WO2023151662A1 - Androgen receptor activity regulator and use thereof - Google Patents

Androgen receptor activity regulator and use thereof Download PDF

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Publication number
WO2023151662A1
WO2023151662A1 PCT/CN2023/075450 CN2023075450W WO2023151662A1 WO 2023151662 A1 WO2023151662 A1 WO 2023151662A1 CN 2023075450 W CN2023075450 W CN 2023075450W WO 2023151662 A1 WO2023151662 A1 WO 2023151662A1
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optionally substituted
alkyl
pharmaceutically acceptable
compound
acceptable salt
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PCT/CN2023/075450
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French (fr)
Chinese (zh)
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郑乾刚
江相清
李靖
曾庆龙
许明
陈耀忠
钟晓峰
李果
朱继东
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上海奕拓医药科技有限责任公司
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Priority to CN202380021245.XA priority Critical patent/CN118715210A/en
Publication of WO2023151662A1 publication Critical patent/WO2023151662A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/46—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom
    • C07D333/48—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • 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
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to an androgen receptor activity modulator and its application.
  • Prostate cancer is an epithelial malignant tumor that occurs in the prostate gland, and is one of the most common malignant tumors in the male genitourinary system.
  • the incidence of prostate cancer varies widely around the world, and the incidence of Asians is much lower than that of Europeans and Americans. In the United States, the incidence of prostate cancer ranks first among all malignant tumors in men, and the mortality rate is second only to lung cancer. Among them, metastatic prostate cancer is particularly malignant, and the 5-year survival rate is only 30%.
  • Androgen deprivation therapy alone or in combination with chemotherapy is usually used as the initial treatment for metastatic prostate cancer.
  • Standard approaches to ADT include bilateral orchiectomy, or medical castration with a gonadotropin-releasing hormone agonist alone or in combination with an antiandrogen.
  • the initial remission rate is 80%-90%, almost all patients will eventually progress after ADT, which is called castration-resistant prostate cancer (CRPC).
  • Androgen receptor plays a very important role in maintaining the function of the prostate and promoting the formation of prostate cancer, and it is also an important target in the drug treatment of prostate cancer.
  • the functional domains of AR include carboxy-terminal ligand-binding domain (LBD), DNA-binding domain (DBD) and N-terminal domain (NTD), which can regulate the expression of various genes.
  • LBD carboxy-terminal ligand-binding domain
  • DBD DNA-binding domain
  • NTD N-terminal domain
  • AR inhibitors include nonsteroidal antiandrogens targeting the AR LBD domain, such as bicalutamide, nilutamide, flutamide, and enzalutamide, and steroid antiandrogens such as Cyproterone acetate and spironolactone.
  • AR-Vs AR splice variants
  • LBD domain activation mutations AR-Vs lacked the carboxy-terminal LBD domain, but retained the NTD and DBD domains, It can be stimulated into the nucleus independently of androgen to activate the transcription of downstream target genes.
  • AR-V7 is the most common in clinical samples.
  • the expression level of AR-V7 showed a significant upward trend with the progression of CRPC, and CRPC patients expressing AR-V7 were not sensitive to new endocrine therapy drugs (such as abiraterone or enzalutamide).
  • AR-Vs has been confirmed to be closely related to the occurrence and development of CRPC in more and more studies, but so far no drug targeting AR-Vs has been approved for marketing. All AR-Vs retain the NTD domain, which contains a transcriptional activation domain (activation function-1, AF-1) that can interact with a variety of transcriptional co-regulatory factors (cofactors) and is critical for the transcriptional activity of AR . Therefore, inhibitors targeting the AR NTD domain can simultaneously inhibit the transcriptional activity of AR full-length and spliced variants, which is expected to become a new therapeutic strategy to overcome CRPC.
  • activation function-1 activation function-1
  • the invention provides the compound shown in following formula 1-I:
  • Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • X is C, N, O or S
  • R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
  • R and R are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, Optionally substituted alkoxy or -NR a R a , or R and R together with X form an optionally substituted
  • R and R are each independently H, halogen, cyano, oxo , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally Substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b ;
  • Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a - or -(CH 2 ) r -NR a -CO-;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y 2 is a bond, O, NH or S, "*" indicates the connection point between Z 2 and ring A, "**” indicates the connection point between Z 2 and ring C;
  • Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g ;
  • each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
  • R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -NR a R a ; or R c , R d together with the S atom to which they are attached Forming an optionally substituted 4-10 membered heterocyclyl;
  • R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • Each R g is independently H, -SO 2 R f , optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R g together with the N atoms to which they are attached form an optionally Substituted 4-10 membered heterocyclic group;
  • r 0, 1, 2 or 3;
  • s 0, 1, 2 or 3;
  • n and p are each independently 0, 1, 2 or 3.
  • the invention provides compounds represented by the following formula 2-I:
  • Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • X is C, N, O or S
  • R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
  • R 3 and R 4 are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH 2 ) r NR a R a OR -OR b ;
  • Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a - or -(CH 2 ) r -NR a -CO-;
  • R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR h R h ;
  • each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
  • R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a or -NR a R a ; or R c , R d are connected to them
  • the S atoms together form an optionally substituted 4-10 membered heterocyclic group
  • R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R g is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkane Base, optionally substituted 4-10 membered heterocyclic group or -NR h R h ;
  • R h are each independently H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered Heterocyclyl;
  • r 0, 1, 2 or 3;
  • s 0, 1, 2 or 3;
  • n and p are each independently 0, 1, 2 or 3.
  • the present invention provides a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound of formula 1-I or 2-I of the present invention or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition may also contain pharmaceutically acceptable carrier.
  • the present invention provides a compound of formula 1-I or 2-I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for treating androgen receptor-mediated diseases It also provides the compound of formula 1-I or 2-I of the present invention or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention for treating diseases mediated by androgen receptor.
  • the present invention provides a method for treating or preventing an androgen receptor-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1-I or 2-I of the present invention, Its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof.
  • the present invention provides a method for treating or preventing diseases mediated by androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I or 2-I of the present invention
  • Formula 1-I or 2-I of the present invention Compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or pharmaceutical combinations thereof things.
  • the present invention provides a method of treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of a formula of the present invention 1-I or 2-I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs Or metabolites or pharmaceutical compositions thereof.
  • AR-Vs androgen receptor splice variants
  • the present invention provides a method for treating or preventing an AR-V7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1-I or 2-I of the present invention, its Pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs Forms, prodrugs or metabolites or pharmaceutical compositions thereof.
  • the present invention provides a method of treating or preventing diseases mediated by androgen receptor and androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I of the present invention or 2-I compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or its pharmaceutical composition.
  • the present invention provides a method of treating or preventing diseases mediated by androgen receptor and androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of The compound of formula 1-I or 2-I of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, solvate, isotope substitution, polymorphic form Drugs, prodrugs or metabolites or pharmaceutical compositions thereof.
  • AR-Vs androgen receptor and androgen receptor splice variants
  • the present invention provides a method for treating or preventing diseases mediated by androgen receptor and AR-V7, said method comprising administering to a subject in need a therapeutically effective amount of Formula 1-I or 2 of the present invention -I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical composition.
  • the present invention provides a method for treating or preventing diseases mediated by androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I or 2-I of the present invention
  • Formula 1-I or 2-I of the present invention Compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or pharmaceutical combinations thereof things.
  • the present invention provides a method of treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of a formula of the present invention 1-I or 2-I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs Or metabolites or pharmaceutical compositions thereof.
  • AR-Vs androgen receptor splice variants
  • the present invention provides a method for treating or preventing an AR-V7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1-I or 2-I of the present invention, its Pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof.
  • linking substituents are described in various places in this application. If the structure clearly requires a linking group, the Markush changes listed for that group are to be understood as linking groups. For example, if a structure requires a linking group and the Markush group definition for that variable lists “alkyl,” then “alkyl” is understood to represent a linking alkylene.
  • Cyano refers to a -CN group.
  • Halogen refers to a fluoro, chloro, bromo or iodo group.
  • Haldroxy means an -OH group.
  • C i -C j denotes a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer point in between , where j is greater than i.
  • C 1 -C 6 represents a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms and 6 carbon atoms.
  • the term “C 1 -C 12” means 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3 or especially 1 to 2 carbon atoms.
  • alkyl refers to a fully saturated straight or branched hydrocarbon chain group connected by a single bond to the rest of the molecule.
  • Ci - Cj alkyl refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms.
  • the alkyl group contains 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms , 1 to 4 carbon atoms, 1 to 3 carbon atoms or 1 to 2 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Unless specifically stated otherwise in this specification, an alkyl group may be optionally substituted.
  • alkenyl groups contain 2 to 12 carbon atoms.
  • alkenyl groups contain 2 to 11 carbon atoms.
  • alkenyl contains 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms , 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms.
  • alkenyl examples include vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butene Base, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-heptenyl, 5-heptenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- Octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-octenyl Nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 2-
  • alkynyl refers to a straight or branched hydrocarbon chain group having one or more carbon-carbon triple bonds (-C ⁇ C-). In some embodiments, alkynyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms , 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms.
  • alkynyl examples include ethynyl, propynyl, butynyl, pentynyl, and the like. Unless specifically stated otherwise in this specification, an alkynyl group may be optionally substituted.
  • cycloalkyl as a group or part of another group, means a stable non-aromatic monocyclic or polycyclic hydrocarbon group (such as alkyl, alkenyl, group or alkynyl), which may be attached to the rest of the molecule by a single bond via any suitable carbon atom.
  • the carbon atoms in the cycloalkyl group can be optionally oxidized, and the cycloalkyl group can be optionally substituted.
  • cycloalkyl groups may contain from 3 to 12 ring carbon atoms, from 3 to 10 ring carbon atoms, from 3 to 9 ring carbon atoms, from 3 to 8 ring carbon atoms, from 3 to 7 ring carbon atoms, 3 to 6 ring carbon atoms, 3 to 5 ring carbon atoms, 4 to 12 ring carbon atoms, 4 to 10 ring carbon atoms, 4 to 9 ring carbon atoms , 4 to 8 ring carbon atoms, 4 to 7 ring carbon atoms, 4 to 6 ring carbon atoms, 4 to 5 ring carbon atoms.
  • the cycloalkyl group may be a non-aromatic monocyclic hydrocarbon group, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopentyl -2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexyl Hexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • cycloalkyl groups can be non-aromatic polycyclic (eg, bicyclic and tricyclic) hydrocarbon groups, which can be fused, spiro, or bridged ring systems.
  • fused ring means a ring system having two rings sharing two adjacent atoms
  • spiro means a ring system having two rings joined by a single common atom
  • bridged ring refers to a ring system having two rings that share three or more atoms.
  • fused cycloalkyls include, but are not limited to, H-indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro -Naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8 ,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2 .1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo [3. [
  • spirocyclyl groups include, but are not limited to, spiro[5.5]undecyl, spiro-pentadienyl, spiro[3.6]-decyl, and the like.
  • bridged ring groups include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl , Bicyclo[3.3.1]nonyl, bicyclo[3.3.3]undecane, etc.
  • heterocyclyl as a group or part of another group, means a group consisting of carbon atoms (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13 or 14 carbon atoms) and a stable non-aromatic cyclic group consisting of heteroatoms (eg, 1 to 6 heteroatoms) selected from nitrogen, phosphorus, oxygen and sulfur.
  • a heterocyclyl group can contain from 3 to 20 ring-forming atoms, from 3 to 19 ring-forming atoms, from 3 to 18 ring-forming atoms, from 3 to 17 ring-forming atoms, from 3 to 16 ring-forming atoms , 3 to 15 ring-forming atoms, 4 to 12 ring-forming atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming atoms, 4 to 8 ring-forming atoms, 4 to 7 ring-forming atoms, 4 to 6 ring atoms, 4 to 5 ring atoms.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system.
  • the nitrogen, carbon or sulfur atoms in the heterocyclyl group can be optionally oxidized and the nitrogen atoms can be optionally quaternized.
  • a heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond.
  • a heterocyclyl group can be carbon-, nitrogen-, or sulfur-linked.
  • the heterocyclyl is carbon attached.
  • the heterocyclyl is nitrogen-linked.
  • the heterocyclyl is sulfur-linked.
  • Heterocyclyl also includes groups in which a heterocyclyl group is fused to a saturated, partially unsaturated, or fully unsaturated (ie, aromatic) carbocyclic or heterocyclic ring.
  • a heterocyclyl group comprising fused rings, one or more rings may be aryl or heteroaryl as defined below.
  • fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, e.g.
  • quinolinyl isoquinolinyl, quinoxalinyl, quinazinyl, quinazolinyl, azaindorazinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolinyl Indolyl, indorazinyl, indazolyl, purinyl, benzofuryl, isobenzofuryl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phen Thiazinyl, phenanthridinyl, imidazo[1,2-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,3]triazolo [4,3-a]pyridyl, etc.
  • the heterocyclyl group is a stable 4- to 12-membered, 5- to 12-membered, or 4- to 10-membered non-aromatic unit comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Cyclic, bicyclic, bridged or spirocyclic groups for example stable 5- to 10-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonyl Alkane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, aza Cyclobutanyl, oxetanyl, thietanyl, thiolanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxane Amyl, imidazolidinyl, imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, pyrrol
  • aryl refers to a group having 6 to 18 carbon atoms (eg 6 to 14 carbon atoms or 6 to 10 carbon atoms, eg , 9 or 10 carbon atoms) conjugated hydrocarbon ring system group.
  • Aryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system and can also be fused to a cycloalkyl or heterocyclyl as defined above. In the case of multiple ring systems, only one ring needs to be aromatic, although all rings may be aromatic.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazin-3(4H)-on-7-yl and the like. Unless specifically stated otherwise in this specification, the term "aryl" includes optionally substituted aryl groups.
  • heteroaryl as a group or part of another group, means a ring having carbon atoms (for example, 1 to 15 carbon atoms, 1 to 14 carbon atoms, 1 to 13 carbon atoms , 1 to 12 carbon atoms, 1 to 11 carbon atoms, 1 to 10 carbon atoms, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms) and selected from nitrogen , oxygen and sulfur heteroatoms (eg 1 to 6 heteroatoms) conjugated ring system groups.
  • carbon atoms for example, 1 to 15 carbon atoms, 1 to 14 carbon atoms, 1 to 13 carbon atoms , 1 to 12 carbon atoms, 1 to 11 carbon atoms, 1 to 10 carbon atoms, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms
  • nitrogen , oxygen and sulfur heteroatoms eg 1 to 6 heteroatoms
  • the heteroaryl group can contain from 5 to 20 ring-forming atoms, from 5 to 19 ring-forming atoms, from 5 to 18 ring-forming atoms, from 5 to 17 ring-forming atoms, from 5 to 16 ring-forming atoms, 5 to 15 ring atoms, 5 to 14 ring atoms, 5 to 13 ring atoms, 5 to 12 ring atoms, 5 to 10 ring carbon atoms, 5 to 9 ring atoms, 5 to 8 ring atoms, 5 to 7 ring atoms, or 5 to 6 ring atoms.
  • heteroaryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and can also be fused with a cycloalkyl or heterocyclyl as defined above.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized, and the nitrogen atoms can be optionally quaternized.
  • heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 heteroatoms selected from A stable 5- to 10-membered aromatic group of heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl, Benzimidazolyl, Benzmorpholinyl, Benzisodiazolyl, Benzotriazolyl, Imidazopyridinyl, Pyridomorpholinyl, Pyrazolopyridinyl, Indolyl, Furanyl Base, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolyl, diazine Base, naphthyridinyl, quinoxalinyl, iso
  • substituted means that one or more hydrogens of the specified moiety are replaced by a suitable substituent. It will be understood that “substituted” or “substituted by” includes the implied proviso that such substitutions are made according to the permissible valences of the substituting atoms and that the substitutions result in stable or chemically feasible compounds, e.g. A compound that undergoes transformation spontaneously by rearrangement, cyclization, elimination, etc.
  • an "optionally substituted” group may have suitable substitutions at each substitutable position of the group and when more than one position in any given structure may be substituted with one or more substituents selected from a specified group, the substituents may be the same or different at each position.
  • substituents themselves may be substituted, as appropriate.
  • references to chemical moieties herein are understood to include substituted variants.
  • reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variations.
  • substituents described in this application include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, Cyano, hydroxy, amino, monoalkylamino, dialkylamino, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl etc.; these groups as substituents include alkyl, alkenyl, alkynyl, alkyl in haloalkyl, alkenyl in haloalkenyl, alkynyl in haloalkynyl, alkoxy, mono The alkyl group in the alkylamino group, the alkyl group in the dialkylamino group, the aryl group, the heteroaryl group, the cyclohydrocarbyl group and the heterocyclyl group can also
  • the number of substituents can be one or more, ie 1, 2, 3, 4, 5 or 6 or more, depending on the group to be substituted and the nature of the substituent.
  • the substituent is halogen
  • the group may be substituted by 1-6 substituents, such as trifluoromethyl, pentafluoroethyl, etc., according to the structure of the substituted group.
  • moiety As used herein, the terms “moiety”, “structural moiety”, “chemical moiety”, “group”, “chemical group” refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules.
  • the functional groups of intermediate compounds may need to be protected by appropriate protecting groups.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl esters, aryl esters or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, TW and PGMWuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., in Wiley.
  • the protecting group can also be a polymeric resin.
  • a "subject” can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, and the like.
  • Subjects may be suspected to have or are suffering from such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, intrauterine Cancers such as menstrual carcinoma, salivary gland cancer, or suspected or at risk of alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration middle.
  • prostate cancer breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial cancer
  • Diagnostic methods for various cancers such as salivary gland cancer, and for alopecia, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration
  • prostate cancer breast cancer Clinical depiction of cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, Diagnosis and clinical delineation of hirsutism, ovarian cysts, polycystic ovary disease, precocious pu
  • “Mammal” includes: humans; domestic animals, such as laboratory animals and household pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals, etc.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by, for example, the U.S. Food and Drug Administration (FDA) for use in humans or domesticated animals , glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
  • FDA U.S. Food and Drug Administration
  • the compounds disclosed herein may exist in many different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, geometric isomers, salts, prodrugs, solvates, different crystal forms or polymorphs, and active metabolites.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetic acid salt, trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, caproate Dialate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleic acid Salt, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine,
  • prodrugs of the compounds of the present application may include simple esters of compounds containing carboxylic acids (for example, esters obtained by condensation with C 1-4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (for example, according to this invention art-known methods; esters obtained by condensation with C 1-4 carboxylic acids, C 3-6 diacids or their anhydrides such as succinic anhydride and fumaric anhydride); imines of compounds containing amino groups (e.g. according to art-known Process imines obtained by condensation with C 1-4 aldehydes or ketones); carbamates of compounds containing amino groups, such as Leu et al.
  • carboxylic acids for example, esters obtained by condensation with C 1-4 alcohols according to methods known in the art
  • esters of compounds containing hydroxyl groups for example, according to this invention art-known methods; esters obtained by condensation with C 1-4 carboxylic acids, C 3-6 diacids or their anhydrides such as succinic anhydride and fum
  • solvate refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the invention may exist as hydrates, including Including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as existing as corresponding solvated forms.
  • the compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may retain only the adventitious water or a mixture of water plus some adventitious solvent.
  • stereoisomer refers to a compound composed of the same atoms bonded by the same bond, but having a different three-dimensional structure. This application will cover the various stereoisomers and mixtures thereof.
  • the compounds of the present application are intended to include both E- and Z-geometric isomers.
  • Tautomer refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the application are also intended to be encompassed within the scope of the application.
  • Compounds of the present application may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as I- or (S)- based on stereochemistry.
  • This application is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the preparation of the compounds of the present application can select racemates, diastereomers or enantiomers as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • the present invention also includes all suitable isotopic variations of the compounds of the present invention or pharmaceutically acceptable salts thereof.
  • Isotopic variations of a compound of the present invention, or a pharmaceutically acceptable salt thereof are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from that normally found in nature.
  • Isotopes that may be incorporated into compounds of the present invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F, 36 Cl, and 125 I.
  • Isotopic variants of the compounds of the present invention or pharmaceutically acceptable salts thereof can be obtained by conventional techniques, Prepared using appropriate isotopic variants of appropriate reagents.
  • each structural formula or group generally indicates the position where the structural formula or group is connected to other parts in the compound.
  • crystal form and “polymorph” are used interchangeably and mean that a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements (all having the same elemental composition) crystal structure.
  • Different crystal forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate.
  • Polymorphs of a compound can be prepared by crystallization under different conditions.
  • active metabolite is a pharmacologically active compound or a compound that is further metabolized to a pharmacologically active compound that is a derivative produced by a metabolic process in a subject.
  • metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug.
  • the active metabolite is the pharmacologically active derivative compound.
  • a “pharmaceutical composition” refers to a formulation of a compound of the invention and an art-recognized vehicle for the delivery of a biologically active compound to a mammal (eg, a human).
  • a mammal eg, a human
  • Such medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • Effective amount refers to a therapeutically effective amount or a prophylactically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as decreased tumor size, increased lifespan, or increased life expectancy.
  • a therapeutically effective amount of a compound can vary depending on factors such as the disease state, age, sex and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount means an amount effective, at doses and for periods of time necessary, to achieve the desired prophylactic result (e.g., smaller tumors, increased lifespan, increased life expectancy, or prevention of progression of prostate cancer to a castration-resistant form). quantity.
  • a prophylactic dose is administered to a subject before or at an early stage of the disease, such that the prophylactically effective amount may be less than the therapeutically effective amount.
  • treatment encompasses the treatment of a disease or condition of interest in a mammal, preferably a human, suffering from the disease or condition of interest, and includes:
  • administering refers to methods capable of delivering a compound or composition to the desired site of biological action.
  • Administration methods known in the art can be used in the present invention. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), Topical and rectal administration.
  • the compounds of formula I of the present invention their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, and isotopic substitutions are administered orally , polymorph, prodrug or metabolite or pharmaceutical composition thereof.
  • combination refers to drug therapy obtained by mixing or combining more than one active ingredient, which includes fixed and unfixed active ingredients Combination, or the combination of two or more different treatments.
  • fixed combination refers to the simultaneous administration to a patient of at least one compound described herein and at least one co-agent in the form of a single entity or single dosage form.
  • variable combination refers to simultaneous, concomitant or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent as separate entities to a patient. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
  • the application provides the compound shown in the following formula 1-I:
  • Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • X is C, N, O or S
  • R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
  • R and R are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, Optionally substituted alkoxy or -NR a R a , or R 1 and R 2 together with X form optionally substituted
  • R and R are each independently H, halogen, cyano, oxo , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally Substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b ;
  • Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a -, or -(CH 2 ) r -NR a -CO-;
  • R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y 2 is a bond, O, NH or S, "*" indicates the connection point between Z 2 and ring A, "**” indicates the connection point between Z 2 and ring C;
  • Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g ;
  • each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
  • R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -NR a R a ; or R c , R d together with the S atom to which they are attached Forming an optionally substituted 4-10 membered heterocyclyl;
  • R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • Each R g is independently H, -SO 2 R f , optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R g together with the N atoms to which they are attached form an optionally Substituted 4-10 membered heterocyclic group;
  • r 0, 1, 2 or 3;
  • s 0, 1, 2 or 3;
  • n and p are each independently 0, 1, 2 or 3.
  • Ring A is aryl. In certain embodiments, Ring A is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring A is phenyl or naphthyl. In certain embodiments, Ring A is phenyl.
  • Ring A is heteroaryl. In certain embodiments, Ring A is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • ring A is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazole group, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl or pyrazinyl.
  • Ring A is pyridyl, pyrimidinyl or thienyl. In certain embodiments, Ring A is pyridyl.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring B is aryl. In certain embodiments, Ring B is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring B is phenyl or naphthyl.
  • Ring B is heteroaryl. In certain embodiments, Ring B is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • Ring B is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl, furyl, pyrrolyl, triazolyl, triazinyl, pyridonyl, benzomorpholinyl, pyridomorpholinyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridine Base, benzotriazolyl, benzimidazolyl, tetrahydroisoquinolyl, imidazopyridyl, pyridomorpholinyl, benzisodiazolyl, indolyl, quinolinyl, isoquinolyl , quinazolinyl, quinoxalinyl, decahydroisoquinolyl, indolinyl, octahydroindolyl
  • Ring B is selected from pyridyl, pyridonyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridyl, benzomorpholinyl, pyridomorpholinyl, benzo Triazolyl, benzimidazolyl, tetrahydroisoquinolinyl, imidazopyridinyl or pyridomorpholinyl.
  • Ring C is a bond.
  • Ring C is cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • Ring C is aryl or heteroaryl.
  • Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
  • Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • Ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, Pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
  • Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl.
  • X is N, O, or S, and R and R are absent.
  • X is C, and R and R are each independently H, hydroxyl, or optionally substituted alkyl .
  • X is C, and R and R are both optionally substituted alkyl optionally replaced by one or more independently selected from halogen, hydroxy, cyano Substituent group and -NR a R a substituent.
  • X is C, and R 1 and R 2 are each independently optionally substituted C 1 -C 4 alkyl.
  • X is C and R and R are both methyl.
  • X is C, one of R and R is optionally substituted alkyl, the other is H or hydroxy, and the optionally substituted alkyl is optionally replaced by one or Substituents independently selected from halogen, hydroxy, cyano and -NR a R a are substituted.
  • X is C
  • one of R and R is optionally substituted C 1 -C 4 alkyl
  • the other is H or hydroxyl
  • the optionally substituted C 1 - C4alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NRaRa .
  • X is C, and one of R and R is methyl and the other is hydroxy.
  • X is C, and R and R are taken together with X to form an optionally substituted
  • X is C, and R and R together form X
  • R and R are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( CH ) r NR a R a or -OR b .
  • each R3 is independently H, halo, optionally substituted alkyl, optionally substituted alkoxy, or -ORb .
  • each R3 is independently H, halo, optionally substituted alkyl, or -ORb .
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl or optionally substituted C 1 -C 4 alkoxy.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl or optionally substituted C 1 -C 4 alkoxy, said optionally substituted C 1 -C 4 alkyl and optionally substituted C 1 -C 4 alkoxy is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -NR a R a .
  • each R 3 is independently H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy.
  • each R 3 is independently selected from halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy.
  • each R3 is independently fluoro, chloro, methyl, methoxy.
  • R 3 is fluoro
  • R 3 is chloro
  • R 3 is methyl
  • R 3 is methoxy
  • R3 is H.
  • each R is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b , wherein R a is each independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted Alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally represented by one or more independently Substituents selected from halogen, hydroxyl, cyano and -NR a R a .
  • each R4 is independently H, halo, cyano, oxo, cyclopropyl, -( CH2 ) rNRaRa , or -ORb , wherein each Ra is independently H, any Optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
  • each R4 is independently H, chloro, cyano, oxo, or -OCH3 .
  • Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
  • Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
  • Z 1 is a bond, -O-, -CO-, or -NR a -, wherein R a is H or optionally substituted C 1 -C 4 alkyl.
  • Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
  • Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, or -NR a -.
  • Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, or -NR a -, wherein each R a is independently H, Optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -COR b .
  • Z 1 is a bond, -O- or -CO-
  • R 5 is H, optionally substituted C 1 -C 4 alkyl, said optionally substituted C 1 -C 4 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR a R a .
  • Z 1 is a bond, -O-, -CO-, or -NR a -, wherein R a is H or optionally substituted alkyl.
  • Z is a bond, -O-, -CO-, -NH- or -NHCO-.
  • Z is a bond, -O- or -CO-.
  • R 5 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, any Optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxy, Substituted by cyano and -NR a R a substituents.
  • R is H, optionally substituted C 1 -C 4 alkyl, or optionally substituted C 2 -C 4 alkenyl
  • the optionally substituted C 1 -C 4 alkyl and optionally substituted C 2 -C 4 alkenyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.
  • R is H, methyl, ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine , Hydroxy or cyano substituents.
  • Z 1 is a bond or -O-
  • R 5 is H, optionally substituted C 1 -C 4 alkyl optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
  • Z is a bond or -O-
  • R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from halogen, hydroxy or cyano are substituted.
  • Z is a bond or -O-
  • R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from fluorine, chlorine or hydroxyl are substituted.
  • R 5 is optionally substituted C 2 -C 4 alkenyl, the optionally substituted
  • the C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
  • Z 1 is -CO-
  • R 5 is optionally substituted C 2 -C 4 alkenyl optionally replaced by one or more independently Substituents selected from halogen, hydroxyl, cyano or -NR a R a .
  • Z 1 is -C(O)- and R 5 is vinyl.
  • -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
  • Z 1 is a bond, -O- or -CO-
  • R 5 is H, optionally substituted C 1 -C 4 alkyl, and the optionally substituted C 1 -C 4 alkyl is any is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
  • Y 1 is a bond and Y 2 is O, NH or S.
  • Y 1 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl
  • Y 2 is a bond or O
  • said optionally substituted alkyl, optionally substituted Alkenyl or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, alkyl or oxo.
  • Y is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl
  • Y is a bond or O
  • the optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl is optionally substituted by one or more independently selected from halogen, hydroxy, cyano or oxo of substituents.
  • Y is optionally substituted alkyl or optionally substituted alkynyl
  • Y is a bond or O
  • optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano, alkyl or oxo.
  • Y is optionally substituted alkyl or optionally substituted alkynyl
  • Y is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or oxo.
  • Y 1 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkynyl
  • Y 2 is a bond or O, wherein optionally substituted C 1 -C 4 Alkyl and optionally substituted C 2 -C 4 alkynyl are optionally substituted with one or more substituents independently selected from hydroxy or oxo.
  • Y 1 is C 1 -C 4 alkyl optionally substituted with one or more substituents independently selected from hydroxy or oxo, and Y 2 is O.
  • Y 1 is C 2 -C 4 alkynyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo, and Y 2 is a bond.
  • Z is selected from -O-, **-(C 1-3 alkyl)-O-*, ethynyl or propynyl, wherein -(C 1-3 alkyl)-O-
  • the C 1-3 alkyl in is optionally substituted by one or more hydroxyl or oxo.
  • Z2 is **- CH2O- * or ethynyl.
  • R 6 is -N ⁇ S(O)R c R d
  • R c and R d are each independently selected from optionally substituted alkyl or -NR a R a , wherein each R a is independently H or optionally substituted alkyl.
  • R 6 is —N ⁇ S(O)R c R d , R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
  • R 6 is —N ⁇ S(O)R c R d , R c and R d are each independently methyl.
  • R 6 is
  • R 6 is -N ⁇ S(O)R c R d , one of R c and R d is optionally substituted C 1 -C 4 alkyl, and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
  • said Optionally substituted 4-6 membered heterocyclyl is optionally substituted by one or more Rh , wherein Rh is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkyne Group, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or an optionally substituted C 1 -C 4 alkyl group, the above-mentioned optionally substituted C 1 -C 4 alkyl group, optionally
  • R is selected from the group consisting of:
  • Rh is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 Cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O) R g , -C(O)NR a R a , -S(O) R f or -SO 2 R f , wherein R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkanes
  • the group is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR b , wherein R b is optionally substituted C 1
  • Rh is selected from the group consisting of C optionally substituted with one or more substituents independently selected from hydroxyl, halogen, cyano, or -O( C2 - C4alkynyl ). 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-9 membered heterocyclyl optionally substituted by one or more C 1 -C 4 alkyl, -NH 2.
  • R is selected from the group consisting of:
  • R 6 is —N ⁇ S(O)R c R d
  • ring C is a bond or heteroaryl
  • R e is H, cyano, or optionally substituted alkyl
  • R f is optionally substituted alkyl wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
  • R e is H, cyano, or optionally substituted C 1 -C 4 alkyl
  • R f is an optionally substituted C 1 -C 4 alkyl, wherein the optionally substituted C 1 -C 4 alkyl is optionally selected from one or more independently selected from halogen, hydroxyl, cyano or -NR a R The substituent of a is substituted.
  • ring C is aryl or heteroaryl.
  • each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
  • each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
  • the application provides compounds having the formula:
  • V and V are each independently N or CH;
  • Ring C is a bond, aryl or heteroaryl
  • Z 1 is a bond, -O-, -CO-, -NR a - or -(CH 2 ) r -NR a -CO-;
  • Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl or optionally substituted alkynyl, and Y 2 is a bond or O;
  • R and R are each independently hydroxyl or optionally substituted alkyl
  • R 3 is H, halogen or optionally substituted alkyl
  • Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -( CH2 ) rNR a R a or -OR b ;
  • R is optionally substituted alkyl or optionally substituted alkenyl
  • Each R 7 is independently halogen, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g ; each R a is independently H, any Select substituted alkyl or -COR b ;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
  • R is optionally substituted alkyl
  • Each R g is independently H, -SO 2 R f or optionally substituted alkyl; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
  • r, s, m, n and p are each independently 0, 1 or 2.
  • Ring C is a bond.
  • Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
  • Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
  • Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl.
  • R 1 and R 2 are each independently H, hydroxy, or optionally substituted alkyl.
  • both R and R are optionally substituted alkyl optionally substituted with one or more independently selected from halogen, hydroxy, cyano, and -NR a Substituent substituent of R a .
  • R 1 and R 2 are each independently optionally substituted C 1 -C 4 alkyl.
  • R 1 and R 2 are both methyl.
  • one of R and R is optionally substituted alkyl and the other is H or hydroxy, optionally substituted by one or more independently Substituents selected from halogen, hydroxy, cyano and -NR a R a are substituted.
  • one of R and R is optionally substituted C 1 -C 4 alkyl and the other is H or hydroxy, said optionally substituted C 1 -C 4 alkyl Optionally by one or more independently selected from halogen, hydroxyl, cyano and the substituent of -NR a R a is substituted.
  • one of R and R is methyl and the other is hydroxy.
  • R and R together with the carbon atom to which they are attached form an optionally substituted
  • R and R together with the carbon atom to which they are attached form
  • each R3 is independently H, halo, optionally substituted alkyl, or -ORb .
  • each R3 is independently H, or optionally substituted alkyl.
  • each R 3 is independently H, fluoro, chloro, optionally substituted C 1 -C 4 alkyl.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
  • each R3 is independently selected from halogen.
  • R 3 is fluoro
  • R 3 is chloro
  • R3 is H.
  • each R is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b , wherein R a is each independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted Alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally represented by one or more independently Substituents selected from halogen, hydroxyl, cyano and -NR a R a .
  • each R4 is independently H, halo, cyano, oxo, cyclopropyl, -( CH2 ) rNRaRa , or -ORb , wherein each Ra is independently H, any Optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
  • each R4 is independently H, chloro, cyano, oxo, cyclopropyl, or -OCH3 .
  • Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
  • Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
  • Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
  • R 5 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, any Optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxy, Substituted by cyano and -NR a R a substituents.
  • R 5 is H, optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and Optionally substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy or cyano.
  • R is H, methyl, ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine , Hydroxy or cyano substituents.
  • Z 1 is a bond or -O-
  • R 5 is H, optionally substituted C 1 -C 4 alkyl optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
  • Z is a bond or -O-
  • R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from halogen, hydroxy or cyano are substituted.
  • Z is a bond or -O-
  • R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from fluorine, chlorine or hydroxyl are substituted.
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-
  • R 5 is optionally substituted C 2 -C 4 alkenyl
  • said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
  • -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
  • Y 1 is a bond and Y 2 is O, NH or S.
  • Y is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl
  • Y is a bond or O
  • the optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl is optionally selected from one or more independently selected from halogen, hydroxy, cyano, alkyl Or oxo substituent substitution.
  • Y 1 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl
  • Y 2 is a bond or O
  • said optionally substituted alkyl, optionally substituted Alkenyl or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano or oxo.
  • Y is optionally substituted alkyl or optionally substituted alkynyl
  • Y is a bond or O
  • optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano, alkyl or oxo.
  • Y is optionally substituted alkyl or optionally substituted alkynyl
  • Y is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or oxo.
  • Y 1 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkynyl
  • Y 2 is a bond or O, wherein optionally substituted C 1 -C 4 Alkyl and optionally substituted C 2 -C 4 alkynyl are optionally substituted with one or more substituents independently selected from hydroxy or oxo.
  • Y 1 is C 1 -C 4 alkyl optionally substituted with one or more substituents independently selected from hydroxy or oxo, and Y 2 is O.
  • Y 1 is C 2 -C 4 alkynyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo, and Y 2 is a bond.
  • Z is selected from -O-, **-(C 1-3 alkyl)-O-*, ethynyl or propynyl, wherein -(C 1-3 alkyl)-O-
  • the C 1-3 alkyl in is optionally substituted by one or more hydroxyl or oxo.
  • Z2 is **- CH2O- * or ethynyl.
  • R c and R d are each independently selected from optionally substituted alkyl or -NR a Ra , wherein each R a is independently H or optionally substituted alkyl.
  • R c and R d are each independently selected from optionally substituted C 1 -C 4 alkyl or -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
  • R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
  • one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally Substituted C 1 -C 4 alkyl.
  • both Rc and Rd are -CH3- , or one of Rc and Rd is -CH3 and the other is -NHCH3 .
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl optionally replaced by one or a plurality of R h substitutions, wherein R h is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, - NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or an optionally substituted alkane
  • the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen, hydroxy, cyano and -OR b substituent substitution, wherein
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl optionally substituted by One or more R h substitutions, wherein R h is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, Optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl is optionally substituted by one
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
  • Rh is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 Cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O) R g , -C(O)NR a R a , -S(O) R f or -SO 2 R f , wherein R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, and -OR b , wherein R b is optionally substituted C 1 -C
  • Rh is selected from the group consisting of C optionally substituted with one or more substituents independently selected from hydroxyl, halogen, cyano, or -O( C2 - C4alkynyl ). 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-9 membered heterocyclyl optionally substituted by one or more C 1 -C 4 alkyl, -NH 2.
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
  • Ring C is a bond or heteroaryl.
  • each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
  • each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
  • the application provides compounds having the formula:
  • V 3 is N or CH
  • Ring C is a bond, aryl or heteroaryl
  • Ring D is heterocyclyl or heteroaryl
  • Z 1 is a bond, -O-, -CO-, -NR a - or -(CH 2 ) r -NR a -CO-;
  • Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl or optionally substituted alkynyl, Y 2 is a bond or O;
  • R and R are each independently hydroxyl or optionally substituted alkyl
  • R is H, halogen, optionally substituted alkyl or optionally substituted alkoxy
  • Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -( CH2 ) rNR a R a or -OR b ;
  • R is H, optionally substituted alkyl or optionally substituted alkenyl
  • Each R7 is independently halogen, cyano , optionally substituted alkyl, -ORa , -S(O) Rf , -SO2Rf , or -NRgRg ;
  • each R a is independently H, optionally substituted alkyl, or -COR b ;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
  • R is optionally substituted alkyl
  • Each R g is independently H, -SO 2 R f or optionally substituted alkyl; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
  • r, s, m, n and p are each independently 0, 1 or 2.
  • ring D is substituted with 1, 2, or 3 R 9 , R 9 is H, halogen, or optionally substituted alkyl.
  • Ring D is substituted with 1 , 2 or 3 R 9 selected from H, F, Cl, CH 3 and CF 3 .
  • Attachment to -Z 1 R 5 is through a saturated N atom on ring D.
  • Ring C is a bond.
  • Ring C is aryl or heteroaryl.
  • Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
  • Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
  • Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl.
  • R 1 and R 2 are each independently H, hydroxy, or optionally substituted alkyl.
  • R and R are both optionally substituted alkyl optionally substituted Substituted by one or more substituents independently selected from halogen, hydroxy, cyano and -NR a R a .
  • R 1 and R 2 are each independently optionally substituted C 1 -C 4 alkyl.
  • R 1 and R 2 are both methyl.
  • one of R and R is optionally substituted alkyl and the other is H or hydroxy, optionally substituted by one or more independently Substituents selected from halogen, hydroxy, cyano and -NR a R a are substituted.
  • one of R and R is optionally substituted C 1 -C 4 alkyl and the other is H or hydroxy, said optionally substituted C 1 -C 4 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -NR a R a .
  • one of R and R is methyl and the other is hydroxy.
  • R and R together with the carbon atom to which they are attached form an optionally substituted
  • R and R together with the carbon atom to which they are attached form
  • each R3 is independently H or optionally substituted alkyl.
  • each R3 is independently H, halo, or optionally substituted alkyl.
  • each R3 is independently H, halo, optionally substituted alkyl, or -ORb .
  • each R3 is independently H, halo, optionally substituted alkyl, optionally substituted alkoxy, or -ORb .
  • each R 3 is independently H, fluoro, chloro, optionally substituted C 1 -C 4 alkyl, or optionally substituted C 1 -C 4 alkoxy.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl.
  • each R 3 is independently optionally substituted C 1 -C 4 alkoxy.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
  • each R 3 is independently optionally substituted C 1 -C 4 alkoxy optionally substituted by one or more independently selected from Substituents of halogen, hydroxyl, cyano and -NR a R a are substituted.
  • each R 3 is independently C 1 -C 4 alkyl.
  • each R 3 is independently C 1 -C 4 alkoxy.
  • each R3 is independently methyl.
  • each R 3 is independently methoxy.
  • each R3 is independently selected from halogen.
  • R 3 is fluoro
  • R 3 is chloro
  • R3 is H.
  • each R is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b , wherein R a is each independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted Alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally represented by one or more independently Substituents selected from halogen, hydroxyl, cyano and -NR a R a .
  • each R4 is independently H, halo, cyano, oxo, cyclopropyl, -( CH2 ) rNRaRa , or -ORb , wherein each Ra is independently H, any Optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
  • each R4 is independently H, chloro, cyano, oxo, cyclopropyl, or -OCH3 .
  • Z 1 is a bond, -O-, -CO-, or -NR a -, wherein R a is H, optionally substituted alkyl, or -COR b .
  • Z is a bond, -O- or -CO-.
  • Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
  • Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
  • Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
  • R 5 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, any Optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally
  • the substituted C2 - C4alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NRaRa .
  • R 5 is H, optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and Optionally substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy or cyano.
  • R 5 is optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen, hydroxy , cyano or -NR a R a substituent substitution.
  • R 5 is optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from fluorine, chlorine , bromine, hydroxyl, cyano or -NR a R a substituent substitution.
  • R 5 is optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from fluorine, chlorine , Hydroxy or cyano substituents.
  • R 5 is -(CH 2 )Cl, -CH 2 CH 2 (OH)CH 3 .
  • R 5 is optionally substituted C 2 -C 4 alkenyl optionally substituted by one or more independently selected from halogen, hydroxy , cyano or -NR a R a substituent substitution.
  • R is methyl , ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine, hydroxy Or cyano substituent substitution.
  • R 5 is vinyl
  • Z 1 is a bond or -O-
  • R 5 is H, optionally substituted C 1 -C 4 alkyl optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
  • Z is a bond or -O-
  • R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from halogen, hydroxy or cyano are substituted.
  • Z is a bond or -O-
  • R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from fluorine, chlorine or hydroxyl are substituted.
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-
  • R 5 is optionally substituted C 2 -C 4 alkenyl
  • said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
  • -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
  • Y 1 is a bond and Y 2 is O, NH or S.
  • Y 1 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl
  • Y 2 is a bond or O
  • said optionally substituted alkyl, optionally substituted Alkenyl or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano or oxo.
  • Y is optionally substituted alkyl or optionally substituted alkynyl
  • Y is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or oxo.
  • Y 1 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkynyl
  • Y 2 is a bond or O, wherein optionally substituted C 1 -C 4 Alkyl and optionally substituted C 2 -C 4 alkynyl are optionally substituted with one or more substituents independently selected from hydroxy or oxo.
  • Y 1 is C 1 -C 4 alkyl optionally substituted with one or more substituents independently selected from hydroxy or oxo, and Y 2 is O.
  • Y 1 is C 2 -C 4 alkynyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo, and Y 2 is a bond.
  • Z 2 is -O-, C 2 -C 4 alkynyl, or **-(optionally substituted C 1- C 4 alkyl)-O-*, wherein said optionally substituted C 1- C4alkyl is optionally substituted with one or more substituents selected from hydroxyl, C1-C4alkyl or oxo.
  • Z 2 is -O-, C 2 -C 4 alkynyl, or **-(optionally substituted C 1- C 4 alkyl)-O-*, wherein said optionally substituted C 1- C4alkyl is optionally substituted with one or more substituents selected from hydroxy, or oxo.
  • Z is selected from -O-, **-(C 1-3 alkyl)-O-*, ethynyl or propynyl, wherein -(C 1-3 alkyl)-O-
  • the C 1-3 alkyl in is optionally substituted by one or more hydroxyl or oxo.
  • Z2 is **- CH2O- * or ethynyl.
  • R c and R d are each independently selected from optionally substituted alkyl or -NR a Ra , wherein each R a is independently H or optionally substituted alkyl.
  • one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
  • one of Rc and Rd is -CH3 and the other is -NHCH3 .
  • R c and R d are each independently selected from optionally substituted C 1 -C 4 alkyl or -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
  • R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
  • Rc and Rd are each independently optionally substituted methyl.
  • both R c and R d are methyl.
  • one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally Substituted C 1 -C 4 alkyl.
  • both Rc and Rd are -CH3- , or one of Rc and Rd is -CH3 and the other is -NHCH3 .
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl optionally replaced by one or a plurality of R h substitutions, wherein R h is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, - NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or an optionally substituted alkane
  • the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen, hydroxy, cyano and -OR b substituent substitution, wherein
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl optionally substituted by One or more R h substitutions, wherein R h is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, Optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl is optionally substituted by one
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
  • Rh is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 Cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O) R g , -C(O)NR a R a , -S(O) R f or -SO 2 R f , wherein R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, and -OR b , wherein R b is optionally substituted C 1 -C
  • Rh is selected from the group consisting of C optionally substituted with one or more substituents independently selected from hydroxyl, halogen, cyano, or -O( C2 - C4alkynyl ). 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-9 membered heterocyclyl optionally substituted by one or more C 1 -C 4 alkyl, -NH 2.
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
  • Ring C is a bond or heteroaryl.
  • each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
  • each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
  • R c and R d in the compounds of formula 1-IIa and formula 1-IIb are each independently C 1 -C 4 Alkyl or -NH-(C 1 -C 4 alkyl).
  • R and R in compounds of Formula 1-IIa and Formula 1- IIb together with the S atom to which they are attached form a 4-10 membered heterocyclic ring optionally substituted by one or more Rh base.
  • Z 2 in compounds of formula 1-IIa and formula 1-IIb is -O-, C 2 -C 4 alkynyl or **-(optionally substituted C 1- C 4 alkyl)- O-*, wherein the optionally substituted C 1 -C 4 alkyl is optionally substituted with one or more substituents selected from hydroxy or oxo.
  • Ring C in the compounds of Formula 1-IIa and Formula 1-IIb is a bond, phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, or oxazolyl.
  • the application provides the compound shown in the following formula 2-I:
  • Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • X is C, N, O or S
  • R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
  • R 3 and R 4 are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH 2 ) r NR a R a OR -OR b ;
  • Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a - or -(CH 2 ) r -NR a -CO-;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR h R h ;
  • each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
  • R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a or -NR a R a ; or R c , R d are connected to them
  • the S atoms together form an optionally substituted 4-10 membered heterocyclic group
  • R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R g is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-10 membered heterocyclyl, or -NR h R h ;
  • R h are each independently H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered Heterocyclyl;
  • r 0, 1, 2 or 3;
  • s 0, 1, 2 or 3;
  • n and p are each independently 0, 1, 2 or 3.
  • Ring A is aryl. In certain embodiments, Ring A is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring A is phenyl or naphthyl. In certain embodiments, Ring A is phenyl.
  • Ring A is heteroaryl. In certain embodiments, Ring A is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • ring A is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazole group, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl or pyrazinyl.
  • Ring A is pyridyl, pyrimidinyl or thienyl. In certain embodiments, Ring A is pyridyl.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring B is heterocyclyl. In certain embodiments, Ring B is 5-14 membered heterocyclyl, 5-12 membered heterocyclyl, 5-10 membered heterocyclyl, 5-8 membered heterocyclyl. In certain embodiments, Ring B is pyridinonyl.
  • Ring B is aryl. In certain embodiments, Ring B is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring B is phenyl or naphthyl. In certain embodiments, Ring B is phenyl.
  • Ring B is heteroaryl. In certain embodiments, Ring B is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • Ring B is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazole Base, Triazinyl, Pyridonyl, Benzomorpholinyl, Indazolyl, Dihydrobenzoxazinyl, Pyrazolopyridyl, Benzotriazolyl, Benzimidazolyl, Tetrahydroisoquinoline base, indazolyl, imidazopyridyl, pyridomorpholinyl, benzisodiazolyl, indolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, decahydroiso Quinolinyl, indolinyl, octahydroindolyl or o
