＝4.8Hz,1H),7.44(d,J＝1.6Hz,1H),7.15～7.18(m,2H),6.87～6.90(m,2H),5.29(s,2H),4.77(t,J＝5.6Hz,2H),4.07(t,J＝5.6Hz,2H),3.39(s,3H),1.71(s,6H).Add compound 25-5 (0.44 g, 920.49 μmol) and DCM (10 mL) to a 100 mL single-necked bottle, cool to 0°C in an ice-water bath, and add m- CPBA (561 mg, 2.76 mmol, 85% purity), slowly warm to room temperature and stir for 20 hours. TLC (PE: EA = 1: 1) shows that the reaction is complete. Add saturated aqueous ammonium chloride solution (50 mL) to quench the reaction, and extract with DCM (50 + 30 mL). The organic phases are combined, washed with sodium carbonate solution (30 mL), and evaporated to dryness under reduced pressure to obtain a light yellow liquid. Purify by normal phase silica gel column (EA/PE = 0 ~ 50%) to obtain 0.44 g of the title compound 25-6. 1 H NMR (400 MHz, CDCl 3 ) δ8.93 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 7.90 (d, J=2 Hz, 1H), 7.85 (d, J=4.8 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.15-7.18 (m, 2H), 6.87-6.90 (m, 2H), 5.29 (s, 2H), 4.77 (t, J=5.6 Hz, 2H), 4.07 (t, J=5.6 Hz, 2H), 3.39 (s, 3H), 1.71 (s, 6H).
化合物25的合成Synthesis of compound 25
往100mL单口瓶加化合物25-6(0.25g，490.19μmol)，K2CO3(545.00mg，3.94mmol)，CH3CN(10mL)和二甲基氧化膦(310.00mg，3.97mmol)，升至80℃搅拌18小时。LCMS监测显示反应完全。冷却至室温。加饱和氯化铵水溶液(50mL)淬灭反应，乙酸乙酯萃取(100+50+50mL)三次。有机相合并，减压蒸干，得棕黄色液体。通过正相硅胶柱纯化(MeOH/EA＝0～10％)，得155mg粘稠物。制备HPLC纯化，得40.5mg标题化合物25。LC-MS(ESI):m/z 508.4[M+H]+.1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.13(s,1H),7.90(s,1H),7.69(s,1H),7.45(s,1H),7.15(d,J＝8Hz,2H),6.89(d,J＝8Hz,2H),5.24(s,2H),4.77(t,J＝5.6Hz,2H),4.07(t,J＝5.6Hz,2H),1.90(d,J＝13.2Hz,6H),1.70(s,6H).31P NMR(162MHz,CDCl3)δ35.08(s,1P).Compound 25-6 (0.25 g, 490.19 μmol), K 2 CO 3 (545.00 mg, 3.94 mmol), CH 3 CN (10 mL) and dimethylphosphine oxide (310.00 mg, 3.97 mmol) were added to a 100 mL single-mouth bottle, and the temperature was raised to 80°C and stirred for 18 hours. LCMS monitoring showed that the reaction was complete. Cooled to room temperature. Saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100+50+50 mL) three times. The organic phases were combined and evaporated to dryness under reduced pressure to obtain a brown-yellow liquid. Purification by normal phase silica gel column (MeOH/EA=0-10%) obtained 155 mg of viscous material. Purification by preparative HPLC obtained 40.5 mg of the title compound 25. LC-MS (ESI): m/z 508.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ8.89 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 7.15 (d, J=8 Hz, 2H), 6.89 (d, J=8 Hz, 2H), 5.24 (s, 2H), 4.77 (t, J=5.6 Hz, 2H), 4.07 (t, J=5.6 Hz, 2H), 1.90 (d, J=13.2 Hz, 6H), 1.70 (s, 6H). 31 P NMR (162 MHz, CDCl 3 ) δ35.08 (s, 1P).
实施例26：化合物26的制备
Example 26: Preparation of Compound 26
化合物26-2的合成Synthesis of compound 26-2
往100mL单口瓶加化合物26-1(5g，20.40mmol)，无水DMF(40mL)，原甲酸三乙酯(4.54g，30.66mmol，5.10mL)和对甲苯磺酸一水合物(400.00mg，2.10mmol，8.98μL)，室温搅拌2小时，LCMS显示反应完全。冷却至室温，析出固体，抽滤，滤饼乙酸乙酯淋洗(3mL)，减压蒸干，得1.07g标题化合物。滤液合并，加水(200mL)，乙酸乙酯萃取(150mL*3)三次。有机相合并，水洗(150mL*3)三次，无水硫酸钠干燥，抽滤，滤液减压蒸干，得3.7g灰色固体。用乙酸乙酯(30mL)结晶，再得3.2g标题化合物26-2。LC-MS(ESI):m/z 255.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.52(s,1H),8.17(s,1H),7.97(s,1H),3.89(s,3H).Add compound 26-1 (5 g, 20.40 mmol), anhydrous DMF (40 mL), triethyl orthoformate (4.54 g, 30.66 mmol, 5.10 mL) and p-toluenesulfonic acid monohydrate (400.00 mg, 2.10 mmol, 8.98 μL) to a 100 mL single-mouth bottle and stir at room temperature for 2 hours. LCMS shows that the reaction is complete. Cool to room temperature, precipitate solid, filter, rinse the filter cake with ethyl acetate (3 mL), and evaporate to dryness under reduced pressure to obtain 1.07 g of the title compound. Combine the filtrates, add water (200 mL), and extract with ethyl acetate (150 mL*3) three times. Combine the organic phases, wash with water (150 mL*3) three times, dry with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain 3.7 g of gray solid. Crystallize with ethyl acetate (30 mL) to obtain 3.2 g of the title compound 26-2. LC-MS (ESI): m/z 255.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.52 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 3.89 (s, 3H).
化合物26-3和26-3A的合成 Synthesis of compounds 26-3 and 26-3A
往50mL单口瓶加化合物26-2(4.1g，16.07mmol)，DMF(60mL)，K2CO3(6.68g，48.36mmol)，1-溴-2-氯乙烷(3.53g，24.63mmol，2.05mL)，25℃搅拌22小时，TLC(PE:EA＝1:1和PE:EA＝0:1)显示反应完全。冷却至室温，加饱和氯化铵溶液(150mL)淬灭反应，乙酸乙酯萃取(100+80mL)。有机相合并，水洗(150mL*3)，饱和氯化钠洗(30mL)，减压蒸干，所得残余物用用乙酸乙酯/甲醇(9：1)结晶纯化，得2.8g标题化合物26-3A。LC-MS(ESI):m/z 317.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.39(d,J＝1.2Hz,1H),8.01(d,J＝1.2Hz,1H),4.78(t,J＝5.6Hz,2H),4.08(t,J＝5.6Hz,2H),3.91(s,3H).母液合并，减压蒸干，通过正相硅胶柱纯化(PE/DCM＝0～50％)，得0.93g标题化合物26-3。LC-MS(ESI):m/z 317.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.24(d,J＝1.6Hz,1H),8.00(d,J＝1.6Hz,1H),4.91(t,J＝6.0Hz,2H),4.09(t,J＝6.0Hz,2H),3.89(s,3H).Add compound 26-2 (4.1 g, 16.07 mmol), DMF (60 mL), K 2 CO 3 (6.68 g, 48.36 mmol), 1-bromo-2-chloroethane (3.53 g, 24.63 mmol, 2.05 mL) to a 50 mL single-mouth bottle and stir at 25°C for 22 hours. TLC (PE:EA=1:1 and PE:EA=0:1) shows that the reaction is complete. Cool to room temperature, add saturated ammonium chloride solution (150 mL) to quench the reaction, and extract with ethyl acetate (100+80 mL). Combine the organic phases, wash with water (150 mL*3), wash with saturated sodium chloride (30 mL), evaporate to dryness under reduced pressure, and the residue is purified by crystallization with ethyl acetate/methanol (9:1) to obtain 2.8 g of the title compound 26-3A. LC-MS (ESI): m/z 317.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.60 (s, 1H), 8.39 (d, J = 1.2 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 4.78 (t, J = 5.6 Hz, 2H), 4.08 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H). The mother liquors were combined, evaporated to dryness under reduced pressure, and purified by normal phase silica gel column (PE/DCM = 0-50%) to obtain 0.93 g of the title compound 26-3. LC-MS (ESI): m/z 317.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 4.91 (t, J = 6.0 Hz, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H).
化合物26-4的合成Synthesis of compound 26-4
往100mL单口瓶加化合物26-3A(2.6g，8.19mmol)，Zn(CN)2(1.92g，16.38mmol)，Pd(PPh3)4(1.90g，1.64mmol)和DMF(52mL)，氮气置换三次，于145℃搅拌18小时。TLC(PE:EA＝1:1)显示反应完全。LCMS显示原料反应完全。冷却至室温。加水(120mL)，乙酸乙酯(80mL)，混合，垫硅藻土滤除不溶性固体，乙酸乙酯(60mL)淋洗滤饼。滤液合并，混合，静置、分层、分液。水相乙酸乙酯萃取(60mL)。有机相合并，水洗(100mL*2)，无水硫酸钠干燥，抽滤，滤液减压蒸干，得3.6g浅黄色固体。用乙酸乙酯(40mL)结晶，得1.21g标题化合物26-4。LC-MS(ESI):m/z 264.1[M+H]+.Add compound 26-3A (2.6 g, 8.19 mmol), Zn(CN) 2 (1.92 g, 16.38 mmol), Pd(PPh 3 ) 4 (1.90 g, 1.64 mmol) and DMF (52 mL) to a 100 mL single-mouth bottle, replace with nitrogen three times, and stir at 145°C for 18 hours. TLC (PE:EA＝1:1) shows that the reaction is complete. LCMS shows that the raw material is completely reacted. Cool to room temperature. Add water (120 mL) and ethyl acetate (80 mL), mix, filter out insoluble solids through diatomaceous earth pad, and rinse the filter cake with ethyl acetate (60 mL). Combine the filtrates, mix, stand, separate the layers, and separate the liquids. Extract the aqueous phase with ethyl acetate (60 mL). Combine the organic phases, wash with water (100 mL*2), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain 3.6 g of light yellow solid. Crystallization with ethyl acetate (40 mL) gave 1.21 g of the title compound 26-4. LC-MS (ESI): m/z 264.1 [M+H] + .
化合物26-5的合成Synthesis of compound 26-5
往伴有氮气球的100mL三口瓶加化合物26-4(1.2g，4.55mmol)，THF(15mL)，搅拌溶解，氮气置换三次。冷却至0℃，滴加CH3MgBr(3M，15.93mmol，5.31mL)。滴加完毕，保温搅拌4小时。TLC监测显示反应完全。将反应液缓慢倒入氯化铵溶液(50mL)中，将THF减压蒸除，乙酸乙酯萃取(50mL+30mL)。有机相合并，水洗(20mL)，无水硫酸钠干燥，抽滤，滤液减压蒸干，得1.35g标题化合物26-5。未经纯化，直接用于下一步。Add compound 26-4 (1.2 g, 4.55 mmol) and THF (15 mL) to a 100 mL three-necked flask with a nitrogen balloon, stir to dissolve, and replace with nitrogen three times. Cool to 0°C, and add CH 3 MgBr (3M, 15.93 mmol, 5.31 mL) dropwise. After the addition is complete, stir for 4 hours. TLC monitoring shows that the reaction is complete. Slowly pour the reaction solution into an ammonium chloride solution (50 mL), evaporate THF under reduced pressure, and extract with ethyl acetate (50 mL + 30 mL). Combine the organic phases, wash with water (20 mL), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to dryness to obtain 1.35 g of the title compound 26-5. Use it directly in the next step without purification.
化合物26-6的合成Synthesis of Compound 26-6
往100mL单口瓶中加化合物26-5(1.35g，5.12mmol)，苯酚(0.97g，10.31mmol)和DCM(30mL)，冰水浴冷却，滴加BF3-Et2O(1.45g，10.24mmol，1.26mL)，缓慢升至室温搅拌16小时。LCMS显示反应完全。加饱和氯化铵溶液淬灭反应(80mL)，DCM萃取(80mL+40mL)，有机相合并，水洗(50mL)，减压蒸干，得黄色粘稠物。通过正相硅胶柱纯化(EA/PE＝0～50％)，得0.53g标题化合物26-6。LC-MS(ESI):m/z 340.0[M+H]+.1H NMR(400MHz,CDCl3)δ7.90(d,J＝1.6Hz,1H),7.57(d,J＝1.6Hz,1H),7.06～7.09(m,2H),6.75～6.79(m,2H),5.02(t,J＝6.0Hz,2H),4.01(t,J＝6.0Hz,2H),1.71(s,6H).Add compound 26-5 (1.35 g, 5.12 mmol), phenol (0.97 g, 10.31 mmol) and DCM (30 mL) to a 100 mL single-mouth bottle, cool in an ice-water bath, dropwise add BF 3 -Et 2 O (1.45 g, 10.24 mmol, 1.26 mL), slowly warm to room temperature and stir for 16 hours. LCMS shows that the reaction is complete. Add saturated ammonium chloride solution to quench the reaction (80 mL), extract with DCM (80 mL + 40 mL), combine the organic phases, wash with water (50 mL), and evaporate to dryness under reduced pressure to obtain a yellow viscous substance. Purify by normal phase silica gel column (EA/PE = 0-50%) to obtain 0.53 g of the title compound 26-6. LC-MS (ESI): m/z 340.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ7.90 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.06-7.09 (m, 2H), 6.75-6.79 (m, 2H), 5.02 (t, J=6.0 Hz, 2H), 4.01 (t, J=6.0 Hz, 2H), 1.71 (s, 6H).
化合物26-7的合成Synthesis of compound 26-7
氮气氛围下，往100mL单口瓶加化合物26-6(0.48g，1.41mmol)，化合物2-甲硫基嘧啶-4-基甲醇(340.00mg，2.18mmol)，TMAD(730mg，4.24mmol)和THF(10mL)，搅拌溶解，冷却至0℃，滴加Bu3P(900mg，4.45mmol，1.11mL)。滴加完毕，缓慢升至室温25℃搅拌3小时，LCMS显示原料反应完全。往反应体系加饱和氯化铵溶液(60mL)，DCM萃取(80+40mL)。有机相合并，无水硫酸钠干燥，抽滤，滤液减压蒸干，得棕黄色液体。通过正相硅胶柱纯化(EA/PE＝0～50％)得0.92g标题化合物26-7。LC-MS(ESI):m/z 478.0[M+H]+.Under nitrogen atmosphere, add compound 26-6 (0.48 g, 1.41 mmol), compound 2-methylthiopyrimidin-4-ylmethanol (340.00 mg, 2.18 mmol), TMAD (730 mg, 4.24 mmol) and THF (10 mL) to a 100 mL single-mouth bottle, stir to dissolve, cool to 0°C, and drop Bu 3 P (900 mg, 4.45 mmol, 1.11 mL). After the addition is complete, slowly warm to room temperature 25°C and stir for 3 hours. LCMS shows that the raw material is completely reacted. Add saturated ammonium chloride solution (60 mL) to the reaction system and extract with DCM (80+40 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain a brown-yellow liquid. Purify by normal phase silica gel column (EA/PE=0-50%) to obtain 0.92 g of the title compound 26-7. LC-MS (ESI): m/z 478.0 [M+H] + .
化合物26-8的合成Synthesis of Compound 26-8
往100mL单口瓶加化合物26-7(0.92g，1.92mmol)，DCM(20mL)，搅拌溶解，加m-CPBA(1.18g，5.81mmol，85％纯度)，25℃下搅拌16小时。TLC显示原料反应完全。加饱和碳酸钠溶液(50mL)淬灭反应，DCM萃取(50+50mL)。有机相合并，水洗(50mL)，减压蒸干，得棕黄色液体。通过正相硅胶纯化(EA/PE＝0～75％)得0.42g标题化合物26-8。LC-MS(ESI):m/z 510.0[M+H]+. Add compound 26-7 (0.92 g, 1.92 mmol) and DCM (20 mL) to a 100 mL single-mouth bottle, stir to dissolve, add m-CPBA (1.18 g, 5.81 mmol, 85% purity), and stir at 25°C for 16 hours. TLC shows that the raw material has reacted completely. Add saturated sodium carbonate solution (50 mL) to quench the reaction, and extract with DCM (50+50 mL). The organic phases are combined, washed with water (50 mL), and evaporated to dryness under reduced pressure to obtain a brown-yellow liquid. Purify by normal phase silica gel (EA/PE=0-75%) to obtain 0.42 g of the title compound 26-8. LC-MS (ESI): m/z 510.0 [M+H] + .
化合物26的合成Synthesis of compound 26
往100mL单口瓶加化合物26-8(370mg，725.48μmol)，K2CO3(814.00mg，5.89mmol)，CH3CN(10mL)和二甲基氧化膦(458mg，5.87mmol)，升温回流17小时。LCMS显示反应完全。加饱和氯化铵溶液(50mL)淬灭反应，乙酸乙酯萃取(60mL*3)三次。有机相合并，减压蒸干，得浅棕黄色粘稠物。通过正相硅胶柱纯化(MeOH/EA＝0～15％)，制备HPLC纯化，得5.5mg标题化合物26。LC-MS(ESI):m/z 508.4[M+H]+.1H NMR(400MHz,CDCl3)δ8.874(d,J＝5.2Hz,1H),8.09(s,1H),7.687(t,J＝4.4Hz,1H),7.51(s,1H),7.47(s,1H),7.15(d,J＝8.4Hz,2H),6.90(d,J＝8.4Hz,2H),5.25(d,2H),4.54(t,J＝5.6Hz,2H),3.85(t,J＝5.6Hz,2H),1.88(d,J＝13.6Hz,6H),1.74(s,6H).31P NMR(162MHz,CDCl3)δ34.98(s,1P).Compound 26-8 (370 mg, 725.48 μmol), K 2 CO 3 (814.00 mg, 5.89 mmol), CH 3 CN (10 mL) and dimethylphosphine oxide (458 mg, 5.87 mmol) were added to a 100 mL single-mouth bottle and refluxed for 17 hours. LCMS showed that the reaction was complete. Saturated ammonium chloride solution (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (60 mL*3) three times. The organic phases were combined and evaporated to dryness under reduced pressure to obtain a light brown viscous product. The product was purified by normal phase silica gel column (MeOH/EA=0-15%) and preparative HPLC to obtain 5.5 mg of the title compound 26. LC-MS (ESI): m/z 508.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ8.874 (d, J=5.2 Hz, 1H), 8.09 (s, 1H), 7.687 (t, J=4.4 Hz, 1H), 7.51 (s, 1H), 7.47 (s, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 5.25 (d, 2H), 4.54 (t, J=5.6 Hz, 2H), 3.85 (t, J=5.6 Hz, 2H), 1.88 (d, J=13.6 Hz, 6H), 1.74 (s, 6H). 31 P NMR (162 MHz, CDCl 3 ) δ34.98 (s, 1P).
实施例27:化合物27的制备
Example 27: Preparation of Compound 27
化合物27-2的制备Preparation of compound 27-2
将化合物镁(2.45g，101.8mmol)和碘(20mg，78μmol)加入干燥的三口瓶中，向瓶中加入干燥的THF(100mL)，反应体系用氮气置换三次，升温至75℃反应。将化合物1,4-二溴戊烷(10.0g，46.3mmol)缓慢滴加到反应体系，滴毕，室温反应1小时。将反应体降温至-20℃，滴加化合物亚磷酸二乙酯(5.4g，39.3mmol)。LCMS监测反应至反应完全，滴加乙醇(100mL)淬灭反应，反应体系减压浓缩得粗产品，通过先用正相硅胶柱(DCM/MeOH＝0～15％)分离纯化得到粗品1.2g，再用反相(ACN/H2O＝0～10％)分离纯化得到50mg标题化合物27-2，收率0.98％。LC-MS(ESI):m/z 119.3[M+H]+.Compound magnesium (2.45 g, 101.8 mmol) and iodine (20 mg, 78 μmol) were added to a dry three-necked flask, and dry THF (100 mL) was added to the flask. The reaction system was replaced with nitrogen three times and heated to 75°C for reaction. Compound 1,4-dibromopentane (10.0 g, 46.3 mmol) was slowly added dropwise to the reaction system. After the addition was completed, the reaction was allowed to react at room temperature for 1 hour. The reaction body was cooled to -20°C, and compound diethyl phosphite (5.4 g, 39.3 mmol) was added dropwise. LCMS monitored the reaction until the reaction was complete, and ethanol (100 mL) was added dropwise to quench the reaction. The reaction system was concentrated under reduced pressure to obtain a crude product, which was first separated and purified using a normal phase silica gel column (DCM/MeOH=0-15%) to obtain 1.2 g of a crude product, and then separated and purified using a reverse phase (ACN/H 2 O=0-10%) to obtain 50 mg of the title compound 27-2, with a yield of 0.98%. LC-MS (ESI): m/z 119.3 [M+H] + .
化合物27-3的制备Preparation of compound 27-3
将化合物1-6(200mg，0.5mmol)加入三口瓶中，依次加入无水DCM(10mL)，(2-甲硫基嘧啶-4-基)甲醇(155mg，1.0mmol)，三苯基膦(260mg，1.0mmol)，用氮气替换三次，在0℃下加入偶氮二甲酸二异丙酯(200mg，1.0mmol)。反应在25℃下搅拌反应16小时。反应结束后，加水(30mL)，用EtOAc(30mL×3)萃取，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到标题化合物27-3(100mg)，收率38％。LC-MS(ESI):488.12[M+H]+。Compound 1-6 (200 mg, 0.5 mmol) was added to a three-necked flask, followed by anhydrous DCM (10 mL), (2-methylthiopyrimidin-4-yl)methanol (155 mg, 1.0 mmol), triphenylphosphine (260 mg, 1.0 mmol), replaced with nitrogen three times, and diisopropyl azodicarboxylate (200 mg, 1.0 mmol) was added at 0°C. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL×3). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-20%) to obtain the title compound 27-3 (100 mg) with a yield of 38%. LC-MS (ESI): 488.12 [M+H] + .
化合物27-4的制备Preparation of compound 27-4
将化合物27-3(1.2g，2.46mmol)加入干燥的三口瓶中，向瓶中加入干燥的DCM(50mL)和间氯过氧苯甲酸(1.2g，6.15mmol，85％纯度)，室温反应3小时，LCMS跟踪反应至完全，加入饱和硫代硫酸钠(50mL)淬灭，有机相再用饱和碳酸钠(50mL)洗涤，无水硫酸钠干燥，浓缩得到标题化合物27-4，未经纯化，直接用于下步反应。LC-MS(ESI):m/z 521.8[M+H]+。Compound 27-3 (1.2 g, 2.46 mmol) was added to a dry three-necked flask, and dry DCM (50 mL) and m-chloroperbenzoic acid (1.2 g, 6.15 mmol, 85% purity) were added to the flask. The reaction was allowed to react at room temperature for 3 hours. The reaction was followed by LCMS until it was complete. Saturated sodium thiosulfate (50 mL) was added to quench the reaction. The organic phase was then washed with saturated sodium carbonate (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 27-4, which was used directly in the next step without purification. LC-MS (ESI): m/z 521.8 [M+H] + .
化合物27的制备Preparation of compound 27
将粗品化合物27-3(300mg，0.57mmol)溶于四氢呋喃(4mL)中，加入碳酸钾(406mg，1.25mmol)， 和化合物27-2(50mg，0.42mmol)，反应体系用氮气置换三次，升温至85℃反应6小时。LCMS监测至反应结束，过滤，滤液中加入水(10mL),乙酸乙酯萃取(10mL×2)，合并有机相。有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥、抽滤，滤液浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:15％-55％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到9mg标题化合物27，收率3.8％。LC-MS(ESI):m/z 557.9[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.02(d,J＝5.2Hz,1H),7.74(dd,J＝5.2,2.3Hz,1H),7.64(d,J＝2.3Hz,1H),7.58(d,J＝2.3Hz,1H),7.18–7.20(m,2H),6.99–7.01(m,2H),5.31(s,2H),4.41(t,J＝4.0Hz,2H),3.95(t,J＝4.0Hz,2H),2.38-2.46(m,2H),1.83-1.98(m,4H),1.63(s,6H),1.23–1.36(m,4H).31P NMR(162MHz,DMSO-d6)δ34.16(s,1P)。The crude compound 27-3 (300 mg, 0.57 mmol) was dissolved in tetrahydrofuran (4 mL), and potassium carbonate (406 mg, 1.25 mmol) was added. and compound 27-2 (50 mg, 0.42 mmol), the reaction system was replaced with nitrogen three times, and the temperature was raised to 85°C for 6 hours. LCMS monitoring until the reaction was completed, filtered, water (10 mL) was added to the filtrate, extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 15%-55% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 9 mg of the title compound 27, with a yield of 3.8%. LC-MS (ESI): m/z 557.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.02 (d, J = 5.2 Hz, 1H), 7.74 (dd, J = 5.2, 2.3 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.18–7.20 (m, 2H), 6.99–7.01 (m, 2H), 5.31 (s, 2H), 4.41 (t, J = 4.0 Hz, 2H), 3.95 (t, J = 4.0 Hz, 2H), 2.38–2.46 (m, 2H), 1.83–1.98 (m, 4H), 1.63 (s, 6H), 1.23–1.36 (m, 4H). 31 P NMR (162 MHz, DMSO-d6) δ 34.16 (s, 1P).
实施例28：化合物28的制备
Example 28: Preparation of Compound 28
化合物28的制备Preparation of Compound 28
三口瓶中加入化合物9(0.25g，0.446mmol)，TEA(90mg，0.894mmol)，氮气置换，加入DCM(5mL)。在0℃下，将溶有乙酰氯(70mg，0.894mmol)二氯甲烷(0.5mL)溶液缓慢滴加入反应体系中，滴加完毕反应30分钟。反应体系加饱和碳酸氢钠(10mL)淬灭，分离有机相，干燥浓缩得粗品，该粗品经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Agilent10Prep-C18250×21.2mm；柱温:25℃；梯度:55％-75％乙腈在12分钟内梯度洗脱；流速:30mL/min)得110mg标题化合物28，收率40％。LC-MS(ESI):m/z 601.0[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.92(s,1H),7.75(s,1H),7.45(d,J＝2.2Hz,1H),7.30(d,J＝2.2Hz,1H),7.13(d,J＝7.8Hz,2H),6.91(d,J＝7.8Hz,2H),5.24(s,2H),4.42(t,J＝6.1Hz,2H),4.35-4.20(m,1H),4.13-3.90(m,1H),3.87(t,J＝6.1Hz,2H),3.59–5.67(m,2H),2.75-2.55(m,2H),2.35-2.28(m,2H),2.19(s,3H),1.65(s,6H).31P NMR(162MHz,Chloroform-d)δ29.93(s,1P).Compound 9 (0.25 g, 0.446 mmol), TEA (90 mg, 0.894 mmol) were added to a three-necked flask, replaced with nitrogen, and DCM (5 mL) was added. At 0°C, a solution of acetyl chloride (70 mg, 0.894 mmol) in dichloromethane (0.5 mL) was slowly added dropwise to the reaction system, and the reaction lasted for 30 minutes after the addition was completed. The reaction system was quenched with saturated sodium bicarbonate (10 mL), the organic phase was separated, dried and concentrated to obtain a crude product, and the crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent10Prep-C18250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain 110 mg of the title compound 28, with a yield of 40%. LC-MS(ESI):m/z 601.0[M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.92 (s, 1H), 7.75 (s, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 7.8 Hz, 2H), 5.24 (s, 2H), 4.42 (t, J = 6.1 Hz, 2H), 4.35-4.20 (m, 1H), 4.13-3.90 (m, 1H), 3.87 (t, J = 6.1 Hz, 2H), 3.59-5.67 (m, 2H), 2.75-2.55 (m, 2H), 2.35-2.28 (m, 2H), 2.19 (s, 3H), 1.65 (s, 6H ). NMR (162 MHz, Chloroform-d) δ 29.93 (s, 1P).
实施例29：化合物29的制备
Example 29: Preparation of Compound 29
化合物29的制备Preparation of compound 29
三口瓶中加入化合物9(60mg，0.107mmol)，TEA(22mg，0.214mmol)，抽换氮气，加入DCM(2mL)。在0℃下，将溶有甲基磺酰氯(24mg，0.214mmol)的二氯甲烷(0.5mL)溶液缓慢滴加入反应体系中，滴加完毕，反应30分钟。反应体系用饱和碳酸氢钠(10mL)淬灭，分出有机相，干燥浓缩，得粗品，该粗品经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Agilent 10Prep-C18 250×21.2mm；柱温:25℃；梯度:55％-75％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到30mg标题化合物29，收率47％。LC-MS(ESI):m/z 637.0[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.87(d,J＝5.2Hz,1H),7.72(dd,J＝5.2,3.2Hz,1H),7.38(d,J＝2.4Hz,1H),7.24(d,J＝2.4Hz,1H),7.06–7.08(m,2H),6.83–6.85(m,2H),5.16(s,2H),4.35(t,J＝6.2Hz,2H),3.80(t,J＝6.2Hz,2H),2.85(s,3H),2.63-2.71(m,2H),2.31–2.46(m,2H),1.58(s,6H).31P NMR(162MHz,Chloroform-d)δ32.56(s,1P).Compound 9 (60 mg, 0.107 mmol) and TEA (22 mg, 0.214 mmol) were added to a three-necked flask, nitrogen was replaced, and DCM (2 mL) was added. At 0°C, a solution of methanesulfonyl chloride (24 mg, 0.214 mmol) in dichloromethane (0.5 mL) was slowly added dropwise to the reaction system, and the addition was completed and the reaction was continued for 30 minutes. The reaction system was quenched with saturated sodium bicarbonate (10 mL), the organic phase was separated, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 30 mg of the title compound 29, with a yield of 47%. LC-MS (ESI): m/z 637.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.87 (d, J = 5.2 Hz, 1H), 7.72 (dd, J = 5.2, 3.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.06–7.08 (m, 2H), 6.83–6.85 (m, 2H), 5.16 (s, 2H), 4.35 (t, J = 6.2 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 2.85 (s, 3H), 2.63-2.71 (m, 2H), 2.31–2.46 (m, 2H), 1.58 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ 32.56 (s, 1P).
