WO2024067783A1 - Composé contenant du phosphore, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Composé contenant du phosphore, son procédé de préparation et son utilisation pharmaceutique 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
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alkyl
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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

L'invention concerne un composé représenté par la formule (I), un isomère optique de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, et l'utilisation du composé en tant qu'inhibiteur du récepteur aux androgènes (RA).
PCT/CN2023/122463 2022-09-28 2023-09-28 Composé contenant du phosphore, son procédé de préparation et son utilisation pharmaceutique WO2024067783A1 (fr)

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CN116265453A (zh) * 2021-12-17 2023-06-20 南京圣和药业股份有限公司 作为ar抑制剂的化合物及其应用
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