  • Ring B is selected from pyridyl, pyridonyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridyl, benzotriazolyl, benzimidazolyl, tetrahydroiso Quinolinyl, indazolyl, imidazopyridinyl or pyridomorpholinyl.
  • Ring B is selected from indazolyl, dihydrobenzoxazinyl, benzimidazolyl, benzomorpholinyl, pyridomorpholinyl, pyrazolopyridinyl, or benzotriazole base.
  • Ring C is a bond.
  • Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
  • Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
  • Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl.
  • Ring C is pyrimidinyl, pyrazinyl or pyridinyl.
  • X is N, O, or S, and R and R are absent.
  • X is C, and R and R are each independently H, hydroxyl, or optionally substituted alkyl .
  • X is C, and R and R are both optionally substituted alkyl optionally replaced by one or more independently selected from halogen, hydroxy, cyano Substituent group and -NR a R a substituent.
  • X is C, and R 1 and R 2 are each independently optionally substituted C 1 -C 4 alkyl.
  • X is C and R and R are both methyl.
  • X is C, one of R and R is optionally substituted alkyl, the other is H or hydroxy, and the optionally substituted alkyl is optionally replaced by one or Substituents independently selected from halogen, hydroxy, cyano and -NR a R a are substituted.
  • X is C
  • one of R and R is optionally substituted C 1 -C 4 alkyl
  • the other is H or hydroxyl
  • the optionally substituted C 1 - C4alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NRaRa .
  • X is C, and one of R and R is methyl and the other is hydroxy.
  • each R3 is independently H, halo, ORb , or optionally substituted alkyl.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
  • each R3 is independently H or halo.
  • each R3 is independently selected from halogen.
  • each R3 is independently fluoro or chloro.
  • R 3 is fluoro
  • R 3 is chloro
  • R3 is H.
  • each R4 is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRa R a or -OR b , wherein each R a is independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkyne wherein the optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl are optionally replaced by one or more independently selected from halogen, hydroxyl, cyano and -NR a R a Substituents replace.
  • each R 4 is independently H, halo, cyano, oxo, -(CH 2 ) r NR a R a , or -OR b , wherein each R a is independently H, optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkyne base.
  • each R4 is independently H, chloro, cyano, oxo, or -OCH3 .
  • Z 1 is a bond, -O-, -CO-, or -NR a -, wherein R a is H or optionally substituted alkyl.
  • Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, or -NR a -.
  • Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, or -NR a -, wherein R a is H, optionally substituted is alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -COR b , wherein R b is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.
  • Z1 is a bond, -O-, -CO-, or -( CH2 ) r - NRa -CO-, wherein Ra is H or optionally substituted alkyl.
  • Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
  • Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
  • R 5 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, the optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxyl, cyano and the substituent of -NR a R a is substituted.
  • R 5 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and optionally Substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.
  • R is methyl , ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine, hydroxy Or cyano substituent substitution.
  • Z 1 is a bond or -O-
  • R 5 is optionally substituted C 1 -C 4 alkyl optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
  • Z is a bond or -O-
  • R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of halogen, hydroxy or cyano are substituted.
  • Z is a bond or -O-
  • R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of fluorine, chlorine or hydroxyl are substituted.
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-
  • R 5 is optionally substituted C 2 -C 4 alkenyl
  • said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
  • -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
  • R 6 is -N ⁇ S(O)R c R d or -NR a -SO 2 R g .
  • R 6 is -N ⁇ S(O)R c R d , each of R c and R d is independently selected from optionally substituted alkyl, -OR a, or -NR a R a , wherein R a Each is independently H, optionally substituted alkyl, or optionally substituted alkynyl.
  • R 6 is -N ⁇ S(O)R c R d , each of R c and R d is independently selected from optionally substituted C 1 -C 4 alkyl, -OR a , or -NR a R a , wherein each R a is independently H, optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkynyl.
  • R 6 is —N ⁇ S(O)R c R d , R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
  • R 6 is -N ⁇ S(O)R c R d , one of R c and R d is optionally substituted C 1 -C 4 alkyl, and the other is -OR a or -NR a R a , wherein each R a is independently H, optionally substituted C 1 -C 4 alkyl, or optionally substituted C 2 -C 4 alkynyl.
  • R 6 is -N ⁇ S(O)R c R d , one of R c and R d is optionally substituted C 1 -C 4 alkyl, and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
  • said Optionally substituted 4-6 membered heterocyclyl is optionally substituted by one or more R i , wherein R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkyne radical, optionally substituted C 3 -C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently is H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 ring Alky
  • R is selected from the group consisting of:
  • R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alken
  • R i is selected from the group consisting of optionally replaced by one or more hydroxyl, cyano, -O(C 1 -C 4 alkyl) or -O(C 2 -C 4 alkynyl) Substituted C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -C(O)NH 2 and -SO 2 (C 1 -C 4 alkyl), wherein the C 1 -C 4 alkyl in -NH(C 1 -C 4 alkyl) is optionally substituted with one or more halogen or hydroxy.
  • R is selected from the group consisting of:
  • R 6 is —N ⁇ S(O)R c R d
  • ring C is a bond or heteroaryl.
  • R 6 is —N ⁇ S(O)R c R d
  • Ring C is a bond, pyrimidinyl or pyrazinyl.
  • R e is H, cyano, or optionally substituted alkyl
  • R f is optionally substituted alkyl wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
  • R e is H, cyano, or optionally substituted C 1 - C 4 alkyl
  • R f is an optionally substituted C 1 -C 4 alkyl, wherein the optionally substituted C 1 -C 4 alkyl is optionally selected from one or more independently selected from halogen, hydroxyl, Substituted by a cyano group or a substituent of -NR a R a .
  • ring C is aryl or heteroaryl.
  • ring C is phenyl, pyridyl or pyrimidinyl.
  • R 6 is -NR a -SO 2 R g
  • R a is H or optionally substituted alkyl
  • R g is optionally substituted alkyl, optionally substituted 4-10 membered heterocycle group or -NR h R h .
  • R 6 is —NR a —SO 2 R g
  • Ra is H or alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.
  • R 6 is -NR a -SO 2 R g
  • Ra is H or -(CH 2 ) 2 OH.
  • R 6 is -NR a -SO 2 R g , R g is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, or -NR a R a alkyl. In certain embodiments, R 6 is -NR a -SO 2 R g , R g is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, or -NR a R a C 1 -C 4 alkyl. In certain embodiments, R 6 is -NR a -SO 2 R g , and R g is methyl, -(CH 2 ) 2 NH 2 or -(CH 2 ) 2 N(CH 3 ) 2 .
  • R 6 is -NR a -SO 2 R g , R g is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, or -NR a R a 4-10 membered heterocyclyl, wherein R a is independently selected from hydrogen or alkyl.
  • R 6 is -NR a -SO 2 R g , and R g is piperidinyl or tetrahydropyranyl.
  • R 6 is -NR a -SO 2 R g
  • R g is -NR h R h
  • each R h is independently hydrogen or is optionally selected from one or more independently selected from halogen, Alkyl substituted by substituents of hydroxy or cyano, or two Rh together with the N atoms to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
  • R 6 is -NR a -SO 2 R g
  • R g is -NR h R h
  • each R h is independently hydrogen, methyl, or -(CH 2 ) 2 OH, or both
  • Each Rh together with the N atom to which they are attached form piperazinyl.
  • each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
  • each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , where Each R g is independently H, -SO 2 (C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4 -10 membered heterocyclic group.
  • the application provides compounds having the formula:
  • V and V are each independently N or CH;
  • Ring C is a bond, aryl or heteroaryl
  • Z 1 is a bond, -O-, -CO-, -NR a - or -(CH 2 ) r -NR a -CO-;
  • R and R are each independently hydroxyl or optionally substituted alkyl
  • R 3 is H, OR b or optionally substituted alkyl
  • Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRaRa or -ORb ;
  • Each R 7 is independently halogen, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f or -NR h R h ; each R a is independently H, any Select substituted alkyl or -COR b ;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
  • R is optionally substituted alkyl
  • Each R h is independently H, -SO 2 R f or an optionally substituted alkyl group; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
  • r, s, m, n and p are each independently 0, 1 or 2.
  • Ring C is a bond.
  • Ring C is aryl or heteroaryl.
  • Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
  • Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
  • Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl.
  • Ring C is pyrimidinyl, pyrazinyl or pyridinyl.
  • each R3 is independently H, halo, ORb , or optionally substituted alkyl.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
  • each R3 is independently H or halo.
  • each R3 is independently selected from halogen.
  • each R3 is independently fluoro or chloro.
  • R 3 is fluoro
  • R 3 is chloro
  • R3 is H.
  • each R4 is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRa R a or -OR b , wherein each R a is independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkyne wherein the optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl are optionally replaced by one or more independently selected from halogen, hydroxyl, cyano and -NR a R a Substituents replace.
  • each R 4 is independently H, halo, cyano, oxo, -(CH 2 ) r NR a R a , or -OR b , wherein each R a is independently H, optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkyne base.
  • each R4 is independently H, chloro, cyano, oxo, or -OCH3 .
  • Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
  • Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
  • Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
  • Z is a bond, -O- or -CO-.
  • R 5 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, the optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxyl, cyano and the substituent of -NR a R a is substituted.
  • R 5 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and optionally Substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.
  • R is methyl , ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine, hydroxy Or cyano substituent substitution.
  • Z 1 is a bond or -O-
  • R 5 is optionally substituted C 1 -C 4 alkyl optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
  • Z is a bond or -O-
  • R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of halogen, hydroxy or cyano are substituted.
  • Z is a bond or -O-
  • R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of fluorine, chlorine or hydroxyl are substituted.
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-
  • R 5 is optionally substituted C 2 -C 4 alkenyl
  • said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
  • -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
  • R c and R d are each independently selected from optionally substituted alkyl or -NR a Ra , wherein each R a is independently H or optionally substituted alkyl.
  • R c and R d are each independently selected from optionally substituted C 1 -C 4 alkyl or -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
  • R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
  • one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
  • both Rc and Rd are -CH3- , or one of Rc and Rd is -CH3 and the other is -NHCH3 .
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl optionally replaced by one or a plurality of R i substitutions, wherein R i is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered hetero Cyclic group, -C(O)R j -, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or Optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen , hydroxy, cyano, and -OR
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl optionally substituted by One or more R i are substituted, wherein R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted C 1 -C 4 alkyl,
  • the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally selected from one or more independently selected from halogen , hydroxy, cyano and -OR b substituents
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
  • R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alken
  • R i is selected from the group consisting of optionally replaced by one or more hydroxyl, cyano, -O(C 1 -C 4 alkyl) or -O(C 2 -C 4 alkynyl) Substituted C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -C(O)NH 2 and -SO 2 (C 1 -C 4 alkyl), wherein the C 1 -C 4 alkyl in -NH(C 1 -C 4 alkyl) is optionally substituted with one or more halogen or hydroxy.
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
  • Ring C is a bond or heteroaryl. In certain embodiments, Ring C is a bond, pyrimidinyl, or pyrazinyl.
  • each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
  • each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
  • the application provides compounds having the formula:
  • V 3 is N or CH
  • Ring C is a bond, aryl or heteroaryl
  • Ring D is heterocyclyl or heteroaryl
  • Z 1 is a bond, -O-, -CO-, -NR a - or -(CH 2 ) r -NR a -CO-;
  • R and R are each independently hydroxyl or optionally substituted alkyl
  • R 3 is H, OR b or optionally substituted alkyl
  • Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRaRa or -ORb ;
  • R is optionally substituted alkyl or optionally substituted alkenyl
  • Each R 7 is independently halogen, cyano , optionally substituted alkyl, -ORa , -S(O) Rf , -SO2Rf , or -NRhRh ;
  • each R a is independently H, optionally substituted alkyl, or -COR b ;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
  • R is optionally substituted alkyl
  • Each R h is independently H, -SO 2 R f or an optionally substituted alkyl group; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
  • r, s, m, n and p are each independently 0, 1 or 2.
  • ring D is substituted with 1, 2, or 3 R 9 that are H, halogen, or optionally Substituted alkyl.
  • Attachment to -Z 1 R 5 is through a saturated N atom on ring D.
  • the ring C bond In some embodiments, the ring C bond.
  • Ring C is aryl or heteroaryl.
  • Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
  • Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl.
  • ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
  • Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl.
  • Ring C is pyrimidinyl, pyrazinyl or pyridinyl.
  • each R3 is independently H, halo, ORb , or optionally substituted alkyl.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl.
  • each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
  • each R3 is independently H or halo.
  • each R3 is independently selected from halogen.
  • each R3 is independently fluoro or chloro.
  • R 3 is fluoro
  • R 3 is chloro
  • R3 is H.
  • each R4 is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRa R a or -OR b , wherein each R a is independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkyne wherein the optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl are optionally replaced by one or more independently selected from halogen, hydroxyl, cyano and -NR a R a Substituents replace.
  • each R 4 is independently H, halo, cyano, oxo, -(CH 2 ) r NR a R a , or -OR b , wherein each R a is independently H, optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkyne base.
  • each R4 is independently H, chloro, cyano, oxo, or -OCH3 .
  • Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
  • Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
  • Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
  • Z is a bond, -O- or -CO-.
  • R 5 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, the optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxyl, cyano and the substituent of -NR a R a is substituted.
  • R 5 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and optionally Substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.
  • R is methyl , ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine, hydroxy Or cyano substituent substitution.
  • Z 1 is a bond or -O-
  • R 5 is optionally substituted C 1 -C 4 alkyl optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
  • Z is a bond or -O-
  • R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of halogen, hydroxy or cyano are substituted.
  • Z is a bond or -O-
  • R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of fluorine, chlorine or hydroxyl are substituted.
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-
  • R 5 is optionally substituted C 2 -C 4 alkenyl
  • said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
  • Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
  • -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
  • R c and R d are each independently selected from optionally substituted alkyl or -NR a Ra , wherein each R a is independently H or optionally substituted alkyl.
  • R c and R d are each independently selected from optionally substituted C 1 -C 4 alkyl or -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
  • R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
  • one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
  • both Rc and Rd are -CH3- , or one of Rc and Rd is -CH3 and the other is -NHCH3 .
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl optionally replaced by one or a plurality of R i substitutions, wherein R i is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered hetero Cyclic group, -C(O)R j -, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or Optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen , hydroxy, cyano, and -OR
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl optionally substituted by One or more R i are substituted, wherein R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted C 1 -C 4 alkyl,
  • the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally selected from one or more independently selected from halogen , hydroxy, cyano and -OR b substituents
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
  • R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally replaced by one or more independently selected from halogen, Substituents of hydroxy, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alken
  • R i is selected from the group consisting of optionally replaced by one or more hydroxyl, cyano, -O(C 1 -C 4 alkyl) or -O(C 2 -C 4 alkynyl) Substituted C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -C(O)NH 2 and -SO 2 (C 1 -C 4 alkyl), wherein the C 1 -C 4 alkyl in -NH(C 1 -C 4 alkyl) is optionally substituted with one or more halogen or hydroxy.
  • R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
  • Ring C is a bond or heteroaryl. In certain embodiments, Ring C is a bond, pyrimidinyl, or pyrazinyl.
  • each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
  • each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
  • R and R in compounds of Formula 2-Ia and Formula 2-Ib together with the S atom to which they are attached form a 4-10 membered heterocyclic ring optionally substituted by one or more R base.
  • Ring C in the compounds of Formula 2-Ia and Formula 2-Ib is a bond, phenyl, pyridyl, pyrimidinyl, or pyrazinyl.
  • Ring A' and ring B' are each independently cycloalkyl, aryl, heteroaryl or heterocyclyl;
  • X' is O, S, N or C
  • R 11 is absent, or is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, hydroxyl, -NH 2 , -NHR 1a or -NR 1a R 1a ;
  • R 12 is absent, or is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, hydroxyl, -NH 2 , -NHR 1a or -NR 1a R 1a ;
  • Each R 13 is independently H, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, —NH 2 , —NHR 1a , or — NR 1a R 1a ;
  • Each R is independently H, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, oxo, -NH2 , -NHR 1a or -NR 1a R 1a ;
  • Z 11 does not exist, or is -O-, -NR'-, -NR'-CO- or -S-;
  • Z 12 is an alkylene group, an alkenylene group, an alkynylene group or -R"-Y 11 -R"'-; wherein, R" and R"' are each a bond, an alkylene group, an alkenylene group or an alkynylene group , and R" and R"' are not bonds at the same time, Y 11 is O, NH or S; wherein, Z 12 is optionally substituted;
  • R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • each R' is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkoxy;
  • R 17 and R 18 are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -NH 2 , -NHR 1a or -NR 1a R 1a ; or R 17 , R 18 Together with the S atoms to which they are attached, an optionally substituted 4-10 membered heterocyclic group is formed;
  • R 19 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, -NH 2 , -NHR 1a or -NR 1a R 1a ;
  • Each R is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • n' and m' are each independently an integer of 0, 1, 2 or 3.
  • ring A' is aryl or heteroaryl, preferably 6-14 membered aryl or 5-10 membered heteroaryl, and the 5-10 membered heteroaryl is preferably 5-10 membered Ring or bicyclic heteroaryl; more preferably, the ring A' is selected from: phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazine group, pyridazinyl, furyl, pyrrolyl, triazolyl and triazinyl, more preferably phenyl or pyridyl.
  • Ring B' is aryl, heteroaryl or heterocyclic group, preferably 6-14 membered aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, the 5- The 10-membered heteroaryl is preferably a 5-10-membered monocyclic or bicyclic heteroaryl; more preferably, the ring B' is selected from: phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, Oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazolyl, triazinyl, benzomorpholinyl, pyridomorpholinyl, benzimidazolyl, benzene Isoxadiazolyl, indolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalin
  • X' is O or S, R 11 and R 12 are absent; or X' is N, one of R 11 and R 12 is absent, and one is H or an optionally substituted C 1 -C 6 alkyl; or X' is C, R 11 and R 12 are each independently H, hydroxyl or optionally substituted C 1 -C 6 alkyl; preferably, said optionally substituted alkyl is optionally replaced by 1 -3 substituents selected from halogen, hydroxyl, cyano, -NH 2 , -NHR 1a and -NR 1a R 1a , wherein each R 1a is independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; preferably, X' is C, R 11 is C 1 -C 4 alkyl, R 12 is C 1 -C 4 alkyl or hydroxyl; more Preferably, X' is C, R 11 and R 12 are each independently H,
  • each R is independently H, halogen, or optionally substituted C1-C6 alkyl; preferably, said optionally substituted alkyl is optionally replaced by 1-3 members selected from halogen, hydroxy, Substituents of cyano, -NH 2 , -NHR 1a and -NR 1a R 1a , wherein each of R 1a is independently C 1 -C 4 alkyl, hydroxyl substituted C 1 -C 4 alkyl or Halogenated C 1 -C 4 alkyl; wherein, when R 13 is a non-hydrogen substituent, n' is preferably 1 or 2; preferably, R 13 is H.
  • each R 14 is independently H, cyano, halogen, optionally substituted C 1 -C 4 alkoxy, optionally substituted alkyl C 1 -C 4 , or oxo; preferably, the The optionally substituted C 1 -C 4 alkyl and the optionally substituted C 1 -C 4 alkoxy are each optionally replaced by 1-3 members selected from halogen, hydroxyl, cyano, C 2 -C 4 alkynyl , -NH 2 , -NHR 1a and -NR 1a R 1a are substituted by substituents, wherein, R 1a is each independently C 1 -C 4 alkyl, hydroxyl substituted C 1 -C 4 alkyl or halogenated C 1 - C 4 alkyl; preferably, R 14 is a non-hydrogen substituent, m' is 1 or 2; more preferably, m is 2, and 2 R 14 are cyano and halogen respectively, or both are cyano, or respectively
  • Z 11 is absent, or is -O- or -NR'-CO-; preferably, the R' is H or C 1 -C 4 alkyl.
  • R 15 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, more preferably optionally Substituted C 1 -C 4 alkyl; preferably, the substituent of R 15 is selected from halogen, hydroxyl, -NH 2 , -NHR 1a , -NR 1a R 1a and -CH 2 NR 1b R 1b , wherein, R 1a Preferably each is independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl, R 1b is preferably each independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl, or two R 1b together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group or
  • -Z 11 -R 15 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, -NR'-CO-(optionally substituted C 2 -C 4 alkenyl) or -NR'-CO-(optionally substituted C 1 -C 4 alkyl), wherein, in the C 1 -C 4 alkyl and C 1 -C 4 alkoxy
  • the alkyl moiety and the C 2 -C 4 alkenyl are optionally substituted by 1, 2 or 3 substituents selected from halogen and hydroxy, and preferably the C 1 -C 4 alkyl, the alkyl moiety or alkenyl
  • the most terminal C of is substituted by at least one substituent selected from said halogen and hydroxyl; preferably, -Z 11 -R 15 is optionally substituted C 1 - C 4 alkyl or optionally substituted C 1 -C 4 alkoxy, wherein, the C 1 -C 4 alkyl
  • Z 12 is C 2 -C 4 alkenylene, C 2 -C 4 alkynylene or -R"-Y 11 -R"'-, more preferably C 2 -C 4 alkynylene or -R"-Y 11 -R"'-; preferably, R" and R"' are each a bond, C 1 -C 4 alkylene, C 2 -C 4 alkenylene or C 2 -C 4 alkylene Alkynyl, and R" and R"' are not bonds at the same time; preferably, Z 12 is (C 1 -C 4 alkylene)-O-, (C 2 -C 4 alkenylene) -O-, ( C 2 -C 4 alkynylene)-O-, (C 1 -C 4 alkynylene) -NH-, (C 2 -C 4 alkenylene) -NH-, (C 2 -C 4 alkynylene )-NH-, (C 1 -C 4 alkenylene
  • R 16 is substituted 6-14 membered aryl, substituted 5-10 membered heteroaryl, substituted 4-10 membered heterocyclyl or substituted C 3 -C 8 cycloalkyl; preferably
  • the 6-14 membered aryl group includes phenyl and naphthyl
  • the 4-10 membered heterocyclic group includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
  • the 5-10 membered heteroaryl groups include thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazolyl and triazinyl; more preferably, R 16 is substituted pyrazinyl, substituted pyrazin
  • R is substituted 6-14 membered aryl, substituted 5-10 membered heteroaryl, substituted 4-10 membered heterocyclyl or substituted C 3 -C 8 cycloalkyl,
  • substituent -N In S(O)R 17 R 18 :
  • R 17 and R 18 are each independently an optionally substituted alkyl group, preferably an optionally substituted C 1 -C 4 alkyl group; preferably, the alkyl group is optionally 1-3 selected from the group consisting of Substituents of the group: hydroxy, -NH 2 , -NHR 1a , -NR 1a R 1a , halogen, optionally 1 or 2 selected from halogen, cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a C 1 -C 4 alkyl substituted by substituents of R 1a , and optionally 1 or 2 selected from halogen, cyano, C 2 -C 4 alkynyl, hydroxyl, -NH 2 , -NHR 1a and - C 1 -C 4 alkoxy substituted by a substituent of NR 1a R 1a ; or
  • R 17 , R 18 together with the S atoms they are connected to form an optionally substituted 4-10 membered S-containing heterocyclic group optionally containing 1 or 2 heteroatoms selected from O and N, preferably Including thietanyl, thiolanyl, thietanyl, thiomorpholinyl and 1,4-oxathiolanyl; preferably, the heterocyclyl is optionally C 1 -C 4 alkane optionally substituted by 1 or 2 substituents selected from halogen, optionally 1 or 2 substituents selected from halogen, cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a C 2 -C 4 alkynyl, C 1 -C 4 alkane optionally substituted by 1 or 2 substituents selected from halogen, cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a C 2 -C 4 alkynyl
  • the substituents on R' are 1-3 substituents selected from halogen, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a , wherein R 1a is preferably each independently C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by hydroxy, or halogenated C 1 -C 4 alkyl; preferably, R' is H or C 1 -C 4 alkyl optionally substituted by hydroxy.
  • R 19 is optionally substituted C 1 -C 4 alkyl, optionally substituted 4-10 membered heterocyclyl, -NHR 1a or -NR 1a R 1a , wherein each R 1a is independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; preferably, the heterocyclic group is a 4-10 membered nitrogen and/or oxygen-containing hetero Cyclic group, preferably selected from piperidinyl, piperazinyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl and morpholinyl; preferably, R 19 When substituted, the substituents are 1, 2 or 3 selected from halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hal
  • substituents on R 16 optionally include , 2 or 3 selected from cyano, optionally substituted C 1 -C 4 alkyl, hydroxyl, -NH 2 , -NHR 1a , -NR 1a R 1a , halogen, optionally substituted C 1 -C 4 alkane Oxygen, 4-10 membered heterocyclic group, substituents of -NR 110 -S(O) 2 -R 19' and -S(O) 2 -R 19' , wherein, R 110 is H or C 1 -C 4 alkyl, R 19' is C 1 -C 4 alkyl, R 1a is each independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; Said optionally substituted C 1 -
  • the atoms together form an optionally substituted 4-10 membered S-containing heterocyclic group optionally containing 1 or 2 heteroatoms selected from O and N, preferably including thietanyl, thietanyl , thiacyclohexyl, thiomorpholinyl and 1,4-oxathiocyclohexyl;
  • the heterocyclyl is optionally selected from 1 or 2 halogen, optionally 1 or C 1 -C 4 alkyl, C 2 -C 4 alkynyl substituted by 2 substituents selected from halogen , cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a , optionally replaced by 1 or C 1 -C 4 alkoxy substituted by 2 substituents selected from halogen, cyano, hydroxyl, hydroxyl
  • R 16 is -N(R')-S(O) 2 -R 19 ; wherein, R' is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, Optionally substituted C 2 -C 4 alkynyl or optionally substituted C 1 -C 4 alkoxy; when R' is substituted, its substituents are preferably 1-3 selected from halogen, hydroxyl, -NH 2 , -NHR 1a and -NR 1a are substituents for R 1a , wherein R 1a is preferably each independently C 1 -C 4 alkyl, hydroxyl substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; Preferably, R' is H or C 1 -C 4 alkyl optionally substituted by hydroxyl; R 19 is optionally substituted C 1 -C 4 alkyl, optionally substituted 4-10 membered heterocyclic group, - NHR
  • the ring containing S and X 11 is a 4-6 membered heterocycle
  • X 11 is CH 2 or NH or O
  • R 111 is selected from: H, C 1 -C 4 alkyl optionally substituted by hydroxyl or halogen, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl)-O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a , wherein R 1a is preferably Each is independently C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by hydroxy, or Halogenated C 1 -C 4 alkyl; when X 11 is substituted by R 111 , X 11 is CH or N.
  • Ring A' is phenyl or pyridyl
  • Ring B' is phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl;
  • X' is C
  • R 11 is C 1 -C 4 alkyl or hydroxyl
  • R 12 is C 1 -C 4 alkyl or hydroxyl
  • n 1;
  • R 13 is H or C 1 -C 4 alkyl, preferably H
  • n 1 or 2;
  • R 14 is selected from cyano, halogen, C 1 -C 4 alkyl, oxo and C 1 -C 4 alkoxy optionally substituted by C 2 -C 4 alkynyl;
  • Z 11 does not exist, or is -O- or -NR'-CO-;
  • Z 12 is C 2 -C 4 alkynylene or -R"-Y 11 -R"'-, wherein R" and R"' are each a bond or optionally substituted C 1 -C 4 alkylene, and R" and R"' are not bonds at the same time, Y 11 is O, and the C 1 -C 4 alkylene is optionally substituted by one substituent selected from oxo and hydroxyl;
  • R 15 is C 1 -C 4 alkyl or C 2 -C 4 alkenyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably any A C 1 -C 4 alkyl group selected from 1-3 substituents selected from halogen and hydroxy, more preferably a C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxy, and the last carbon of the alkyl group is substituted with at least one substituent selected from halogen and hydroxyl;
  • R' is H or C 1 -C 4 alkyl optionally substituted by hydroxy
  • R 17 and R 18 are each independently unsubstituted C 1 -C 4 alkyl, or R 17 and R 18 together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group, the 4-
  • the 10-membered heterocyclic group optionally contains 1 or 2 heteroatoms selected from O and N
  • the 4-10-membered heterocyclic group is preferably thietanyl, thiolane group, thianyl group, thiomorpholinyl group and 1,4-oxathione group; preferably, the 4-10 membered heterocyclic group is optionally selected from 1-3 Group substituent substitution: C 1 -C 4 alkyl, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl)- optionally substituted by 1 or 2 substituents selected from cyano and hydroxy O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a
  • R 19 is: C 1 -C 4 alkyl optionally substituted by a substituent selected from -NH 2 , -NHR 1a and -NR 1a R 1a , -NH 2 , -NHR 1a , -NR 1a R 1a or 4 -10 membered heterocyclyl; and
  • Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
  • Ring A' is phenyl or pyridyl
  • Ring B' is phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl;
  • X' is C
  • R 11 is C 1 -C 4 alkyl or hydroxyl
  • R 12 is C 1 -C 4 alkyl or hydroxyl
  • n 1;
  • R 13 is H or C 1 -C 4 alkyl, preferably H
  • n 1 or 2;
  • R 14 is selected from cyano, halogen, C 1 -C 4 alkyl, oxo and C 1 -C 4 alkoxy optionally substituted by C 2 -C 4 alkynyl;
  • Z 11 does not exist, or is -O- or -NR'-CO-;
  • Z 12 is C 2 -C 4 alkynylene or -C 1 -C 4 alkylene-O-, wherein the C 1 -C 4 alkylene is optionally selected from one Substituents from oxo and hydroxy;
  • R 15 is C 1 -C 4 alkyl or C 2 -C 4 alkenyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably any A C 1 -C 4 alkyl group selected from 1-3 substituents selected from halogen and hydroxy, more preferably a C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxy, And the last C of the alkyl group is substituted by at least one substituent selected from halogen and hydroxyl;
  • R 17 and R 18 are each independently unsubstituted C 1 -C 4 alkyl, or R 17 and R 18 together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group, the 4-
  • the 10-membered heterocyclic group optionally contains 1 or 2 heteroatoms selected from O and N
  • the 4-10-membered heterocyclic group is preferably thietanyl, thiolane group, thianyl group, thiomorpholinyl group and 1,4-oxathione group; preferably, the 4-10 membered heterocyclic group is optionally selected from 1-3 Group substituent substitution: C 1 -C 4 alkyl, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl)- optionally substituted by 1 or 2 substituents selected from cyano and hydroxy O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a
  • R' is H or C 1 -C 4 alkyl
  • Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
  • Ring A' is phenyl or pyridyl
  • Ring B' is phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl, preferably phenyl;
  • X' is C
  • R 11 is C 1 -C 4 alkyl or hydroxyl
  • R 12 is C 1 -C 4 alkyl or hydroxyl
  • n 1;
  • R 13 is H or C 1 -C 4 alkyl, preferably H
  • n 1 or 2;
  • R 14 is selected from cyano, halogen, C 1 -C 4 alkyl, oxo and C 1 -C 4 alkoxy;
  • Z 11 does not exist, or is -O-;
  • Z 12 is C 2 -C 4 alkynylene
  • R 15 is C 1 -C 4 alkyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably optionally substituted by 1-3 substituents selected from C 1 -C 4 alkyl substituted by halogen and hydroxyl substituents, more preferably C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxyl, and the last of the alkyl C is substituted by at least one substituent selected from halogen and hydroxyl;
  • R 17 and R 18 are each independently unsubstituted C 1 -C 4 alkyl, or R 17 and R 18 together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group, the 4- In addition to S, the 10-membered heterocyclic group optionally contains 1 or 2 heteroatoms selected from O and N.
  • the 4-10-membered heterocyclic group is preferably thietanyl, thietanyl Alkyl, thiacyclohexyl, thiomorpholinyl and 1,4-oxathiocyclohexyl; preferably, the 4-10 membered heterocyclic group is optionally selected from 1-3 Substitution with substituents from the group: C 1 -C 4 alkyl optionally substituted by 1 or 2 substituents selected from cyano and hydroxy, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl) -O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a ;
  • R' is H or C 1 -C 4 alkyl optionally substituted by hydroxy
  • R 19 is: C 1 -C 4 alkyl optionally substituted by a substituent selected from -NH 2 , -NHR 1a and -NR 1a R 1a , -NH 2 , -NHR 1a , -NR 1a R 1a or 4 -10 membered heterocyclyl;
  • Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
  • R 11 is C 1 -C 4 alkyl or hydroxyl
  • R 12 is C 1 -C 4 alkyl or hydroxyl
  • R 14 ' is H, halogen or cyano
  • R 14 ′′ is H, halogen, cyano or optionally substituted C 1 -C 4 alkoxy, such as being optionally replaced by 1-3 members selected from halogen, hydroxyl, cyano, C 2 -C 4 alkynyl, - C 1 -C 4 alkoxy substituted by substituents of NH 2 , -NHR 1a and -NR 1a R 1a ;
  • Z 11 is O or -NR'-CO-
  • R 15 is C 1 -C 4 alkyl or C 2 -C 4 alkenyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably any A C 1 -C 4 alkyl group selected from 1-3 substituents selected from halogen and hydroxy, more preferably a C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxy, And the last C of the alkyl group is substituted by at least one substituent selected from halogen and hydroxyl;
  • Z 12 is C 1 -C 4 alkylene-O- or C 2 -C 4 alkynyl
  • the ring containing S and X 11 is a 4-6 membered heterocycle
  • X 11 is CH 2 or NH or O
  • R 111 is selected from: H, C 1 -C 4 alkyl optionally substituted by hydroxyl, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl) -O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a , wherein, R 1a is preferably each Independently C1-C4 alkyl, hydroxy-substituted C1 - C4 alkyl or halogenated C1 - C4 alkyl; wherein, when R 111 is located on X 11 , X 11 is CH or N;
  • R 112 is H or C 1 -C 4 alkyl
  • R 113 is selected from: optionally substituted C 1 -C 4 alkoxy, -S(O) 2 -R 19' , cyano, -NR 110 -S(O) 2 -R 19' , -NH 2 , -NHR 1a , -NR 1a R 1a and 4-10 membered heterocyclyl, wherein, R 110 is H or C 1 -C 4 alkyl, R 19' is C 1 -C 4 alkyl; preferably, the Optionally substituted C 1 -C 4 alkoxy is preferably optionally replaced by 1 or 2 members selected from halogen, cyano, C 2 -C 4 alkynyl, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a C 1 -C 4 alkoxy substituted by substituents, such as C 1 -C 4 alkoxy optionally substituted by C 2 -C 4 alkynyl; preferably, the 4-10 membered heterocyclic group
  • Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
  • R 11 is C 1 -C 4 alkyl or hydroxyl
  • R 12 is C 1 -C 4 alkyl or hydroxyl
  • R 14 ' is H, halogen or cyano
  • R 14 ′′ is H, halogen, cyano or C 1 -C 4 alkoxy optionally substituted by C 2 -C 4 alkynyl;
  • R 15 is C 1 -C 4 alkyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably optionally substituted by 1-3 substituents selected from C 1 -C 4 alkyl substituted by halogen and hydroxyl substituents, more preferably C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxyl, and the last of the alkyl C is substituted by at least one substituent selected from halogen and hydroxyl;
  • Z 12 is C 2 -C 4 alkynyl
  • One of X 12 and X 13 is CH, and the other is N;
  • R 114 is -N(R')-S(O) 2 -R 19 ; wherein, R' is H or C 1 -C 4 alkyl optionally substituted by hydroxyl; R 19 is optionally selected from -NH 2.
  • Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
  • the application provides a compound selected from the group consisting of:
  • a compound of the present application is not a compound of:
  • the preparation process of some compounds of the present invention is illustrated by the following formula II-6 as an example.
  • the preparation method at least includes steps such as the alkylation substitution reaction, catalytic coupling, and Grignard reaction described below.
  • the exemplary reaction process can be as follows I show. It should be understood that other compounds of the present invention can be prepared by similar methods or improved methods. A similar synthesis is performed.
  • the reaction conditions of each step are shown in the reaction scheme.
  • the intermediate II-1 reacts with different halogenated alkanes to obtain II-2 with different substituents.
  • the reaction is carried out in an organic solvent (preferably DMF or acetonitrile) under the action of a base (preferably cesium carbonate).
  • a base preferably cesium carbonate.
  • the reaction is catalyzed by a base (preferably cesium carbonate), catalyzed by a palladium reagent (preferably palladium acetate) in an organic solvent (preferably toluene or dioxane), and reacted under heating conditions to obtain II-6.
  • a base preferably cesium carbonate
  • a palladium reagent preferably palladium acetate
  • organic solvent preferably toluene or dioxane
  • Some compounds of the present invention are illustrated by taking the preparation process of the compound of formula III-3 as an example.
  • the preparation method at least includes steps such as catalytic coupling and esterification described below.
  • An exemplary reaction scheme can be shown in the following scheme II. It should be understood that other compounds of the present invention can be similarly synthesized by similar methods or improved methods arrive.
  • intermediate II-4 undergoes a one-step esterification reaction to generate III-1; III-1 is catalytically coupled with an alkyne compound to obtain intermediate III-2; III-2 is again catalytically coupled with a halide to obtain compound III- 3.
  • III-1 is catalytically coupled with an alkyne compound to obtain intermediate III-2; III-2 is again catalytically coupled with a halide to obtain compound III- 3.
  • the reaction conditions of each step are shown in the reaction scheme.
  • W is halogen, preferably chlorine, bromine and iodine.
  • the intermediate III-1 introduces an alkynyl group through coupling with an alkyne compound.
  • Intermediate III-2 and different halides, preferably aromatic haloalkanes undergo a coupling reaction to obtain compound III-3 with different substituents.
  • the reaction is carried out under the action of a base (preferably diisopropylethylamine), under the catalysis of a metal catalyst (preferably Pd(PPh 3 ) 4 and cuprous iodide); in an organic solvent (preferably tetrahydrofuran) by heating conduct.
  • a base preferably diisopropylethylamine
  • a metal catalyst preferably Pd(PPh 3 ) 4 and cuprous iodide
  • organic solvent preferably tetrahydrofuran
  • the above scheme includes the step of removing the Boc protecting group.
  • the deprotection reaction can be carried out in a conventional manner.
  • the compounds provided in this application are modulators of androgen receptor (AR), and can be used to regulate the activity of AR. Modulating AR activity is useful in the treatment and/or prevention of androgen receptor mediated diseases.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound of the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present application may also contain other therapeutic agents, especially therapeutic agents for the treatment of the androgen receptor-mediated diseases described herein.
  • additional therapeutic agents are useful in the treatment of prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts , polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
  • examples of additional therapeutic agents include, but are not limited to, enzalutamide, galeterone, ODN-201 abiraterone, bicalutamide, nilutamide, flutamide, cycloacetate Propegesterone, Docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, Sunitinib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab anti), OGX 427, OGX 011, finasteride, dutasteride, torosteride, bechloride, aizontel, FCE 28260, SKF105, 111, ODM-201ODM-204, niclosalide amine, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide or related compounds.
  • Suitable pharmaceutical compositions can be formulated by methods known in the art and their mode of administration and dosage as determined by the skilled practitioner.
  • parenteral administration the compounds can be dissolved in sterile water or physiological saline or a pharmaceutically acceptable vehicle for administering water-insoluble compounds such as those used for vitamin K.
  • enteral administration the compounds can be administered in tablet, capsule form or dissolved in liquid form. Tablets or capsules may be enteric coated, or formulated for sustained release.
  • suitable formulations are known, including polymeric or protein particles encapsulating the compound to be released, ointments, pastes, gels, hydrogels or solutions, which may be applied topically or topically to the compound. Sustained release patches or implants may be used to provide release over an extended period of time.
  • Formulations for parenteral administration may, for example, contain excipients polyalkylene glycols such as polyethylene glycol, oils of vegetable origin or hydrogenated naphthalenes.
  • polyalkylene glycols such as polyethylene glycol, oils of vegetable origin or hydrogenated naphthalenes.
  • Biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compounds.
  • Other potentially useful parenteral delivery systems for modulating compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, Implantable infusion systems and liposomes.
  • Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be presented as nasal drops. as an oily solution to be applied in the form of a gel, or in the form of a gel.
  • dose values may vary with the precise imaging protocol. With respect to any particular subject, the particular dosing regimen may be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.
  • the dosage ranges described herein are exemplary only, and do not limit the range of dosages that can be selected by a medical practitioner.
  • the amount of active compound in the composition may vary according to factors such as the disease state, age, sex and weight of the subject. Dosing regimens can be adjusted to provide optimal imaging results. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally decreased or increased as indicated by the imaging results. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • the present application provides the use of the compound of the present application or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing diseases mediated by androgen receptors.
  • the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of androgen receptor-mediated diseases.
  • the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diseases mediated by androgen receptor variants.
  • the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diseases mediated by androgen receptor splicing variants (AR-Vs).
  • AR-Vs androgen receptor splicing variants
  • the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of AR-V7-mediated diseases.
  • the application provides a method for treating or preventing an androgen receptor-mediated disease in a subject, the method comprising administering to the subject a therapeutically effective amount or a preventively effective amount of a compound of the present application or a pharmaceutically acceptable salt, or a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound of the present application or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for treating or preventing diseases mediated by androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I or 2-I of the present invention
  • Formula 1-I or 2-I of the present invention Compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or pharmaceutical combinations thereof things.
  • the present invention provides a method of treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of a formula of the present invention 1-I or 2-I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs Or metabolites or pharmaceutical compositions thereof.
  • AR-Vs androgen receptor splice variants
  • the present invention provides a method for treating or preventing an AR-V7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1-I or 2-I of the present invention, its Pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof.
  • the present invention provides a method of treating or preventing diseases mediated by androgen receptor and androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I of the present invention or 2-I compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or its pharmaceutical composition.
  • the present invention provides a method of treating or preventing diseases mediated by androgen receptor and androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of The compound of formula 1-I or 2-I of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, solvate, isotope substitution, polymorphic form Drugs, prodrugs or metabolites or pharmaceutical compositions thereof.
  • AR-Vs androgen receptor and androgen receptor splice variants
  • the present invention provides a method for treating or preventing diseases mediated by androgen receptor and AR-V7, said method comprising administering to a subject in need a therapeutically effective amount of Formula 1-I or 2 of the present invention -I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical composition.
  • Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, as described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compound of the present application or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present application is administered orally.
  • the application compound or its pharmaceutically acceptable The salt or the pharmaceutical composition of the present application can be used in combination with other pharmacologically active compounds to treat or prevent various diseases mediated by the androgen receptor described herein.
  • the compound of the present application or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present application can be administered simultaneously, sequentially or separately in combination with one or more drugs selected from the following: enzalutamide, galeterone , ODN-201 Abiraterone, Bicalutamide, Nilutamide, Flutamide, Cyproterone Acetate, Docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, Shu Nitinib, ZD-4054, cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX 427, OGX011, finasteride, dutasteride, torosteride, bechloride Lai
  • androgen receptor mediated diseases may include: prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, Hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration, and combinations thereof.
  • the androgen receptor mediated disease is prostate cancer.
  • the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC) or hormone-sensitive prostate cancer.
  • the prostate cancer is androgen-dependent prostate cancer.
  • the spinal and bulbar muscular atrophy is Kennedy's disease.
  • the starting materials used in the following examples can be purchased from chemical distributors such as Aldrich, TCI, Alfa Aesar, Bid, Anaji, etc., or can be synthesized by known methods.
  • Step 1 Dissolve raw material I-A1-1 (80g, 429mmol) in dichloromethane (1000mL), stir at 0°C for 5 minutes, then add NIS (116g, 515mmol) at 0°C. The above mixture was reacted at room temperature for 16 hours, and the reaction was found to be complete by LC-MS detection. The reaction mixture was poured into water (1000ml), extracted with dichloromethane (1000mL*2), the organic phases were combined, washed with saturated brine (1000mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was recrystallized using acetonitrile to obtain product I-A1-2 (117 g, yield: 87.3%) as a white solid.
  • Step 3 Dissolve the intermediate I-A1-4 (53g, 141.3mmol) in N-methylpyrrolidone (600mL), add CuCN (19g, 200mmol), and stir the reaction at 160°C for 3 hours under the protection of nitrogen . TLC detects that the reaction is complete.
  • the reaction mixture was quenched with aqueous ammonia (2000 mL, 23%), and extracted with ethyl acetate (1000 mL*3).
  • Step 2 At room temperature, I-A2-1 (6g, 12.5mmol) and trimethylsilylacetylene (12g, 122.2mmol), Pd(PPh 3 ) 2 Cl 2 (1.6g, 2.3mmol), iodide Cuprous (1.3 g, 6.8 mmol) and triethylamine (23.31 g, 230.4 mmol) were dissolved in acetonitrile (133 ml). The mixture was stirred at 80° C. under nitrogen protection for 16 hours, and the reaction was complete as detected by TLC. The reaction mixture was concentrated and purified by column chromatography to obtain the desired product I-A2-2 (4.2 g, yield: 69%) as an orange oily liquid.
  • Step 4 Dissolve methylmagnesium bromide (33mL, 99.0mmol) in anhydrous tetrahydrofuran (80mL), lower it to 0°C, and add intermediate I-A3-4 (4.5g, 16.5mmol) in batches , and then stirred at room temperature for 2 hours, and TLC detected that the reaction was complete.
  • the reaction system was quenched by adding saturated aqueous ammonium chloride solution (40 mL), and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (70 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the desired product I-A3-5 (4.5 g, yield: 99%) as a yellow oil.
  • Step 5 Dissolve intermediate I-A3-5 (4.5g, 16.5mmol) and phenol (7.8g, 82.4mmol) in dichloromethane (130mL), lower the temperature to -78°C, and slowly drop into Boron trifluoride diethyl ether (7.0 g, 49.4 mmol), then naturally warmed to room temperature, stirred overnight.
  • I-A4 was synthesized by three-step reaction with I-A3 instead of I-A1.
  • intermediate I-A5 was synthesized from the starting material I-A3-1 through a five-step reaction.
  • Step 1 Dissolve raw material I-A6-1 (23g, 126.25mmol) in dichloromethane (300mL), stir at 20°C for 5 minutes, then add NIS (32.76g, 189.38mmol) at 20°C. above mixture at room temperature (20° C.) for 4 hours.
  • the reaction mixture was poured into water (200 mL), extracted with dichloromethane (200 mL*2), the organic phases were combined, washed with saturated brine (200 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was recrystallized using acetonitrile to obtain the product I-A6-2 (24 g, yield: 62%) as a white solid.
  • Step 4 Dissolve I-A6-4 (12.5g, 46.5mmol) in tetrahydrofuran (200mL), add dropwise to nitrogen-protected methylmagnesium bromide (124mL, 3M solution in tetrahydrofuran) at room temperature, add dropwise After completion, react at room temperature for 3 hours.
  • the reaction mixture was slowly added to saturated ammonium chloride solution at 0°C, and extracted with ethyl acetate (100 mL*3).
  • the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered. After concentrating the filtrate, the desired crude product I-A6-5 (12.5 g, yield: 100%) was obtained as a yellow solid, which was directly used in the next reaction.
  • Step 5 Dissolve I-A6-5 (12.5g, 46.34mmol), phenol (17.45g, 185.37mmol) in dichloromethane (120mL), add trifluoride dropwise under nitrogen protection at -78°C Boron ether solution (17.5ml, 47%) was naturally warmed to room temperature and reacted for 2 hours after the dropwise addition. TLC detects that the reaction is complete.
  • Step 1 Dissolve raw material I-A7-1 (19.5g, 128mmol) in 50% acetic acid aqueous solution (1400mL), add potassium iodide (53g, 320mmol) at room temperature, then slowly add sodium hydrogen peroxide (80.4g ,512mmol). The above mixture was reacted at 60° C. for 3 hours, and TLC detection showed that the reaction was complete. Put the reaction mixture into a vigorously stirred mixed solution of dichloromethane and saturated sodium sulfite, extract with dichloromethane (500mL*3), combine the organic phases, wash with saturated brine (1000mL*2), and wash the organic phase with anhydrous sulfuric acid Dry over sodium and concentrate. After concentration, the product I-A7-2 (50 g, yield: 96.5%) was obtained as a white solid.
  • Step 3 Dissolve intermediate I-A7-3 (30g, 64.4mmol) in N-methylpyrrolidone (500mL), add CuCN (17.3g, 193.2mmol), and stir the reaction at 160°C under nitrogen protection 3 hours. TLC detects that the reaction is complete.
  • the reaction mixture was quenched with aqueous ammonia (1000 mL, 23%), and extracted with ethyl acetate (500 mL*3).
  • the organic phase was washed with saturated brine (1500 mL) and dried over anhydrous sodium sulfate.
  • Step 2 Dissolve intermediate I-A8-3 (2.5g, 14.6mmol) in dichloromethane (30mL) at room temperature, add NIS (3.3g, 14.6mmol) at 0°C, and stir the mixture at room temperature for 16 Hours, LC-MS detected that the reaction was complete.
  • the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL*3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered.
  • the desired product I-A8-4 (4.0 g, yield: 93%) was obtained after concentrating the filtrate as a brown solid.
  • Step 4 Dissolve intermediate I-A8-7 (909mg, 3.85mmol) in tetrahydrofuran (5mL) and add n-butyllithium (2.6ml, 1.6M n-hexane solution) dropwise under nitrogen atmosphere at -77°C ), reacted at -77°C for 30 minutes after the dropwise addition, then added the solution of intermediate I-A8-6 (900mg, 3.5mmol) in tetrahydrofuran (4mL) dropwise to the above mixture, and kept at -77°C after the dropwise addition React for 2 hours. LC-MS detected that the reaction was complete.
  • intermediate I-A1 replace I-A1-3 with methyl iodide, and perform four-step reaction to obtain intermediate I-A9.
  • Step 3 Mix raw materials I-A10-2 (1.5g, 6mmol) and zinc cyanide (1.60g, 15mmol) and add NMP (2mL), then add tri-tert-butylphosphopalladium (1.0g, 1.96 mmol). The above mixed solution was reacted at 150° C. (microwave) for 1 hour. The reaction mixture was lowered to room temperature, 30 mL of ethyl acetate and 50 mL of water were added to the reaction liquid, and then extracted with ethyl acetate (10 mL*2), the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (pure petroleum ether) to obtain the desired product I-A10-3 (900 mg, yield: 76%) as a yellow solid.
  • Step 5 Add methylmagnesium bromide (2 mL, 2 mmol, 1M in THF) dropwise to a solution of intermediate I-A10-4 (170 mg, 0.64 mmol) in tetrahydrofuran (5 mL) at room temperature. The above mixture was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete.
  • intermediate I-A6 is used to replace intermediate I-A1, and 2-(2-chloroethoxy)-5-(2-(4-ethynylbenzene) is synthesized through a three-step reaction yl)propan-2-yl)-3-methoxybenzonitrile (intermediate I-A11).
  • intermediate I-A7 is used to replace intermediate I-A1, and 2-(2-chloroethoxy)-5-(2-(4-ethynylbenzene) is synthesized through a three-step reaction yl)propan-2-yl)isophthalonitrile (Intermediate I-A12) as a yellow oily liquid.
  • Step 1 Intermediate I-A10 (200 mg, 0.59 mmol) was dissolved in DCM (5 mL), and triethylamine (179 mg, 1.77 mmol) was added. Tf 2 O (250 mg, 0.88 mmol) was added at 0°C, and the mixture was reacted at 25°C for 1 hour. TLC detects that the reaction is complete. The mixture was separated on a preparative silica gel plate to obtain the product I-A13-1 (207 mg, yield: 74.5%) as a yellow oily liquid.
  • Step 1 Dissolve raw material I-A14-1 (5g, 19.5mmol) in N,N-dimethylformamide (50mL), add Zn(CN) 2 (1.35g, 11.7mmol), Pd (PPh 3 ) 4 (1.8 g, 1.56 mmol). The above mixture was stirred and reacted at 100° C. for 16 hours under the protection of nitrogen, and the reaction was found to be complete by TLC detection. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine (150 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was subjected to column chromatography to obtain the product I-A14-2 (1.6 g, yield: 53.3%) as a yellow solid.
  • Step 2 I-A14-2 (1.6g, 10.3mmol) was dissolved in methanolic hydrogen chloride solution (4M, 26ml, 104mmol) at room temperature, and the mixture was stirred at 80°C for 20 hours. LC-MS detected that the reaction was complete. The reaction solution It was filtered through silica gel, and the filtrate was concentrated to obtain a yellow solid. The yellow solid was dissolved in hot 1,4-dioxane (100 mL, 65° C.), hot n-hexane (100 mL) was added to the solution, the solution was slowly cooled to room temperature, and the mixture was filtered. The solid was washed with n-hexane, and the filtered solid was collected and vacuum-dried to obtain the product I-A14-3 (1.7 g, yield: 88.1%) as a yellow solid.
  • methanolic hydrogen chloride solution 4M, 26ml, 104mmol
  • Step 3 The raw material I-A14-3 (1.7 g, 9.1 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NIS (3.07 g, 13.65 mmol) was added. The above mixture was reacted at 100° C. for 16 hours, and the reaction was found to be complete by LC-MS detection. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (100 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product I-A14-4 (3.9 g) was obtained after concentration as a reddish-brown solid.
  • Step 5 Dissolve intermediate I-A14-5 (1.6g, 4.3mmol) in N-methylpyrrolidone (20mL), add CuCN (614mg, 6.9mmol), and stir the reaction at 160°C under nitrogen protection 3 hours. TLC detects that the reaction is complete.
  • Step 7 Dissolve I-A14-7 (140mg, 0.51mmol), phenol (240mg, 2.55mmol) in 1,2-dichloroethane (6mL), and add anhydrous AlCl 3 (136mg, 1.02 mmol), the above mixture was reacted at 100°C for 3 hours.
  • the reaction mixture was added to water (10 mL), and extracted with dichloromethane (10 mL*3).
  • the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered.
  • Step 1 Add I-A19-1 (2g, 9.71mmol), ethylene glycol (1.21g, 19.42mmol) and Cs 2 CO 3 (9.49g, 29.12mmol) into the solvent DMF (25mL), at 100°C , microwave reaction for 2 hours.
  • the reaction solution was cooled to room temperature, MeI (1.17g, 8.27mmol) was added, and the reaction was stirred at 25°C for 2 hours.
  • Step 2 Dissolve I-A19-2 (1.0g, 3.37mmol) in THF (8mL), replace with nitrogen three times, add MeMgBr (1M, 20.20mL) dropwise at 25°C, and continue stirring for 0.5 hours after the addition is complete .
  • Step 3 Add intermediate I-A19-3 (0.16g, 1.99mmol), phenol (934.30mg, 9.93mmol) and AlCl 3 (529.50mg, 3.97mmol) into solvent DCE (5mL), heat up to 80°C and stir React for 2 hours.
  • Step 4 Add SOCl 2 (5 mL) dropwise to intermediate I-A19-4 (0.5 g, 1.62 mmol) at 0° C., and continue stirring at this temperature for 2 hours.
  • LC-MS detection found that the reaction was complete, and the pH of the reaction solution was adjusted to neutral with sodium bicarbonate solution, extracted with ethyl acetate (20mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain intermediate I- A19 (200.00 mg, crude product), as a white solid.
  • Step 5 According to the operation steps of I-A10-2 to I-A10-3, intermediate I-A19-5 is generated from intermediate I-A19 in one step.
  • Step 3 Add methylmagnesium bromide (123 mL, 123 mmol, 1M in THF) dropwise to a solution of I-A20-3 (3.0 g, 12.3 mmol) in tetrahydrofuran (20 mL) at room temperature. The above mixture was stirred at room temperature for 4 hours.
  • Step 6 Add boron trifluoride ether solution (2.98mL) to I-A20-4 (800mg, 3.28mmol) and phenol (1.54g, 16.4mmol) in 1,2-dichloroethane (10mL) solution at room temperature g, 9.85mmol). The above mixture was stirred at 100° C. to room temperature for 3 hours.
  • Step 1 Dissolve 3-chloro-4-fluorobenzoic acid (500mg, 2.86mmol) in H 2 SO 4 (3mL) at 0°C, drop in HNO 3 (416.51mg, 4.30mmol, 297.50 ⁇ L, purity 65%). After the reaction solution was reacted at 25°C for 1 hour, the reaction solution was poured into ice water, and a white solid was precipitated, then filtered, the white solid was collected, and freeze-dried to obtain the product I-A21-1 (350 mg, yield: 50.09%). It is a white solid.
  • Step 2 Dissolve I-A21-1 (100mg, 455.47 ⁇ mol) in SOCl 2 (162.56mg, 1.37mmol), react at 70°C for 3 hours, then drop the reaction solution into MeOH (10mL) at 0°C , after stirring for 30 minutes, concentrated to obtain the product I-A21-2 (100 mg, yield: 84.60%) as a white solid.