实施例30：化合物30的制备
Example 30: Preparation of Compound 30
详细实验步骤参考实施例9。LC-MS(ESI):m/z 659.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.90(d,J＝5.2Hz,1H),7.71(dd,J＝5.2,3.1Hz,1H),7.44(d,J＝2.4Hz,1H),7.30(d,J＝2.4Hz,1H),7.10–7.14(m,2H),6.88–6.91(m,2H),5.23(s,2H),4.41(t,J＝6.1Hz,2H),4.21-4.05(m,2H),3.87(t,J＝6.1Hz,2H),3.34-3.31(m,2H),2.65-2.58(m,2H),2.30-2.10(m,2H),1.64(s,6H),1.48(s,9H).31P NMR(162MHz,Chloroform-d)δ29.83(s,1P).For detailed experimental steps, refer to Example 9. LC-MS (ESI): m/z 659.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.90 (d, J = 5.2 Hz, 1H), 7.71 (dd, J = 5.2, 3.1 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.10–7.14 (m, 2H), 6.88–6.91 (m, 2H), 5.23 (s, 2H), 4.41 (t, J = 6.1 Hz, 2H), 4.21-4.05 (m, 2H), 3.87 (t, J = 6.1 Hz, 2H), 3.34-3.31 (m, 2H), 2.65-2.58 ( m, 2H), 2.30-2.10 (m, 2H), 1.64 (s, 6H), 1.48 (s, 9H). NMR (162 MHz, Chloroform-d) δ 29.83 (s, 1P).
实施例31：化合物31的制备
Example 31: Preparation of Compound 31
化合物31-3的制备Preparation of compound 31-3
将化合物31-1(1g，4.46mmol)，化合物31-2(1.71g，5.80mmol)，碳酸铯(2.91g，8.92mmol)，Xantphos(516.40mg，892.47μmol)，三(二亚苄基丙酮)钯(408.63mg，446.24μmol)和1,4-二氧六环(5mL)加入反应瓶中，氮气保护下100℃反应16小时。反应结束后，加饱和氯化铵溶液(20mL)淬灭反应，反应体系过滤后用二氯甲烷(20mL)萃取3次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0～50％)分离纯化得到1.7g标题化合物31-3，收率87％。LC-MS(ESI):m/z 436.9[M+H]+.Compound 31-1 (1 g, 4.46 mmol), compound 31-2 (1.71 g, 5.80 mmol), cesium carbonate (2.91 g, 8.92 mmol), Xantphos (516.40 mg, 892.47 μmol), tris(dibenzylideneacetone)palladium (408.63 mg, 446.24 μmol) and 1,4-dioxane (5 mL) were added to a reaction bottle and reacted at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction, the reaction system was filtered and extracted with dichloromethane (20 mL) for 3 times, the organic phases were combined, dried and concentrated to obtain a crude product, and separated and purified by a normal phase silica gel column (EtOAc/PE=0-50%) to obtain 1.7 g of the title compound 31-3, with a yield of 87%. LC-MS (ESI): m/z 436.9 [M+H] + .
化合物31-4的制备Preparation of compound 31-4
将化合物31-3(900mg，2.05mmol)，碘单质(3.91g，15.41mmol)，NaHCO3(1.73g，20.54mmol)，THF(10mL)和水(3mL)加入反应瓶中，50℃下搅拌2小时。LCMS监测反应完全。加饱和亚硫酸钠水溶液(10mL)淬灭，反应体系过滤后用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0～50％)分离纯化得到580mg标题化合物31-4，收率62％.LC-MS(ESI):m/z 450.9[M+H]+.Compound 31-3 (900 mg, 2.05 mmol), iodine (3.91 g, 15.41 mmol), NaHCO 3 (1.73 g, 20.54 mmol), THF (10 mL) and water (3 mL) were added to a reaction flask and stirred at 50°C for 2 hours. The reaction was complete after LCMS monitoring. Saturated sodium sulfite aqueous solution (10 mL) was added to quench the reaction system, and the reaction system was filtered and extracted with dichloromethane (10 mL) three times. The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-50%) to obtain 580 mg of the title compound 31-4, with a yield of 62%. LC-MS (ESI): m/z 450.9 [M+H] + .
化合物31-5的制备Preparation of compound 31-5
将化合物31-4(580mg，1.28mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(93.09mg，128.28μmol)，联硼酸频那醇酯(488.64mg，1.92mmol)，醋酸钾(377.70mg，3.85mmol)和二氧六环(12mL)加入反应瓶中。氮气保护下，100℃反应4小时。过滤、旋干，加二氧六环(5mL)后，于0℃滴加双氧水(1.45g，12.83mmol，30％)。滴毕，室温下搅拌20分钟，LCMS监测反应完全。缓慢滴加亚硫酸钠水溶液(30ml)淬灭反应，反应体系过滤后用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到400mg标题化合物31-5，收率80％.LC-MS(ESI):m/z 389.0[M+H]+.Compound 31-4 (580 mg, 1.28 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (93.09 mg, 128.28 μmol), biboric acid pinacol ester (488.64 mg, 1.92 mmol), potassium acetate (377.70 mg, 3.85 mmol) and dioxane (12 mL) were added to the reaction bottle. Under nitrogen protection, the mixture was reacted at 100 °C for 4 hours. After filtering and drying, dioxane (5 mL) was added, and then hydrogen peroxide (1.45 g, 12.83 mmol, 30%) was added dropwise at 0 °C. After the addition was completed, the mixture was stirred at room temperature for 20 minutes, and the reaction was complete after monitoring by LCMS. Sodium sulfite aqueous solution (30 ml) was slowly added dropwise to quench the reaction. The reaction system was filtered and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-50%) to obtain 400 mg of the title compound 31-5, with a yield of 80%. LC-MS (ESI): m/z 389.0 [M+H] + .
化合物31-6的制备Preparation of compound 31-6
氮气保护下，将化合物31-5(300mg，770.75μmol)，(2-(甲巯基)嘧啶-4-基)甲醇(180.59mg，1.16mmol)，TMAD(398.13mg，2.31mmol)，DCM(2mL)加入反应瓶中。于0℃下，滴加三丁基膦(467.80mg，2.31 mmol)后，室温下搅拌1小时。LCMS监测反应完全。加水(10mL)，二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0～50％)分离纯化得到400mg标题化合物31-6，收率54％.LC-MS(ESI):m/z 527.0[M+H]+.Under nitrogen protection, compound 31-5 (300 mg, 770.75 μmol), (2-(methylmercapto)pyrimidin-4-yl)methanol (180.59 mg, 1.16 mmol), TMAD (398.13 mg, 2.31 mmol), and DCM (2 mL) were added to the reaction flask. Tributylphosphine (467.80 mg, 2.31 mmol), stirred at room temperature for 1 hour. LCMS monitored the reaction to be complete. Water (10 mL) was added, and dichloromethane (10 mL) was used for extraction three times. The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-50%) to obtain 400 mg of the title compound 31-6, with a yield of 54%. LC-MS (ESI): m/z 527.0 [M+H] + .
化合物31-7的制备Preparation of compound 31-7
将化合物31-6(220mg，417.12μmol)，过氧单磺酸钾(722.27mg，2.09mmol)，水(2mL)和THF(2mL)加入反应瓶中，于30℃下反应16小时。加水(10mL)，后用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0～50％)分离纯化得到200mg标题化合物31-7，收率54％.LC-MS(ESI):m/z 559.0[M+H]+.Compound 31-6 (220 mg, 417.12 μmol), potassium peroxymonosulfonate (722.27 mg, 2.09 mmol), water (2 mL) and THF (2 mL) were added to a reaction flask and reacted at 30°C for 16 hours. Water (10 mL) was added, and then extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-50%) to obtain 200 mg of the title compound 31-7, with a yield of 54%. LC-MS (ESI): m/z 559.0 [M+H] + .
化合物31的制备Preparation of compound 31
将化合物31-7(110mg，196.63μmol)，二甲基氧化膦(76.74mg，983.16μmol)，碳酸钾(135.88mg，983.16μmol)和乙腈(2mL)于80℃反应5小时。LCMS监测反应完全。加水(10mL)，后用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经制备分离纯化(制备方法：流动相：A:0.1％甲酸水溶液；B:乙腈；色谱柱：Agilent 10Prep-C18 250×21.2mm；柱温：25℃；梯度：35％-95％乙腈in 20min；流速：30mL/min)，得到10mg标题化合物31，收率9％.LC-MS(ESI):m/z 557.9[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.07(d,J＝2.5Hz,1H),8.03(d,J＝2.5Hz,1H),7.73(dd,J＝5.1,3.0Hz,1H),7.04(d,J＝2.1Hz,1H),6.90–6.96(m,2H),5.27(s,2H),4.53(t,J＝8Hz,2H),4.02(t,J＝8Hz,2H),1.77(d,J＝13.7Hz,6H),1.69–1.61(m,2H).31P NMR(162MHz,DMSO-d6)δ34.07(s,1P).Compound 31-7 (110 mg, 196.63 μmol), dimethylphosphine oxide (76.74 mg, 983.16 μmol), potassium carbonate (135.88 mg, 983.16 μmol) and acetonitrile (2 mL) were reacted at 80°C for 5 hours. The reaction was complete when monitored by LCMS. Water (10 mL) was added, and then extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 35%-95% acetonitrile in 20 min; flow rate: 30 mL/min) to obtain 10 mg of the title compound 31, with a yield of 9%. LC-MS (ESI): m/z 557.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.01(s,1H),8.07(d,J＝2.5Hz,1H),8.03(d,J＝2.5Hz,1H),7.73(dd,J＝5.1,3.0Hz,1H),7.04(d,J＝2.1Hz,1H),6.90–6.96(m,2H),5.27(s,2H),4.53(t,J＝8Hz,2H),4.02(t,J＝8Hz,2H),1.77(d,J＝13.7Hz,6H),1.69–1.61(m,2H). 31 P NMR (162MHz,DMSO-d 6 )δ34.07(s,1P).
实施例32：化合物32的制备
Example 32: Preparation of Compound 32
化合物32的制备Preparation of compound 32
将化合物1-7(300mg，0.63mmol)溶解于DMF(5.0mL)中，依次加入二甲基氧化膦(333mg，3.2mmol)、三乙胺(191mg，1.9mmol)、三(二亚苄基丙酮)二钯(115mg，0.13mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(73mg，0.13mmol)。反应体系用氮气置换三次，在120℃下微波搅拌反应2小时。反应结束后，滤除不溶性固体，滤液加水(10mL)，二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥、浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到10mg标题化合物32，收率3％。LC-MS(ESI):m/z 546.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.98(d,J＝5.2Hz,1H),7.71(dd,J1＝4.9,J2＝3.1Hz,1H),7.64(d,J＝2.3Hz,1H),7.57(d,J＝2.3Hz,1H),7.19(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,2H),5.29(s,2H),4.41(t,J＝5.1Hz,2H),3.95(t,J＝5.1Hz,2H),1.97-2.06(m,4H),1.63(s,6H),1.23(s,6H).31P NMR(162MHz,DMSO-d6)δ42.35(s,1P).Compound 1-7 (300 mg, 0.63 mmol) was dissolved in DMF (5.0 mL), and dimethylphosphine oxide (333 mg, 3.2 mmol), triethylamine (191 mg, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (115 mg, 0.13 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (73 mg, 0.13 mmol) were added in sequence. The reaction system was replaced with nitrogen three times, and the reaction was stirred in a microwave at 120°C for 2 hours. After the reaction, the insoluble solid was filtered off, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 10 mg of the title compound 32, with a yield of 3%. LC-MS (ESI): m/z 546.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.98 (d, J = 5.2 Hz, 1H), 7.71 (dd, J1 = 4.9, J2 = 3.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 5.29 (s, 2H), 4.41 (t, J = 5.1 Hz, 2H), 3.95 (t, J = 5.1 Hz, 2H), 1.97-2.06 (m, 4H), 1.63 (s, 6H), 1.23 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 42.35 (s, 1P).
实施例33：化合物33的制备
Example 33: Preparation of Compound 33
化合物33-2的制备Preparation of compound 33-2
将化合物31-2(1.76g，5.98mmol)溶解于1,4-二氧六环(20.0mL)中，依次加入5-甲氧基吲哚(800mg，5.44mmol)、碳酸铯(3.54g，10.87mmol)、三(二亚苄基丙酮)二钯(498mg，0.54mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(628mg，1.09mmol)。反应体系用氮气置换三次，120℃下微波搅拌反应2小时。反应结束后，滤除不溶性固体，滤液加水(20mL)，乙酸乙酯萃取(20mL)两次，合并有机相，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥、浓缩得粗产品，经正相硅胶层析柱(EA/PE＝0～30％)纯化得到800mg标题化合物33-2，收率41％。LC-MS(ESI):m/z 361.0[M+H]+.Compound 31-2 (1.76 g, 5.98 mmol) was dissolved in 1,4-dioxane (20.0 mL), and 5-methoxyindole (800 mg, 5.44 mmol), cesium carbonate (3.54 g, 10.87 mmol), tris(dibenzylideneacetone)dipalladium (498 mg, 0.54 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (628 mg, 1.09 mmol) were added in sequence. The reaction system was replaced with nitrogen three times, and the reaction was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the insoluble solid was filtered off, the filtrate was added with water (20 mL), and extracted with ethyl acetate (20 mL) twice, the organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by normal phase silica gel chromatography (EA/PE=0-30%) to obtain 800 mg of the title compound 33-2, with a yield of 41%. LC-MS(ESI):m/z 361.0[M+H] + .
化合物33-3的制备Preparation of compound 33-3
将化合物33-2(800mg，2.21mmol)溶解于二氯甲烷(15mL)中，氮气保护-60℃下滴加三溴化硼(2.22g，8.86mmol，17％的DCM溶液)，滴毕室温反应过夜。LCMS监测至反应结束后，加水(20mL)淬灭，二氯甲烷萃取(20mL)两次，合并有机相，无水硫酸钠干燥、浓缩得粗产品，经正相硅胶层析柱(EA/PE＝0～30％)纯化得到150mg标题化合物33-3，收率20％。LC-MS(ESI):m/z 347.0[M+H]+.Compound 33-2 (800 mg, 2.21 mmol) was dissolved in dichloromethane (15 mL), and boron tribromide (2.22 g, 8.86 mmol, 17% DCM solution) was added dropwise under nitrogen protection at -60°C. The reaction was allowed to react overnight at room temperature. After the reaction was completed by LCMS monitoring, water (20 mL) was added to quench the reaction, and dichloromethane (20 mL) was extracted twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by normal phase silica gel chromatography (EA/PE=0-30%) to obtain 150 mg of the title compound 33-3, with a yield of 20%. LC-MS (ESI): m/z 347.0 [M+H] + .
化合物33-4的制备Preparation of compound 33-4
将化合物33-3(150mg，0.43mmol)溶于DMF(5mL)中，搅拌下加入碳酸钾(119mg，0.86mmol)，反应5分钟后再加入2-氯-4-氯甲基嘧啶(85mg，0.52mmol)，80℃下反应4小时。LCMS监测至反应完全，将反应液倒入饱和氯化铵溶液(20mL)中，乙酸乙酯萃取(20mL×2)，合并有机相，无水硫酸钠干燥、浓缩得粗产品，经正相硅胶层析柱(EA/PE＝0～30％)纯化得到100mg标题化合物33-4，收率49％。LC-MS(ESI):m/z 473.2[M+H]+.Compound 33-3 (150 mg, 0.43 mmol) was dissolved in DMF (5 mL), potassium carbonate (119 mg, 0.86 mmol) was added under stirring, and 2-chloro-4-chloromethylpyrimidine (85 mg, 0.52 mmol) was added after 5 minutes of reaction, and the reaction was carried out at 80°C for 4 hours. LCMS monitored the reaction until it was complete, and the reaction solution was poured into a saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by normal phase silica gel chromatography (EA/PE=0-30%) to obtain 100 mg of the title compound 33-4, with a yield of 49%. LC-MS (ESI): m/z 473.2[M+H] + .
化合物33的制备Preparation of compound 33
将化合物33-4(50mg，0.11mmol)溶解于N,N-二甲基甲酰胺(3.0mL)中，依次加入二甲基氧化膦(25mg，0.32mmol)、N,N-二异丙基乙胺(41mg，0.32mmol)、三(二亚苄基丙酮)二钯(10mg，0.01mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(12mg，0.02mmol)。用氮气置换三次后，微波110℃下反应2小时。LCMS监测至完全。将反应液过滤，滤液减压蒸干，粗品经制备分离纯化(制备方法:色谱柱:Welch Xtimate C18 250x 21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)得到10mg标题化合物33，收率18％。LC-MS(ESI):m/z 473.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝8Hz,1H),8.11–8.14(m,2H),7.71–7.76(m,2H),7.59(d,J＝8.0Hz,1H),7.29(d,J＝2.6Hz,1H),7.04(dd,J＝8.0,2.6Hz,1H),6.66(d,J＝3.4Hz,1H),5.34(s,2H),4.50(t,J＝4Hz,2H),4.02(t,J＝4Hz,2H),1.78(d,J＝16Hz,6H).31P NMR(162MHz,DMSO-d6)δ34.12(s,1P).Compound 33-4 (50 mg, 0.11 mmol) was dissolved in N, N-dimethylformamide (3.0 mL), and dimethylphosphine oxide (25 mg, 0.32 mmol), N, N-diisopropylethylamine (41 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (12 mg, 0.02 mmol) were added in sequence. After replacing with nitrogen three times, the mixture was reacted at 110° C. in a microwave for 2 hours. LCMS monitoring was complete. The reaction solution was filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x 21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/ L NH4HCO3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 10 mg of the title compound 33, with a yield of 18%. LC-MS (ESI): m/z 473.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ8.99 (d, J=8 Hz, 1H), 8.11–8.14 (m, 2H), 7.71–7.76 (m, 2H), 7.59 (d, J=8.0 Hz, 1H), 7.29 (d, J=2.6 Hz, 1H), 7.04 (dd, J=8.0, 2.6 Hz, 1H), 6.66 (d, J=3.4 Hz, 1H), 5.34 (s, 2H), 4.50 (t, J=4 Hz, 2H), 4.02 (t, J=4 Hz, 2H), 1.78 (d, J=16 Hz, 6H). 31 P NMR (162 MHz, DMSO-d 6 ) δ34.12 (s, 1P).
实施例34：化合物34的制备
Example 34: Preparation of Compound 34
化合物34-2的制备 Preparation of compound 34-2
将化合物34-1(5g，16mmol)，碳酸铯(10.43g，32mmol)溶于DMF(50mL)，向其中加入碘甲烷(1.5mL，24mmol)。加毕，将体系于室温搅拌16h。向体系中加冰水(100mL)淬灭反应后，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL x 2)后，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶柱层析纯化(EtOAc/PE＝0～10％)得4.2g标题化合物34-2，收率80％。Compound 34-1 (5 g, 16 mmol) and cesium carbonate (10.43 g, 32 mmol) were dissolved in DMF (50 mL), and iodomethane (1.5 mL, 24 mmol) was added thereto. After the addition, the system was stirred at room temperature for 16 h. After adding ice water (100 mL) to the system to quench the reaction, it was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by normal phase silica gel column chromatography (EtOAc/PE=0-10%) to obtain 4.2 g of the title compound 34-2, with a yield of 80%.
化合物34-3的制备Preparation of compound 34-3
将化合物34-2(4.2g，12.9mmol)溶于DMF(50mL)，向其中加入氰化亚铜(2.3g，25.8mmol)。加毕，将体系于120℃搅拌16h。向体系中加水(50mL)稀释后，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶柱层析纯化(EtOAc/PE(v/v)＝0～10％)得2.5g标题化合物34-3，收率86％。Compound 34-2 (4.2 g, 12.9 mmol) was dissolved in DMF (50 mL), and cuprous cyanide (2.3 g, 25.8 mmol) was added thereto. After the addition, the system was stirred at 120°C for 16 h. After dilution with water (50 mL), the system was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0-10%) to obtain 2.5 g of the title compound 34-3, with a yield of 86%.
化合物34-4的制备Preparation of compound 34-4
将化合物34-3(2.5g，11.1mmol)溶于四氢呋喃(50mL)中，在-78℃条件下，向其中加入甲基溴化镁(3.0M,11.1mL)。加毕，将体系于室温搅拌2h。向反应体系中加饱和氯化铵溶液(50mL)，淬灭反应后，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶柱层析纯化(EtOAc/PE(v/v)＝0～25％)得2.3g标题化合物34-4，收率92％。Compound 34-3 (2.5 g, 11.1 mmol) was dissolved in tetrahydrofuran (50 mL), and methylmagnesium bromide (3.0 M, 11.1 mL) was added thereto at -78 °C. After the addition, the system was stirred at room temperature for 2 h. Saturated ammonium chloride solution (50 mL) was added to the reaction system, and after quenching the reaction, it was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0-25%) to obtain 2.3 g of the title compound 34-4, with a yield of 92%.
化合物34-5的制备Preparation of compound 34-5
将化合物34-4(2.3g，10.2mmol)，苯酚(1.2g，12.2mmol)溶于二氯甲烷(50mL)中，在0℃条件下，向其中加入三氟化硼乙醚(48％，2.68mL)。加毕，将体系于室温搅拌2h。向体系中加水(50mL)淬灭反应后，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)三次，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶柱层析纯化(EtOAc/PE(v/v)＝0～25％)得标题化合物34-5，收率49％。LC-MS(ESI):300.2[M-H]-.Compound 34-4 (2.3 g, 10.2 mmol) and phenol (1.2 g, 12.2 mmol) were dissolved in dichloromethane (50 mL). Boron trifluoride etherate (48%, 2.68 mL) was added thereto at 0°C. After the addition, the system was stirred at room temperature for 2 h. Water (50 mL) was added to the system to quench the reaction, and then the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed with saturated brine (50 mL) three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0-25%) to obtain the title compound 34-5 with a yield of 49%. LC-MS (ESI): 300.2 [MH] - .
化合物34-6的制备Preparation of compound 34-6
将化合物34-5(1.2g，3.98mmol)，化合物(2-(甲硫基)嘧啶-4-基)甲磺酸甲酯(1.86g，7.96mmol)溶于DMF(30mL)中，向其中加入碳酸铯(3.88g，11.94mmol)。加毕，将体系于80℃搅拌2h。向体系中加水(50mL)稀释后，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶柱层析纯化(EtOAc/PE(v/v)＝0～35％)得标题化合物34-6，收率74.3％。LC-MS(ESI):439.8[M+H]+.Compound 34-5 (1.2 g, 3.98 mmol) and compound (2-(methylthio)pyrimidin-4-yl)methanesulfonic acid methyl ester (1.86 g, 7.96 mmol) were dissolved in DMF (30 mL), and cesium carbonate (3.88 g, 11.94 mmol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After dilution with water (50 mL), the system was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0-35%) to obtain the title compound 34-6 with a yield of 74.3%. LC-MS (ESI): 439.8 [M+H] + .
化合物34-7的制备Preparation of compound 34-7
将化合物34-6(1.2g，2.73mmol)溶于二氯甲烷(30mL)中，加入间氯过氧苯甲酸(1.41g，8.19mmol)。加毕，将体系于室温搅拌2h。向体系中加饱和碳酸钠溶液(50mL)淬灭反应，用二氯甲烷萃取(50mL)三次，合并有机相，用饱和碳酸氢钠洗涤(50mL)三次，经无水硫酸钠干燥，过滤，滤液浓缩得标题化合物34-7粗品，收率93％，未经纯化直接用于下一步反应。LC-MS(ESI):471.8[M+H]+.Compound 34-6 (1.2 g, 2.73 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperbenzoic acid (1.41 g, 8.19 mmol) was added. After the addition, the system was stirred at room temperature for 2 h. Saturated sodium carbonate solution (50 mL) was added to the system to quench the reaction, and the mixture was extracted with dichloromethane (50 mL) three times. The organic phases were combined, washed with saturated sodium bicarbonate (50 mL) three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of the title compound 34-7 with a yield of 93%. It was directly used in the next step without purification. LC-MS (ESI): 471.8 [M + H] + .
化合物34的制备Preparation of compound 34
将粗品化合物34-7(1.2g，2.54mmol)和二甲基氧化膦(1.92g，25.4mmol)溶于乙腈(30mL)中，向其中加入碳酸钾(1.04g，7.6mmol)。加毕，将体系于80℃搅拌8h。向体系中加水(50mL)稀释后，乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经高效制备液相(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(0.1％FA)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)纯化得标题化合物34。LC-MS(ESI):469.8[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.88(s,1H),7.69(s,1H),7.43(d,J＝2.3Hz,1H),7.30(d,J＝2.3Hz,1H),7.13(d,J＝8.5Hz,2H),6.90(d,J＝8.5Hz,2H),5.25(s,2H),4.05(s,3H),1.91(d,J＝13.5Hz,6H),1.64(s,6H).31P NMR(162MHz,Chloroform-d)δ35.22(s,1P). The crude compound 34-7 (1.2 g, 2.54 mmol) and dimethylphosphine oxide (1.92 g, 25.4 mmol) were dissolved in acetonitrile (30 mL), and potassium carbonate (1.04 g, 7.6 mmol) was added thereto. After the addition, the system was stirred at 80°C for 8 h. After dilution with water (50 mL), the system was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by high-efficiency preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 34. LC-MS (ESI): 469.8 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.88 (s, 1H), 7.69 (s, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 5.25 (s, 2H), 4.05 (s, 3H), 1.91 (d, J = 13.5 Hz, 6H), 1.64 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ35.22 (s, 1P).
实施例35：化合物35的制备
Example 35: Preparation of Compound 35
化合物35的制备Preparation of compound 35
将化合物34(850mg，1.81mmol)溶于二氯甲烷(30mL)中，在0℃条件下，向其中加入三溴化硼(3.62mL，3.62mmol)。加毕，将体系于0℃搅拌3h。向体系中加水(10mL)稀释后，二氯甲烷萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经高效制备液相(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)纯化得标题化合物35。LC-MS(ESI):456.0[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.89(s,1H),7.70(s,1H),7.37(d,J＝2.4Hz,1H),7.28(d,J＝2.4Hz,1H),7.12(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.22(s,2H),1.93(d,J＝8Hz,6H),1.63(s,6H).31P NMR(162MHz,Chloroform-d)δ35.82(s,1P)。Compound 34 (850 mg, 1.81 mmol) was dissolved in dichloromethane (30 mL), and boron tribromide (3.62 mL, 3.62 mmol) was added thereto at 0°C. After the addition, the system was stirred at 0°C for 3 h. Water (10 mL) was added to the system for dilution, and dichloromethane (50 mL) was used for extraction three times. The organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 35. LC-MS (ESI): 456.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.89 (s, 1H), 7.70 (s, 1H), 7.37 (d, J＝2.4 Hz, 1H), 7.28 (d, J＝2.4 Hz, 1H), 7.12 (d, J＝8.4 Hz, 2H), 6.89 (d, J＝8.4 Hz, 2H), 5.22 (s, 2H), 1.93 (d, J＝8 Hz, 6H), 1.63 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ35.82 (s, 1P).
实施例36：化合物36的制备
Example 36: Preparation of Compound 36
化合物36的制备Preparation of compound 36
将化合物35(100mg，0.22mmol)，烯丙基溴(0.047mL，0.66mol)溶于DMF(5mL)中，加入碳酸铯(360mg，1.11mmol)。加毕，将体系于70℃搅拌16h。向体系中加饱和氯化铵溶液(10mL)淬灭反应，乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经高效制备液相(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(0.1％FA)-乙腈；流动相乙腈比例50％-70％在12分钟内梯度洗脱；流速30mL/min)纯化得标题化合物36。LC-MS(ESI):495.8[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.89(d,J＝5.0Hz,1H),7.69(t,J＝4.0Hz,1H),7.43(d,J＝2.4Hz,1H),7.30(d,J＝2.4Hz,1H),7.11–7.4(m,2H),6.89–6.91(m,2H),6.10–6.17(m,1H),5.43(dt,J＝17.2,1.4Hz,1H),5.32(dq,J＝10.3,1.2Hz,1H),5.25(s,2H),4.71(dt,J＝6.0,1.3Hz,2H),1.92(d,J＝13.7Hz,6H),1.64(s,6H).31P NMR(162MHz,Chloroform-d)δ36.13(s,1P).Compound 35 (100 mg, 0.22 mmol) and allyl bromide (0.047 mL, 0.66 mol) were dissolved in DMF (5 mL), and cesium carbonate (360 mg, 1.11 mmol) was added. After the addition, the system was stirred at 70 ° C for 16 h. Saturated ammonium chloride solution (10 mL) was added to the system to quench the reaction, and ethyl acetate was extracted three times (50 mL). The organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25 ° C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 36. LC-MS (ESI): 495.8 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.89 (d, J = 5.0 Hz, 1H), 7.69 (t, J = 4.0 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.11–7.4 (m, 2H), 6.89–6.91 (m, 2H), 6.10–6.17 (m, 1H), 5.43 (dt, J = 17.2, 1.4 Hz, 1H), 5.32 (dq, J = 10.3, 1.2 Hz, 1H), 5.25 (s, 2H), 4.71 (dt, J = 6.0, 1.3 Hz , 2H), 1.92 (d, J = 13.7 Hz, 6H), 1.64 (s, 6H). NMR (162 MHz, Chloroform-d) δ 36.13 (s, 1P).