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Abstract

Provided are an androgen receptor activity regulator and the use thereof. The androgen receptor activity regulator has a structure as represented by formula 1-I or formula 2-I, wherein R1-R7, X, ring A, ring B, ring C, n, m, p, Z1 and Z2 are as described herein. Further provided are a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitute, polymorph, prodrug or metabolite of a compound of formula 1-I or formula 2-I, and a pharmaceutical composition thereof and the pharmaceutical use thereof.

Description

雄激素受体活性调节剂及其应用Androgen receptor activity modulator and its application 技术领域technical field
本发明涉及雄激素受体活性调节剂及其应用。The present invention relates to an androgen receptor activity modulator and its application.
背景技术Background technique
前列腺癌是指发生在前列腺的上皮性恶性肿瘤，是男性泌尿生殖系统最常见的恶性肿瘤之一。前列腺癌的发病率在世界范围内差别很大，亚洲人的发病率远低于欧美人。在美国，前列腺癌发病率位居男性所有恶性肿瘤的第一位，死亡率仅次于肺癌位于第二位。其中转移性前列腺癌尤为恶性，5年生存率仅为30％。Prostate cancer is an epithelial malignant tumor that occurs in the prostate gland, and is one of the most common malignant tumors in the male genitourinary system. The incidence of prostate cancer varies widely around the world, and the incidence of Asians is much lower than that of Europeans and Americans. In the United States, the incidence of prostate cancer ranks first among all malignant tumors in men, and the mortality rate is second only to lung cancer. Among them, metastatic prostate cancer is particularly malignant, and the 5-year survival rate is only 30%.
雄激素剥夺治疗(androgen deprivation therapy,ADT)单用或与化疗联用通常作为转移性前列腺癌的初始治疗。ADT的标准方法包括双侧睾丸切除术，或者促性腺激素释放激素激动剂单用或与抗雄激素药物联用进行药物去势。尽管初始缓解率为80％-90％，但几乎所有患者在ADT后最终都会发生进展，这被称为去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC)。Androgen deprivation therapy (ADT) alone or in combination with chemotherapy is usually used as the initial treatment for metastatic prostate cancer. Standard approaches to ADT include bilateral orchiectomy, or medical castration with a gonadotropin-releasing hormone agonist alone or in combination with an antiandrogen. Although the initial remission rate is 80%-90%, almost all patients will eventually progress after ADT, which is called castration-resistant prostate cancer (CRPC).
雄激素受体(Androgen receptor，AR)在维持前列腺的功能和促进前列腺癌形成的过程中发挥着非常重要的作用,也是前列腺癌药物治疗中的重要靶标。AR的功能结构域包括羧基末端配体结合结构域(LBD)、DNA结合结构域(DBD)和N末端结构域(NTD)，可以调控多种基因的表达。雄激素结合LBD后，AR发生构象变化，与热休克蛋白分离并转入核内，通过DBD识别并结合DNA上的雄激素反应元件，进而调节前列腺特异性抗原(PSA)等靶基因的转录。目前临床上可获得的AR的抑制剂包括靶向AR LBD结构域的非类固醇抗雄激素，如比卡鲁胺、尼鲁米特、氟他胺和恩杂鲁胺，以及类固醇抗雄激素如乙酸环丙孕酮和螺内酯。Androgen receptor (AR) plays a very important role in maintaining the function of the prostate and promoting the formation of prostate cancer, and it is also an important target in the drug treatment of prostate cancer. The functional domains of AR include carboxy-terminal ligand-binding domain (LBD), DNA-binding domain (DBD) and N-terminal domain (NTD), which can regulate the expression of various genes. After androgen binds to LBD, AR undergoes a conformational change, separates from heat shock proteins and transfers into the nucleus, recognizes and binds to the androgen response element on DNA through DBD, and then regulates the transcription of target genes such as prostate-specific antigen (PSA). Currently clinically available AR inhibitors include nonsteroidal antiandrogens targeting the AR LBD domain, such as bicalutamide, nilutamide, flutamide, and enzalutamide, and steroid antiandrogens such as Cyproterone acetate and spironolactone.
大量研究结果表明，导致CRPC患者对新型内分泌治疗药物耐药的因素很多，包括AR异常扩增、AR剪切体变异(AR splice variants，AR-Vs)以及LBD结构域激活突变等。AR-Vs缺少了羧基末端的LBD结构域，但保留了NTD和DBD结构域， 可不依赖于雄激素刺激入核进而激活下游靶基因的转录。目前发现的AR-Vs有20余种，其中AR-V7在临床样本中最为多见。AR-V7表达水平随CRPC疾病进展而呈现显著升高趋势，表达AR-V7的CRPC患者对新型内分泌治疗药物(如阿比特龙或恩杂鲁胺)均不敏感。A large number of research results have shown that there are many factors leading to the resistance of CRPC patients to new endocrine therapy drugs, including abnormal amplification of AR, AR splice variants (AR splice variants, AR-Vs), and LBD domain activation mutations. AR-Vs lacked the carboxy-terminal LBD domain, but retained the NTD and DBD domains, It can be stimulated into the nucleus independently of androgen to activate the transcription of downstream target genes. There are more than 20 AR-Vs discovered so far, among which AR-V7 is the most common in clinical samples. The expression level of AR-V7 showed a significant upward trend with the progression of CRPC, and CRPC patients expressing AR-V7 were not sensitive to new endocrine therapy drugs (such as abiraterone or enzalutamide).
AR-Vs在越来越多的研究中被证实与CRPC的发生发展密切相关，但至今尚未有靶向AR-Vs治疗的药物批准上市。所有的AR-Vs都保留有NTD结构域，其包含的转录激活域(activation function-1，AF-1)可与多种转录共调控因子(cofactor)相互作用，对AR的转录活性至关重要。因此，靶向AR NTD结构域的抑制剂可同时抑制AR全长与剪切变异体的转录活性，有望成为攻克CRPC新的治疗策略。AR-Vs has been confirmed to be closely related to the occurrence and development of CRPC in more and more studies, but so far no drug targeting AR-Vs has been approved for marketing. All AR-Vs retain the NTD domain, which contains a transcriptional activation domain (activation function-1, AF-1) that can interact with a variety of transcriptional co-regulatory factors (cofactors) and is critical for the transcriptional activity of AR . Therefore, inhibitors targeting the AR NTD domain can simultaneously inhibit the transcriptional activity of AR full-length and spliced variants, which is expected to become a new therapeutic strategy to overcome CRPC.
发明内容Contents of the invention
在一方面，本发明提供了下式1-I所示的化合物：
In one aspect, the invention provides the compound shown in following formula 1-I:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中：in:
环A和环B各自独立为环烷基、杂环基、芳基或杂芳基；Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
环C为键、环烷基、杂环基、芳基或杂芳基；Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
X为C、N、O或S；X is C, N, O or S;
R1和R2各自独立地为不存在、H、卤素、氰基、羟基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基或-NRaRa；R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
前提是当X为C时，R1和R2各自独立地为不存在、H、卤素、氰基、羟基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基或-NRaRa， 或者R1和R2与X一起形成任选取代的 provided that when X is C, R and R are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, Optionally substituted alkoxy or -NR a R a , or R and R together with X form an optionally substituted
R3和R4各自独立地为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烷氧基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、-(CH2)rNRaRa或-ORb；R and R are each independently H, halogen, cyano, oxo , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally Substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b ;
Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-、-NRa-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a - or -(CH 2 ) r -NR a -CO-;
R5为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Z2为**-Y1-Y2-*，其中Y1为键、任选取代的烷基、任选取代的烯基或任选取代的炔基，Y2为键、O、NH或S，“*”表示Z2与环A的连接点，“**”表示Z2与环C的连接点；Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y 2 is a bond, O, NH or S, "*" indicates the connection point between Z 2 and ring A, "**" indicates the connection point between Z 2 and ring C;
R6为-N＝S(O)RcRd或-(CH2)sS(O)(＝NRe)Rf；R 6 is -N=S(O)R c R d or -(CH 2 ) s S(O)(=NR e )R f ;
R7各自独立地为卤素、氰基、任选取代的烷基、任选取代的烯基、任选取代的炔基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg；Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g ;
Ra各自独立为H、任选取代的烷基、任选取代的烯基、任选取代的炔基或-CORb；each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
Rb为H、任选取代的烷基、任选取代的烯基或任选取代的炔基； R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rc和Rd各自独立选自任选取代的烷基、任选取代的烯基、任选取代的炔基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -NR a R a ; or R c , R d together with the S atom to which they are attached Forming an optionally substituted 4-10 membered heterocyclyl;
Re为H、氰基、任选取代的烷基、任选取代的烯基或任选取代的炔基；R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rf为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rg各自独立为H、-SO2Rf、任选取代的烷基、任选取代的烯基或任选取代的炔基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基；Each R g is independently H, -SO 2 R f , optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R g together with the N atoms to which they are attached form an optionally Substituted 4-10 membered heterocyclic group;
r为0、1、2或3；r is 0, 1, 2 or 3;
s为0、1、2或3；且s is 0, 1, 2 or 3; and
m、n和p各自独立为0、1、2或3。m, n and p are each independently 0, 1, 2 or 3.
在另一方面，本发明提供了下式2-I所示的化合物：
In another aspect, the invention provides compounds represented by the following formula 2-I:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中：in:
环A和环B各自独立为环烷基、杂环基、芳基或杂芳基；Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
环C为键、环烷基、杂环基、芳基或杂芳基；Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
X为C、N、O或S；X is C, N, O or S;
R1和R2各自独立地为不存在、H、卤素、氰基、羟基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基或-NRaRa；R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
R3和R4各自独立地为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb；R 3 and R 4 are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH 2 ) r NR a R a OR -OR b ;
Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-、-NRa-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a - or -(CH 2 ) r -NR a -CO-;
R5为H、任选取代的烷基、任选取代的烯基或任选取代的炔基； R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
R6为-N＝S(O)RcRd、-(CH2)sS(O)(＝NRe)Rf或-NRa-SO2Rg；R 6 is -N=S(O)R c R d , -(CH 2 ) s S(O)(=NR e )R f or -NR a -SO 2 R g ;
R7各自独立地为卤素、氰基、任选取代的烷基、任选取代的烯基、任选取代的炔基、-ORa、-S(O)Rf、-SO2Rf或-NRhRh；Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR h R h ;
Ra各自独立为H、任选取代的烷基、任选取代的烯基、任选取代的炔基或-CORb；each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
Rb为H、任选取代的烷基、任选取代的烯基或任选取代的炔基； R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rc和Rd各自独立选自任选取代的烷基、任选取代的烯基、任选取代的炔基、-ORa或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a or -NR a R a ; or R c , R d are connected to them The S atoms together form an optionally substituted 4-10 membered heterocyclic group;
Re为H、氰基、任选取代的烷基、任选取代的烯基或任选取代的炔基；R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rf为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rg选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷 基、任选取代的4-10元杂环基或-NRhRh；R g is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkane Base, optionally substituted 4-10 membered heterocyclic group or -NR h R h ;
Rh各自独立为H、任选取代的烷基、任选取代的烯基或任选取代的炔基；或者两个Rh与它们所连接的N原子一起形成任选取代的4-10元杂环基；R h are each independently H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered Heterocyclyl;
r为0、1、2或3；r is 0, 1, 2 or 3;
s为0、1、2或3；且s is 0, 1, 2 or 3; and
m、n和p各自独立为0、1、2或3。m, n and p are each independently 0, 1, 2 or 3.
在再一方面，本发明提供了含有治疗或预防有效量的本发明的式1-I或2-I化合物或其药学上可接受的盐的药物组合物，该药物组合物还可含有药学上可接受的载体。In yet another aspect, the present invention provides a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound of formula 1-I or 2-I of the present invention or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition may also contain pharmaceutically acceptable carrier.
在又一方面，本发明提供了式1-I或2-I化合物或其药学上可接受的盐，或者本发明的药物组合物在用于制备治疗雄激素受体介导的疾病的药物中的用途，还提供了用于治疗雄激素受体介导的疾病的本发明的式1-I或2-I化合物或其药学上可接受的盐或者本发明的药物组合物。In yet another aspect, the present invention provides a compound of formula 1-I or 2-I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for treating androgen receptor-mediated diseases It also provides the compound of formula 1-I or 2-I of the present invention or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention for treating diseases mediated by androgen receptor.
在另一方面，本发明提供了一种治疗或预防雄激素受体介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method for treating or preventing an androgen receptor-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1-I or 2-I of the present invention, Its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof.
在另一方面，本发明提供了一种治疗或预防雄激素受体变异体介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method for treating or preventing diseases mediated by androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I or 2-I of the present invention Compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or pharmaceutical combinations thereof things.
在另一方面，本发明提供了一种治疗或预防雄激素受体剪切变异体(AR-Vs)介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method of treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of a formula of the present invention 1-I or 2-I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs Or metabolites or pharmaceutical compositions thereof.
在另一方面，本发明提供了一种治疗或预防AR-V7介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶 型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method for treating or preventing an AR-V7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1-I or 2-I of the present invention, its Pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs Forms, prodrugs or metabolites or pharmaceutical compositions thereof.
在另一方面，本发明提供了一种治疗或预防雄激素受体和雄激素受体变异体介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method of treating or preventing diseases mediated by androgen receptor and androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I of the present invention or 2-I compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or its pharmaceutical composition.
在另一方面，本发明提供了一种治疗或预防雄激素受体和雄激素受体剪切变异体(AR-Vs)介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method of treating or preventing diseases mediated by androgen receptor and androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of The compound of formula 1-I or 2-I of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, solvate, isotope substitution, polymorphic form Drugs, prodrugs or metabolites or pharmaceutical compositions thereof.
在另一方面，本发明提供了一种治疗或预防雄激素受体和AR-V7介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method for treating or preventing diseases mediated by androgen receptor and AR-V7, said method comprising administering to a subject in need a therapeutically effective amount of Formula 1-I or 2 of the present invention -I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical composition.
在另一方面，本发明提供了一种治疗或预防雄激素受体变异体介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method for treating or preventing diseases mediated by androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I or 2-I of the present invention Compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or pharmaceutical combinations thereof things.
在另一方面，本发明提供了一种治疗或预防雄激素受体剪切变异体(AR-Vs)介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method of treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of a formula of the present invention 1-I or 2-I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs Or metabolites or pharmaceutical compositions thereof.
在另一方面，本发明提供了一种治疗或预防AR-V7介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method for treating or preventing an AR-V7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1-I or 2-I of the present invention, its Pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof.
本发明的更详细的技术方案及描述如下文所述。The more detailed technical solutions and descriptions of the present invention are as follows.
具体实施方式 Detailed ways
在以下描述中，陈述了某些具体细节以便提供多个实施方案的全面理解。然而，本领域技术人员应理解，本发明可在不具有这些细节的情况下实施。在其他情况下，未详细地示出或描述众所周知的结构，以避免不必要地使对所述实施方案的描述模糊。除非上下文另外要求，否则在整个说明书和以下权利要求书中，措词“包含”和其变化形式，如“包括”和“含有”将以开放、包括含义来解释，也就是说解释为“包括但不限于”。此外，本文所提供的标题仅出于便利目的并且不解释要求保护的本发明的范围或含义。In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Throughout the specification and the following claims, unless the context requires otherwise, the word "comprise" and variations thereof, such as "comprises" and "comprises", are to be construed in an open, inclusive sense, that is to say as "comprising but not limited to". Furthermore, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
在本说明书中提及“一个实施方案”意指关于所述实施方案所描述的特定特点、结构或特征包括在至少一个实施方案中。因此，在本说明书中的多个地方出现短语“在一个实施方案中”不必要全部是指同一实施方案。此外，所述特定特点、结构或特征可以任何合适方式组合于一个或多个实施方案中。另外，除非上下文另外明确规定，否则如本说明书和权利要求书中所用，单数形式“一个”和“所述”包括多个提及物。还应注意，除非上下文另外明确规定，否则术语“或”一般以其包括“和/或”的含义使用。Reference in this specification to "one embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" in various places in this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in the specification and claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.
r.术语r. Terminology
特定官能团和化学术语的定义在下面更详细地描述。为了本公开的目的，根据元素周期表(CAS版，Handbook of Chemistry and Physics，第75版，内封面)来认定化学元素，并且具体的官能团通常如本文所述进行定义。Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements (CAS edition, Handbook of Chemistry and Physics, 75th Edition, inside cover), and specific functional groups are generally defined as described herein.
在本申请的不同地方描述了连接取代基。如果该结构明显需要一个连接基团，则为该基团列出的马库什变化应理解为连接基团。例如，如果结构需要连接基团并且该变量的马库什基团定义列出“烷基”，则应理解“烷基”代表连接亚烷基。Linking substituents are described in various places in this application. If the structure clearly requires a linking group, the Markush changes listed for that group are to be understood as linking groups. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl," then "alkyl" is understood to represent a linking alkylene.
当连接至取代基的键显示为与环中连接两个原子的键交叉时，该取代基可键连至环中的任意原子。当列出取代基但未指明该取代基通过何种原子键连至给定式的化合物的其余部分时，该取代基可通过所述式中的任意原子键连。取代基和/或变量的组合是允许的，但前提是该组合得到稳定的化合物。When a bond to a substituent is shown to cross a bond connecting two atoms in the ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating through which atom the substituent is bonded to the rest of the compound of a given formula, the substituent may be bonded through any atom in the formula. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
“氰基”指-CN基团。 "Cyano" refers to a -CN group.
“卤素”指氟、氯、溴或碘基团。"Halogen" refers to a fluoro, chloro, bromo or iodo group.
“羟基”指-OH基团。"Hydroxy" means an -OH group.
“氧代”指＝O。"Oxo" means =O.
“-CO-”指-C(＝O)-"-CO-" means -C(=O)-
在本申请中，术语“Ci-Cj”表示碳原子数的范围，其中i和j是整数，并且碳原子数的范围包括端点(即，i和j)以及之间的每个整数点，其中j大于i。例如，C1-C6表示1至6个碳原子的范围，包括1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子和6个碳原子。在一些实施方案中，术语“C1-C12”表示1至12个，特别是1至10个，特别是1至8个，特别是1至6个，特别是1至5个，特别是1至4个，特别是1至3个或特别是1至2个碳原子。In this application, the term "C i -C j " denotes a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer point in between , where j is greater than i. For example, C 1 -C 6 represents a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms and 6 carbon atoms. In some embodiments, the term "C 1 -C 12 " means 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3 or especially 1 to 2 carbon atoms.
在本申请中，作为基团或是其它基团的一部分，“烷基”指通过单键连接至分子的其余部分的完全饱和的直链或支链烃链基团。术语“Ci-Cj烷基”指具有i至j个碳原子的烷基。在一些实施方案中，烷基含有1至12个碳原子。在一些实施方案中，烷基含有1至11个碳原子。在一些实施方案中，烷基含有1至10个碳原子，1至9个碳原子，1至8个碳原子，1至7个碳原子，1至6个碳原子，1至5个碳原子，1至4个碳原子，1至3个碳原子或1至2个碳原子。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、仲丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、叔戊基、正己基、正庚基、正辛基、正壬基、正癸基、正十一烷基和正十二烷基。除非本说明书中另外特别地规定，否则烷基可任选地被取代。In this application, "alkyl", as a group or part of another group, refers to a fully saturated straight or branched hydrocarbon chain group connected by a single bond to the rest of the molecule. The term " Ci - Cj alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms , 1 to 4 carbon atoms, 1 to 3 carbon atoms or 1 to 2 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Unless specifically stated otherwise in this specification, an alkyl group may be optionally substituted.
在本申请中，作为基团或是其它基团的一部分，“烯基”指具有一个或多个碳碳双键(-C＝C-)的直链或支链烃链基团。在一些实施方案中，烯基含有2至12个碳原子。在一些实施方案中，烯基含有2至11个碳原子。在一些实施方案中，烯基含有2至10个碳原子，2至9个碳原子，2至8个碳原子，2至7个碳原子，2至6个碳原子，2至5个碳原子，2至4个碳原子，2至3个碳原子，并且在一些实施方案中，烯基含有2个碳原子。烯基的非限制性实例包括乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、5-庚烯基、6-庚烯基、1-辛烯基、 2-辛烯基、3-辛烯基、4-辛烯基、5-辛烯基、6-辛烯基、7-辛烯基、1-壬烯基、2-壬烯基、3-壬烯基、4-壬烯基、5-壬烯基、6-壬烯基、7-壬烯基、8-壬烯基、1-癸烯基、2-癸烯基、3-癸烯基、4-癸烯基、5-癸烯基、6-癸烯基、7-癸烯基、8-癸烯基、9-癸烯基、1-十一碳烯基、2-十一碳烯基、3-十一碳烯基、4-十一碳烯基、5-十一碳烯基、6-十一碳烯基、7-十一碳烯基、8-十一碳烯基、9-十一碳烯基、10-十一碳烯基、1-十二碳烯基、2-十二碳烯基、3-十二碳烯基、4-十二碳烯基、5-十二碳烯基、6-十二碳烯基、7-十二碳烯基、8-十二碳烯基、9-十二碳烯基、10-十二碳烯基和11-十二碳烯基。除非本说明书中另外特别地规定，否则烯基可任选地被取代。In this application, "alkenyl", as a group or a part of other groups, refers to a straight or branched hydrocarbon chain group having one or more carbon-carbon double bonds (-C=C-). In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, alkenyl contains 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms , 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Non-limiting examples of alkenyl include vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butene Base, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-heptenyl, 5-heptenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- Octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-octenyl Nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decene Base, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl Carbenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl Base, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl and 11-dodecenyl dodecenyl. Unless specifically stated otherwise in this specification, alkenyl groups may be optionally substituted.
在本申请中，作为基团或是其它基团的一部分，“炔基”指具有一个或多个碳碳三键(-C≡C-)的直链或支链烃链基团。在一些实施方案中，炔基含有2至12个碳原子。在一些实施方案中，炔基含有2至11个碳原子。在一些实施方案中，炔基含有2至10个碳原子，2至9个碳原子，2至8个碳原子，2至7个碳原子，2至6个碳原子，2至5个碳原子，2至4个碳原子，2至3个碳原子，并且在一些实施方案中，炔基含有2个碳原子。炔基的非限制性实例包括乙炔基、丙炔基、丁炔基、戊炔基等。除非本说明书中另外特别地规定，否则炔基可任选地被取代。In this application, as a group or part of other groups, "alkynyl" refers to a straight or branched hydrocarbon chain group having one or more carbon-carbon triple bonds (-C≡C-). In some embodiments, alkynyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms , 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, and the like. Unless specifically stated otherwise in this specification, an alkynyl group may be optionally substituted.
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基(例如烷基、烯基或炔基)，其可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化，并且环烷基可任选地被取代。In this application, the term "cycloalkyl", as a group or part of another group, means a stable non-aromatic monocyclic or polycyclic hydrocarbon group (such as alkyl, alkenyl, group or alkynyl), which may be attached to the rest of the molecule by a single bond via any suitable carbon atom. Unless specifically stated otherwise in this specification, the carbon atoms in the cycloalkyl group can be optionally oxidized, and the cycloalkyl group can be optionally substituted.
在一些实施方案中，环烷基可含有3至12个成环碳原子，3至10个成环碳原子，3至9个成环碳原子，3至8个成环碳原子，3至7个成环碳原子，3至6个成环碳原子，3至5个成环碳原子，4至12个成环碳原子，4至10个成环碳原子，4至9个成环碳原子，4至8个成环碳原子，4至7个成环碳原子，4至6个成环碳原子，4至5个成环碳原子。In some embodiments, cycloalkyl groups may contain from 3 to 12 ring carbon atoms, from 3 to 10 ring carbon atoms, from 3 to 9 ring carbon atoms, from 3 to 8 ring carbon atoms, from 3 to 7 ring carbon atoms, 3 to 6 ring carbon atoms, 3 to 5 ring carbon atoms, 4 to 12 ring carbon atoms, 4 to 10 ring carbon atoms, 4 to 9 ring carbon atoms , 4 to 8 ring carbon atoms, 4 to 7 ring carbon atoms, 4 to 6 ring carbon atoms, 4 to 5 ring carbon atoms.
在一些实施方案中，环烷基可以是非芳香族的单环烃基，其实例包括但不限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基和环十二烷基。 In some embodiments, the cycloalkyl group may be a non-aromatic monocyclic hydrocarbon group, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopentyl -2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexyl Hexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
在一些实施方案中，环烷基可以是非芳香族的多环(例如，双环和三环)烃基，其可为稠合环体系，螺环体系或桥环体系。术语“稠合环”是指具有两个环共享两个相邻原子的环体系，术语“螺环”是指具有通过一个单个共同原子连接的两个环的环体系，以及术语“桥环”指具有两个共享三个或三个以上原子的环的环体系。稠合的环烷基的实例包括但不限于H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯并基等。螺环基的实例包括但不限于螺[5.5]十一烷基、螺-戊二烯基、螺[3.6]-癸基等。桥环基的实例包括但不限于双环[1,1,1]戊烯基、双环[2,2,1]庚烯基、双环[2.2.1]庚基、双环[2.2.2]辛基、双环[3.3.1]壬基、双环[3.3.3]十一烷等。In some embodiments, cycloalkyl groups can be non-aromatic polycyclic (eg, bicyclic and tricyclic) hydrocarbon groups, which can be fused, spiro, or bridged ring systems. The term "fused ring" means a ring system having two rings sharing two adjacent atoms, the term "spiro" means a ring system having two rings joined by a single common atom, and the term "bridged ring" Refers to a ring system having two rings that share three or more atoms. Examples of fused cycloalkyls include, but are not limited to, H-indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro -Naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8 ,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2 .1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo [3.2.1] Octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl, octahydro-2,5-methylene-pentalenyl, and the like. Examples of spirocyclyl groups include, but are not limited to, spiro[5.5]undecyl, spiro-pentadienyl, spiro[3.6]-decyl, and the like. Examples of bridged ring groups include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl , Bicyclo[3.3.1]nonyl, bicyclo[3.3.3]undecane, etc.
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由碳原子(例如2、3、4、5、6、7、8、9、10、11、12、13或14个碳原子)以及选自氮、磷、氧和硫的杂原子(例如1至6个杂原子)组成的稳定的非芳香族环状基团。在一些实施方案中，杂环基可含有3至20个成环原子，3至19个成环原子，3至18个成环原子，3至17个成环原子，3至16个成环原子，3至15个成环原子，4至12个成环原子，4至10个成环碳原子，4至9个成环原子，4至8个成环原子，4至7个成环原子，4至6个成环原子，4至5个成环原子。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系。杂环基中的氮、碳或硫原子可任选地被氧化，氮原子可任选地被季铵化。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在一些情况中，杂环基可以是碳连接的、氮连接的或硫连接的。在一些实施方案中，杂环基是碳连接的。在一些实施方案中，杂环基是氮连接的。在一些实施方案中，杂环基是硫连接的。In this application, the term "heterocyclyl", as a group or part of another group, means a group consisting of carbon atoms (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13 or 14 carbon atoms) and a stable non-aromatic cyclic group consisting of heteroatoms (eg, 1 to 6 heteroatoms) selected from nitrogen, phosphorus, oxygen and sulfur. In some embodiments, a heterocyclyl group can contain from 3 to 20 ring-forming atoms, from 3 to 19 ring-forming atoms, from 3 to 18 ring-forming atoms, from 3 to 17 ring-forming atoms, from 3 to 16 ring-forming atoms , 3 to 15 ring-forming atoms, 4 to 12 ring-forming atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming atoms, 4 to 8 ring-forming atoms, 4 to 7 ring-forming atoms, 4 to 6 ring atoms, 4 to 5 ring atoms. Unless otherwise specified in this specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system. The nitrogen, carbon or sulfur atoms in the heterocyclyl group can be optionally oxidized and the nitrogen atoms can be optionally quaternized. A heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In some cases, a heterocyclyl group can be carbon-, nitrogen-, or sulfur-linked. In some embodiments, the heterocyclyl is carbon attached. In some embodiments, the heterocyclyl is nitrogen-linked. In some embodiments, the heterocyclyl is sulfur-linked.
杂环基还包括其中杂环基基团与饱和的、部分不饱和的或完全不饱和的(即，芳族的)碳环或杂环稠合的基团。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基。稠合杂环基的实例包括但不限于苯基稠合环或吡啶基稠合环、 例如喹啉基、异喹啉基、喹喔啉基、喹嗪基、喹唑啉基、氮杂吲哚嗪基、蝶啶基、色烯基、异色烯基、吲哚基、异吲哚基、吲哚嗪基、吲唑基、嘌呤基、苯并呋喃基、异苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并噻唑基、咔唑基、吩嗪基、吩噻嗪基、菲啶基、咪唑并[1,2-a]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、[1,2,3]三唑并[4,3-a]吡啶基等。Heterocyclyl also includes groups in which a heterocyclyl group is fused to a saturated, partially unsaturated, or fully unsaturated (ie, aromatic) carbocyclic or heterocyclic ring. In a heterocyclyl group comprising fused rings, one or more rings may be aryl or heteroaryl as defined below. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, e.g. quinolinyl, isoquinolinyl, quinoxalinyl, quinazinyl, quinazolinyl, azaindorazinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolinyl Indolyl, indorazinyl, indazolyl, purinyl, benzofuryl, isobenzofuryl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phen Thiazinyl, phenanthridinyl, imidazo[1,2-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,3]triazolo [4,3-a]pyridyl, etc.
在一些实施方案中，杂环基为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至12元、5元至12元、或4元至10元非芳香性单环、双环、桥环或螺环基团，例如包含1至3个选自氮、氧和硫的杂原子的稳定的5元至10元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、硫杂环戊烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、吡唑烷基、邻苯二甲酰亚氨基、二氧代硫代吗啉基、二氧代硫杂环戊烷基、二氧代硫杂环丁烷基、硫杂环己烷基、二氧代硫代环己烷基、硫代吗啉基、1,4-氧硫杂环己烷基等。In some embodiments, the heterocyclyl group is a stable 4- to 12-membered, 5- to 12-membered, or 4- to 10-membered non-aromatic unit comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Cyclic, bicyclic, bridged or spirocyclic groups, for example stable 5- to 10-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonyl Alkane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, aza Cyclobutanyl, oxetanyl, thietanyl, thiolanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxane Amyl, imidazolidinyl, imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, pyrazolidinyl, phthalimido, dioxothiomorpholine Dioxothiolanyl, dioxothietanyl, thiacyclohexyl, dioxothiocyclohexyl, thiomorpholinyl, 1,4-oxo Thianyl, etc.
在本申请中，作为基团或是其它基团的一部分，“芳基”指具有6至18个碳原子(例如6至14个碳原子或6至10个碳原子，例如6、7、8、9或10个碳原子)的共轭烃环体系基团。芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合。在多环体系的情况下，尽管所有环可以是芳香族的，但是仅一个环需要是芳香族的。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。除非本说明书中另外特别地规定，否则术语“芳基”包括任选地被取代的芳基。In this application, "aryl", as a group or part of another group, refers to a group having 6 to 18 carbon atoms (eg 6 to 14 carbon atoms or 6 to 10 carbon atoms, eg , 9 or 10 carbon atoms) conjugated hydrocarbon ring system group. Aryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system and can also be fused to a cycloalkyl or heterocyclyl as defined above. In the case of multiple ring systems, only one ring needs to be aromatic, although all rings may be aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazin-3(4H)-on-7-yl and the like. Unless specifically stated otherwise in this specification, the term "aryl" includes optionally substituted aryl groups.
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有碳原子(例如1至15个碳原子，1至14个碳原子，1至13个碳原子，1至12个碳原子，1至11个碳原子，1至10个碳原子，例如1、2、3、4、5、6、7、8、9或10个碳原子)和选自氮、氧和硫的杂原子(例如1至6个杂原子)的共轭环系基团。在一 些实施方案中，杂芳基可含有5至20个成环原子，5至19个成环原子，5至18个成环原子，5至17个成环原子，5至16个成环原子，5至15个成环原子，5至14个成环原子，5至13个成环原子，5至12个成环原子，5至10个成环碳原子，5至9个成环原子，5至8个成环原子，5至7个成环原子，或5至6个成环原子。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合。杂芳基中的氮、碳或硫原子可任选地被氧化，氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。In this application, the term "heteroaryl", as a group or part of another group, means a ring having carbon atoms (for example, 1 to 15 carbon atoms, 1 to 14 carbon atoms, 1 to 13 carbon atoms , 1 to 12 carbon atoms, 1 to 11 carbon atoms, 1 to 10 carbon atoms, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms) and selected from nitrogen , oxygen and sulfur heteroatoms (eg 1 to 6 heteroatoms) conjugated ring system groups. In a In some embodiments, the heteroaryl group can contain from 5 to 20 ring-forming atoms, from 5 to 19 ring-forming atoms, from 5 to 18 ring-forming atoms, from 5 to 17 ring-forming atoms, from 5 to 16 ring-forming atoms, 5 to 15 ring atoms, 5 to 14 ring atoms, 5 to 13 ring atoms, 5 to 12 ring atoms, 5 to 10 ring carbon atoms, 5 to 9 ring atoms, 5 to 8 ring atoms, 5 to 7 ring atoms, or 5 to 6 ring atoms. Unless otherwise specified in this specification, heteroaryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and can also be fused with a cycloalkyl or heterocyclyl as defined above. The nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized, and the nitrogen atoms can be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 heteroatoms selected from A stable 5- to 10-membered aromatic group of heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吗啉基、苯并异二唑基、苯并三唑基、咪唑并吡啶基、吡啶并吗啉基、吡唑并吡啶基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪、四氢异喹啉基、十氢异喹啉基、二氢吲哚基、八氢吲哚基和八氢异吲哚基等。Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl, Benzimidazolyl, Benzmorpholinyl, Benzisodiazolyl, Benzotriazolyl, Imidazopyridinyl, Pyridomorpholinyl, Pyrazolopyridinyl, Indolyl, Furanyl Base, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolyl, diazine Base, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzene Thienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthrenyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4 ,5,6,7-Tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]tri Azolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, Imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, tetrahydroisoquinolyl, decahydroisoquinolyl, di Hydroindolyl, octahydroindolyl and octahydroisoindolyl, etc.
在本申请中，“任选”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。In this application, "optional" or "optionally" means that the subsequently described event or situation may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or situation.
在本申请中，术语“取代”，无论之前是否有术语“任选地”，是指指定部分的一个或多个氢被合适的取代基取代。将理解的是，“取代”或“被...取代”包括隐含的条件，即此类取代根据取代原子的允许价数进行，并且取代产生稳定或化学上可行的化合物，例如不会例如通过重排、环化、消除等自发发生转化的化合物。除非另有说明，“任选取代的”基团可在该基团的每个可取代位置上具有合适的取代 基，并且当任何给定结构中的一个以上的位置可以被选自指定组的一个以上的取代基取代时，该取代基在每个位置上可以相同或不同。本领域技术人员将理解，如果合适，取代基本身可以被取代。除非特别指明为“未取代的”，否则本文中提及的化学部分应理解为包括取代的变体。例如，提及“芳基”基团或部分隐含包括取代和未取代的变体。In this application, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced by a suitable substituent. It will be understood that "substituted" or "substituted by" includes the implied proviso that such substitutions are made according to the permissible valences of the substituting atoms and that the substitutions result in stable or chemically feasible compounds, e.g. A compound that undergoes transformation spontaneously by rearrangement, cyclization, elimination, etc. Unless otherwise stated, an "optionally substituted" group may have suitable substitutions at each substitutable position of the group and when more than one position in any given structure may be substituted with one or more substituents selected from a specified group, the substituents may be the same or different at each position. Those skilled in the art will appreciate that the substituents themselves may be substituted, as appropriate. Unless specifically indicated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variations.
在本申请中所述的“任选”的取代基包括但不限于本文所述的烷基、烯基、炔基、卤素、卤代烷基、卤代烯基、卤代炔基、烷氧基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、硝基、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环基等；作为取代基的这些基团，包括烷基、烯基、炔基、卤代烷基中的烷基、卤代烯基中的烯基、卤代炔基中的炔基、烷氧基、单烷基氨基中的烷基、二烷基氨基中的烷基、芳基、杂芳基、环烃基和杂环基，还可任选地被选自烷基、卤素、卤代烷基、烷氧基、羟基、氨基、单烷基氨基、二烷基氨基、硝基、芳基、杂芳基、环烃基和杂环基中的一个或多个基团取代。本文中，取代基的数量可为一个或多个，即1、2、3、4、5或6个或更多个，根据被取代的基团以及取代基的性质决定。例如，当取代基为卤素时，根据被取代的基团的结构，该基团可被1-6个取代基取代，如三氟甲基、五氟乙基等。The "optional" substituents described in this application include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, Cyano, hydroxy, amino, monoalkylamino, dialkylamino, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl etc.; these groups as substituents include alkyl, alkenyl, alkynyl, alkyl in haloalkyl, alkenyl in haloalkenyl, alkynyl in haloalkynyl, alkoxy, mono The alkyl group in the alkylamino group, the alkyl group in the dialkylamino group, the aryl group, the heteroaryl group, the cyclohydrocarbyl group and the heterocyclyl group can also optionally be selected from the group consisting of alkyl, halogen, haloalkyl, alkoxy , hydroxy, amino, monoalkylamino, dialkylamino, nitro, aryl, heteroaryl, cycloalkyl and heterocyclyl are substituted by one or more groups. Herein, the number of substituents can be one or more, ie 1, 2, 3, 4, 5 or 6 or more, depending on the group to be substituted and the nature of the substituent. For example, when the substituent is halogen, the group may be substituted by 1-6 substituents, such as trifluoromethyl, pentafluoroethyl, etc., according to the structure of the substituted group.
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules.
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R“(其中R“为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基酯类、芳基酯类或芳烷基酯类类。Those skilled in the art will also understand that in the methods described below, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl esters, aryl esters or aralkyl esters.
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi  Synthesis，(1999)，4th Ed.，Wiley中。保护基还可为聚合物树脂。Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, TW and PGMWuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., in Wiley. The protecting group can also be a polymeric resin.
如本文所用，“受试者”可以是人、非人灵长类动物、哺乳动物、大鼠、小鼠、牛、马、猪、绵羊、山羊、狗、猫等。受试者可疑似患有或处于患有如前列腺癌、乳腺癌、卵巢癌、膀胱癌、胶质母细胞瘤、黑色素瘤、肾细胞癌、套细胞淋巴瘤、胰腺癌、肝细胞癌、子宫内膜癌、唾液腺癌等癌症的风险中，或疑似患有或处于患有脱发、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、年龄相关性黄斑变性的风险中。本领域技术人员已知针对如前列腺癌、乳腺癌、卵巢癌、膀胱癌、胶质母细胞瘤、黑色素瘤、肾细胞癌、套细胞淋巴瘤、胰腺癌、肝细胞癌、子宫内膜癌、唾液腺癌等多种癌症的诊断方法，和针对脱发、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或年龄相关性黄斑变性的诊断方法，和前列腺癌、乳腺癌、卵巢癌、膀胱癌、胶质母细胞瘤、黑色素瘤、肾细胞癌、套细胞淋巴瘤、胰腺癌、肝细胞癌、子宫内膜癌、唾液腺癌等癌症的临床描绘，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或年龄相关性黄斑变性的诊断和临床描绘。As used herein, a "subject" can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, and the like. Subjects may be suspected to have or are suffering from such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, intrauterine Cancers such as menstrual carcinoma, salivary gland cancer, or suspected or at risk of alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration middle. Those skilled in the art know against such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, Diagnostic methods for various cancers such as salivary gland cancer, and for alopecia, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration, and prostate cancer, breast cancer Clinical depiction of cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, Diagnosis and clinical delineation of hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
“哺乳动物”包括：人；饲养动物，如实验室动物和家庭宠物(例如，猫、狗、猪、牛、绵羊、山羊、马、兔)，和非饲养动物，如野生动物等。"Mammal" includes: humans; domestic animals, such as laboratory animals and household pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals, etc.
“药学上可接受的载体、稀释剂或赋形剂”包括但不限于已经由例如美国食品和药物管理局(FDA)批准可接受用于人类或饲养动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、风味增强剂、表面活性剂、湿润剂、分散剂、悬浮剂、稳定剂、等张剂、溶剂或乳化剂。"Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by, for example, the U.S. Food and Drug Administration (FDA) for use in humans or domesticated animals , glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
本申请公开的化合物可以多种不同形式或衍生物存在，所有这些均在本公开内容的范围内。这些包括例如互变异构体、立体异构体、外消旋混合物、几何异构体、盐、前药、溶剂化物、不同的晶体形式或多晶型物以及活性代谢物。The compounds disclosed herein may exist in many different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, geometric isomers, salts, prodrugs, solvates, different crystal forms or polymorphs, and active metabolites.
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸 盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetic acid salt, trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, caproate Dialate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleic acid Salt, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate Salt, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.
本申请化合物的前药的实例可包括含有羧酸的化合物的简单酯(例如依据本领域已知方法通过与C1-4醇缩合而获得的酯)；含有羟基的化合物的酯(例如依据本领域已知方法通过与C1-4羧酸、C3-6二酸或其酸酐例如琥珀酸酐和富马酸酐缩合而获得的酯)；含有氨基的化合物的亚胺(例如依据本领域已知方法通过与C1-4醛或酮缩合而获得的亚胺)；含有氨基的化合物的氨基甲酸酯，例如Leu等人(J.Med.Chem.，42：3623-3628(1999))和Greenwald等人(J.Med.Chem.，42：3657-3667(1999))描述的那些酯；含有醇的化合物的醛缩醇或酮缩醇(例如依据本领域已知方法通过与氯甲基甲基醚或氯甲基乙基醚缩合而获得的那些缩醇)。Examples of prodrugs of the compounds of the present application may include simple esters of compounds containing carboxylic acids (for example, esters obtained by condensation with C 1-4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (for example, according to this invention art-known methods; esters obtained by condensation with C 1-4 carboxylic acids, C 3-6 diacids or their anhydrides such as succinic anhydride and fumaric anhydride); imines of compounds containing amino groups (e.g. according to art-known Process imines obtained by condensation with C 1-4 aldehydes or ketones); carbamates of compounds containing amino groups, such as Leu et al. (J.Med.Chem., 42:3623-3628 (1999)) and Those esters described by Greenwald et al. (J.Med.Chem., 42:3657-3667 (1999)); aldols or ketals of alcohol-containing compounds (e.g. by reacting with chloromethyl Those acetals obtained by condensation of methyl ether or chloromethyl ethyl ether).
如本文所用，术语“溶剂化物”指包含本发明化合物的一个或多个分子与一个或多个溶剂分子的聚集体。所述溶剂可以是水，在所述情况下溶剂化物可以是水合物。或者，所述溶剂可以是有机溶剂。因此，本发明化合物可作为水合物存在，包 括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及作为相应溶剂化形式存在。本发明化合物可以是真溶剂化物，而在其他情况下，本发明化合物可仅仅保持不定水或水加上一些不定溶剂的混合物。As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the invention may exist as hydrates, including Including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as existing as corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may retain only the adventitious water or a mixture of water plus some adventitious solvent.
本文中，“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本申请将涵盖各种立体异构体及其混合物。Herein, "stereoisomer" refers to a compound composed of the same atoms bonded by the same bond, but having a different three-dimensional structure. This application will cover the various stereoisomers and mixtures thereof.
当本申请的化合物中含有烯双键时，除非另有说明，否则本申请的化合物旨在包含E-和Z-几何异构体。When olefinic double bonds are contained in the compounds of the present application, unless otherwise stated, the compounds of the present application are intended to include both E- and Z-geometric isomers.
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本申请的化合物的所有互变异构形式也将包含在本申请的范围内。"Tautomer" refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the application are also intended to be encompassed within the scope of the application.
本申请的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为I-或(S)-。本申请旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本申请的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。Compounds of the present application, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms. Each chiral carbon atom can be defined as I- or (S)- based on stereochemistry. This application is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present application can select racemates, diastereomers or enantiomers as raw materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见GeRald Gübitz and Martin G.Schmid(Eds.),ChiRal SepaRations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,ChiRal SepaRations,Annu.Rev.Anal.Chem.3：341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRaCTICAL ORGANIC CHEMISTRY.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography. ), see, for example, GeRald Gübitz and Martin G. Schmid (Eds.), ChiRal SepaRations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; A.M.Stalcup, ChiRal SepaRations, Annu.Rev.Anal.Chem.3 : 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRaCTICAL ORGANIC CHEMISTRY.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc.Chem. Res. 1990, 23, 128.
本发明还包括本发明的化合物或其药学上可接受的盐的所有适宜的同位素变体。本发明的化合物或其药学上可接受的盐的同位素变体被定义为其中至少一个原子被具有相同原子数、但原子质量与自然界经常发现的原子质量不同的原子所替换的那些。可以掺入到本发明的化合物及其药学上可接受的盐中的同位素包括但不限于H、C、N和O的同位素，例如2H、3H、11C、13C、14C、15N、17O、18O、35S、18F、36Cl和125I。本发明所述化合物或其药学上可接受的盐的同位素变体可以通过常规技术、 采用适宜试剂的适当同位素变体来制备。The present invention also includes all suitable isotopic variations of the compounds of the present invention or pharmaceutically acceptable salts thereof. Isotopic variations of a compound of the present invention, or a pharmaceutically acceptable salt thereof, are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from that normally found in nature. Isotopes that may be incorporated into compounds of the present invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F, 36 Cl, and 125 I. Isotopic variants of the compounds of the present invention or pharmaceutically acceptable salts thereof can be obtained by conventional techniques, Prepared using appropriate isotopic variants of appropriate reagents.
本文中，如无特别说明，各结构式或基团上的波浪线一般表示该结构式或基团与化合物中其它部分连接的位置。Herein, unless otherwise specified, the wavy line on each structural formula or group generally indicates the position where the structural formula or group is connected to other parts in the compound.
如本文所用，术语“晶体形式”和“多晶型物”可以互换使用，并且是指化合物(或其盐或溶剂化物)可以在不同的晶体堆积排列(全部具有相同的元素组成)中结晶的晶体结构。不同的晶体形式通常具有不同的X射线衍射图、红外光谱、熔点、密度硬度、晶体形状、光学和电学性质、稳定性和溶解性。重结晶溶剂、结晶速率、储存温度和其他因素可能导致一种晶型占主导地位。化合物的多晶型物可以通过在不同条件下结晶来制备。As used herein, the terms "crystal form" and "polymorph" are used interchangeably and mean that a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements (all having the same elemental composition) crystal structure. Different crystal forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Polymorphs of a compound can be prepared by crystallization under different conditions.
如本文所用，术语“活性代谢物”是药理活性化合物或进一步代谢成药理活性化合物的化合物，所述药理活性化合物是由受试者体内代谢过程产生的衍生物。例如，这种代谢物可以由所施用的化合物或盐或前药的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯化、酶促裂解等产生。其中，活性代谢物是这种药理活性的衍生物化合物。As used herein, the term "active metabolite" is a pharmacologically active compound or a compound that is further metabolized to a pharmacologically active compound that is a derivative produced by a metabolic process in a subject. For example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Among them, the active metabolite is the pharmacologically active derivative compound.
“药物组合物”指本发明化合物和所属领域中公认用于递送生物活性化合物至哺乳动物(例如，人)的介质的制剂。这种介质包括其所有药学上可接受的载体、稀释剂或赋形剂。A "pharmaceutical composition" refers to a formulation of a compound of the invention and an art-recognized vehicle for the delivery of a biologically active compound to a mammal (eg, a human). Such medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
“有效量”是指治疗有效量或预防有效量。“治疗有效量”是指在必需剂量下和持续必需时间段，有效实现所需治疗结果(如降低的肿瘤大小、增加的寿命或增加的预期寿命)的量。化合物的治疗有效量可根据如下因素改变，如受试者的疾病状态、年龄、性别和重量，和所述化合物在所述受试者中引起所需反应的能力。给药方案可经过调节以提供最佳治疗反应。治疗有效量也为其中所述化合物的任何毒性或有害效应均由治疗有益效应超过的量。“预防有效量”是指在必需剂量下和持续必需时间段，有效实现所需预防结果(如较小肿瘤、增加的寿命、增加的预期寿命或预防前列腺癌进展至去势抵抗性形式)的量。通常，预防剂量在疾病的早期阶段之前或在疾病的早期阶段用于受试者中，使得预防有效量可以小于治疗有效量。"Effective amount" refers to a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as decreased tumor size, increased lifespan, or increased life expectancy. A therapeutically effective amount of a compound can vary depending on factors such as the disease state, age, sex and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. "Prophylactically effective amount" means an amount effective, at doses and for periods of time necessary, to achieve the desired prophylactic result (e.g., smaller tumors, increased lifespan, increased life expectancy, or prevention of progression of prostate cancer to a castration-resistant form). quantity. Typically, a prophylactic dose is administered to a subject before or at an early stage of the disease, such that the prophylactically effective amount may be less than the therapeutically effective amount.
如本文所用，“治疗”涵盖患有所关注的疾病或病状的哺乳动物(优选为人)中的所关注的疾病或病状的治疗，并且包括： As used herein, "treatment" encompasses the treatment of a disease or condition of interest in a mammal, preferably a human, suffering from the disease or condition of interest, and includes:
(r)预防所述疾病或病状在哺乳动物中发生，特别是当所述哺乳动物易患所述病状但尚未经诊断患有所述病状时；(r) preventing said disease or condition from occurring in a mammal, especially when said mammal is susceptible to said condition but has not been diagnosed with said condition;
(ii)抑制所述疾病或病状，即，遏制其发展；(ii) inhibiting said disease or condition, i.e. arresting its development;
(iii)减轻所述疾病或病状，即，使所述疾病或病状消退；或(iii) alleviating the disease or condition, i.e. causing regression of the disease or condition; or
(iv)减轻由所述疾病或病状引起的症状，即，减轻疼痛而未解决潜在疾病或病状。(iv) Alleviating symptoms caused by the disease or condition, ie, alleviating pain without addressing the underlying disease or condition.
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。本领域周知的给药方法均可用于本发明。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括肺内、鼻内、鞘内、静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington‘s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，通过口服施用本发明的式I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。As used herein, the terms "administering", "administering", "administering" and the like refer to methods capable of delivering a compound or composition to the desired site of biological action. Administration methods known in the art can be used in the present invention. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), Topical and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, as described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co. ., those discussed in Easton, Pa. In a preferred embodiment, the compounds of formula I of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, and isotopic substitutions are administered orally , polymorph, prodrug or metabolite or pharmaceutical composition thereof.
本文中，“联用”、“药物联用”、“联合用药”或“联合治疗”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合，或者指两种或两种以上不同的治疗手段的组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。Herein, "combination", "drug combination", "combination drug" or "combination therapy" etc. refers to drug therapy obtained by mixing or combining more than one active ingredient, which includes fixed and unfixed active ingredients Combination, or the combination of two or more different treatments. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one co-agent in the form of a single entity or single dosage form. The term "variable combination" refers to simultaneous, concomitant or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent as separate entities to a patient. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
II.化合物II. Compounds
在一方面，本申请提供下式1-I所示的化合物：
In one aspect, the application provides the compound shown in the following formula 1-I:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中：in:
环A和环B各自独立为环烷基、杂环基、芳基或杂芳基；Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
环C为键、环烷基、杂环基、芳基或杂芳基；Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
X为C、N、O或S；X is C, N, O or S;
R1和R2各自独立地为不存在、H、卤素、氰基、羟基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基或-NRaRa；R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
前提是当X为C时，R1和R2各自独立地为不存在、H、卤素、氰基、羟基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基或-NRaRa，或者R1和R2与X一起形成任选取代的 provided that when X is C, R and R are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, Optionally substituted alkoxy or -NR a R a , or R 1 and R 2 together with X form optionally substituted
R3和R4各自独立地为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烷氧基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、-(CH2)rNRaRa或-ORb；R and R are each independently H, halogen, cyano, oxo , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally Substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b ;
Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-、-NRa-、或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a -, or -(CH 2 ) r -NR a -CO-;
R5为H、任选取代的烷基、任选取代的烯基或任选取代的炔基； R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Z2为**-Y1-Y2-*，其中Y1为键、任选取代的烷基、任选取代的烯基或任选取代的炔基，Y2为键、O、NH或S，“*”表示Z2与环A的连接点，“**”表示Z2与环C的连接点；Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y 2 is a bond, O, NH or S, "*" indicates the connection point between Z 2 and ring A, "**" indicates the connection point between Z 2 and ring C;
R6为-N＝S(O)RcRd或-(CH2)sS(O)(＝NRe)Rf；R 6 is -N=S(O)R c R d or -(CH 2 ) s S(O)(=NR e )R f ;
R7各自独立地为卤素、氰基、任选取代的烷基、任选取代的烯基、任选取代的炔基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg； Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g ;
Ra各自独立为H、任选取代的烷基、任选取代的烯基、任选取代的炔基或-CORb；each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
Rb为H、任选取代的烷基、任选取代的烯基或任选取代的炔基； R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rc和Rd各自独立选自任选取代的烷基、任选取代的烯基、任选取代的炔基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -NR a R a ; or R c , R d together with the S atom to which they are attached Forming an optionally substituted 4-10 membered heterocyclyl;
Re为H、氰基、任选取代的烷基、任选取代的烯基或任选取代的炔基；R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rf为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rg各自独立为H、-SO2Rf、任选取代的烷基、任选取代的烯基或任选取代的炔基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基；Each R g is independently H, -SO 2 R f , optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R g together with the N atoms to which they are attached form an optionally Substituted 4-10 membered heterocyclic group;
r为0、1、2或3；r is 0, 1, 2 or 3;
s为0、1、2或3；且s is 0, 1, 2 or 3; and
m、n和p各自独立为0、1、2或3。m, n and p are each independently 0, 1, 2 or 3.
在一些实施方案中，环A为芳基。在某些实施方案中，环A为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环A为苯基或萘基。在某些实施方案中，环A为苯基。In some embodiments, Ring A is aryl. In certain embodiments, Ring A is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring A is phenyl or naphthyl. In certain embodiments, Ring A is phenyl.
在一些实施方案中，环A为杂芳基。在某些实施方案中，环A为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环A选自噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、吡咯基、三唑基、三嗪基、咪唑基、吡唑基、吡咯基、吡啶基、嘧啶基或吡嗪基。In some embodiments, Ring A is heteroaryl. In certain embodiments, Ring A is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, ring A is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazole group, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl or pyrazinyl.
在某些实施方案中，环A为吡啶基、嘧啶基或噻吩基。在某些实施方案中，环A为吡啶基。In certain embodiments, Ring A is pyridyl, pyrimidinyl or thienyl. In certain embodiments, Ring A is pyridyl.
在某些实施方案中，环A为 In certain embodiments, Ring A is
在一些实施方案中，环B为芳基。在某些实施方案中，环B为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环B为苯基或萘基。In some embodiments, Ring B is aryl. In certain embodiments, Ring B is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring B is phenyl or naphthyl.
在一些实施方案中，环B为杂芳基。在某些实施方案中，环B为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环B选自噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、 哒嗪基、呋喃基、吡咯基、三唑基、三嗪基、吡啶酮基、苯并吗啉基、吡啶并吗啉基、吲唑基、二氢苯并恶嗪基、吡唑并吡啶基、苯并三唑基、苯并咪唑基、四氢异喹啉基、咪唑并吡啶基、吡啶并吗啉基、苯并异二唑基、吲哚基、喹啉基、异喹啉基、喹唑啉基、喹噁啉基、十氢异喹啉基、二氢吲哚基、八氢吲哚基或八氢异吲哚基。In some embodiments, Ring B is heteroaryl. In certain embodiments, Ring B is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, Ring B is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl, furyl, pyrrolyl, triazolyl, triazinyl, pyridonyl, benzomorpholinyl, pyridomorpholinyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridine Base, benzotriazolyl, benzimidazolyl, tetrahydroisoquinolyl, imidazopyridyl, pyridomorpholinyl, benzisodiazolyl, indolyl, quinolinyl, isoquinolyl , quinazolinyl, quinoxalinyl, decahydroisoquinolyl, indolinyl, octahydroindolyl or octahydroisoindolyl.
在某些实施方案中，环B选自吡啶基、吡啶酮基、吲唑基、二氢苯并恶嗪基、吡唑并吡啶基、苯并吗啉基、吡啶并吗啉基、苯并三唑基、苯并咪唑基、四氢异喹啉基、咪唑并吡啶基或吡啶并吗啉基。In certain embodiments, Ring B is selected from pyridyl, pyridonyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridyl, benzomorpholinyl, pyridomorpholinyl, benzo Triazolyl, benzimidazolyl, tetrahydroisoquinolinyl, imidazopyridinyl or pyridomorpholinyl.
在某些实施方案中，选自下组：
In some embodiments, Select from the group:
在一些实施方案中，环C为键。In some embodiments, Ring C is a bond.
在一些实施方案中，环C为环烷基、杂环基、芳基或杂芳基。In some embodiments, Ring C is cycloalkyl, heterocyclyl, aryl, or heteroaryl.
在一些实施方案中，环C为芳基或杂芳基。In some embodiments, Ring C is aryl or heteroaryl.
在一些实施方案中，环C为芳基。在某些实施方案中，环C为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环C为苯基或萘基。在某些实施方案中，环C为苯基。In some embodiments, Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
在一些实施方案中，环C为杂芳基。在某些实施方案中，环C为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环C选自嘧啶基、吡嗪基、吡啶基、哌啶基、哌嗪基、吗啉基、噻吩基、咪唑基、 吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、哒嗪基、呋喃基、吡咯基、三唑基或三嗪基。In some embodiments, Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, Ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, Pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
在某些实施方案中，环C为嘧啶基、吡嗪基、吡啶基、噻唑基或噁唑基。In certain embodiments, Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl.
在某些实施方案中，选自下组：
In some embodiments, Select from the group:
在一些实施方案中，X为N、O或S，且R1和R2不存在。In some embodiments, X is N, O, or S, and R and R are absent.
在一些实施方案中，X为C，R1和R2各自独立为H、羟基或任选取代的烷基。In some embodiments, X is C, and R and R are each independently H, hydroxyl, or optionally substituted alkyl .
在某些实施方案中，X为C，R1和R2均为任选取代的烷基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。在某些实施方案中，X为C，R1和R2各自独立地为任选取代的C1-C4烷基。In certain embodiments, X is C, and R and R are both optionally substituted alkyl optionally replaced by one or more independently selected from halogen, hydroxy, cyano Substituent group and -NR a R a substituent. In certain embodiments, X is C, and R 1 and R 2 are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，X为C，R1和R2均为甲基。In certain embodiments, X is C and R and R are both methyl.
在某些实施方案中，X为C，R1和R2中的一者为任选取代的烷基，另一者为H或羟基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, X is C, one of R and R is optionally substituted alkyl, the other is H or hydroxy, and the optionally substituted alkyl is optionally replaced by one or Substituents independently selected from halogen, hydroxy, cyano and -NR a R a are substituted.
在某些实施方案中，X为C，R1和R2中的一者为任选取代的C1-C4烷基，另一者为H或羟基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。 In certain embodiments, X is C, one of R and R is optionally substituted C 1 -C 4 alkyl, the other is H or hydroxyl, and the optionally substituted C 1 - C4alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NRaRa .
在某些实施方案中，X为C，R1和R2中的一者为甲基，另一者为羟基。In certain embodiments, X is C, and one of R and R is methyl and the other is hydroxy.
在某些实施方案中，X为C，R1和R2与X一起形成任选取代的 In certain embodiments, X is C, and R and R are taken together with X to form an optionally substituted
在某些实施方案中，X为C，R1和R2与X一起形成 In certain embodiments, X is C, and R and R together form X
在一些实施方案中，R3和R4各自独立地为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb。In some embodiments, R and R are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( CH ) r NR a R a or -OR b .
在一些实施方案中，各R3独立为H、卤素、任选取代的烷基、任选取代的烷氧基或-ORb。In some embodiments, each R3 is independently H, halo, optionally substituted alkyl, optionally substituted alkoxy, or -ORb .
在一些实施方案中，各R3独立为H、卤素、任选取代的烷基或-ORb。In some embodiments, each R3 is independently H, halo, optionally substituted alkyl, or -ORb .
在一些实施方案中，各R3独立为任选取代的C1-C4烷基或任选取代的C1-C4烷氧基。In some embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl or optionally substituted C 1 -C 4 alkoxy.
在某些实施方案中，各R3独立为任选取代的C1-C4烷基或任选取代的C1-C4烷氧基，所述任选取代的C1-C4烷基和任选取代的C1-C4烷氧基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl or optionally substituted C 1 -C 4 alkoxy, said optionally substituted C 1 -C 4 alkyl and optionally substituted C 1 -C 4 alkoxy is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -NR a R a .
在一些实施方案中，各R3独立为H、卤素、C1-C4烷基或C1-C4烷氧基。In some embodiments, each R 3 is independently H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy.
在一些实施方案中，各R3独立选自卤素、C1-C4烷基或C1-C4烷氧基。In some embodiments, each R 3 is independently selected from halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy.
在一些实施方案中，各R3独立为氟、氯、甲基、甲氧基。In some embodiments, each R3 is independently fluoro, chloro, methyl, methoxy.
在一些实施方案中，R3为氟。In some embodiments, R 3 is fluoro.
在一些实施方案中，R3为氯。In some embodiments, R 3 is chloro.
在一些实施方案中，R3为甲基。In some embodiments, R 3 is methyl.
在一些实施方案中，R3为甲氧基。In some embodiments, R 3 is methoxy.
在某些实施方案中，R3为H。In certain embodiments, R3 is H.
在一些实施方案中，各R4独立为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的烷基或-CORb，Rb为H、任选取代的烷基、任选取代的烯基、任选取代的炔基，其中所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。 In some embodiments, each R is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b , wherein R a is each independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted Alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally represented by one or more independently Substituents selected from halogen, hydroxyl, cyano and -NR a R a .
在某些实施方案中，各R4独立为H、卤素、氰基、氧代、环丙基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的C2-C4烯基或-CORb，Rb为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。In certain embodiments, each R4 is independently H, halo, cyano, oxo, cyclopropyl, -( CH2 ) rNRaRa , or -ORb , wherein each Ra is independently H, any Optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
在某些实施方案中，各R4独立为H、氯、氰基、氧代、环丙基、-OCH3、-OC≡CH或-CH2NH(CH＝CH2)。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, cyclopropyl, -OCH3 , -OC≡CH, or -CH2NH (CH= CH2 ).
在某些实施方案中，各R4独立为H、氯、氰基、氧代或-OCH3。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, or -OCH3 .
在一些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的烷基。In some embodiments, Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的C1-C4烷基。In certain embodiments, Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、或-NRa-，其中Ra为H或任选取代的C1-C4烷基。In certain embodiments, Z 1 is a bond, -O-, -CO-, or -NR a -, wherein R a is H or optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NH-、-NHCO-或-CH2NHCO-。In certain embodiments, Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
在某些实施方案中，Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-或-NRa-。In certain embodiments, Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, or -NR a -.
在某些实施方案中，Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-或-NRa-，其中，Ra各自独立为H、任选取代的烷基、任选取代的烯基、任选取代的炔基或-CORb。In certain embodiments, Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, or -NR a -, wherein each R a is independently H, Optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -COR b .
在某些实施方案中，Z1为键、-O-或-CO-，R5为H、任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In certain embodiments, Z 1 is a bond, -O- or -CO-, R 5 is H, optionally substituted C 1 -C 4 alkyl, said optionally substituted C 1 -C 4 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR a R a .
在某些实施方案中，Z1为键、-O-、-CO-或-NRa-，其中Ra为H或任选取代的烷基。In certain embodiments, Z 1 is a bond, -O-, -CO-, or -NR a -, wherein R a is H or optionally substituted alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NH-或-NHCO-。In certain embodiments, Z is a bond, -O-, -CO-, -NH- or -NHCO-.
在某些实施方案中，Z1为键、-O-或-CO-。In certain embodiments, Z is a bond, -O- or -CO-.
在一些实施方案中，R5为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，所述任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, R 5 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, any Optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxy, Substituted by cyano and -NR a R a substituents.
在某些实施方案中，R5为H、任选取代的C1-C4烷基或任选取代的C2-C4烯基， 所述任选取代的C1-C4烷基和任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, R is H, optionally substituted C 1 -C 4 alkyl, or optionally substituted C 2 -C 4 alkenyl, The optionally substituted C 1 -C 4 alkyl and optionally substituted C 2 -C 4 alkenyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.
在某些实施方案中，R5为H、甲基、乙基、丙基或乙烯基，所述甲基、乙基、丙基和乙烯基任选地被一个或多个独立地选自氯、羟基或氰基的取代基取代。In certain embodiments, R is H, methyl, ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine , Hydroxy or cyano substituents.
在一些实施方案中，Z1为键或-O-，R5为H、任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is a bond or -O-, R 5 is H, optionally substituted C 1 -C 4 alkyl optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
在某些实施方案中，Z1为键或-O-，R5为H、甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, Z is a bond or -O-, R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from halogen, hydroxy or cyano are substituted.
在某些实施方案中，Z1为键或-O-，R5为H、甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自氟、氯或羟基的取代基取代。In certain embodiments, Z is a bond or -O-, R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from fluorine, chlorine or hydroxyl are substituted.
在一些实施方案中，Z1为-CO-或-(CH2)r-NRa-C(＝O)-，R5为任选取代的C2-C4烯基，所述任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -C(=O)-, R 5 is optionally substituted C 2 -C 4 alkenyl, the optionally substituted The C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
在一些实施方案中，Z1为-CO-，R5为任选取代的C2-C4烯基，所述任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is -CO-, R 5 is optionally substituted C 2 -C 4 alkenyl optionally replaced by one or more independently Substituents selected from halogen, hydroxyl, cyano or -NR a R a .
在某些实施方案中，Z1为-C(O)-，R5为乙烯基。In certain embodiments, Z 1 is -C(O)- and R 5 is vinyl.
在某些实施方案中，Z1为-C(O)-或-(CH2)r-NRa-C(＝O)-，R5为乙烯基。In certain embodiments, Z 1 is -C(O)- or -(CH 2 ) r -NR a -C(=O)-, and R 5 is vinyl.
在一些实施方案中，-Z1-R5选自-(CH2)rCl、-O(CH2)rF、-O(CH2)rCl或-O(CH2)rOH，其中r为1、2或3。In some embodiments, -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
在一些实施方案中，Z1为键、-O-或-CO-，R5为H、任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is a bond, -O- or -CO-, R 5 is H, optionally substituted C 1 -C 4 alkyl, and the optionally substituted C 1 -C 4 alkyl is any is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
在一些实施方案中，Y1为键，Y2为O、NH或S。In some embodiments, Y 1 is a bond and Y 2 is O, NH or S.
在一些实施方案中，Y1为任选取代的烷基、任选取代的烯基或任选取代的炔基，Y2为键或O，所述任选取代的烷基、任选取代的烯基或任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基、烷基或氧代的取代基取代。In some embodiments, Y 1 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, Y 2 is a bond or O, said optionally substituted alkyl, optionally substituted Alkenyl or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, alkyl or oxo.
在一些实施方案中，Y1为任选取代的烷基、任选取代的烯基或任选取代的炔基， Y2为键或O，所述任选取代的烷基、任选取代的烯基或任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基或氧代的取代基取代。In some embodiments, Y is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, Y is a bond or O, and the optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl is optionally substituted by one or more independently selected from halogen, hydroxy, cyano or oxo of substituents.
在某些实施方案中，Y1为任选取代的烷基或任选取代的炔基，Y2为键或O，其中任选取代的烷基和任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基、烷基或氧代的取代基取代。In certain embodiments, Y is optionally substituted alkyl or optionally substituted alkynyl, Y is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano, alkyl or oxo.
在某些实施方案中，Y1为任选取代的烷基或任选取代的炔基，Y2为键或O，其中任选取代的烷基和任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基或氧代的取代基取代。In certain embodiments, Y is optionally substituted alkyl or optionally substituted alkynyl, Y is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or oxo.
在某些实施方案中，Y1为任选取代的C1-C4烷基或任选取代的C2-C4炔基，Y2为键或O，其中任选取代的C1-C4烷基和任选取代的C2-C4炔基任选地被一个或多个独立地选自羟基或氧代的取代基取代。In certain embodiments, Y 1 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkynyl, Y 2 is a bond or O, wherein optionally substituted C 1 -C 4 Alkyl and optionally substituted C 2 -C 4 alkynyl are optionally substituted with one or more substituents independently selected from hydroxy or oxo.
在某些实施方案中，Y1为任选被一个或多个独立地选自羟基或氧代的取代基取代的C1-C4烷基，Y2为O。In certain embodiments, Y 1 is C 1 -C 4 alkyl optionally substituted with one or more substituents independently selected from hydroxy or oxo, and Y 2 is O.
在某些实施方案中，Y1为任选地被一个或多个独立地选自卤素、羟基、氰基或氧代的取代基取代的C2-C4炔基，Y2为键。In certain embodiments, Y 1 is C 2 -C 4 alkynyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo, and Y 2 is a bond.
在一些实施方案中，Z2选自-O-、**-(C1-3烷基)-O-*、乙炔基或丙炔基，其中-(C1-3烷基)-O-中的C1-3烷基任选地被一个或多个羟基或氧代取代。In some embodiments, Z is selected from -O-, **-(C 1-3 alkyl)-O-*, ethynyl or propynyl, wherein -(C 1-3 alkyl)-O- The C 1-3 alkyl in is optionally substituted by one or more hydroxyl or oxo.
在某些实施方案中，Z2为**-CH2O-*或乙炔基。In certain embodiments, Z2 is **- CH2O- * or ethynyl.
在一些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd各自独立选自任选取代的烷基或-NRaRa，其中Ra各自独立为H或任选取代的烷基。In some embodiments, R 6 is -N═S(O)R c R d , R c and R d are each independently selected from optionally substituted alkyl or -NR a R a , wherein each R a is independently H or optionally substituted alkyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd各自独立选自任选取代的C1-C4烷基或-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。In certain embodiments, R 6 is -N=S(O)R c R d , each of R c and R d is independently selected from optionally substituted C 1 -C 4 alkyl or -NR a R a , wherein Each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd各自独立地为任选取代的C1-C4烷基。In certain embodiments, R 6 is —N═S(O)R c R d , R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd各自独立地为任选取代的甲基。In certain embodiments, R6 is -N=S(O) RcRd , Rc and Rd are each independently optionally substituted methyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd各自独立地为甲基。In certain embodiments, R 6 is —N═S(O)R c R d , R c and R d are each independently methyl.
在某些实施方案中，R6为 In certain embodiments, R 6 is
在某些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd中的一者为任选取代的C1-C4烷基，另一者为-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。In certain embodiments, R 6 is -N═S(O)R c R d , one of R c and R d is optionally substituted C 1 -C 4 alkyl, and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在一些实施方案中，R6为-N＝S(O)(CH3)2或-N＝S(O)(CH3)(NHCH3)。In some embodiments, R 6 is -N=S(O)(CH 3 ) 2 or -N=S(O)(CH 3 )(NHCH 3 ).
在一些实施方案中，R6为-N＝S(O)RcRd，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述任选取代的4-10元杂环基任选地被一个或多个Rh取代，其中Rh选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，Rg为任选取代的烷基或任选取代的环烷基。In some embodiments, R 6 is -N=S(O)R c R d , R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group, any of which The optionally substituted 4-10 membered heterocyclyl is optionally substituted by one or more Rh , wherein Rh is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally Substituted cycloalkyl, optionally substituted heterocyclyl, -NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl, optionally Substituted by one or more substituents independently selected from halogen, hydroxy, cyano, and -OR b , wherein R b is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, R g is optionally substituted alkyl or optionally substituted cycloalkyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc、Rd与它们所连接的S原子一起形成任选取代的4-6元杂环基，所述任选取代的4-6元杂环基任选地被一个或多个Rh取代，其中Rh选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、任选取代的4-9元杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，Rg为任选取代的C1-C4烷基或任选取代的C2-C4环烷基。In certain embodiments, R 6 is -N=S(O)R c R d , R c , R d together with the S atom they are attached to form an optionally substituted 4-6 membered heterocyclic group, said Optionally substituted 4-6 membered heterocyclyl is optionally substituted by one or more Rh , wherein Rh is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkyne Group, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or an optionally substituted C 1 -C 4 alkyl group, the above-mentioned optionally substituted C 1 -C 4 alkyl group, optionally Substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, R g is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 cycloalkyl.
在某些实施方案中，R6选自下组：
In certain embodiments, R is selected from the group consisting of:
其各自任选地被一个或多个Rh取代，其中Rh选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、任选取代的4-9元杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷 基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，Rg为任选取代的C1-C4烷基或任选取代的C2-C4环烷基。Each of which is optionally substituted by one or more Rh , wherein Rh is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 Cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O) R g , -C(O)NR a R a , -S(O) R f or -SO 2 R f , wherein R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkanes The group is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, R g is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 cycloalkyl.
在某些实施方案中，Rh选自下组：任选地被一个或多个独立地选自羟基、卤素、氰基或-O(C2-C4炔基)的取代基取代的C1-C4烷基、C2-C4炔基、C3-C6环烷基、任选被一个或多个C1-C4烷基取代的4-9元杂环基、-NH2、-NH(C1-C4烷基)、-C(O)-(C1-C4烷基)、-C(O)-(C2-C4环烷基)、-C(O)NH2和-SO2(C1-C4烷基)，其中-NH(C1-C4烷基)和-C(O)-(C1-C4烷基)中的C1-C4烷基任选地被一个或多个卤素或羟基取代。In certain embodiments, Rh is selected from the group consisting of C optionally substituted with one or more substituents independently selected from hydroxyl, halogen, cyano, or -O( C2 - C4alkynyl ). 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-9 membered heterocyclyl optionally substituted by one or more C 1 -C 4 alkyl, -NH 2. -NH(C 1 -C 4 alkyl), -C(O)-(C 1 -C 4 alkyl), -C(O)-(C 2 -C 4 cycloalkyl), -C( O) NH 2 and -SO 2 (C 1 -C 4 alkyl), wherein -NH (C 1 -C 4 alkyl) and -C (O)-(C 1 -C 4 alkyl) in C 1 -C4alkyl is optionally substituted with one or more halogen or hydroxy.
在一些实施方案中，R6选自下组：