实施例37：化合物37的制备
Example 37: Preparation of Compound 37
化合物37的制备Preparation of compound 37
将化合物36(100mg，0.22mmol)，环氧氯丙烷(0.051mL，0.66mol)溶于DMF(5mL)中，向其中加入碳酸铯(360mg，1.11mmol)。加毕，将体系于70℃搅拌16h。向体系中加饱和氯化铵溶液(10mL)淬灭反应，乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经高效制备液相(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(0.1％FA)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)纯化得标题化合物37.LC-MS(ESI):512.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.88(s,1H),7.68(s,1H),7.44(d,J＝2.4Hz,1H),7.31(d,J＝2.4Hz,1H),7.18–7.10(m,2H),6.90(d,J＝8.8Hz,2H),5.25(s,2H),4.40(dd,J＝11.2,3.5Hz,1H),4.17(dd,J＝11.2,6.1Hz,1H),3.46(ddd,J＝6.2,5.0,3.3Hz,1H),2.90(t,J＝4.5Hz,1H),2.74(dd,J＝4.8,2.6Hz,1H),1.90(d,J＝13.5Hz,6H),1.64(s,6H).31P NMR(162MHz,Chloroform-d)δ35.27(s,1P). Compound 36 (100 mg, 0.22 mmol) and epichlorohydrin (0.051 mL, 0.66 mol) were dissolved in DMF (5 mL), and cesium carbonate (360 mg, 1.11 mmol) was added thereto. After the addition, the system was stirred at 70° C. for 16 h. Saturated ammonium chloride solution (10 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain the title compound 37. LC-MS (ESI): 512.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.88 (s, 1H), 7.68 (s, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.18–7.10 (m, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.25 (s, 2H), 4.40 (dd, J = 11.2, 3.5 Hz, 1H), 4.17 (dd, J = 11.2, 6.1 Hz, 1H), 3.46 (ddd, J = 6.2, 5.0, 3.3 Hz, 1H), 2.90 (t, J = 4.5 Hz, 1H), 2.74 (dd, J = 4.8 , 2.6 Hz, 1H), 1.90 (d, J = 13.5 Hz, 6H), 1.64 (s, 6H). P NMR (162 MHz, Chloroform-d) δ 35.27 (s, 1P).
实施例38：化合物38的制备
Example 38: Preparation of Compound 38
化合物38-2的制备Preparation of compound 38-2
将化合物38-1(500mg，1.9mmol)溶于四氢呋喃(30mL)中，在-78℃条件下，向其中加入甲基溴化镁(3.0M,1.9mL)。加毕，将体系于室温搅拌2h。向体系中加饱和氯化铵溶液(20mL)淬灭反应，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶柱层析纯化(EtOAc/PE(v/v)＝0～25％)得500mg标题化合物38-2，收率98％。LC-MS(ESI):m/z 264.2[M-H]+.Compound 38-1 (500 mg, 1.9 mmol) was dissolved in tetrahydrofuran (30 mL), and methylmagnesium bromide (3.0 M, 1.9 mL) was added thereto at -78 °C. After the addition, the system was stirred at room temperature for 2 h. Saturated ammonium chloride solution (20 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0-25%) to obtain 500 mg of the title compound 38-2, with a yield of 98%. LC-MS (ESI): m/z 264.2 [MH] + .
化合物38-3的制备Preparation of compound 38-3
将化合物38-2(450mg，1.71mmol)，苯酚(193mg，2.05mmol)溶于二氯甲烷(50mL)中，在0℃条件下，向其中加入三氟化硼乙醚(48％，0.9mL)。加毕，将体系于室温搅拌2h。向体系中加水(20mL)淬灭反应后，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)三次，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶中压柱层析纯化(EtOAc/PE(v/v)＝0～25％)得400mg标题化合物38-3,收率68％。LC-MS(ESI):m/z 340.0[M+H]+.Compound 38-2 (450 mg, 1.71 mmol) and phenol (193 mg, 2.05 mmol) were dissolved in dichloromethane (50 mL). Boron trifluoride etherate (48%, 0.9 mL) was added at 0°C. After the addition, the system was stirred at room temperature for 2 h. Water (20 mL) was added to the system to quench the reaction, and then the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed with saturated brine (50 mL) three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel medium pressure column chromatography (EtOAc/PE (v/v) = 0-25%) to obtain 400 mg of the title compound 38-3, with a yield of 68%. LC-MS (ESI): m/z 340.0 [M+H] + .
化合物38-4的制备Preparation of compound 38-4
将化合物38-3(350mg，1.03mmol)，化合物(2-(甲硫基)嘧啶-4-基)甲磺酸甲酯(481mg，2.06mmol)溶于DMF(20mL)中，向其中加入碳酸铯(1.00g，3.09mmol)。加毕，将体系于80℃搅拌2h。向体系中加水(20mL)稀释后，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶柱层析纯化(EtOAc/PE(v/v)＝0～35％)得250mg标题化合物38-4，收率50.8％。LC-MS(ESI):m/z 478.2[M+H]+.Compound 38-3 (350 mg, 1.03 mmol) and compound (2-(methylthio)pyrimidin-4-yl)methanesulfonic acid methyl ester (481 mg, 2.06 mmol) were dissolved in DMF (20 mL), and cesium carbonate (1.00 g, 3.09 mmol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After dilution with water (20 mL), the system was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0-35%) to obtain 250 mg of the title compound 38-4, with a yield of 50.8%. LC-MS (ESI): m/z 478.2 [M+H] + .
化合物38-5的制备Preparation of compound 38-5
将化合物38-4(200mg，0.42mmol)溶于二氯甲烷(30mL)中，加入间氯过氧苯甲酸(216mg，1.26mmol)。加毕，将体系于室温搅拌2h。向体系中饱和碳酸钠溶液(20mL)淬灭反应，用二氯甲烷萃取(50mL)三次，合并有机相，用饱和碳酸氢钠洗涤(50mL)三次，经无水硫酸钠干燥，过滤，滤液浓缩得200mg粗品标题化合物38-5，收率93.7％，未经纯化直接用于下一步反应。LC-MS(ESI):m/z 510.2[M+H]+.Compound 38-4 (200 mg, 0.42 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperbenzoic acid (216 mg, 1.26 mmol) was added. After the addition, the system was stirred at room temperature for 2 h. The reaction was quenched with a saturated sodium carbonate solution (20 mL) in the system, extracted with dichloromethane (50 mL) three times, the organic phases were combined, washed with saturated sodium bicarbonate (50 mL) three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 200 mg of the crude title compound 38-5, with a yield of 93.7%, which was directly used in the next step without purification. LC-MS (ESI): m/z 510.2 [M + H] + .
化合物38的制备Preparation of compound 38
将粗品化合物38-5(150mg，0.29mmol)和二甲基氧化膦(223mg，2.9mmol)溶于乙腈(5mL)中，向其中加入碳酸钾(120mg，0.87mmol)。加毕，将体系于80℃搅拌8h。向体系中加饱和氯化铵溶液(10mL)淬灭，乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经高效制备液相(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(0.1％10mM/L NH4HCO3)-乙腈；流动相乙腈比例40％-40％在12分钟内梯度洗脱；流速30mL/min)纯化得标题化合物38。LC-MS(ESI):m/z 508.2[M+H]+.1H NMR(400MHz,Methanol-d4)δ8.84(d,J＝5.2Hz,1H),8.27(s,1H),7.79(d,J＝1.6Hz,1H),7.66(t,J＝1.6Hz,1H),7.44(d,J＝1.6Hz,1H),7.14–7.10(m,2H),6.85–6.89(m,2H),5.19(s,2H),4.78(d,J＝8Hz,2H),3.95(d,J＝8Hz,2H),1.81(d,J＝13.9Hz,6H),1.65(s,6H).31P NMR(162MHz,Chloroform-d)δ41.18(s,1P)。 The crude compound 38-5 (150 mg, 0.29 mmol) and dimethylphosphine oxide (223 mg, 2.9 mmol) were dissolved in acetonitrile (5 mL), and potassium carbonate (120 mg, 0.87 mmol) was added thereto. After the addition, the system was stirred at 80°C for 8 h. Saturated ammonium chloride solution (10 mL) was added to the system to quench, and ethyl acetate (50 mL) was extracted three times. The organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-efficiency preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% 10 mM/L NH 4 HCO 3 )-acetonitrile; the mobile phase acetonitrile ratio was 40%-40% in 12 minutes with gradient elution; flow rate was 30 mL/min) to obtain the title compound 38. LC-MS (ESI): m/z 508.2 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ8.84 (d, J＝5.2 Hz, 1H), 8.27 (s, 1H), 7.79 (d, J＝1.6 Hz, 1H), 7.66 (t, J＝1.6 Hz, 1H), 7.44 (d, J＝1.6 Hz, 1H), 7.14–7.10 (m, 2H), 6.85–6.89 (m, 2H), 5.19 (s, 2H), 4.78 (d, J＝8 Hz, 2H), 3.95 (d, J＝8 Hz, 2H), 1.81 (d, J＝13.9 Hz, 6H), 1.65 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ41.18 (s, 1P).
实施例39：化合物39的制备
Example 39: Preparation of Compound 39
化合物39-2的制备Preparation of compound 39-2
将化合物39-1(2g，10.7mmol)，三乙胺(4.5mL，32.1mmol)溶于二氯甲烷(60mL)中，在0℃下，向其中加入甲基磺酰氯(2.45g，21.4mmol)。加毕，将体系于室温搅拌2h。向体系中加饱和氯化铵溶液(30mL)淬灭反应，用二氯甲烷萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，经无水硫酸钠干燥，过滤，滤液浓缩得2.1g粗品标题化合物39-2，收率74.1％。LC-MS(ESI):m/z 210.0[M-55]+.Compound 39-1 (2 g, 10.7 mmol) and triethylamine (4.5 mL, 32.1 mmol) were dissolved in dichloromethane (60 mL). Methanesulfonyl chloride (2.45 g, 21.4 mmol) was added thereto at 0°C. After the addition, the system was stirred at room temperature for 2 h. Saturated ammonium chloride solution (30 mL) was added to the system to quench the reaction, and the mixture was extracted with dichloromethane (50 mL) three times. The organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 2.1 g of crude title compound 39-2, with a yield of 74.1%. LC-MS (ESI): m/z 210.0 [M-55] + .
化合物39-3的制备Preparation of compound 39-3
将化合物39-2(906mg，3.42mmol)，化合物1-6(800mg，2.29mmol)溶于DMF(20mL)中，向其中加入碳酸铯(1.5g，4.58mol)。加毕，将体系于80℃搅拌2h。向体系中加水(20mL)稀释后，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶柱层析纯化(EtOAc/PE(v/v)＝0～50％)得800mg标题化合物39-3，收率68.5％。LC-MS(ESI):m/z 463.2[M-55]+.Compound 39-2 (906 mg, 3.42 mmol) and compound 1-6 (800 mg, 2.29 mmol) were dissolved in DMF (20 mL), and cesium carbonate (1.5 g, 4.58 mol) was added thereto. After the addition, the system was stirred at 80°C for 2 h. After dilution with water (20 mL), the system was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0-50%) to obtain 800 mg of the title compound 39-3, with a yield of 68.5%. LC-MS (ESI): m/z 463.2 [M-55] + .
化合物39-4的制备Preparation of compound 39-4
将化合物39-3(800mg，1.54mmol)，溶于乙酸乙酯(2mL)中，向其中加入氯化氢的乙酸乙酯溶液(1M，20mL)。加毕，将体系于室温搅拌16h。浓缩得550mg粗品标题化合物39-4，收率85％。LC-MS(ESI):m/z 419.2[M+H]+.Compound 39-3 (800 mg, 1.54 mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrogen chloride in ethyl acetate (1 M, 20 mL) was added thereto. After the addition, the system was stirred at room temperature for 16 h. The mixture was concentrated to obtain 550 mg of the crude title compound 39-4, with a yield of 85%. LC-MS (ESI): m/z 419.2 [M+H] + .
化合物39-5的制备Preparation of compound 39-5
将化合物39-3(550mg，1.31mmol)，化合物4-氯-2-甲磺酰基嘧啶(252mg，1.31mmol)溶于四氢呋喃(20mL)中，向其中加入三乙胺(132mg，1.31mmol)。加毕，将体系于室温搅拌16h。向体系中加水(10mL)稀释后，用乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经正相硅胶柱层析纯化(EtOAc/PE(v/v)＝0～60％)得500mg标题化合物39-5，收率72.8％。LC-MS(ESI):m/z 575.2[M+H]+.Compound 39-3 (550 mg, 1.31 mmol) and compound 4-chloro-2-methylsulfonylpyrimidine (252 mg, 1.31 mmol) were dissolved in tetrahydrofuran (20 mL), and triethylamine (132 mg, 1.31 mmol) was added thereto. After the addition, the system was stirred at room temperature for 16 h. After dilution with water (10 mL), the system was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column chromatography (EtOAc/PE (v/v) = 0-60%) to obtain 500 mg of the title compound 39-5, with a yield of 72.8%. LC-MS (ESI): m/z 575.2 [M+H] + .
化合物39的制备Preparation of compound 39
将粗品化合物39-5(200mg，0.35mmol)和二甲基氧化膦(269mg，3.5mmol)溶于乙腈(10mL)中，向其中加入碳酸钾(145mg，1.05mmol)。加毕，将体系于80℃搅拌16h。向体系中加饱和氯化铵溶液(20mL)稀释后，乙酸乙酯萃取(50mL)三次，合并有机相，用饱和食盐水洗涤(50mL)两次，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经高效制备液相(制备方法:色谱柱:Welch Xtimate C18250x21.2mm；柱温:25℃；流动相:水(0.1％10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％在12 分钟内梯度洗脱；流速30mL/min)纯化得标题化合物39，LC-MS(ESI):m/z 573.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.32(s,1H),7.46(d,J＝2.4Hz,1H),7.31(d,J＝2.4Hz,1H),7.11(d,J＝8.8Hz,2H),6.82(d,J＝8.8Hz,2H),6.38(s,1H),5.06(s,1H),4.42(t,J＝6.1Hz,2H),4.04(s,1H),3.88(t,J＝6.1Hz,3H),3.61–3.75(m,3H),2.25–2.44(m,2H),1.85(d,J＝13.6Hz,6H),1.64(s,7H).31P NMR(162MHz,Chloroform-d)δ35.46(s,1P).
The crude compound 39-5 (200 mg, 0.35 mmol) and dimethylphosphine oxide (269 mg, 3.5 mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (145 mg, 1.05 mmol) was added thereto. After the addition, the system was stirred at 80°C for 16 h. After dilution with saturated ammonium chloride solution (20 mL), the system was extracted with ethyl acetate (50 mL) three times, the organic phases were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to high-efficiency preparative liquid chromatography (preparation method: chromatographic column: Welch Xtimate C18250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% 10 mM/L NH 4 HCO 3 )-acetonitrile; the mobile phase acetonitrile ratio was 45%-65% at 12 The title compound 39 was purified by gradient elution within 10 minutes; flow rate 30 mL/min, LC-MS (ESI): m/z 573.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.32 (s, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.38 (s, 1H), 5.06 (s, 1H), 4.42 (t, J = 6.1 Hz, 2H), 4.04 (s, 1H), 3.88 (t, J = 6.1 Hz, 3H), 3.61–3.75 (m, 3H), 2.25–2.44 (m, 2H), 1.85 (d, J = 13.6 Hz, 6H), 1.64 (s, 7H). 31 P NMR (162 MHz, Chloroform-d) δ35.46 (s, 1P).
化合物39A和39B的制备Preparation of compounds 39A and 39B
将化合物39(38.55mg，0.067mmol)经SFC(制备方法:色谱柱:ChiralPak AD,250×30mm I.D.,10μm；柱温:38℃；流动相:A为CO2，B为乙醇(含0.1％氨水)；流动相B比例30％in 8min；流速150mL/min)手性拆分得11.11mg标题化合物39A(手性柱保留时间为11.11min)和17.34mg化合物39B(手性柱保留时间为7.60min)。化合物39A：LC-MS(ESI):573.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.34–8.19(m,1H),7.46(d,J＝2.3Hz,1H),7.31(d,J＝2.4Hz,1H),7.10–7.12(m,2H),6.81–6.82(m,2H),6.34(m,1H),5.05(m,1H),4.42(t,J＝6.2Hz,2H),4.03(m,1H),3.88(t,J＝6.2Hz,2H),3.60(m,3H),2.26–2.42(m,2H),1.82(d,J＝13.4Hz,6H),1.64(s,6H).31P NMR(162MHz,Chloroform-d)δ35.20(s,1P).Compound 39 (38.55 mg, 0.067 mmol) was chirally separated by SFC (preparation method: chromatographic column: ChiralPak AD, 250×30 mm ID, 10 μm; column temperature: 38°C; mobile phase: A is CO 2 , B is ethanol (containing 0.1% ammonia water); mobile phase B ratio 30% in 8 min; flow rate 150 mL/min) to obtain 11.11 mg of the title compound 39A (chiral column retention time of 11.11 min) and 17.34 mg of compound 39B (chiral column retention time of 7.60 min). Compound 39A: LC-MS (ESI): 573.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.34–8.19 (m, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.10–7.12 (m, 2H), 6.81–6.82 (m, 2H), 6.34 (m, 1H), 5.05 (m, 1H), 4.42 (t, J = 6.2 Hz, 2H), 4.03 (m, 1H), 3.88 (t, J = 6.2 Hz, 2H), 3.60 (m, 3H), 2.26–2.42 (m, 2H), 1.82 (d, J = 13.4 Hz, 6H), 1.64 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ 35.20 (s, 1P).
化合物39B：LC-MS(ESI):573.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.33(s,1H),7.45(d,J＝2.3Hz,1H),7.31(d,J＝2.3Hz,1H),7.09–7.11(m,2H),6.81–6.83(m,2H),6.37(s,1H),5.04(s,1H),4.42(t,J＝6.1Hz,2H),3.99(m,1H),3.87(t,J＝6.1Hz,2H),3.58–3.71(m,3H),2.28–2.41(m,2H),1.83(d,J＝13.6Hz,6H),1.64(s,6H).31P NMR(162MHz,Chloroform-d)δ36.84(s,1P).Compound 39B: LC-MS (ESI): 573.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.33 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.09–7.11 (m, 2H), 6.81–6.83 (m, 2H), 6.37 (s, 1H), 5.04 (s, 1H), 4.42 (t, J = 6.1 Hz, 2H), 3.99 (m, 1H), 3.87 (t, J = 6.1 Hz, 2H), 3.58–3.71 (m, 3H), 2.28–2.41 (m, 2H), 1.83 (d, J = 13.6 Hz, 6H), 1.64 (s, 6H). 31 P NMR (162 MHz, Chloroform-d) δ 36.84 (s, 1P).
实施例40：化合物40的制备
Example 40: Preparation of Compound 40
化合物40-3的制备Preparation of compound 40-3
将化合物40-2(500mg，3.62mmol)溶于THF(5mL)中，反应体系用氮气置换三次，干冰浴降温至-20℃，滴加烯丙基溴化镁(1M，9.05mL，9.05mmol)，反应体系在-5℃下搅拌反应2小时，反应结束。冰浴下向反应体系缓慢加入饱和氯化铵水溶液(20mL)淬灭反应。反应液浓缩后冻干，用EA(10mL)溶解粗品，过滤，浓缩有机相得粗产品，用正相硅胶柱层析(DCM/MeOH＝0～10％)分离纯化得到364mg标题化合物40-3，收率77％。LC-MS(ESI):m/z 131.1[M+H]+.Compound 40-2 (500 mg, 3.62 mmol) was dissolved in THF (5 mL), the reaction system was replaced with nitrogen three times, the temperature was cooled to -20 ° C in a dry ice bath, and allyl magnesium bromide (1M, 9.05 mL, 9.05 mmol) was added dropwise. The reaction system was stirred at -5 ° C for 2 hours, and the reaction was completed. Saturated aqueous ammonium chloride solution (20 mL) was slowly added to the reaction system under ice bath to quench the reaction. The reaction solution was concentrated and freeze-dried, and the crude product was dissolved with EA (10 mL), filtered, and the organic phase was concentrated to obtain a crude product. It was separated and purified by normal phase silica gel column chromatography (DCM/MeOH=0-10%) to obtain 364 mg of the title compound 40-3, with a yield of 77%. LC-MS (ESI): m/z 131.1 [M+H] + .
化合物40的制备Preparation of Compound 40
将化合物27-3(100mg，192umol)溶于2-甲基四氢呋喃(2mL)中，依次加入碳酸铯(156mg,480umol)和化合物40-3(37.5mg，288umol)，反应体系用氮气置换三次。将反应体系升温至85℃反应1.5h。反应结束，过滤，滤液中加入水(4mL)，乙酸乙酯萃取(10mL)两次，合并有机相。有机相使用饱和食盐水(10mL)洗涤，无水硫酸钠干燥、浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈洗 脱12分钟；流速:30mL/min)得到45mg标题化合物40，收率14％。LC-MS(ESI):m/z 570.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝5.2Hz,1H),7.72(dd,J＝5.1,3.2Hz,1H),7.63(d,J＝2.4Hz,1H),7.57(d,J＝2.4Hz,1H),7.19(d,J＝8.3Hz,2H),6.99(d,J＝8.4Hz,2H),5.70-5.78(m,2H),5.30(s,2H),5.03–5.19(m,4H),4.41(t,J＝5.1Hz,2H),3.95(t,J＝5.1Hz,2H),2.91–3.06(m,4H),1.63(s,6H).31P NMR(162MHz,DMSO-d6)δ34.13(s,1P).Compound 27-3 (100 mg, 192 umol) was dissolved in 2-methyltetrahydrofuran (2 mL), and cesium carbonate (156 mg, 480 umol) and compound 40-3 (37.5 mg, 288 umol) were added in sequence. The reaction system was replaced with nitrogen three times. The reaction system was heated to 85 ° C for 1.5 h. After the reaction was completed, it was filtered, and water (4 mL) was added to the filtrate, and ethyl acetate (10 mL) was extracted twice, and the organic phases were combined. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 ° C; gradient: 45%-65% acetonitrile washing The reaction mixture was evaporated for 12 minutes; flow rate: 30 mL/min) to give 45 mg of the title compound 40, with a yield of 14%. LC-MS (ESI): m/z 570.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.99 (d, J = 5.2 Hz, 1H), 7.72 (dd, J = 5.1, 3.2 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 5.70-5.78 (m, 2H), 5.30 (s, 2H), 5.03-5.19 (m, 4H), 4.41 (t, J = 5.1 Hz, 2H), 3.95 (t, J = 5.1 Hz, 2H), 2.91-3.06 (m, 4H), 1.63 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.13 (s, 1P).
实施例41：化合物41的制备
Example 41: Preparation of Compound 41
化合物41-2的制备Preparation of compound 41-2
将化合物镁(2.45g，101.8mmol)和碘(20mg，78umol)加入干燥的三口瓶中，向瓶中加入干燥的THF(100mL)，反应体系用氮气置换三次，升温至35℃反应。将化合物1,4-二溴丁烷(10.0g，46.3mmol)缓慢滴加到反应体系，滴毕，室温反应1小时。将反应体降温至-20℃，滴加化合物亚磷酸二乙酯(5.4g，39.3mmol)。LCMS监测反应至完全，滴加乙醇(100mL)淬灭反应，反应体系用浓缩得粗产品，通过正相硅胶柱(DCM/MeOH＝0～15％)分离纯化得到320mg标题化合物41-2，收率6.6％。LC-MS(ESI):m/z105.2[M+H]+.Add compound magnesium (2.45g, 101.8mmol) and iodine (20mg, 78umol) to a dry three-necked flask, add dry THF (100mL) to the flask, replace the reaction system with nitrogen three times, and heat to 35℃ for reaction. Add compound 1,4-dibromobutane (10.0g, 46.3mmol) slowly dropwise to the reaction system, and react at room temperature for 1 hour after the dropwise addition. Cool the reaction body to -20℃, and dropwise add compound diethyl phosphite (5.4g, 39.3mmol). LCMS monitors the reaction until it is complete, and ethanol (100mL) is added dropwise to quench the reaction. The reaction system is concentrated to obtain a crude product, which is separated and purified by a normal phase silica gel column (DCM/MeOH=0-15%) to obtain 320mg of the title compound 41-2, with a yield of 6.6%. LC-MS (ESI): m/z105.2[M+H] + .
化合物41的制备Preparation of compound 41
将化合物27-3(322mg，0.62mmol)溶于2-甲基四氢呋喃(4ml)中，加入碳酸钾(406mg，1.25mmol)，和化合物41-2(130mg，1.25mmol)，反应体系用氮气置换三次，升温至85℃反应1.5小时。LCMS监测反应，待反应结束后，过滤，滤液中加入水(20mL)，乙酸乙酯萃取(20mL)两次，合并有机相。有机相使用饱和食盐水(10mL)洗涤，无水硫酸钠干燥、浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:15％-55％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到21mg标题化合物41，收率6.2％。LC-MS(ESI):m/z 544.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝5.1Hz,1H),7.71(dd,J＝5.2,3.1Hz,1H),7.64(d,J＝2.3Hz,1H),7.58(d,J＝2.4Hz,1H),7.18-7.22(m,2H),6.97-7.01(m,2H),5.30(s,2H),4.41(t,J＝5.8Hz,2H),3.96(t,J＝5.8Hz,2H),2.27–2.34(m,2H),1.91-1.97(m,2H),1.66–1.87(m,4H),1.63(s,6H).31P NMR(162MHz,DMSO-d6)δ59.94(s,1P).Compound 27-3 (322 mg, 0.62 mmol) was dissolved in 2-methyltetrahydrofuran (4 ml), potassium carbonate (406 mg, 1.25 mmol), and compound 41-2 (130 mg, 1.25 mmol) were added, and the reaction system was replaced with nitrogen three times, and the temperature was raised to 85 ° C for 1.5 hours. The reaction was monitored by LCMS. After the reaction was completed, it was filtered, water (20 mL) was added to the filtrate, and ethyl acetate (20 mL) was extracted twice, and the organic phase was combined. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 ° C; gradient: 15%-55% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain 21 mg of the title compound 41, with a yield of 6.2%. LC-MS (ESI): m/z 544.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.99 (d, J = 5.1 Hz, 1H), 7.71 (dd, J = 5.2, 3.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.18-7.22 (m, 2H), 6.97-7.01 (m, 2H), 5.30 (s, 2H), 4.41 (t, J = 5.8 Hz, 2H), 3.96 (t, J = 5.8 Hz, 2H), 2.27-2.34 (m, 2H), 1.91-1.97 (m, 2H), 1.66-1.87 (m, 4H), 1.63 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 59.94 (s, 1P).
实施例42：化合物42的制备
Example 42: Preparation of Compound 42
化合物42-1的制备Preparation of compound 42-1
将化合物34-6(600mg，2.2mmol)加入三口瓶中，再加入DCM(10mL)，反应体系用氩气置换三次，在-15℃下滴加三溴化硼(1M，4.4mL，4.4mmol)，冰浴下搅拌反应2小时。反应结束后，加碳酸氢钠(4mL，1M)，用二氯甲烷(20mL)萃取三次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE ＝0-30％)分离纯化得到460mg标题化合物42-1，收率85％。LC-MS(ESI):m/z 426.2[M+H]+.Compound 34-6 (600 mg, 2.2 mmol) was added to a three-necked flask, and then DCM (10 mL) was added. The reaction system was replaced with argon three times, and boron tribromide (1 M, 4.4 mL, 4.4 mmol) was added dropwise at -15 °C, and stirred for 2 hours under ice bath. After the reaction was completed, sodium bicarbonate (4 mL, 1 M) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried and concentrated to obtain a crude product, and then filtered through a normal phase silica gel column (EtOAc/PE =0-30%) was separated and purified to obtain 460 mg of the title compound 42-1, with a yield of 85%. LC-MS (ESI): m/z 426.2 [M+H] + .
化合物42-2的制备Preparation of compound 42-2
将化合物42-1(460mg，1.082mmol)，无水THF(5mL)加入三口瓶中，反应体系氩气置换三次，冰浴下加入氢化钠(54mg，1.35mmol，60％)，滴加2,3-二氯丙酸甲酯(255mg，1.624mmol)，反应体系室温搅拌反应4小时。反应结束后，在冰浴下向反应体系缓慢加入氯化铵水溶液(10mL)，用DCM(10mL)萃取三次，合并有机相，干燥浓缩得粗品，通过正相硅胶柱纯化(EtOAc/PE＝0～40％)得到280mg标题化合物42-2，收率47％。LC-MS(ESI):546.3[M+H]+.Compound 42-1 (460 mg, 1.082 mmol) and anhydrous THF (5 mL) were added to a three-necked flask, the reaction system was replaced with argon three times, sodium hydride (54 mg, 1.35 mmol, 60%) was added under ice bath, methyl 2,3-dichloropropionate (255 mg, 1.624 mmol) was added dropwise, and the reaction system was stirred at room temperature for 4 hours. After the reaction was completed, an aqueous solution of ammonium chloride (10 mL) was slowly added to the reaction system under ice bath, and extracted three times with DCM (10 mL), the organic phases were combined, dried and concentrated to obtain a crude product, and purified by normal phase silica gel column (EtOAc/PE=0-40%) to obtain 280 mg of the title compound 42-2, with a yield of 47%. LC-MS (ESI): 546.3 [M+H] + .
化合物42-3的制备Preparation of compound 42-3
将化合物42-2(280mg，0.514mmol)加入三口瓶中，加入四氢呋喃(10mL)。在锥形瓶中加入5mL水，加入过氧单磺酸钾(788mg，2.4mmol)，搅拌溶解，冰浴下滴加到上述反应体系中，升至室温下搅拌反应16小时。反应液过滤，旋干得到粗品，通过正相硅胶柱(EtOAc/PE＝0～60％)分离纯化得到230mg标题化合物42-3，收率77％。LC-MS(ESI):m/z 578.2[M+H]+.Compound 42-2 (280 mg, 0.514 mmol) was added to a three-necked flask, and tetrahydrofuran (10 mL) was added. 5 mL of water was added to a conical flask, and potassium peroxymonosulfonate (788 mg, 2.4 mmol) was added, stirred to dissolve, and added dropwise to the above reaction system under an ice bath, and stirred and reacted at room temperature for 16 hours. The reaction solution was filtered and dried to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-60%) to obtain 230 mg of the title compound 42-3, with a yield of 77%. LC-MS (ESI): m/z 578.2 [M+H] + .
化合物42-4的制备Preparation of compound 42-4
将化合物42-3(230mg，0.399mmol)溶解于2-甲基四氢呋喃(4mL)中，依次加入二甲基氧化膦(78mg，1.0mmol)、碳酸钾(325mg，1.0mmol)。反应体系在80℃下搅拌反应1.5小时。反应结束后，反应体系过滤，滤液加水(20mL)，用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到110mg标题化合物42-4，收率46％。LC-MS(ESI):m/z 576.3[M+H]+.Compound 42-3 (230 mg, 0.399 mmol) was dissolved in 2-methyltetrahydrofuran (4 mL), and dimethylphosphine oxide (78 mg, 1.0 mmol) and potassium carbonate (325 mg, 1.0 mmol) were added in sequence. The reaction system was stirred at 80°C for 1.5 hours. After the reaction was completed, the reaction system was filtered, the filtrate was added with water (20 mL), extracted three times with dichloromethane (10 mL), the organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain 110 mg of the title compound 42-4, with a yield of 46%. LC-MS (ESI): m/z 576.3 [M+H] + .
化合物42的制备Preparation of compound 42
将化合物42-4(110mg，0.191mmol)溶于MeOH(5ml)，氮气置换三次后，在0℃冷却温度下分批加入硼氢化钠(14.5mg，0.382mmol)。反应体系在0℃下搅拌反应2小时。反应结束后，加水(10mL)淬灭反应，用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:15％-45％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到29mg标题化合物42，收率28％。LC-MS(ESI):m/z 548.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝5.2Hz,1H),7.72(dd,J＝5.2,3.2Hz,1H),7.61(d,J＝2.3Hz,1H),7.56(d,J＝2.4Hz,1H),7.19-7.22(m,2H),6.98-7.03(m,2H),5.61(d,J＝5.3Hz,1H),5.29(s,2H),4.18(d,J＝5.4Hz,2H),4.06(m,J＝5.3Hz,1H),3.83(dd,J＝11.2,4.6Hz,1H),3.72(dd,J＝11.2,5.6Hz,1H),1.74(d,J＝18.7Hz,3H),1.63(s,6H).Compound 42-4 (110 mg, 0.191 mmol) was dissolved in MeOH (5 ml), and after nitrogen replacement three times, sodium borohydride (14.5 mg, 0.382 mmol) was added in batches at a cooling temperature of 0°C. The reaction system was stirred at 0°C for 2 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, and dichloromethane (10 mL) was used for extraction three times. The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 15%-45% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 29 mg of the title compound 42, with a yield of 28%. LC-MS (ESI): m/z 548.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.99(d,J＝5.2Hz,1H),7.72(dd,J＝5.2,3.2Hz,1H),7.61(d,J＝2.3Hz,1H),7.56(d,J＝2.4Hz,1H),7.19-7.22(m,2H),6.98-7.03(m,2H),5.61(d,J＝5.3Hz,1H),5.29(s,2H),4.18(d,J＝5.4Hz,2H),4.06(m,J＝5.3Hz,1H),3.83(dd,J＝11.2,4.6Hz,1H),3.72(dd,J＝11.2,5.6Hz,1H),1.74(d,J＝18.7Hz,3H),1.63(s,6H).
实施例43：化合物43A和43B的制备

Example 43: Preparation of Compounds 43A and 43B

化合物43-3的制备Preparation of compound 43-3
氮气保护下，依次将化合物43-1(12g，68.12mmol)，化合物43-2(25.78g，108.99mmol)，DCM(60mL)，正己烷(300mL)，三氟甲磺酸酐(960.93mg，3.41mmol)加入反应瓶中。室温搅拌16小时。LCMS监测反应完全。过滤，滤液用饱和碳酸氢钠水溶液(300mL)洗涤两次。滤液浓缩旋干，浓缩残留物经正相硅胶柱(EtOAc/PE＝0-10％)分离纯化得到15g标题化合物43-3，收率82％.LC-MS(ESI):267.2[M+H]+.Under nitrogen protection, compound 43-1 (12 g, 68.12 mmol), compound 43-2 (25.78 g, 108.99 mmol), DCM (60 mL), n-hexane (300 mL), trifluoromethanesulfonic anhydride (960.93 mg, 3.41 mmol) were added to the reaction bottle in sequence. Stir at room temperature for 16 hours. LCMS monitored the reaction to be complete. Filter, and wash the filtrate twice with saturated sodium bicarbonate aqueous solution (300 mL). The filtrate was concentrated and dried, and the concentrated residue was separated and purified by normal phase silica gel column (EtOAc/PE=0-10%) to obtain 15 g of the title compound 43-3, with a yield of 82%. LC-MS (ESI): 267.2 [M+H] + .
化合物43-4的制备Preparation of compound 43-4
将化合物43-3(13g，48.82mmol)，THF(150mL)加入反应瓶中。于0℃下分批加入氢化铝锂(5.56g，146.46mmol)，室温搅拌16小时。LCMS监测反应完全。反应体系降温至0℃后，缓慢滴加冰水(5.56mL)淬灭反应。再加入15％的氢氧化钠水溶液(5.56mL)，搅拌20分钟后再加入水(16.68mL)。反应体系过滤，滤饼用DCM(50mL)洗涤两次，滤液经无水硫酸钠干燥，浓缩旋干，得到6.3g标题化合物43-4粗品，收率61％.LC-MS(ESI):211.2[M+H]+.Compound 43-3 (13 g, 48.82 mmol) and THF (150 mL) were added to the reaction flask. Lithium aluminum hydride (5.56 g, 146.46 mmol) was added in batches at 0°C and stirred at room temperature for 16 hours. The reaction was complete when monitored by LCMS. After the reaction system was cooled to 0°C, ice water (5.56 mL) was slowly added dropwise to quench the reaction. A 15% aqueous sodium hydroxide solution (5.56 mL) was added, and water (16.68 mL) was added after stirring for 20 minutes. The reaction system was filtered, and the filter cake was washed twice with DCM (50 mL). The filtrate was dried over anhydrous sodium sulfate, concentrated and dried to give 6.3 g of the crude product of the title compound 43-4, with a yield of 61%. LC-MS (ESI): 211.2 [M+H] + .
化合物43-5的制备Preparation of compound 43-5
氮气保护下，将化合物43-4(6g，28.53mmol)，无水二氯甲烷(30mL)，三乙胺(6.35g，62.78mmol)加入反应瓶中。降温至0℃后，将甲磺酰氯(7.19g，62.78mmol)滴加入反应瓶中，升温至室温搅拌16小时。TLC监测反应完全。将反应液直接浓缩旋干，浓缩残留物用丙酮(30mL)溶解。将KBr(9.91g，114.41mmol)加入到反应体系中，升温至40℃搅拌16小时。待反应结束，加水(50mL)，后用二氯甲烷(50mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-10％)分离纯化得到2.1g标题化合物43-5，收率21％.LC-MS(ESI):335.0[M+H]+.Under nitrogen protection, compound 43-4 (6 g, 28.53 mmol), anhydrous dichloromethane (30 mL), and triethylamine (6.35 g, 62.78 mmol) were added to the reaction flask. After cooling to 0 ° C, methanesulfonyl chloride (7.19 g, 62.78 mmol) was added dropwise to the reaction flask, and the temperature was raised to room temperature and stirred for 16 hours. TLC monitored the reaction to be complete. The reaction solution was directly concentrated and dried, and the concentrated residue was dissolved with acetone (30 mL). KBr (9.91 g, 114.41 mmol) was added to the reaction system, and the temperature was raised to 40 ° C and stirred for 16 hours. After the reaction was completed, water (50 mL) was added, and then extracted three times with dichloromethane (50 mL), the organic phases were combined, and dried and concentrated to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (EtOAc/PE=0-10%) to obtain 2.1 g of the title compound 43-5, with a yield of 21%. LC-MS (ESI): 335.0 [M+H] + .
化合物43-6的制备Preparation of compound 43-6
氮气保护下，将次磷酸铵(778.23mg，9.37mmol)，六甲基二硅基胺(3.8mL)加入反应瓶中，升温至120℃并搅拌4小时后降温至0℃。将化合物43-5(2.1g，6.25mmol)于0℃加入到反应体系中，升温至120℃继续搅拌4小时。将体系降温至0℃后，滴加无水乙醇(12mL)。升温回流搅拌1小时。体系降温至室温，过滤，滤饼用DCM(10mL)洗涤两次。滤液浓缩旋干即得到1.5g粗品标题化合物43-6，收率100％.LC-MS(ESI):241.2[M+H]+.Under nitrogen protection, ammonium hypophosphite (778.23 mg, 9.37 mmol) and hexamethyldisilazide (3.8 mL) were added to the reaction flask, heated to 120 ° C and stirred for 4 hours, then cooled to 0 ° C. Compound 43-5 (2.1 g, 6.25 mmol) was added to the reaction system at 0 ° C, heated to 120 ° C and continued to stir for 4 hours. After the system was cooled to 0 ° C, anhydrous ethanol (12 mL) was added dropwise. The mixture was heated to reflux and stirred for 1 hour. The system was cooled to room temperature, filtered, and the filter cake was washed twice with DCM (10 mL). The filtrate was concentrated and dried to obtain 1.5 g of crude title compound 43-6, with a yield of 100%. LC-MS (ESI): 241.2 [M + H] + .
化合物43-7的制备Preparation of compound 43-7
氮气保护下，将化合物43-6(2.5g，10.41mmol)，无水二氯甲烷(40mL)加入反应瓶中，降温至℃后滴加草酰氯(3.96g，31.22mmol)。缓慢升温至室温并搅拌16小时。将反应液浓缩至干，浓缩残留物用甲苯(25mL)溶解后旋干。浓缩残留物加入二氯甲烷(40mL)溶解，于-78℃滴加二异丁基氢化铝(1M，15.61mmol，15.61mL)，-78℃下搅拌两小时后，滴加甲醇(8mL)淬灭反应。升温至0℃后，向体系中加入10％醋酸水溶液(25mL)，室温下搅拌10分钟，体系用二氯甲烷(20mL)萃取5次，合并有机相，旋干，浓缩残留物经制备分离纯化(制备方法：流动相：A:0.1％甲酸水溶液；B:乙腈；色谱柱：Agilent 10Prep-C18 250×21.2mm；柱温：25℃；梯度：10％-75％乙腈在20分钟内梯度洗脱；流速：30mL/min)得到120mg标题化合物43-7，收率5％.LC-MS(ESI):225.0[M+H]+. Under nitrogen protection, compound 43-6 (2.5 g, 10.41 mmol) and anhydrous dichloromethane (40 mL) were added to the reaction flask, and oxalyl chloride (3.96 g, 31.22 mmol) was added dropwise after cooling to ℃. The temperature was slowly raised to room temperature and stirred for 16 hours. The reaction solution was concentrated to dryness, and the concentrated residue was dissolved in toluene (25 mL) and then spin-dried. The concentrated residue was dissolved in dichloromethane (40 mL), and diisobutylaluminum hydride (1 M, 15.61 mmol, 15.61 mL) was added dropwise at -78 ℃. After stirring for two hours at -78 ℃, methanol (8 mL) was added dropwise to quench the reaction. After the temperature was raised to 0°C, 10% acetic acid aqueous solution (25 mL) was added to the system and stirred at room temperature for 10 minutes. The system was extracted with dichloromethane (20 mL) for 5 times, the organic phases were combined, dried by rotation, and the concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-75% acetonitrile in 20 minutes; flow rate: 30 mL/min) to obtain 120 mg of the title compound 43-7, with a yield of 5%. LC-MS (ESI): 225.0 [M+H] + .
化合物43-8的制备Preparation of Compound 43-8
氮气保护下，将化合物43-7(60mg，267.58μmol)，无水二氯甲烷(1mL)加入反应瓶中，于0℃下缓慢加入BBr3(1M，2.00mmol，2mL)，室温搅拌20分钟。LCMS监测反应完全。于0℃下缓慢滴加甲醇(12mL)以淬灭反应。反应体系直接浓缩旋干，得到35mg标题化合物43-8粗品，产率97％.LC-MS(ESI):135.0[M+H]+.Under nitrogen protection, compound 43-7 (60 mg, 267.58 μmol) and anhydrous dichloromethane (1 mL) were added to a reaction flask, and BBr 3 (1 M, 2.00 mmol, 2 mL) was slowly added at 0°C and stirred at room temperature for 20 minutes. LCMS monitored the reaction to be complete. Methanol (12 mL) was slowly added dropwise at 0°C to quench the reaction. The reaction system was directly concentrated and dried to obtain 35 mg of the crude product of the title compound 43-8, with a yield of 97%. LC-MS (ESI): 135.0 [M+H] + .
化合物43A和43B的制备Preparation of Compounds 43A and 43B
将化合物43-8(35mg，260.97μmol)，化合物1-7(200mg，419.48μmol)，DIPEA(216.86mg，1.68mmol)，Xantphos(48.54mg，83.90μmol)，Pd2(dba)3(38.41mg，41.95μmol)和DMF(2mL)加入微波管中。氮气保护下，120℃搅拌6小时。LCMS监测反应完全。加水(10mL)，后用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经制备分离纯化(制备方法：流动相：A:0.1％甲酸水溶液；B:乙腈；色谱柱：Agilent 10Prep-C18 250×21.2mm；柱温：25℃；梯度：10％-95％乙腈在20分钟内梯度洗脱；流速：30mL/min)，得到5mg标题化合物43A(收率2％)和10mg标题化合物43B(收率4％).Compound 43-8 (35 mg, 260.97 μmol), compound 1-7 (200 mg, 419.48 μmol), DIPEA (216.86 mg, 1.68 mmol), Xantphos (48.54 mg, 83.90 μmol), Pd 2 (dba) 3 (38.41 mg, 41.95 μmol) and DMF (2 mL) were added into a microwave tube. Stir at 120° C. for 6 hours under nitrogen protection. The reaction was complete when monitored by LCMS. Water (10 mL) was added, and then the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-95% acetonitrile in 20 minutes; flow rate: 30 mL/min) to obtain 5 mg of the title compound 43A (yield 2%) and 10 mg of the title compound 43B (yield 4%).
化合物43A：(HPLC分析方法：色谱柱：Agilent ZORBAX Extend-C18 4.6*150mm,3.5μm；柱温：30℃；流动相:水(0.1mL/1L三氟乙酸)-乙腈(0.4mL/4L三氟乙酸)；乙腈:5％-95％8min，95％7min；流速：1mL/min，保留时间Rt：7.685min).LC-MS(ESI):574.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.03(d,J＝5.2Hz,1H),7.75(dd,J＝5.2,2.9Hz,1H),7.64(d,J＝2.3Hz,1H),7.57(d,J＝2.3Hz,1H),7.20(d,J＝8.8Hz,2H),7.01(d,J＝8.8Hz,2H),5.31(s,2H),4.69(br.s,1H),4.41(t,J＝5.1Hz,2H),3.95(t,J＝5.1Hz,2H),3.77–3.62(m,1H),2.49–2.36(m,2H),2.07–1.87(m,4H),1.63(s,6H),1.44–1.28(m,2H).31P NMR(162MHz,DMSO-d6)δ33.84(s,1P).Compound 43A: (HPLC analysis method: chromatographic column: Agilent ZORBAX Extend-C18 4.6*150mm, 3.5μm; column temperature: 30°C; mobile phase: water (0.1mL/1L trifluoroacetic acid)-acetonitrile (0.4mL/4L trifluoroacetic acid); acetonitrile: 5%-95% 8min, 95% 7min; flow rate: 1mL/min, retention time Rt: 7.685min). LC-MS (ESI): 574.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.03(d,J＝5.2Hz,1H),7.75(dd,J＝5.2,2.9Hz,1H),7.64(d,J＝2.3Hz,1H),7.57(d,J＝2.3Hz,1H),7.20(d,J＝8.8Hz,2H),7.01(d,J＝8.8Hz,2H),5.31(s,2H),4.69(br.s,1H),4.41(t,J＝5.1Hz,2H),3.95(t,J＝5.1Hz,2H),3.77–3.62(m,1H),2.49–2.36(m,2H),2.07–1.87(m,4H),1.63(s,6H),1.44–1.28(m,2H). 31 P NMR (162MHz,DMSO-d 6 )δ33.84(s,1P).
化合物43B：(HPLC分析方法：色谱柱：Agilent ZORBAX Extend-C18 4.6*150mm,3.5μm；柱温：30℃；流动相:水(0.1mL/1L三氟乙酸)-乙腈(0.4mL/4L三氟乙酸)；乙腈:5％-95％8min，95％7min；流速：1mL/min，保留时间Rt：7.816min).LC-MS(ESI):574.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.01(d,J＝5.2Hz,1H),7.74(dd,J＝5.2,3.0Hz,1H),7.64(d,J＝2.3Hz,1H),7.57(d,J＝2.3Hz,1H),7.19(d,J＝8.8Hz,2H),6.99(d,J＝8.8Hz,2H),5.29(s,2H),4.82(d,J＝3.4Hz,1H),4.41(t,J＝5.3Hz,2H),3.95(t,J＝5.3Hz,2H),3.66(br.s,1H),2.29–2.10(m,4H),2.03–1.89(m,2H),1.63(s,6H),1.53–1.44(m,2H).31P NMR(162MHz,DMSO-d6)δ32.90(s,1P).Compound 43B: (HPLC analysis method: chromatographic column: Agilent ZORBAX Extend-C18 4.6*150mm, 3.5μm; column temperature: 30°C; mobile phase: water (0.1mL/1L trifluoroacetic acid)-acetonitrile (0.4mL/4L trifluoroacetic acid); acetonitrile: 5%-95% 8min, 95% 7min; flow rate: 1mL/min, retention time Rt: 7.816min). LC-MS (ESI): 574.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.01(d,J＝5.2Hz,1H),7.74(dd,J＝5.2,3.0Hz,1H),7.64(d,J＝2.3Hz,1H),7.57(d,J＝2.3Hz,1H),7.19(d,J＝8.8Hz,2H),6.99(d,J＝8.8Hz,2H),5.29(s,2H),4.82(d,J＝3.4Hz,1H),4.41(t,J＝5.3Hz,2H),3.95(t,J＝5.3Hz,2H),3.66(br.s,1H),2.29–2.10(m,4H),2.03–1.89(m,2H),1.63(s,6H),1.53–1.44(m,2H). 31 P NMR (162 MHz, DMSO-d 6 ) δ 32.90 (s, 1P).
实施例44：化合物44的制备
Example 44: Preparation of Compound 44
化合物44-1的制备 Preparation of compound 44-1
氮气保护下，将化合物(2-氯嘧啶-4-基)甲醇(1g，6.92mmol)，TBSCl(1.15g，7.61mmol)，乙腈(10mL)加入反应瓶中。于0℃下加入咪唑(941.86mg，13.84mmol)并搅拌10分钟，升温至室温并加入DMF(3mL)。室温下搅拌1小时，LCMS检测反应完全。加水(30mL)淬灭反应，后用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-10％)分离纯化得到标题化合物44-1(1.63g)，产率91％。LC-MS(ESI):259.0[M+H]+.Under nitrogen protection, compound (2-chloropyrimidin-4-yl) methanol (1g, 6.92mmol), TBSCl (1.15g, 7.61mmol), acetonitrile (10mL) were added to the reaction bottle. Imidazole (941.86mg, 13.84mmol) was added at 0°C and stirred for 10 minutes, then the mixture was warmed to room temperature and DMF (3mL) was added. Stirring was performed at room temperature for 1 hour, and the reaction was complete after LCMS detection. Water (30mL) was added to quench the reaction, and then the mixture was extracted three times with dichloromethane (10mL), the organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE=0-10%) to obtain the title compound 44-1 (1.63g) with a yield of 91%. LC-MS (ESI): 259.0 [M+H] + .
化合物44-2的制备Preparation of compound 44-2
将化合物44-1(771.94mg，2.98mmol)，化合物43-8(400mg，2.98mmol)，DIPEA(1.54g，11.93mmol，2.08mL)，Xantphos(345.15mg,596.51μmol)，Pd2(dba)3(273.12mg,298.26μmol)和DMF(8mL)加入微波管中。氮气保护下，120℃搅拌6小时。LC-MS检测反应完全。加水(30mL)，后用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-100％)分离纯化，得到标题化合物44-2(240mg)，产率22％。LC-MS(ESI):356.5[M+H]+.Compound 44-1 (771.94 mg, 2.98 mmol), compound 43-8 (400 mg, 2.98 mmol), DIPEA (1.54 g, 11.93 mmol, 2.08 mL), Xantphos (345.15 mg, 596.51 μmol), Pd 2 (dba) 3 (273.12 mg, 298.26 μmol) and DMF (8 mL) were added to a microwave tube. Stir at 120 °C for 6 hours under nitrogen protection. LC-MS detected that the reaction was complete. Water (30 mL) was added, and then extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE=0-100%) to obtain the title compound 44-2 (240 mg) with a yield of 22%. LC-MS (ESI): 356.5 [M+H] + .
化合物44-3的制备Preparation of compound 44-3
将化合物44-2(200mg，561.06μmol)，DMP(475.93mg，1.12mmol)，DCM(2mL)加入反应瓶中，室温下搅拌2小时。LC-MS显示反应完全。加水(20mL)淬灭反应，用二氯甲烷(10mL)萃取三次。合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-100％)分离纯化，得到标题化合物44-3(100mg)，产率50％。LC-MS(ESI):355.0[M+H]+.Compound 44-2 (200 mg, 561.06 μmol), DMP (475.93 mg, 1.12 mmol), and DCM (2 mL) were added to the reaction flask and stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. Water (20 mL) was added to quench the reaction and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE=0-100%) to obtain the title compound 44-3 (100 mg) with a yield of 50%. LC-MS (ESI): 355.0 [M+H] + .
化合物44-4的制备Preparation of compound 44-4
将化合物44-3(200mg，564.25μmol)，DCM(2mL)加入反应瓶中，于0℃下滴加DAST(136.43mg，846.37μmol)。室温下搅拌2小时，TLC检测反应完全，加水(20mL)淬灭反应，后用二氯甲烷(20mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-100％)分离纯化得到标题化合物44-4(90mg)，产率42％。Compound 44-3 (200 mg, 564.25 μmol) and DCM (2 mL) were added to a reaction flask, and DAST (136.43 mg, 846.37 μmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction was complete after TLC detection. Water (20 mL) was added to quench the reaction, and then the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE=0-100%) to obtain the title compound 44-4 (90 mg) with a yield of 42%.
化合物44-5的制备Preparation of compound 44-5
将化合物44-4(24mg，63.75μmol)，TBAF(1M，63.75μmol，63.75μL)和THF加入反应瓶中，室温下搅拌1小时。LCMS检测反应完全。加水(5mL)淬灭反应，后用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-100％)分离纯化得到标题化合物44-5(10mg)，产率59％。LC-MS(ESI):263.0[M+H]+.Compound 44-4 (24 mg, 63.75 μmol), TBAF (1 M, 63.75 μmol, 63.75 μL) and THF were added to the reaction flask and stirred at room temperature for 1 hour. LCMS detected that the reaction was complete. Water (5 mL) was added to quench the reaction, and then extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE=0-100%) to obtain the title compound 44-5 (10 mg) with a yield of 59%. LC-MS (ESI): 263.0 [M+H] + .
化合物44的制备Preparation of compound 44
氮气保护下，将化合物1-6(53.43mg，152.56μmol)，化合物44-5(20mg，76.28μmol)，TMAD(65.67mg，381.40μmol)，DCM(2mL)加入反应瓶中，0℃下滴加三丁基膦(77.16mg，381.40μmol)并搅拌20分钟。LCMS检测反应完全。加水(10mL)，后用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经制备分离纯化(制备方法：流动相：A:0.1％甲酸水溶液；B:乙腈；色谱柱：Agilent 10Prep-C18 250×21.2mm；柱温：25℃；梯度：10％-80％乙腈洗脱30分钟；流速：30mL/min)，得到标题化合物44(3mg)，收率6％。LC-MS(ESI):594.0[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.93(brs,1H),7.76(brs,1H),7.45(d,J＝2.3Hz,1H),7.31(d,J＝2.3Hz,1H),7.12–7.15(m,2H),6.90–6.92(m,2H),5.26(s,2H),4.42(t,J＝6.1Hz,2H),3.88(t,J＝6.1Hz,2H),2.70–2.58(m,2H),2.58–2.47(m,2H),2.46–2.36(m,2H),2.36–2.27(m,2H),1.65(s,6H).19F NMR(376MHz,Chloroform-d)δ-97.07(d,J＝246.3Hz,1F),-98.73(d,J＝246.3Hz,1F). Under nitrogen protection, compound 1-6 (53.43 mg, 152.56 μmol), compound 44-5 (20 mg, 76.28 μmol), TMAD (65.67 mg, 381.40 μmol), and DCM (2 mL) were added to a reaction flask, and tributylphosphine (77.16 mg, 381.40 μmol) was added dropwise at 0°C and stirred for 20 minutes. LCMS detected that the reaction was complete. Water (10 mL) was added, and then extracted three times with dichloromethane (10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile elution over 30 minutes; flow rate: 30 mL/min) to give the title compound 44 (3 mg) in a yield of 6%. LC-MS (ESI): 594.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.93 (brs, 1H), 7.76 (brs, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.12–7.15 (m, 2H), 6.90–6.92 (m, 2H), 5.26 (s, 2H), 4.42 (t, J = 6.1 Hz, 2H), 3.88 (t, J = 6.1 Hz, 2H), 2.70–2.58 (m, 2H), 2.58–2.47 (m, 2H), 2.46–2.36 (m, 2H), 2.36–2.27 (m, 2H), 1.65 (s, 6H). 19 F NMR (376 MHz, Chloroform-d) δ -97.07 (d, J = 246.3 Hz, 1F), -98.73 (d, J = 246.3 Hz, 1F).
实施例45：化合物45的制备
Example 45: Preparation of Compound 45
化合物45-1的制备Preparation of compound 45-1
往100ml单口瓶加1-6(1g，2.86mmol)，DCM(15mL)和吡啶(451.69mg，5.71mmol，460.02μL)，冷却至0℃，氮气置换，滴加Tf2O(1.21g，4.28mmol，720.54μL)。升至室温搅拌18小时，TLC监测反应完全(PE:EA＝3:1)。将反应液倒入水(50ml)中，DCM(60ml)萃取两次。有机相合并，水(50ml)洗，减压浓缩得黄色油状物。快速层析柱纯化(EA/PE＝0～100％)得1.2g标题化合物，收率87％。1H NMR(400MHz,CDCl3)δ7.42(d,J＝8Hz,1H),7.34(d,J＝8Hz,1H),7.21–7.27(m,4H),4.44t(,J＝4Hz,2H),3.88(t,J＝4Hz,2H),1.68(s,3H).Add 1-6 (1 g, 2.86 mmol), DCM (15 mL) and pyridine (451.69 mg, 5.71 mmol, 460.02 μL) to a 100 ml single-mouth bottle, cool to 0 ° C, replace with nitrogen, and add Tf2O (1.21 g, 4.28 mmol, 720.54 μL) dropwise. Warm to room temperature and stir for 18 hours. TLC monitors the reaction to be complete (PE: EA = 3: 1). Pour the reaction solution into water (50 ml) and extract twice with DCM (60 ml). Combine the organic phases, wash with water (50 ml), and concentrate under reduced pressure to obtain a yellow oil. Purify by flash chromatography (EA/PE = 0-100%) to obtain 1.2 g of the title compound with a yield of 87%. 1 H NMR (400 MHz, CDCl 3 ) δ7.42 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 7.21-7.27 (m, 4H), 4.44 t (, J=4 Hz, 2H), 3.88 (t, J=4 Hz, 2H), 1.68 (s, 3H).