In some embodiments, R is selected from the group consisting of:

在一些实施方案中，R6为-N＝S(O)RcRd，环C为键或杂芳基。In some embodiments, R 6 is —N═S(O)R c R d , and ring C is a bond or heteroaryl.
在一些实施方案中，R6为-(CH2)sS(O)(＝NRe)Rf，Re为H、氰基或任选取代的烷基，Rf为任选取代的烷基，其中所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, R 6 is -(CH 2 ) s S(O)(=NR e )R f , R e is H, cyano, or optionally substituted alkyl, R f is optionally substituted alkyl wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
在某些实施方案中，R6为-(CH2)sS(O)(＝NRe)Rf，Re为H、氰基或任选取代的C1-C4烷基，Rf为任选取代的C1-C4烷基，其中所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In certain embodiments, R 6 is -(CH 2 ) s S(O)(=NR e )R f , R e is H, cyano, or optionally substituted C 1 -C 4 alkyl, R f is an optionally substituted C 1 -C 4 alkyl, wherein the optionally substituted C 1 -C 4 alkyl is optionally selected from one or more independently selected from halogen, hydroxyl, cyano or -NR a R The substituent of a is substituted.
在某些实施方案中，R6为-(CH2)sS(O)(＝NRe)Rf，Re为H、氰基或甲基，Rf为甲基，s为0或1。In certain embodiments, R 6 is -(CH 2 ) s S(O)(=NR e )R f , R e is H, cyano, or methyl, R f is methyl, s is 0 or 1 .
在一些实施方案中，R6为-(CH2)sS(O)(＝NRe)Rf，环C为芳基或杂芳基。In some embodiments, R 6 is -(CH 2 ) s S(O)(=NR e )R f , and ring C is aryl or heteroaryl.
在一些实施方案中，R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg。In some embodiments, each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
在某些实施方案中，R7各自独立地为卤素、氰基、任选取代的C1-C4烷基、-O(C1-C4烷基)、-O(C2-C4炔基)、-S(O)(C1-C4烷基)、-SO2(C1-C4烷基)或-NRgRg，其中Rg各自独立为H、-SO2(C1-C4烷基)或羟基取代的C1-C4烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基。In certain embodiments, each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
在一些实施方案中，本申请提供了具有下式的化合物：
In some embodiments, the application provides compounds having the formula:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中in
V1和V2各自独立地为N或CH；V and V are each independently N or CH;
环C为键、芳基或杂芳基；Ring C is a bond, aryl or heteroaryl;
Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -CO-, -NR a - or -(CH 2 ) r -NR a -CO-;
Z2为**-Y1-Y2-*，其中Y1为键、任选取代的烷基或任选取代的炔基，Y2为键或O；Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl or optionally substituted alkynyl, and Y 2 is a bond or O;
R1和R2各自独立地为羟基或任选取代的烷基；或者R and R are each independently hydroxyl or optionally substituted alkyl; or
R1和R2与其所连接的碳原子一起形成任选取代的 R and R together with the carbon atom to which they are attached form an optionally substituted
R3为H、卤素或任选取代的烷基；R 3 is H, halogen or optionally substituted alkyl;
R4各自独立地为卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、-(CH2)rNRaRa或-ORb； Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -( CH2 ) rNR a R a or -OR b ;
R5为任选取代的烷基或任选取代的烯基； R is optionally substituted alkyl or optionally substituted alkenyl;
R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg；Ra各自独立为H、任选取代的烷基或-CORb；Each R 7 is independently halogen, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g ; each R a is independently H, any Select substituted alkyl or -COR b ;
Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rc和Rd各自独立选自任选取代的烷基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
Rf为任选取代的烷基； R is optionally substituted alkyl;
Rg各自独立为H、-SO2Rf或任选取代的烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基；且Each R g is independently H, -SO 2 R f or optionally substituted alkyl; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
r、s、m、n和p各自独立为0、1或2。r, s, m, n and p are each independently 0, 1 or 2.
在一些实施方案中，为苯基、吡啶基或吡啶酮基。In some embodiments, is phenyl, pyridyl or pyridonyl.
在一些实施方案中，环C为键。In some embodiments, Ring C is a bond.
在一些实施方案中，环C为芳基。在某些实施方案中，环C为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环C为苯基或萘基。在某些实施方案中，环C为苯基。 In some embodiments, Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
在一些实施方案中，环C为杂芳基。在某些实施方案中，环C为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环C选自嘧啶基、吡嗪基、吡啶基、哌啶基、哌嗪基、吗啉基、噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、哒嗪基、呋喃基、吡咯基、三唑基或三嗪基。In some embodiments, Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
在某些实施方案中，环C为嘧啶基、吡嗪基、吡啶基、噻唑基或噁唑基。In certain embodiments, Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl.
在某些实施方案中，选自下组：
In some embodiments, Select from the group:
在一些实施方案中，R1和R2各自独立为H、羟基或任选取代的烷基。In some embodiments, R 1 and R 2 are each independently H, hydroxy, or optionally substituted alkyl.
在某些实施方案中，R1和R2均为任选取代的烷基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。在某些实施方案中，R1和R2各自独立地为任选取代的C1-C4烷基。In certain embodiments, both R and R are optionally substituted alkyl optionally substituted with one or more independently selected from halogen, hydroxy, cyano, and -NR a Substituent substituent of R a . In certain embodiments, R 1 and R 2 are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，R1和R2均为甲基。In certain embodiments, R 1 and R 2 are both methyl.
在某些实施方案中，R1和R2中的一者为任选取代的烷基，另一者为H或羟基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, one of R and R is optionally substituted alkyl and the other is H or hydroxy, optionally substituted by one or more independently Substituents selected from halogen, hydroxy, cyano and -NR a R a are substituted.
在某些实施方案中，R1和R2中的一者为任选取代的C1-C4烷基，另一者为H或羟基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基 和-NRaRa的取代基取代。In certain embodiments, one of R and R is optionally substituted C 1 -C 4 alkyl and the other is H or hydroxy, said optionally substituted C 1 -C 4 alkyl Optionally by one or more independently selected from halogen, hydroxyl, cyano and the substituent of -NR a R a is substituted.
在某些实施方案中，R1和R2中的一者为甲基，另一者为羟基。In certain embodiments, one of R and R is methyl and the other is hydroxy.
在某些实施方案中，R1和R2与其所连接的碳原子一起形成任选取代的 In certain embodiments, R and R together with the carbon atom to which they are attached form an optionally substituted
在某些实施方案中，R1和R2与其所连接的碳原子一起形成 In certain embodiments, R and R together with the carbon atom to which they are attached form
在一些实施方案中，各R3独立为H、卤素、任选取代的烷基或-ORb。In some embodiments, each R3 is independently H, halo, optionally substituted alkyl, or -ORb .
在一些实施方案中，各R3独立为H、或任选取代的烷基。In some embodiments, each R3 is independently H, or optionally substituted alkyl.
在一些实施方案中，各R3独立为H、氟、氯、任选取代的C1-C4烷基。In some embodiments, each R 3 is independently H, fluoro, chloro, optionally substituted C 1 -C 4 alkyl.
在一些实施方案中，各R3独立为任选取代的C1-C4烷基。In some embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，各R3独立为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
在一些实施方案中，各R3独立地选自卤素。In some embodiments, each R3 is independently selected from halogen.
在一些实施方案中，R3为氟。In some embodiments, R 3 is fluoro.
在一些实施方案中，R3为氯。In some embodiments, R 3 is chloro.
在某些实施方案中，R3为H。In certain embodiments, R3 is H.
在一些实施方案中，各R4独立为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的烷基或-CORb，Rb为H、任选取代的烷基、任选取代的烯基、任选取代的炔基，其中所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, each R is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b , wherein R a is each independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted Alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally represented by one or more independently Substituents selected from halogen, hydroxyl, cyano and -NR a R a .
在某些实施方案中，各R4独立为H、卤素、氰基、氧代、环丙基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的C2-C4烯基或-CORb，Rb为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。In certain embodiments, each R4 is independently H, halo, cyano, oxo, cyclopropyl, -( CH2 ) rNRaRa , or -ORb , wherein each Ra is independently H, any Optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
在某些实施方案中，各R4独立为H、氯、氰基、氧代、环丙基、-OCH3、-OC≡CH或-CH2NH(CH＝CH2)。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, cyclopropyl, -OCH3 , -OC≡CH, or -CH2NH (CH= CH2 ).
在某些实施方案中，各R4独立为H、氯、氰基、氧代、环丙基或-OCH3。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, cyclopropyl, or -OCH3 .
在一些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为 H或任选取代的烷基。In some embodiments, Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的C1-C4烷基。In certain embodiments, Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NH-、-NHCO-或-CH2NHCO-。In certain embodiments, Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
在一些实施方案中，R5为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，所述任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, R 5 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, any Optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxy, Substituted by cyano and -NR a R a substituents.
在某些实施方案中，R5为H、任选取代的C1-C4烷基或任选取代的C2-C4烯基，所述任选取代的C1-C4烷基和任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, R 5 is H, optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and Optionally substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy or cyano.
在某些实施方案中，R5为H、甲基、乙基、丙基或乙烯基，所述甲基、乙基、丙基和乙烯基任选地被一个或多个独立地选自氯、羟基或氰基的取代基取代。In certain embodiments, R is H, methyl, ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine , Hydroxy or cyano substituents.
在一些实施方案中，Z1为键或-O-，R5为H、任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is a bond or -O-, R 5 is H, optionally substituted C 1 -C 4 alkyl optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
在某些实施方案中，Z1为键或-O-，R5为H、甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, Z is a bond or -O-, R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from halogen, hydroxy or cyano are substituted.
在某些实施方案中，Z1为键或-O-，R5为H、甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自氟、氯或羟基的取代基取代。In certain embodiments, Z is a bond or -O-, R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from fluorine, chlorine or hydroxyl are substituted.
在一些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为任选取代的C2-C4烯基，所述任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, R 5 is optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
在某些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为乙烯基。In certain embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
在一些实施方案中，-Z1-R5选自-(CH2)rCl、-O(CH2)rF、-O(CH2)rCl或-O(CH2)rOH，其中r为1、2或3。In some embodiments, -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
在一些实施方案中，Y1为键，Y2为O、NH或S。In some embodiments, Y 1 is a bond and Y 2 is O, NH or S.
在一些实施方案中，Y1为任选取代的烷基、任选取代的烯基或任选取代的炔基， Y2为键或O，所述任选取代的烷基、任选取代的烯基或任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基、烷基或氧代的取代基取代。In some embodiments, Y is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, Y is a bond or O, and the optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl is optionally selected from one or more independently selected from halogen, hydroxy, cyano, alkyl Or oxo substituent substitution.
在一些实施方案中，Y1为任选取代的烷基、任选取代的烯基或任选取代的炔基，Y2为键或O，所述任选取代的烷基、任选取代的烯基或任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基或氧代的取代基取代。In some embodiments, Y 1 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, Y 2 is a bond or O, said optionally substituted alkyl, optionally substituted Alkenyl or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano or oxo.
在某些实施方案中，Y1为任选取代的烷基或任选取代的炔基，Y2为键或O，其中任选取代的烷基和任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基、烷基或氧代的取代基取代。In certain embodiments, Y is optionally substituted alkyl or optionally substituted alkynyl, Y is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano, alkyl or oxo.
在某些实施方案中，Y1为任选取代的烷基或任选取代的炔基，Y2为键或O，其中任选取代的烷基和任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基或氧代的取代基取代。In certain embodiments, Y is optionally substituted alkyl or optionally substituted alkynyl, Y is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or oxo.
在某些实施方案中，Y1为任选取代的C1-C4烷基或任选取代的C2-C4炔基，Y2为键或O，其中任选取代的C1-C4烷基和任选取代的C2-C4炔基任选地被一个或多个独立地选自羟基或氧代的取代基取代。In certain embodiments, Y 1 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkynyl, Y 2 is a bond or O, wherein optionally substituted C 1 -C 4 Alkyl and optionally substituted C 2 -C 4 alkynyl are optionally substituted with one or more substituents independently selected from hydroxy or oxo.
在某些实施方案中，Y1为任选被一个或多个独立地选自羟基或氧代的取代基取代的C1-C4烷基，Y2为O。In certain embodiments, Y 1 is C 1 -C 4 alkyl optionally substituted with one or more substituents independently selected from hydroxy or oxo, and Y 2 is O.
在某些实施方案中，Y1为任选地被一个或多个独立地选自卤素、羟基、氰基或氧代的取代基取代的C2-C4炔基，Y2为键。In certain embodiments, Y 1 is C 2 -C 4 alkynyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo, and Y 2 is a bond.
在一些实施方案中，Z2选自-O-、**-(C1-3烷基)-O-*、乙炔基或丙炔基，其中-(C1-3烷基)-O-中的C1-3烷基任选地被一个或多个羟基或氧代取代。In some embodiments, Z is selected from -O-, **-(C 1-3 alkyl)-O-*, ethynyl or propynyl, wherein -(C 1-3 alkyl)-O- The C 1-3 alkyl in is optionally substituted by one or more hydroxyl or oxo.
在某些实施方案中，Z2为**-CH2O-*或乙炔基。In certain embodiments, Z2 is **- CH2O- * or ethynyl.
在一些实施方案中，Rc和Rd各自独立选自任选取代的烷基或-NRaRa，其中Ra各自独立为H或任选取代的烷基。In some embodiments, R c and R d are each independently selected from optionally substituted alkyl or -NR a Ra , wherein each R a is independently H or optionally substituted alkyl.
在某些实施方案中，Rc和Rd各自独立选自任选取代的C1-C4烷基或-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。In certain embodiments, R c and R d are each independently selected from optionally substituted C 1 -C 4 alkyl or -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，Rc和Rd各自独立地为任选取代的C1-C4烷基。In certain embodiments, R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，Rc和Rd中的一者为任选取代的C1-C4烷基，另一者为-NRaRa，其中Ra各自均独立为H或任选取代的C1-C4烷基。 In certain embodiments, one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally Substituted C 1 -C 4 alkyl.
在一些实施方案中，Rc和Rd均为-CH3-，或者Rc和Rd中的一者为-CH3，另一者为-NHCH3。In some embodiments, both Rc and Rd are -CH3- , or one of Rc and Rd is -CH3 and the other is -NHCH3 .
在一些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述任选取代的4-10元杂环基任选地被一个或多个Rh取代，其中Rh选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，Rg为任选取代的烷基或任选取代的环烷基。In some embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl optionally replaced by one or a plurality of R h substitutions, wherein R h is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, - NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or an optionally substituted alkane The optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen, hydroxy, cyano and -OR b substituent substitution, wherein R b is an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl, and R is an optionally substituted alkyl or an optionally substituted cycloalkane base.
在某些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-6元杂环基，所述任选取代的4-6元杂环基任选地被一个或多个Rh取代，其中Rh选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、任选取代的4-9元杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，Rg为任选取代的C1-C4烷基或任选取代的C2-C4环烷基。In certain embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl optionally substituted by One or more R h substitutions, wherein R h is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, Optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, Optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, R g is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 cycloalkane base.
在某些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基选自下组：
In certain embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
其各自任选地被一个或多个Rh取代，其中Rh选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、任选取代的4-9元杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb 为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，Rg为任选取代的C1-C4烷基或任选取代的C2-C4环烷基。Each of which is optionally substituted by one or more Rh , wherein Rh is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 Cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O) R g , -C(O)NR a R a , -S(O) R f or -SO 2 R f , wherein R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, R is optionally substituted C 1 -C 4 alkane or optionally substituted C 2 -C 4 cycloalkyl.
在某些实施方案中，Rh选自下组：任选地被一个或多个独立地选自羟基、卤素、氰基或-O(C2-C4炔基)的取代基取代的C1-C4烷基、C2-C4炔基、C3-C6环烷基、任选被一个或多个C1-C4烷基取代的4-9元杂环基、-NH2、-NH(C1-C4烷基)、-C(O)-(C1-C4烷基)、-C(O)-(C2-C4环烷基)、-C(O)NH2和-SO2(C1-C4烷基)，其中-NH(C1-C4烷基)和-C(O)-(C1-C4烷基)中的C1-C4烷基任选地被一个或多个卤素或羟基取代。In certain embodiments, Rh is selected from the group consisting of C optionally substituted with one or more substituents independently selected from hydroxyl, halogen, cyano, or -O( C2 - C4alkynyl ). 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-9 membered heterocyclyl optionally substituted by one or more C 1 -C 4 alkyl, -NH 2. -NH(C 1 -C 4 alkyl), -C(O)-(C 1 -C 4 alkyl), -C(O)-(C 2 -C 4 cycloalkyl), -C( O) NH 2 and -SO 2 (C 1 -C 4 alkyl), wherein -NH (C 1 -C 4 alkyl) and -C (O)-(C 1 -C 4 alkyl) in C 1 -C4alkyl is optionally substituted with one or more halogen or hydroxy.
在一些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基选自下组：

In some embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:

在一些实施方案中，环C为键或杂芳基。In some embodiments, Ring C is a bond or heteroaryl.
在一些实施方案中，R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg。In some embodiments, each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
在某些实施方案中，R7各自独立地为卤素、氰基、任选取代的C1-C4烷基、-O(C1-C4烷基)、-O(C2-C4炔基)、-S(O)(C1-C4烷基)、-SO2(C1-C4烷基)或-NRgRg，其中Rg各自独立为H、-SO2(C1-C4烷基)或羟基取代的C1-C4烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基。In certain embodiments, each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
在一些实施方案中，本申请提供了具有下式的化合物：
In some embodiments, the application provides compounds having the formula:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中in
V3为N或CH；V 3 is N or CH;
环C为键、芳基或杂芳基；Ring C is a bond, aryl or heteroaryl;
环D为杂环基或杂芳基；Ring D is heterocyclyl or heteroaryl;
Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -CO-, -NR a - or -(CH 2 ) r -NR a -CO-;
Z2为**-Y1-Y2-*，其中Y1为键、任选取代的烷基或任选取代的炔基，Y2为键或 O；Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl or optionally substituted alkynyl, Y 2 is a bond or O;
R1和R2各自独立地为羟基或任选取代的烷基；或者R and R are each independently hydroxyl or optionally substituted alkyl; or
R1和R2与其所连接的碳原子一起形成任选取代的 R and R together with the carbon atom to which they are attached form an optionally substituted
R3为H、卤素、任选取代的烷基或任选取代的烷氧基； R is H, halogen, optionally substituted alkyl or optionally substituted alkoxy;
R4各自独立地为卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、-(CH2)rNRaRa或-ORb； Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -( CH2 ) rNR a R a or -OR b ;
R5为H、任选取代的烷基或任选取代的烯基； R is H, optionally substituted alkyl or optionally substituted alkenyl;
R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg； Each R7 is independently halogen, cyano , optionally substituted alkyl, -ORa , -S(O) Rf , -SO2Rf , or -NRgRg ;
Ra各自独立为H、任选取代的烷基或-CORb；each R a is independently H, optionally substituted alkyl, or -COR b ;
Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rc和Rd各自独立选自任选取代的烷基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
Rf为任选取代的烷基； R is optionally substituted alkyl;
Rg各自独立为H、-SO2Rf或任选取代的烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基；且Each R g is independently H, -SO 2 R f or optionally substituted alkyl; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
r、s、m、n和p各自独立为0、1或2。r, s, m, n and p are each independently 0, 1 or 2.
在一些实施方案中，其中选自：
In some embodiments, where selected from:
在一些实施方案中，环D被1、2或3个R9取代，R9为H、卤素或任选取代的烷基。In some embodiments, ring D is substituted with 1, 2, or 3 R 9 , R 9 is H, halogen, or optionally substituted alkyl.
在一些实施方案中，环D被1、2或3个R9取代，R9选自H、F、Cl、CH3和CF3。 In some embodiments, Ring D is substituted with 1 , 2 or 3 R 9 selected from H, F, Cl, CH 3 and CF 3 .
在一些实施方案中，通过环D上的饱和N原子与-Z1R5连接。In some embodiments, Attachment to -Z 1 R 5 is through a saturated N atom on ring D.
在一些实施方案中，环C为键。In some embodiments, Ring C is a bond.
在一些实施方案中，环C为芳基或杂芳基。In some embodiments, Ring C is aryl or heteroaryl.
在一些实施方案中，环C为芳基。在某些实施方案中，环C为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环C为苯基或萘基。在某些实施方案中，环C为苯基。In some embodiments, Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
在一些实施方案中，环C为杂芳基。在某些实施方案中，环C为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环C选自嘧啶基、吡嗪基、吡啶基、哌啶基、哌嗪基、吗啉基、噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、哒嗪基、呋喃基、吡咯基、三唑基或三嗪基。In some embodiments, Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
在某些实施方案中，环C为嘧啶基、吡嗪基、吡啶基、噻唑基或噁唑基。In certain embodiments, Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl.
在某些实施方案中，选自下组：
In some embodiments, Select from the group:
在一些实施方案中，R1和R2各自独立为H、羟基或任选取代的烷基。In some embodiments, R 1 and R 2 are each independently H, hydroxy, or optionally substituted alkyl.
在某些实施方案中，R1和R2均为任选取代的烷基，所述任选取代的烷基任选地 被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。在某些实施方案中，R1和R2各自独立地为任选取代的C1-C4烷基。In certain embodiments, R and R are both optionally substituted alkyl optionally substituted Substituted by one or more substituents independently selected from halogen, hydroxy, cyano and -NR a R a . In certain embodiments, R 1 and R 2 are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，R1和R2均为甲基。In certain embodiments, R 1 and R 2 are both methyl.
在某些实施方案中，R1和R2中的一者为任选取代的烷基，另一者为H或羟基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, one of R and R is optionally substituted alkyl and the other is H or hydroxy, optionally substituted by one or more independently Substituents selected from halogen, hydroxy, cyano and -NR a R a are substituted.
在某些实施方案中，R1和R2中的一者为任选取代的C1-C4烷基，另一者为H或羟基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, one of R and R is optionally substituted C 1 -C 4 alkyl and the other is H or hydroxy, said optionally substituted C 1 -C 4 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -NR a R a .
在某些实施方案中，R1和R2中的一者为甲基，另一者为羟基。In certain embodiments, one of R and R is methyl and the other is hydroxy.
在某些实施方案中，R1和R2与其所连接的碳原子一起形成任选取代的 In certain embodiments, R and R together with the carbon atom to which they are attached form an optionally substituted
在某些实施方案中，R1和R2与其所连接的碳原子一起形成 In certain embodiments, R and R together with the carbon atom to which they are attached form
在一些实施方案中，各R3独立为H或任选取代的烷基。In some embodiments, each R3 is independently H or optionally substituted alkyl.
在一些实施方案中，各R3独立为H、卤素或任选取代的烷基。In some embodiments, each R3 is independently H, halo, or optionally substituted alkyl.
在一些实施方案中，各R3独立为H、卤素、任选取代的烷基或-ORb。In some embodiments, each R3 is independently H, halo, optionally substituted alkyl, or -ORb .
在一些实施方案中，各R3独立为H、卤素、任选取代的烷基、任选取代的烷氧基或-ORb。In some embodiments, each R3 is independently H, halo, optionally substituted alkyl, optionally substituted alkoxy, or -ORb .
在一些实施方案中，各R3独立为H、氟、氯、任选取代的C1-C4烷基或任选取代的C1-C4烷氧基。In some embodiments, each R 3 is independently H, fluoro, chloro, optionally substituted C 1 -C 4 alkyl, or optionally substituted C 1 -C 4 alkoxy.
在一些实施方案中，各R3独立为任选取代的C1-C4烷基。In some embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl.
在一些实施方案中，各R3独立为任选取代的C1-C4烷氧基。In some embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkoxy.
在某些实施方案中，各R3独立为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
在某些实施方案中，各R3独立为任选取代的C1-C4烷氧基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkoxy optionally substituted by one or more independently selected from Substituents of halogen, hydroxyl, cyano and -NR a R a are substituted.
在一些实施方案中，各R3独立为C1-C4烷基。In some embodiments, each R 3 is independently C 1 -C 4 alkyl.
在一些实施方案中，各R3独立为C1-C4烷氧基。 In some embodiments, each R 3 is independently C 1 -C 4 alkoxy.
在一些实施方案中，各R3独立为甲基。In some embodiments, each R3 is independently methyl.
在一些实施方案中，各R3独立为甲氧基。In some embodiments, each R 3 is independently methoxy.
在一些实施方案中，各R3独立地选自卤素。In some embodiments, each R3 is independently selected from halogen.
在一些实施方案中，R3为氟。In some embodiments, R 3 is fluoro.
在一些实施方案中，R3为氯。In some embodiments, R 3 is chloro.
在某些实施方案中，R3为H。In certain embodiments, R3 is H.
在一些实施方案中，各R4独立为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的烷基或-CORb，Rb为H、任选取代的烷基、任选取代的烯基、任选取代的炔基，其中所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, each R is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b , wherein R a is each independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted Alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally represented by one or more independently Substituents selected from halogen, hydroxyl, cyano and -NR a R a .
在某些实施方案中，各R4独立为H、卤素、氰基、氧代、环丙基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的C2-C4烯基或-CORb，Rb为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。In certain embodiments, each R4 is independently H, halo, cyano, oxo, cyclopropyl, -( CH2 ) rNRaRa , or -ORb , wherein each Ra is independently H, any Optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
在某些实施方案中，各R4独立为H、氯、氰基、氧代、环丙基、-OCH3、-OC≡CH或-CH2NH(CH＝CH2)。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, cyclopropyl, -OCH3 , -OC≡CH, or -CH2NH (CH= CH2 ).
在某些实施方案中，各R4独立为H、氯、氰基、氧代、环丙基或-OCH3。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, cyclopropyl, or -OCH3 .
在一些实施方案中，Z1为键、-O-、-CO-或-NRa-，其中Ra为H、任选取代的烷基或-CORb。In some embodiments, Z 1 is a bond, -O-, -CO-, or -NR a -, wherein R a is H, optionally substituted alkyl, or -COR b .
在一些实施方案中，Z1为键、-O-或-CO-。In some embodiments, Z is a bond, -O- or -CO-.
在一些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的烷基。In some embodiments, Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的C1-C4烷基。In certain embodiments, Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NH-、-NHCO-或-CH2NHCO-。In certain embodiments, Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
在一些实施方案中，R5为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，所述任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选 取代的C2-C4炔基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, R 5 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, any Optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally The substituted C2 - C4alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NRaRa .
在某些实施方案中，R5为H、任选取代的C1-C4烷基或任选取代的C2-C4烯基，所述任选取代的C1-C4烷基和任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, R 5 is H, optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and Optionally substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy or cyano.
在某些实施方案中，R5为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In certain embodiments, R 5 is optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen, hydroxy , cyano or -NR a R a substituent substitution.
在某些实施方案中，R5为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自氟、氯、溴、羟基、氰基或-NRaRa的取代基取代。In certain embodiments, R 5 is optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from fluorine, chlorine , bromine, hydroxyl, cyano or -NR a R a substituent substitution.
在某些实施方案中，R5为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自氟、氯、羟基或氰基的取代基取代。In certain embodiments, R 5 is optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from fluorine, chlorine , Hydroxy or cyano substituents.
在某些实施方案中，R5为-(CH2)Cl、-CH2CH2(OH)CH3。In certain embodiments, R 5 is -(CH 2 )Cl, -CH 2 CH 2 (OH)CH 3 .
在某些实施方案中，R5为任选取代的C2-C4烯基，所述任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In certain embodiments, R 5 is optionally substituted C 2 -C 4 alkenyl optionally substituted by one or more independently selected from halogen, hydroxy , cyano or -NR a R a substituent substitution.
在某些实施方案中，R5为甲基、乙基、丙基或乙烯基，所述甲基、乙基、丙基和乙烯基任选地被一个或多个独立地选自氯、羟基或氰基的取代基取代。In certain embodiments, R is methyl , ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine, hydroxy Or cyano substituent substitution.
在某些实施方案中，R5为乙烯基。In certain embodiments, R 5 is vinyl.
在一些实施方案中，Z1为键或-O-，R5为H、任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is a bond or -O-, R 5 is H, optionally substituted C 1 -C 4 alkyl optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
在某些实施方案中，Z1为键或-O-，R5为H、甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, Z is a bond or -O-, R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from halogen, hydroxy or cyano are substituted.
在某些实施方案中，Z1为键或-O-，R5为H、甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自氟、氯或羟基的取代基取代。In certain embodiments, Z is a bond or -O-, R is H, methyl, ethyl, or propyl, optionally replaced by one or more independently Substituents selected from fluorine, chlorine or hydroxyl are substituted.
在一些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为任选取代的C2-C4烯基，所述任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, R 5 is optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
在某些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为乙烯基。 In certain embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
在一些实施方案中，-Z1-R5选自-(CH2)rCl、-O(CH2)rF、-O(CH2)rCl或-O(CH2)rOH，其中r为1、2或3。In some embodiments, -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
在一些实施方案中，Y1为键，Y2为O、NH或S。In some embodiments, Y 1 is a bond and Y 2 is O, NH or S.
在一些实施方案中，Y1为任选取代的烷基、任选取代的烯基或任选取代的炔基，Y2为键或O，所述任选取代的烷基、任选取代的烯基或任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基或氧代的取代基取代。In some embodiments, Y 1 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, Y 2 is a bond or O, said optionally substituted alkyl, optionally substituted Alkenyl or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano or oxo.
在某些实施方案中，Y1为任选取代的烷基或任选取代的炔基，Y2为键或O，其中任选取代的烷基和任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基或氧代的取代基取代。In certain embodiments, Y is optionally substituted alkyl or optionally substituted alkynyl, Y is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally replaced by one or multiple substituents independently selected from halogen, hydroxyl, cyano or oxo.
在某些实施方案中，Y1为任选取代的C1-C4烷基或任选取代的C2-C4炔基，Y2为键或O，其中任选取代的C1-C4烷基和任选取代的C2-C4炔基任选地被一个或多个独立地选自羟基或氧代的取代基取代。In certain embodiments, Y 1 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkynyl, Y 2 is a bond or O, wherein optionally substituted C 1 -C 4 Alkyl and optionally substituted C 2 -C 4 alkynyl are optionally substituted with one or more substituents independently selected from hydroxy or oxo.
在某些实施方案中，Y1为任选被一个或多个独立地选自羟基或氧代的取代基取代的C1-C4烷基，Y2为O。In certain embodiments, Y 1 is C 1 -C 4 alkyl optionally substituted with one or more substituents independently selected from hydroxy or oxo, and Y 2 is O.
在某些实施方案中，Y1为任选地被一个或多个独立地选自卤素、羟基、氰基或氧代的取代基取代的C2-C4炔基，Y2为键。In certain embodiments, Y 1 is C 2 -C 4 alkynyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo, and Y 2 is a bond.
在一些实施方案中，Z2为-O-、C2-C4炔基或**-(任选取代的C1-C4烷基)-O-*、其中所述任选取代的C1-C4烷基任选地被一个或多个选自羟基、C1-C4烷基或氧代的取代基取代。In some embodiments, Z 2 is -O-, C 2 -C 4 alkynyl, or **-(optionally substituted C 1- C 4 alkyl)-O-*, wherein said optionally substituted C 1- C4alkyl is optionally substituted with one or more substituents selected from hydroxyl, C1-C4alkyl or oxo.
在一些实施方案中，Z2为-O-、C2-C4炔基或**-(任选取代的C1-C4烷基)-O-*、其中所述任选取代的C1-C4烷基任选地被一个或多个选自羟基、或氧代的取代基取代。In some embodiments, Z 2 is -O-, C 2 -C 4 alkynyl, or **-(optionally substituted C 1- C 4 alkyl)-O-*, wherein said optionally substituted C 1- C4alkyl is optionally substituted with one or more substituents selected from hydroxy, or oxo.
在一些实施方案中，Z2选自-O-、**-(C1-3烷基)-O-*、乙炔基或丙炔基，其中-(C1-3烷基)-O-中的C1-3烷基任选地被一个或多个羟基或氧代取代。In some embodiments, Z is selected from -O-, **-(C 1-3 alkyl)-O-*, ethynyl or propynyl, wherein -(C 1-3 alkyl)-O- The C 1-3 alkyl in is optionally substituted by one or more hydroxyl or oxo.
在某些实施方案中，Z2为**-CH2O-*或乙炔基。In certain embodiments, Z2 is **- CH2O- * or ethynyl.
在一些实施方案中，Rc和Rd各自独立选自任选取代的烷基或-NRaRa，其中Ra各自独立为H或任选取代的烷基。In some embodiments, R c and R d are each independently selected from optionally substituted alkyl or -NR a Ra , wherein each R a is independently H or optionally substituted alkyl.
在某些实施方案中，Rc和Rd中的一者为任选取代的C1-C4烷基，另一者为-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。 In certain embodiments, one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在一些实施方案中，Rc和Rd中的一者为-CH3，另一者为-NHCH3。In some embodiments, one of Rc and Rd is -CH3 and the other is -NHCH3 .
在某些实施方案中，Rc和Rd各自独立选自任选取代的C1-C4烷基或-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。In certain embodiments, R c and R d are each independently selected from optionally substituted C 1 -C 4 alkyl or -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，Rc和Rd各自独立地为任选取代的C1-C4烷基。In certain embodiments, R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，Rc和Rd各自独立地为任选取代的甲基。In certain embodiments, Rc and Rd are each independently optionally substituted methyl.
在某些实施方案中，Rc和Rd均为甲基。In certain embodiments, both R c and R d are methyl.
在某些实施方案中，Rc和Rd中的一者为任选取代的C1-C4烷基，另一者为-NRaRa，其中Ra各自均独立为H或任选取代的C1-C4烷基。In certain embodiments, one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally Substituted C 1 -C 4 alkyl.
在一些实施方案中，Rc和Rd均为-CH3-，或者Rc和Rd中的一者为-CH3，另一者为-NHCH3。In some embodiments, both Rc and Rd are -CH3- , or one of Rc and Rd is -CH3 and the other is -NHCH3 .
在一些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述任选取代的4-10元杂环基任选地被一个或多个Rh取代，其中Rh选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，Rg为任选取代的烷基或任选取代的环烷基。In some embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl optionally replaced by one or a plurality of R h substitutions, wherein R h is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, - NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or an optionally substituted alkane The optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen, hydroxy, cyano and -OR b substituent substitution, wherein R b is an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl, and R is an optionally substituted alkyl or an optionally substituted cycloalkane base.
在某些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-6元杂环基，所述任选取代的4-6元杂环基任选地被一个或多个Rh取代，其中Rh选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、任选取代的4-9元杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，Rg为任选取代的C1-C4烷基或任选取代的C2-C4环烷基。In certain embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl optionally substituted by One or more R h substitutions, wherein R h is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, Optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, Optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, R g is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 cycloalkane base.
在某些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基选自下组：
In certain embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
其各自任选地被一个或多个Rh取代，其中Rh选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、任选取代的4-9元杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，Rg为任选取代的C1-C4烷基或任选取代的C2-C4环烷基。Each of which is optionally substituted by one or more Rh , wherein Rh is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 Cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O) R g , -C(O)NR a R a , -S(O) R f or -SO 2 R f , wherein R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, R g is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 cycloalkyl.
在某些实施方案中，Rh选自下组：任选地被一个或多个独立地选自羟基、卤素、氰基或-O(C2-C4炔基)的取代基取代的C1-C4烷基、C2-C4炔基、C3-C6环烷基、任选被一个或多个C1-C4烷基取代的4-9元杂环基、-NH2、-NH(C1-C4烷基)、-C(O)-(C1-C4烷基)、-C(O)-(C2-C4环烷基)、-C(O)NH2和-SO2(C1-C4烷基)，其中-NH(C1-C4烷基)和-C(O)-(C1-C4烷基)中的C1-C4烷基任选地被一个或多个卤素或羟基取代。In certain embodiments, Rh is selected from the group consisting of C optionally substituted with one or more substituents independently selected from hydroxyl, halogen, cyano, or -O( C2 - C4alkynyl ). 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-9 membered heterocyclyl optionally substituted by one or more C 1 -C 4 alkyl, -NH 2. -NH(C 1 -C 4 alkyl), -C(O)-(C 1 -C 4 alkyl), -C(O)-(C 2 -C 4 cycloalkyl), -C( O) NH 2 and -SO 2 (C 1 -C 4 alkyl), wherein -NH (C 1 -C 4 alkyl) and -C (O)-(C 1 -C 4 alkyl) in C 1 -C4alkyl is optionally substituted with one or more halogen or hydroxy.
在一些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基选自下组：

In some embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:

在一些实施方案中，环C为键或杂芳基。In some embodiments, Ring C is a bond or heteroaryl.
在一些实施方案中，R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg。In some embodiments, each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
在某些实施方案中，R7各自独立地为卤素、氰基、任选取代的C1-C4烷基、-O(C1-C4烷基)、-O(C2-C4炔基)、-S(O)(C1-C4烷基)、-SO2(C1-C4烷基)或-NRgRg，其中Rg各自独立为H、-SO2(C1-C4烷基)或羟基取代的C1-C4烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基。In certain embodiments, each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
在一些实施方案中，式1-IIa和式1-IIb化合物中的Rc和Rd各自独立地为C1-C4 烷基或-NH-(C1-C4烷基)。In some embodiments, R c and R d in the compounds of formula 1-IIa and formula 1-IIb are each independently C 1 -C 4 Alkyl or -NH-(C 1 -C 4 alkyl).
在一些实施方案中，式1-IIa和式1-IIb化合物中的Rc和Rd与它们所连接的S原子一起形成任选地被一个或多个Rh取代的4-10元杂环基。In some embodiments, R and R in compounds of Formula 1-IIa and Formula 1- IIb together with the S atom to which they are attached form a 4-10 membered heterocyclic ring optionally substituted by one or more Rh base.
在一些实施方案中，式1-IIa和式1-IIb化合物中的Z2为-O-、C2-C4炔基或**-(任选取代的C1-C4烷基)-O-*、其中所述任选取代的C1-C4烷基任选地被一个或多个选自羟基或氧代的取代基取代。In some embodiments, Z 2 in compounds of formula 1-IIa and formula 1-IIb is -O-, C 2 -C 4 alkynyl or **-(optionally substituted C 1- C 4 alkyl)- O-*, wherein the optionally substituted C 1 -C 4 alkyl is optionally substituted with one or more substituents selected from hydroxy or oxo.
在一些实施方案中，式1-IIa和式1-IIb化合物中的环C为键、苯基、吡啶基、嘧啶基、吡嗪基、噻唑基或噁唑基。In some embodiments, Ring C in the compounds of Formula 1-IIa and Formula 1-IIb is a bond, phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, or oxazolyl.
在一方面，本申请提供下式2-I所示的化合物：
In one aspect, the application provides the compound shown in the following formula 2-I:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中：in:
环A和环B各自独立为环烷基、杂环基、芳基或杂芳基；Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
环C为键、环烷基、杂环基、芳基或杂芳基；Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
X为C、N、O或S；X is C, N, O or S;
R1和R2各自独立地为不存在、H、卤素、氰基、羟基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基或-NRaRa；R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
R3和R4各自独立地为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb；R 3 and R 4 are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH 2 ) r NR a R a OR -OR b ;
Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-、-NRa-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a - or -(CH 2 ) r -NR a -CO-;
R5为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
R6为-N＝S(O)RcRd、-(CH2)sS(O)(＝NRe)Rf或-NRa-SO2Rg；R 6 is -N=S(O)R c R d , -(CH 2 ) s S(O)(=NR e )R f or -NR a -SO 2 R g ;
R7各自独立地为卤素、氰基、任选取代的烷基、任选取代的烯基、任选取代的炔基、-ORa、-S(O)Rf、-SO2Rf或-NRhRh；Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR h R h ;
Ra各自独立为H、任选取代的烷基、任选取代的烯基、任选取代的炔基或-CORb；each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
Rb为H、任选取代的烷基、任选取代的烯基或任选取代的炔基； R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rc和Rd各自独立选自任选取代的烷基、任选取代的烯基、任选取代的炔基、-ORa或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a or -NR a R a ; or R c , R d are connected to them The S atoms together form an optionally substituted 4-10 membered heterocyclic group;
Re为H、氰基、任选取代的烷基、任选取代的烯基或任选取代的炔基；R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rf为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rg选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的4-10元杂环基或-NRhRh；R g is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-10 membered heterocyclyl, or -NR h R h ;
Rh各自独立为H、任选取代的烷基、任选取代的烯基或任选取代的炔基；或者两个Rh与它们所连接的N原子一起形成任选取代的4-10元杂环基；R h are each independently H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered Heterocyclyl;
r为0、1、2或3；r is 0, 1, 2 or 3;
s为0、1、2或3；且s is 0, 1, 2 or 3; and
m、n和p各自独立为0、1、2或3。m, n and p are each independently 0, 1, 2 or 3.
在一些实施方案中，环A为芳基。在某些实施方案中，环A为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环A为苯基或萘基。在某些实施方案中，环A为苯基。In some embodiments, Ring A is aryl. In certain embodiments, Ring A is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring A is phenyl or naphthyl. In certain embodiments, Ring A is phenyl.
在一些实施方案中，环A为杂芳基。在某些实施方案中，环A为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环A选自噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、吡咯基、三唑基、三嗪基、咪唑基、吡唑基、吡咯基、吡啶基、嘧啶基或吡嗪基。In some embodiments, Ring A is heteroaryl. In certain embodiments, Ring A is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, ring A is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazole group, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl or pyrazinyl.
在某些实施方案中，环A为吡啶基、嘧啶基或噻吩基。在某些实施方案中，环A为吡啶基。 In certain embodiments, Ring A is pyridyl, pyrimidinyl or thienyl. In certain embodiments, Ring A is pyridyl.
在某些实施方案中，环A为 In certain embodiments, Ring A is
在一些实施方案中，环B为杂环基。在某些实施方案中，环B为5-14元杂环基，5-12元杂环基，5-10元杂环基，5-8元杂环基。在某些实施方案中，环B为吡啶酮基。In some embodiments, Ring B is heterocyclyl. In certain embodiments, Ring B is 5-14 membered heterocyclyl, 5-12 membered heterocyclyl, 5-10 membered heterocyclyl, 5-8 membered heterocyclyl. In certain embodiments, Ring B is pyridinonyl.
在一些实施方案中，环B为芳基。在某些实施方案中，环B为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环B为苯基或萘基。在某些实施方案中，环B为苯基。In some embodiments, Ring B is aryl. In certain embodiments, Ring B is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring B is phenyl or naphthyl. In certain embodiments, Ring B is phenyl.
在一些实施方案中，环B为杂芳基。在某些实施方案中，环B为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环B选自噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、吡咯基、三唑基、三嗪基、吡啶酮基、苯并吗啉基、吲唑基、二氢苯并恶嗪基、吡唑并吡啶基、苯并三唑基、苯并咪唑基、四氢异喹啉基、吲唑基、咪唑并吡啶基、吡啶并吗啉基、苯并异二唑基、吲哚基、喹啉基、异喹啉基、喹唑啉基、喹噁啉基、十氢异喹啉基、二氢吲哚基、八氢吲哚基或八氢异吲哚基。In some embodiments, Ring B is heteroaryl. In certain embodiments, Ring B is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, Ring B is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazole Base, Triazinyl, Pyridonyl, Benzomorpholinyl, Indazolyl, Dihydrobenzoxazinyl, Pyrazolopyridyl, Benzotriazolyl, Benzimidazolyl, Tetrahydroisoquinoline base, indazolyl, imidazopyridyl, pyridomorpholinyl, benzisodiazolyl, indolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, decahydroiso Quinolinyl, indolinyl, octahydroindolyl or octahydroisoindolyl.
在某些实施方案中，环B选自吡啶基、吡啶酮基、吲唑基、二氢苯并恶嗪基、吡唑并吡啶基、苯并三唑基、苯并咪唑基、四氢异喹啉基、吲唑基、咪唑并吡啶基或吡啶并吗啉基。在某些实施方案中，环B选自吲唑基、二氢苯并恶嗪基、苯并咪唑基、苯并吗啉基、吡啶并吗啉基、吡唑并吡啶基或苯并三唑基。In certain embodiments, Ring B is selected from pyridyl, pyridonyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridyl, benzotriazolyl, benzimidazolyl, tetrahydroiso Quinolinyl, indazolyl, imidazopyridinyl or pyridomorpholinyl. In certain embodiments, Ring B is selected from indazolyl, dihydrobenzoxazinyl, benzimidazolyl, benzomorpholinyl, pyridomorpholinyl, pyrazolopyridinyl, or benzotriazole base.
在某些实施方案中，选自下组：
In some embodiments, Select from the group:
在一些实施方案中，环C为键。In some embodiments, Ring C is a bond.
在一些实施方案中，环C为芳基。在某些实施方案中，环C为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环C为苯基或萘基。在某些实施方案中，环C为苯基。In some embodiments, Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
在一些实施方案中，环C为杂芳基。在某些实施方案中，环C为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环C选自嘧啶基、吡嗪基、吡啶基、哌啶基、哌嗪基、吗啉基、噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、哒嗪基、呋喃基、吡咯基、三唑基或三嗪基。在某些实施方案中，环C为嘧啶基、吡嗪基、吡啶基、噻唑基或噁唑基。在某些实施方案中，环C为嘧啶基、吡嗪基或吡啶基。In some embodiments, Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl. In certain embodiments, Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl. In certain embodiments, Ring C is pyrimidinyl, pyrazinyl or pyridinyl.
在某些实施方案中，选自下组：
In some embodiments, Select from the group:
在一些实施方案中，X为N、O或S，且R1和R2不存在。In some embodiments, X is N, O, or S, and R and R are absent.
在一些实施方案中，X为C，R1和R2各自独立为H、羟基或任选取代的烷基。In some embodiments, X is C, and R and R are each independently H, hydroxyl, or optionally substituted alkyl .
在某些实施方案中，X为C，R1和R2均为任选取代的烷基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。在某些实施方案中，X为C，R1和R2各自独立地为任选取代的C1-C4烷基。 In certain embodiments, X is C, and R and R are both optionally substituted alkyl optionally replaced by one or more independently selected from halogen, hydroxy, cyano Substituent group and -NR a R a substituent. In certain embodiments, X is C, and R 1 and R 2 are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，X为C，R1和R2均为甲基。In certain embodiments, X is C and R and R are both methyl.
在某些实施方案中，X为C，R1和R2中的一者为任选取代的烷基，另一者为H或羟基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, X is C, one of R and R is optionally substituted alkyl, the other is H or hydroxy, and the optionally substituted alkyl is optionally replaced by one or Substituents independently selected from halogen, hydroxy, cyano and -NR a R a are substituted.
在某些实施方案中，X为C，R1和R2中的一者为任选取代的C1-C4烷基，另一者为H或羟基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, X is C, one of R and R is optionally substituted C 1 -C 4 alkyl, the other is H or hydroxyl, and the optionally substituted C 1 - C4alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NRaRa .
在某些实施方案中，X为C，R1和R2中的一者为甲基，另一者为羟基。In certain embodiments, X is C, and one of R and R is methyl and the other is hydroxy.
在一些实施方案中，各R3独立为H、卤素、ORb或任选取代的烷基。In some embodiments, each R3 is independently H, halo, ORb , or optionally substituted alkyl.
在一些实施方案中，各R3独立为任选取代的C1-C4烷基。In some embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，各R3独立为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
在一些实施方案中，各R3独立为H或卤素。In some embodiments, each R3 is independently H or halo.
在一些实施方案中，各R3独立选自卤素。In some embodiments, each R3 is independently selected from halogen.
在一些实施方案中，各R3独立为氟或氯。In some embodiments, each R3 is independently fluoro or chloro.
在一些实施方案中，R3为氟。In some embodiments, R 3 is fluoro.
在一些实施方案中，R3为氯。In some embodiments, R 3 is chloro.
在某些实施方案中，R3为H。In certain embodiments, R3 is H.
在一些实施方案中，各R4独立为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的烷基或-CORb，Rb为H、任选取代的烷基、任选取代的烯基、任选取代的炔基，其中所述任选取代的烷基、任选取代的烯基和任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, each R4 is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRa R a or -OR b , wherein each R a is independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkyne wherein the optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl are optionally replaced by one or more independently selected from halogen, hydroxyl, cyano and -NR a R a Substituents replace.
在某些实施方案中，各R4独立为H、卤素、氰基、氧代、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的C2-C4烯基或-CORb，Rb为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。In certain embodiments, each R 4 is independently H, halo, cyano, oxo, -(CH 2 ) r NR a R a , or -OR b , wherein each R a is independently H, optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkyne base.
在某些实施方案中，各R4独立为H、氯、氰基、氧代、-OCH3、-OC≡CH或-CH2NH(CH＝CH2)。 In certain embodiments, each R4 is independently H, chloro, cyano, oxo, -OCH3 , -OC≡CH, or -CH2NH (CH= CH2 ).
在某些实施方案中，各R4独立为H、氯、氰基、氧代或-OCH3。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, or -OCH3 .
在一些实施方案中，Z1为键、-O-、-CO-或-NRa-，其中Ra为H或任选取代的烷基。In some embodiments, Z 1 is a bond, -O-, -CO-, or -NR a -, wherein R a is H or optionally substituted alkyl.
在一些实施方案中，Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-或-NRa-。In some embodiments, Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, or -NR a -.
在一些实施方案中，Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-或-NRa-，其中，Ra为H、任选取代的烷基、任选取代的烯基、任选取代的炔基或-CORb，其中，Rb为H、任选取代的烷基、任选取代的烯基或任选取代的炔基。In some embodiments, Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, or -NR a -, wherein R a is H, optionally substituted is alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -COR b , wherein R b is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.
在一些实施方案中，Z1为键、-O-、-CO-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的烷基。In some embodiments, Z1 is a bond, -O-, -CO-, or -( CH2 ) r - NRa -CO-, wherein Ra is H or optionally substituted alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的C1-C4烷基。In certain embodiments, Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NH-、-NHCO-或-CH2NHCO-。In certain embodiments, Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
在一些实施方案中，R5为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，所述任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, R 5 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, the optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxyl, cyano and the substituent of -NR a R a is substituted.
在某些实施方案中，R5为任选取代的C1-C4烷基或任选取代的C2-C4烯基，所述任选取代的C1-C4烷基和任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, R 5 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and optionally Substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.
在某些实施方案中，R5为甲基、乙基、丙基或乙烯基，所述甲基、乙基、丙基和乙烯基任选地被一个或多个独立地选自氯、羟基或氰基的取代基取代。In certain embodiments, R is methyl , ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine, hydroxy Or cyano substituent substitution.
在一些实施方案中，Z1为键或-O-，R5为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is a bond or -O-, R 5 is optionally substituted C 1 -C 4 alkyl optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
在某些实施方案中，Z1为键或-O-，R5为甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, Z is a bond or -O-, R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of halogen, hydroxy or cyano are substituted.
在某些实施方案中，Z1为键或-O-，R5为甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自氟、氯或羟基的取代基取代。 In certain embodiments, Z is a bond or -O-, R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of fluorine, chlorine or hydroxyl are substituted.
在一些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为任选取代的C2-C4烯基，所述任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, R 5 is optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
在某些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为乙烯基。In certain embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
在一些实施方案中，-Z1-R5选自-(CH2)rCl、-O(CH2)rF、-O(CH2)rCl或-O(CH2)rOH，其中r为1、2或3。In some embodiments, -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
在一些实施方案中，R6为-N＝S(O)RcRd或-NRa-SO2Rg。In some embodiments, R 6 is -N═S(O)R c R d or -NR a -SO 2 R g .
在一些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd各自独立选自任选取代的烷基、-ORa或-NRaRa，其中Ra各自独立为H、任选取代的烷基或任选取代的炔基。In some embodiments, R 6 is -N═S(O)R c R d , each of R c and R d is independently selected from optionally substituted alkyl, -OR a, or -NR a R a , wherein R a Each is independently H, optionally substituted alkyl, or optionally substituted alkynyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd各自独立选自任选取代的C1-C4烷基、-ORa或-NRaRa，其中Ra各自独立为H、任选取代的C1-C4烷基或任选取代的C2-C4炔基。In certain embodiments, R 6 is -N═S(O)R c R d , each of R c and R d is independently selected from optionally substituted C 1 -C 4 alkyl, -OR a , or -NR a R a , wherein each R a is independently H, optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkynyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd各自独立地为任选取代的C1-C4烷基。In certain embodiments, R 6 is —N═S(O)R c R d , R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd中的一者为任选取代的C1-C4烷基，另一者为-ORa或-NRaRa，其中Ra各自独立为H、任选取代的C1-C4烷基或任选取代的C2-C4炔基。In certain embodiments, R 6 is -N═S(O)R c R d , one of R c and R d is optionally substituted C 1 -C 4 alkyl, and the other is -OR a or -NR a R a , wherein each R a is independently H, optionally substituted C 1 -C 4 alkyl, or optionally substituted C 2 -C 4 alkynyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc和Rd中的一者为任选取代的C1-C4烷基，另一者为-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。In certain embodiments, R 6 is -N═S(O)R c R d , one of R c and R d is optionally substituted C 1 -C 4 alkyl, and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在一些实施方案中，R6为-N＝S(O)(CH3)2或-N＝S(O)(CH3)(NHCH3)。In some embodiments, R 6 is -N=S(O)(CH 3 ) 2 or -N=S(O)(CH 3 )(NHCH 3 ).
在一些实施方案中，R6为-N＝S(O)RcRd，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述任选取代的4-10元杂环基任选地被一个或多个Ri取代，其中Ri选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的4-9元杂环基、-C(O)Rj-、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，Rj为任选取代的烷基或者环烷基。 In some embodiments, R 6 is -N=S(O)R c R d , R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group, any of which The optionally substituted 4-10 membered heterocyclyl is optionally substituted by one or more R , wherein R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally Substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -C(O)R j -, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted ring Alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -OR , where R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted The alkynyl group, R j is optionally substituted alkyl or cycloalkyl.
在某些实施方案中，R6为-N＝S(O)RcRd，Rc、Rd与它们所连接的S原子一起形成任选取代的4-6元杂环基，所述任选取代的4-6元杂环基任选地被一个或多个Ri取代，其中Ri选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。In certain embodiments, R 6 is -N=S(O)R c R d , R c , R d together with the S atom they are attached to form an optionally substituted 4-6 membered heterocyclic group, said Optionally substituted 4-6 membered heterocyclyl is optionally substituted by one or more R i , wherein R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkyne radical, optionally substituted C 3 -C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently is H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 ring Alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
在某些实施方案中，R6选自下组：
In certain embodiments, R is selected from the group consisting of:
其各自任选地被一个或多个Ri取代，其中Ri选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。Each of which is optionally substituted by one or more R i , wherein R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally Substituted C 2 -C 4 alkynyl.
在某些实施方案中，Ri选自下组：任选地被一个或多个羟基、氰基、-O(C1-C4烷基)或-O(C2-C4炔基)取代的C1-C4烷基、C2-C4炔基、C3-C6环烷基、-NH2、-NH(C1-C4烷基)、-C(O)NH2和-SO2(C1-C4烷基)，其中-NH(C1-C4烷基)中的C1-C4烷基任选地被一个或多个卤素或羟基取代。In certain embodiments, R i is selected from the group consisting of optionally replaced by one or more hydroxyl, cyano, -O(C 1 -C 4 alkyl) or -O(C 2 -C 4 alkynyl) Substituted C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -C(O)NH 2 and -SO 2 (C 1 -C 4 alkyl), wherein the C 1 -C 4 alkyl in -NH(C 1 -C 4 alkyl) is optionally substituted with one or more halogen or hydroxy.
在一些实施方案中，R6选自下组：