化合物45-3的制备Preparation of compound 45-3
将化合物45-1(500mg，1.04mmol)溶解于1,4-二氧六环(5mL)中，依次加入45-2(290mg，1.56mmol)、碳酸铯(676mg，2.08mmol)、醋酸钯(23mg，0.1mmol)和Xantphos(30mg，0.05mmol)。用氮气置换三次，反应体系在100℃下微波搅拌反应2小时。反应结束后，反应体系过滤后向滤液中加入10mL饱和氯化钠水溶液淬灭反应，用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-35％)分离纯化得到110mg标题化合物，收率20％。LC-MS(ESI):518.1[M+H]+.Compound 45-1 (500 mg, 1.04 mmol) was dissolved in 1,4-dioxane (5 mL), and 45-2 (290 mg, 1.56 mmol), cesium carbonate (676 mg, 2.08 mmol), palladium acetate (23 mg, 0.1 mmol) and Xantphos (30 mg, 0.05 mmol) were added in sequence. The mixture was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 100 ° C for 2 hours. After the reaction was completed, the reaction system was filtered and 10 mL of saturated sodium chloride aqueous solution was added to the filtrate to quench the reaction, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-35%) to obtain 110 mg of the title compound with a yield of 20%. LC-MS (ESI): 518.1 [M+H] + .
化合物45-4的制备Preparation of compound 45-4
将化合物45-3(110mg，0.212mmol)溶解于二氯甲烷中(3.0mL)中，滴加三氟乙酸(0.1mL)，反应体系在室温下搅拌2小时。反应结束后，向滤液中加入10mL饱和碳酸氢钠溶液淬灭反应，用二氯甲烷(10mL)萃取三次，合并有机相，干燥浓缩得到85mg标题化合物，收率96％。LC-MS(ESI):418.2[M+H]+.Compound 45-3 (110 mg, 0.212 mmol) was dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (0.1 mL) was added dropwise, and the reaction system was stirred at room temperature for 2 hours. After the reaction was completed, 10 mL of saturated sodium bicarbonate solution was added to the filtrate to quench the reaction, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried and concentrated to obtain 85 mg of the title compound, with a yield of 96%. LC-MS (ESI): 418.2 [M + H] + .
化合物45-5的制备Preparation of compound 45-5
将化合物45-4(85mg，203umol)溶解于四氢呋喃(2.0mL)中，冰浴下加入三乙胺(51mg，507umol)和2-氯-4-溴嘧啶(39mg，203mmol)，室温下搅拌4小时。反应结束后，向反应液中加入10mL饱和氯化钠水溶液淬灭反应，用乙酸乙酯(10mL)萃取三次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝20-70％)分离纯化得到60mg标题化合物，收率20％。LC-MS(ESI):530.3[M+H]+.Compound 45-4 (85 mg, 203 umol) was dissolved in tetrahydrofuran (2.0 mL), triethylamine (51 mg, 507 umol) and 2-chloro-4-bromopyrimidine (39 mg, 203 mmol) were added under ice bath, and stirred at room temperature for 4 hours. After the reaction was completed, 10 mL of saturated sodium chloride aqueous solution was added to the reaction solution to quench the reaction, and ethyl acetate (10 mL) was used for extraction three times. The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by normal phase silica gel column (EtOAc/PE=20-70%) to obtain 60 mg of the title compound, with a yield of 20%. LC-MS (ESI): 530.3 [M+H] + .
化合物45的制备Preparation of compound 45
将化合物45-5(60mg，113umol)溶解于N,N-二甲基甲酰胺(1mL)中，依次加入二甲基氧化膦(44mg，565umol)、三乙胺(35mg，282umol)、Pd2(dba)3(4.6mg，5umol)和Xantphos(3mg，5μmmol)。用氮气置换三次，反应体系在120℃下微波搅拌反应2小时。反应结束后，冷却至室温，过滤反应液，滤 液加水(20mL)，用二氯甲烷(20mL)萃取三次，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:10％-45％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到7.2mg标题化合物，产率11％。LC-MS(ESI):m/z 572.0[M+H]+.31P NMR(162MHz,DMSO-d6)δ33.47.1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.99(d,J＝6.5Hz,1H),7.60(d,J＝2.3Hz,1H),7.53(d,J＝2.3Hz,1H),7.05–7.07(m,2H),6.54(s,1H),6.48–6.50(m,2H),4.63(m,1H),4.40(t,J＝4Hz,2H),3.95(t,J＝4Hz,2H),3.59–3.63(m,1H),3.49-3.22(m,2H),3.12-3.15(m,1H),2.28–2.33(m,1H),1.99-2.04(m,1H),1.67(d,J＝13.5Hz,6H),1.60(s,6H).Compound 45-5 (60 mg, 113 umol) was dissolved in N,N-dimethylformamide (1 mL), and dimethylphosphine oxide (44 mg, 565 umol), triethylamine (35 mg, 282 umol), Pd 2 (dba) 3 (4.6 mg, 5 umol) and Xantphos (3 mg, 5 μmmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was added. The mixture was added with water (20 mL), extracted with dichloromethane (20 mL) three times, the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-45% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 7.2 mg of the title compound with a yield of 11%. LC-MS (ESI): m/z 572.0 [M+H] + . 31 P NMR (162 MHz, DMSO-d 6 ) δ 33.47. 1 H NMR (400 MHz, DMSO-d 6 )δ8.16(s,1H),7.99(d,J＝6.5Hz,1H),7.60(d,J＝2.3Hz,1H),7.53(d,J＝2.3Hz,1H),7.05–7.07(m,2H),6.54(s,1H),6.48–6.50(m,2H),4.63(m,1H),4.40(t,J＝4Hz,2H),3.95(t,J＝4Hz,2H),3.59–3.63(m,1H),3.49-3.22(m,2H),3.12-3.15(m,1H),2.28–2.33(m,1H),1.99-2.04(m,1H),1.67(d,J＝13.5Hz,6H),1.60(s,6H).
实施例46：化合物46的制备
Example 46: Preparation of Compound 46
化合物46-2的制备Preparation of compound 46-2
将化合物45-1(1g，2.07mmol)、46-1(734mg，2.49mmol)、Pd(dppf)Cl2(152mg，0.21mmol)和碳酸钠(440mg，4.15mmol)溶解于1,4-二氧六环(20.0mL)和水(4.0mL)的混合溶剂中，反应体系用氮气置换三次，90℃下微波搅拌反应2小时。反应结束后，滤除不溶性固体，滤液加水(20mL)，乙酸乙酯萃取(20mL)两次，合并有机相，饱和食盐水(20mL)洗涤两次，无水硫酸钠干燥、浓缩得粗产品，经正相硅胶层析柱(EA/PE＝0-30％)纯化得到720mg标题化合物，收率69％。LC-MS(ESI):m/z 445.0[M+H-56]+.Compound 45-1 (1 g, 2.07 mmol), 46-1 (734 mg, 2.49 mmol), Pd(dppf)Cl 2 (152 mg, 0.21 mmol) and sodium carbonate (440 mg, 4.15 mmol) were dissolved in a mixed solvent of 1,4-dioxane (20.0 mL) and water (4.0 mL). The reaction system was replaced with nitrogen three times and stirred in a microwave at 90°C for 2 hours. After the reaction, the insoluble solid was filtered off, the filtrate was added with water (20 mL), extracted with ethyl acetate (20 mL) twice, the organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by normal phase silica gel chromatography (EA/PE=0-30%) to obtain 720 mg of the title compound, with a yield of 69%. LC-MS (ESI): m/z 445.0[M+H-56] + .
化合物46-3的制备Preparation of compound 46-3
将化合物46-2(700mg，1.40mmol)溶解于乙酸乙酯(15mL)中，加入10％的湿钯碳(70mg)，氢气球置换三次后室温反应过夜。LCMS跟踪反应至反应完全，滤除不溶性固体，浓缩得粗产品，经正相硅胶层析柱(EA/PE＝0-30％)纯化得到470mg标题化合物，收率67％。LC-MS(ESI):m/z 447.0[M+H-56]+.Compound 46-2 (700 mg, 1.40 mmol) was dissolved in ethyl acetate (15 mL), 10% wet palladium carbon (70 mg) was added, and the mixture was replaced by a hydrogen balloon three times and reacted at room temperature overnight. LCMS was used to track the reaction until the reaction was complete, and the insoluble solid was filtered out and concentrated to obtain a crude product, which was purified by normal phase silica gel chromatography (EA/PE=0-30%) to obtain 470 mg of the title compound, with a yield of 67%. LC-MS (ESI): m/z 447.0 [M+H-56] + .
化合物46-4的制备Preparation of compound 46-4
将化合物46-3(430mg，0.85mmol)溶于1,4-二氧六环(5.0mL)中，搅拌下滴加4M的氯化氢/1,4-二氧六环溶液(2.13mL，8.54mmol)，滴毕室温反应过夜。次日LCMS跟踪反应至完全后浓缩得320mg标题化合物粗品，收率93％。未经纯化，直接用于下一步。LC-MS(ESI):m/z 403.0[M+H]+.Compound 46-3 (430 mg, 0.85 mmol) was dissolved in 1,4-dioxane (5.0 mL), and 4M hydrogen chloride/1,4-dioxane solution (2.13 mL, 8.54 mmol) was added dropwise under stirring. The reaction was allowed to react overnight at room temperature. The next day, LCMS was used to track the reaction until it was complete and then concentrated to obtain 320 mg of the crude title compound with a yield of 93%. It was used directly in the next step without purification. LC-MS (ESI): m/z 403.0 [M+H] + .
化合物46-5的制备Preparation of compound 46-5
将化合物46-4(300mg，0.74mmol)和DIPEA(240mg，1.86mmol)溶于四氢呋喃(8.0mL)中，搅拌5分钟后加入2,4-二氯嘧啶(122mg，0.82mmol)，加毕60℃搅拌反应2小时。反应结束后，将反应液倒入冰水(20mL)中淬灭反应，乙酸乙酯萃取(20mL)两次，合并有机相，饱和食盐水(20mL)洗涤两次，无水硫酸钠干燥、浓缩得粗产品，经正相硅胶层析柱(EA/PE＝0-30％)纯化得到220mg标题化合物，收率57％。LC-MS(ESI):m/z 515.0[M+H]+.Compound 46-4 (300 mg, 0.74 mmol) and DIPEA (240 mg, 1.86 mmol) were dissolved in tetrahydrofuran (8.0 mL), and 2,4-dichloropyrimidine (122 mg, 0.82 mmol) was added after stirring for 5 minutes. The mixture was stirred at 60°C for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL) to quench the reaction, extracted with ethyl acetate (20 mL) twice, the organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by normal phase silica gel chromatography (EA/PE=0-30%) to obtain 220 mg of the title compound with a yield of 57%. LC-MS (ESI): m/z 515.0 [M+H] + .
化合物46的制备 Preparation of Compound 46
将化合物46-5(60mg，0.12mmol)溶解于1,4-二氧六环(3mL)中，依次加入二甲基氧化膦(18mg，0.23mmol)、DIPEA(38mg，0.29mmol)、Pd2(dba)3(11mg，0.01mmol)和Xantphos(13mg，0.02mmol)。用氮气置换三次后微波100℃下搅拌反应3小时。LCMS跟踪反应至完全后，将反应液过滤，减压蒸干，滤液粗品经制备分离纯化(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)得到18mg标题化合物，产率28％。LC-MS(ESI):m/z 557.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.27(t,J＝7.2Hz,1H),7.67(d,J＝2.2Hz,1H),7.61(d,J＝2.2Hz,1H),7.30(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),6.61(dd,J＝6.2,3.2Hz,1H),4.42(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz,2H),3.92–3.78(m,1H),3.64–3.38(m,3H),2.48–2.25(m,2H),2.20–1.99(m,1H),1.74–1.58(m,12H).31P NMR(162MHz,DMSO-d6)δ33.35(s,1P).Compound 46-5 (60 mg, 0.12 mmol) was dissolved in 1,4-dioxane (3 mL), and dimethylphosphine oxide (18 mg, 0.23 mmol), DIPEA (38 mg, 0.29 mmol), Pd 2 (dba) 3 (11 mg, 0.01 mmol) and Xantphos (13 mg, 0.02 mmol) were added in sequence. After nitrogen replacement three times, the mixture was stirred at 100°C in a microwave for 3 hours. After the reaction was completed by LCMS tracking, the reaction solution was filtered and evaporated to dryness under reduced pressure. The crude filtrate was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 18 mg of the title compound with a yield of 28%. LC-MS (ESI): m/z 557.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.27(t,J＝7.2Hz,1H),7.67(d,J＝2.2Hz,1H),7.61(d,J＝2.2Hz,1H),7.30(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),6.61(dd,J＝6.2,3.2Hz,1H),4.42(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz,2H),3.92–3.78(m,1H),3.64–3.38(m,3H),2.48–2.25(m,2H),2.20–1.99(m,1H),1.74–1.58(m,12H). 31 P NMR (162MHz,DMSO-d 6 )δ33.35(s,1P).
实施例47：化合物47的制备
Example 47: Preparation of Compound 47
化合物47-2的制备Preparation of compound 47-2
将化合物47-1(3.0g，12.8mmol)、化合物溴氯乙烷(2.7g，19.2mmol)和碳酸铯(8.3g，25.6mmol)溶于无水DMF(50mL)中，80℃反应4小时。LCMS监测至反应完全，加水(20mL)淬灭反应，反应体系用EtOAc(50mL)萃取两次。合并有机相，干燥浓缩，通过正相硅胶柱(EtOAc/PE＝0-20％)分离纯化得到1.8g标题化合物，收率47.5％。1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.16(d,J＝2.0Hz,1H),8.05(d,J＝2.0Hz,1H),4.36(t,J＝4.0Hz,2H),4.01(t,J＝4.0Hz,2H)Compound 47-1 (3.0 g, 12.8 mmol), compound bromochloroethane (2.7 g, 19.2 mmol) and cesium carbonate (8.3 g, 25.6 mmol) were dissolved in anhydrous DMF (50 mL) and reacted at 80°C for 4 hours. LCMS monitored the reaction until it was complete, and water (20 mL) was added to quench the reaction. The reaction system was extracted twice with EtOAc (50 mL). The organic phases were combined, dried and concentrated, and separated and purified by a normal phase silica gel column (EtOAc/PE=0-20%) to obtain 1.8 g of the title compound with a yield of 47.5%. 1 H NMR (400 MHz, DMSO-d 6 ) δ9.91 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 4.36 (t, J=4.0 Hz, 2H), 4.01 (t, J=4.0 Hz, 2H)
化合物47-4的制备Preparation of compound 47-4
将化合物47-2(1.8g，5.06mmol)加入三口瓶中，再加入无水THF(20mL)，加入LiHMDS(6mL，6mmol)，室温搅拌反应0.5小时后，加入47-3(1.0g,6.0mmol)，50℃下反应。TLC监测显示2小时后反应完全。加氯化铵(50mL)淬灭反应，EA(50mL)萃取。合并有机相，干燥浓缩，正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到620mg标题化合物，收率33.5％。LC-MS(ESI):m/z 365.9[M+H]+.Compound 47-2 (1.8 g, 5.06 mmol) was added to a three-necked flask, and then anhydrous THF (20 mL) was added, and LiHMDS (6 mL, 6 mmol) was added. After stirring at room temperature for 0.5 hours, 47-3 (1.0 g, 6.0 mmol) was added and reacted at 50°C. TLC monitoring showed that the reaction was complete after 2 hours. Ammonium chloride (50 mL) was added to quench the reaction, and EA (50 mL) was used for extraction. The organic phases were combined, dried and concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE=0-50%) to obtain 620 mg of the title compound, with a yield of 33.5%. LC-MS (ESI): m/z 365.9 [M+H] + .
化合物47-5的制备Preparation of compound 47-5
将化合物47-4(620mg，1.7mmol)溶解于无水DMF(10.0mL)中，加入氰化锌(994mg，8.5mmol), 然后加入Pd(PPh3)4(346mg，0.3mmol)，氮气置换三次后，微波150℃反应3小时，反应完全。将有机相倒入水(50mL)中，用EA(50mL)萃取两次。合并有机相，干燥浓缩，通过正相硅胶柱(EtOAc/PE＝20-50％)分离纯化得到330mg标题化合物，收率62％。LC-MS(ESI):m/z 313.0[M+H]+.Compound 47-4 (620 mg, 1.7 mmol) was dissolved in anhydrous DMF (10.0 mL), and zinc cyanide (994 mg, 8.5 mmol) was added. Then Pd(PPh 3 ) 4 (346 mg, 0.3 mmol) was added, and the atmosphere was replaced with nitrogen three times. The reaction was completed by microwave at 150°C for 3 hours. The organic phase was poured into water (50 mL) and extracted twice with EA (50 mL). The organic phases were combined, dried and concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE=20-50%) to obtain 330 mg of the title compound with a yield of 62%. LC-MS (ESI): m/z 313.0 [M+H] + .
化合物47-7的制备Preparation of compound 47-7
将化合物47-5(330mg，1.05mmol)溶解于无水1,4-二氧六环中(10mL)中，加入47-6(335mg，1.26mmol，加入CuI(19mg，0.1mmol)，1,2-环己二胺(19mg，0.2mmol)。氮气置换三次后，微波150℃反应2小时。反应结束后，将反应液倒入水中，用EA(30mL)萃取两次，合并有机相，干燥浓缩，正相硅胶柱(EtOAc/PE＝20-40％)分离纯化得到210mg标题化合物，收率44％。LC-MS(ESI):m/z 449.2[M+H]+.Compound 47-5 (330 mg, 1.05 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL), and 47-6 (335 mg, 1.26 mmol, CuI (19 mg, 0.1 mmol), 1,2-cyclohexanediamine (19 mg, 0.2 mmol) were added. After nitrogen replacement three times, microwave reaction was carried out at 150°C for 2 hours. After the reaction, the reaction solution was poured into water, extracted twice with EA (30 mL), the organic phases were combined, dried and concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE=20-40%) to obtain 210 mg of the title compound with a yield of 44%. LC-MS (ESI): m/z 449.2 [M+H] + .
化合物47-8的制备Preparation of Compound 47-8
将化合物47-7(210mg，0.46mmol)溶解于THF中(10mL)中，加入浓盐酸(5ml)，室温下反应2小时，TLC点板监测至反应完全。将反应液倒入水(30mL)中，然后用EA(20mL)萃取两次，合并有机相，干燥浓缩，得到180mg标题化合物粗品。未经纯化，直接用于下一步反应。Compound 47-7 (210 mg, 0.46 mmol) was dissolved in THF (10 mL), concentrated hydrochloric acid (5 ml) was added, and the mixture was reacted at room temperature for 2 hours. The reaction was monitored by TLC plate until the reaction was complete. The reaction solution was poured into water (30 mL), and then extracted twice with EA (20 mL). The organic phases were combined, dried and concentrated to obtain 180 mg of the crude title compound. The crude product was used directly in the next step without purification.
化合物47-9的制备Preparation of Compound 47-9
将化合物47-8(180mg，粗品)溶解于DMF中(10.0mL)中，加入碳酸铯(218mg，0.66mmol)，加入2-氯-4-(氯甲基)嘧啶(91mg，0.5mmol)，50℃下反应2小时。反应结束后，将有机相倒入水(30mL)中，用EA(20mL)萃取两次。合并有机相，干燥浓缩，通过正相硅胶柱(EtOAc/PE＝10-40％)分离纯化得到110mg标题化合物，两步收率44％。LC-MS(ESI):m/z 531.2[M+H]+.Compound 47-8 (180 mg, crude product) was dissolved in DMF (10.0 mL), cesium carbonate (218 mg, 0.66 mmol) was added, 2-chloro-4-(chloromethyl)pyrimidine (91 mg, 0.5 mmol) was added, and the mixture was reacted at 50°C for 2 hours. After the reaction, the organic phase was poured into water (30 mL) and extracted twice with EA (20 mL). The organic phases were combined, dried and concentrated, and separated and purified by a normal phase silica gel column (EtOAc/PE=10-40%) to obtain 110 mg of the title compound, with a two-step yield of 44%. LC-MS (ESI): m/z 531.2 [M+H] + .
化合物47的制备Preparation of compound 47
将化合物47-9(110mg，0.20mmol)溶解于DMF(10mL)中，依次加入二甲基氧化膦(78mg，1mmol)、DIEA(129mg，1mmol)、Pd2(dba)3(27mg，0.03mmol)和Xantphos(35mg，0.06mmol)。用氮气置换三次后，于微波120℃下反应2小时。LCMS监测反应至反应完全。将反应液过滤，滤液粗品经制备分离纯化(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)得到45mg标题化合物47，收率33％。LC-MS(ESI):m/z 573.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.98(d,J＝5.2Hz,1H),7.74-7.69(m,3H),7.22-7.20(m,2H),7.07-7.05(m,2H),5.26(s,2H),5.07(s,1H),4.46(t,J＝5.2Hz,2H),3.97(t,J＝5.2Hz,2H),1.75(d,J＝13.6Hz,6H),1.44(s,3H),0.78(s,3H).31P NMR(162MHz,DMSO-d6)δ34.04(s,1P).Compound 47-9 (110 mg, 0.20 mmol) was dissolved in DMF (10 mL), and dimethylphosphine oxide (78 mg, 1 mmol), DIEA (129 mg, 1 mmol), Pd 2 (dba) 3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. After nitrogen replacement three times, the reaction was carried out at 120°C in a microwave for 2 hours. The reaction was monitored by LCMS until the reaction was complete. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 45 mg of the title compound 47, with a yield of 33%. LC-MS (ESI): m/z 573.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.98 (d, J=5.2 Hz, 1H), 7.74-7.69 (m, 3H), 7.22-7.20 (m, 2H), 7.07-7.05 (m, 2H), 5.26 (s, 2H), 5.07 (s, 1H), 4.46 (t, J=5.2 Hz, 2H), 3.97 (t, J=5.2 Hz, 2H), 1.75 (d, J=13.6 Hz, 6H), 1.44 (s, 3H), 0.78 (s, 3H). 31 P NMR (162 MHz, DMSO-d6) δ34.04 (s, 1P).
实施例48：化合物48的制备
Example 48: Preparation of Compound 48
化合物48-2的合成：Synthesis of compound 48-2:
往100ml单口瓶加化合物48-1(2.5g，16.00mmol)，DMF(10mL)，咪唑(2.20g，32.32mmol)，加TBDPSCl(4.83g，17.57mmol，4.57mL)，室温搅拌3小时。LCMS显示反应完全。加乙酸乙酯(200mL)稀释反应液，水洗(100mL)三次，无水硫酸钠干燥，抽滤，滤液减压蒸干，得6.8g标题化合物粗品。未经纯化，直接用于下一步。LC-MS(ESI):395.0[M+H]+.Add compound 48-1 (2.5 g, 16.00 mmol), DMF (10 mL), imidazole (2.20 g, 32.32 mmol), TBDPSCl (4.83 g, 17.57 mmol, 4.57 mL) to a 100 ml single-mouth bottle and stir at room temperature for 3 hours. LCMS shows that the reaction is complete. Add ethyl acetate (200 mL) to dilute the reaction solution, wash with water (100 mL) three times, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain 6.8 g of the crude title compound. Use it directly in the next step without purification. LC-MS (ESI): 395.0 [M + H] + .
化合物48-3的合成：Synthesis of compound 48-3:
往250mL单口瓶加化合物48-2(6.8g，17.23mmol)，DCM(100mL)，冰水浴冷却至0℃，分4批加m-CPBA(10.50g，51.70mmol，85％purity)，缓慢升至室温(20℃)搅拌16小时，TLC(PE：EA＝3：1)显示反应完全。加碳酸钠饱和溶液(100ml)淬灭反应，乙酸乙酯萃取(100ml)两次。有机相合并，饱和碳酸钠溶液洗涤(30ml)一次，水洗(30ml)一次，无水硫酸钠干燥，抽滤，滤液减压蒸干，得6.28g标题化合物。1H NMR(400MHz,CDCl3)δ8.93(d,J＝5.2Hz,1H),7.95(d,J＝5.2Hz,1H),7.63-7.66(m,4H),7.44–7.48(m,2H),7.37-7.41(4,H),4.92(s,2H),3.30(s,3H),1.15(s,9H).Add compound 48-2 (6.8 g, 17.23 mmol) and DCM (100 mL) to a 250 mL single-mouth bottle, cool to 0 ° C in an ice-water bath, add m-CPBA (10.50 g, 51.70 mmol, 85% purity) in 4 batches, slowly warm to room temperature (20 ° C) and stir for 16 hours. TLC (PE: EA = 3: 1) shows that the reaction is complete. Add saturated sodium carbonate solution (100 ml) to quench the reaction, and extract with ethyl acetate (100 ml) twice. The organic phases are combined, washed once with saturated sodium carbonate solution (30 ml), washed once with water (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain 6.28 g of the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ8.93 (d, J=5.2 Hz, 1H), 7.95 (d, J=5.2 Hz, 1H), 7.63-7.66 (m, 4H), 7.44-7.48 (m, 2H), 7.37-7.41 (4, H), 4.92 (s, 2H), 3.30 (s, 3H), 1.15 (s, 9H).
化合物48-4的合成：Synthesis of compound 48-4:
往100mL三口瓶加三甲基氧化膦(330.00mg，3.58mmol)，THF(20mL)，搅拌下冷却至-60℃，滴加n-BuLi(2M，4.69mmol，2.34mL)，滴加完毕，升至室温搅拌0.5小时，-60℃下滴加化合物48-3(1g，2.34mmol)的THF(10mL)溶液，滴加完毕，保温搅拌3小时，TLC(PE：EA＝3：1和EA：MeOH＝3：1)显示原料反应完全。低温下滴加氯化铵溶液(50mL)淬灭反应，将四氢呋喃减压蒸干，乙酸乙酯萃取(40mL)两次。有机相合并，无水硫酸钠干燥，抽滤，滤液减压蒸干，得浅黄色液体。自动过柱机纯化(EA:MeOH＝1:0～10:1～5:1)，得210mg标题化合物。LC-MS(ESI):439.0[M+H]+.1H NMR(400MHz,CDCl3)δ8.72(d,J＝5.2Hz,H),7.64–7.67(m,4H),7.60(d,J＝5.2Hz,1H),7.27-7.47(m,6H),4.78(s,2H),3.54(d,J＝16.8Hz,2H),1.53(d,J＝13.2Hz,6H),1.14(s,9H).31P NMR(162MHz,CDCl3)δ41.91(s,1P).Add trimethylphosphine oxide (330.00 mg, 3.58 mmol) and THF (20 mL) to a 100 mL three-necked flask, cool to -60 °C with stirring, add n-BuLi (2M, 4.69 mmol, 2.34 mL) dropwise, warm to room temperature and stir for 0.5 hours, add compound 48-3 (1 g, 2.34 mmol) in THF (10 mL) dropwise at -60 °C, add dropwise, keep warm and stir for 3 hours, TLC (PE: EA = 3: 1 and EA: MeOH = 3: 1) shows that the raw material has reacted completely. Add ammonium chloride solution (50 mL) dropwise at low temperature to quench the reaction, evaporate tetrahydrofuran to dryness under reduced pressure, and extract with ethyl acetate (40 mL) twice. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain a light yellow liquid. Purify by automatic column chromatography (EA: MeOH = 1: 0 ~ 10: 1 ~ 5: 1) to obtain 210 mg of the title compound. LC-MS (ESI): 439.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ8.72 (d, J=5.2 Hz, H), 7.64–7.67 (m, 4H), 7.60 (d, J=5.2 Hz, 1H), 7.27–7.47 (m, 6H), 4.78 (s, 2H), 3.54 (d, J=16.8 Hz, 2H), 1.53 (d, J=13.2 Hz, 6H), 1.14 (s, 9H). 31 P NMR (162 MHz, CDCl 3 ) δ41.91 (s, 1P).
化合物48-5的合成：Synthesis of compound 48-5:
往50ml单口瓶加化合物48-4(210mg，478.83μmol)，THF(2mL)，加TBAF(1M，1.00mmol，1mL)，室温(20℃)搅拌16小时。TLC(EA:MeOH＝3:1)显示反应完全。减压蒸除THF，自动过柱机纯化(EA:MeOH＝1:0～10:1)，得157mg标题化合物。LC-MS(ESI):201.0[M+H]+.1H NMR(400MHz,CDCl3)δ8.63(d,J＝5.2Hz,1H),7.44(d,J＝5.2Hz,H),4.74(s,2H),3.59(d,J＝16.8Hz,2H),1.57(d,J＝13.2Hz,6H).31P NMR(162MHz,CDCl3)δ41.76(s,1P).Add compound 48-4 (210 mg, 478.83 μmol), THF (2 mL), and TBAF (1 M, 1.00 mmol, 1 mL) to a 50 ml single-mouth bottle and stir at room temperature (20°C) for 16 hours. TLC (EA: MeOH = 3:1) shows that the reaction is complete. Evaporate THF under reduced pressure and purify by automatic column chromatography (EA: MeOH = 1:0-10:1) to obtain 157 mg of the title compound. LC-MS (ESI): 201.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ8.63 (d, J=5.2 Hz, 1H), 7.44 (d, J=5.2 Hz, H), 4.74 (s, 2H), 3.59 (d, J=16.8 Hz, 2H), 1.57 (d, J=13.2 Hz, 6H). 31 P NMR (162 MHz, CDCl 3 ) δ41.76 (s, 1P).