In some embodiments, R is selected from the group consisting of:

在一些实施方案中，R6为-N＝S(O)RcRd，环C为键或杂芳基。在某些实施方案中，R6为-N＝S(O)RcRd，环C为键、嘧啶基或吡嗪基。In some embodiments, R 6 is —N═S(O)R c R d , and ring C is a bond or heteroaryl. In certain embodiments, R 6 is —N═S(O)R c R d , Ring C is a bond, pyrimidinyl or pyrazinyl.
在一些实施方案中，R6为-(CH2)sS(O)(＝NRe)Rf，Re为H、氰基或任选取代的烷基，Rf为任选取代的烷基，其中所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, R 6 is -(CH 2 ) s S(O)(=NR e )R f , R e is H, cyano, or optionally substituted alkyl, R f is optionally substituted alkyl wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
在某些实施方案中，R6为-(CH2)sS(O)(＝NRe)Rf，Re为H、氰基或任选取代的C1- C4烷基，Rf为任选取代的C1-C4烷基，其中所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In certain embodiments, R 6 is -(CH 2 ) s S(O)(=NR e )R f , R e is H, cyano, or optionally substituted C 1 - C 4 alkyl, R f is an optionally substituted C 1 -C 4 alkyl, wherein the optionally substituted C 1 -C 4 alkyl is optionally selected from one or more independently selected from halogen, hydroxyl, Substituted by a cyano group or a substituent of -NR a R a .
在某些实施方案中，R6为-(CH2)sS(O)(＝NRe)Rf，Re为H、氰基或甲基，Rf为甲基，s为0或1。In certain embodiments, R 6 is -(CH 2 ) s S(O)(=NR e )R f , R e is H, cyano, or methyl, R f is methyl, s is 0 or 1 .
在一些实施方案中，R6为-(CH2)sS(O)(＝NRe)Rf，环C为芳基或杂芳基。在某些实施方案中，R6为-(CH2)sS(O)(＝NRe)Rf，环C为苯基、吡啶基或嘧啶基。In some embodiments, R 6 is -(CH 2 ) s S(O)(=NR e )R f , and ring C is aryl or heteroaryl. In certain embodiments, R 6 is -(CH 2 ) s S(O)(=NR e )R f , and ring C is phenyl, pyridyl or pyrimidinyl.
在一些实施方案中，R6为-NRa-SO2Rg，Ra为H或任选取代的烷基，Rg为任选取代的烷基、任选取代的4-10元杂环基或-NRhRh。In some embodiments, R 6 is -NR a -SO 2 R g , R a is H or optionally substituted alkyl, R g is optionally substituted alkyl, optionally substituted 4-10 membered heterocycle group or -NR h R h .
在某些实施方案中，R6为-NRa-SO2Rg，Ra为H或任选被一个或多个独立地选自卤素、羟基或氰基的取代基取代的烷基。在某些实施方案中，R6为-NRa-SO2Rg，Ra为H或-(CH2)2OH。In certain embodiments, R 6 is —NR a —SO 2 R g , and Ra is H or alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano. In certain embodiments, R 6 is -NR a -SO 2 R g , and Ra is H or -(CH 2 ) 2 OH.
在某些实施方案中，R6为-NRa-SO2Rg，Rg为任选被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代的烷基。在某些实施方案中，R6为-NRa-SO2Rg，Rg为任选被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代的C1-C4烷基。在某些实施方案中，R6为-NRa-SO2Rg，Rg为甲基、-(CH2)2NH2或-(CH2)2N(CH3)2。In certain embodiments, R 6 is -NR a -SO 2 R g , R g is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, or -NR a R a alkyl. In certain embodiments, R 6 is -NR a -SO 2 R g , R g is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, or -NR a R a C 1 -C 4 alkyl. In certain embodiments, R 6 is -NR a -SO 2 R g , and R g is methyl, -(CH 2 ) 2 NH 2 or -(CH 2 ) 2 N(CH 3 ) 2 .
在某些实施方案中，R6为-NRa-SO2Rg，Rg为任选被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代的4-10元杂环基，其中Ra独立地选自氢或烷基。在某些实施方案中，R6为-NRa-SO2Rg，Rg为哌啶基或四氢吡喃基。In certain embodiments, R 6 is -NR a -SO 2 R g , R g is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, or -NR a R a 4-10 membered heterocyclyl, wherein R a is independently selected from hydrogen or alkyl. In certain embodiments, R 6 is -NR a -SO 2 R g , and R g is piperidinyl or tetrahydropyranyl.
在某些实施方案中，R6为-NRa-SO2Rg，Rg为-NRhRh，其中Rh各自独立地为氢或任选被一个或多个独立地选自卤素、羟基或氰基的取代基取代的烷基，或者两个Rh与它们所连接的N原子一起形成任选取代的4-10元杂环基。在某些实施方案中，R6为-NRa-SO2Rg，Rg为-NRhRh，其中Rh各自独立地为氢、甲基或-(CH2)2OH，或者两个Rh与它们所连接的N原子一起形成哌嗪基。In certain embodiments, R 6 is -NR a -SO 2 R g , R g is -NR h R h , wherein each R h is independently hydrogen or is optionally selected from one or more independently selected from halogen, Alkyl substituted by substituents of hydroxy or cyano, or two Rh together with the N atoms to which they are attached form an optionally substituted 4-10 membered heterocyclic group. In certain embodiments, R 6 is -NR a -SO 2 R g , R g is -NR h R h , wherein each R h is independently hydrogen, methyl, or -(CH 2 ) 2 OH, or both Each Rh together with the N atom to which they are attached form piperazinyl.
在一些实施方案中，R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg。In some embodiments, each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
在某些实施方案中，R7各自独立地为卤素、氰基、任选取代的C1-C4烷基、-O(C1-C4烷基)、-O(C2-C4炔基)、-S(O)(C1-C4烷基)、-SO2(C1-C4烷基)或-NRgRg，其中 Rg各自独立为H、-SO2(C1-C4烷基)或羟基取代的C1-C4烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基。In certain embodiments, each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , where Each R g is independently H, -SO 2 (C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4 -10 membered heterocyclic group.
在一些实施方案中，本申请提供了具有下式的化合物：
In some embodiments, the application provides compounds having the formula:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中in
V1和V2各自独立地为N或CH；V and V are each independently N or CH;
环C为键、芳基或杂芳基；Ring C is a bond, aryl or heteroaryl;
Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -CO-, -NR a - or -(CH 2 ) r -NR a -CO-;
R1和R2各自独立地为羟基或任选取代的烷基；R and R are each independently hydroxyl or optionally substituted alkyl;
R3为H、ORb或任选取代的烷基；R 3 is H, OR b or optionally substituted alkyl;
R4各自独立地为卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb； Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRaRa or -ORb ;
R5为任选取代的烷基或任选取代的烯基； R is optionally substituted alkyl or optionally substituted alkenyl;
R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRhRh；Ra各自独立为H、任选取代的烷基或-CORb；Each R 7 is independently halogen, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f or -NR h R h ; each R a is independently H, any Select substituted alkyl or -COR b ;
Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rc和Rd各自独立选自任选取代的烷基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
Rf为任选取代的烷基； R is optionally substituted alkyl;
Rh各自独立为H、-SO2Rf或任选取代的烷基；或者两个Rh与它们所连接的N原子一起形成任选取代的4-10元杂环基；且Each R h is independently H, -SO 2 R f or an optionally substituted alkyl group; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
r、s、m、n和p各自独立为0、1或2。 r, s, m, n and p are each independently 0, 1 or 2.
在一些实施方案中，为苯基、吡啶基或吡啶酮基。In some embodiments, is phenyl, pyridyl or pyridonyl.
在某些实施方案中，选自下组：
In some embodiments, Select from the group:
在一些实施方案中，环C为键。In some embodiments, Ring C is a bond.
在一些实施方案中，环C为芳基或杂芳基。In some embodiments, Ring C is aryl or heteroaryl.
在一些实施方案中，环C为芳基。在某些实施方案中，环C为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环C为苯基或萘基。在某些实施方案中，环C为苯基。In some embodiments, Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
在一些实施方案中，环C为杂芳基。在某些实施方案中，环C为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环C选自嘧啶基、吡嗪基、吡啶基、哌啶基、哌嗪基、吗啉基、噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、哒嗪基、呋喃基、吡咯基、三唑基或三嗪基。在某些实施方案中，环C为嘧啶基、吡嗪基、吡啶基、噻唑基或噁唑基。在某些实施方案中，环C为嘧啶基、吡嗪基或吡啶基。In some embodiments, Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl. In certain embodiments, Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl. In certain embodiments, Ring C is pyrimidinyl, pyrazinyl or pyridinyl.
在某些实施方案中，选自下组：

In some embodiments, Select from the group:

在一些实施方案中，各R3独立为H、卤素、ORb或任选取代的烷基。In some embodiments, each R3 is independently H, halo, ORb , or optionally substituted alkyl.
在一些实施方案中，各R3独立为任选取代的C1-C4烷基。In some embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，各R3独立为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
在一些实施方案中，各R3独立为H或卤素。In some embodiments, each R3 is independently H or halo.
在一些实施方案中，各R3独立选自卤素。In some embodiments, each R3 is independently selected from halogen.
在一些实施方案中，各R3独立为氟或氯。In some embodiments, each R3 is independently fluoro or chloro.
在一些实施方案中，R3为氟。In some embodiments, R 3 is fluoro.
在一些实施方案中，R3为氯。In some embodiments, R 3 is chloro.
在某些实施方案中，R3为H。In certain embodiments, R3 is H.
在一些实施方案中，各R4独立为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的烷基或-CORb，Rb为H、任选取代的烷基、任选取代的烯基、任选取代的炔基，其中所述任选取代的烷基、任选取代的烯基和任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, each R4 is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRa R a or -OR b , wherein each R a is independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkyne wherein the optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl are optionally replaced by one or more independently selected from halogen, hydroxyl, cyano and -NR a R a Substituents replace.
在某些实施方案中，各R4独立为H、卤素、氰基、氧代、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的C2-C4烯基或-CORb，Rb为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。In certain embodiments, each R 4 is independently H, halo, cyano, oxo, -(CH 2 ) r NR a R a , or -OR b , wherein each R a is independently H, optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkyne base.
在某些实施方案中，各R4独立为H、氯、氰基、氧代、-OCH3、-OC≡CH或-CH2NH(CH＝CH2)。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, -OCH3 , -OC≡CH, or -CH2NH (CH= CH2 ).
在某些实施方案中，各R4独立为H、氯、氰基、氧代或-OCH3。 In certain embodiments, each R4 is independently H, chloro, cyano, oxo, or -OCH3 .
在一些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的烷基。In some embodiments, Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的C1-C4烷基。In certain embodiments, Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NH-、-NHCO-或-CH2NHCO-。In certain embodiments, Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
在某些实施方案中，Z1为键、-O-或-CO-。In certain embodiments, Z is a bond, -O- or -CO-.
在一些实施方案中，R5为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，所述任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, R 5 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, the optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxyl, cyano and the substituent of -NR a R a is substituted.
在某些实施方案中，R5为任选取代的C1-C4烷基或任选取代的C2-C4烯基，所述任选取代的C1-C4烷基和任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, R 5 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and optionally Substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.
在某些实施方案中，R5为甲基、乙基、丙基或乙烯基，所述甲基、乙基、丙基和乙烯基任选地被一个或多个独立地选自氯、羟基或氰基的取代基取代。In certain embodiments, R is methyl , ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine, hydroxy Or cyano substituent substitution.
在一些实施方案中，Z1为键或-O-，R5为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is a bond or -O-, R 5 is optionally substituted C 1 -C 4 alkyl optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
在某些实施方案中，Z1为键或-O-，R5为甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, Z is a bond or -O-, R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of halogen, hydroxy or cyano are substituted.
在某些实施方案中，Z1为键或-O-，R5为甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自氟、氯或羟基的取代基取代。In certain embodiments, Z is a bond or -O-, R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of fluorine, chlorine or hydroxyl are substituted.
在一些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为任选取代的C2-C4烯基，所述任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, R 5 is optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
在某些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为乙烯基。In certain embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
在一些实施方案中，-Z1-R5选自-(CH2)rCl、-O(CH2)rF、-O(CH2)rCl或-O(CH2)rOH，其中r为1、2或3。 In some embodiments, -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
在一些实施方案中，Rc和Rd各自独立选自任选取代的烷基或-NRaRa，其中Ra各自独立为H或任选取代的烷基。In some embodiments, R c and R d are each independently selected from optionally substituted alkyl or -NR a Ra , wherein each R a is independently H or optionally substituted alkyl.
在某些实施方案中，Rc和Rd各自独立选自任选取代的C1-C4烷基或-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。In certain embodiments, R c and R d are each independently selected from optionally substituted C 1 -C 4 alkyl or -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，Rc和Rd各自独立地为任选取代的C1-C4烷基。In certain embodiments, R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，Rc和Rd中的一者为任选取代的C1-C4烷基，另一者为-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。In certain embodiments, one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在一些实施方案中，Rc和Rd均为-CH3-，或者Rc和Rd中的一者为-CH3，另一者为-NHCH3。In some embodiments, both Rc and Rd are -CH3- , or one of Rc and Rd is -CH3 and the other is -NHCH3 .
在一些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述任选取代的4-10元杂环基任选地被一个或多个Ri取代，其中Ri选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的4-9元杂环基、-C(O)Rj-、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，Rj为任选取代的烷基或者环烷基。In some embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl optionally replaced by one or a plurality of R i substitutions, wherein R i is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered hetero Cyclic group, -C(O)R j -, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or Optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen , hydroxy, cyano, and -OR b substituents, wherein R b is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and R j is optionally substituted alkyl or ring alkyl.
在某些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-6元杂环基，所述任选取代的4-6元杂环基任选地被一个或多个Ri取代，其中Ri选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。In certain embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl optionally substituted by One or more R i are substituted, wherein R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted C 1 -C 4 alkyl, The above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally selected from one or more independently selected from halogen , hydroxy, cyano and -OR b substituents, where R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
在某些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基选自下组：
In certain embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
其各自任选地被一个或多个Ri取代，其中Ri选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。Each of which is optionally substituted by one or more R i , wherein R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally Substituted C 2 -C 4 alkynyl.
在某些实施方案中，Ri选自下组：任选地被一个或多个羟基、氰基、-O(C1-C4烷基)或-O(C2-C4炔基)取代的C1-C4烷基、C2-C4炔基、C3-C6环烷基、-NH2、-NH(C1-C4烷基)、-C(O)NH2和-SO2(C1-C4烷基)，其中-NH(C1-C4烷基)中的C1-C4烷基任选地被一个或多个卤素或羟基取代。In certain embodiments, R i is selected from the group consisting of optionally replaced by one or more hydroxyl, cyano, -O(C 1 -C 4 alkyl) or -O(C 2 -C 4 alkynyl) Substituted C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -C(O)NH 2 and -SO 2 (C 1 -C 4 alkyl), wherein the C 1 -C 4 alkyl in -NH(C 1 -C 4 alkyl) is optionally substituted with one or more halogen or hydroxy.
在一些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基选自下组：

In some embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:

在一些实施方案中，环C为键或杂芳基。在某些实施方案中，环C为键、嘧啶基或吡嗪基。In some embodiments, Ring C is a bond or heteroaryl. In certain embodiments, Ring C is a bond, pyrimidinyl, or pyrazinyl.
在一些实施方案中，R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg。In some embodiments, each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
在某些实施方案中，R7各自独立地为卤素、氰基、任选取代的C1-C4烷基、-O(C1-C4烷基)、-O(C2-C4炔基)、-S(O)(C1-C4烷基)、-SO2(C1-C4烷基)或-NRgRg，其中Rg各自独立为H、-SO2(C1-C4烷基)或羟基取代的C1-C4烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基。In certain embodiments, each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
在一些实施方案中，本申请提供了具有下式的化合物：
In some embodiments, the application provides compounds having the formula:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中in
V3为N或CH；V 3 is N or CH;
环C为键、芳基或杂芳基；Ring C is a bond, aryl or heteroaryl;
环D为杂环基或杂芳基；Ring D is heterocyclyl or heteroaryl;
Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -CO-, -NR a - or -(CH 2 ) r -NR a -CO-;
R1和R2各自独立地为羟基或任选取代的烷基；R and R are each independently hydroxyl or optionally substituted alkyl;
R3为H、ORb或任选取代的烷基；R 3 is H, OR b or optionally substituted alkyl;
R4各自独立地为卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb； Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRaRa or -ORb ;
R5为任选取代的烷基或任选取代的烯基； R is optionally substituted alkyl or optionally substituted alkenyl;
R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRhRh；Each R 7 is independently halogen, cyano , optionally substituted alkyl, -ORa , -S(O) Rf , -SO2Rf , or -NRhRh ;
Ra各自独立为H、任选取代的烷基或-CORb；each R a is independently H, optionally substituted alkyl, or -COR b ;
Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
Rc和Rd各自独立选自任选取代的烷基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
Rf为任选取代的烷基； R is optionally substituted alkyl;
Rh各自独立为H、-SO2Rf或任选取代的烷基；或者两个Rh与它们所连接的N原子一起形成任选取代的4-10元杂环基；且Each R h is independently H, -SO 2 R f or an optionally substituted alkyl group; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
r、s、m、n和p各自独立为0、1或2。r, s, m, n and p are each independently 0, 1 or 2.
在一些实施方案中，其中选自：
In some embodiments, where selected from:
在一些实施方案中，环D被1、2或3个R9取代，所述R9为H、卤素或任选取 代的烷基。In some embodiments , ring D is substituted with 1, 2, or 3 R 9 that are H, halogen, or optionally Substituted alkyl.
在一些实施方案中，通过环D上的饱和N原子与-Z1R5连接。In some embodiments, Attachment to -Z 1 R 5 is through a saturated N atom on ring D.
在一些实施方案中，环C键。In some embodiments, the ring C bond.
在一些实施方案中，环C为芳基或杂芳基。In some embodiments, Ring C is aryl or heteroaryl.
在一些实施方案中，环C为芳基。在某些实施方案中，环C为6-14元芳基，6-12元芳基，6-10元芳基，6-8元芳基。在某些实施方案中，环C为苯基或萘基。在某些实施方案中，环C为苯基。In some embodiments, Ring C is aryl. In certain embodiments, Ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In certain embodiments, Ring C is phenyl or naphthyl. In certain embodiments, Ring C is phenyl.
在一些实施方案中，环C为杂芳基。在某些实施方案中，环C为5-14元杂芳基，5-12元杂芳基，5-10元杂芳基，5-8元杂芳基，5-6元杂芳基。在某些实施方案中，环C选自嘧啶基、吡嗪基、吡啶基、哌啶基、哌嗪基、吗啉基、噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、哒嗪基、呋喃基、吡咯基、三唑基或三嗪基。在某些实施方案中，环C为嘧啶基、吡嗪基、吡啶基、噻唑基或噁唑基。在某些实施方案中，环C为嘧啶基、吡嗪基或吡啶基。In some embodiments, Ring C is heteroaryl. In certain embodiments, Ring C is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl. In certain embodiments, Ring C is pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, or oxazolyl. In certain embodiments, Ring C is pyrimidinyl, pyrazinyl or pyridinyl.
在某些实施方案中，选自下组：

In some embodiments, Select from the group:

在一些实施方案中，各R3独立为H、卤素、ORb或任选取代的烷基。In some embodiments, each R3 is independently H, halo, ORb , or optionally substituted alkyl.
在一些实施方案中，各R3独立为任选取代的C1-C4烷基。In some embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，各R3独立为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In certain embodiments, each R 3 is independently optionally substituted C 1 -C 4 alkyl optionally substituted by one or more independently selected from halogen , hydroxyl, cyano and -NR a R a substituents.
在一些实施方案中，各R3独立为H或卤素。In some embodiments, each R3 is independently H or halo.
在一些实施方案中，各R3独立选自卤素。In some embodiments, each R3 is independently selected from halogen.
在一些实施方案中，各R3独立为氟或氯。In some embodiments, each R3 is independently fluoro or chloro.
在一些实施方案中，R3为氟。In some embodiments, R 3 is fluoro.
在一些实施方案中，R3为氯。In some embodiments, R 3 is chloro.
在某些实施方案中，R3为H。In certain embodiments, R3 is H.
在一些实施方案中，各R4独立为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的烷基或-CORb，Rb为H、任选取代的烷基、任选取代的烯基、任选取代的炔基，其中所述任选取代的烷基、任选取代的烯基和任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, each R4 is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRa R a or -OR b , wherein each R a is independently H, optionally substituted alkyl, or -COR b , R b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkyne wherein the optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl are optionally replaced by one or more independently selected from halogen, hydroxyl, cyano and -NR a R a Substituents replace.
在某些实施方案中，各R4独立为H、卤素、氰基、氧代、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的C2-C4烯基或-CORb，Rb为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。In certain embodiments, each R 4 is independently H, halo, cyano, oxo, -(CH 2 ) r NR a R a , or -OR b , wherein each R a is independently H, optionally substituted C 2 -C 4 alkenyl or -COR b , R b is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkyne base.
在某些实施方案中，各R4独立为H、氯、氰基、氧代、-OCH3、-OC≡CH或-CH2NH(CH＝CH2)。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, -OCH3 , -OC≡CH, or -CH2NH (CH= CH2 ).
在某些实施方案中，各R4独立为H、氯、氰基、氧代或-OCH3。In certain embodiments, each R4 is independently H, chloro, cyano, oxo, or -OCH3 .
在一些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的烷基。In some embodiments, Z 1 is a bond, -O-, -CO-, -NR a -, or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的C1-C4烷基。In certain embodiments, Z1 is a bond, -O-, -CO-, -NRa- , or -( CH2 ) r -NRa - CO-, wherein Ra is H or optionally substituted C1 -C 4 alkyl.
在某些实施方案中，Z1为键、-O-、-CO-、-NH-、-NHCO-或-CH2NHCO-。 In certain embodiments, Z1 is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH2NHCO- .
在某些实施方案中，Z1为键、-O-或-CO-。In certain embodiments, Z is a bond, -O- or -CO-.
在一些实施方案中，R5为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，所述任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。In some embodiments, R 5 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, the optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally selected from one or more independently selected from halogen, hydroxyl, cyano and the substituent of -NR a R a is substituted.
在某些实施方案中，R5为任选取代的C1-C4烷基或任选取代的C2-C4烯基，所述任选取代的C1-C4烷基和任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, R 5 is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 1 -C 4 alkyl and optionally Substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.
在某些实施方案中，R5为甲基、乙基、丙基或乙烯基，所述甲基、乙基、丙基和乙烯基任选地被一个或多个独立地选自氯、羟基或氰基的取代基取代。In certain embodiments, R is methyl , ethyl, propyl or vinyl optionally selected from one or more independently selected from chlorine, hydroxy Or cyano substituent substitution.
在一些实施方案中，Z1为键或-O-，R5为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is a bond or -O-, R 5 is optionally substituted C 1 -C 4 alkyl optionally replaced by one or more Substituents independently selected from halogen, hydroxyl, cyano or -NR a R a .
在某些实施方案中，Z1为键或-O-，R5为甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自卤素、羟基或氰基的取代基取代。In certain embodiments, Z is a bond or -O-, R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of halogen, hydroxy or cyano are substituted.
在某些实施方案中，Z1为键或-O-，R5为甲基、乙基或丙基，所述甲基、乙基和丙基任选地被一个或多个独立地选自氟、氯或羟基的取代基取代。In certain embodiments, Z is a bond or -O-, R is methyl , ethyl or propyl, optionally one or more of which are independently selected from Substituents of fluorine, chlorine or hydroxyl are substituted.
在一些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为任选取代的C2-C4烯基，所述任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。In some embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, R 5 is optionally substituted C 2 -C 4 alkenyl, said optionally substituted C 2 - C alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
在某些实施方案中，Z1为-CO-或-(CH2)r-NRa-CO-，R5为乙烯基。In certain embodiments, Z 1 is -CO- or -(CH 2 ) r -NR a -CO-, and R 5 is vinyl.
在一些实施方案中，-Z1-R5选自-(CH2)rCl、-O(CH2)rF、-O(CH2)rCl或-O(CH2)rOH，其中r为1、2或3。In some embodiments, -Z 1 -R 5 is selected from -(CH 2 ) r Cl, -O(CH 2 ) r F, -O(CH 2 ) r Cl, or -O(CH 2 ) r OH, wherein r is 1, 2 or 3.
在一些实施方案中，Rc和Rd各自独立选自任选取代的烷基或-NRaRa，其中Ra各自独立为H或任选取代的烷基。In some embodiments, R c and R d are each independently selected from optionally substituted alkyl or -NR a Ra , wherein each R a is independently H or optionally substituted alkyl.
在某些实施方案中，Rc和Rd各自独立选自任选取代的C1-C4烷基或-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。In certain embodiments, R c and R d are each independently selected from optionally substituted C 1 -C 4 alkyl or -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，Rc和Rd各自独立地为任选取代的C1-C4烷基。 In certain embodiments, R c and R d are each independently optionally substituted C 1 -C 4 alkyl.
在某些实施方案中，Rc和Rd中的一者为任选取代的C1-C4烷基，另一者为-NRaRa，其中Ra各自独立为H或任选取代的C1-C4烷基。In certain embodiments, one of R c and R d is optionally substituted C 1 -C 4 alkyl and the other is -NR a R a , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl.
在一些实施方案中，Rc和Rd均为-CH3-，或者Rc和Rd中的一者为-CH3，另一者为-NHCH3。In some embodiments, both Rc and Rd are -CH3- , or one of Rc and Rd is -CH3 and the other is -NHCH3 .
在一些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述任选取代的4-10元杂环基任选地被一个或多个Ri取代，其中Ri选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的4-9元杂环基、-C(O)Rj-、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，Rj为任选取代的烷基或者环烷基。In some embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl optionally replaced by one or a plurality of R i substitutions, wherein R i is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered hetero Cyclic group, -C(O)R j -, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or Optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen , hydroxy, cyano, and -OR b substituents, wherein R b is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and R j is optionally substituted alkyl or ring alkyl.
在某些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-6元杂环基，所述任选取代的4-6元杂环基任选地被一个或多个Ri取代，其中Ri选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。In certain embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl optionally substituted by One or more R i are substituted, wherein R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted C 1 -C 4 alkyl, The above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally selected from one or more independently selected from halogen , hydroxy, cyano and -OR b substituents, where R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
在某些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基选自下组：
In certain embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:
其各自任选地被一个或多个Ri取代，其中Ri选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、 羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基。Each of which is optionally substituted by one or more R i , wherein R i is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 cycloalkyl, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein each R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally replaced by one or more independently selected from halogen, Substituents of hydroxy, cyano and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 Alkynyl.
在某些实施方案中，Ri选自下组：任选地被一个或多个羟基、氰基、-O(C1-C4烷基)或-O(C2-C4炔基)取代的C1-C4烷基、C2-C4炔基、C3-C6环烷基、-NH2、-NH(C1-C4烷基)、-C(O)NH2和-SO2(C1-C4烷基)，其中-NH(C1-C4烷基)中的C1-C4烷基任选地被一个或多个卤素或羟基取代。In certain embodiments, R i is selected from the group consisting of optionally replaced by one or more hydroxyl, cyano, -O(C 1 -C 4 alkyl) or -O(C 2 -C 4 alkynyl) Substituted C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -C(O)NH 2 and -SO 2 (C 1 -C 4 alkyl), wherein the C 1 -C 4 alkyl in -NH(C 1 -C 4 alkyl) is optionally substituted with one or more halogen or hydroxy.
在一些实施方案中，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基选自下组：

In some embodiments, R c , R d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the group consisting of:

在一些实施方案中，环C为键或杂芳基。在某些实施方案中，环C为键、嘧啶基或吡嗪基。In some embodiments, Ring C is a bond or heteroaryl. In certain embodiments, Ring C is a bond, pyrimidinyl, or pyrazinyl.
在一些实施方案中，R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg。In some embodiments, each R 7 is independently halo, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g .
在某些实施方案中，R7各自独立地为卤素、氰基、任选取代的C1-C4烷基、-O(C1-C4烷基)、-O(C2-C4炔基)、-S(O)(C1-C4烷基)、-SO2(C1-C4烷基)或-NRgRg，其中Rg各自独立为H、-SO2(C1-C4烷基)或羟基取代的C1-C4烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基。In certain embodiments, each R 7 is independently halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -O(C 2 -C 4 alkynyl), -S(O)(C 1 -C 4 alkyl), -SO 2 (C 1 -C 4 alkyl) or -NR g R g , wherein each R g is independently H, -SO 2 ( C 1 -C 4 alkyl) or C 1 -C 4 alkyl substituted by hydroxy; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
在一些实施方案中，式2-Ia和式2-Ib化合物中的Rc和Rd各自独立地为C1-C4烷基或-NH-(C1-C4烷基)。In some embodiments, R c and R d in the compounds of Formula 2-Ia and Formula 2-Ib are each independently C 1 -C 4 alkyl or -NH-(C 1 -C 4 alkyl).
在一些实施方案中，式2-Ia和式2-Ib化合物中的Rc和Rd与它们所连接的S原子一起形成任选地被一个或多个Ri取代的4-10元杂环基。In some embodiments, R and R in compounds of Formula 2-Ia and Formula 2-Ib together with the S atom to which they are attached form a 4-10 membered heterocyclic ring optionally substituted by one or more R base.
在一些实施方案中，式2-Ia和式2-Ib化合物中的环C为键、苯基、吡啶基、嘧啶基或吡嗪基。In some embodiments, Ring C in the compounds of Formula 2-Ia and Formula 2-Ib is a bond, phenyl, pyridyl, pyrimidinyl, or pyrazinyl.
在又一方面，本申请提供了下式III所示的化合物：
In another aspect, the application provides the compound shown in the following formula III:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中：in:
环A’和环B’各自独立为环烷基、芳基、杂芳基或杂环基；Ring A' and ring B' are each independently cycloalkyl, aryl, heteroaryl or heterocyclyl;
X’为O、S、N或C；X' is O, S, N or C;
R11不存在，或者为H、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、卤素、羟基、-NH2、-NHR1a或-NR1aR1a；R 11 is absent, or is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, hydroxyl, -NH 2 , -NHR 1a or -NR 1a R 1a ;
R12不存在，或者为H、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、卤素、羟基、-NH2、-NHR1a或-NR1aR1a；R 12 is absent, or is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, hydroxyl, -NH 2 , -NHR 1a or -NR 1a R 1a ;
各R13独立为H、氰基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、卤素、-NH2、-NHR1a或-NR1aR1a；Each R 13 is independently H, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, —NH 2 , —NHR 1a , or — NR 1a R 1a ;
各R14独立为H、氰基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、卤素、氧代、-NH2、-NHR1a或-NR1aR1a；Each R is independently H, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, oxo, -NH2 , -NHR 1a or -NR 1a R 1a ;
Z11不存在，或者为-O-、-NR’-、-NR’-CO-或-S-；Z 11 does not exist, or is -O-, -NR'-, -NR'-CO- or -S-;
Z12为亚烷基、亚烯基、亚炔基或-R”-Y11-R”’-；其中，R”和R”’各自为键、亚烷基、亚烯基或亚炔基，且R”和R”’不同时为键，Y11为O、NH或S；其中，Z12任选地被取代；Z 12 is an alkylene group, an alkenylene group, an alkynylene group or -R"-Y 11 -R"'-; wherein, R" and R"' are each a bond, an alkylene group, an alkenylene group or an alkynylene group , and R" and R"' are not bonds at the same time, Y 11 is O, NH or S; wherein, Z 12 is optionally substituted;
R15为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
R16为-N＝S(O)R17R18、-N(R’)-S(O)2-R19、取代的芳基、取代的杂芳基、取代的杂环基或取代的环烷基；其中，所述取代的芳基、取代的杂芳基、取代的杂环基和取代的环烷基上的取代基中至少有一个为-N＝S(O)R17R18或-N(R’)-S(O)2-R19；条件是，当所述取代的芳基、取代的杂芳基、取代的杂环基和取代的环烷基仅被一个取代基取代且该取代基为-N(R’)-S(O)2-R19时，Z12为含有碳碳三键的基团；R 16 is -N=S(O)R 17 R 18 , -N(R')-S(O) 2 -R 19 , substituted aryl, substituted heteroaryl, substituted heterocyclic or substituted Cycloalkyl; wherein, at least one of the substituents on the substituted aryl, substituted heteroaryl, substituted heterocyclic and substituted cycloalkyl is -N=S(O)R 17 R 18 or -N(R')-S(O) 2 -R 19 ; provided that when the substituted aryl, substituted heteroaryl, substituted heterocyclyl and substituted cycloalkyl are replaced by only one substituent When the substituent is -N(R')-S(O) 2 -R 19 , Z 12 is a group containing a carbon-carbon triple bond;
各R’独立为H、任选取代的烷基、任选取代的烯基、任选取代的炔基或任选取代的烷氧基； each R' is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkoxy;
R17和R18各自独立选自任选取代的烷基、任选取代的烯基、任选取代的炔基、-NH2、-NHR1a或-NR1aR1a；或R17、R18与它们所连接的S原子一起形成任选取代的4-10元杂环基；R 17 and R 18 are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -NH 2 , -NHR 1a or -NR 1a R 1a ; or R 17 , R 18 Together with the S atoms to which they are attached, an optionally substituted 4-10 membered heterocyclic group is formed;
R19为任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的杂环基、-NH2、-NHR1a或-NR1aR1a；R 19 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, -NH 2 , -NHR 1a or -NR 1a R 1a ;
R1a各自独立为任选取代的烷基、任选取代的烯基或任选取代的炔基； Each R is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
n’和m’各自独立为0、1、2或3的整数。n' and m' are each independently an integer of 0, 1, 2 or 3.
在一些实施方案中，环A’为芳基或杂芳基，优选为6-14元芳基或5-10元杂芳基，所述5-10元杂芳基优选为5-10元单环或双环杂芳基；更优选地，所述环A’选自：苯基、萘基、噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、吡咯基、三唑基和三嗪基，更优选为为苯基或吡啶基。In some embodiments, ring A' is aryl or heteroaryl, preferably 6-14 membered aryl or 5-10 membered heteroaryl, and the 5-10 membered heteroaryl is preferably 5-10 membered Ring or bicyclic heteroaryl; more preferably, the ring A' is selected from: phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazine group, pyridazinyl, furyl, pyrrolyl, triazolyl and triazinyl, more preferably phenyl or pyridyl.
在一些实施方案中，环B’为芳基、杂芳基或杂环基，优选为6-14元芳基、5-10元杂芳基或4-10元杂环基，所述5-10元杂芳基优选为5-10元单环或双环杂芳基；更优选地，所述环B’选自：苯基、萘基、噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、吡咯基、三唑基、三嗪基、苯并吗啉基、吡啶并吗啉基、苯并咪唑基、苯并异二唑基、吲哚基、喹啉基、异喹啉基、喹唑啉基、喹噁啉基、四氢异喹啉基、十氢异喹啉基、二氢吲哚基、八氢吲哚基和八氢异吲哚基，更优选为苯基、吡啶基、吲唑基、二氢吲哚基或苯并吗啉基。In some embodiments, Ring B' is aryl, heteroaryl or heterocyclic group, preferably 6-14 membered aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, the 5- The 10-membered heteroaryl is preferably a 5-10-membered monocyclic or bicyclic heteroaryl; more preferably, the ring B' is selected from: phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, Oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazolyl, triazinyl, benzomorpholinyl, pyridomorpholinyl, benzimidazolyl, benzene Isoxadiazolyl, indolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, tetrahydroisoquinolyl, decahydroisoquinolyl, dihydroindolyl, octahydroisoquinolyl, Indolinyl and octahydroisoindolyl are more preferably phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl.
在一些实施方案中，X’为O或S，R11和R12不存在；或X’为N，R11和R12中的一个不存在，一个为H或任选取代的C1-C6烷基；或X’为C，R11和R12各自独立为H、羟基或任选取代的C1-C6烷基；优选地，所述任选取代的烷基任选地被1-3个选自卤素、羟基、氰基、-NH2、-NHR1a和-NR1aR1a的取代基取代，其中，各R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；优选地，X’为C，R11为C1-C4烷基，R12为C1-C4烷基或羟基；更优选地，X’为C，R11和R12各自独立为C1-C4烷基。In some embodiments, X' is O or S, R 11 and R 12 are absent; or X' is N, one of R 11 and R 12 is absent, and one is H or an optionally substituted C 1 -C 6 alkyl; or X' is C, R 11 and R 12 are each independently H, hydroxyl or optionally substituted C 1 -C 6 alkyl; preferably, said optionally substituted alkyl is optionally replaced by 1 -3 substituents selected from halogen, hydroxyl, cyano, -NH 2 , -NHR 1a and -NR 1a R 1a , wherein each R 1a is independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; preferably, X' is C, R 11 is C 1 -C 4 alkyl, R 12 is C 1 -C 4 alkyl or hydroxyl; more Preferably, X' is C, R 11 and R 12 are each independently C 1 -C 4 alkyl.
在一些实施方案中，各R13独立为H、卤素或任选取代的C1-C6烷基；优选地，所述任选取代的烷基任选地被1-3个选自卤素、羟基、氰基、-NH2、-NHR1a和-NR1aR1a的取代基取代，其中，R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或 卤代C1-C4烷基；其中，当R13为非氢取代基时，n’优选为1或2；优选地，R13为H。In some embodiments, each R is independently H, halogen, or optionally substituted C1-C6 alkyl; preferably, said optionally substituted alkyl is optionally replaced by 1-3 members selected from halogen, hydroxy, Substituents of cyano, -NH 2 , -NHR 1a and -NR 1a R 1a , wherein each of R 1a is independently C 1 -C 4 alkyl, hydroxyl substituted C 1 -C 4 alkyl or Halogenated C 1 -C 4 alkyl; wherein, when R 13 is a non-hydrogen substituent, n' is preferably 1 or 2; preferably, R 13 is H.
在一些实施方案中，各R14独立为H、氰基、卤素、任选取代的C1-C4烷氧基、任选取代的烷基C1-C4或氧代；优选地，所述任选取代的C1-C4烷基和任选取代的C1-C4烷氧基各自任选地被1-3个选自卤素、羟基、氰基、C2-C4炔基、-NH2、-NHR1a和-NR1aR1a的取代基取代，其中，R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；优选地，R14为非氢取代基，m’为1或2；更优选地，m为2，2个R14分别为氰基和卤素，或均为氰基，或分别为C1-C4烷基和氧代，或分别为氰基和C1-C4烷氧基，或分别为卤素和任选被C2-C4炔基取代的C1-C4烷氧基；进一步优选地，m’为2，两个R14分别为氰基和卤素。In some embodiments, each R 14 is independently H, cyano, halogen, optionally substituted C 1 -C 4 alkoxy, optionally substituted alkyl C 1 -C 4 , or oxo; preferably, the The optionally substituted C 1 -C 4 alkyl and the optionally substituted C 1 -C 4 alkoxy are each optionally replaced by 1-3 members selected from halogen, hydroxyl, cyano, C 2 -C 4 alkynyl , -NH 2 , -NHR 1a and -NR 1a R 1a are substituted by substituents, wherein, R 1a is each independently C 1 -C 4 alkyl, hydroxyl substituted C 1 -C 4 alkyl or halogenated C 1 - C 4 alkyl; preferably, R 14 is a non-hydrogen substituent, m' is 1 or 2; more preferably, m is 2, and 2 R 14 are cyano and halogen respectively, or both are cyano, or respectively C 1 -C 4 alkyl and oxo, or cyano and C 1 -C 4 alkoxy , respectively, or halogen and C 1 -C 4 alkane optionally substituted by C 2 -C 4 alkynyl, respectively Oxygen; further preferably, m' is 2, and two R 14 are cyano and halogen respectively.
在一些实施方案中，Z11不存在，或者为-O-或-NR’-CO-；优选地，该R’为H或C1-C4烷基。In some embodiments, Z 11 is absent, or is -O- or -NR'-CO-; preferably, the R' is H or C 1 -C 4 alkyl.
在一些实施方案中，R15为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，更优选为任选取代的C1-C4烷基；优选地，R15的取代基选自卤素、羟基、-NH2、-NHR1a、-NR1aR1a和-CH2NR1bR1b，其中，R1a优选各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基，R1b优选各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基，或两个R1b与它们所连接的氮原子一起形成4-6元杂环基或5-6元杂芳基，所述4-6元杂环基或5-6元杂芳基任选被1、2或3个选自卤素、羟基、氰基、C1-C4烷基、卤代C1-C4烷基、-NH2、-NHR1a、-NR1aR1a、C1-C4烷氧基、卤代C1-C4烷氧基和C2-C4炔基取代的C1-C4烷氧基的取代基取代；优选地，R15为任选被1-3个选自卤素、羟基、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基，更优选为任选被1-3个选自卤素和羟基的取代基取代的C1-C4烷基，更优选为被1-3个选自卤素和羟基的取代基取代的C1-C4烷基，且该烷基的最末尾的碳被至少一个选自卤素和羟基的取代基取代。In some embodiments, R 15 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, more preferably optionally Substituted C 1 -C 4 alkyl; preferably, the substituent of R 15 is selected from halogen, hydroxyl, -NH 2 , -NHR 1a , -NR 1a R 1a and -CH 2 NR 1b R 1b , wherein, R 1a Preferably each is independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl, R 1b is preferably each independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl, or two R 1b together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group or a 5-6 membered heteroaryl group, said 4-6 membered heterocyclic group or 5-6 membered heteroaryl group is optionally replaced by 1, 2 or 3 members selected from halogen, hydroxyl, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl , -NH 2 , -NHR 1a , -NR 1a R 1a , C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy and C 2 -C 4 alkynyl substituted C 1 -C 4 alkane Oxygen substituents are substituted; preferably, R 15 is C 1 -C 4 alkyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably C 1 -C 4 alkyl optionally substituted by 1-3 substituents selected from halogen and hydroxy, more preferably C 1 -C 4 alkane substituted by 1-3 substituents selected from halogen and hydroxy and the last carbon of the alkyl group is substituted with at least one substituent selected from halogen and hydroxyl.
在一些实施方案中，-Z11-R15为任选取代的C1-C4烷基、任选取代的C1-C4烷氧基、-NR’-CO-(任选取代的C2-C4烯基)或-NR’-CO-(任选取代的C1-C4烷基)，其中，所述C1-C4烷基和C1-C4烷氧基中的烷基部分以及所述C2-C4烯基任选被1、2或3个选自卤素和羟基的取代基取代，且优选该C1-C4烷基、该烷基部分或烯基的最末端的C被至少一个选自所述卤素和羟基的取代基取代；优选地，-Z11-R15为任选取代的C1- C4烷基或任选取代的C1-C4烷氧基，其中，所述C1-C4烷基和C1-C4烷氧基中的烷基部分任选被1、2或3个选自卤素和羟基的取代基取代，且优选该C1-C4烷基或该烷基部分的最末端的碳被至少一个选自所述卤素和羟基的取代基取代。In some embodiments, -Z 11 -R 15 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, -NR'-CO-(optionally substituted C 2 -C 4 alkenyl) or -NR'-CO-(optionally substituted C 1 -C 4 alkyl), wherein, in the C 1 -C 4 alkyl and C 1 -C 4 alkoxy The alkyl moiety and the C 2 -C 4 alkenyl are optionally substituted by 1, 2 or 3 substituents selected from halogen and hydroxy, and preferably the C 1 -C 4 alkyl, the alkyl moiety or alkenyl The most terminal C of is substituted by at least one substituent selected from said halogen and hydroxyl; preferably, -Z 11 -R 15 is optionally substituted C 1 - C 4 alkyl or optionally substituted C 1 -C 4 alkoxy, wherein, the C 1 -C 4 alkyl and the alkyl part in the C 1 -C 4 alkoxy are optionally replaced by 1, 2 or 3 substituents selected from halogen and hydroxy, and preferably the C 1 -C 4 alkyl or the most terminal carbon of the alkyl moiety is substituted with at least one substituent selected from said halogen and hydroxy.
在一些实施方案中，Z12为C2-C4亚烯基、C2-C4亚炔基或-R”-Y11-R”’-，更优选为C2-C4亚炔基或-R”-Y11-R”’-；优选地，R”和R”’各自为键、C1-C4亚烷基、C2-C4亚烯基或C2-C4亚炔基，且R”和R”’不同时为键；优选地，Z12为(C1-C4亚烷基)-O-、(C2-C4亚烯基)-O-、(C2-C4亚炔基)-O-、(C1-C4亚烷基)-NH-、(C2-C4亚烯基)-NH-、(C2-C4亚炔基)-NH-、(C1-C4亚烷基)-S-、(C2-C4亚烯基)-S-和(C2-C4亚炔基)-S-；优选地，Z2为C2-C4亚炔基或(C1-C4亚烷基)-O-；优选地，Z2任选地被1-3个选自卤素、羟基、氨基、氧代(＝O)和C1-C4烷氧基的取代基取代。In some embodiments, Z 12 is C 2 -C 4 alkenylene, C 2 -C 4 alkynylene or -R"-Y 11 -R"'-, more preferably C 2 -C 4 alkynylene or -R"-Y 11 -R"'-; preferably, R" and R"' are each a bond, C 1 -C 4 alkylene, C 2 -C 4 alkenylene or C 2 -C 4 alkylene Alkynyl, and R" and R"' are not bonds at the same time; preferably, Z 12 is (C 1 -C 4 alkylene)-O-, (C 2 -C 4 alkenylene) -O-, ( C 2 -C 4 alkynylene)-O-, (C 1 -C 4 alkynylene) -NH-, (C 2 -C 4 alkenylene) -NH-, (C 2 -C 4 alkynylene )-NH-, (C 1 -C 4 alkylene) -S-, (C 2 -C 4 alkenylene) -S- and (C 2 -C 4 alkynylene) -S-; preferably, Z 2 is C 2 -C 4 alkynylene or (C 1 -C 4 alkylene)-O-; preferably, Z 2 is optionally substituted by 1-3 selected from halogen, hydroxyl, amino, oxo ( =O) and substituents of C 1 -C 4 alkoxy.
在一些实施方案中，R16为取代的6-14元芳基、取代的5-10元杂芳基、取代的4-10元杂环基或取代的C3-C8环烷基；优选地，所述6-14元芳基包括苯基和萘基，所述4-10元杂环基包括氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基，所述5-10元杂芳基包括噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、吡咯基、三唑基和三嗪基；更优选地，R16为取代的吡嗪基、取代的嘧啶基、取代的哒嗪基、取代的吡唑基或取代的咪唑基。In some embodiments, R 16 is substituted 6-14 membered aryl, substituted 5-10 membered heteroaryl, substituted 4-10 membered heterocyclyl or substituted C 3 -C 8 cycloalkyl; preferably Preferably, the 6-14 membered aryl group includes phenyl and naphthyl, and the 4-10 membered heterocyclic group includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, The 5-10 membered heteroaryl groups include thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazolyl and triazinyl; more preferably, R 16 is substituted pyrazinyl, substituted pyrimidinyl, substituted pyridazinyl, substituted pyrazolyl or substituted imidazolyl.
在某些实施方案中，R16为取代的6-14元芳基、取代的5-10元杂芳基、取代的4-10元杂环基或取代的C3-C8环烷基，且在所述取代的6-14元芳基、取代的5-10元杂芳基、取代的4-10元杂环基或取代的C3-C8环烷基上的取代基-N＝S(O)R17R18中：In certain embodiments, R is substituted 6-14 membered aryl, substituted 5-10 membered heteroaryl, substituted 4-10 membered heterocyclyl or substituted C 3 -C 8 cycloalkyl, And the substituent -N = In S(O)R 17 R 18 :
(i)R17和R18各自独立为任选取代的烷基，优选为任选取代的C1-C4烷基；优选地，所述烷基任选地被1-3个选自下组的取代基取代：羟基，-NH2，-NHR1a，-NR1aR1a，卤素，任选被1或2个选自卤素、氰基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基，以及任选被1或2个选自卤素、氰基、C2-C4炔基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷氧基；或(i) R 17 and R 18 are each independently an optionally substituted alkyl group, preferably an optionally substituted C 1 -C 4 alkyl group; preferably, the alkyl group is optionally 1-3 selected from the group consisting of Substituents of the group: hydroxy, -NH 2 , -NHR 1a , -NR 1a R 1a , halogen, optionally 1 or 2 selected from halogen, cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a C 1 -C 4 alkyl substituted by substituents of R 1a , and optionally 1 or 2 selected from halogen, cyano, C 2 -C 4 alkynyl, hydroxyl, -NH 2 , -NHR 1a and - C 1 -C 4 alkoxy substituted by a substituent of NR 1a R 1a ; or
(ii)R17、R18与它们所连接的S原子一起形成任选取代的4-10元含S并任选地含有1或2个选自O和N的杂原子的杂环基，优选包括硫杂环丁烷基、硫杂环戊烷基、硫杂环己烷基、硫代吗啉基和1,4-氧硫杂环己烷基；优选地，所述杂环基任选 地被1或2个选自卤素，任选被1或2个选自卤素、氰基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基，C2-C4炔基，任选被1或2个选自卤素、氰基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷氧基，(C2-C4炔基)-O-(C1-C4亚烷基)，-NH2，-NHR1a和-NR1aR1a的取代基取代，其中，Ra优选各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基。(ii) R 17 , R 18 together with the S atoms they are connected to form an optionally substituted 4-10 membered S-containing heterocyclic group optionally containing 1 or 2 heteroatoms selected from O and N, preferably Including thietanyl, thiolanyl, thietanyl, thiomorpholinyl and 1,4-oxathiolanyl; preferably, the heterocyclyl is optionally C 1 -C 4 alkane optionally substituted by 1 or 2 substituents selected from halogen, optionally 1 or 2 substituents selected from halogen, cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a C 2 -C 4 alkynyl, C 1 -C 4 alkane optionally substituted by 1 or 2 substituents selected from halogen, cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a Oxygen, (C 2 -C 4 alkynyl) -O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a are substituted by substituents of R 1a , wherein R a is preferably each are independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl.
在一些实施方案中，R’上的取代基为1-3个选自卤素、羟基、-NH2，-NHR1a和-NR1aR1a的取代基，其中，R1a优选各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；优选地，R’为H或任选被羟基取代的C1-C4烷基。In some embodiments, the substituents on R' are 1-3 substituents selected from halogen, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a , wherein R 1a is preferably each independently C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by hydroxy, or halogenated C 1 -C 4 alkyl; preferably, R' is H or C 1 -C 4 alkyl optionally substituted by hydroxy.
在一些实施方案中，R19为任选取代的C1-C4烷基、任选取代的4-10元杂环基、-NHR1a或-NR1aR1a，其中，R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；优选地，所述杂环基为4-10元含氮和/或氧的杂环基，优选选自哌啶基、哌嗪基、四氢吡喃基、氧杂环丁烷基、四氢呋喃基、氮杂环丁烷基、吡咯烷基和吗啉基；优选地，R19被取代时，取代基是1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、羟基、-NH2、-NHR1a或-NR1aR1a的取代基，其中，R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；优选地，所述杂环基未被取代，或被选自C1-C4烷基和卤素的基团取代。In some embodiments, R 19 is optionally substituted C 1 -C 4 alkyl, optionally substituted 4-10 membered heterocyclyl, -NHR 1a or -NR 1a R 1a , wherein each R 1a is independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; preferably, the heterocyclic group is a 4-10 membered nitrogen and/or oxygen-containing hetero Cyclic group, preferably selected from piperidinyl, piperazinyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl and morpholinyl; preferably, R 19 When substituted, the substituents are 1, 2 or 3 selected from halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, hydroxyl, -NH 2 , -NHR 1a or -NR 1a substituents of R 1a , wherein each of R 1a is independently C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by hydroxyl or Halogenated C 1 -C 4 alkyl; preferably, the heterocyclic group is unsubstituted or substituted by a group selected from C 1 -C 4 alkyl and halogen.
在一些实施方案中，R16上的取代基除所述-N＝S(O)R17R18或-N(R’)-S(O)2-R19外，还任选地包括1、2或3个选自氰基、任选取代的C1-C4烷基、羟基、-NH2、-NHR1a、-NR1aR1a、卤素、任选取代的C1-C4烷氧基、4-10元杂环基、-NR110-S(O)2-R19’和-S(O)2-R19’的取代基，其中，R110为H或C1-C4烷基，R19’为C1-C4烷基，R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；所述任选取代的C1-C4烷基优选任选被1或2个选自卤素、氰基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基取代，所述任选取代的C1-C4烷氧基优选任选被1或2个选自卤素、氰基、C2-C4炔基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷氧基，其中，Ra各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；优选地，所述取代基中的4-10杂环基为含氮杂环基，更优选为氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基或吗啉基。In some embodiments, in addition to the -N=S(O)R 17 R 18 or -N(R')-S(O) 2 -R 19 , substituents on R 16 optionally include , 2 or 3 selected from cyano, optionally substituted C 1 -C 4 alkyl, hydroxyl, -NH 2 , -NHR 1a , -NR 1a R 1a , halogen, optionally substituted C 1 -C 4 alkane Oxygen, 4-10 membered heterocyclic group, substituents of -NR 110 -S(O) 2 -R 19' and -S(O) 2 -R 19' , wherein, R 110 is H or C 1 -C 4 alkyl, R 19' is C 1 -C 4 alkyl, R 1a is each independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; Said optionally substituted C 1 -C 4 alkyl is preferably optionally substituted by 1 or 2 substituents selected from halogen, cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a , said Optionally substituted C 1 -C 4 alkoxy is preferably optionally replaced by 1 or 2 members selected from halogen, cyano, C 2 -C 4 alkynyl, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a A C 1 -C 4 alkoxy group substituted by a substituent, wherein each of R a is independently a C 1 -C 4 alkyl group, a hydroxy substituted C 1 -C 4 alkyl group or a halogenated C 1 -C 4 alkyl group; Preferably, the 4-10 heterocyclic groups in the substituents are nitrogen-containing heterocyclic groups, more preferably azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
在一些实施方案中，R16为-N＝S(O)R17R18；优选地，R17、R18与它们所连接的S 原子一起形成任选取代的4-10元含S并任选地含有1或2个选自O和N的杂原子的杂环基，优选包括硫杂环丁烷基、硫杂环戊烷基、硫杂环己烷基、硫代吗啉基和1,4-氧硫杂环己烷基；优选地，所述杂环基任选地被1或2个选自卤素，任选被1或2个选自卤素、氰基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基，C2-C4炔基，任选被1或2个选自卤素、氰基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷氧基，(C2-C4炔基)-O-(C1-C4亚烷基)，-NH2，-NHR1a和-NR1aR1a的取代基取代，其中，R1a优选各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；或In some embodiments, R 16 is -N=S(O)R 17 R 18 ; preferably, R 17 , R 18 and the S to which they are attached The atoms together form an optionally substituted 4-10 membered S-containing heterocyclic group optionally containing 1 or 2 heteroatoms selected from O and N, preferably including thietanyl, thietanyl , thiacyclohexyl, thiomorpholinyl and 1,4-oxathiocyclohexyl; preferably, the heterocyclyl is optionally selected from 1 or 2 halogen, optionally 1 or C 1 -C 4 alkyl, C 2 -C 4 alkynyl substituted by 2 substituents selected from halogen , cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a , optionally replaced by 1 or C 1 -C 4 alkoxy substituted by 2 substituents selected from halogen, cyano, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a , (C 2 -C 4 alkynyl)-O -(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a are substituted by substituents, wherein, R 1a is preferably independently C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; or
R16为-N(R’)-S(O)2-R19；其中，R’为H、任选取代的C1-C4烷基、任选取代的C2-C4烯基、任选取代的C2-C4炔基或任选取代的C1-C4烷氧基；R’被取代时，其取代基优选为1-3个选自卤素、羟基、-NH2，-NHR1a和-NR1aR1a的取代基，其中，R1a优选各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；优选地，R’为H或任选被羟基取代的C1-C4烷基；R19为任选取代的C1-C4烷基、任选取代的4-10元杂环基、-NHR1a或-NR1aR1a，其中，R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；R19被取代时，取代基是1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基，其中，R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；优选地，所述4-10元杂环基为4-10元含氮和/或氧的杂环基，优选选自哌啶基、哌嗪基、四氢吡喃基、氧杂环丁烷基、四氢呋喃基、氮杂环丁烷基、吡咯烷基和吗啉基；优选地，所述杂环基未被取代，或被选自C1-C4烷基和卤素的基团取代。R 16 is -N(R')-S(O) 2 -R 19 ; wherein, R' is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, Optionally substituted C 2 -C 4 alkynyl or optionally substituted C 1 -C 4 alkoxy; when R' is substituted, its substituents are preferably 1-3 selected from halogen, hydroxyl, -NH 2 , -NHR 1a and -NR 1a are substituents for R 1a , wherein R 1a is preferably each independently C 1 -C 4 alkyl, hydroxyl substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; Preferably, R' is H or C 1 -C 4 alkyl optionally substituted by hydroxyl; R 19 is optionally substituted C 1 -C 4 alkyl, optionally substituted 4-10 membered heterocyclic group, - NHR 1a or -NR 1a R 1a , wherein each of R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; when R 19 is substituted , the substituent is 1, 2 or 3 selected from halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy group, hydroxyl, -NH 2 , -NHR 1a and -NR 1a substituents of R 1a , wherein each of R 1a is independently C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by hydroxyl or halogenated C 1 -C 4 alkyl; Preferably, the 4-10 membered heterocyclic group is a 4-10 membered nitrogen and/or oxygen-containing heterocyclic group, preferably selected from piperidinyl, piperazinyl, tetrahydropyran group, oxetanyl group, tetrahydrofuranyl group, azetidinyl group, pyrrolidinyl group and morpholinyl group; preferably, the heterocyclyl group is unsubstituted, or is selected from C 1 -C 4 alkyl Substituted with a halogen group.
在一些实施方案中，R16为具有以下结构的-N＝S(O)R17R18：
In some embodiments, R 16 is -N=S(O)R 17 R 18 having the following structure:
其中，含S和X11的环为4-6元杂环，X11为CH2或NH或O，R111选自：H，任选被羟基或卤素取代的C1-C4烷基，C2-C4炔基，(C2-C4炔基)-O-(C1-C4亚烷基)，-NH2，-NHR1a和-NR1aR1a，其中，R1a优选各自独立为C1-C4烷基、羟基取代的C1-C4烷基或 卤代C1-C4烷基；当X11被R111取代时，X11为CH或N。Wherein, the ring containing S and X 11 is a 4-6 membered heterocycle, X 11 is CH 2 or NH or O, R 111 is selected from: H, C 1 -C 4 alkyl optionally substituted by hydroxyl or halogen, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl)-O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a , wherein R 1a is preferably Each is independently C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by hydroxy, or Halogenated C 1 -C 4 alkyl; when X 11 is substituted by R 111 , X 11 is CH or N.
在某些实施方案中，R16为具有以下结构的-N＝S(O)R7R8：
In certain embodiments, R 16 is -N=S(O)R 7 R 8 having the following structure:
在一些实施方案中，In some embodiments,
环A’为苯基或吡啶基；Ring A' is phenyl or pyridyl;
环B’为苯基、吡啶基、吲唑基、二氢吲哚基或苯并吗啉基；Ring B' is phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl;
X’为C；X' is C;
R11为C1-C4烷基或羟基；R 11 is C 1 -C 4 alkyl or hydroxyl;
R12为C1-C4烷基或羟基；R 12 is C 1 -C 4 alkyl or hydroxyl;
n为1；n is 1;
R13为H或C1-C4烷基，优选为H；R 13 is H or C 1 -C 4 alkyl, preferably H;
m为1或2；m is 1 or 2;
R14选自氰基、卤素、C1-C4烷基、氧代和任选被C2-C4炔基取代的C1-C4烷氧基；R 14 is selected from cyano, halogen, C 1 -C 4 alkyl, oxo and C 1 -C 4 alkoxy optionally substituted by C 2 -C 4 alkynyl;
Z11不存在，或者为-O-或-NR’-CO-；Z 11 does not exist, or is -O- or -NR'-CO-;
Z12为C2-C4亚炔基或-R”-Y11-R”’-，其中，R”和R”’各自为键或任选取代的C1-C4亚烷基，且R”和R”’不同时为键，Y11为O，所述C1-C4亚烷基任选被1个选自氧代和羟基的取代基取代；Z 12 is C 2 -C 4 alkynylene or -R"-Y 11 -R"'-, wherein R" and R"' are each a bond or optionally substituted C 1 -C 4 alkylene, and R" and R"' are not bonds at the same time, Y 11 is O, and the C 1 -C 4 alkylene is optionally substituted by one substituent selected from oxo and hydroxyl;
R15为任选被1-3个选自卤素、羟基、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基或C2-C4烯基，更优选为任选被1-3个选自卤素和羟基的取代基取代的C1-C4烷基，更优选为被1-3个选自卤素和羟基的取代基取代的C1-C4烷基、且该烷基的最末尾的碳被至少一个选自卤素和羟基的取代基取代；R 15 is C 1 -C 4 alkyl or C 2 -C 4 alkenyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably any A C 1 -C 4 alkyl group selected from 1-3 substituents selected from halogen and hydroxy, more preferably a C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxy, and the last carbon of the alkyl group is substituted with at least one substituent selected from halogen and hydroxyl;
R16为-N＝S(O)R17R18、-N(R’)-S(O)2-R19或取代的杂芳基；其中，所述杂芳基为噻唑基、异噻唑基、嘧啶基、吡嗪基或哒嗪基，优选为噻唑基、吡嗪基或嘧啶基；其中，所述杂芳基上的取代基至少包括-N＝S(O)R17R18或-N(R’)-S(O)2-R19，且除所述-N＝S(O)R17R18或-N(R’)-S(O)2-R19外，还任选地包括1个选自任选被C2-C4炔基取代 的C1-C4烷氧基、-S(O)2-R19’、氰基、-NR110-S(O)2-R19’、-NH2、-NHR1a、-NR1aR1a和4-10元杂环基的取代基，其中，R110为H或C1-C4烷基，R19’为C1-C4烷基；其中，当所述杂芳基仅被一个取代基取代且该取代基为-N(R’)-S(O)2-R19时，Z12为含有碳碳三键的基团，且其中，当R16为所述-N(R’)-S(O)2-R19，Z12为含有碳碳三键的基团，优选为C2-C4亚炔基；R 16 is -N=S(O)R 17 R 18 , -N(R')-S(O) 2 -R 19 or substituted heteroaryl; wherein, the heteroaryl is thiazolyl, isothiazole Base, pyrimidinyl, pyrazinyl or pyridazinyl, preferably thiazolyl, pyrazinyl or pyrimidinyl; wherein, the substituents on the heteroaryl include at least -N=S(O)R 17 R 18 or -N(R')-S(O) 2 -R 19 , and in addition to said -N=S(O)R 17 R 18 or -N(R')-S(O) 2 -R 19 , also Optionally includes 1 selected from the group optionally substituted by C 2 -C 4 alkynyl C 1 -C 4 alkoxy, -S(O) 2 -R 19' , cyano, -NR 110 -S(O) 2 -R 19' , -NH 2 , -NHR 1a , -NR 1a R 1a and a substituent of 4-10 membered heterocyclic groups, wherein R 110 is H or C 1 -C 4 alkyl, R 19' is C 1 -C 4 alkyl; wherein, when the heteroaryl is only When a substituent is substituted and the substituent is -N(R')-S(O) 2 -R 19 , Z 12 is a group containing a carbon-carbon triple bond, and wherein, when R 16 is the -N( R')-S(O) 2 -R 19 , Z 12 is a group containing a carbon-carbon triple bond, preferably a C 2 -C 4 alkynylene group;
R’为H或任选被羟基取代的C1-C4烷基；R' is H or C 1 -C 4 alkyl optionally substituted by hydroxy;
R17和R18各自独立为未取代的C1-C4烷基，或R17、R18与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述4-10元杂环基除含有S外，还任选含有1或2个选自O和N的杂原子，所述4-10元杂环基优选为硫杂环丁烷基、硫杂环戊烷基、硫杂环己烷基、硫代吗啉基和1,4-氧硫杂环己烷基；优选地，所述4-10元杂环基任选地被1-3个选自下组的取代基取代：任选被1或2个选自氰基和羟基的取代基取代的C1-C4烷基，C2-C4炔基，(C2-C4炔基)-O-(C1-C4亚烷基)，-NH2，-NHR1a和-NR1aR1a；R 17 and R 18 are each independently unsubstituted C 1 -C 4 alkyl, or R 17 and R 18 together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group, the 4- In addition to S, the 10-membered heterocyclic group optionally contains 1 or 2 heteroatoms selected from O and N, and the 4-10-membered heterocyclic group is preferably thietanyl, thiolane group, thianyl group, thiomorpholinyl group and 1,4-oxathione group; preferably, the 4-10 membered heterocyclic group is optionally selected from 1-3 Group substituent substitution: C 1 -C 4 alkyl, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl)- optionally substituted by 1 or 2 substituents selected from cyano and hydroxy O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a ;
R19为：任选被选自-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基，-NH2，-NHR1a，-NR1aR1a或4-10元杂环基；和R 19 is: C 1 -C 4 alkyl optionally substituted by a substituent selected from -NH 2 , -NHR 1a and -NR 1a R 1a , -NH 2 , -NHR 1a , -NR 1a R 1a or 4 -10 membered heterocyclyl; and
R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基。Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
在一些实施方案中，In some embodiments,
环A’为苯基或吡啶基；Ring A' is phenyl or pyridyl;
环B’为苯基、吡啶基、吲唑基、二氢吲哚基或苯并吗啉基；Ring B' is phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl;
X’为C；X' is C;
R11为C1-C4烷基或羟基；R 11 is C 1 -C 4 alkyl or hydroxyl;
R12为C1-C4烷基或羟基；R 12 is C 1 -C 4 alkyl or hydroxyl;
n为1；n is 1;
R13为H或C1-C4烷基，优选为H；R 13 is H or C 1 -C 4 alkyl, preferably H;
m为1或2；m is 1 or 2;
R14选自氰基、卤素、C1-C4烷基、氧代和任选被C2-C4炔基取代的C1-C4烷氧基；R 14 is selected from cyano, halogen, C 1 -C 4 alkyl, oxo and C 1 -C 4 alkoxy optionally substituted by C 2 -C 4 alkynyl;
Z11不存在，或者为-O-或-NR’-CO-；Z 11 does not exist, or is -O- or -NR'-CO-;
Z12为C2-C4亚炔基或-C1-C4亚烷基-O-，其中，所述C1-C4亚烷基任选被1个选 自氧代和羟基的取代基取代；Z 12 is C 2 -C 4 alkynylene or -C 1 -C 4 alkylene-O-, wherein the C 1 -C 4 alkylene is optionally selected from one Substituents from oxo and hydroxy;
R15为任选被1-3个选自卤素、羟基、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基或C2-C4烯基，更优选为任选被1-3个选自卤素和羟基的取代基取代的C1-C4烷基，更优选为被1-3个选自卤素和羟基的取代基取代的C1-C4烷基、且该烷基的最末尾的C被至少一个选自卤素和羟基的取代基取代；R 15 is C 1 -C 4 alkyl or C 2 -C 4 alkenyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably any A C 1 -C 4 alkyl group selected from 1-3 substituents selected from halogen and hydroxy, more preferably a C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxy, And the last C of the alkyl group is substituted by at least one substituent selected from halogen and hydroxyl;
R16为-N＝S(O)R17R18取代的杂芳基；其中，所述杂芳基为噻唑基、异噻唑基、嘧啶基、吡嗪基或哒嗪基，优选为噻唑基、吡嗪基或嘧啶基；其中，所述杂芳基上的取代基至少包括-N＝S(O)R17R18，除所述-N＝S(O)R17R18外，还任选地包括1个选自C1-C4烷氧基、-S(O)2-R19’、氰基、-NR110-S(O)2-R19’、-NH2、-NHR1a、-NR1aR1a和4-10元杂环基的取代基，其中，R110为H或C1-C4烷基，R19’为C1-C4烷基；R 16 is a heteroaryl group substituted by -N=S(O)R 17 R 18 ; wherein, the heteroaryl group is thiazolyl, isothiazolyl, pyrimidinyl, pyrazinyl or pyridazinyl, preferably thiazolyl , pyrazinyl or pyrimidinyl; wherein, the substituents on the heteroaryl include at least -N=S(O)R 17 R 18 , in addition to the -N=S(O)R 17 R 18 , also Optionally include one member selected from C 1 -C 4 alkoxy, -S(O) 2 -R 19' , cyano, -NR 110 -S(O) 2 -R 19' , -NH 2 , - Substituents of NHR 1a , -NR 1a R 1a and 4-10 membered heterocyclic groups, wherein R 110 is H or C 1 -C 4 alkyl, R 19' is C 1 -C 4 alkyl;
R17和R18各自独立为未取代的C1-C4烷基，或R17、R18与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述4-10元杂环基除含有S外，还任选含有1或2个选自O和N的杂原子，所述4-10元杂环基优选为硫杂环丁烷基、硫杂环戊烷基、硫杂环己烷基、硫代吗啉基和1,4-氧硫杂环己烷基；优选地，所述4-10元杂环基任选地被1-3个选自下组的取代基取代：任选被1或2个选自氰基和羟基的取代基取代的C1-C4烷基，C2-C4炔基，(C2-C4炔基)-O-(C1-C4亚烷基)，-NH2，-NHR1a和-NR1aR1a；R 17 and R 18 are each independently unsubstituted C 1 -C 4 alkyl, or R 17 and R 18 together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group, the 4- In addition to S, the 10-membered heterocyclic group optionally contains 1 or 2 heteroatoms selected from O and N, and the 4-10-membered heterocyclic group is preferably thietanyl, thiolane group, thianyl group, thiomorpholinyl group and 1,4-oxathione group; preferably, the 4-10 membered heterocyclic group is optionally selected from 1-3 Group substituent substitution: C 1 -C 4 alkyl, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl)- optionally substituted by 1 or 2 substituents selected from cyano and hydroxy O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a ;
R’为H或C1-C4烷基；和R' is H or C 1 -C 4 alkyl; and
R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基。Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
在一些实施方案中，In some embodiments,
环A’为苯基或吡啶基；Ring A' is phenyl or pyridyl;
环B’为苯基、吡啶基、吲唑基、二氢吲哚基或苯并吗啉基，优选苯基；Ring B' is phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl, preferably phenyl;
X’为C；X' is C;
R11为C1-C4烷基或羟基；R 11 is C 1 -C 4 alkyl or hydroxyl;
R12为C1-C4烷基或羟基；R 12 is C 1 -C 4 alkyl or hydroxyl;
n为1；n is 1;
R13为H或C1-C4烷基，优选为H；R 13 is H or C 1 -C 4 alkyl, preferably H;
m为1或2； m is 1 or 2;
R14选自氰基、卤素、C1-C4烷基、氧代和C1-C4烷氧基；R 14 is selected from cyano, halogen, C 1 -C 4 alkyl, oxo and C 1 -C 4 alkoxy;
Z11不存在，或者为-O-；Z 11 does not exist, or is -O-;
Z12为C2-C4亚炔基；Z 12 is C 2 -C 4 alkynylene;
R15为任选被1-3个选自卤素、羟基、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基，更优选为任选被1-3个选自卤素和羟基的取代基取代的C1-C4烷基，更优选为被1-3个选自卤素和羟基的取代基取代的C1-C4烷基、且该烷基的最末尾的C被至少一个选自卤素和羟基的取代基取代；R 15 is C 1 -C 4 alkyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably optionally substituted by 1-3 substituents selected from C 1 -C 4 alkyl substituted by halogen and hydroxyl substituents, more preferably C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxyl, and the last of the alkyl C is substituted by at least one substituent selected from halogen and hydroxyl;
R16为-N＝S(O)R17R18、-N(R’)-S(O)2-R19或取代的杂芳基；其中，所述杂芳基为噻唑基、异噻唑基、嘧啶基、吡嗪基或哒嗪基，优选为噻唑基、吡嗪基或嘧啶基；其中，所述杂芳基上的取代基至少包括-N＝S(O)R17R18或-N(R’)-S(O)2-R19；R 16 is -N=S(O)R 17 R 18 , -N(R')-S(O) 2 -R 19 or substituted heteroaryl; wherein, the heteroaryl is thiazolyl, isothiazole Base, pyrimidinyl, pyrazinyl or pyridazinyl, preferably thiazolyl, pyrazinyl or pyrimidinyl; wherein, the substituents on the heteroaryl include at least -N=S(O)R 17 R 18 or -N(R')-S(O) 2 -R 19 ;
R17和R18各自独立为未取代的C1-C4烷基，或R17、R18与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述4-10元杂环基除含有S外，还任选含有1或2个选自O和N的杂原子，所述4-10元杂环基，优选为硫杂环丁烷基、硫杂环戊烷基、硫杂环己烷基、硫代吗啉基和1,4-氧硫杂环己烷基；优选地，所述4-10元杂环基任选地被1-3个选自下组的取代基取代：任选被1或2个选自氰基和羟基的取代基取代的C1-C4烷基，C2-C4炔基，(C2-C4炔基)-O-(C1-C4亚烷基)，-NH2，-NHR1a和-NR1aR1a；R 17 and R 18 are each independently unsubstituted C 1 -C 4 alkyl, or R 17 and R 18 together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group, the 4- In addition to S, the 10-membered heterocyclic group optionally contains 1 or 2 heteroatoms selected from O and N. The 4-10-membered heterocyclic group is preferably thietanyl, thietanyl Alkyl, thiacyclohexyl, thiomorpholinyl and 1,4-oxathiocyclohexyl; preferably, the 4-10 membered heterocyclic group is optionally selected from 1-3 Substitution with substituents from the group: C 1 -C 4 alkyl optionally substituted by 1 or 2 substituents selected from cyano and hydroxy, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl) -O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a ;
R’为H或任选被羟基取代的C1-C4烷基；R' is H or C 1 -C 4 alkyl optionally substituted by hydroxy;
R19为：任选被选自-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基，-NH2，-NHR1a，-NR1aR1a或4-10元杂环基；R 19 is: C 1 -C 4 alkyl optionally substituted by a substituent selected from -NH 2 , -NHR 1a and -NR 1a R 1a , -NH 2 , -NHR 1a , -NR 1a R 1a or 4 -10 membered heterocyclyl;
R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基。Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
在另一方面，本申请提供了具有下式IV所示的结构的化合物：
In another aspect, the application provides a compound having the structure shown in the following formula IV:
或其药学上可接受的盐， or a pharmaceutically acceptable salt thereof,
其中：in:
R11为C1-C4烷基或羟基；R 11 is C 1 -C 4 alkyl or hydroxyl;
R12为C1-C4烷基或羟基；R 12 is C 1 -C 4 alkyl or hydroxyl;
R14’为H、卤素或氰基；R 14 ' is H, halogen or cyano;
R14”为H、卤素、氰基或任选取代的C1-C4烷氧基，如任选被1-3个选自卤素、羟基、氰基、C2-C4炔基、-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷氧基；R 14 ″ is H, halogen, cyano or optionally substituted C 1 -C 4 alkoxy, such as being optionally replaced by 1-3 members selected from halogen, hydroxyl, cyano, C 2 -C 4 alkynyl, - C 1 -C 4 alkoxy substituted by substituents of NH 2 , -NHR 1a and -NR 1a R 1a ;
Z11为O或-NR’-CO-；Z 11 is O or -NR'-CO-;
R15为任选被1-3个选自卤素、羟基、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基或C2-C4烯基，更优选为任选被1-3个选自卤素和羟基的取代基取代的C1-C4烷基，更优选为被1-3个选自卤素和羟基的取代基取代的C1-C4烷基、且该烷基的最末尾的C被至少一个选自卤素和羟基的取代基取代；R 15 is C 1 -C 4 alkyl or C 2 -C 4 alkenyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably any A C 1 -C 4 alkyl group selected from 1-3 substituents selected from halogen and hydroxy, more preferably a C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxy, And the last C of the alkyl group is substituted by at least one substituent selected from halogen and hydroxyl;
Z12为C1-C4亚烷基-O-或C2-C4炔基；Z 12 is C 1 -C 4 alkylene-O- or C 2 -C 4 alkynyl;
所述-N＝S(O)R17R18具有以下结构：
The -N=S(O)R 17 R 18 has the following structure:
式中，含S和X11的环为4-6元杂环，X11为CH2或NH或O，R111选自：H，任选被羟基取代的C1-C4烷基，C2-C4炔基，(C2-C4炔基)-O-(C1-C4亚烷基)，-NH2，-NHR1a和-NR1aR1a，其中，R1a优选各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基；其中，当R111位于X11上，X11为CH或N；In the formula, the ring containing S and X 11 is a 4-6 membered heterocycle, X 11 is CH 2 or NH or O, R 111 is selected from: H, C 1 -C 4 alkyl optionally substituted by hydroxyl, C 2 -C 4 alkynyl, (C 2 -C 4 alkynyl) -O-(C 1 -C 4 alkylene), -NH 2 , -NHR 1a and -NR 1a R 1a , wherein, R 1a is preferably each Independently C1-C4 alkyl, hydroxy-substituted C1 - C4 alkyl or halogenated C1 - C4 alkyl; wherein, when R 111 is located on X 11 , X 11 is CH or N;
R112为H或C1-C4烷基；R 112 is H or C 1 -C 4 alkyl;
R113选自：任选取代的C1-C4烷氧基、-S(O)2-R19’、氰基、-NR110-S(O)2-R19’、-NH2、-NHR1a、-NR1aR1a和4-10元杂环基，其中，R110为H或C1-C4烷基，R19’为C1-C4烷基；优选地，所述任选取代的C1-C4烷氧基优选任选被1或2个选自卤素、氰基、C2-C4炔基、羟基、-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷氧基，如任选被C2-C4炔基取代的C1-C4烷氧基；优选地，所述4-10元杂环基为含氮杂环基，更优选为氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基；和R 113 is selected from: optionally substituted C 1 -C 4 alkoxy, -S(O) 2 -R 19' , cyano, -NR 110 -S(O) 2 -R 19' , -NH 2 , -NHR 1a , -NR 1a R 1a and 4-10 membered heterocyclyl, wherein, R 110 is H or C 1 -C 4 alkyl, R 19' is C 1 -C 4 alkyl; preferably, the Optionally substituted C 1 -C 4 alkoxy is preferably optionally replaced by 1 or 2 members selected from halogen, cyano, C 2 -C 4 alkynyl, hydroxyl, -NH 2 , -NHR 1a and -NR 1a R 1a C 1 -C 4 alkoxy substituted by substituents, such as C 1 -C 4 alkoxy optionally substituted by C 2 -C 4 alkynyl; preferably, the 4-10 membered heterocyclic group is Azacyclyl, more preferably azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl; and
R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基。 Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
在又一方面，本申请提供了具有下式V所示的结构的化合物：
In yet another aspect, the application provides a compound having the structure shown in the following formula V:
或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
其中：in:
R11为C1-C4烷基或羟基；R 11 is C 1 -C 4 alkyl or hydroxyl;
R12为C1-C4烷基或羟基；R 12 is C 1 -C 4 alkyl or hydroxyl;
R14’为H、卤素或氰基；R 14 ' is H, halogen or cyano;
R14”为H、卤素、氰基或任选被C2-C4炔基取代的C1-C4烷氧基；R 14 ″ is H, halogen, cyano or C 1 -C 4 alkoxy optionally substituted by C 2 -C 4 alkynyl;
Z11为O；Z 11 is O;
R15为任选被1-3个选自卤素、羟基、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基，更优选为任选被1-3个选自卤素和羟基的取代基取代的C1-C4烷基，更优选为被1-3个选自卤素和羟基的取代基取代的C1-C4烷基、且该烷基的最末尾的C被至少一个选自卤素和羟基的取代基取代；R 15 is C 1 -C 4 alkyl optionally substituted by 1-3 substituents selected from halogen, hydroxyl, -NHR 1a and -NR 1a R 1a , more preferably optionally substituted by 1-3 substituents selected from C 1 -C 4 alkyl substituted by halogen and hydroxyl substituents, more preferably C 1 -C 4 alkyl substituted by 1-3 substituents selected from halogen and hydroxyl, and the last of the alkyl C is substituted by at least one substituent selected from halogen and hydroxyl;
Z12为C2-C4炔基；Z 12 is C 2 -C 4 alkynyl;
X12和X13之一为CH，另一为N；One of X 12 and X 13 is CH, and the other is N;
R114为-N(R’)-S(O)2-R19；其中，R’为H或任选被羟基取代的C1-C4烷基；R19为任选被选自-NH2、-NHR1a和-NR1aR1a的取代基取代的C1-C4烷基，-NH2，-NHR1a，-NR1aR1a或4-10元杂环基；优选地，所述4-10元杂环基选自哌啶基、哌嗪基、四氢吡喃基、氧杂环丁烷基、四氢呋喃基、氮杂环丁烷基和吡咯烷基；和R 114 is -N(R')-S(O) 2 -R 19 ; wherein, R' is H or C 1 -C 4 alkyl optionally substituted by hydroxyl; R 19 is optionally selected from -NH 2. C 1 -C 4 alkyl substituted by substituents of -NHR 1a and -NR 1a R 1a , -NH 2 , -NHR 1a , -NR 1a R 1a or 4-10 membered heterocyclic groups; preferably, the The 4-10 membered heterocyclic group is selected from piperidinyl, piperazinyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, azetidinyl and pyrrolidinyl; and
R1a各自独立为C1-C4烷基、羟基取代的C1-C4烷基或卤代C1-C4烷基。Each R 1a is independently C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or halogenated C 1 -C 4 alkyl.
在一些实施方案中，本申请提供了选自下组的化合物：