化合物48的合成：Synthesis of compound 48:
往50mL单口瓶加化合物48-5(100mg，499.56μmol)，化合物1-6(174.00mg，496.80μmol)，TMAD(260.00mg，1.51mmol)和DCM(4mL)，氮气置换三次，冷却至0℃，滴加Bu3P(307.80mg，1.52mmol，380.00μL)，滴加完毕，升至室温搅拌16小时，LCMS监测反应完全。减压蒸干，制备液相纯化，得24.45mg标题化合物。LC-MS(ESI):532.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.77(d,J＝5.2Hz,1H),7.64(s,1H),7.57(s,1H),7.46(d,J＝5.2Hz,1H),7.18–7.20(m,2H),6.96–6.98(m,2H),5.18(s,2H),4.41(t,J＝5.2Hz,2H),3.95(t,J＝5.2Hz,2H),3.52(d,J＝16Hz,2H),1.62(s,6H),1.46(d,J＝13.2Hz,6H).31P NMR(162MHz,DMSO-d6)δ39.49(s,1P). Compound 48-5 (100 mg, 499.56 μmol), compound 1-6 (174.00 mg, 496.80 μmol), TMAD (260.00 mg, 1.51 mmol) and DCM (4 mL) were added to a 50 mL single-mouth bottle, replaced with nitrogen three times, cooled to 0°C, and Bu 3 P (307.80 mg, 1.52 mmol, 380.00 μL) was added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred for 16 hours. The reaction was monitored by LCMS. The mixture was evaporated to dryness under reduced pressure and purified by preparative liquid phase to obtain 24.45 mg of the title compound. LC-MS (ESI): 532.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ8.77 (d, J=5.2 Hz, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.46 (d, J=5.2 Hz, 1H), 7.18–7.20 (m, 2H), 6.96–6.98 (m, 2H), 5.18 (s, 2H), 4.41 (t, J=5.2 Hz, 2H), 3.95 (t, J=5.2 Hz, 2H), 3.52 (d, J=16 Hz, 2H), 1.62 (s, 6H), 1.46 (d, J=13.2 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ39.49 (s, 1P).
实施例49：化合物49的制备
Example 49: Preparation of Compound 49
化合物49-2的制备Preparation of compound 49-2
氮气保护下，将化合物45-1(600mg，1.24mmol)，49-1(264.09mg，1.24mmol)，碳酸铯(810.66mg，2.49mmol)，BINAP(193.66mg，311.01μmol)，Pd(OAc)2(27.93mg，124.40μmol)和二氧六环(6mL)加入反应瓶中。升温至70℃搅拌16小时。LCMS检测反应完全。加水(5mL)淬灭反应，后用二氯甲烷(5mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-10％)分离纯化得到350mg标题化合物，收率51％。LC-MS(ESI):544.3[M+H]+.Under nitrogen protection, compound 45-1 (600 mg, 1.24 mmol), 49-1 (264.09 mg, 1.24 mmol), cesium carbonate (810.66 mg, 2.49 mmol), BINAP (193.66 mg, 311.01 μmol), Pd(OAc) 2 (27.93 mg, 124.40 μmol) and dioxane (6 mL) were added to the reaction flask. The temperature was raised to 70 ° C and stirred for 16 hours. LCMS detected that the reaction was complete. Water (5 mL) was added to quench the reaction, and then extracted with dichloromethane (5 mL) three times. The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (EtOAc/PE=0-10%) to obtain 350 mg of the title compound, with a yield of 51%. LC-MS (ESI): 544.3 [M+H] + .
化合物49-3的制备Preparation of compound 49-3
将化合物49-2(350mg，642.78μmol)溶于DCM(6mL)中，室温下将TFA(3mL)滴加入反应体系中，并搅拌2小时。LCMS检测反应完全，反应液浓缩至干即得到260mg标题化合物粗品，收率91％。LC-MS(ESI):444.0[M+H]+.Compound 49-2 (350 mg, 642.78 μmol) was dissolved in DCM (6 mL), TFA (3 mL) was added dropwise to the reaction system at room temperature, and stirred for 2 hours. LCMS detected that the reaction was complete, and the reaction solution was concentrated to dryness to obtain 260 mg of the crude title compound, with a yield of 91%. LC-MS (ESI): 444.0 [M+H] + .
化合物49-4的制备Preparation of compound 49-4
将4-氯-2-甲砜基-嘧啶(260.07mg，1.35mmol)，化合物49-3(150mg，337.54μmol)，三乙胺(341.55mg，3.38mmol，470.78μL)和THF(2mL)加入反应瓶中。室温下搅拌2小时。LCMS检测反应完全。加水(5mL)，用二氯甲烷(5mL)萃取三次，合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到120mg标题化合物，收率59％。LC-MS(ESI):600.0[M+H]+.4-Chloro-2-methylsulfonyl-pyrimidine (260.07 mg, 1.35 mmol), compound 49-3 (150 mg, 337.54 μmol), triethylamine (341.55 mg, 3.38 mmol, 470.78 μL) and THF (2 mL) were added to the reaction flask. Stir at room temperature for 2 hours. LCMS detected that the reaction was complete. Add water (5 mL), extract with dichloromethane (5 mL) three times, combine the organic phases, dry and concentrate to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (EtOAc/PE=0-30%) to obtain 120 mg of the title compound, with a yield of 59%. LC-MS (ESI): 600.0 [M+H] + .
化合物49的制备Preparation of compound 49
将化合物49-4(60mg，99.91μmol)，K2CO3(69.04mg，499.54μmol)，二甲基氧化膦(39mg，499.54μmol)和乙腈(2mL)加入反应瓶中。于80℃反应16小时。LCMS检测反应完全。往反应体系中加入水(5mL)淬灭反应，用乙酸乙酯(5mL)萃取三次，合并有机相，干燥浓缩得粗产品，粗品经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Agilent 10Prep-C18 250×21.2mm；柱温:25℃；梯度:10％-80％乙腈在20分钟内梯度洗脱；流速:30mL/min)得到10mg标题化合物，产率16％。LC-MS(ESI):598.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.28(d,J＝6.0Hz,1H),7.60(d,J＝2.2Hz,1H),7.54(d,J＝2.2Hz,1H),7.04–7.07(d,J＝8.8Hz,2H),6.47–6.49(m,3H),4.39–4.42(m,2H),4.13–4.01(m,4H),3.94–3.96(m,2H),3.48(s,2H),3.29–3.31(m,2H),2.25(t,J＝6.8Hz,2H),1.65(d,J＝13.6Hz,6H),1.60(s,6H). Compound 49-4 (60 mg, 99.91 μmol), K 2 CO 3 (69.04 mg, 499.54 μmol), dimethylphosphine oxide (39 mg, 499.54 μmol) and acetonitrile (2 mL) were added to a reaction flask. The reaction was carried out at 80°C for 16 hours. The reaction was complete when detected by LCMS. Water (5 mL) was added to the reaction system to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile in 20 minutes; flow rate: 30 mL/min) to obtain 10 mg of the title compound with a yield of 16%. LC-MS (ESI): 598.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (d, J = 6.0 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.04–7.07 (d, J = 8.8 Hz, 2H), 6.47–6.49 (m, 3H), 4.39–4.42 (m, 2H), 4.13–4.01 (m, 4H), 3.94–3.96 (m, 2H), 3.48 (s, 2H), 3.29–3.31 (m, 2H), 2.25 (t, J = 6.8 Hz, 2H), 1.65 (d, J = 13.6 Hz, 6H), 1.60 (s, 6H).
实施例50：化合物50的制备
Example 50: Preparation of Compound 50
化合物50-1的制备Preparation of Compound 50-1
将化合物2,4-嘧啶(2g，13.42mol)溶于DMF(80mL)中，依次加入NaH(537mg，13.42mol)、化合物4-碘-1H-咪唑(2.6g，13.42μmol)，室温反应16h。反应结束，过滤，滤液中加入水(200mL),乙酸乙酯萃取(200mL)两次，饱和食盐水(200mL)洗涤有机相三次，无水硫酸钠干燥，浓缩有机相并用正相硅胶层析柱(EA/PE＝0-30％)纯化得到1.3g标题化合物，收率31％。1H NMR(400MHz,DMSO-d6)δ8.91(d,J＝5.6Hz,1H),8.63(d,J＝1.4Hz,1H),8.27(d,J＝1.4Hz,1H),7.97(d,J＝5.6Hz,1H).Compound 2,4-pyrimidine (2g, 13.42mol) was dissolved in DMF (80mL), and NaH (537mg, 13.42mol) and compound 4-iodo-1H-imidazole (2.6g, 13.42μmol) were added in sequence, and the mixture was reacted at room temperature for 16h. After the reaction was completed, the mixture was filtered, and water (200mL) was added to the filtrate. The mixture was extracted with ethyl acetate (200mL) twice, and the organic phase was washed with saturated brine (200mL) three times, dried with anhydrous sodium sulfate, and the organic phase was concentrated and purified with a normal phase silica gel chromatography column (EA/PE=0-30%) to obtain 1.3g of the title compound, with a yield of 31%. 1 H NMR (400MHz, DMSO-d6) δ8.91 (d, J=5.6Hz, 1H), 8.63 (d, J=1.4Hz, 1H), 8.27 (d, J=1.4Hz, 1H), 7.97 (d, J=5.6Hz, 1H).
化合物50-2的制备Preparation of compound 50-2
将化合物45-1(800mg，1.66mmol)溶解于无水二氧六环溶液(5mL)中，加入B2Pin2(547mg，2.16mmol)，醋酸钾(488mg，4.98mmol)，和Pd(dppf)Cl2(361mg)。置换氮气，反应体系80℃温度下搅拌36小时。待反应结束后，将体系冷却至室温，加入乙酸乙酯稀释(50mL)，依次用饱和食盐水(300mL)洗两次，水洗(300mL)两次，有机相经无水硫酸钠干燥，过滤，滤液浓缩得得到粗品，粗品经中压柱层析纯化(甲醇/二氯甲烷(v/v)＝0～5％)得400mg标题化合物。1H NMR(400MHz,CDCl3)δ7.77–7.75(m,2H),7.41(d,J＝2.3Hz,1H),7.32(d,J＝2.3Hz,1H),7.20–7.18(m,2H),4.41(t,J＝6.2Hz,2H),3.87(t,J＝6.2Hz,2H),1.66(s,6H),1.34(s,12H).Compound 45-1 (800 mg, 1.66 mmol) was dissolved in anhydrous dioxane solution (5 mL), and B 2 Pin 2 (547 mg, 2.16 mmol), potassium acetate (488 mg, 4.98 mmol), and Pd(dppf)Cl 2 (361 mg) were added. The nitrogen atmosphere was replaced, and the reaction system was stirred at 80°C for 36 hours. After the reaction was completed, the system was cooled to room temperature, ethyl acetate (50 mL) was added for dilution, and the system was washed twice with saturated brine (300 mL) and twice with water (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure column chromatography (methanol/dichloromethane (v/v) = 0-5%) to obtain 400 mg of the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ 7.77–7.75 (m, 2H), 7.41 (d, J=2.3 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.20–7.18 (m, 2H), 4.41 (t, J=6.2 Hz, 2H), 3.87 (t, J=6.2 Hz, 2H), 1.66 (s, 6H), 1.34 (s, 12H).
化合物50-3的制备Preparation of compound 50-3
将化合物50-1(800mg，2.61mmol)溶解于1,4-二氧六环(50mL)和水(10mL)中，依次加入化合物50-2(1.2g，2.61mmol)，碳酸钾(1.08g，7.83mmol)，Pd(dppf)Cl2(189mg，0261mmol)。反应体系用氮气置换三次，在90℃下搅拌反应2小时。反应结束后，滤除不溶性固体，滤液加水(10mL)，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤两次，无水硫酸钠干燥、浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到270mg标题化合物，收率20％。LC-MS(ESI):m/z 512.08[M+H]+.Compound 50-1 (800 mg, 2.61 mmol) was dissolved in 1,4-dioxane (50 mL) and water (10 mL), and compound 50-2 (1.2 g, 2.61 mmol), potassium carbonate (1.08 g, 7.83 mmol), and Pd(dppf)Cl 2 (189 mg, 0261 mmol) were added in sequence. The reaction system was replaced with nitrogen three times and stirred at 90° C. for 2 hours. After the reaction, the insoluble solid was filtered off, water (10 mL) was added to the filtrate, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 270 mg of the title compound, with a yield of 20%. LC-MS (ESI): m/z 512.08 [M+H] + .
化合物50的制备Preparation of compound 50
将化合物50-3(110mg，0.214mmol)溶解于DMF(5.0mL)中，依次加入二甲基氧化膦(50mg，0.643mmol)、DIEA(83mg，0.643mmol)、Pd2(dba)3(20mg，0.021mmol)和Xantphos(12mg，0.021mmol)。反应体系用氮气置换三次，在120℃下微波搅拌反应2小时。反应结束后，冷却至室温，滤除不溶性固体，滤液加水(10mL)，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤两次，无水硫酸钠干燥、浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到50mg标题化合物6，收率42％。LC-MS(ESI):m/z 554.0[M+H]+.1H NMR(400MHz, DMSO-d6)δ9.12(s,1H),8.86(d,J＝1.3Hz,1H),8.60(d,J＝1.3Hz,1H),8.05–8.08(m,1H),7.86(d,J＝8.5Hz,2H),7.69(d,J＝2.3Hz,1H),7.62(d,J＝2.3Hz,1H),7.33(d,J＝8.5Hz,2H),4.43(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz 2H),1.85(d,J＝13.6Hz,6H),1.69(s,6H).31P NMR(162MHz,DMSO-d6)δ34.85(s,1P).Compound 50-3 (110 mg, 0.214 mmol) was dissolved in DMF (5.0 mL), and dimethylphosphine oxide (50 mg, 0.643 mmol), DIEA (83 mg, 0.643 mmol), Pd 2 (dba) 3 (20 mg, 0.021 mmol) and Xantphos (12 mg, 0.021 mmol) were added in sequence. The reaction system was replaced with nitrogen three times and stirred in a microwave at 120° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, the insoluble solid was filtered off, water (10 mL) was added to the filtrate, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 50 mg of the title compound 6, with a yield of 42%. LC-MS (ESI): m/z 554.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.12 (s, 1H), 8.86 (d, J = 1.3 Hz, 1H), 8.60 (d, J = 1.3 Hz, 1H), 8.05–8.08 (m, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 4.43 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz 2H), 1.85 (d, J = 13.6 Hz, 6H), 1.69 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ34.85 (s, 1P).
实施例51：化合物51的制备
Example 51: Preparation of Compound 51
化合物51-1的制备Preparation of compound 51-1
将化合物2-碘苯胺(1g，4.57mmol)溶解于DMF(5mL)中，依次加入二甲基氧化膦(356mg，4.57mmol)、DIEA(1.77g，13.70mmol)、Pd2(dba)3(418mg，0.456mmol)和Xantphos(264mg，0.456mmol)。反应体系用氮气置换三次，在120℃下微波搅拌反应2小时。反应结束后，滤除不溶性固体，滤液加水(50mL)，二氯甲烷(30mL)萃取两次，合并有机相，饱和食盐水(20mL)洗涤两次，无水硫酸钠干燥、浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到600mg标题化合物，收率77％。LC-MS(ESI):m/z 170.0[M+H]+.1H NMR(400MHz,CDCl3)δ7.23-7.19(m,1H),7.08-7.02(m,1H),6.70–6.62(m,2H),1.74(d,J＝13.0Hz,6H).31P NMR(162MHz,DMSO-d6)δ42.07(s,1P).The compound 2-iodoaniline (1 g, 4.57 mmol) was dissolved in DMF (5 mL), and dimethylphosphine oxide (356 mg, 4.57 mmol), DIEA (1.77 g, 13.70 mmol), Pd 2 (dba) 3 (418 mg, 0.456 mmol) and Xantphos (264 mg, 0.456 mmol) were added in sequence. The reaction system was replaced with nitrogen three times and stirred in a microwave at 120° C. for 2 hours. After the reaction, the insoluble solid was filtered off, water (50 mL) was added to the filtrate, and the mixture was extracted twice with dichloromethane (30 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL/min) to obtain 600 mg of the title compound with a yield of 77%. LC-MS (ESI): m/z 170.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ7.23-7.19 (m, 1H), 7.08-7.02 (m, 1H), 6.70–6.62 (m, 2H), 1.74 (d, J=13.0 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ42.07 (s, 1P).
化合物51-2的制备Preparation of compound 51-2
往高压釜中加入化合物45-1(1.0g，2.1mmol)及溶剂DMF(20mL)，搅拌溶清，然后加入三乙基硅烷(366mg，3.2mmol)，三乙胺(425mg，4.2mmol)及Pd(dppf)Cl2(146mg,0.2mmol)，反应体系用一氧化碳置换四次(气压2.0MPa)，并在2.0MPa的一氧化碳气压下，加热升温至80℃搅拌16小时。TLC检测显示反应结束。反应体系降至室温后，加入水(60mL)，用乙酸乙酯(100mL)萃取三次，合并有机相，用饱和食盐水(150mL)洗涤三次，无水硫酸钠干燥，浓缩残留物经柱层析(乙酸乙酯/石油醚＝0-30％)得到680mg标题化合物，收率75.6％。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),7.84–7.87(m,2H),7.69(d,J＝2.4Hz,1H),7.63(d,J＝2.4Hz,1H),7.48–7.50(m,2H),4.43(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz,2H),1.70(s,6H).Compound 45-1 (1.0 g, 2.1 mmol) and solvent DMF (20 mL) were added to the autoclave, stirred to dissolve, then triethylsilane (366 mg, 3.2 mmol), triethylamine (425 mg, 4.2 mmol) and Pd(dppf)Cl 2 (146 mg, 0.2 mmol) were added, the reaction system was replaced with carbon monoxide four times (pressure 2.0 MPa), and heated to 80°C under 2.0 MPa carbon monoxide pressure and stirred for 16 hours. TLC detection showed that the reaction was complete. After the reaction system cooled to room temperature, water (60 mL) was added, and extracted three times with ethyl acetate (100 mL), the organic phases were combined, washed three times with saturated brine (150 mL), dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (ethyl acetate/petroleum ether = 0-30%) to obtain 680 mg of the title compound, with a yield of 75.6%. 1 H NMR (400 MHz, DMSO-d6) δ9.98 (s, 1H), 7.84–7.87 (m, 2H), 7.69 (d, J=2.4 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.48–7.50 (m, 2H), 4.43 (t, J=5.2 Hz, 2H), 3.96 (t, J=5.2 Hz, 2H), 1.70 (s, 6H).
化合物51的制备Preparation of compound 51
将化合物51-2(100mg，0.276mmol)溶解在MeOH(3.0mL)中，并加入化合物51-1(47mg，0.276mmol)，室温下搅拌1小时后，随后加入醋酸硼氢化钠(58mg，0276mmol)。反应体系在室温下搅拌1小时。反应结束后，将反应液过滤，滤液经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Agilent 10Prep-C18 250×21.2mm；柱温:25℃；梯度:55％-75％乙腈在12分钟内梯度洗脱；流速:30mL/min)得到20mg标题化合物，收率14％。LC-MS(ESI):m/z 515.5[M+H]+.1H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.37(d,J＝2.3Hz,1H),7.26(d,J＝2.3Hz,1H),7.25–7.18(m,3H),7.06–6.99 (m,3H),6.58(t,J＝7.4Hz,1H),6.51–6.54(m,1H),4.34(t,J＝6.0Hz,2H),4.29(s,2H),3.80(t,J＝6.0Hz,2H),1.72(d,J＝12.8Hz,6H),1.57(s,6H).31P NMR(162MHz,DMSO-d6)δ43.94(s,1P).Compound 51-2 (100 mg, 0.276 mmol) was dissolved in MeOH (3.0 mL), and compound 51-1 (47 mg, 0.276 mmol) was added. After stirring at room temperature for 1 hour, sodium acetate borohydride (58 mg, 0276 mmol) was subsequently added. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile gradient elution within 12 minutes; flow rate: 30 mL/min) to obtain 20 mg of the title compound, with a yield of 14%. LC-MS (ESI): m/z 515.5 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ7.64 (s, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.25–7.18 (m, 3H), 7.06–6.99 (m, 3H), 6.58 (t, J = 7.4 Hz, 1H), 6.51–6.54 (m, 1H), 4.34 (t, J = 6.0 Hz, 2H), 4.29 (s, 2H), 3.80 (t, J = 6.0 Hz, 2H), 1.72 (d, J = 12.8 Hz, 6H), 1.57 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 43.94 (s, 1P).
实施例52：化合物52的制备
Example 52: Preparation of Compound 52
化合物52-2的制备Preparation of compound 52-2
三口瓶中加入化合物52-1(1g，5.79mmol)，三乙胺(0.645g，6.37mmol)抽换氮气，加入THF(15mL)。在0℃下，滴加氯甲酸异丁酯(0.870g，6.37mmol)，滴加完毕反应30min。反应体系用饱和食盐水(15mL)淬灭，用乙酸乙酯(15mL)萃取三次，合并有机相，干燥浓缩得无色油状物。加入二氯甲烷(15mL)和水(3mL)，冷却到0℃，分批加入硼氢化钠(0.438g，11.59mmol)。完毕反应体系室温搅拌2小时，LCMS检测反应完成，加入硅胶拌样，通过正相硅胶柱(MeOH/DCM＝0-5％)分离纯化得到0.4g标题化合物，产率43％。LC-MS(ESI):m/z 159.0[M+H]+.Compound 52-1 (1 g, 5.79 mmol) and triethylamine (0.645 g, 6.37 mmol) were added to a three-necked flask to replace nitrogen, and THF (15 mL) was added. At 0°C, isobutyl chloroformate (0.870 g, 6.37 mmol) was added dropwise, and the reaction was continued for 30 min after the addition was completed. The reaction system was quenched with saturated brine (15 mL), extracted three times with ethyl acetate (15 mL), and the organic phases were combined, dried and concentrated to obtain a colorless oil. Dichloromethane (15 mL) and water (3 mL) were added, cooled to 0°C, and sodium borohydride (0.438 g, 11.59 mmol) was added in batches. After the reaction system was completed, it was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, and silica gel was added to mix the sample. The title compound was separated and purified by a normal phase silica gel column (MeOH/DCM=0-5%) to obtain 0.4 g of the title compound with a yield of 43%. LC-MS (ESI): m/z 159.0 [M+H] + .
化合物52-3的制备Preparation of compound 52-3
将化合物52-2(400mg，2.52mmol)溶解于DMF溶液(1mL)中，加入化合物二甲基氧化膦(590mg，7.57mmol)和DIEA(590mg，7.57mmol)。反应体系150℃封管搅拌1小时。待反应体系冷却后,过滤，滤液加入适量水冻干，残留物通过正相硅胶柱(MeOH/DCM＝0-5％)分离纯化得到标题化合物(50mg)为黄色固体，产率9％。LC-MS(ESI):m/z 201.4[M+H]+.Compound 52-2 (400 mg, 2.52 mmol) was dissolved in DMF solution (1 mL), and dimethylphosphine oxide (590 mg, 7.57 mmol) and DIEA (590 mg, 7.57 mmol) were added. The reaction system was sealed and stirred at 150°C for 1 hour. After the reaction system was cooled, it was filtered, and the filtrate was freeze-dried by adding an appropriate amount of water. The residue was separated and purified by a normal phase silica gel column (MeOH/DCM=0-5%) to obtain the title compound (50 mg) as a yellow solid with a yield of 9%. LC-MS (ESI): m/z 201.4 [M+H] + .
化合物52的制备Preparation of compound 52
将化合物52-3(50mg，0.249mmol)，化合物1-6(96mg，0.274mmol)和Bu3P(126mg，0.624mmol)分别加入三口瓶中，加入二氯甲烷(10mL)，氮气保护，冰水浴下加入TMAD(624mg，0.624mmol)，反应体系在室温下搅拌反应16小时。反应液过滤，滤液粗品经制备分离纯化(制备方法:色谱柱:Agilent10Prep-C18 250x21.2mm；柱温:25℃；流动相:水(0.1％TFA)-乙腈；流动相乙腈比例50％-70％在12分钟内梯度洗脱；流速30mL/min)得到10mg标题化合物，收率7％。LC-MS(ESI):m/z 532.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.69(s,1H),7.44(d,J＝2.4Hz,1H),7.29(d,J＝2.4Hz,1H),7.08–7.10(m,2H),6.89-6.92(m,2H),5.24(s,2H),4.42(t,J＝6.0Hz,2H),3.87(t,J＝6.0Hz,2H),2.48(s,3H),1.86(d,J＝13.6Hz,6H),1.63(s,6H).31P NMR(162MHz,DMSO-d6)δ35.33(s,1P). Compound 52-3 (50 mg, 0.249 mmol), compound 1-6 (96 mg, 0.274 mmol) and Bu 3 P (126 mg, 0.624 mmol) were added to a three-necked flask, and dichloromethane (10 mL) was added. Under nitrogen protection, TMAD (624 mg, 0.624 mmol) was added under ice-water bath, and the reaction system was stirred at room temperature for 16 hours. The reaction liquid was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent10Prep-C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 10 mg of the title compound, with a yield of 7%. LC-MS (ESI): m/z 532.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ8.69 (s, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.08–7.10 (m, 2H), 6.89-6.92 (m, 2H), 5.24 (s, 2H), 4.42 (t, J=6.0 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 2.48 (s, 3H), 1.86 (d, J=13.6 Hz, 6H), 1.63 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ35.33 (s, 1P).
实施例53：化合物53的制备
Example 53: Preparation of Compound 53
化合物53-2的制备Preparation of compound 53-2
将化合物53-1(500mg，2.48mmol)、化合物1-6(868mg，2.48mmol)和三苯基膦(974mg，3.72mmol)溶于无水四氢呋喃(10mL)中，室温下缓慢滴加偶氮二甲酸二乙酯(863mg，4.96mmol)，50℃反应4小时。LCMS跟踪反应至完全后，加水(20mL)淬灭反应，反应体系用EtOAc(50mL×2)萃取两次，合并有机相，干燥浓缩，正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到420mg标题化合物53-2，收率31.8％。LC-MS(ESI):m/z 477.0[M-56]+.Compound 53-1 (500 mg, 2.48 mmol), compound 1-6 (868 mg, 2.48 mmol) and triphenylphosphine (974 mg, 3.72 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), diethyl azodicarboxylate (863 mg, 4.96 mmol) was slowly added dropwise at room temperature, and the mixture was reacted at 50°C for 4 hours. After the reaction was complete as tracked by LCMS, water (20 mL) was added to quench the reaction, and the reaction system was extracted twice with EtOAc (50 mL×2), the organic phases were combined, dried and concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE=0-30%) to obtain 420 mg of the title compound 53-2, with a yield of 31.8%. LC-MS (ESI): m/z 477.0[M-56] + .
化合物53-3的制备Preparation of compound 53-3
将化合物53-2(420mg，0.78mmol)溶解在DCM(10mL)中，加入三氟乙酸(10mL)，室温搅拌反应1小时。反应结束后，合并有机相，干燥浓缩得粗品标题化合物53-3(580mg)。未经纯化，直接用于下步反应。LC-MS(ESI):433.0[M+H]+.Compound 53-2 (420 mg, 0.78 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the organic phases were combined, dried and concentrated to obtain the crude title compound 53-3 (580 mg). The crude product was used directly in the next step without purification. LC-MS (ESI): 433.0 [M+H] + .
化合物53-4的制备Preparation of compound 53-4
将化合物53-3粗品(580mg)溶解于无水甲醇(10mL)中，加入DIPEA(516mg，4mmol)，0℃下搅拌5分钟后，加入化合物2,4-二氯嘧啶(325mg，2.2mmol)，升温至25℃反应1小时，反应结束后，加饱和氯化铵溶液(10mL)淬灭反应，加乙酸乙酯(30mL)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到150mg标题化合物53-4，两步收率35％。LC-MS(ESI):544.9[M+H]+.The crude compound 53-3 (580 mg) was dissolved in anhydrous methanol (10 mL), and DIPEA (516 mg, 4 mmol) was added. After stirring at 0°C for 5 minutes, the compound 2,4-dichloropyrimidine (325 mg, 2.2 mmol) was added, and the temperature was raised to 25°C for reaction for 1 hour. After the reaction was completed, a saturated ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (30 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE=0-50%) to obtain 150 mg of the title compound 53-4, with a two-step yield of 35%. LC-MS (ESI): 544.9 [M+H] + .