In some embodiments, the application provides a compound selected from the group consisting of:



或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.
在一些实施方案中，本申请的化合物不是如下化合物：
In some embodiments, a compound of the present application is not a compound of:
III.化合物的制备III. Preparation of compounds
本发明的部分化合物制备过程以下式II-6为例进行说明，其制备方法至少包括下文所述的烷基化取代反应、催化偶联、格式反应等步骤，示例性的反应流程可如以下流程I所示。应理解，本发明的其他化合物可通过类似的方法或者改进的方法进 行类似的合成得到。The preparation process of some compounds of the present invention is illustrated by the following formula II-6 as an example. The preparation method at least includes steps such as the alkylation substitution reaction, catalytic coupling, and Grignard reaction described below. The exemplary reaction process can be as follows I show. It should be understood that other compounds of the present invention can be prepared by similar methods or improved methods. A similar synthesis is performed.
流程I
Process I
流程I中，中间体II-1经烷基化反应得中间体II-2；II-2与格式试剂反应得到中间体II-3；II-3在路易斯酸催化下经傅克烷基化得到中间体II-4；II-4经烷基化反应后生成化合物II-5；化合物II-5与亚磺亚胺类中间体RcRdS(O)＝NH偶联反应生成化合物II-6。各步骤的反应条件如反应流程所示。In scheme I, intermediate II-1 is subjected to alkylation reaction to obtain intermediate II-2; II-2 is reacted with Grignard reagent to obtain intermediate II-3; II-3 is subjected to Friedel-Crafts alkylation under Lewis acid catalysis to obtain intermediate II-4; II-4 undergoes an alkylation reaction to generate compound II-5; compound II-5 reacts with a sulfenimine intermediate R c R d S(O)=NH to generate compound II-6. The reaction conditions of each step are shown in the reaction scheme.
反应流程I的各式中，各基团的定义如上文中所述，W为卤素，优选氯或者溴。In the various formulas of the reaction scheme I, the definition of each group is as described above, and W is halogen, preferably chlorine or bromine.
本发明的制备方法中，中间体II-1和不同的卤代烷烃反应得到具有不同取代基的II-2。反应在碱(优选碳酸铯)的作用下，在有机溶剂(优选DMF或乙腈)中进行。中间体II-3到中间体II-4的傅克烷基化反应构建了二苯亚基结构。In the preparation method of the present invention, the intermediate II-1 reacts with different halogenated alkanes to obtain II-2 with different substituents. The reaction is carried out in an organic solvent (preferably DMF or acetonitrile) under the action of a base (preferably cesium carbonate). Friedel-Crafts alkylation of intermediate II-3 to intermediate II-4 constructs the diphenylene structure.
II-5与不同的亚磺亚胺类化合物中间体RcRdS(O)＝NH进行偶联反应，用于构建带有不同取代基的左边片段。反应在碱的催化下(优选碳酸铯)，在有机溶剂(优选甲苯或二氧六环)中用钯试剂催化(优选醋酸钯)，在加热的条件下进行反应得到II-6。The coupling reaction of II-5 with different sulfenimine compound intermediates R c R d S(O)=NH is used to construct the left fragment with different substituents. The reaction is catalyzed by a base (preferably cesium carbonate), catalyzed by a palladium reagent (preferably palladium acetate) in an organic solvent (preferably toluene or dioxane), and reacted under heating conditions to obtain II-6.
本发明的部分化合物以式III-3化合物制备过程为例说明，其制备方法至少包括下文所述的催化偶联、酯化反应等步骤，示例性的反应流程可如以下流程II所示。应理解，本发明的其他化合物可通过类似的方法或者改进的方法进行类似的合成得 到。Some compounds of the present invention are illustrated by taking the preparation process of the compound of formula III-3 as an example. The preparation method at least includes steps such as catalytic coupling and esterification described below. An exemplary reaction scheme can be shown in the following scheme II. It should be understood that other compounds of the present invention can be similarly synthesized by similar methods or improved methods arrive.
流程II
Process II
流程II中，中间体II-4进行一步酯化反应生成III-1；III-1与炔类化合物催化偶联得到中间体III-2；III-2再次与卤代物催化偶联得到化合物III-3。各步骤的反应条件如反应流程所示。In scheme II, intermediate II-4 undergoes a one-step esterification reaction to generate III-1; III-1 is catalytically coupled with an alkyne compound to obtain intermediate III-2; III-2 is again catalytically coupled with a halide to obtain compound III- 3. The reaction conditions of each step are shown in the reaction scheme.
反应流程II的各式中，各基团的定义如上文中所述，W为卤素，优选为氯、溴和碘。In each formula of Reaction Scheme II, the definition of each group is as described above, and W is halogen, preferably chlorine, bromine and iodine.
本发明的制备方法中，中间体III-1通过与炔类化合物偶联，引入了炔基基团。中间体III-2和不同的卤代物，优选芳香卤代烷，发生偶联反应得到含有不同取代基的化合物III-3。反应在碱(优选二异丙基乙基胺)的作用下，金属催化剂的催化下(优选Pd(PPh3)4和碘化亚铜)进行；在有机溶剂(优选四氢呋喃)中通过加热的条件进行。In the preparation method of the present invention, the intermediate III-1 introduces an alkynyl group through coupling with an alkyne compound. Intermediate III-2 and different halides, preferably aromatic haloalkanes, undergo a coupling reaction to obtain compound III-3 with different substituents. The reaction is carried out under the action of a base (preferably diisopropylethylamine), under the catalysis of a metal catalyst (preferably Pd(PPh 3 ) 4 and cuprous iodide); in an organic solvent (preferably tetrahydrofuran) by heating conduct.
上述方案中如包括脱Boc保护基步骤。可采用常规的方式进行所述脱保护基反应。For example, the above scheme includes the step of removing the Boc protecting group. The deprotection reaction can be carried out in a conventional manner.
上述方案中，如终产物有手性中心且需要手性拆分时，可采用本领域常规的方法，比如SFC或者手性HPLC进行手性拆分。In the above scheme, if the final product has a chiral center and chiral resolution is required, conventional methods in the art, such as SFC or chiral HPLC, can be used for chiral resolution.
上述方案中，当需要纯化时，可采用本领域常规的方法进行纯化，例如可先进行萃取，然后再进行柱层析。 In the above scheme, when purification is required, conventional methods in the art can be used for purification, for example, extraction can be performed first, and then column chromatography can be performed.
IV.药物组合物、用途和治疗方法IV. Pharmaceutical compositions, uses and methods of treatment
本申请提供的化合物是雄激素受体(AR)的调节剂，可用于调节AR的活性。调节AR活性可用于治疗和/或预防雄激素受体介导的疾病。The compounds provided in this application are modulators of androgen receptor (AR), and can be used to regulate the activity of AR. Modulating AR activity is useful in the treatment and/or prevention of androgen receptor mediated diseases.
在一方面，本申请提供了含有治疗或预防有效量的本申请化合物或其药学上可接受的盐，以及药学上可接受的载体的药物组合物。In one aspect, the present application provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound of the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
在一些实施方案中，本申请的药物组合物还可含有其它的治疗剂，尤其是用于治疗本文所述的雄激素受体介导的疾病的治疗剂。In some embodiments, the pharmaceutical composition of the present application may also contain other therapeutic agents, especially therapeutic agents for the treatment of the androgen receptor-mediated diseases described herein.
在某些实施方案中，其它的治疗剂可用于治疗前列腺癌、乳腺癌、卵巢癌、膀胱癌、胰腺癌、肝细胞癌、子宫内膜癌、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或年龄相关性黄斑变性。In certain embodiments, additional therapeutic agents are useful in the treatment of prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts , polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
在某些实施方案中，其它的治疗剂的例子包括但不限于恩杂鲁胺、加来特龙、ODN-201阿比特龙、比卡鲁胺、尼鲁米特、氟他胺、乙酸环丙孕酮、多西紫杉醇、贝伐单抗(阿伐斯汀)、OSU-HDAC42、VITAXIN、舒尼替尼、ZD-4054、卡巴他赛(XRP-6258)、MDX-010(伊匹单抗)、OGX 427、OGX 011、非那雄胺、度他雄胺、妥罗雄脲、贝氯特来、艾宗特来、FCE 28260、SKF105,111、ODM-201ODM-204、氯硝柳胺、阿帕鲁胺、ARV-330、VPC-14449、TAS3681、3E10-AR441bsAb、sintokamide或其相关化合物。In certain embodiments, examples of additional therapeutic agents include, but are not limited to, enzalutamide, galeterone, ODN-201 abiraterone, bicalutamide, nilutamide, flutamide, cycloacetate Propegesterone, Docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, Sunitinib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab anti), OGX 427, OGX 011, finasteride, dutasteride, torosteride, bechloride, aizontel, FCE 28260, SKF105, 111, ODM-201ODM-204, niclosalide amine, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide or related compounds.
合适的药物组合物可以通过本领域中已知的方法和由熟练从业者确定的其施用模式和剂量来配制。关于肠胃外施用，可以将化合物溶解于无菌水或生理盐水或用于施用非水溶性化合物的药学上可接受的媒剂(如用于维生素K的那些)中。关于经肠施用，化合物可以以片剂、胶囊形式施用或者溶解于液体形式中。片剂或胶囊可以是包覆肠溶包衣的，或者呈用于持续释放的制剂形式。已知多种合适制剂，包括封装待释放的化合物的聚合物或蛋白质微粒、软膏、糊剂、凝胶、水凝胶或溶液，其可经表面或局部地用于化合物。可以使用持续释放贴剂或植入物以在一段延长时期内提供释放。用于肠胃外施用的制剂可以例如含有赋形剂聚亚烷基二醇(如聚乙二醇)、植物起源的油或氢化萘。生物可相容、生物可降解的丙交酯聚合物、丙交酯/乙交酯共聚物或聚氧乙烯-聚氧丙烯共聚物可用于控制所述化合物的释放。用于调节化合物的其他潜在有用的肠胃外递送系统包括乙烯-乙酸乙烯酯共聚物粒子、渗透泵、 可植入的输注系统和脂质体。用于吸入的制剂可以含有赋形剂，例如乳糖，或者可以是含有例如聚氧乙烯-9-月桂基醚、甘胆酸盐和脱氧胆酸盐的水溶液，或者可以是用于以滴鼻剂形式施用的油性溶液，或者呈凝胶形式。Suitable pharmaceutical compositions can be formulated by methods known in the art and their mode of administration and dosage as determined by the skilled practitioner. For parenteral administration, the compounds can be dissolved in sterile water or physiological saline or a pharmaceutically acceptable vehicle for administering water-insoluble compounds such as those used for vitamin K. For enteral administration, the compounds can be administered in tablet, capsule form or dissolved in liquid form. Tablets or capsules may be enteric coated, or formulated for sustained release. A variety of suitable formulations are known, including polymeric or protein particles encapsulating the compound to be released, ointments, pastes, gels, hydrogels or solutions, which may be applied topically or topically to the compound. Sustained release patches or implants may be used to provide release over an extended period of time. Formulations for parenteral administration may, for example, contain excipients polyalkylene glycols such as polyethylene glycol, oils of vegetable origin or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compounds. Other potentially useful parenteral delivery systems for modulating compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, Implantable infusion systems and liposomes. Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be presented as nasal drops. as an oily solution to be applied in the form of a gel, or in the form of a gel.
应注意，剂量值可随精确的成像方案而变化。关于任何特定受试者，具体给药方案可以根据个体需要和施用或监督施用所述组合物的人的专业判断随时间加以调节。本文所述的剂量范围仅为示例性的，并且不限制医学从业者可以选择的剂量范围。所述组合物中的活性化合物的量可以根据如受试者的疾病状态、年龄、性别和重量等因素变化。给药方案可经过调节以提供最佳成像结果。例如，可施用单一大丸药，可随时间施用数个分次剂量，或剂量可如成像结果所指示按比例降低或增加。以易于施用和实现剂量均匀性的单位剂量形式配制肠胃外组合物可以是有利的。It should be noted that dose values may vary with the precise imaging protocol. With respect to any particular subject, the particular dosing regimen may be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition. The dosage ranges described herein are exemplary only, and do not limit the range of dosages that can be selected by a medical practitioner. The amount of active compound in the composition may vary according to factors such as the disease state, age, sex and weight of the subject. Dosing regimens can be adjusted to provide optimal imaging results. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally decreased or increased as indicated by the imaging results. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
在另一方面，本申请提供了本申请化合物或其药学上可接受的盐在制备治疗或预防雄激素受体介导的疾病的药物中的应用。In another aspect, the present application provides the use of the compound of the present application or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing diseases mediated by androgen receptors.
在又一方面，本申请提供了用于治疗或预防雄激素受体介导的疾病的本申请化合物或其药学上可接受的盐。In yet another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of androgen receptor-mediated diseases.
在又一方面，本申请提供了用于治疗或预防雄激素受体变异体介导的疾病的本申请化合物或其药学上可接受的盐。In yet another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diseases mediated by androgen receptor variants.
在又一方面，本申请提供了用于治疗或预防雄激素受体剪切变异体(AR-Vs)介导的疾病的本申请化合物或其药学上可接受的盐。In yet another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diseases mediated by androgen receptor splicing variants (AR-Vs).
在又一方面，本申请提供了用于治疗或预防AR-V7介导的疾病的本申请化合物或其药学上可接受的盐。In yet another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of AR-V7-mediated diseases.
在又一方面，本申请提供了治疗或预防对象雄激素受体介导的疾病的方法，所述方法包括给予所述对象治疗有效量或预防有效量的本申请化合物或其药学上可接受的盐，或含有治疗有效量或预防有效量的本申请化合物或其药学上可接受的盐的药物组合物。In yet another aspect, the application provides a method for treating or preventing an androgen receptor-mediated disease in a subject, the method comprising administering to the subject a therapeutically effective amount or a preventively effective amount of a compound of the present application or a pharmaceutically acceptable salt, or a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound of the present application or a pharmaceutically acceptable salt thereof.
在另一方面，本发明提供了一种治疗或预防雄激素受体变异体介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。 In another aspect, the present invention provides a method for treating or preventing diseases mediated by androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I or 2-I of the present invention Compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or pharmaceutical combinations thereof things.
在另一方面，本发明提供了一种治疗或预防雄激素受体剪切变异体(AR-Vs)介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method of treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of a formula of the present invention 1-I or 2-I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs Or metabolites or pharmaceutical compositions thereof.
在另一方面，本发明提供了一种治疗或预防AR-V7介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method for treating or preventing an AR-V7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1-I or 2-I of the present invention, its Pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof.
在另一方面，本发明提供了一种治疗或预防雄激素受体和雄激素受体变异体介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method of treating or preventing diseases mediated by androgen receptor and androgen receptor variants, said method comprising administering to a subject in need thereof a therapeutically effective amount of Formula 1-I of the present invention or 2-I compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof or its pharmaceutical composition.
在另一方面，本发明提供了一种治疗或预防雄激素受体和雄激素受体剪切变异体(AR-Vs)介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method of treating or preventing diseases mediated by androgen receptor and androgen receptor splice variants (AR-Vs), said method comprising administering to a subject in need thereof a therapeutically effective amount of The compound of formula 1-I or 2-I of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, solvate, isotope substitution, polymorphic form Drugs, prodrugs or metabolites or pharmaceutical compositions thereof.
在另一方面，本发明提供了一种治疗或预防雄激素受体和AR-V7介导的疾病的方法，所述方法包括给予需要的对象治疗有效量的本发明的式1-I或2-I化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物或其药物组合物。In another aspect, the present invention provides a method for treating or preventing diseases mediated by androgen receptor and AR-V7, said method comprising administering to a subject in need a therapeutically effective amount of Formula 1-I or 2 of the present invention -I compounds, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical composition.
可通过口服途径、十二指肠途径、胃肠外注射(包括肺内、鼻内、鞘内、静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给予药物。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，通过口服施用本申请化合物或其药学上可接受的盐或者本申请的药物组合物。Oral route, duodenal route, parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and via The drug is given rectally. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, as described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In a preferred embodiment, the compound of the present application or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present application is administered orally.
本文所述的治疗方法、预防方法和用途中，本申请化合物或其药学上可接受的 盐或者本申请的药物组合物可与其它具有药理活性的化合物联用，以治疗或预防本文所述的雄激素受体介导的各类疾病。例如，本申请化合物或其药学上可接受的盐或者本申请的药物组合物可以与一种或多种选自如下的药物组合地同时、依次或分别施用：恩杂鲁胺、加来特龙、ODN-201阿比特龙、比卡鲁胺、尼鲁米特、氟他胺、乙酸环丙孕酮、多西紫杉醇、贝伐单抗(阿伐斯汀)、OSU-HDAC42、VITAXIN、舒尼替尼、ZD-4054、卡巴他赛(XRP-6258)、MDX-010(伊匹单抗)、OGX 427、OGX011、非那雄胺、度他雄胺、妥罗雄脲、贝氯特来、艾宗特来、FCE 28260、SKF105,111、ODM-201ODM-204、氯硝柳胺、阿帕鲁胺、ARV-330、VPC-14449、TAS3681、3E10-AR441bsAb、sintokamide和其相关化合物中的一种或多种。或者，本申请化合物或其药学上可接受的盐或者本申请的药物组合物可与常规的放疗联用。In the treatment method, prevention method and use described herein, the application compound or its pharmaceutically acceptable The salt or the pharmaceutical composition of the present application can be used in combination with other pharmacologically active compounds to treat or prevent various diseases mediated by the androgen receptor described herein. For example, the compound of the present application or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present application can be administered simultaneously, sequentially or separately in combination with one or more drugs selected from the following: enzalutamide, galeterone , ODN-201 Abiraterone, Bicalutamide, Nilutamide, Flutamide, Cyproterone Acetate, Docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, Shu Nitinib, ZD-4054, cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX 427, OGX011, finasteride, dutasteride, torosteride, bechloride Lai, Ai Zong Telai, FCE 28260, SKF105,111, ODM-201ODM-204, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide and its related compounds one or more of . Alternatively, the compound of the present application or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present application can be used in combination with conventional radiotherapy.
在一些实施方案中，雄激素受体介导的疾病可包括：前列腺癌、乳腺癌、卵巢癌、膀胱癌、胶质母细胞瘤、黑色素瘤、肾细胞癌、套细胞淋巴瘤、胰腺癌、肝细胞癌、子宫内膜癌、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、年龄相关性黄斑变性和其组合。In some embodiments, androgen receptor mediated diseases may include: prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, Hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration, and combinations thereof.
在一些实施方案中，雄激素受体介导的疾病为前列腺癌。在一些实施方案中，所述前列腺癌为原发性/局限性前列腺癌、局部晚期前列腺癌、复发性前列腺癌、转移性前列腺癌、晚期前列腺癌或转移性去势抵抗性前列腺癌(CRPC)或激素敏感性前列腺癌。在其他实施方案中，所述前列腺癌为雄激素依赖性前列腺癌。在一些实施方案中，所述脊髓和延髓肌肉萎缩是肯尼迪氏病。In some embodiments, the androgen receptor mediated disease is prostate cancer. In some embodiments, the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC) or hormone-sensitive prostate cancer. In other embodiments, the prostate cancer is androgen-dependent prostate cancer. In some embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease.
实施例Example
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.
下述实施例中所用的起始物可由化学品销售商如Aldrich、TCI、Alfa Aesar、毕得、安耐吉等处购得，或者可通过已知的方法来合成。


The starting materials used in the following examples can be purchased from chemical distributors such as Aldrich, TCI, Alfa Aesar, Bid, Anaji, etc., or can be synthesized by known methods.


中间体合成intermediate synthesis
中间体I-A1的合成：3-氯-2-(2-氯乙氧基)-5-(2-(4-羟基苯基)丙烷-2-基)苯腈
Synthesis of Intermediate I-A1: 3-Chloro-2-(2-chloroethoxy)-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile
步骤一：将原料I-A1-1(80g,429mmol)溶解在二氯甲烷(1000mL)，0℃搅拌5分钟后，在0℃下加入NIS(116g,515mmol)。上述混合物室温反应16小时，LC-MS检测发现反应完全。将反应混合物投入到水中(1000ml)，用二氯甲烷萃取(1000mL*2)，合并有机相，用饱和食盐水清洗(1000mL*2)，有机相用无水硫酸钠干燥后浓缩。浓缩后的混合物使用乙腈重结晶得到产物I-A1-2(117g,产率：87.3％)，为白色固体。Step 1: Dissolve raw material I-A1-1 (80g, 429mmol) in dichloromethane (1000mL), stir at 0°C for 5 minutes, then add NIS (116g, 515mmol) at 0°C. The above mixture was reacted at room temperature for 16 hours, and the reaction was found to be complete by LC-MS detection. The reaction mixture was poured into water (1000ml), extracted with dichloromethane (1000mL*2), the organic phases were combined, washed with saturated brine (1000mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was recrystallized using acetonitrile to obtain product I-A1-2 (117 g, yield: 87.3%) as a white solid.
LC-MS[M-1]-＝310.7LC-MS[M-1] - = 310.7
步骤二：室温下，将I-A1-2(100g,320mmol)和I-A1-3(91g,640mmol)溶解于N,N-二甲基甲酰胺(1200mL)中，然后加碳酸铯(208g,640mmol)。混合物在70℃下搅拌16小时，TLC检测反应完全。反应混合投入到水中(1500ml)后并用乙酸乙酯(1000mL*3)萃取。有机相用饱和食盐水(1000mL)洗并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝10/1)，得到所需的产物I-A1-4(103.4g,产率：86.1％)为无色油状液体。Step 2: Dissolve I-A1-2 (100g, 320mmol) and I-A1-3 (91g, 640mmol) in N,N-dimethylformamide (1200mL) at room temperature, then add cesium carbonate (208g ,640mmol). The mixture was stirred at 70°C for 16 hours, and the reaction was complete by TLC. The reaction mixture was poured into water (1500ml) and extracted with ethyl acetate (1000mL*3). The organic phase was washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the desired product I-A1-4 (103.4 g, yield: 86.1%) as a colorless oily liquid.
LC-MS[M+1]+＝374.7LC-MS [M+1] + = 374.7
步骤三：将中间体I-A1-4(53g,141.3mmol)溶解于N-甲基吡咯烷酮(600mL)中，加入CuCN(19g,200mmol)，在160℃下，在氮气保护下搅拌反应3小时。TLC检测反应完全。反应混合物用氨水(2000mL，23％)淬灭后，用乙酸乙酯(1000mL*3)萃取。有机相用饱和食盐水(1000mL)洗并用无水硫酸钠干燥。将滤液浓 缩后进行柱层析分离(石油醚/乙酸乙酯＝10/1)，得到所需的产物I-A1-5(21g,产率：54.3％)，为白色固体。Step 3: Dissolve the intermediate I-A1-4 (53g, 141.3mmol) in N-methylpyrrolidone (600mL), add CuCN (19g, 200mmol), and stir the reaction at 160°C for 3 hours under the protection of nitrogen . TLC detects that the reaction is complete. The reaction mixture was quenched with aqueous ammonia (2000 mL, 23%), and extracted with ethyl acetate (1000 mL*3). The organic phase was washed with saturated brine (1000 mL) and dried over anhydrous sodium sulfate. Concentrate the filtrate Afterwards, column chromatography separation (petroleum ether/ethyl acetate=10/1) was carried out to obtain the desired product I-A1-5 (21 g, yield: 54.3%) as a white solid.
LC-MS[M+1]+＝274.0LC-MS [M+1] + = 274.0
步骤四：将I-A1-5(21g,76.6mmol)溶解于四氢呋喃(100mL)中在室温下滴加到氮气保护的甲基溴化镁(613ml,1M的四氢呋喃溶液)中，滴加完后室温反应2小时。TLC检测反应完全。反应混合物缓慢的加入到0℃下的饱和氯化铵水溶液中，并用乙酸乙酯(300mL*3)萃取。有机相用饱和食盐水洗(500mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A1-6(17g,产率：80.9％)，为黄色油状液体。Step 4: Dissolve I-A1-5 (21g, 76.6mmol) in tetrahydrofuran (100mL) and add dropwise to nitrogen-protected methylmagnesium bromide (613ml, 1M solution in tetrahydrofuran) at room temperature. After the addition is complete React at room temperature for 2 hours. TLC detects that the reaction is complete. The reaction mixture was slowly added to saturated aqueous ammonium chloride at 0°C, and extracted with ethyl acetate (300 mL*3). The organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A1-6 (17 g, yield: 80.9%) as a yellow oily liquid.
LC-MS[M+17]+＝290.9LC-MS [M+17] + = 290.9
步骤五：将I-A1-6(17g,62mmol)，I-A1-7(19.2g,310mmol)溶解于二氯甲烷(200mL)中在-78℃下，在氮气保护下滴加三氟化硼乙醚溶液(34ml,47％)，滴加完后自然升温至室温反应2小时。TLC检测反应完全,反应混合物加入到水(200ml)中，并用二氯甲烷(100mL*3)萃取。有机相用饱和食盐水洗(300mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物中间体I-A1(18g,产率：83％)为黄色油状液体。Step 5: Dissolve I-A1-6 (17g, 62mmol), I-A1-7 (19.2g, 310mmol) in dichloromethane (200mL) and add trifluoride dropwise under nitrogen protection at -78°C Boron ether solution (34ml, 47%), after the dropwise addition, the temperature was naturally raised to room temperature for 2 hours. TLC detected that the reaction was complete, and the reaction mixture was added into water (200ml), and extracted with dichloromethane (100mL*3). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product intermediate I-A1 (18 g, yield: 83%) as a yellow oily liquid.
1H NMR(400MHz,Chloroform-d)δ7.44(d,J＝2.4Hz,1H),7.33(dd,J＝4.9,2.4Hz,1H),7.06–7.02(m,2H),6.80–6.76(m,2H),4.41(t,J＝6.2Hz,2H),3.87(t,J＝6.2Hz,2H),1.63(s,6H). 1 H NMR (400MHz, Chloroform-d) δ7.44 (d, J = 2.4Hz, 1H), 7.33 (dd, J = 4.9, 2.4Hz, 1H), 7.06–7.02 (m, 2H), 6.80–6.76 (m,2H),4.41(t,J=6.2Hz,2H),3.87(t,J=6.2Hz,2H),1.63(s,6H).
LC-MS[M-1]-＝347.9LC-MS[M-1] - = 347.9
中间体I-A2的合成：3-氯-2-(2-氯乙氧基)-5-(2-(4-乙炔基苯基)丙烷-2-基)苯腈
Synthesis of Intermediate I-A2: 3-Chloro-2-(2-chloroethoxy)-5-(2-(4-ethynylphenyl)propan-2-yl)benzonitrile
步骤一：将I-A1(5.8g,16mmol)，三乙胺(4.87g,48mmol)溶解在二氯甲烷(100mL)，0℃搅拌5分钟后加入Tf2O(6.78g,24mmol)。上述混合物在25℃反应2小时，TLC检测发现反应完全。将反应混合物浓缩后使用柱层析(石油醚/乙酸乙酯＝30/1)得到产物I-A2-1(6g,产率：78％)，为橙色油状体。Step 1: Dissolve I-A1 (5.8g, 16mmol), triethylamine (4.87g, 48mmol) in dichloromethane (100mL), stir at 0°C for 5 minutes, then add Tf 2 O (6.78g, 24mmol). The above mixture was reacted at 25° C. for 2 hours, and TLC showed that the reaction was complete. The reaction mixture was concentrated and column chromatography (petroleum ether/ethyl acetate=30/1) was used to obtain the product I-A2-1 (6 g, yield: 78%) as an orange oil.
步骤二：室温下，将I-A2-1(6g,12.5mmol)和三甲基硅基乙炔(12g,122.2mmol)，Pd(PPh3)2Cl2(1.6g,2.3mmol)，碘化亚铜(1.3g,6.8mmol)以及三乙胺(23.31g,230.4mmol)溶解于乙腈(133ml)中。混合物在80℃下，在氮气保护下搅拌16小时，TLC检测反应完全。反应混合物浓缩后使用柱层析纯化得到所需的产物I-A2-2(4.2g,产率：69％)，为橙色油状液体。Step 2: At room temperature, I-A2-1 (6g, 12.5mmol) and trimethylsilylacetylene (12g, 122.2mmol), Pd(PPh 3 ) 2 Cl 2 (1.6g, 2.3mmol), iodide Cuprous (1.3 g, 6.8 mmol) and triethylamine (23.31 g, 230.4 mmol) were dissolved in acetonitrile (133 ml). The mixture was stirred at 80° C. under nitrogen protection for 16 hours, and the reaction was complete as detected by TLC. The reaction mixture was concentrated and purified by column chromatography to obtain the desired product I-A2-2 (4.2 g, yield: 69%) as an orange oily liquid.
步骤三：将中间体I-A2-2(4.2g,9.79mmol)溶解甲醇(650mL)中，加入氟化钾(4.2g,72.3mmol)，在25℃下，在氮气保护下搅拌反应12小时。TLC检测反应完全。反应混合物浓缩后进行柱层析分离(石油醚/乙酸乙酯＝10/1)，得到所需的产物中间体I-A2(2.8g,产率：80％)为橙色油状液体。Step 3: Dissolve the intermediate I-A2-2 (4.2g, 9.79mmol) in methanol (650mL), add potassium fluoride (4.2g, 72.3mmol), and stir the reaction at 25°C for 12 hours under the protection of nitrogen . TLC detects that the reaction is complete. The reaction mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the desired product intermediate I-A2 (2.8 g, yield: 80%) as an orange oily liquid.
1H NMR(400MHz,Chloroform-d)δ7.48–7.42(m,2H),7.41(d,J＝2.4Hz,1H),7.33(d,J＝2.4Hz,1H),7.16–7.11(m,2H),4.42(t,J＝6.2Hz,2H),3.88(t,J＝6.2Hz,2H),3.07(s,1H),1.65(s,6H). 1 H NMR (400MHz, Chloroform-d) δ7.48–7.42(m, 2H), 7.41(d, J=2.4Hz, 1H), 7.33(d, J=2.4Hz, 1H), 7.16–7.11(m ,2H),4.42(t,J=6.2Hz,2H),3.88(t,J=6.2Hz,2H),3.07(s,1H),1.65(s,6H).
中间体I-A3的合成：4-(2-(7-氯-1-(2-氯乙氧基)-1H-吲唑-5-基)丙烷-2-基)苯酚
Synthesis of Intermediate I-A3: 4-(2-(7-Chloro-1-(2-chloroethoxy)-1H-indazol-5-yl)propan-2-yl)phenol
步骤一：将中间体I-A3-1(30.0g,182mmol)溶解在乙腈(240mL)中，在75℃下分批加入NCS(29.1g,218mmol)，75℃下搅拌2小时后，将反应混合物浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)得到产物I-A3-2(35g,产率：97％),为黄色固体。Step 1: Dissolve intermediate I-A3-1 (30.0g, 182mmol) in acetonitrile (240mL), add NCS (29.1g, 218mmol) in batches at 75°C, and stir at 75°C for 2 hours, then react The mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the product I-A3-2 (35 g, yield: 97%) as a yellow solid.
LCMS[M+1]+＝199.9 LCMS[M+1] + =199.9
步骤二：将中间体I-A3-2(4.00g,6.55mmol)溶解于醋酸(100mL)和去离子水(5mL)中，在0℃下缓慢滴入亚硝酸钠(6.2g，90.2mmol)的水溶液(5mL)，室温下搅拌4小时后，将此混合液降浓缩后，用饱和碳酸氢钠溶液调至pH＝8，然后用乙酸乙酯(500mL*2)萃取，有机相浓缩后进行柱层析分离(二氯甲烷/甲醇＝100/4)得到产物I-A3-3(14g,产率：88％)，为黄色固体。Step 2: Intermediate I-A3-2 (4.00g, 6.55mmol) was dissolved in acetic acid (100mL) and deionized water (5mL), and sodium nitrite (6.2g, 90.2mmol) was slowly added dropwise at 0°C After stirring at room temperature for 4 hours, the mixture was concentrated, adjusted to pH=8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (500mL*2), and the organic phase was concentrated and carried out Column chromatography separation (dichloromethane/methanol=100/4) gave the product I-A3-3 (14 g, yield: 88%) as a yellow solid.
LCMS[M+1]+＝210.9LCMS[M+1] + =210.9
步骤三：将中间体I-A3-3(10.8g,51.3mmol)和碳酸钾(17.7g,128mmol)溶解于DMF(160mL)中，然后加入1-溴-2-氯乙烷(29.4g，205mmol)，将此混合液在75℃下搅拌反应4小时。将反应液浓缩后进行HPLC分离(ACN/H2O＝40/60)，得到所需的产物I-A3-4(4.7g,产率：34％)，为黄色固体。Step 3: Dissolve intermediate I-A3-3 (10.8g, 51.3mmol) and potassium carbonate (17.7g, 128mmol) in DMF (160mL), then add 1-bromo-2-chloroethane (29.4g, 205mmol), the mixture was stirred and reacted at 75°C for 4 hours. The reaction solution was concentrated and separated by HPLC (ACN/H 2 O=40/60) to obtain the desired product I-A3-4 (4.7 g, yield: 34%) as a yellow solid.
1H NMR(400MHz,Chloroform-d)δ8.40(s,1H),8.16(s,1H),8.07(s,1H),5.12(t,J＝8.0Hz,2H),3.96-3.94(m,5H). 1 H NMR (400MHz, Chloroform-d) δ8.40(s, 1H), 8.16(s, 1H), 8.07(s, 1H), 5.12(t, J=8.0Hz, 2H), 3.96-3.94(m ,5H).
LCMS[M+1]+＝273.0.LCMS[M+1] + =273.0.
步骤四：将甲基溴化镁(33mL,99.0mmol)溶解于无水四氢呋喃(80mL)中，将其降至0℃后，分批加入中间体I-A3-4(4.5g,16.5mmol)，然后在室温下搅拌2个小时，TLC检测反应完全。反应体系加入饱和氯化铵水溶液(40mL)淬灭，并用乙酸乙酯(50mL*3)萃取。有机相用用饱和食盐水洗(70mL)并用无水硫酸钠上干燥并过滤。将滤液浓缩得到所需的产物I-A3-5(4.5g,产率：99％)为黄色油状物.Step 4: Dissolve methylmagnesium bromide (33mL, 99.0mmol) in anhydrous tetrahydrofuran (80mL), lower it to 0°C, and add intermediate I-A3-4 (4.5g, 16.5mmol) in batches , and then stirred at room temperature for 2 hours, and TLC detected that the reaction was complete. The reaction system was quenched by adding saturated aqueous ammonium chloride solution (40 mL), and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (70 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the desired product I-A3-5 (4.5 g, yield: 99%) as a yellow oil.
LCMS[M+1]+＝273.0LCMS[M+1] + =273.0
步骤五：将中间体I-A3-5(4.5g,16.5mmol)和苯酚(7.8g,82.4mmol)溶解于二氯甲烷(130mL)中，将其温度降至-78℃后，缓慢滴入三氟化硼乙醚(7.0g,49.4mmol)，然后自然升至室温，搅拌过夜。反应体系加入蒸馏水(100mL)淬灭，并用二氯甲烷(200mL*2)萃取。有机相用用饱和食盐水洗(100mL)并用无水硫酸钠干燥并过滤。将混合物浓缩后进行柱层析分离(石油醚/乙酸乙酯＝6/1)得到产物中间体I-A3(3.9g,产率：68％)，为黄色油状物。Step 5: Dissolve intermediate I-A3-5 (4.5g, 16.5mmol) and phenol (7.8g, 82.4mmol) in dichloromethane (130mL), lower the temperature to -78°C, and slowly drop into Boron trifluoride diethyl ether (7.0 g, 49.4 mmol), then naturally warmed to room temperature, stirred overnight. The reaction system was quenched by adding distilled water (100 mL), and extracted with dichloromethane (200 mL*2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=6/1) to obtain the product intermediate I-A3 (3.9 g, yield: 68%) as a yellow oil.
LCMS[M+1]+＝349.0LCMS[M+1] + =349.0
中间体I-A4的合成：7-氯-1-(2-氯乙氧基)-5-(2-(4-乙炔基苯基)丙烷-2-基)-1H-吲唑
Synthesis of Intermediate I-A4: 7-Chloro-1-(2-chloroethoxy)-5-(2-(4-ethynylphenyl)propan-2-yl)-1H-indazole
参考中间体I-A2的合成路线。用I-A3代替I-A1，经过三步反应合成I-A4。Refer to the synthetic route of intermediate I-A2. I-A4 was synthesized by three-step reaction with I-A3 instead of I-A1.
LCMS[M+1]+＝357.1LCMS[M+1] + =357.1
中间体I-A5的合成：4-(2-(7-氯-2-(2-氯乙基)-2H-吲唑-5-基)丙烷-2-基)苯酚
Synthesis of Intermediate I-A5: 4-(2-(7-Chloro-2-(2-chloroethyl)-2H-indazol-5-yl)propan-2-yl)phenol
参考中间体I-A3的合成路线。从原料I-A3-1经过五步反应合成中间体I-A5。Refer to the synthetic route of intermediate I-A3. The intermediate I-A5 was synthesized from the starting material I-A3-1 through a five-step reaction.
LCMS[M+1]+＝349.0LCMS[M+1] + =349.0
中间体I-A6的合成：2-(2-氯乙氧基)-5-(2-(4-羟基苯基)丙烷-2-基)-3-甲氧基苯甲苯腈
Synthesis of Intermediate I-A6: 2-(2-Chloroethoxy)-5-(2-(4-hydroxyphenyl)propan-2-yl)-3-methoxybenzonitrile
步骤一：将原料I-A6-1(23g,126.25mmol)溶解在二氯甲烷(300mL)，在20℃下搅拌5分钟后，在20℃下加入NIS(32.76g,189.38mmol)。上述混合物在室温 (20℃)下反应4小时。将反应混合物倒入到水中(200mL)，用二氯甲烷萃取(200mL*2)，合并有机相，用饱和食盐水清洗(200mL*2)，有机相用无水硫酸钠干燥后浓缩。浓缩后的混合物使用乙腈重结晶得到产物I-A6-2(24g,产率：62％)，为白色固体。Step 1: Dissolve raw material I-A6-1 (23g, 126.25mmol) in dichloromethane (300mL), stir at 20°C for 5 minutes, then add NIS (32.76g, 189.38mmol) at 20°C. above mixture at room temperature (20° C.) for 4 hours. The reaction mixture was poured into water (200 mL), extracted with dichloromethane (200 mL*2), the organic phases were combined, washed with saturated brine (200 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was recrystallized using acetonitrile to obtain the product I-A6-2 (24 g, yield: 62%) as a white solid.
LC-MS[M+1]+＝308.9LC-MS [M+1] + = 308.9
步骤二：室温下将I-A6-2(24g,77.9mmol)和1-溴-2-氯乙烷(22.34g,155.81mmol)溶解于N,N-二甲基甲酰胺(250mL)中，然后加碳酸铯(50.7g,155.81mmol)。混合物在70℃下搅拌16小时。将反应混合物投入到水中(200ml)后并用乙酸乙酯(200mL*3)萃取。有机相用饱和食盐水(200mL)洗并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A6-3(19.5g,产率：68％)，为无色固体。Step 2: Dissolve I-A6-2 (24g, 77.9mmol) and 1-bromo-2-chloroethane (22.34g, 155.81mmol) in N,N-dimethylformamide (250mL) at room temperature, Cesium carbonate (50.7 g, 155.81 mmol) was then added. The mixture was stirred at 70°C for 16 hours. The reaction mixture was poured into water (200ml) and extracted with ethyl acetate (200mL*3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A6-3 (19.5 g, yield: 68%) as a colorless solid.
步骤三：将中间体I-A6-3(19.5g,52.62mmol)溶解于N-甲基吡咯烷酮(200mL)中，加入CuCN(5.662g,63.15mmol)，在160℃下，氮气保护下搅拌反应3小时。TLC检测反应完全。反应混合物用氨水(200mL，23％)淬灭后，用乙酸乙酯(200mL*3)萃取。有机相用饱和食盐水(200mL)洗并用无水硫酸钠干燥。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A6-4(12.5g,产率：88％)，为白色固体。Step 3: Dissolve intermediate I-A6-3 (19.5g, 52.62mmol) in N-methylpyrrolidone (200mL), add CuCN (5.662g, 63.15mmol), and stir the reaction at 160°C under nitrogen protection 3 hours. TLC detects that the reaction is complete. After the reaction mixture was quenched with ammonia water (200 mL, 23%), it was extracted with ethyl acetate (200 mL*3). The organic phase was washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A6-4 (12.5 g, yield: 88%) as a white solid.
LC-MS[M+1]+＝269.90LC-MS [M+1] + = 269.90
步骤四：将I-A6-4(12.5g,46.5mmol)溶解于四氢呋喃(200mL)中，在室温下滴加到氮气保护的甲基溴化镁(124mL,3M的四氢呋喃溶液)中，滴加完后室温反应3小时。将反应混合物缓慢的加入到0℃下的饱和氯化铵溶液中，并用乙酸乙酯(100mL*3)萃取。有机相用饱和食盐水洗(200mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后得到所需的粗产物I-A6-5(12.5g,产率：100％)为黄色固体，该粗品直接用于下一步反应。Step 4: Dissolve I-A6-4 (12.5g, 46.5mmol) in tetrahydrofuran (200mL), add dropwise to nitrogen-protected methylmagnesium bromide (124mL, 3M solution in tetrahydrofuran) at room temperature, add dropwise After completion, react at room temperature for 3 hours. The reaction mixture was slowly added to saturated ammonium chloride solution at 0°C, and extracted with ethyl acetate (100 mL*3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered. After concentrating the filtrate, the desired crude product I-A6-5 (12.5 g, yield: 100%) was obtained as a yellow solid, which was directly used in the next reaction.
步骤五：将I-A6-5(12.5g,46.34mmol)，苯酚(17.45g,185.37mmol)溶解于二氯甲烷(120mL)中，在-78℃下，在氮气保护下滴加三氟化硼乙醚溶液(17.5ml,47％)，滴加完后自然升温至室温反应2小时。TLC检测反应完全。反应混合物加入到水(200ml)中，并用二氯甲烷(100mL*3)萃取。有机相用饱和食盐水洗(200 mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物中间体I-A6(14g,产率：87％)，为无色油状液体。Step 5: Dissolve I-A6-5 (12.5g, 46.34mmol), phenol (17.45g, 185.37mmol) in dichloromethane (120mL), add trifluoride dropwise under nitrogen protection at -78°C Boron ether solution (17.5ml, 47%) was naturally warmed to room temperature and reacted for 2 hours after the dropwise addition. TLC detects that the reaction is complete. The reaction mixture was added to water (200ml), and extracted with dichloromethane (100mL*3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product intermediate I-A6 (14 g, yield: 87%) as a colorless oily liquid.
LC-MS[M+1]+＝346.10.LC-MS [M+1] + = 346.10.
中间体I-A7的合成：2-(2-氯乙氧基)-5-(2-(4-羟基苯基)丙烷-2-基)间苯二甲腈
Synthesis of Intermediate I-A7: 2-(2-Chloroethoxy)-5-(2-(4-hydroxyphenyl)propan-2-yl)isophthalonitrile
步骤一：将原料I-A7-1(19.5g,128mmol)溶解在50％的乙酸水溶液中(1400mL)，室温下加入碘化钾(53g,320mmol),然后缓慢的加入过氧化氢碳酸钠(80.4g,512mmol)。上述混合物60℃下反应3小时，TLC检测发现反应完全。将反应混合物投入剧烈搅拌的二氯甲烷与饱和亚硫酸钠的混合溶液中，用二氯甲烷萃取(500mL*3)，合并有机相，用饱和食盐水清洗(1000mL*2)，有机相用无水硫酸钠干燥后浓缩。浓缩后得到产物I-A7-2(50g,产率：96.5％)，为白色固体。Step 1: Dissolve raw material I-A7-1 (19.5g, 128mmol) in 50% acetic acid aqueous solution (1400mL), add potassium iodide (53g, 320mmol) at room temperature, then slowly add sodium hydrogen peroxide (80.4g ,512mmol). The above mixture was reacted at 60° C. for 3 hours, and TLC detection showed that the reaction was complete. Put the reaction mixture into a vigorously stirred mixed solution of dichloromethane and saturated sodium sulfite, extract with dichloromethane (500mL*3), combine the organic phases, wash with saturated brine (1000mL*2), and wash the organic phase with anhydrous sulfuric acid Dry over sodium and concentrate. After concentration, the product I-A7-2 (50 g, yield: 96.5%) was obtained as a white solid.
LC-MS[M+1]+＝404.6LC-MS [M+1] + = 404.6
步骤二：室温下将I-A7-2(50g,124mmol)和1-氯-2-溴乙烷(35.5g,248mmol)溶解于N,N-二甲基甲酰胺(500mL)中，然后加碳酸铯(80.8g,248mmol)。混合物在70℃下搅拌16小时，TLC检测反应完全。反应混合投入到水中(500ml)后并用乙酸乙酯(300mL*2)萃取。有机相用饱和食盐水(1000mL)洗并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A7-3(41.3g,产率：71.6％)，为白色固体。Step 2: Dissolve I-A7-2 (50g, 124mmol) and 1-chloro-2-bromoethane (35.5g, 248mmol) in N,N-dimethylformamide (500mL) at room temperature, then add Cesium carbonate (80.8 g, 248 mmol). The mixture was stirred at 70°C for 16 hours, and the reaction was complete by TLC. The reaction mixture was poured into water (500ml) and extracted with ethyl acetate (300mL*2). The organic phase was washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A7-3 (41.3 g, yield: 71.6%) as a white solid.
1H-NMR(400MHz,Chloroform-d)δ8.42(s,2H),4.25(d,J＝6.2Hz,2H),3.98–3.93(m,2H),3.89(s,3H). 1 H-NMR (400MHz, Chloroform-d) δ8.42(s, 2H), 4.25(d, J=6.2Hz, 2H), 3.98–3.93(m, 2H), 3.89(s, 3H).
步骤三：将中间体I-A7-3(30g,64.4mmol)溶解于N-甲基吡咯烷酮(500mL)中，加入CuCN(17.3g,193.2mmol)，在160℃下，在氮气保护下搅拌反应3小时。 TLC检测反应完全。反应混合物用氨水(1000mL，23％)淬灭后，用乙酸乙酯(500mL*3)萃取。有机相用饱和食盐水(1500mL)洗并用无水硫酸钠干燥。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A7-4(5.6g,产率：32.9％)，为棕色固体。Step 3: Dissolve intermediate I-A7-3 (30g, 64.4mmol) in N-methylpyrrolidone (500mL), add CuCN (17.3g, 193.2mmol), and stir the reaction at 160°C under nitrogen protection 3 hours. TLC detects that the reaction is complete. The reaction mixture was quenched with aqueous ammonia (1000 mL, 23%), and extracted with ethyl acetate (500 mL*3). The organic phase was washed with saturated brine (1500 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A7-4 (5.6 g, yield: 32.9%) as a brown solid.
1H-NMR(400MHz,Chloroform-d)δ8.44(s,2H),4.86(s,2H),3.96(s,3H),3.90(s,2H). 1 H-NMR (400MHz, Chloroform-d) δ8.44(s,2H),4.86(s,2H),3.96(s,3H),3.90(s,2H).
步骤四：将I-A7-4(1.7g,6.4mmol)溶解于四氢呋喃(15mL)中在-10℃下，在氮气氛围中滴加甲基溴化镁(6.4ml,3M的四氢呋喃溶液)，滴加完后-10℃反应4小时。反应混合物缓慢的加入到0℃下的饱和氯化铵溶液中，并用乙酸乙酯(50mL*3)萃取。有机相用饱和食盐水洗(60mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A7-5(1.14g,产率：67％)，为黄色油固体。Step 4: Dissolve I-A7-4 (1.7g, 6.4mmol) in tetrahydrofuran (15mL) and add methylmagnesium bromide (6.4ml, 3M solution in tetrahydrofuran) dropwise in a nitrogen atmosphere at -10°C, After the dropwise addition, react at -10°C for 4 hours. The reaction mixture was slowly added to saturated ammonium chloride solution at 0°C, and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A7-5 (1.14 g, yield: 67%) as a yellow oily solid.
1H-NMR(400MHz,Chloroform-d)δ7.92(s,2H),4.68(s,2H),3.89(s,2H),1.55(s,6H). 1 H-NMR (400MHz, Chloroform-d) δ7.92(s,2H),4.68(s,2H),3.89(s,2H),1.55(s,6H).
步骤五：将I-A7-5(1.14g,4.3mmol)，苯酚(2.0g,21.5mmol)溶解于二氯甲烷(12mL)中，在-78℃下，在氮气保护下滴加三氟化硼乙醚溶液(1.8g,47％)，滴加完后自然升温至室温反应3小时。TLC检测反应完全,反应混合物加入到水(20mL)中，并用二氯甲烷(50mL*3)萃取。有机相用饱和食盐水洗(60mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物中间体I-A7(1.0g,产率：68％)，为黄色固体。Step 5: Dissolve I-A7-5 (1.14g, 4.3mmol), phenol (2.0g, 21.5mmol) in dichloromethane (12mL), add trifluoride dropwise under nitrogen protection at -78°C Boron ether solution (1.8 g, 47%) was naturally warmed to room temperature and reacted for 3 hours after the dropwise addition. TLC detected that the reaction was complete, and the reaction mixture was added into water (20 mL), and extracted with dichloromethane (50 mL*3). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product intermediate I-A7 (1.0 g, yield: 68%) as a yellow solid.
1H-NMR(400MHz,Chloroform-d)δ7.61(s,2H),7.02(d,J＝8.7Hz,2H),6.79(d,J＝7.2Hz,2H),4.67(d,J＝7.0Hz,2H),3.86(d,J＝6.3Hz,2H),1.63(s,6H). 1 H-NMR (400MHz, Chloroform-d) δ7.61(s, 2H), 7.02(d, J=8.7Hz, 2H), 6.79(d, J=7.2Hz, 2H), 4.67(d, J= 7.0Hz, 2H), 3.86(d, J=6.3Hz, 2H), 1.63(s, 6H).
中间体I-A8的合成：3-氯-2-(2-氯乙氧基)-5-(1-(4-乙炔基苯基)-1-羟基乙基)苯腈
Synthesis of Intermediate I-A8: 3-Chloro-2-(2-chloroethoxy)-5-(1-(4-ethynylphenyl)-1-hydroxyethyl)benzonitrile
步骤一：将原料I-A8-1(7.0g,51.4mmol)溶解在甲苯(100mL)0℃搅拌下加入二异丙基胺盐酸盐(358mg,2.6mmol)和中间体I-A8-2(10.1g,51.4mmol)。上述混合物0℃反应4小时。将反应用饱和的亚硫酸钠水溶液猝灭，用二氯甲烷萃取(150mL*2)，合并有机相，用饱和食盐水清洗(100mL*2)，有机相用无水硫酸钠干燥后浓缩。浓缩后的混合物使用柱层析(石油醚/乙酸乙酯＝5/1)得到产物I-A8-3(2.5g,产率：28.5％)，为白色固体。Step 1: Dissolve raw material I-A8-1 (7.0g, 51.4mmol) in toluene (100mL) and add diisopropylamine hydrochloride (358mg, 2.6mmol) and intermediate I-A8-2 under stirring at 0°C (10.1 g, 51.4 mmol). The above mixture was reacted at 0°C for 4 hours. The reaction was quenched with saturated aqueous sodium sulfite, extracted with dichloromethane (150 mL*2), combined the organic phases, washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the product I-A8-3 (2.5 g, yield: 28.5%) as a white solid.
LC-MS[M+1]+-＝170.9LC-MS [M+1] +- = 170.9
步骤二：室温下，将中间体I-A8-3(2.5g,14.6mmol)溶解于二氯甲烷(30mL)，在0℃下加入NIS(3.3g,14.6mmol)，混合物在室温下搅拌16小时，LC-MS检测反应完全。反应混合投入到水中(50mL)后并用二氯甲烷(50mL*3)萃取。有机相用饱和食盐水(100mL)洗并用无水硫酸钠干燥并过滤。将滤液浓缩后得到所需的产物I-A8-4(4.0g,产率：93％)，为棕色固体。Step 2: Dissolve intermediate I-A8-3 (2.5g, 14.6mmol) in dichloromethane (30mL) at room temperature, add NIS (3.3g, 14.6mmol) at 0°C, and stir the mixture at room temperature for 16 Hours, LC-MS detected that the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL*3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The desired product I-A8-4 (4.0 g, yield: 93%) was obtained after concentrating the filtrate as a brown solid.
LC-MS[M+1]+＝296.8LC-MS [M+1] + = 296.8
步骤三：将I-A8-4(6.7g,22.6mmol)溶解于N，N-二甲基甲酰胺(100mL)中，加入1-溴-2氯乙烷(6.5g,45.2mmol)，碳酸铯(14.7g，45.2mmol)。混合物在70℃下搅拌反应16小时。TLC检测反应完全。反应混合投入到水中(100mL)后并用乙酸乙酯(100mL*3)萃取。有机相用饱和食盐水(300mL)洗并用无水硫酸钠干燥并过滤。将滤液浓缩后经柱层析(石油醚/乙酸乙酯＝5/1)得到所需的产物I-A8-5 (5.6g,产率：69％)，为黄色固体。Step 3: Dissolve I-A8-4 (6.7g, 22.6mmol) in N,N-dimethylformamide (100mL), add 1-bromo-2chloroethane (6.5g, 45.2mmol), carbonic acid Cesium (14.7 g, 45.2 mmol). The mixture was stirred and reacted at 70°C for 16 hours. TLC detects that the reaction is complete. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL*3). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate and filtered. After the filtrate was concentrated, the desired product I-A8-5 was obtained by column chromatography (petroleum ether/ethyl acetate=5/1) (5.6 g, Yield: 69%) as a yellow solid.
1H NMR(400MHz,Chloroform-d)δ8.24(s,1H),7.94(s,1H),4.30(s,2H),3.91(s,2H),2.55(s,3H). 1 H NMR (400MHz, Chloroform-d) δ8.24(s,1H),7.94(s,1H),4.30(s,2H),3.91(s,2H),2.55(s,3H).
步骤三：将中间体I-A8-5(5.6g,15.6mmol)溶解于N-甲基吡咯烷酮(60mL)中，加入CuCN(2.1g，23.4mmol)。混合物在氮气氛围下，在160℃下，搅拌反应3小时。TLC检测反应完全，反应混合物用氨水(300mL，23％)淬灭后，用乙酸乙酯(200mL*3)萃取。有机相用饱和食盐水(500mL)洗并用无水硫酸钠干燥。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A8-6(3.0g,产率：75％)，为黄色固体。Step 3: Intermediate I-A8-5 (5.6 g, 15.6 mmol) was dissolved in N-methylpyrrolidone (60 mL), and CuCN (2.1 g, 23.4 mmol) was added. The mixture was stirred and reacted at 160° C. for 3 hours under nitrogen atmosphere. TLC detected that the reaction was complete, and the reaction mixture was quenched with ammonia water (300 mL, 23%), and then extracted with ethyl acetate (200 mL*3). The organic phase was washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A8-6 (3.0 g, yield: 75%) as a yellow solid.
步骤四：将中间体I-A8-7(909mg,3.85mmol)溶解于四氢呋喃(5mL)中在-77℃下，在氮气氛围下滴加正丁基锂(2.6ml,1.6M的正己烷溶液)，滴加完后在-77℃下反应30分钟后将中间体I-A8-6(900mg，3.5mmol)的四氢呋喃(4mL)溶液滴加到上述混合物中，滴加完成后保持-77℃反应2小时。LC-MS检测反应完全。将反应混合物缓慢地加入到0℃下的饱和氯化铵溶液中，并用乙酸乙酯(20mL*3)萃取。有机相用饱和食盐水洗(60mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A8-8(1.1g,产率：76.4％)，为黄色油状液体。Step 4: Dissolve intermediate I-A8-7 (909mg, 3.85mmol) in tetrahydrofuran (5mL) and add n-butyllithium (2.6ml, 1.6M n-hexane solution) dropwise under nitrogen atmosphere at -77°C ), reacted at -77°C for 30 minutes after the dropwise addition, then added the solution of intermediate I-A8-6 (900mg, 3.5mmol) in tetrahydrofuran (4mL) dropwise to the above mixture, and kept at -77°C after the dropwise addition React for 2 hours. LC-MS detected that the reaction was complete. The reaction mixture was slowly added to saturated ammonium chloride solution at 0°C, and extracted with ethyl acetate (20 mL*3). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A8-8 (1.1 g, yield: 76.4%) as a yellow oily liquid.
LC-MS[M+23]+＝437.9LC-MS [M+23] + = 437.9
步骤五：室温下，将中间体I-A8-8(1.1g,2.65mmol)和三甲基硅基乙炔(2.6g,26.5mmol)，Pd(PPh3)2Cl2(190mg,0.27mmol),碘化亚铜(51mg,0.27mmol)，N,N-二异丙基乙胺(6.8g,53mmol)溶解于四氢呋喃(10ml)中。混合物在80℃下，在氮气保护下搅拌16小时，TLC检测反应完全。反应混合物浓缩后使用柱层析(石油醚/乙酸乙酯＝10/1)纯化得到所需的产物I-A8-9(900mg,产率：78.3％)，为黄色油状液体。Step 5: At room temperature, intermediate I-A8-8 (1.1g, 2.65mmol) and trimethylsilylacetylene (2.6g, 26.5mmol), Pd(PPh 3 ) 2 Cl 2 (190mg, 0.27mmol) , cuprous iodide (51mg, 0.27mmol), N,N-diisopropylethylamine (6.8g, 53mmol) were dissolved in tetrahydrofuran (10ml). The mixture was stirred at 80° C. under nitrogen protection for 16 hours, and the reaction was complete as detected by TLC. The reaction mixture was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the desired product I-A8-9 (900 mg, yield: 78.3%) as a yellow oily liquid.
1H NMR(400MHz,Chloroform-d)δ7.60(s,1H),7.50(s,1H),7.43(s,2H),7.32(s,2H),4.42–4.38(m,2H),3.87–3.83(m,2H),1.90(s,3H),0.23(s,9H) 1 H NMR (400MHz, Chloroform-d) δ7.60(s,1H),7.50(s,1H),7.43(s,2H),7.32(s,2H),4.42–4.38(m,2H),3.87 –3.83(m,2H),1.90(s,3H),0.23(s,9H)
步骤六：将中间体I-A8-9(900mg,2.1mmol)溶解甲醇(10mL)中，加入氟化钾(974mg,16.8mmol)，在25℃下，在氮气保护下搅拌反应16小时。TLC检测反应 完全。反应混合物浓缩后进行柱层析分离(石油醚/乙酸乙酯＝10/1)，得到所需的产物中间体I-A8(590mg,产率：78.7％)，为黄色油状液体。Step 6: Intermediate I-A8-9 (900mg, 2.1mmol) was dissolved in methanol (10mL), potassium fluoride (974mg, 16.8mmol) was added, and the reaction was stirred at 25°C for 16 hours under nitrogen protection. TLC detection reaction completely. The reaction mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the desired product intermediate I-A8 (590 mg, yield: 78.7%) as a yellow oily liquid.
1H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.52(s,1H),7.49–7.44(m,2H),7.35(s,2H),4.39(s,2H),3.87(s,2H),3.08(s,1H),1.91(s,3H). 1 H NMR (400MHz, Chloroform-d) δ7.64(s,1H),7.52(s,1H),7.49–7.44(m,2H),7.35(s,2H),4.39(s,2H),3.87 (s,2H),3.08(s,1H),1.91(s,3H).
中间体I-A9的合成：3-氯-5-(2-(4-羟基苯基)丙烷-2-基)-2-甲氧基苯腈
Synthesis of Intermediate I-A9: 3-Chloro-5-(2-(4-hydroxyphenyl)propan-2-yl)-2-methoxybenzonitrile
参考中间体I-A1的合成方法，用碘甲烷代替I-A1-3，进行四步反应得到中间体I-A9。Refer to the synthesis method of intermediate I-A1, replace I-A1-3 with methyl iodide, and perform four-step reaction to obtain intermediate I-A9.
LC-MS[M+18]+＝319.1LC-MS [M+18] + = 319.1
中间体I-A10的合成：1-(2-氯乙基)-5-(2-(4-羟基苯基)丙烷-2-基)-1H-吲唑-7-甲腈
Synthesis of Intermediate I-A10: 1-(2-Chloroethyl)-5-(2-(4-hydroxyphenyl)propan-2-yl)-1H-indazole-7-carbonitrile
步骤一：向原料I-A3-1(30g,181mmol)的乙腈(400mL)中加入NBS(48g,272mmol)。上述混合溶液在室温下反应3小时，LCMS检测有产物生成。将反应混合物降至室温，向反应液中加入200mL饱和亚硫酸钠，乙腈减压浓缩后用乙酸乙酯 (100mL*2)萃取,有机相用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚：乙酸乙酯＝20％)，得到所需的产物中间体I-A10-1(35g,产率：78％)，为黄色固体。Step 1: Add NBS (48 g, 272 mmol) to starting material I-A3-1 (30 g, 181 mmol) in acetonitrile (400 mL). The above mixed solution was reacted at room temperature for 3 hours, and the product was detected by LCMS. The reaction mixture was lowered to room temperature, and 200 mL of saturated sodium sulfite was added to the reaction solution, and the acetonitrile was concentrated under reduced pressure with ethyl acetate (100mL*2) extraction, the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether: ethyl acetate = 20%) to obtain the desired product intermediate I-A10-1 (35 g, yield: 78%) as a yellow solid.
LC-MS[M+1]+＝243.8/245.8LC-MS [M+1] + = 243.8/245.8
步骤二：将中间体I-A10-1(11g,45.07mmol)溶解在100mL乙酸中，在0℃下加入亚硝酸钠饱和溶液，混合物在室温条件下搅拌3小时。LCMS检测反应完全。将乙酸减压除去后柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A10-2(8.4g,产率：73％)，为棕色固体。Step 2: Intermediate I-A10-1 (11 g, 45.07 mmol) was dissolved in 100 mL of acetic acid, a saturated solution of sodium nitrite was added at 0° C., and the mixture was stirred at room temperature for 3 hours. LCMS detected that the reaction was complete. The acetic acid was removed under reduced pressure and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A10-2 (8.4 g, yield: 73%) as a brown solid.
LC-MS[M+1]+-＝254.9/356.9LC-MS [M+1] +- = 254.9/356.9
步骤三：将原料I-A10-2(1.5g,6mmol)和氰化锌(1.60g,15mmol)混合后加入NMP(2mL)，然后向混合物中加入三叔丁基磷钯(1.0g,1.96mmol)。上述混合溶液在150℃(微波)下反应1小时。将反应混合物降至室温，向反应液中加入30mL乙酸乙酯和50mL水，然后用乙酸乙酯(10mL*2)萃取,有机相用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(纯石油醚)，得到所需的产物I-A10-3(900mg,产率：76％)，为黄色固体。Step 3: Mix raw materials I-A10-2 (1.5g, 6mmol) and zinc cyanide (1.60g, 15mmol) and add NMP (2mL), then add tri-tert-butylphosphopalladium (1.0g, 1.96 mmol). The above mixed solution was reacted at 150° C. (microwave) for 1 hour. The reaction mixture was lowered to room temperature, 30 mL of ethyl acetate and 50 mL of water were added to the reaction liquid, and then extracted with ethyl acetate (10 mL*2), the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (pure petroleum ether) to obtain the desired product I-A10-3 (900 mg, yield: 76%) as a yellow solid.
1H-NMR(400MHz,Chloroform-d)δ8.75(d,J＝1.1Hz,1H),8.42(s,1H),8.31(s,1H),3.98-3.95(m,3H) 1 H-NMR (400MHz, Chloroform-d) δ8.75 (d, J = 1.1Hz, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 3.98-3.95 (m, 3H)
步骤四：将中间体I-A10-3(0.8g,3.98mmol)和碳酸钾(550mg,3.98mmol)混合在10mL DMF中，加入1-氯-2-溴乙烷(2.0g,13.9mmol)，混合物在75℃下搅拌1小时。LCMS检测反应完全。将反应混合物导入50mL水中，用乙酸乙酯萃取。萃取液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A10-4(170mg,产率：16％)，为黄色油状。Step 4: Mix intermediate I-A10-3 (0.8g, 3.98mmol) and potassium carbonate (550mg, 3.98mmol) in 10mL DMF, add 1-chloro-2-bromoethane (2.0g, 13.9mmol) , and the mixture was stirred at 75 °C for 1 h. LCMS detected that the reaction was complete. The reaction mixture was introduced into 50 mL of water and extracted with ethyl acetate. The extract was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A10-4 (170 mg, yield: 16%) as a yellow oil.
LC-MS[M+1]-＝263.8LC-MS[M+1] - = 263.8
步骤五：在室温下向中间体I-A10-4(170mg,0.64mmol)的四氢呋喃(5mL)溶液中滴加甲基溴化镁(2mL,2mmol,1M in THF)。上述混合液在室温下搅拌2小时。LCMS检测反应完全。将反应液缓慢倒入0℃下的饱和氯化铵水溶液(10mL)中，用乙酸乙酯(15mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝2/1)， 得到所需的产物I-A10-5(160mg,产率：94％)，为无色油状物。Step 5: Add methylmagnesium bromide (2 mL, 2 mmol, 1M in THF) dropwise to a solution of intermediate I-A10-4 (170 mg, 0.64 mmol) in tetrahydrofuran (5 mL) at room temperature. The above mixture was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete. The reaction solution was slowly poured into saturated aqueous ammonium chloride solution (10 mL) at 0°C, extracted with ethyl acetate (15 mL*3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and After filtration, the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=2/1), The desired product I-A10-5 (160 mg, yield: 94%) was obtained as a colorless oil.
LC-MS[M+1]+＝264.1LC-MS [M+1] + = 264.1
步骤六：在-78℃下向中间体I-A10-5(160mg,0.6mmol)和苯酚(142mg,1.5mmol)的二氯甲烷(6mL)溶液中加入三氟化硼乙醚溶液(213mg,1.5mmol)。上述混合液在-78℃下搅拌2小时。TLC检测反应完全。将反应液用水淬灭(20mL)中，用二氯甲烷(20mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝1/1)，得到所需的产物中间体I-A10(200mg,产率：97％)，为无色油状物。Step 6: Add boron trifluoride diethyl ether solution (213 mg, 1.5 mmol). The above mixture was stirred at -78°C for 2 hours. TLC detects that the reaction is complete. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL*3), the combined organic phase was washed with saturated brine (10 mL), dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated and subjected to column chromatography Analysis and separation (petroleum ether/ethyl acetate=1/1) gave the desired product intermediate I-A10 (200 mg, yield: 97%) as a colorless oil.
LC-MS[M+1]+＝339.9LC-MS [M+1] + = 339.9
中间体I-A11的合成：2-(2-氯乙氧基)-5-(2-(4-乙炔基苯基)丙烷-2-基)-3-甲氧基苯腈
Synthesis of Intermediate I-A11: 2-(2-Chloroethoxy)-5-(2-(4-ethynylphenyl)propan-2-yl)-3-methoxybenzonitrile
参考中间体I-A2的合成路线，用中间体I-A6代替中间体I-A1，经过三步反应合成2-(2-氯乙氧基)-5-(2-(4-乙炔基苯基)丙烷-2-基)-3-甲氧基苯腈(中间体I-A11)。With reference to the synthetic route of intermediate I-A2, intermediate I-A6 is used to replace intermediate I-A1, and 2-(2-chloroethoxy)-5-(2-(4-ethynylbenzene) is synthesized through a three-step reaction yl)propan-2-yl)-3-methoxybenzonitrile (intermediate I-A11).
1H NMR(400MHz,Chloroform-d)δ7.42(d,J＝2.0Hz,1H),7.40(d,J＝2.0Hz,1H),7.15(d,J＝2.0Hz,1H),7.12(d,J＝2.0Hz,1H),7.04(d,J＝1.6Hz,1H),6.80(d,J＝2.4Hz,1H),4.37(t,J＝6.4Hz,2H),3.80(t,J＝6.3Hz,2H),3.73(s,3H),3.05(s,1H),1.63(s,6H). 1 H NMR (400MHz, Chloroform-d) δ7.42(d, J=2.0Hz, 1H), 7.40(d, J=2.0Hz, 1H), 7.15(d, J=2.0Hz, 1H), 7.12( d,J=2.0Hz,1H),7.04(d,J=1.6Hz,1H),6.80(d,J=2.4Hz,1H),4.37(t,J=6.4Hz,2H),3.80(t, J＝6.3Hz,2H),3.73(s,3H),3.05(s,1H),1.63(s,6H).
LC-MS[M+1]+＝354.10。LC-MS [M+1] + = 354.10.
中间体I-A12的合成：2-(2-氯乙氧基)-5-(2-(4-乙炔基苯基)丙烷-2-基)间苯二甲腈
Synthesis of Intermediate I-A12: 2-(2-Chloroethoxy)-5-(2-(4-ethynylphenyl)propan-2-yl)isophthalonitrile
参考中间体I-A2的合成路线，用中间体I-A7代替中间体I-A1，经过三步反应合成2-(2-氯乙氧基)-5-(2-(4-乙炔基苯基)丙烷-2-基)间苯二甲腈(中间体I-A12)，为黄色油状液体。With reference to the synthetic route of intermediate I-A2, intermediate I-A7 is used to replace intermediate I-A1, and 2-(2-chloroethoxy)-5-(2-(4-ethynylbenzene) is synthesized through a three-step reaction yl)propan-2-yl)isophthalonitrile (Intermediate I-A12) as a yellow oily liquid.
LC-MS[M+23]+＝371.1LC-MS [M+23] + = 371.1
中间体I-A13的合成：1-(2-氯乙基)-5-(2-(4-乙炔基苯基)丙烷-2-基)-1H-吲唑-7-氰基
Synthesis of Intermediate I-A13: 1-(2-Chloroethyl)-5-(2-(4-ethynylphenyl)propan-2-yl)-1H-indazol-7-cyano
步骤一：将中间体I-A10(200mg,0.59mmol)溶解于DCM(5mL)中，加入三乙胺(179mg,1.77mmol)。在0℃下加入Tf2O(250mg,0.88mmol)，混合物在25℃下反应1小时。TLC检测反应完全。将混合物经制备硅胶板分离得到产物I-A13-1(207mg,产率：74.5％)，为黄色油状液体。Step 1: Intermediate I-A10 (200 mg, 0.59 mmol) was dissolved in DCM (5 mL), and triethylamine (179 mg, 1.77 mmol) was added. Tf 2 O (250 mg, 0.88 mmol) was added at 0°C, and the mixture was reacted at 25°C for 1 hour. TLC detects that the reaction is complete. The mixture was separated on a preparative silica gel plate to obtain the product I-A13-1 (207 mg, yield: 74.5%) as a yellow oily liquid.
LC-MS[M+1]+＝472.0LC-MS [M+1] + = 472.0
步骤八：将I-A13-1(2.0g,4.24mmol)和三甲基硅基乙炔(1.25g,12.72mmol)，三乙胺(2.14g,21.19mmol,2.96mL)溶解在ACN(20mL)中，加入CuI(80.72mg,423.84μmol)，Pd(PPh3)2Cl2(297.53mg,423.84μmol)，混合物氮气置换气3次，在80℃下反 应5小时。混合物浓缩后经柱层析分离(石油醚/乙酸乙酯＝95/5)得到产物I-A13-2(1.7g，产率：93.3％)为棕色油状液体。Step 8: Dissolve I-A13-1 (2.0g, 4.24mmol), trimethylsilylacetylene (1.25g, 12.72mmol), triethylamine (2.14g, 21.19mmol, 2.96mL) in ACN (20mL) Add CuI (80.72mg, 423.84μmol), Pd(PPh 3 ) 2 Cl 2 (297.53mg, 423.84μmol), and replace the mixture with nitrogen for 3 times, then react at 80℃ Should be 5 hours. The mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=95/5) to obtain the product I-A13-2 (1.7 g, yield: 93.3%) as a brown oily liquid.
LC-MS[M+1]+＝420.3LC-MS [M+1] + = 420.3
步骤九：将I-A13-2(1.7g,4.5mmol)加入到MeOH(20mL)，室温下加入KF(1.7g,29.3mmol)将反应液在30℃下反应4小时。混合物浓缩后经柱层析分离(石油醚/乙酸乙酯＝5/1)得到中间体I-A13(1.1g，产率：76.6％)为黄色固体。Step 9: I-A13-2 (1.7g, 4.5mmol) was added to MeOH (20mL), KF (1.7g, 29.3mmol) was added at room temperature, and the reaction solution was reacted at 30°C for 4 hours. The mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain intermediate I-A13 (1.1 g, yield: 76.6%) as a yellow solid.
LC-MS[M+1]+＝348.3LC-MS [M+1] + = 348.3
中间体I-A14的合成：2-氯-3-(2-氯乙氧基)-6-(2-(4-羟基苯基)丙烷-2-基)异烟腈
Synthesis of Intermediate I-A14: 2-Chloro-3-(2-chloroethoxy)-6-(2-(4-hydroxyphenyl)propan-2-yl)isonicotinonitrile
步骤一：将原料I-A14-1(5g,19.5mmol)溶解在N,N-二甲基甲酰胺(50mL)，在溶液中加入在Zn(CN)2(1.35g,11.7mmol)，Pd(PPh3)4(1.8g,1.56mmol)。上述混合物在氮气保护下在100℃下搅拌反应16小时，TLC检测发现反应完全。将反应混合物投入到水中(100mL)，用乙酸乙酯萃取(100mL*2)，合并有机相，用饱和食盐水清洗(150mL*2)，有机相用无水硫酸钠干燥后浓缩。浓缩后的混合物经柱层析后得到产物I-A14-2(1.6g,产率：53.3％)，为黄色固体。Step 1: Dissolve raw material I-A14-1 (5g, 19.5mmol) in N,N-dimethylformamide (50mL), add Zn(CN) 2 (1.35g, 11.7mmol), Pd (PPh 3 ) 4 (1.8 g, 1.56 mmol). The above mixture was stirred and reacted at 100° C. for 16 hours under the protection of nitrogen, and the reaction was found to be complete by TLC detection. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine (150 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was subjected to column chromatography to obtain the product I-A14-2 (1.6 g, yield: 53.3%) as a yellow solid.
LC-MS[M+1]+＝155.0LC-MS [M+1] + = 155.0
步骤二：室温下将I-A14-2(1.6g,10.3mmol)和溶解于氯化氢甲醇溶液中(4M,26ml,104mmol)中，混合物在80℃下搅拌20小时，LC-MS检测反应完全。反应液 使用硅胶过滤，滤液浓缩后得到黄色固体。黄色固体使用热的1,4-二氧六环溶解(100mL,65℃)，在溶液中加入热的正己烷(100mL)，溶液缓慢冷却到室温，混合物过滤。固体使用正己烷冲洗，收集过滤后的固体真空干燥后的到产物I-A14-3(1.7g,产率：88.1％)为黄色固体。Step 2: I-A14-2 (1.6g, 10.3mmol) was dissolved in methanolic hydrogen chloride solution (4M, 26ml, 104mmol) at room temperature, and the mixture was stirred at 80°C for 20 hours. LC-MS detected that the reaction was complete. The reaction solution It was filtered through silica gel, and the filtrate was concentrated to obtain a yellow solid. The yellow solid was dissolved in hot 1,4-dioxane (100 mL, 65° C.), hot n-hexane (100 mL) was added to the solution, the solution was slowly cooled to room temperature, and the mixture was filtered. The solid was washed with n-hexane, and the filtered solid was collected and vacuum-dried to obtain the product I-A14-3 (1.7 g, yield: 88.1%) as a yellow solid.
LC-MS[M+1]+＝188.0LC-MS [M+1] + = 188.0
步骤三：将原料I-A14-3(1.7g,9.1mmol)溶解在N,N-二甲基甲酰胺(20mL)，加入NIS(3.07g,13.65mmol)。上述混合物在100℃反应下16小时，LC-MS检测发现反应完全。将反应混合物投入到水中(100mL)，用乙酸乙酯萃取(50mL*2)，合并有机相，用饱和食盐水清洗(100mL*2)，有机相用无水硫酸钠干燥后浓缩。浓缩后得到粗产物I-A14-4(3.9g)，为红棕色固体。Step 3: The raw material I-A14-3 (1.7 g, 9.1 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NIS (3.07 g, 13.65 mmol) was added. The above mixture was reacted at 100° C. for 16 hours, and the reaction was found to be complete by LC-MS detection. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (100 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product I-A14-4 (3.9 g) was obtained after concentration as a reddish-brown solid.
LC-MS[M+1]+＝313.9LC-MS [M+1] + = 313.9
步骤四：室温下，将I-A14-4(3.9,12.5mmol)和1-溴-2-氯乙烷(8.9g,62.5mmol)溶解于N,N-二甲基甲酰胺(40mL)中，然后加碳酸铯(8g,25mmol)。混合物在70℃下搅拌16小时，TLC检测反应完全。反应混合投入到水中(50mL)后并用乙酸乙酯(50mL*3)萃取。有机相用饱和食盐水(100mL)洗并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A14-5(1.6g,产率：47％)，为黄色固体。Step 4: Dissolve I-A14-4 (3.9, 12.5mmol) and 1-bromo-2-chloroethane (8.9g, 62.5mmol) in N,N-dimethylformamide (40mL) at room temperature , then cesium carbonate (8 g, 25 mmol) was added. The mixture was stirred at 70°C for 16 hours, and the reaction was complete by TLC. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A14-5 (1.6 g, yield: 47%) as a yellow solid.
步骤五：将中间体I-A14-5(1.6g,4.3mmol)溶解于N-甲基吡咯烷酮(20mL)中，加入CuCN(614mg,6.9mmol)，在160℃下，在氮气保护下搅拌反应3小时。TLC检测反应完全。反应混合物用投入水(100mL)中，用乙酸乙酯(50mL*3)萃取。有机相用饱和食盐水(100mL)洗并用无水硫酸钠干燥。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝10/1)，得到所需的产物I-A14-6(270mg,产率：23％)，为黄色固体。Step 5: Dissolve intermediate I-A14-5 (1.6g, 4.3mmol) in N-methylpyrrolidone (20mL), add CuCN (614mg, 6.9mmol), and stir the reaction at 160°C under nitrogen protection 3 hours. TLC detects that the reaction is complete. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the desired product I-A14-6 (270 mg, yield: 23%) as a yellow solid.
LC-MS[M+1]+＝274.9LC-MS [M+1] + = 274.9
步骤六：将I-A14-6(200mg,0.7mmol)溶解于四氢呋喃(6mL)中，氮气置换3次，在-77℃下滴加甲基溴化镁(1.3mL,1M的四氢呋喃溶液)，滴加完后在-77℃下反应30分钟。LC-MS检测反应完全。反应混合物缓慢的加入到0℃下的饱和氯化铵水溶液中，并用乙酸乙酯(10mL*3)萃取。有机相用饱和食盐水洗(50mL)，并 用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A14-7(150mg,产率：75％)，为黄色油状液体。Step 6: Dissolve I-A14-6 (200mg, 0.7mmol) in tetrahydrofuran (6mL), replace with nitrogen three times, add methylmagnesium bromide (1.3mL, 1M solution in tetrahydrofuran) dropwise at -77°C, After the dropwise addition, react at -77°C for 30 minutes. LC-MS detected that the reaction was complete. The reaction mixture was slowly added to saturated aqueous ammonium chloride at 0°C, and extracted with ethyl acetate (10 mL*3). The organic phase was washed with saturated brine (50 mL), and Dry over anhydrous sodium sulfate and filter. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A14-7 (150 mg, yield: 75%) as a yellow oily liquid.
1H NMR(400MHz,Chloroform-d)δ7.63(s,1H),4.53–4.44(m,2H),3.89(t,J＝5.7Hz,2H),1.56(s,6H). 1 H NMR (400MHz, Chloroform-d) δ7.63(s, 1H), 4.53–4.44(m, 2H), 3.89(t, J=5.7Hz, 2H), 1.56(s, 6H).
步骤七：将I-A14-7(140mg,0.51mmol)，苯酚(240mg,2.55mmol)溶解于1,2-二氯乙烷(6mL)中，在溶液中加入无水AlCl3(136mg,1.02mmol)，上述混合物在100℃下反应3小时。反应混合物加入到水(10mL)中，并用二氯甲烷(10mL*3)萃取。有机相用饱和食盐水洗(30mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A14(55mg,产率：62％)，为黄色油状液体。Step 7: Dissolve I-A14-7 (140mg, 0.51mmol), phenol (240mg, 2.55mmol) in 1,2-dichloroethane (6mL), and add anhydrous AlCl 3 (136mg, 1.02 mmol), the above mixture was reacted at 100°C for 3 hours. The reaction mixture was added to water (10 mL), and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A14 (55 mg, yield: 62%) as a yellow oily liquid.
1H NMR(400MHz,Chloroform-d)δ7.11(d,J＝10.3Hz,2H),7.07(s,1H),6.78(d,J＝8.4Hz,2H),4.46(s,2H),3.86(s,2H),1.68(s,6H). 1 H NMR (400MHz, Chloroform-d) δ7.11(d, J=10.3Hz, 2H), 7.07(s, 1H), 6.78(d, J=8.4Hz, 2H), 4.46(s, 2H), 3.86(s,2H),1.68(s,6H).
按照上面中间体的合成方法或参考文献分别合成下列中间体：
Synthesize the following intermediates respectively according to the synthetic method or references of the above intermediates:
中间体I-A18的合成：4-(2-氯乙基)-7-(2-(4-羟基苯基)丙烷-2-基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-5-腈
Synthesis of Intermediate I-A18: 4-(2-Chloroethyl)-7-(2-(4-hydroxyphenyl)propan-2-yl)-3,4-dihydro-2H-benzo[b ][1,4]oxazine-5-carbonitrile
步骤一：将I-A18-1(5.0g,29.91mmol)溶解于DCM(100mL)和DMF(10mL)中，在0℃下，分批加入NBS(6.92g,38.88mmol)。该反应液在30℃下，搅拌2小时后，加入H2O(50mL)，水层用DCM(100mL)萃取三次，合并有机相，干燥，浓缩，通过柱层析(石油醚/乙酸乙酯＝3：1)纯化得到I-A18-2(2.50g,收率：27.09％)，为棕色固体。Step 1: I-A18-1 (5.0 g, 29.91 mmol) was dissolved in DCM (100 mL) and DMF (10 mL), and NBS (6.92 g, 38.88 mmol) was added in portions at 0°C. The reaction solution was stirred at 30°C for 2 hours, then H 2 O (50 mL) was added, the aqueous layer was extracted three times with DCM (100 mL), the organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate =3:1) Purification gave I-A18-2 (2.50 g, yield: 27.09%) as a brown solid.
LC-MS[M+1]+＝245.9LC-MS [M+1] + = 245.9
步骤二：将I-A18-2(2.3g,9.35mmol)和K2CO3(6.45g,46.74mmol)溶解于DMF(140mL)中，加入1,2-二溴乙烷(4.39g,23.37mmol)。该反应液在800C下搅拌18小时后，浓缩，通过柱层析(石油醚/乙酸乙酯＝5：1)纯化得到I-A18-3(1.10g,收率：41.09％)，为淡黄色固体。Step 2: Dissolve I-A18-2 (2.3g, 9.35mmol) and K 2 CO 3 (6.45g, 46.74mmol) in DMF (140mL), add 1,2-dibromoethane (4.39g, 23.37 mmol). The reaction solution was stirred at 80 ° C for 18 hours, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=5:1) to obtain I-A18-3 (1.10g, yield: 41.09%), as Pale yellow solid.
LC-MS[M+1]+＝272.0LC-MS [M+1] + = 272.0
步骤三：将I-A18-3(1g,3.68mmol)和K2CO3(1.01g,7.35mmol)溶解于DMF(20mL)中，分别加入Zn(CN)2(863.12mg,7.35mmol)和Pd(PPh3)4(849.70mg,735.04μmol)后，在120℃下微波反应4小时。该反应液浓缩后，通过柱层析(石油醚/乙酸乙酯＝3：1)纯化得到I-A18-4(620.00mg,收率：68.03％)，为白色固体。Step 3: Dissolve I-A18-3 (1g, 3.68mmol) and K 2 CO 3 (1.01g, 7.35mmol) in DMF (20mL), add Zn(CN) 2 (863.12mg, 7.35mmol) and After Pd(PPh 3 ) 4 (849.70 mg, 735.04 μmol), microwave reaction was carried out at 120° C. for 4 hours. After the reaction solution was concentrated, it was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to obtain I-A18-4 (620.00 mg, yield: 68.03%) as a white solid.
LC-MS[M+1]+＝219.1LC-MS [M+1] + = 219.1
步骤四：将I-A18-4(1g,4.58mmol)和Cs2CO3(2.24g,6.87mmol)溶解于DMF(30mL)中，加入2-氯乙基甲烷磺酸盐(1.45g,9.17mmol)后，在50℃下反应18小时后，浓缩，通过柱层析(石油醚/乙酸乙酯＝3：1)纯化得到I-A18-5(270.00mg,收率：18.89％)，为无色油状。Step 4: Dissolve I-A18-4 (1g, 4.58mmol) and Cs 2 CO 3 (2.24g, 6.87mmol) in DMF (30mL), add 2-chloroethyl methanesulfonate (1.45g, 9.17 mmol), reacted at 50°C for 18 hours, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=3:1) to obtain I-A18-5 (270.00mg, yield: 18.89%), as Colorless oil.
LC-MS[M+1]+＝281.1LC-MS [M+1] + = 281.1
步骤五：将I-A18-5(270mg,961.86μmol)溶解于THF(2mL)中，在30℃下，加入 MeMgBr(1M,4.81mL,4.81mmol)后，在40℃下，搅拌1.5小时后，用饱和NH4Cl(10mL)淬灭，而后用乙酸乙酯(30mL)萃取三次，合并有机相浓缩，通过柱层析(石油醚/乙酸乙酯＝3：1)纯化得到I-A18-6(30.00mg,收率：10.00％)，为无色液体。Step 5: Dissolve I-A18-5 (270mg, 961.86μmol) in THF (2mL), at 30°C, add After MeMgBr (1M, 4.81mL, 4.81mmol), after stirring for 1.5 hours at 40°C, it was quenched with saturated NH 4 Cl (10mL), then extracted three times with ethyl acetate (30mL), the combined organic phases were concentrated, passed Purification by column chromatography (petroleum ether/ethyl acetate=3:1) gave I-A18-6 (30.00 mg, yield: 10.00%) as a colorless liquid.
LC-MS[M+1]+＝281.1LC-MS [M+1] + = 281.1
步骤六：将I-A18-6(60mg,213.71μmol)和苯酚(100.56mg,1.07mmol)溶解于DCE(4mL)中，在0℃下，加入AlCl3(56.85mg,427.43μmol)后，在0℃下，反应3小时。用饱和NaHCO3(10mL)淬灭，而后用乙酸乙酯(30mL)萃取三次，合并有机相浓缩，通过柱层析(石油醚/乙酸乙酯＝3：1)纯化得到I-A18(40.00mg,收率：31.47％)，棕色油状。Step 6: Dissolve I-A18-6 (60mg, 213.71μmol) and phenol (100.56mg, 1.07mmol) in DCE (4mL), add AlCl 3 (56.85mg, 427.43μmol) at 0°C, and then At 0°C, react for 3 hours. Quenched with saturated NaHCO 3 (10 mL), then extracted three times with ethyl acetate (30 mL), the combined organic phases were concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=3:1) to obtain I-A18 (40.00 mg , yield: 31.47%), brown oil.
LCMS:m/z 357.13[M+H]+ LCMS: m/z 357.13[M+H] +
中间体I-A19与I-A19-5的合成：
Synthesis of intermediates I-A19 and I-A19-5:
步骤一：将I-A19-1(2g，9.71mmol)，乙二醇(1.21g，19.42mmol)和Cs2CO3(9.49g，29.12mmol)加入溶剂DMF(25mL)中，在100℃下，微波反应2小时。反应液冷至室温，加入MeI(1.17g,8.27mmol)，25℃条件下搅拌反应2小时。反应液中加入60mL水淬灭，用乙酸乙酯萃取(20mL*5)，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液旋蒸除溶剂，柱层析分离(石油醚/四氢呋喃＝1：1)得到中间体I-A19-2(1.0g,产率：44.44％)，为白色固体。Step 1: Add I-A19-1 (2g, 9.71mmol), ethylene glycol (1.21g, 19.42mmol) and Cs 2 CO 3 (9.49g, 29.12mmol) into the solvent DMF (25mL), at 100°C , microwave reaction for 2 hours. The reaction solution was cooled to room temperature, MeI (1.17g, 8.27mmol) was added, and the reaction was stirred at 25°C for 2 hours. The reaction solution was quenched by adding 60 mL of water, extracted with ethyl acetate (20 mL*5), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was rotary evaporated to remove the solvent, and separated by column chromatography (petroleum ether/tetrahydrofuran = 1 : 1) Intermediate I-A19-2 (1.0 g, yield: 44.44%) was obtained as a white solid.
LC-MS[M+1]+＝232.10LC-MS [M+1] + = 232.10
步骤二：将I-A19-2(1.0g,3.37mmol)溶于THF(8mL)中，氮气置换三次，25℃条件下滴加MeMgBr(1M,20.20mL)，加完后继续搅拌反应0.5小时。反应液用0℃ 下的饱和氯化铵水溶液淬灭，乙酸乙酯(20mL*2)萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除溶剂，柱层析分离(石油醚/四氢呋喃＝6：4)，得到中间体I-A19-3(800.00mg,产率：75.99％)，为淡黄色固体。Step 2: Dissolve I-A19-2 (1.0g, 3.37mmol) in THF (8mL), replace with nitrogen three times, add MeMgBr (1M, 20.20mL) dropwise at 25°C, and continue stirring for 0.5 hours after the addition is complete . The reaction solution is used at 0°C Quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (20mL*2), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove solvent, and separated by column chromatography (petroleum ether/tetrahydrofuran=6:4) , to obtain intermediate I-A19-3 (800.00 mg, yield: 75.99%) as a pale yellow solid.
LC-MS[M+1]+＝232.10LC-MS [M+1] + = 232.10
步骤三：将中间体I-A19-3(0.16g,1.99mmol)，苯酚(934.30mg,9.93mmol)和AlCl3(529.50mg,3.97mmol)加入溶剂DCE(5mL)中，升温至80℃搅拌反应2小时。LC-MS检测发现反应完全，柱层析分离(石油醚/四氢呋喃＝5/1)，得到中间体I-A19-4(500.00mg,粗品)，为淡黄色油状物。Step 3: Add intermediate I-A19-3 (0.16g, 1.99mmol), phenol (934.30mg, 9.93mmol) and AlCl 3 (529.50mg, 3.97mmol) into solvent DCE (5mL), heat up to 80°C and stir React for 2 hours. LC-MS detection showed that the reaction was complete, and it was separated by column chromatography (petroleum ether/tetrahydrofuran=5/1) to obtain intermediate I-A19-4 (500.00 mg, crude product) as a pale yellow oil.
LC-MS[M+1]+＝308.20LC-MS [M+1] + = 308.20
步骤四：在0℃条件下将SOCl2(5mL)滴加入中间体I-A19-4(0.5g,1.62mmol)中，此温度下继续搅拌反应2小时。LC-MS检测发现反应完全，碳酸氢钠溶液将反应液pH调至中性，乙酸乙酯萃取(20mL*3)，用饱和食盐水洗涤，无水硫酸钠干燥，旋蒸得到中间体I-A19(200.00mg,粗品)，为白色固体。Step 4: Add SOCl 2 (5 mL) dropwise to intermediate I-A19-4 (0.5 g, 1.62 mmol) at 0° C., and continue stirring at this temperature for 2 hours. LC-MS detection found that the reaction was complete, and the pH of the reaction solution was adjusted to neutral with sodium bicarbonate solution, extracted with ethyl acetate (20mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain intermediate I- A19 (200.00 mg, crude product), as a white solid.
LC-MS[M+1]+＝326.30LC-MS [M+1] + = 326.30
步骤五：按照I-A10-2到I-A10-3的操作步骤，从中间体I-A19一步反应生成中间体I-A19-5。Step 5: According to the operation steps of I-A10-2 to I-A10-3, intermediate I-A19-5 is generated from intermediate I-A19 in one step.
LC-MS[M+1]+＝317.20LC-MS [M+1] + = 317.20
中间体I-A20的合成：1-(3-氯丙烷)-4-(2-(4-羟基苯基)丙烷-2-基)-6-甲基吡啶-2(1H)-酮
Synthesis of intermediate I-A20: 1-(3-chloropropane)-4-(2-(4-hydroxyphenyl)propan-2-yl)-6-methylpyridin-2(1H)-one
步骤一：将I-A20-1(10g,59.82mmol)，1,3-氯溴丙烷(28.25g,179.5mmol) 溶解在乙腈(120mL)中，加入Cs2CO3(38.88g,119.6mmol)。反应液在80℃下反应16小时。将反应液浓缩后的进行柱层析分离(石油醚/四氢呋喃＝1/1)，得到所需的产物I-A20-2(5.4g,产率：40％)，为黄色油状液体。Step 1: Combine I-A20-1 (10g, 59.82mmol), 1,3-chlorobromopropane (28.25g, 179.5mmol) Dissolve in acetonitrile (120 mL) and add Cs 2 CO 3 (38.88 g, 119.6 mmol). The reaction solution was reacted at 80° C. for 16 hours. The reaction solution was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran=1/1) to obtain the desired product I-A20-2 (5.4 g, yield: 40%) as a yellow oily liquid.
LC-MS[M+1]+＝226.2LC-MS [M+1] + = 226.2
步骤二：I-A20-2(5.4g,23.97mmol)溶解在二氯甲烷(50mL)中，在0℃下加入SOCl2(11.4g,95.9mmol)，反应液在室温下搅拌3小时。混合物旋干后进行柱层析分离(石油醚/四氢呋喃＝1/1)，得到所需的产物I-A20-3(3.0g,产率：27.5％)，为黄色固体。Step 2: I-A20-2 (5.4g, 23.97mmol) was dissolved in dichloromethane (50mL), and SOCl 2 (11.4g, 95.9mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 3 hours. The mixture was spin-dried and separated by column chromatography (petroleum ether/tetrahydrofuran=1/1) to obtain the desired product I-A20-3 (3.0 g, yield: 27.5%) as a yellow solid.
LC-MS[M+1]+＝244.2LC-MS [M+1] + = 244.2
步骤三：在室温下向I-A20-3(3.0g,12.3mmol)的四氢呋喃(20mL)溶液中滴加甲基溴化镁(123mL,123mmol,1M in THF)。上述混合液在室温下搅拌4小时。将反应液缓慢倒入0℃下的饱和氯化铵水溶液(100mL)中，用乙酸乙酯(100mL*3)萃取，合并的有机相用饱和食盐水(300mL)洗涤，并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/四氢呋喃＝1/1)，得到所需的产物I-A20-4(1.1g,产率：26.76％)，为淡黄色油状物。Step 3: Add methylmagnesium bromide (123 mL, 123 mmol, 1M in THF) dropwise to a solution of I-A20-3 (3.0 g, 12.3 mmol) in tetrahydrofuran (20 mL) at room temperature. The above mixture was stirred at room temperature for 4 hours. The reaction solution was slowly poured into saturated aqueous ammonium chloride solution (100 mL) at 0°C, extracted with ethyl acetate (100 mL*3), the combined organic phases were washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate And filtered, the filtrate was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran=1/1) to obtain the desired product I-A20-4 (1.1 g, yield: 26.76%) as a light yellow oil.
LC-MS[M+1]+＝244.2LC-MS [M+1] + = 244.2
步骤六：在室温下向I-A20-4(800mg,3.28mmol)和苯酚(1.54g,16.4mmol)的1,2-二氯乙烷(10mL)溶液中加入三氟化硼乙醚溶液(2.98g,9.85mmol)。上述混合液在100℃至室温下搅拌3小时。将反应液用水淬灭(20mL)，用二氯甲烷(20mL*3)萃取，合并的有机相用饱和食盐水(60mL)洗涤，并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/四氢呋喃＝1/1)，得到所需的产物I-A20(340mg,产率：22.1％)，为黄色油状物。Step 6: Add boron trifluoride ether solution (2.98mL) to I-A20-4 (800mg, 3.28mmol) and phenol (1.54g, 16.4mmol) in 1,2-dichloroethane (10mL) solution at room temperature g, 9.85mmol). The above mixture was stirred at 100° C. to room temperature for 3 hours. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL*3), the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and subjected to column chromatography Analysis and separation (petroleum ether/tetrahydrofuran=1/1) gave the desired product I-A20 (340 mg, yield: 22.1%) as a yellow oil.
LC-MS[M+1]+＝320.3LC-MS [M+1] + = 320.3
参考I-A20的合成方法合成I-A33。

Synthesize I-A33 with reference to the synthesis method of I-A20.