化合物53的制备Preparation of compound 53
将化合物53-4(100mg，0.18mmol)溶解于DMF(10.0mL)中，依次加入二甲基氧化膦(140mg，1.8mmol)、三乙胺(182mg，1.8mmol)、Pd2(dba)3(27mg，0.03mmol)和Xantphos(35mg，0.06mmol)。用氮气置换三次后微波100℃下反应12小时。LCMS跟踪反应至完全后，将反应液过滤，滤液粗品经制备分离纯化(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)得到20mg标题化合物53，收率18.8％。LC-MS(ESI):m/z 586.8[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.30–8.28(m,1H),7.65(d,J＝2.4Hz,1H),7.59(d,J＝2.4Hz,1H),7.18–7.15(m,2H),6.97–6.93(m,3H),4.66–4.65(m,1H),4.41(t,J＝5.2Hz,2H),4.07–3.99(m,2H),3.96(t,J＝5.2Hz,2H),3.53-3.34(m,2H),1.96–2.03(m,2H),1.69(d,J＝13.2Hz,6H),1.63(s,6H),1.62-1.57(m,2H).31P NMR(162MHz,DMSO-d6)δ33.42(s,1P)。 Compound 53-4 (100 mg, 0.18 mmol) was dissolved in DMF (10.0 mL), and dimethylphosphine oxide (140 mg, 1.8 mmol), triethylamine (182 mg, 1.8 mmol), Pd 2 (dba) 3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. After nitrogen replacement three times, the mixture was reacted at 100° C. in a microwave oven for 12 hours. After the reaction was completed by LCMS tracking, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25° C.; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 20 mg of the title compound 53, with a yield of 18.8%. LC-MS (ESI): m/z 586.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.30–8.28(m,1H),7.65(d,J＝2.4Hz,1H),7.59(d,J＝2.4Hz,1H),7.18–7.15(m,2H),6.97–6.93(m,3H),4.66–4.65(m,1H),4.41(t,J＝5.2Hz,2H),4.07–3.99(m,2H),3.96(t,J＝5.2Hz,2H),3.53-3.34(m,2H),1.96–2.03(m,2H),1.69(d,J＝13.2Hz,6H),1.63(s,6H),1.62-1.57(m,2H). 31 P NMR (162MHz,DMSO-d6)δ33.42(s,1P).
实施例54：化合物54的制备
Example 54: Preparation of Compound 54
化合物54-2的制备Preparation of compound 54-2
将化合物1-6(250mg，0.71mmol)溶解在DMF(5mL)中，然后加入化合物54-1(213mg，0.85mmol)和碳酸铯(326mg，1.06mmol)，50℃反应4小时。LCMS监测反应完全后，加水(20mL)淬灭反应，反应体系用EtOAc(50mL)萃取两次，合并有机相，干燥浓缩，正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到160mg标题化合物54-2，收率43.5％。LC-MS(ESI):m/z 463.0[M-56]+.Compound 1-6 (250 mg, 0.71 mmol) was dissolved in DMF (5 mL), and then compound 54-1 (213 mg, 0.85 mmol) and cesium carbonate (326 mg, 1.06 mmol) were added and reacted at 50°C for 4 hours. After the reaction was complete as monitored by LCMS, water (20 mL) was added to quench the reaction, and the reaction system was extracted twice with EtOAc (50 mL), the organic phases were combined, dried and concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE=0-30%) to obtain 160 mg of the title compound 54-2, with a yield of 43.5%. LC-MS (ESI): m/z 463.0[M-56] + .
化合物54-3的制备Preparation of compound 54-3
将化合物54-2(160mg，0.30mmol)溶解在DCM(10mL)中，加入三氟乙酸(8mL)，室温搅拌反应1小时。反应结束后，合并有机相，干燥浓缩得180mg标题化合物粗品54-3。未经纯化，直接用于下一步反应。LC-MS(ESI):419.0[M+H]+.Compound 54-2 (160 mg, 0.30 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (8 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the organic phases were combined, dried and concentrated to obtain 180 mg of the crude title compound 54-3. It was used directly in the next step without purification. LC-MS (ESI): 419.0 [M+H] + .
化合物54-5的制备Preparation of compound 54-5
将化合物54-3粗品(180mg)溶解于无水甲醇(10mL)中，加入DIPEA(516mg，4mmol)，0℃下搅拌5分钟后，加入化合物2,4-二氯嘧啶(300mg，2.0mmol)，升温至25℃反应1小时，反应结束后，加饱和氯化铵溶液(10mL)淬灭反应，加乙酸乙酯(30mL)萃取两次。有机相用无水硫酸钠干燥，过滤，浓缩，正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到120mg标题化合物54-5，两步收率75％。LC-MS(ESI):531.0[M+H]+.The crude compound 54-3 (180 mg) was dissolved in anhydrous methanol (10 mL), and DIPEA (516 mg, 4 mmol) was added. After stirring at 0°C for 5 minutes, the compound 2,4-dichloropyrimidine (300 mg, 2.0 mmol) was added, and the temperature was raised to 25°C for reaction for 1 hour. After the reaction was completed, a saturated ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (30 mL) was added to extract twice. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by a normal phase silica gel column (EtOAc/PE=0-50%) to obtain 120 mg of the title compound 54-5, with a two-step yield of 75%. LC-MS (ESI): 531.0 [M+H] + .
化合物54的制备Preparation of compound 54
将化合物54-5(100mg，0.19mmol)溶解于DMF(10mL)中，依次加入二甲基氧化膦(140mg，1.8mmol)、三乙胺(182mg，1.8mmol)、Pd2(dba)3(27mg，0.03mmol)和Xantphos(35mg，0.06mmol)。用氮气置换三次后微波120℃下反应12小时。LCMS监测至反应完全。将反应液过滤，滤液粗品经制备分离纯化(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例35％-65％在12分钟内梯度洗脱；流速30mL/min)得到4.67mg标题化合物54，收率4.29％。LC-MS(ESI):m/z 573.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.26–8.27(m,1H),7.63(d,J＝2.4Hz,1H),7.56(d,J＝2.4Hz,1H),7.18–7.15(m,2H),6.91-6.88(m,2H),6.51–6.49(m,1H),4.41(t,J＝5.2Hz,2H),4.23–4.18(m,4H),3.95(t,J＝5.2Hz,2H),3.89–3.93(m,2H),2.03-1.96(m,1H),1.64(d,J＝13.6Hz,6H),1.62(s,6H).31P NMR(162MHz,DMSO-d6)δ33.45(s,1P). Compound 54-5 (100 mg, 0.19 mmol) was dissolved in DMF (10 mL), and dimethylphosphine oxide (140 mg, 1.8 mmol), triethylamine (182 mg, 1.8 mmol), Pd 2 (dba) 3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. After nitrogen replacement three times, the mixture was reacted at 120° C. in a microwave oven for 12 hours. LCMS was monitored until the reaction was complete. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Welch Xtimate C18 250x21.2 mm; column temperature: 25° C.; mobile phase: water (10 mM/L NH 4 HCO 3 )-acetonitrile; mobile phase acetonitrile ratio 35%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 4.67 mg of the title compound 54, with a yield of 4.29%. LC-MS (ESI): m/z 573.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26–8.27 (m, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.18–7.15 (m, 2H), 6.91-6.88 (m, 2H), 6.51–6.49 (m, 1H), 4.41 (t, J=5.2 Hz, 2H), 4.23–4.18 (m, 4H), 3.95 (t, J=5.2 Hz, 2H), 3.89–3.93 (m, 2H), 2.03-1.96 (m, 1H), 1.64 (d, J=13.6 Hz, 6H), 1.62 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 33.45 (s, 1P).
实施例55：化合物55的制备
Example 55: Preparation of Compound 55
化合物55-2的制备Preparation of compound 55-2
将化合物31-2(1.83g，6.20mmol)溶解于1,4-二氧六环(20.0mL)中，依次加入5-甲氧基-2-甲基吲哚(1g，6.2mmol)、碳酸铯(4.04g，10.87mmol)、三(二亚苄基丙酮)二钯(498mg，0.54mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(628mg，12.41mmol)。反应体系用氮气置换三次，110℃下封管搅拌反应12小时。反应结束后，滤除不溶性固体，滤液加水(20mL)，乙酸乙酯萃取(20mL)两次，合并有机相，饱和食盐水(20mL)洗涤两次，无水硫酸钠干燥、浓缩得粗产品，经正相硅胶层析柱(EA/PE＝0～30％)纯化得到500mg标题化合物55-2，收率21％。LC-MS(ESI):m/z 375.2[M+H]+.Compound 31-2 (1.83 g, 6.20 mmol) was dissolved in 1,4-dioxane (20.0 mL), and 5-methoxy-2-methylindole (1 g, 6.2 mmol), cesium carbonate (4.04 g, 10.87 mmol), tris(dibenzylideneacetone)dipalladium (498 mg, 0.54 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (628 mg, 12.41 mmol) were added in sequence. The reaction system was replaced with nitrogen three times, and the reaction was stirred at 110°C for 12 hours under sealed tube. After the reaction was completed, the insoluble solid was filtered off, the filtrate was added with water (20 mL), and extracted with ethyl acetate (20 mL) twice, the organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by normal phase silica gel chromatography (EA/PE=0-30%) to obtain 500 mg of the title compound 55-2, with a yield of 21%. LC-MS(ESI):m/z 375.2[M+H] + .
化合物55-3的制备Preparation of compound 55-3
将化合物55-2(250mg，0.666mmol)溶解于二氯甲烷(15mL)中，氮气保护下，-60℃下滴加三溴化硼(1.11g，4.43mmol，17％的DCM溶液)，滴毕，-5℃反应2个小时。LCMS监测至反应结束后，加水(20mL)淬灭，二氯甲烷萃取(20mL)两次，合并有机相，无水硫酸钠干燥、浓缩得粗产品，经正相硅胶层析柱(EA/PE＝0～30％)纯化得到150mg标题化合物55-3，收率62％。LC-MS(ESI):m/z 361.2[M+H]+.Compound 55-2 (250 mg, 0.666 mmol) was dissolved in dichloromethane (15 mL). Boron tribromide (1.11 g, 4.43 mmol, 17% DCM solution) was added dropwise at -60°C under nitrogen protection. After the addition, the mixture was reacted at -5°C for 2 hours. After the reaction was completed by LCMS monitoring, water (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL) twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by normal phase silica gel chromatography (EA/PE=0-30%) to obtain 150 mg of the title compound 55-3 with a yield of 62%. LC-MS (ESI): m/z 361.2 [M+H] + .
化合物55-4的制备Preparation of compound 55-4
将化合物55-3(200mg，0.55mmol)溶于DMF(2mL)中，搅拌下加入碳酸钾(229mg，1.66mmol)，反应5分钟后再加入2-氯-4-(氯甲基)嘧啶(135mg，0.830mmol)，80℃下反应4小时。LCMS监测至反应完全，将反应液倒入饱和氯化铵溶液(20mL)中，乙酸乙酯萃取(20mL)两次，合并有机相，无水硫酸钠干燥、浓缩得粗产品，经正相硅胶层析柱(EA/PE＝0～30％)纯化得到135mg标题化合物55-4，收率50％。LC-MS(ESI):m/z 487.0[M+H]+.Compound 55-3 (200 mg, 0.55 mmol) was dissolved in DMF (2 mL), potassium carbonate (229 mg, 1.66 mmol) was added under stirring, and 2-chloro-4-(chloromethyl)pyrimidine (135 mg, 0.830 mmol) was added after 5 minutes of reaction, and the reaction was carried out at 80°C for 4 hours. LCMS monitored the reaction until it was complete, and the reaction solution was poured into a saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL) twice, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by normal phase silica gel chromatography (EA/PE=0-30%) to obtain 135 mg of the title compound 55-4, with a yield of 50%. LC-MS (ESI): m/z 487.0 [M+H] + .
化合物55的制备Preparation of compound 55
将化合物55-4(120mg，0.246mmol)溶解于N,N-二甲基甲酰胺(3.0mL)中，依次加入二甲基氧化膦(58mg，0.738mmol)、N,N-二异丙基乙胺(95mg，0.738mmol)、三(二亚苄基丙酮)二钯(22mg，0.024mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(28mg，0.049mmol)。用氮气置换三次后，封管120℃下反应3小时。LCMS监测至完全。将反应液过滤，滤液减压蒸干，粗品经制备分离纯化(制备方法:色谱柱:Welch Xtimate C18 250x 21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％在12分钟内梯度洗脱；流速30mL/min)得到35mg标题化合物55，收率27％。LC-MS(ESI):m/z 529.0[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.86(s,1H),7.71(s,1H),7.63(d,J＝2.5Hz,1H),7.51(d,J＝2.5Hz,1H),7.05(d,J＝2.3Hz,1H),6.99(d,J＝8.8Hz,1H),6.87(dd,J＝9.0,2.3Hz,1H),6.35(s,1H),5.29(s,2H),4.57(t,J＝6.0Hz,2H),3.95(t,J＝6.0Hz,2H),2.30(s,3H),1.91(d,J＝12.9Hz,6H). Compound 55-4 (120 mg, 0.246 mmol) was dissolved in N,N-dimethylformamide (3.0 mL), and dimethylphosphine oxide (58 mg, 0.738 mmol), N,N-diisopropylethylamine (95 mg, 0.738 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 0.024 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (28 mg, 0.049 mmol) were added in sequence. After replacing with nitrogen three times, the tube was sealed and reacted at 120°C for 3 hours. LCMS monitoring was completed. The reaction solution was filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x 21.2 mm; column temperature: 25°C; mobile phase: water (10 mM/ L NH4HCO3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% gradient elution within 12 minutes; flow rate 30 mL/min) to obtain 35 mg of the title compound 55, with a yield of 27%. LC-MS (ESI): m/z 529.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 7.71 (s, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 9.0, 2.3 Hz, 1H), 6.35 (s, 1H), 5.29 (s, 2H), 4.57 (t, J = 6.0 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.30 (s, 3H), 1.91 (d, J = 12.9 Hz, 6H).
实施例56：化合物56的制备
Example 56: Preparation of Compound 56
化合物56-1的制备Preparation of compound 56-1
将化合物53-3(350mg，0.810mmol)，四氢呋喃(5mL)加入单口瓶中，搅拌下加入N,N-二异丙基乙胺(209mg，1.62mmol)，HATU(615mg，1.62mmol)，2-氯嘧啶-4-基甲酸(134mg，0.97mmol)，反应在室温下搅拌反应2小时。反应结束后，向反应体系加入10mL饱和氯化钠水溶液，用EtOAc(10mL)萃取3次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得390mg标题化合物56-1。LC-MS(ESI):573.2[M+H]+.Compound 53-3 (350 mg, 0.810 mmol) and tetrahydrofuran (5 mL) were added to a single-mouth bottle, and N, N-diisopropylethylamine (209 mg, 1.62 mmol), HATU (615 mg, 1.62 mmol), and 2-chloropyrimidin-4-ylcarboxylic acid (134 mg, 0.97 mmol) were added under stirring. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, 10 mL of saturated sodium chloride aqueous solution was added to the reaction system, and the mixture was extracted 3 times with EtOAc (10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-30%) to obtain 390 mg of the title compound 56-1. LC-MS (ESI): 573.2 [M+H] + .
化合物56的制备Preparation of Compound 56
将化合物56-1(120mg，217umol)溶解于N,N-二甲基甲酰胺(2.0mL)中，依次加入二甲基氧化膦(67.6mg，868mmol)、三乙胺(55mg，542umol)、三(二亚苄基丙酮)二钯(27mg，30mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(18mg，30mmol)。用氮气置换三次，反应体系在120℃下微波搅拌反应2小时。反应结束后，反应体系过滤后用二氯甲烷(20mL)萃取3次，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:45％-65％乙腈in 12min；流速:30mL/min)得到23.4mg标题化合物56。LC-MS(ESI):m/z 615.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.06(d,J＝5.2Hz,1H),7.30–7.75(m,1H),7.57(d,J＝2.4Hz,1H),7.51(d,J＝2.4Hz,1H),7.0–7.10(m,2H),6.85–6.88(m,2H),4.59–4.61(m,1H),4.34(d,J＝5.2Hz,2H),3.88(d,J＝5.2Hz,2H),3.45–3.50(m,2H),3.24–3.28(m,1H),2.06-1.93(m,1H),1.85–2.01(m,2H),1.70(d,J＝13.8Hz,6H),1.59–1.63(m,2H),1.56(s,6H).31P NMR(162MHz,DMSO-d6)δ34.46(s,1P)。 Compound 56-1 (120 mg, 217 umol) was dissolved in N,N-dimethylformamide (2.0 mL), and dimethylphosphine oxide (67.6 mg, 868 mmol), triethylamine (55 mg, 542 umol), tris(dibenzylideneacetone)dipalladium (27 mg, 30 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (18 mg, 30 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After the reaction, the reaction system was filtered and extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 min; flow rate: 30 mL/min) to obtain 23.4 mg of the title compound 56. LC-MS (ESI): m/z 615.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.06 (d, J = 5.2 Hz, 1H), 7.30–7.75 (m, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.0–7.10 (m, 2H), 6.85–6.88 (m, 2H), 4.59–4.61 (m, 1H), 4.34 (d, J = 5.2 Hz, 2H), 3.88 (d, J = 5.2 Hz, 2H), 3.45–3.50 (m, 2H), 3.24–3.28 (m, 1H), 2.06-1.93 (m, 1H), 1.85–2.01 (m, 2H), 1.70 (d, J = 13.8 Hz, 6H), 1.59–1.63 (m, 2H), 1.56 (s, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 34.46 (s, 1P).
实施例57：化合物57的制备
Example 57: Preparation of Compound 57
化合物57-2的制备Preparation of compound 57-2
将化合物1-6(400mg，1.14mmol)，57-1(231mg，1.018mmol)，四氢呋喃(6mL)加入单口瓶中，搅拌下加入三苯基膦(598mg，2.28mmol)，反应体系用氮气置换三次，冰浴下滴加偶氮二甲酸二乙酯(397mg，2.28mmol)，30分钟后，反应在室温下搅拌反应8小时。反应结束后，向反应体系加入13mL饱和氯化钠水溶液。用乙酸乙酯(15mL)萃取三次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-25％)分离纯化得到265mg标题化合物57-2。LC-MS(ESI):559.2[M+H]+.Compound 1-6 (400 mg, 1.14 mmol), 57-1 (231 mg, 1.018 mmol), and tetrahydrofuran (6 mL) were added to a single-mouth bottle, and triphenylphosphine (598 mg, 2.28 mmol) was added under stirring. The reaction system was replaced with nitrogen three times, and diethyl azodicarboxylate (397 mg, 2.28 mmol) was added dropwise under ice bath. After 30 minutes, the reaction was stirred at room temperature for 8 hours. After the reaction was completed, 13 mL of saturated sodium chloride aqueous solution was added to the reaction system. The product was extracted three times with ethyl acetate (15 mL), and the organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-25%) to obtain 265 mg of the title compound 57-2. LC-MS (ESI): 559.2 [M+H] + .
化合物57-3的制备Preparation of compound 57-3
将化合物57-2(265mg，475μmol)，二氯甲烷(4mL)加入单口瓶中，冰浴下滴加三氟乙酸(0.5mL)，搅拌30分钟后，升至室温搅拌反应2小时。反应结束后，浓缩得260mg标题化合物57-3。LC-MS(ESI):459.3[M+H]+.Compound 57-2 (265 mg, 475 μmol) and dichloromethane (4 mL) were added to a single-mouth bottle, trifluoroacetic acid (0.5 mL) was added dropwise under ice bath, stirred for 30 minutes, and then heated to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was concentrated to obtain 260 mg of the title compound 57-3. LC-MS (ESI): 459.3 [M+H] + .
化合物57-4的制备Preparation of compound 57-4
将化合物57-3(260mg，453μmol)，二氯甲烷(4mL)加入单口瓶中，搅拌下加入三乙胺(92mg，906μmol)，4-氯-2-甲磺酰基嘧啶(95mg，495μmol)，反应在室温下搅拌反应2小时。反应结束后，向反应体系加入15mL饱和氯化钠水溶液，用EtOAc(8mL)萃取3次，合并有机相，干燥浓缩得粗产品，通过正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到248mg标题化合物57-4。LC-MS(ESI):615.3[M+H]+.Compound 57-3 (260 mg, 453 μmol) and dichloromethane (4 mL) were added to a single-mouth bottle, and triethylamine (92 mg, 906 μmol) and 4-chloro-2-methylsulfonylpyrimidine (95 mg, 495 μmol) were added under stirring. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, 15 mL of saturated sodium chloride aqueous solution was added to the reaction system, and the mixture was extracted with EtOAc (8 mL) for 3 times. The organic phases were combined, dried and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc/PE=0-50%) to obtain 248 mg of the title compound 57-4. LC-MS (ESI): 615.3 [M+H] + .
化合物57的制备Preparation of compound 57
将化合物57-4(160mg，260μmol)溶解于乙腈(5.0mL)中，依次加入二甲基氧化膦(81.1mg，1.04mmol)、碳酸铯(169mg，520μmol)。用氮气替换三次，反应体系在85℃下搅拌反应2小时。反应结束后，反应体系过滤后用二氯甲烷(20mL)萃取3次，合并有机相，干燥浓缩得粗产品，经制备分离纯化(制备方法:流动相:A:0.1％甲酸水溶液；B:乙腈；色谱柱:Welch Ultimate AQ-C18 250×21.2mm；柱温:25℃；梯度:25％-45％乙腈in 12min；流速:30mL/min)得到42mg标题化合物57。LC-MS(ESI):m/z 613.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.64(d,J＝2.4Hz,1H),7.59(d,J＝2.4Hz,1H),7.15–7.18(m,2H),6.82–6.86(m,3H),4.43–4.93(m,2H),4.61–4.63(m,1H),4.42(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz,2H),2.21–2.23(m,2H),2.00–2.21(m,4H),1.87–1.93(m,2H),1.67(d,J＝13.3Hz,6H),1.64(s,6H).31P NMR(162MHz,DMSO-d6)δ33.37(s,1P)。 Compound 57-4 (160 mg, 260 μmol) was dissolved in acetonitrile (5.0 mL), and dimethylphosphine oxide (81.1 mg, 1.04 mmol) and cesium carbonate (169 mg, 520 μmol) were added in sequence. The gas was replaced with nitrogen three times, and the reaction system was stirred at 85°C for 2 hours. After the reaction, the reaction system was filtered and extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 25%-45% acetonitrile in 12 min; flow rate: 30 mL/min) to obtain 42 mg of the title compound 57. LC-MS (ESI): m/z 613.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.31(s,1H),7.64(d,J＝2.4Hz,1H),7.59(d,J＝2.4Hz,1H),7.15–7.18(m,2H),6.82–6.86(m,3H),4.43–4.93(m,2H),4.61–4.63(m,1H),4.42(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz,2H),2.21–2.23(m,2H),2.00–2.21(m,4H),1.87–1.93(m,2H),1.67(d,J＝13.3Hz,6H),1.64(s,6H). 31 P NMR (162MHz,DMSO-d6)δ33.37(s,1P).
实施例58：化合物58的制备
Example 58: Preparation of Compound 58
化合物58-2的制备Preparation of compound 58-2
将化合物三乙胺(3.03g，30mmol)和2,4-二氯嘧啶(2.96g，20mmol)溶于无水甲醇(10mL)中，冷确到0℃，分批次加入58-1(2.0g，10.7mmol)，室温下反应2小时。LCMS跟踪反应至完全后，加水(20mL)，反应体系用EtOAc(50mL)萃取2次，合并有机相，干燥浓缩,通过正相硅胶柱(EtOAc/PE＝0-30％)分离纯化得到1.3g标题化合物58-2。LC-MS(ESI):m/z 243.8[M+H-tBu]+.The compound triethylamine (3.03 g, 30 mmol) and 2,4-dichloropyrimidine (2.96 g, 20 mmol) were dissolved in anhydrous methanol (10 mL), cooled to 0°C, and 58-1 (2.0 g, 10.7 mmol) was added in batches, and the reaction was allowed to react at room temperature for 2 hours. After the reaction was complete as tracked by LCMS, water (20 mL) was added, and the reaction system was extracted twice with EtOAc (50 mL), the organic phases were combined, dried and concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE=0-30%) to obtain 1.3 g of the title compound 58-2. LC-MS (ESI): m/z 243.8 [M+H-tBu] + .
化合物58-3的制备Preparation of compound 58-3
将化合物58-2(600mg，2.0mmol)溶解在DCM(10mL)，加入三氟乙酸(10mL)，室温搅拌反应1小时。原料反应结束后将浓缩得标题化合物58-3(620mg)，粗品直接投下步反应。LC-MS(ESI):m/z 199.2[M+1]+.Compound 58-2 (600 mg, 2.0 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction of the raw material was completed, the title compound 58-3 (620 mg) was obtained by concentration, and the crude product was directly used for the next step reaction. LC-MS (ESI): m/z 199.2 [M+1] + .
化合物58-4的制备Preparation of compound 58-4
将化合物45-1(1.2g，2.28mmol)溶解于无水甲醇(10.0mL)中，加入DMSO(10mL)，三乙胺(1.01g，10mmol)，加入醋酸钯(100mg，0.44mmol)，1,3-二苯基膦丙烷(181mg，0.44mmol)，八羰基二钴(3.42g，10mmol)，氮气置换三次后，升温到75℃反应12小时。反应结束后，加饱和氯化钠溶液(100.0mL)，加乙酸乙酯(50.0mL)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，通过正相硅胶柱(EtOAc/PE＝0-50％)分离纯化得到340mg标题化合物58-4.LC-MS(ESI):392.0[M+H]+.Compound 45-1 (1.2 g, 2.28 mmol) was dissolved in anhydrous methanol (10.0 mL), DMSO (10 mL), triethylamine (1.01 g, 10 mmol), palladium acetate (100 mg, 0.44 mmol), 1,3-diphenylphosphine propane (181 mg, 0.44 mmol), dicobalt octacarbonyl (3.42 g, 10 mmol) were added, and the atmosphere was replaced with nitrogen three times, and the temperature was raised to 75°C for reaction for 12 hours. After the reaction was completed, saturated sodium chloride solution (100.0 mL) was added, and ethyl acetate (50.0 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by normal phase silica gel column (EtOAc/PE=0-50%) to obtain 340 mg of the title compound 58-4. LC-MS (ESI): 392.0 [M+H] + .
化合物58-5的制备Preparation of compound 58-5
将化合物58-4(340mg，0.86mmol)溶解于甲醇(10.0mL)和水的混合液中，然后加入NaOH(344mg，8.6mmol)，室温反应2小时，TLC检测(PE:EA＝3:1)原料反应完毕，将反应液稀盐酸(1mol/L)调pH 5，乙酸乙酯(50ml)萃取，有机相浓缩得到290mg标题化合物58-5.Compound 58-4 (340 mg, 0.86 mmol) was dissolved in a mixture of methanol (10.0 mL) and water, and then NaOH (344 mg, 8.6 mmol) was added. The mixture was reacted at room temperature for 2 hours. TLC detection (PE:EA=3:1) showed that the reaction of the raw materials was complete. The reaction solution was adjusted to pH 5 with dilute hydrochloric acid (1 mol/L), extracted with ethyl acetate (50 ml), and the organic phase was concentrated to obtain 290 mg of the title compound 58-5.
化合物58-6的制备Preparation of compound 58-6
将化合物58-5(290mg，0.76mmol)溶解于无水DMF(10.0mL)中，然后加入58-3(198mg，1mmol)DIEA(303mg，2.2mmol)，HATU(418mg，1.1mmol)，室温反应2小时将反应液倒入水(100mL)中,用乙酸乙酯(50ml)萃取，有机相浓缩，柱层析分离得到230mg标题化合物58-6.LC-MS(ESI):558.2[M+H]+.Compound 58-5 (290 mg, 0.76 mmol) was dissolved in anhydrous DMF (10.0 mL), and then 58-3 (198 mg, 1 mmol) DIEA (303 mg, 2.2 mmol), HATU (418 mg, 1.1 mmol) were added. The mixture was reacted at room temperature for 2 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 ml), and the organic phase was concentrated and separated by column chromatography to obtain 230 mg of the title compound 58-6. LC-MS (ESI): 558.2 [M+H] + .
化合物58的制备Preparation of Compound 58
将化合物58-6(230mg，0.41mmol)溶解于DMF(10.0mL)中，依次加入二甲基氧化膦(140mg，1.8mmol)、DIEA(138mg，1mmol)、Pd2(dba)3(27mg，0.03mmol)和Xantphos(35mg，0.06mmol)。 用氮气置换三次后微波120℃下反应5小时。LCMS跟踪反应至完全后，将反应液过滤，滤液粗品经制备分离纯化(制备方法:色谱柱:Welch Xtimate C18 250x21.2mm；柱温:25℃；流动相:水(10mM/L NH4HCO3)-乙腈；流动相乙腈比例45％-65％in 12min；流速30mL/min)得到57.5mg标题化合物58。LC-MS(ESI):m/z 598.8[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.26(d,J＝6.4Hz,1H),7.64(d,J＝2.4Hz,1H),7.58(d,J＝2.4Hz,1H),7.33–7.35(m,2H),7.26–7.28(m,2H),6.83–6.85(m,1H),4.36(t,J＝5.2Hz,2H),3.89(t,J＝5.2Hz 2H),3.53–3.74(m,6H),3.36–3.48(m,2H),1.61(s,6H),1.60(d,J＝16.4Hz,6H).31P NMR(162MHz,DMSO-d6)δ33.59(s,1P)。Compound 58-6 (230 mg, 0.41 mmol) was dissolved in DMF (10.0 mL), and dimethylphosphine oxide (140 mg, 1.8 mmol), DIEA (138 mg, 1 mmol), Pd 2 (dba) 3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added in sequence. After replacing with nitrogen three times, the mixture was reacted at 120°C in a microwave oven for 5 hours. After the reaction was completed by LCMS tracking, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparative method: chromatographic column: Welch Xtimate C18 250x21.2mm; column temperature: 25°C; mobile phase: water (10mM/L NH4HCO3 )-acetonitrile; mobile phase acetonitrile ratio 45%-65% in 12min; flow rate 30mL/min) to obtain 57.5mg of the title compound 58. LC-MS (ESI): m/z 598.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ8.26 (d, J=6.4 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.33–7.35 (m, 2H), 7.26–7.28 (m, 2H), 6.83–6.85 (m, 1H), 4.36 (t, J=5.2 Hz, 2H), 3.89 (t, J=5.2 Hz 2H), 3.53–3.74 (m, 6H), 3.36–3.48 (m, 2H), 1.61 (s, 6H), 1.60 (d, J=16.4 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 33.59 (s, 1P).
实施例59：化合物59的制备
Example 59: Preparation of Compound 59
化合物59-2的制备Preparation of compound 59-2
氮气保护下，将化合物45-1(500mg，1.04mmol)，化合物59-1(467mg，2.07mmol)，TEA(1.05g，10.37mmol，1.45mL)，Pd(dppf)Cl2(75.86mg，103.67μmol，80.36μL)，Co(CO)8(354.50mg，1.04mmol)和DMF(5mL)加入到反应瓶中，80℃搅拌5小时。加水(10mL)，后用二氯甲烷(10mL)萃取3次，合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-100％)分离纯化得到90mg标题化合物59-2.LC-MS(ESI):585.2[M+H]+.Under nitrogen protection, compound 45-1 (500 mg, 1.04 mmol), compound 59-1 (467 mg, 2.07 mmol), TEA (1.05 g, 10.37 mmol, 1.45 mL), Pd(dppf)Cl 2 (75.86 mg, 103.67 μmol, 80.36 μL), Co(CO) 8 (354.50 mg, 1.04 mmol) and DMF (5 mL) were added to a reaction bottle and stirred at 80°C for 5 hours. Water (10 mL) was added, and then extracted with dichloromethane (10 mL) for 3 times. The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (EtOAc/PE=0-100%) to obtain 90 mg of the title compound 59-2. LC-MS (ESI): 585.2 [M+H] + .
化合物59-3的制备Preparation of compound 59-3
将化合物59-2(90mg，153.70μmol)，m-CPBA(79.57mg，461.11μmol)和DCM(3mL)加入到反应瓶中，室温搅拌2小时。加饱和碳酸钠水溶液(10mL)，二氯甲烷(10mL)萃取3次，合并有机相，干燥浓缩得粗产品。粗品经正相硅胶柱(EtOAc/PE＝0-100％)分离纯化得到90mg标题化合物59-3.LC-MS(ESI):617.0[M+H]+.Compound 59-2 (90 mg, 153.70 μmol), m-CPBA (79.57 mg, 461.11 μmol) and DCM (3 mL) were added to a reaction flask and stirred at room temperature for 2 hours. Saturated sodium carbonate aqueous solution (10 mL) was added, and dichloromethane (10 mL) was used for extraction 3 times. The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc/PE=0-100%) to obtain 90 mg of the title compound 59-3. LC-MS (ESI): 617.0 [M+H] + .
化合物59的制备Preparation of compound 59
将二甲基氧化膦(56.87mg，728.70μmol)，化合物59-3(150mg，242.90μmol)，Cs2CO3(237.42mg，728.70μmol)，乙腈(1mL)加入到反应瓶中。80℃搅拌3小时。过滤，浓缩得粗产品。粗品经制备分离纯化(制备方法：流动相：A:0.1％甲酸水溶液；B:乙腈；色谱柱：Agilent 10Prep-C18 250×21.2mm；柱温：25℃；梯度：20％-90％乙腈in 40min；流速：30mL/min)，得到12mg标题化合物59.LC-MS(ESI):615.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝8.0Hz,1H),7.70(d,J＝2.4Hz,1H),7.64(d,J＝2.0Hz,1H),7.36–7.39(m,2H),7.26–7.35(m,2H),7.04–7.06(m,1H),5.38–5.42(m,1H),4.43(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz,2H),3.37–3.67(m,4H),2.00–2.08(m,2H),1.72–1.75(m,8H),1.68(s,6H).31P NMR(162MHz,DMSO-d6)δ34.09(s,1P).Dimethylphosphine oxide (56.87 mg, 728.70 μmol), compound 59-3 (150 mg, 242.90 μmol), Cs 2 CO 3 (237.42 mg, 728.70 μmol), and acetonitrile (1 mL) were added to a reaction flask. Stirred at 80°C for 3 hours. Filtered and concentrated to obtain a crude product. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 20%-90% acetonitrile in 40 min; flow rate: 30 mL/min) to obtain 12 mg of the title compound 59. LC-MS (ESI): 615.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.68(d, J＝8.0Hz,1H),7.70(d, J＝2.4Hz,1H),7.64(d, J＝2.0Hz,1H),7.36–7.39(m,2H),7.26–7.35(m,2H),7.04–7.06(m,1H),5.38–5.42(m,1H),4.43(t, J＝5.2Hz,2H),3.96(t, J＝5.2Hz,2H),3.37–3.67(m,4H),2.00–2.08(m,2H),1.72–1.75(m,8H),1.68(s,6H). 31 P NMR (162MHz,DMSO-d 6 )δ34.09(s,1P).
测试实例1：小鼠药代动力学测试Test Example 1: Mouse Pharmacokinetic Test
配药：给药溶液当天配制。称取化合物2mg，用给药剂型A:3％DMSO+1.5％Tween80+95.5％Saline溶解，配成浓度为0.1mg/mL的静脉给药溶液；称取2mg化合物，用给药剂型B:3％DMSO+1.5％Tween80 +95.5％Saline溶解，得到0.5mg/mL的口服给药溶液；称取3mg化合物，用给药剂型C:5％DMSO+5％NMP+10％Solutol+80％PEG400溶解，得到3.0mg/mL的口服给药溶液。Preparation: The dosing solution was prepared on the day of the experiment. Weigh 2 mg of the compound and dissolve it in dosage form A: 3% DMSO + 1.5% Tween80 + 95.5% Saline to prepare an intravenous solution with a concentration of 0.1 mg/mL; weigh 2 mg of the compound and dissolve it in dosage form B: 3% DMSO + 1.5% Tween80 +95.5% Saline to obtain a 0.5 mg/mL oral administration solution; weigh 3 mg of the compound and dissolve it with dosage form C: 5% DMSO + 5% NMP + 10% Solutol + 80% PEG400 to obtain a 3.0 mg/mL oral administration solution.
取健康雄性ICR小鼠6只，体重25-30g，分为两组(静脉和口服组)，每组三只，单次给药。小鼠适应性饲养3天后，实验前一晚禁食过夜(10-12h)，实验期间自由饮水，给药后4h恢复进食。静脉和口服给药后开始计时，分别在计划时间点(IV&PO 0.083，0.25，0.5，1，2，4，6，8，24h)经眼眶静脉丛采血，每个点采集30μL全血至内含肝素钠的1.5mL的EP管中，采集的全血置涡旋仪上点振2次混匀，置于湿冰上放置，1h内4℃8000rpm离心5min，取上清血浆置于-80℃冰箱保存直至处理分析。Take healthy male Six ICR mice, weighing 25-30g, were divided into two groups (intravenous and oral groups), three mice in each group, and administered once. After 3 days of adaptive feeding, the mice were fasted overnight (10-12h) before the experiment, and were allowed to drink water freely during the experiment. They resumed eating 4h after administration. Timing began after intravenous and oral administration, and blood was collected through the orbital venous plexus at the planned time points (IV&PO 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h). 30μL of whole blood was collected at each point into a 1.5mL EP tube containing sodium heparin. The collected whole blood was placed on a vortexer and shaken twice to mix, placed on wet ice, centrifuged at 8000rpm for 5min at 4℃ within 1h, and the supernatant plasma was stored in a -80℃ refrigerator until processed and analyzed.
表1：小鼠药代动力学
Table 1: Pharmacokinetics in mice
测试实例2：大鼠药代动力学测试Test Example 2: Pharmacokinetic Test in Rat
配药：给药溶液当天配制。称取化合物2mg，用3％DMSO+1.5％Tween80+95.5％Saline溶解，配成浓度为0.1mg/mL的静脉给药溶液；称取6mg化合物，用3％DMSO+1.5％Tween80+95.5％Saline溶解，得到0.5mg/mL的口服给药溶液。Preparation: The dosing solution was prepared on the day of administration. Weigh 2 mg of the compound and dissolve it in 3% DMSO + 1.5% Tween80 + 95.5% Saline to prepare an intravenous dosing solution with a concentration of 0.1 mg/mL; weigh 6 mg of the compound and dissolve it in 3% DMSO + 1.5% Tween80 + 95.5% Saline to obtain a 0.5 mg/mL oral dosing solution.
取健康雄性SD大鼠6只，体重220-300g，分为两组(静脉和口服组)，每组三只，单次给药。大鼠适应性饲养3天后，实验前一晚禁食过夜(10-12h)，实验期间自由饮水，给药后4h恢复进食。静脉和口服给药后开始计时，分别在计划时间点(IV&PO 0.083，0.25，0.5，1，2，4，6，8，24h)经眼眶静脉丛采血，每个点采集150μL全血至内含肝素钠的EP管中，采集的全血置涡旋仪上点振2次混匀，置于湿冰上放置，1h内4℃8000rpm离心5min，取上清血浆置于-80℃冰箱保存直至处理分析。Six healthy male SD rats weighing 220-300g were taken and divided into two groups (intravenous and oral groups), three rats in each group, and a single dose was given. After 3 days of adaptive feeding, the rats fasted overnight (10-12h) the night before the experiment, had free access to water during the experiment, and resumed eating 4h after administration. Timing began after intravenous and oral administration, and blood was collected through the orbital venous plexus at the planned time points (IV&PO 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h). 150μL of whole blood was collected at each point into an EP tube containing sodium heparin. The collected whole blood was placed on a vortexer and shaken twice to mix, placed on wet ice, centrifuged at 8000rpm for 5min at 4℃ within 1h, and the supernatant plasma was stored in a -80℃ refrigerator until processed and analyzed.
表2：大鼠药代动力学
Table 2: Pharmacokinetics in rats
测试实例3：LNCaP细胞的细胞增殖抑制测试Test Example 3: Cell proliferation inhibition test of LNCaP cells
1.人前列腺癌细胞株LNCaP购置于ATCC，细胞培养基为RPMI-1640+10％FBS，培养于37℃，100％相对湿度，5％CO2培养箱中。1. Human prostate cancer cell line LNCaP was purchased from ATCC, the cell culture medium was RPMI-1640 + 10% FBS, and cultured in a 37°C, 100% relative humidity, 5% CO2 incubator.
2.第一天收集对数生长期细胞，计数，用含10％CD-FBS的无酚红RPMI-1640培养基重新悬浮细胞，调整细胞浓度至合适浓度(依照细胞密度优化试验结果确定)，接种96孔板，加入100μl细胞悬液，使细胞数为3000个/孔。细胞在37℃，5％CO2培养箱中孵育24小时。2. On the first day, cells in the logarithmic growth phase were collected, counted, and resuspended in RPMI-1640 medium without phenol red containing 10% CD-FBS. The cell concentration was adjusted to an appropriate concentration (determined according to the results of the cell density optimization test), inoculated into a 96-well plate, and 100 μl of cell suspension was added to make the cell number 3000/well. The cells were incubated in a 37°C, 5% CO2 incubator for 24 hours.
3.第二天先加入不同浓度的待测化合物，作用1小时后加入0.2nM的DHT，细胞置于37℃，5％CO2培养箱中孵育4天。3. On the second day, different concentrations of the test compound were added, and after 1 hour, 0.2 nM DHT was added. The cells were placed in a 37°C, 5% CO2 incubator and incubated for 4 days.
4.培养结束后，每孔加入与培养基等体积的CellTiter-Glo检测试剂，震荡混匀5分钟后，室温孵育10分钟，应用PerkinElmer EnVision酶标仪读数。4. After the culture is completed, add CellTiter-Glo detection reagent in an equal volume to the culture medium to each well, shake and mix for 5 minutes, incubate at room temperature for 10 minutes, and read using a PerkinElmer EnVision microplate reader.
5.按下式计算药物对各细胞生长的抑制率：细胞生长抑制率％＝[(Ac-As)/(Ac-Ab)]×100％5. Calculate the inhibition rate of the drug on each cell growth according to the following formula: Cell growth inhibition rate % = [(Ac-As)/(Ac-Ab)] × 100%
As:样品的OA(细胞+待测化合物)As: OA of sample (cells + test compound)
Ac:正常生长细胞对照的OA(细胞+DMSO)Ac: OA of normal growth cell control (cells + DMSO)
Ab:空白对照的OA(培养基+DMSO)Ab: blank control OA (culture medium + DMSO)
运用软件Graphpad Prism 8并采用计算公式XY-analysis/Nonlinear regression(curve fit)/Dose response-Inhibition/log(inhibitor)vs.normalized response-Variable slope进行IC50曲线拟合并计算出IC50值。The IC50 curve was fitted and the IC50 value was calculated using the software Graphpad Prism 8 and the calculation formula XY-analysis/Nonlinear regression (curve fit)/Dose response-Inhibition/log (inhibitor) vs. normalized response-Variable slope.
结果显示本发明化合物在LNCaP细胞增殖抑制实验中表现出好的细胞活性。The results showed that the compounds of the present invention exhibited good cell activity in the LNCaP cell proliferation inhibition experiment.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。 Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims (23)

  1. 式(Ⅰ)所示化合物、其光学异构体及其药效上可接受的盐，
    The compound represented by formula (I), its optical isomers and pharmaceutically acceptable salts thereof,
    其中，in,
    R1、R2分别独立地选自H、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C3-6环烯基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C3- 6环烯基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代；R 1 and R 2 are each independently selected from H, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl , C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
    或者，R1与R2连接在一起，形成一个4-8元环，所述4-8元环任选被1、2或3个R取代；Alternatively, R 1 and R 2 are linked together to form a 4-8 membered ring, and the 4-8 membered ring is optionally substituted by 1, 2 or 3 R;
    R3、R4、R5分别独立地选自H、CN、F、Cl、Br、OH、NH2、CN、C1-6烷基、C1-6烷基-O-、C1-6烷基-S-、C1-6烷基-NH-、C2-6烯基-O-、C2-6烯基-S-、C2-6烯基-NH-、C3-6环烷基-O-、C3-6环烷基-S-、C3-6环烷基-NH-、4-6元杂环烷基-O-、4-6元杂环烷基-S-或4-6元杂环烷基-NH-，所述C1-6烷基、C1-6烷基-O-、C1-6烷基-S-、C1-6烷基-NH-、C2-6烯基-O-、C2-6烯基-S-、C2-6烯基-NH-、C3-6环烷基-O-、C3-6环烷基-S-、C3-6环烷基-NH-、4-6元杂环烷基-O-、4-6元杂环烷基-S-和4-6元杂环烷基-NH-任选被1、2或3个R取代；R 3 , R 4 , and R 5 are each independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkyl-O—, C 1-6 alkyl-S—, C 1-6 alkyl-NH—, C 2-6 alkenyl-O—, C 2-6 alkenyl-S—, C 2-6 alkenyl-NH—, C 3-6 cycloalkyl-O—, C 3-6 cycloalkyl-S—, C 3-6 cycloalkyl - NH—, 4-6 membered heterocycloalkyl- O— , 4-6 membered heterocycloalkyl-S—, or 4-6 membered heterocycloalkyl-NH— ; C 3-6 cycloalkyl-O—, C 3-6 cycloalkyl-S—, C 3-6 cycloalkyl-NH—, 4-6 membered heterocycloalkyl-O—, 4-6 membered heterocycloalkyl-S— and 4-6 membered heterocycloalkyl-NH— are optionally substituted with 1, 2 or 3 R;
    R6、R7分别独立地选自H、CN、F、Cl、Br、OH、NH2、C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代；R 6 and R 7 are each independently selected from H, CN, F, Cl, Br, OH, NH 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
    m、n分别独立地选自0、1、2或3；m and n are independently selected from 0, 1, 2 or 3;
    Y选自O或S；Y is selected from O or S;
    L1选自单键、NH、O、CH2、CH2CH2或OCH2，所述CH2、CH2CH2和OCH2任选被1或2个R取代；L 1 is selected from a single bond, NH, O, CH 2 , CH 2 CH 2 or OCH 2 , wherein CH 2 , CH 2 CH 2 and OCH 2 are optionally substituted with 1 or 2 R;
    L2、L3分别独立地选自-(CR8R9)x-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-NR10-、-OR11-或5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R取代；L 2 and L 3 are each independently selected from -(CR 8 R 9 )x-, -O-, -S-, -C(═O)-, -S(═O)-, -S(═O) 2 -, -NR 10 -, -OR 11 - or a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R groups;
    L4选自-(CR8R9)x-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-NR10-、C3-6环烷基或3-6元杂环烷基，所述C3- 6环烷基和3-6元杂环烷基任选被1、2或3个R取代；L 4 is selected from -(CR 8 R 9 )x-, -O-, -S-, -C(═O)-, -S(═O)-, -S(═O) 2 -, -NR 10 -, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
    R8、R9分别独立地选自H、CN、F、Cl、Br、OH、NH2、C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代；R 8 and R 9 are each independently selected from H, CN, F, Cl, Br, OH, NH 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
    或者R8与R9连接在一起，形成一个C4-8环烷基或4-8元杂环烷基，所述C4-8环烷基和4-8元杂环烷基任选被1、2或3个R取代；Or R 8 and R 9 are linked together to form a C 4-8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C 4-8 cycloalkyl and 4-8 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
    R10选自H或C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1- 6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代；R 10 is selected from H or C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
    R11选自C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基或3-10元杂环烷基，所述C1-6烷基、C3-6环烷基、C6-10芳基、5-10元杂芳基、C1-6杂烷基和3-10元杂环烷基任选被1、2或3个R取代；R 11 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
    x选自0、1、2或3；环A选自苯基或5-10元杂芳基；x is selected from 0, 1, 2 or 3; Ring A is selected from phenyl or 5-10 membered heteroaryl;
    环B、环C分别独立地选自苯基、5-10元杂芳基、苯并C5-6环烷基、苯并5-7元杂环烷基、5-6元杂芳基并C5-6环烷基或5-6元杂芳基并5-6元杂环烷基； Ring B and Ring C are each independently selected from phenyl, 5-10 membered heteroaryl, benzo C 5-6 cycloalkyl, benzo 5-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C 5-6 cycloalkyl or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;
    R分别独立地选自H、卤素、＝O、OH、NH2、CN、C1-6烷基、C1-6杂烷基、C3-6环烷基或3-6元杂环烷基，所述C1-6烷基、-C1-6烷基-OH、C3-6杂烷基、C3-6环烷基、C3-6杂环烷基、C1-6烷基-C(＝O)-、C1-6烷基-C(＝O)O-、C1-6烷基-O-C(＝O)-、C1-6烷基-C(＝O)NH-、C1-6烷基-NH-C(＝O)-、C1-6烷基-S(＝O)2-、C1-6烷基-S(＝O)2NH-、C1-6烷基-NHS(＝O)2-、C1-6烷氧基、C1-6烷硫基和C1-6烷氨基任选被1、2或3个R’取代；R is independently selected from H, halogen, =O, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, -C 1-6 alkyl-OH, C 3-6 heteroalkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 1-6 alkyl-C(═O)—, C 1-6 alkyl -C(═O)O—, C 1-6 alkyl-OC(═O)—, C 1-6 alkyl-C(═O)NH—, C 1-6 alkyl-NH—C(═O)—, C 1-6 alkyl-S(═O) 2 —, C 1-6 alkyl-S(═O) 2 NH—, C 1-6 alkyl-NHS(═O) 2 —, C 1-6 alkoxy, C 1-6 alkylthio and C 1-6 alkylamino are optionally substituted by 1, 2 or 3 R′;
    R’选自F、Cl、Br、I、OH、NH2、CN、CH3、CH2F、CHF2和CF3；R' is selected from F, Cl, Br, I, OH, NH2 , CN, CH 3 , CH 2 F, CHF 2 and CF 3 ;
    上述杂芳基、杂烷基或杂环烷基包含1、2或3个独立选自O、NH、S、C(＝O)、C(＝O)O、C(＝O)NH、S(＝O)、S(＝O)2、S(＝O)2NH和N的杂原子或杂原子团；The above heteroaryl, heteroalkyl or heterocycloalkyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(═O), C(═O)O, C(═O)NH, S(═O), S(═O) 2 , S(═O) 2 NH and N;
    且式(I)化合物不选自：
    And the compound of formula (I) is not selected from:
  2. 根据权利要求1所述化合物、其光学异构体及其药效上可接受的盐，其中，R分别独立地选自H、卤素、OH、NH2、CN、＝O、C1-3烷基、C3-6环烷基、C1-3烷基-C(＝O)-、C1-3烷基-S(＝O)2-、C1-3烷基-C(＝O)O-、C1-3烷氧基、C1-3烷硫基或C1-3烷氨基，所述C1-3烷基、C3-6环烷基、C1-3烷基-C(＝O)-、C1-3烷基-S(＝O)2-、C1-3烷基-C(＝O)O-、C1-3烷氧基、C1-3烷硫基和C1-3烷氨基任选被1、2或3个R’取代。The compound according to claim 1, its optical isomers and pharmaceutically acceptable salts thereof, wherein R is independently selected from H, halogen, OH, NH 2 , CN, =O, C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C(=O)-, C 1-3 alkyl-S(=O) 2 -, C 1-3 alkyl-C(=O)O-, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 alkylamino, said C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl-C(=O)-, C 1-3 alkyl-S(=O) 2 -, C 1-3 alkyl-C(=O)O-, C 1-3 alkoxy, C 1-3 alkylthio and C 1-3 alkylamino are optionally substituted by 1, 2 or 3 R'.
  3. 根据权利要求2所述化合物、其光学异构体及其药效上可接受的盐，其中，R分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、＝O、CH3、CH2F、CHF2、CF3、 The compound according to claim 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, ＝O, CH3 , CH2F , CHF2 , CF3 ,
  4. 根据权利要求1～3任意一项所述化合物、其光学异构体及其药效上可接受的盐，其中，R1、R2分别独立地选自C1-3烷基或C1-3烯基，所述C1-3烷基和C1-3烯基任选被1、2或3个R取代。The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are independently selected from C 1-3 alkyl or C 1-3 alkenyl, and the C 1-3 alkyl and C 1-3 alkenyl are optionally substituted by 1, 2 or 3 R.
  5. 根据权利要求4所述化合物、其光学异构体及其药效上可接受的盐，其中，R1、R2分别独立地选自Me、 The compound according to claim 4, its optical isomers and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are independently selected from Me,
  6. 根据权利要求1～3任意一项所述化合物、其光学异构体及其药效上可接受的盐，其中，R1与R2连接在一起，形成环所述任选被1、2或3个R取代。The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein R1 and R2 are connected together to form a ring Said Optionally substituted with 1, 2 or 3 R.
  7. 根据权利要求6所述化合物、其光学异构体及其药效上可接受的盐，其中，R1与R2连接在一起，形成环 The compound according to claim 6, its optical isomers and pharmaceutically acceptable salts thereof, wherein R1 and R2 are connected together to form a ring
  8. 根据权利要求1～3任意一项所述化合物、其光学异构体及其药效上可接受的盐，其中，R3、R4、R5分别独立地选自H、CN、F、Cl、Br、OH、NH2、CN、C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、 C2-3烯基-O-、C2-3烯基-S-、C2-3烯基-NH-、C3-6环烷基-O-、C3-6环烷基-S-、C3-6环烷基-NH-或氧杂环丙烷基-O-，所述C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、C3-6环烷基-O-、C3-6环烷基-S-、C3-6环烷基-NH-和氧杂环丙烷基-O-任选被1、2或3个R取代。The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein R 3 , R 4 and R 5 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkyl-O-, C 1-3 alkyl-S-, C 1-3 alkyl-NH-, C2-3 alkenyl-O—, C2-3 alkenyl-S—, C2-3 alkenyl-NH—, C3-6 cycloalkyl-O—, C3-6 cycloalkyl-S—, C3-6 cycloalkyl-NH— or oxirane-O—, said C1-3 alkyl, C1-3 alkyl-O—, C1-3 alkyl-S—, C1-3 alkyl-NH—, C3-6 cycloalkyl-O—, C3-6 cycloalkyl-S—, C3-6 cycloalkyl-NH— and oxirane-O— are optionally substituted by 1 , 2 or 3 R.
  9. 根据权利要求8所述化合物、其光学异构体及其药效上可接受的盐，其中，R3、R4、R5分别独立地选自H、CN、F、Cl、Br、OH、NH2、CN、Me、 所述Me、任选被1、2或3个R取代。The compound according to claim 8, its optical isomers and pharmaceutically acceptable salts thereof, wherein R 3 , R 4 and R 5 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, Me, The Me, Optionally substituted with 1, 2 or 3 R.
  10. 根据权利要求9所述化合物、其光学异构体及其药效上可接受的盐，其中，R3、R4、R5分别独立地选自H、CN、F、Cl、Br、OH、NH2、CN、Me、 The compound according to claim 9, its optical isomers and pharmaceutically acceptable salts thereof, wherein R 3 , R 4 and R 5 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , CN, Me,
  11. 根据权利要求1～3任意一项所述化合物、其光学异构体及其药效上可接受的盐，其中，R8、R9分别独立地选自H、CN、F、Cl、Br、OH、NH2、Me或 The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein R 8 and R 9 are independently selected from H, CN, F, Cl, Br, OH, NH 2 , Me or
  12. 根据权利要求1～3任意一项所述化合物、其光学异构体及其药效上可接受的盐，其中，R10选自H、Me、 The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein R 10 is selected from H, Me,
  13. 根据权利要求1～3任意一项所述化合物、其光学异构体及其药效上可接受的盐，其中，L2、L3分别独立地选自单键、-CH2-、-CH(CH3)-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-NH-、 The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein L2 and L3 are independently selected from a single bond, -CH2- , -CH( CH3 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) 2- , -NH-,
  14. 根据权利要求1～3任意一项所述化合物、其光学异构体及其药效上可接受的盐，其中，L4选自-CH2-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-NH-、 The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein L4 is selected from -CH2- , -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) 2- , -NH-,
  15. 根据权利要求1～3任意一项所述化合物、其光学异构体及其药效上可接受的盐，其中，环A选自苯基、吡啶基、嘧啶基、吡嗪基、噻唑基、噻吩基、恶唑基和哒嗪基。The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, oxazolyl and pyridazinyl.
  16. 根据权利要求15所述化合物、其光学异构体及其药效上可接受的盐，其中，结构单元选自 The compound according to claim 15, its optical isomers and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from
  17. 根据权利要求1～3任意一项所述化合物、其光学异构体及其药效上可接受的盐，其中，环B选自苯基、苯并环戊烷基、苯并环己烷基、吲哚基和螺[环丙烷-1,3'-二氢吲哚]-2'-酮基。The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein ring B is selected from phenyl, benzocyclopentyl, benzocyclohexyl, indolyl and spiro[cyclopropane-1,3'-dihydroindole]-2'-one.
  18. 根据权利要求17所述化合物、其光学异构体及其药效上可接受的盐，其中，结构单元选自 The compound according to claim 17, its optical isomers and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from
  19. 根据权利要求1所述化合物、其光学异构体及其药效上可接受的盐，其中，环C选自苯基、苯并环戊烷基、苯并环己烷基、1H-吲唑基、2H-吲唑基和1H-苯并[d]咪唑。The compound according to claim 1, its optical isomers and pharmaceutically acceptable salts thereof, wherein ring C is selected from phenyl, benzocyclopentyl, benzocyclohexyl, 1H-indazolyl, 2H-indazolyl and 1H-benzo[d]imidazole.
  20. 根据权利要求10或19所述化合物、其光学异构体及其药效上可接受的盐，其中，结构单元选自 The compound according to claim 10 or 19, its optical isomers and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from
  21. 下式化合物、其光学异构体及其药效上可接受的盐，其选自：


    The compound of the following formula, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from:


  22. 根据权利要求1-21任一项所述化合物、其光学异构体或其药学上可接受的盐在制备治疗与雄激素受体(AR)活性或表达量相关疾病的药物中的用途。Use of the compound according to any one of claims 1 to 21, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with androgen receptor (AR) activity or expression.
  23. 根据权利要求22所述雄激素受体(AR)活性或表达量相关疾病，其选自前列腺癌、卵巢癌、乳腺癌、膀胱癌、胰腺癌、子宫内膜癌、肝细胞癌、肾细胞癌、黑色素瘤、套细胞淋巴瘤、胶质母细胞瘤、唾液腺癌、脱发、痤疮、多毛症、卵巢囊肿、多囊卵巢疾病、性早熟、脊髓和延髓肌肉萎缩和年龄相关性黄斑病变。 According to claim 22, the disease related to androgen receptor (AR) activity or expression is selected from prostate cancer, ovarian cancer, breast cancer, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, renal cell carcinoma, melanoma, mantle cell lymphoma, glioblastoma, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy and age-related macular degeneration.
PCT/CN2023/122463 2022-09-28 2023-09-28 Phosphorus-containing compound, and preparation method therefor and pharmaceutical use thereof WO2024067783A1 (en)

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