中间体I-A21的合成：4-(2-(7-氯-1-(2-氯乙基)-1H-苯并[d][1,2,3]三唑-5-基)丙烷-2-基)苯酚
Synthesis of Intermediate I-A21: 4-(2-(7-Chloro-1-(2-chloroethyl)-1H-benzo[d][1,2,3]triazol-5-yl)propane -2-yl)phenol
步骤一：在0℃下，将3-氯-4-氟苯甲酸(500mg,2.86mmol)溶解于H2SO4(3mL)中，滴入HNO3(416.51mg,4.30mmol,297.50μL,纯度65％)。反应液在25℃下反应1小时后，将反应液倒入冰水中，白色固体析出，而后过滤，收集白色固体，冻干，得到产物I-A21-1(350mg,收率：50.09％)，为白色固体。Step 1: Dissolve 3-chloro-4-fluorobenzoic acid (500mg, 2.86mmol) in H 2 SO 4 (3mL) at 0°C, drop in HNO 3 (416.51mg, 4.30mmol, 297.50μL, purity 65%). After the reaction solution was reacted at 25°C for 1 hour, the reaction solution was poured into ice water, and a white solid was precipitated, then filtered, the white solid was collected, and freeze-dried to obtain the product I-A21-1 (350 mg, yield: 50.09%). It is a white solid.
LC-MS[M-1]-＝218.0LC-MS[M-1] - = 218.0
步骤二：将I-A21-1(100mg,455.47μmol)溶解在SOCl2(162.56mg,1.37mmol)中，在70℃下反应3小时，然后将反应液在0℃下滴入MeOH(10mL)中，搅拌30分钟后，浓缩得到产物I-A21-2(100mg,收率：84.60％)，为白色固体。Step 2: Dissolve I-A21-1 (100mg, 455.47μmol) in SOCl 2 (162.56mg, 1.37mmol), react at 70°C for 3 hours, then drop the reaction solution into MeOH (10mL) at 0°C , after stirring for 30 minutes, concentrated to obtain the product I-A21-2 (100 mg, yield: 84.60%) as a white solid.
LC-MS[M+1]+＝234.0LC-MS [M+1] + = 234.0
步骤三：将I-A21-2(2.1g,8.99mmol)和DIEA(1.14g,11.69mmol)溶解在DMF(20mL)中，在25℃下加入2-胺基乙醇盐酸盐(1.14g,11.69mmol)。反应液在25℃反应18小时。浓缩后，过柱(石油醚/乙酸乙酯＝3：1)纯化得到产物I-A21-3(130mg,收率：6％)，为黄色固体。 Step 3: Dissolve I-A21-2 (2.1g, 8.99mmol) and DIEA (1.14g, 11.69mmol) in DMF (20mL), add 2-aminoethanol hydrochloride (1.14g, 11.69 mmol). The reaction solution was reacted at 25° C. for 18 hours. After concentration, the product was purified by column (petroleum ether/ethyl acetate=3:1) to obtain the product I-A21-3 (130 mg, yield: 6%) as a yellow solid.
LC-MS[M+1]+＝275.1LC-MS [M+1] + = 275.1
步骤四：将I-A21-3(130mg,473.32μmol)和铁粉(132.16mg,2.37mmol)溶解在AcOH(2mL)中。反应液在40℃，反应2小时。反应液用饱和碳酸钠溶液调节pH＝8，用乙酸乙酯(30mL*3)萃取，有机相浓缩得到I-A21-4(110mg,收率：85.49％)，为黄色油状。Step 4: I-A21-3 (130 mg, 473.32 μmol) and iron powder (132.16 mg, 2.37 mmol) were dissolved in AcOH (2 mL). The reaction solution was reacted at 40° C. for 2 hours. The reaction solution was adjusted to pH=8 with saturated sodium carbonate solution, extracted with ethyl acetate (30 mL*3), and the organic phase was concentrated to obtain I-A21-4 (110 mg, yield: 85.49%) as a yellow oil.
LC-MS[M+1]+＝245.1LC-MS [M+1] + = 245.1
步骤五：将I-A21-4(90mg,367.84μmol)溶解于AcOH(2mL)中，降至0℃分批加入NaNO2(30.46mg,441.40μmol)固体，升温至25℃并反应2小时后，用饱和Na2CO3调节pH＝8，用乙酸乙酯(40mL)萃取三次，合并有机相，浓缩后过柱纯化(石油醚/乙酸乙酯＝1：1)得到I-A21-5(90.00mg，收率：90.92％)，为棕色固体。Step 5: Dissolve I-A21-4 (90 mg, 367.84 μmol) in AcOH (2 mL), drop to 0°C and add NaNO 2 (30.46 mg, 441.40 μmol) solid in batches, raise the temperature to 25°C and react for 2 hours , adjusted pH=8 with saturated Na 2 CO 3 , extracted three times with ethyl acetate (40 mL), combined the organic phases, concentrated and purified by column (petroleum ether/ethyl acetate=1:1) to obtain I-A21-5 ( 90.00 mg, yield: 90.92%), as a brown solid.
LC-MS[M+1]+＝256.1LC-MS [M+1] + = 256.1
步骤六：将I-A21-5(70mg,273.80μmol)和PPh3(86.18mg,328.56μmol)溶解在DCM(5mL)中后，在25℃下，加入NCS(43.87mg,328.56μmol)，该反应在25℃下反应3小时后，浓缩，用制备TLC(石油醚/乙酸乙酯＝4:1)纯化得到I-A21-6(56.00mg,收率：70.89％)，为白色固体。Step 6: After dissolving I-A21-5 (70mg, 273.80μmol) and PPh 3 (86.18mg, 328.56μmol) in DCM (5mL), add NCS (43.87mg, 328.56μmol) at 25°C, the After the reaction was reacted at 25°C for 3 hours, it was concentrated and purified by preparative TLC (petroleum ether/ethyl acetate=4:1) to obtain I-A21-6 (56.00 mg, yield: 70.89%) as a white solid.
LC-MS[M+1]+＝274.0LC-MS [M+1] + = 274.0
步骤七：将I-A21-6(55mg,200.65μmol)溶解于无水THF(3mL)中，在0℃下滴入MeMgBr(1M,601.96μL)，该反应液在25℃下搅拌2小时后，用饱和NH4Cl溶液(10mL)淬灭，然后用乙酸乙酯(30mL)萃取三次，合并有机相浓缩，用制备TLC(石油醚/乙酸乙酯＝3：1)纯化得到I-A21-7(50.00mg,收率：90％)，为白色固体。Step 7: Dissolve I-A21-6 (55mg, 200.65μmol) in anhydrous THF (3mL), add MeMgBr (1M, 601.96μL) dropwise at 0°C, and stir the reaction solution at 25°C for 2 hours , was quenched with saturated NH 4 Cl solution (10 mL), then extracted three times with ethyl acetate (30 mL), the combined organic phases were concentrated, and purified by preparative TLC (petroleum ether/ethyl acetate=3:1) to obtain I-A21- 7 (50.00 mg, yield: 90%), as a white solid.
LC-MS[M+1]+＝274.0LC-MS [M+1] + = 274.0
步骤八：将I-A21-7(50mg,182.38μmol)和苯酚(17.16mg,182.38μmol)溶解于无水DCM(2mL)中，加入4A分子筛(50mg)，该混合液冷却至-78℃后，加入BF3·Et2O(25.89mg,182.38μmol)。然后自然升至室温反应2小时后，浓缩，用制备TLC(石油醚/乙酸乙酯＝3：1)纯化得到中间体I-A21(25.00mg,收率：35.22％)，为白色固体。Step 8: Dissolve I-A21-7 (50mg, 182.38μmol) and phenol (17.16mg, 182.38μmol) in anhydrous DCM (2mL), add 4A molecular sieves (50mg), and cool the mixture to -78°C , BF3.Et2O (25.89 mg, 182.38 μmol) was added. After naturally rising to room temperature and reacting for 2 hours, it was concentrated and purified by preparative TLC (petroleum ether/ethyl acetate=3:1) to obtain intermediate I-A21 (25.00 mg, yield: 35.22%) as a white solid.
LC-MS[M+1]+＝350.1 LC-MS [M+1] + = 350.1
中间体I-A22的合成：4-(2-(1-(2-氯乙基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烷-2-基)苯酚
Synthesis of Intermediate I-A22: 4-(2-(1-(2-Chloroethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)propan-2-yl)phenol
步骤一：将I-A22-1(2g，12.26mmol)加入溶剂甲醇(50mL)中，室温条件下缓慢滴加H2SO4(3mL)，加完后温度升至70℃回流反应12小时。旋蒸除去大部分溶剂，反应液倒入冰水中析出淡黄色固体。过滤，将固体冻干得到中间体I-A22-2(1.63g,产率：71.29％)，为淡黄色固体。Step 1: I-A22-1 (2g, 12.26mmol) was added to the solvent methanol (50mL), and H 2 SO 4 (3mL) was slowly added dropwise at room temperature. After the addition, the temperature was raised to 70°C and refluxed for 12 hours. Most of the solvent was removed by rotary evaporation, and the reaction solution was poured into ice water to precipitate a pale yellow solid. Filtration, and lyophilization of the solid gave Intermediate I-A22-2 (1.63 g, yield: 71.29%) as a light yellow solid.
LC-MS[M+1]+＝178.10LC-MS [M+1] + = 178.10
步骤二：将I-A22-2(750mg，4.23mmol)，1-溴-2-氯乙烷(1.82g，12.7mmol)和Cs2CO3(1.17g，5.88mmol)加入N,N-二甲基甲酰胺溶剂(15mL)中，升温至80℃，搅拌反应3小时。反应液中加水淬灭，乙酸乙酯多次萃取(20mL*3)，饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除去溶剂，柱层析分离(石油醚/四氢呋喃＝3/1)得到中间体I-A22-3(711mg,产率：66.57％)，为白色固体。Step 2: Add I-A22-2 (750mg, 4.23mmol), 1-bromo-2-chloroethane (1.82g, 12.7mmol) and Cs 2 CO 3 (1.17g, 5.88mmol) into N,N-di In methylformamide solvent (15 mL), the temperature was raised to 80° C., and the reaction was stirred for 3 hours. The reaction solution was quenched with water, extracted several times with ethyl acetate (20mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and separated by column chromatography (petroleum ether/tetrahydrofuran=3/1) to obtain Intermediate I-A22-3 (711 mg, yield: 66.57%), a white solid.
LC-MS[M+1]+＝240.60LC-MS [M+1] + = 240.60
步骤三：将I-A22-3(580mg，2.24mmol)加入溶剂四氢呋喃(6mL)中，室温条件下搅拌过夜，氮气保护，冰浴条件下加入甲基溴化镁(865.72mg，7.26mmol)加完后撤去冰浴，室温条件下搅拌反应0.5小时。反应液中加0℃下的饱和氯化铵水溶液淬灭，乙酸乙酯多次萃取(20mL*3)，饱和食盐水洗涤，无水硫酸钠干燥，柱层析分离(石油醚/四氢呋喃＝1/1)得到中间体I-A22-4(430mg,产率：73.38％)，为黄色油状物。Step 3: Add I-A22-3 (580mg, 2.24mmol) into the solvent tetrahydrofuran (6mL), stir overnight at room temperature, under nitrogen protection, add methylmagnesium bromide (865.72mg, 7.26mmol) in an ice bath After the completion, the ice bath was removed, and the reaction was stirred at room temperature for 0.5 hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution at 0°C, extracted several times with ethyl acetate (20mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (petroleum ether/tetrahydrofuran=1 /1) Intermediate I-A22-4 (430 mg, yield: 73.38%) was obtained as a yellow oil.
LC-MS[M+1]+＝240.70LC-MS [M+1] + = 240.70
步骤四：将中间体I-A22-4(280mg，1.17mmol)，苯酚(549.67mg,5.84mmol) 溶在1,2-二氯乙烷(4mL)中，室温下加入氯化铝(311.52mg,2.34mmol)。将反应升温至100℃，搅拌反应3小时。LC-MS检测发现反应完全，柱层析分离(石油醚/四氢呋喃＝7/3)，得到中间体I-A22(265mg,产率：71.84％)，为淡黄色固体。Step 4: Intermediate I-A22-4 (280mg, 1.17mmol), phenol (549.67mg, 5.84mmol) Dissolve in 1,2-dichloroethane (4 mL), and add aluminum chloride (311.52 mg, 2.34 mmol) at room temperature. The reaction was warmed to 100 °C and the reaction was stirred for 3 hours. LC-MS detection showed that the reaction was complete, and separation by column chromatography (petroleum ether/tetrahydrofuran=7/3) gave intermediate I-A22 (265 mg, yield: 71.84%) as a pale yellow solid.
LC-MS[M+1]+＝316.30LC-MS [M+1] + = 316.30
中间体I-A23的合成：1-(2-氯乙基)-5-(2-(4-乙炔基苯基)丙烷-2-基)-1H-吡唑并[3,4-b]吡啶
Synthesis of Intermediate I-A23: 1-(2-Chloroethyl)-5-(2-(4-ethynylphenyl)propan-2-yl)-1H-pyrazolo[3,4-b] pyridine
步骤一：将中间体I-A22(1g,3.17mmol)和三乙胺(640.86mg,6.33mmol)加入溶剂二氯甲烷(13mL)中，0℃条件下滴加Tf2O(1.07g,3.80mmol)，加完后继续搅拌1小时。LC-MS检测发现反应完全，旋蒸除溶剂，柱层析分离(石油醚/四氢呋喃＝3/1)得到中间体I-A23-1(900mg,产率：60.29％)，为淡黄色油状物。Step 1: Intermediate I-A22 (1g, 3.17mmol) and triethylamine (640.86mg, 6.33mmol) were added to the solvent dichloromethane (13mL), and Tf 2 O (1.07g, 3.80 mmol), and continued to stir for 1 hour after the addition. LC-MS detection found that the reaction was complete, the solvent was removed by rotary evaporation, and column chromatography separation (petroleum ether/tetrahydrofuran = 3/1) gave intermediate I-A23-1 (900 mg, yield: 60.29%) as a light yellow oil .
1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.14(s,1H),8.13(s,1H),7.39(s,4H),4.71(s,2H),4.08(s,2H),1.73(s,6H). 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.14(s,1H),8.13(s,1H),7.39(s,4H),4.71(s,2H),4.08(s ,2H),1.73(s,6H).
LC-MS[M+1]+＝448.1LC-MS [M+1] + = 448.1
步骤二：将中间体I-A23-1(150mg,334.93μmol)溶于溶剂乙腈(5mL)中，加入三乙基硅乙炔(140.97mg,1.00mmol)，DIEA(216.43mg,1.67mmol)，t-Buxphos Pd G3(26.61mg,33.49μmol)和100mg 4A分子筛，80℃微波反应1小时。LC-MS检测发现反应完全，旋蒸除溶剂，柱层析分离(石油醚/乙酸乙酯＝15/1)，得到中间体I-A23-2(110mg,产率：69.72％)，为黄色油状物。Step 2: Dissolve the intermediate I-A23-1 (150mg, 334.93μmol) in the solvent acetonitrile (5mL), add triethylsilylacetylene (140.97mg, 1.00mmol), DIEA (216.43mg, 1.67mmol), t -Buxphos Pd G3 (26.61mg, 33.49μmol) and 100mg 4A molecular sieves were reacted in microwave at 80°C for 1 hour. LC-MS detection found that the reaction was complete, and the solvent was removed by rotary evaporation, and separated by column chromatography (petroleum ether/ethyl acetate=15/1) to obtain intermediate I-A23-2 (110mg, yield: 69.72%), which was yellow Oil.
LC-MS[M+1]+＝438.4LC-MS [M+1] + = 438.4
步骤三：将中间体I-A23-2(0.1g,228.27μmol)和KF(132.62mg,2.28mmol)加入溶剂甲醇(8mL)中，45℃下搅拌反应12小时。LC-MS检测发现反应完全，旋蒸除 溶剂，柱层析分离(石油醚/乙酸乙酯＝5/1)得到中间体I-A23(60mg,产率：70.62％)，为淡黄色油状物。Step 3: Add intermediate I-A23-2 (0.1 g, 228.27 μmol) and KF (132.62 mg, 2.28 mmol) into solvent methanol (8 mL), and stir at 45° C. for 12 hours. LC-MS detection found that the reaction was complete, and the rotary evaporation removed The solvent was separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain intermediate I-A23 (60 mg, yield: 70.62%) as a pale yellow oil.
1H-NMR(400MHz,DMSO-D6)δ8.34(d,J＝2.2Hz,1H),8.15(t,J＝2.5Hz,2H),7.41(dd,J＝6.5,1.8Hz,2H),7.27(dd,J＝6.6,2.2Hz,2H),4.75(t,J＝5.9Hz,2H),4.13-4.10(m,2H),2.21(s,1H),1.74(s,6H) 1 H-NMR (400MHz, DMSO-D6) δ8.34 (d, J = 2.2Hz, 1H), 8.15 (t, J = 2.5Hz, 2H), 7.41 (dd, J = 6.5, 1.8Hz, 2H) ,7.27(dd,J=6.6,2.2Hz,2H),4.75(t,J=5.9Hz,2H),4.13-4.10(m,2H),2.21(s,1H),1.74(s,6H)
LC-MS[M+1]+＝324.30LC-MS [M+1] + = 324.30
按照上面的中间体I-A23合成方法合成A59。
A59 was synthesized according to the synthesis method of intermediate I-A23 above.
中间体I-A24的合成：2-(2-氯乙氧基)-3-氟-5-(2-(4-羟基苯基)丙烷-2-基)苯甲腈
Synthesis of Intermediate I-A24: 2-(2-Chloroethoxy)-3-fluoro-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile
步骤一：将I-A24-1(4g,23.51mmol)溶解在乙腈(60mL)中，在25℃下搅拌5分钟后，在25℃下加入NIS(10.58g,47.02mmol)。反应液在25℃下反应4小时。将反应液旋干，用乙酸乙酯萃取(300mL*2)，合并有机相，用饱和食盐水清洗(300mL*2)，有机相用无水硫酸钠干燥后浓缩。浓缩后的进行柱层析分离(石油醚/乙酸乙酯＝10/1)，得到所需的产物I-A24-2(6.40g,产率：82.76％)，为淡橙色固体。Step 1: Dissolve I-A24-1 (4g, 23.51mmol) in acetonitrile (60mL), stir at 25°C for 5 minutes, then add NIS (10.58g, 47.02mmol) at 25°C. The reaction solution was reacted at 25° C. for 4 hours. The reaction solution was spin-dried, extracted with ethyl acetate (300 mL*2), combined the organic phases, washed with saturated brine (300 mL*2), dried over anhydrous sodium sulfate and concentrated. The concentrated product was separated by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the desired product I-A24-2 (6.40 g, yield: 82.76%) as a light orange solid.
LC-MS[M+1]+＝297.00 LC-MS [M+1] + = 297.00
步骤二：室温下将I-A24-2(6.4g,21.62mmol)和1,2-二氯乙烷(12.40g,86.48mmol)溶解于DMF(80mL)中，然后加碳酸铯(14.05g,43.24mmol)。混合物在70℃下搅拌3小时，TLC检测反应完全。反应混合投入到水中后并用乙酸乙酯(100mL*3)萃取。有机相用饱和食盐水(100mL*3)洗，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝10/1)，得到所需的产物I-A24-3(7.0g,产率：81.28％)，为无色油状。Step 2: Dissolve I-A24-2 (6.4g, 21.62mmol) and 1,2-dichloroethane (12.40g, 86.48mmol) in DMF (80mL) at room temperature, then add cesium carbonate (14.05g, 43.24 mmol). The mixture was stirred at 70°C for 3 hours, and the reaction was complete by TLC. The reaction mixture was poured into water and extracted with ethyl acetate (100 mL*3). The organic phase was washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the desired product I-A24-3 (7.0 g, yield: 81.28%) as a colorless oil.
LC-MS[M+1]+＝359.00LC-MS[M+1]+=359.00
步骤三：将I-A24-3(1.0g,3.29mmol)溶解于NMP(10mL)中，加入CuCN(522.13mg,5.58mmol)，在160℃下，在氮气保护下搅拌反应1小时。LCMS检测反应完全。反应混合物用氯化铵水溶液(20mL，23％)淬灭后，用乙酸乙酯(50mL*3)萃取。有机相用饱和食盐水(20mL)洗并用无水硫酸钠干燥。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A24-4(700mg,产率：97.41％)，为白色固体。Step 3: Dissolve I-A24-3 (1.0 g, 3.29 mmol) in NMP (10 mL), add CuCN (522.13 mg, 5.58 mmol), and stir the reaction at 160°C for 1 hour under nitrogen protection. LCMS detected that the reaction was complete. After the reaction mixture was quenched with aqueous ammonium chloride (20 mL, 23%), it was extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A24-4 (700 mg, yield: 97.41%) as a white solid.
LC-MS[M+1]+＝258.00LC-MS[M+1]+=258.00
步骤四：在室温下向I-A24-4(700mg,2.72mmol)的四氢呋喃(20mL)溶液中滴加甲基溴化镁(10mL,10.87mmol,1M in THF)。上述混合液在室温下搅拌15分钟。TLC(石油醚/乙酸乙酯＝5/1))检测反应完全。将反应液缓慢倒入0℃下的饱和氯化铵水溶液(100mL)中，用乙酸乙酯(30mL*3)萃取，合并的有机相用食盐水(50mL)洗涤，并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物I-A24-5(560mg,产率：71.99％)，为无色油状液体。Step 4: Add methylmagnesium bromide (10 mL, 10.87 mmol, 1M in THF) dropwise to a solution of I-A24-4 (700 mg, 2.72 mmol) in tetrahydrofuran (20 mL) at room temperature. The above mixture was stirred at room temperature for 15 minutes. TLC (petroleum ether/ethyl acetate=5/1)) detected that the reaction was complete. The reaction solution was slowly poured into saturated aqueous ammonium chloride solution (100 mL) at 0° C., extracted with ethyl acetate (30 mL*3), and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate and After filtration, the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product I-A24-5 (560 mg, yield: 71.99%) as a colorless oily liquid.
步骤五：在-78℃下向I-A24-5(560mg,2.17mmol)和苯酚(409.04mg,4.35mmol)的二氯甲烷(10mL)溶液中加入三氟化硼乙醚溶液(294.73mg,4.35mmol)。上述混合液在-78℃～室温下搅拌2小时。TLC检测反应完全。将反应液用水淬灭(20mL)中，用二氯甲烷(20mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝1/1)，得到所需的产物I-A24(580mg,产率：71.96％)，为无色油状物。Step 5: Add boron trifluoride diethyl ether solution (294.73mg, 4.35 mmol). The above mixture was stirred at -78°C to room temperature for 2 hours. TLC detects that the reaction is complete. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL*3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and subjected to column Chromatographic separation (petroleum ether/ethyl acetate=1/1) gave the desired product I-A24 (580 mg, yield: 71.96%) as a colorless oil.
LC-MS[M+1]+＝334.10 LC-MS[M+1]+=334.10
中间体I-A25的合成：1-(2-氯乙烷)-5-(2-(4-羟基苯基)丙烷-2-基)-1H-苯并[d][1,2,3]三唑-7-氰基
Synthesis of Intermediate I-A25: 1-(2-Chloroethane)-5-(2-(4-hydroxyphenyl)propan-2-yl)-1H-benzo[d][1,2,3 ]triazole-7-cyano
步骤一：在0℃下将I-A25-1(1g,5.02mmol)溶解于H2SO4(5mL)中，加入NBSStep 1: Dissolve I-A25-1 (1g, 5.02mmol) in H 2 SO 4 (5mL) at 0°C, add NBS
(893.78mg,5.02mmol)后，在60℃下，搅拌1.5小时后，TLC检测原料全部转化，将反应液倒入冰水(40mL)中，用乙酸乙酯(40mL)萃取两次，合并有机相浓缩得到中间体I-A25-2(1.50g,粗品)，为白色固体。(893.78mg, 5.02mmol), at 60 °C, after stirring for 1.5 hours, TLC detected that the raw materials were completely converted, the reaction solution was poured into ice water (40mL), extracted twice with ethyl acetate (40mL), and the combined organic Phase concentration afforded Intermediate I-A25-2 (1.50 g, crude) as a white solid.
1H NMR(400MHz,DMSO-d6)δ8.55-8.52(m,2H),3.92(s,3H)。LC-MS[M+1]+＝278.1 1 H NMR (400 MHz, DMSO-d6) δ 8.55-8.52 (m, 2H), 3.92 (s, 3H). LC-MS [M+1] + = 278.1
步骤二：将I-A25-2(350mg,1.26mmol)溶解于DMF(3mL)中，加入DIEA(488.09mg,3.78mmol)和2-胺乙醇(92.27mg,1.51mmol)后，在30℃下，搅拌2小时后，浓缩，通过柱层析(石油醚/乙酸乙酯＝1/1)纯化得到中间体I-A25-3(330.00mg,收率：80.51％)，为黄色液体。Step 2: Dissolve I-A25-2 (350mg, 1.26mmol) in DMF (3mL), add DIEA (488.09mg, 3.78mmol) and 2-aminoethanol (92.27mg, 1.51mmol), at 30°C , stirred for 2 hours, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain intermediate I-A25-3 (330.00 mg, yield: 80.51%) as a yellow liquid.
1H NMR(400MHz,Chloroform-d)δ8.51(d,J＝2.0Hz,1H),8.29(d,J＝2.0Hz,1H),8.67(s,1H),3.90(s,3H),3.87-3.83(m,2H),3.50-3.46(m,2H)。 1 H NMR (400MHz, Chloroform-d) δ8.51(d, J=2.0Hz, 1H), 8.29(d, J=2.0Hz, 1H), 8.67(s, 1H), 3.90(s, 3H), 3.87-3.83 (m, 2H), 3.50-3.46 (m, 2H).
LC-MS[M+1]+＝319.1LC-MS [M+1] + = 319.1
步骤三：将I-A25-3(330mg,1.03mmol)和铁粉(288.76mg,5.17mmol)溶解于AcOH(5mL)中，在40℃下，搅拌3小时，浓缩，用饱和NaHCO3(20mL)调节pH＝8，用乙酸乙酯(40mL)萃取三次，合并有机相后浓缩得到中间体I-A25-4 (270.00mg,收率：90.30％)，为无色油状。Step 3: Dissolve I-A25-3 (330mg, 1.03mmol) and iron powder (288.76mg, 5.17mmol) in AcOH (5mL), stir at 40°C for 3 hours, concentrate, and wash with saturated NaHCO 3 (20mL ) was adjusted to pH=8, extracted three times with ethyl acetate (40mL), and the combined organic phases were concentrated to obtain intermediate I-A25-4 (270.00mg, yield: 90.30%), as a colorless oil.
LC-MS[M+1]+＝289.1LC-MS [M+1] + = 289.1
步骤四：将I-A25-4(270mg,933.85μmol)溶解于AcOH(10mL)中，降温至0℃，分批加入NaNO2(77.32mg,1.12mmol)固体，升温至30℃，反应2小时后，浓缩除去大部分AcOH后，用饱和Na2CO3调节pH＝8，用乙酸乙酯(40mL)萃取三次，合并有机相，浓缩后得到中间体I-A25-5(230.00mg,粗品)，为黑色固体。Step 4: Dissolve I-A25-4 (270mg, 933.85μmol) in AcOH (10mL), cool down to 0°C, add NaNO 2 (77.32mg, 1.12mmol) solid in batches, raise the temperature to 30°C, and react for 2 hours Afterwards, after concentrating to remove most of AcOH, adjust the pH=8 with saturated Na 2 CO 3 , extract three times with ethyl acetate (40 mL), combine the organic phases, and concentrate to obtain intermediate I-A25-5 (230.00 mg, crude product) , is a black solid.
1H NMR(400MHz,Chloroform-d)δ9.00(d,J＝1.6Hz,1H),8.56(d,J＝1.6Hz,1H),5.10(t,J＝5.2Hz,1H),4.27-4.26(m,2H),4.02(s,3H),2.22(s,1H) 1 H NMR (400MHz, Chloroform-d) δ9.00(d, J=1.6Hz, 1H), 8.56(d, J=1.6Hz, 1H), 5.10(t, J=5.2Hz, 1H), 4.27- 4.26(m,2H),4.02(s,3H),2.22(s,1H)
LC-MS[M+1]+＝300.1LC-MS [M+1] + = 300.1
步骤五：将I-A25-5(230mg,766.39μmol)和K2CO3(211.52mg,1.53mmol)溶解于DMF(2mL)中，分别加入Zn(CN)2(179.99mg,1.53mmol)和Pd(PPh3)4(132.89mg,114.96μmol)后，在120℃下，微波反应1小时。浓缩除去DMF后，通过柱层析(石油醚/乙酸乙酯＝2/1)纯化得到中间体I-A25-6(100.00mg,收率：47.69％)，为淡黄色固体。Step 5: Dissolve I-A25-5 (230mg, 766.39μmol) and K 2 CO 3 (211.52mg, 1.53mmol) in DMF (2mL), add Zn(CN) 2 (179.99mg, 1.53mmol) and After Pd(PPh 3 ) 4 (132.89mg, 114.96μmol), microwave reaction was carried out at 120°C for 1 hour. After concentration to remove DMF, the intermediate I-A25-6 (100.00 mg, yield: 47.69%) was purified by column chromatography (petroleum ether/ethyl acetate=2/1) as a pale yellow solid.
LC-MS[M+1]+＝247.1LC-MS [M+1] + = 247.1
步骤六：将I-A25-6(70mg,284.30μmol)和PPh3(89.48mg,341.16μmol)溶解在DCM(3mL)中后，在0℃下，加入NCS(45.56mg,341.16μmol)，该反应在30℃下反应1小时后，浓缩，用柱层析(石油醚/乙酸乙酯＝4/1)纯化得到中间体I-A25-7(70.00mg,收率：83.73％)，为白色固体。Step 6: After dissolving I-A25-6 (70mg, 284.30μmol) and PPh 3 (89.48mg, 341.16μmol) in DCM (3mL), add NCS (45.56mg, 341.16μmol) at 0°C, the After the reaction was reacted at 30°C for 1 hour, it was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=4/1) to obtain intermediate I-A25-7 (70.00 mg, yield: 83.73%) as white solid.
LC-MS[M+1]+＝265.1LC-MS [M+1] + = 265.1
步骤七：将I-A25-7(40mg,151.13μmol)溶解于THF(0.5mL)中，在0℃下，加入MeMgBr(1M,453.40μL)后，搅拌30分钟后，TLC检测原料全部转化，用饱和NH4Cl(10mL)淬灭，而后用乙酸乙酯(30mL)萃取三次，合并有机相浓缩得到中间体I-A25-8(40.00mg,粗品)，为黄色固体。Step 7: Dissolve I-A25-7 (40mg, 151.13μmol) in THF (0.5mL), add MeMgBr (1M, 453.40μL) at 0°C, and stir for 30 minutes. TLC detects that all raw materials have been converted. Quenched with saturated NH 4 Cl (10 mL), then extracted three times with ethyl acetate (30 mL), the combined organic phases were concentrated to give Intermediate I-A25-8 (40.00 mg, crude product) as a yellow solid.
LC-MS[M+1]+＝265.1LC-MS [M+1] + = 265.1
步骤八：将I-A25-8(70mg,264.44μmol)和苯酚(74.66mg,793.32μmol)溶解于DCE(1mL)中，在-78℃下加入BF3·Et2O(112.59mg,793.32μmol)后，在45℃下搅拌1小时后，浓缩后，通过制备TLC(石油醚/乙酸乙酯＝3/1)纯化得到产物I-A25 (25.0mg,收率：27.74％)，为无色油状。Step 8: Dissolve I-A25-8 (70mg, 264.44μmol) and phenol (74.66mg, 793.32μmol) in DCE (1mL), add BF 3 ·Et 2 O (112.59mg, 793.32μmol) at -78°C ), stirred at 45° C. for 1 hour, concentrated, and purified by preparative TLC (petroleum ether/ethyl acetate=3/1) to obtain the product I-A25 (25.0 mg, yield: 27.74%), as a colorless oil.
LC-MS[M+1]+＝341.1LC-MS [M+1] + = 341.1
按照上面的中间体I-A2合成方法从中间体I-A25经过三步合成中间体I-A26；按照I-A25的合成方法合成A38和A52。
Intermediate I-A26 was synthesized from intermediate I-A25 in three steps according to the synthesis method of intermediate I-A2 above; A38 and A52 were synthesized according to the synthesis method of I-A25.
中间体I-A27的合成：1-(2-氯乙基)-5-(2-(4-羟基苯基)丙烷-2-基)-1H-苯并[d]咪唑-7-氰基
Synthesis of Intermediate I-A27: 1-(2-Chloroethyl)-5-(2-(4-hydroxyphenyl)propan-2-yl)-1H-benzo[d]imidazole-7-cyano
步骤一：在0℃下，将I-A27-1(21g,105.46mmol)加入到H2SO4(100mL)中溶解，分批加入NBS(26.28g,147.64mmol)，将温度升至60℃反应1小时，将反应液滴加到0℃下搅拌的H2O(400mL)中淬灭，加入乙酸乙酯(400mL)萃取，有机相干燥浓缩，得到I-A27-2(31.63g,粗品)，为白色固体。Step 1: Dissolve I-A27-1 (21g, 105.46mmol) in H 2 SO 4 (100mL) at 0°C, add NBS (26.28g, 147.64mmol) in batches, and raise the temperature to 60°C After reacting for 1 hour, the reaction solution was added dropwise to H 2 O (400 mL) stirred at 0° C. to quench, added ethyl acetate (400 mL) for extraction, and the organic phase was dried and concentrated to obtain I-A27-2 (31.63 g, crude ), as a white solid.
MS(ESI)m/z＝278.0/279.9[M+H]+ MS(ESI)m/z=278.0/279.9[M+H] +
步骤二：在0℃下，将I-A27-2(31.63g,113.76mmol)加入到DMF(31mL)中，在搅拌下分批加入DIPEA(44.11g,341.28mmol)和2-氨基乙醇(9.03g,147.89mmol)，升至30℃后反应2小时，加入H2O(50mL),乙酸乙酯(100mL)萃取有机相，水相再用乙酸乙酯(50mL)萃取两次，合并有机相干燥浓缩得到I-A27-3(29.62g,粗品)，为黄色固体。Step 2: Add I-A27-2 (31.63g, 113.76mmol) into DMF (31mL) at 0°C, add DIPEA (44.11g, 341.28mmol) and 2-aminoethanol (9.03 g, 147.89mmol), raised to 30°C and reacted for 2 hours, added H 2 O (50mL), extracted the organic phase with ethyl acetate (100mL), extracted the aqueous phase twice with ethyl acetate (50mL), combined the organic phase Drying and concentration afforded I-A27-3 (29.62 g, crude) as a yellow solid.
MS(ESI)m/z＝319.1/321.1[M+H]+ MS(ESI)m/z＝319.1/321.1[M+H] +
步骤三：将I-A27-3(10g,31.34mmol)加入到AcOH(100mL)中搅拌溶解，分批加入铁粉(8.75g,156.69mmol)，将温度升高至40℃，继续反应2小时。反应用饱和NaHCO3(400mL)调节pH为8，用乙酸乙酯(100mL)萃取两次，合并有机相干燥浓缩。通过柱层析(石油醚：四氢呋喃＝2：1)纯化得到I-A27-4(5.17g,17.03mmol,收率：54.33％)，为黄色固体。Step 3: Add I-A27-3 (10g, 31.34mmol) into AcOH (100mL) and stir to dissolve, add iron powder (8.75g, 156.69mmol) in batches, raise the temperature to 40°C, and continue the reaction for 2 hours . The reaction was adjusted to pH 8 with saturated NaHCO 3 (400 mL), extracted twice with ethyl acetate (100 mL), and the combined organic phases were dried and concentrated. Purification by column chromatography (petroleum ether: tetrahydrofuran = 2: 1) gave I-A27-4 (5.17 g, 17.03 mmol, yield: 54.33%) as a yellow solid.
1H-NMR(400MHz,CDCl3)δ7.56(d,J＝1.9Hz,1H),7.23(d,J＝1.6Hz,1H),4.08-3.98(m,2H),3.80(s,3H),3.70-3.66(m,2H),3.16(t,J＝4.8Hz,2H),0.02--0.08(m,2H) 1 H-NMR (400MHz, CDCl 3 ) δ7.56(d, J=1.9Hz, 1H), 7.23(d, J=1.6Hz, 1H), 4.08-3.98(m, 2H), 3.80(s, 3H ),3.70-3.66(m,2H),3.16(t,J＝4.8Hz,2H),0.02--0.08(m,2H)
MS(ESI)m/z＝289.1/291.1[M+H]+ MS(ESI)m/z＝289.1/291.1[M+H] +
步骤四：将I-A27-4(4.7g,16.26mmol)和对甲苯磺酸一水复合物(773.04mg,4.06mmol)溶解于CH(OMe)3(80mL)中，在60℃下，搅拌3小时后，加入1M HCl(100mL)后，用乙酸乙酯(100mL)萃取1次；水相用饱和NaHCO3调节pH～8后，用乙酸乙酯(100mL)萃取3次，合并有机相后浓缩得到I-A27-5(4.50g,13.54mmol,83.29％yield)，为白色固体。Step 4: Dissolve I-A27-4 (4.7g, 16.26mmol) and p-toluenesulfonic acid monohydrate complex (773.04mg, 4.06mmol) in CH(OMe) 3 (80mL), stir at 60°C After 3 hours, after adding 1M HCl (100mL), extract once with ethyl acetate (100mL); adjust the pH to 8 with saturated NaHCO 3 for the aqueous phase, extract three times with ethyl acetate (100mL), combine the organic phases Concentration gave I-A27-5 (4.50 g, 13.54 mmol, 83.29% yield) as a white solid.
1H-NMR(400MHz,CDCl3):δ7.83-7.76(m,3H),4.58(t,J＝4.7Hz,2H),4.09-4.02(m,2H),3.89(s,3H) 1 H-NMR (400MHz, CDCl 3 ): δ7.83-7.76(m, 3H), 4.58(t, J=4.7Hz, 2H), 4.09-4.02(m, 2H), 3.89(s, 3H)
MS(ESI)m/z＝299.0/301.0[M+H]+ MS(ESI)m/z＝299.0/301.0[M+H] +
步骤五：将I-A27-5(1.0g,3.34mmol)和K2CO3(922.71mg,6.69mmol)溶解于DMF(10mL)中，分别加入氰化锌(785.13mg,6.69mmol)和Pd(PPh3)4(386.47mg,334.31μmol)后，在120℃下，微波反应1小时。将反应液浓缩后，通过柱层析(石油醚：乙酸乙酯＝3：1)纯化得到I-A27-6(650.00mg,2.39mmol,收率：71.35％)，为白色固体。Step 5: Dissolve I-A27-5 (1.0g, 3.34mmol) and K 2 CO 3 (922.71mg, 6.69mmol) in DMF (10mL), and add zinc cyanide (785.13mg, 6.69mmol) and Pd respectively After (PPh 3 ) 4 (386.47mg, 334.31μmol), microwave reaction was carried out at 120°C for 1 hour. After the reaction solution was concentrated, it was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain I-A27-6 (650.00 mg, 2.39 mmol, yield: 71.35%) as a white solid.
MS(ESI)m/z＝246.1[M+H]+ MS(ESI)m/z=246.1[M+H] +
步骤六：将I-A27-6(100mg,407.77μmol)和PPh3(128.34mg,489.33μmol)溶解在DCM(3mL)中后，在0℃下，加入NCS(65.34mg,489.33μmol)，该反应在30℃下反应1小时后，将反应液浓缩后，通过制备TLC(石油醚：乙酸乙酯＝1：1)纯化得到I-A27-7(150.00mg,227.55μmol,收率：55.80％)，为白色固体。Step 6: After dissolving I-A27-6 (100mg, 407.77μmol) and PPh 3 (128.34mg, 489.33μmol) in DCM (3mL), add NCS (65.34mg, 489.33μmol) at 0°C, the After reacting at 30°C for 1 hour, the reaction solution was concentrated and purified by preparative TLC (petroleum ether: ethyl acetate = 1:1) to obtain I-A27-7 (150.00mg, 227.55μmol, yield: 55.80% ), as a white solid.
1H-NMR(400MHz,CDCl3):δ8.69-8.78(1H),8.35-8.46(1H),8.12-8.22(1H),4.80-4.96(2H),3.93-4.04(5H) 1 H-NMR (400MHz, CDCl 3 ): δ8.69-8.78(1H), 8.35-8.46(1H), 8.12-8.22(1H), 4.80-4.96(2H), 3.93-4.04(5H)
MS(ESI)m/z＝264.1[M+H]+ MS(ESI)m/z=264.1[M+H] +
步骤七：将I-A27-7(4g,15.17mmol)溶解于THF(40mL)中，在0℃下，加入MeMgBr(1M,45.51mL)后，搅拌30分钟后，TLC检测原料全部转化，用饱和NH4Cl(50mL)淬灭，而后用乙酸乙酯(30mL)萃取三次，合并有机相浓缩后，通过柱层析(石油醚：乙酸乙酯＝1：1)纯化得到I-A27-8(1.84g,6.28mmol,收率：41.39％)，为黄色油状。Step 7: Dissolve I-A27-7 (4g, 15.17mmol) in THF (40mL), add MeMgBr (1M, 45.51mL) at 0°C, stir for 30 minutes, TLC detects that all raw materials have been converted, and use Quenched with saturated NH 4 Cl (50 mL), then extracted three times with ethyl acetate (30 mL), the combined organic phases were concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain I-A27-8 (1.84g, 6.28mmol, yield: 41.39%), as a yellow oil.
1H-NMR(400MHz,CDCl3)δ8.17(d,J＝1.6Hz,1H),8.05(s,1H),7.87(d,J＝1.6 Hz,1H),4.81(t,J＝5.5Hz,2H),3.97(t,J＝5.4Hz,2H),1.66(s,6H),-0.00(s,1H) 1 H-NMR (400MHz, CDCl 3 ) δ8.17(d, J=1.6Hz, 1H), 8.05(s, 1H), 7.87(d, J=1.6 Hz, 1H), 4.81(t, J=5.5Hz, 2H), 3.97(t, J=5.4Hz, 2H), 1.66(s, 6H), -0.00(s, 1H)
MS(ESI)m/z＝264.1[M+H]+ MS(ESI)m/z=264.1[M+H] +
步骤八：将苯酚(107.06mg,1.14mmol)和I-A27-8(100mg,379.19μmol)溶解于DCM(3mL)中，氮气保护下滴加BF3·Et2O(161.45mg,1.14mmol)，滴加完毕后升温至40℃搅拌5小时，TLC检测反应完毕，冷却至室温，加入甲醇(10mL)淬灭反应，反应液浓缩至干，残余物过柱纯化(HPLC，乙腈/水＝0到100％)得到I-A27(90.00mg,254.25μmol,收率：67.05％)，为白色固体。Step 8: Dissolve phenol (107.06mg, 1.14mmol) and I-A27-8 (100mg, 379.19μmol) in DCM (3mL), add BF 3 · Et 2 O (161.45mg, 1.14mmol) dropwise under nitrogen protection , after the completion of the dropwise addition, the temperature was raised to 40°C and stirred for 5 hours, TLC detected that the reaction was complete, cooled to room temperature, added methanol (10mL) to quench the reaction, the reaction solution was concentrated to dryness, and the residue was purified by column (HPLC, acetonitrile/water=0 to 100%) to give I-A27 (90.00 mg, 254.25 μmol, yield: 67.05%) as a white solid.
1H-NMR(400MHz,MeOD):δ8.35(s,1H),7.87(d,J＝1.6Hz,1H),7.56-7.54(m,1H),7.07(dd,J＝6.6,2.2Hz,2H),6.71(dd,J＝6.9,2.2Hz,2H),4.86(s,-2H),4.04(t,J＝5.6Hz,2H),3.31-3.30(m,10H),1.72(s,6H) 1 H-NMR (400MHz, MeOD): δ8.35(s, 1H), 7.87(d, J=1.6Hz, 1H), 7.56-7.54(m, 1H), 7.07(dd, J=6.6, 2.2Hz ,2H),6.71(dd,J=6.9,2.2Hz,2H),4.86(s,-2H),4.04(t,J=5.6Hz,2H),3.31-3.30(m,10H),1.72(s ,6H)
MS(ESI)m/z＝340.2[M+H]+ MS(ESI)m/z=340.2[M+H] +
按照中间体I-A2合成方法，分别从中间体I-A27经过三步合成中间体I-A28；从中间体I-A19经过三步合成中间体I-A29；从中间体I-A19-5经过三步合成中间体I-A30；参考中间体I-A11的合成方法合成中间体I-A31。参照中间体I-A2从中间体I-A31经过三步合成I-A32。

According to the synthesis method of intermediate I-A2, intermediate I-A28 was synthesized from intermediate I-A27 in three steps; intermediate I-A29 was synthesized in three steps from intermediate I-A19; intermediate I-A19-5 was synthesized in three steps Intermediate I-A30 was synthesized through three steps; intermediate I-A31 was synthesized with reference to the synthesis method of intermediate I-A11. I-A32 was synthesized from intermediate I-A31 in three steps with reference to intermediate I-A2.

中间体A6的合成：3-氯-5-(2-(4-乙炔基苯基)丙烷-2-基)-2-甲氧基苯腈
Synthesis of Intermediate A6: 3-Chloro-5-(2-(4-ethynylphenyl)propan-2-yl)-2-methoxybenzonitrile
合成步骤参考中间体I-A1和I-A2的合成方法，用碘甲烷代替I-A1-3，进行七步反应得到中间体A6。Synthetic steps Refer to the synthetic method of intermediates I-A1 and I-A2, replace I-A1-3 with methyl iodide, and carry out seven-step reaction to obtain intermediate A6.
LC-MS[M+18]+＝310.1LC-MS [M+18] + = 310.1
中间体A8的合成：2-氯-3-(2-氯乙氧基)-6-(2-(4-乙炔苯基)丙烷-2-基)异烟腈
Synthesis of Intermediate A8: 2-Chloro-3-(2-chloroethoxy)-6-(2-(4-ethynylphenyl)propan-2-yl)isonicotinonitrile
步骤一：将原料A8-1(5g,19.5mmol)溶解在N,N-二甲基甲酰胺(50mL)，在溶液中加入在Zn(CN)2(1.35g,11.7mmol)，Pd(PPh3)4(1.8g,1.56mmol)。上述混合物在氮气保护下在100℃下搅拌反应16小时，TLC检测发现反应完全。将反应混合物投入到水中(100mL)，用乙酸乙酯萃取(100mL*2)，合并有机相，用饱和食盐水清洗(150mL*2)，有机相用无水硫酸钠干燥后浓缩。浓缩后的混合物经柱层析后得到产物A8-2(1.6g,产率：53.3％)，为黄色固体。Step 1: Dissolve raw material A8-1 (5g, 19.5mmol) in N,N-dimethylformamide (50mL), add Zn(CN) 2 (1.35g, 11.7mmol), Pd(PPh 3 ) 4 (1.8 g, 1.56 mmol). The above mixture was stirred and reacted at 100° C. for 16 hours under the protection of nitrogen, and the reaction was found to be complete by TLC detection. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine (150 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was subjected to column chromatography to obtain the product A8-2 (1.6 g, yield: 53.3%) as a yellow solid.
LC-MS[M+1]+＝155.0LC-MS [M+1] + = 155.0
步骤二：室温下，将A8-2(1.6g,10.3mmol)和溶解于氯化氢甲醇溶液中(4M,26ml,104mmol)中，混合物在80℃下搅拌20小时，LC-MS检测反应完全。反应液使用硅胶过滤，滤液浓缩后得到黄色固体。黄色固体使用热的1,4-二氧六环溶解(100mL,65℃),在溶液中加入热的正己烷(100mL),溶液缓慢冷却到室温，混合物过滤。固体使用正己烷冲洗，收集过滤后的固体真空干燥后的到产物A8-3(1.7g,产率：88.1％)为黄色固体。Step 2: At room temperature, A8-2 (1.6g, 10.3mmol) was dissolved in methanolic hydrogen chloride solution (4M, 26ml, 104mmol), and the mixture was stirred at 80°C for 20 hours. LC-MS detected that the reaction was complete. The reaction solution was filtered using silica gel, and the filtrate was concentrated to obtain a yellow solid. The yellow solid was dissolved in hot 1,4-dioxane (100 mL, 65° C.), hot n-hexane (100 mL) was added to the solution, the solution was slowly cooled to room temperature, and the mixture was filtered. The solid was rinsed with n-hexane, and the filtered solid was collected and vacuum-dried to obtain the product A8-3 (1.7 g, yield: 88.1%) as a yellow solid.
LC-MS[M+1]+＝188.0LC-MS [M+1] + = 188.0
步骤三：将原料A8-3(1.7g,9.1mmol)溶解在N,N-二甲基甲酰胺(20mL)，加入NIS(3.07g,13.65mmol)。上述混合物在100℃反应下16小时，LC-MS检测 发现反应完全。将反应混合物投入到水中(100mL)，用乙酸乙酯萃取(50mL*2)，合并有机相，用饱和食盐水清洗(100mL*2)，有机相用无水硫酸钠干燥后浓缩。浓缩后得到粗产物A8-4(3.9g)，为红棕色固体。Step 3: Dissolve raw material A8-3 (1.7 g, 9.1 mmol) in N,N-dimethylformamide (20 mL), and add NIS (3.07 g, 13.65 mmol). The above mixture was reacted at 100°C for 16 hours, detected by LC-MS The reaction was found to be complete. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (100 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product A8-4 (3.9 g) was obtained after concentration as a reddish-brown solid.
LC-MS[M+1]+＝313.9LC-MS [M+1] + = 313.9
步骤四：室温下将A8-4(3.9,12.5mmol)和1-溴-2-氯乙烷(8.9g,62.5mmol)溶解于N,N-二甲基甲酰胺(40mL)中，然后加碳酸铯(8g,25mmol)。混合物在70℃下搅拌16小时，TLC检测反应完全。反应混合投入到水中(50ml)后并用乙酸乙酯(50mL*3)萃取。有机相用饱和食盐水(100mL)洗并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物A8-5(1.6g,产率：47％)，为黄色固体。Step 4: Dissolve A8-4 (3.9, 12.5mmol) and 1-bromo-2-chloroethane (8.9g, 62.5mmol) in N,N-dimethylformamide (40mL) at room temperature, then add Cesium carbonate (8g, 25mmol). The mixture was stirred at 70°C for 16 hours, and the reaction was complete by TLC. The reaction mixture was poured into water (50ml) and extracted with ethyl acetate (50mL*3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product A8-5 (1.6 g, yield: 47%) as a yellow solid.
步骤五：将化合物A8-5(1.6g,4.3mmol)溶解于N-甲基吡咯烷酮(20mL)中，加入CuCN(614mg,6.9mmol)，在160℃下，在氮气保护下搅拌反应3小时。TLC检测反应完全。反应混合物用投入水(100mL)中，用乙酸乙酯(50mL*3)萃取。有机相用饱和食盐水(100mL)洗并用无水硫酸钠干燥。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝10/1)，得到所需的产物A8-6(270mg,产率：23％)，为黄色固体。Step 5: Compound A8-5 (1.6 g, 4.3 mmol) was dissolved in N-methylpyrrolidone (20 mL), CuCN (614 mg, 6.9 mmol) was added, and the reaction was stirred at 160° C. for 3 hours under nitrogen protection. TLC detects that the reaction is complete. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the desired product A8-6 (270 mg, yield: 23%) as a yellow solid.
LC-MS[M+1]+＝274.9LC-MS [M+1] + = 274.9
步骤六：将A8-6(200mg,0.7mmol)溶解于四氢呋喃(6mL)中，氮气置换3次，在-77℃下滴加甲基溴化镁(1.3ml,1M的四氢呋喃溶液)，滴加完后在-77℃下，反应30分钟。LC-MS检测反应完全。反应混合物缓慢的加入到0℃下的饱和氯化铵溶液中，并用乙酸乙酯(10mL*3)萃取。有机相用饱和食盐水洗(50mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物A8-7(150mg,产率：75％)，为黄色油状液体。Step 6: Dissolve A8-6 (200mg, 0.7mmol) in tetrahydrofuran (6mL), replace nitrogen three times, add methylmagnesium bromide (1.3ml, 1M solution in tetrahydrofuran) dropwise at -77°C, add dropwise After completion, react at -77°C for 30 minutes. LC-MS detected that the reaction was complete. The reaction mixture was slowly added to saturated ammonium chloride solution at 0°C, and extracted with ethyl acetate (10 mL*3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product A8-7 (150 mg, yield: 75%) as a yellow oily liquid.
1H NMR(400MHz,Chloroform-d)δ7.63(s,1H),4.53–4.44(m,2H),3.89(t,J＝5.7Hz,2H),1.56(s,6H). 1 H NMR (400MHz, Chloroform-d) δ7.63(s, 1H), 4.53–4.44(m, 2H), 3.89(t, J=5.7Hz, 2H), 1.56(s, 6H).
步骤七：将A8-7(140mg,0.51mmol)，苯酚(240mg,2.55mmol)溶解于1,2-二氯乙烷(6mL)中，在溶液中加入无水AlCl3(136mg,1.02mmol)，上述混合物在100℃下反应3小时。反应混合物加入到水(10ml)中，并用二氯甲烷(10mL* 3)萃取。有机相用饱和食盐水洗(30mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)，得到所需的产物A8-8(55mg,产率：62％)，为黄色油状液体。Step 7: Dissolve A8-7 (140mg, 0.51mmol), phenol (240mg, 2.55mmol) in 1,2-dichloroethane (6mL), and add anhydrous AlCl 3 (136mg, 1.02mmol) to the solution , the above mixture was reacted at 100° C. for 3 hours. The reaction mixture was added to water (10ml) and washed with dichloromethane (10mL* 3) Extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the desired product A8-8 (55 mg, yield: 62%) as a yellow oily liquid.
1H NMR(400MHz,Chloroform-d)δ7.11(d,J＝10.3Hz,2H),7.07(s,1H),6.78(d,J＝8.4Hz,2H),4.46(s,2H),3.86(s,2H),1.68(s,6H). 1 H NMR (400MHz, Chloroform-d) δ7.11(d, J=10.3Hz, 2H), 7.07(s, 1H), 6.78(d, J=8.4Hz, 2H), 4.46(s, 2H), 3.86(s,2H),1.68(s,6H).
后面三步反应参考中间体I-A2的合成路线，用A8-8代替I-A1，经过三步反应合成中间体A8，为黄色油状液体。Refer to the synthetic route of intermediate I-A2 for the following three-step reactions, replace I-A1 with A8-8, and synthesize intermediate A8 through three-step reactions, which is a yellow oily liquid.
LC-MS[M+1]+＝359.1LC-MS [M+1] + = 359.1
按照上面的合成方法或参考文献分别合成下列中间体：
Synthesize the following intermediates respectively according to the above synthetic method or references:
中间体A11的合成：4-(2-氯乙基)-7-(2-(4-乙炔苯基)丙烷-2-基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-5-氰基
Synthesis of Intermediate A11: 4-(2-Chloroethyl)-7-(2-(4-ethynylphenyl)propan-2-yl)-3,4-dihydro-2H-benzo[b][ 1,4]oxazin-5-cyano
参考中间体I-A2的合成路线，用I-A18代替I-A1，经过三步反应合成中间体A11。LC-MS[M+1]+＝365.1 Refer to the synthesis route of intermediate I-A2, replace I-A1 with I-A18, and synthesize intermediate A11 through three-step reactions. LC-MS [M+1] + = 365.1
中间体A13的合成：1-(3-氯丙烷)-4-(2-(4-炔基苯基)丙烷-2-基)-6-甲基吡啶-2(1H)-酮
Synthesis of intermediate A13: 1-(3-chloropropane)-4-(2-(4-alkynylphenyl)propan-2-yl)-6-methylpyridin-2(1H)-one
步骤一：将A13-1(10g,59.82mmol),1,3-氯溴丙烷(28.25g,179.5mmol)溶解在乙腈(120mL)中，加入Cs2CO3(38.88g,119.6mmol)。反应液在80℃下，反应16小时。将反应液浓缩后的进行柱层析分离(石油醚/四氢呋喃＝1/1)，得到所需的产物A13-2(5.4g,产率：40％)，为黄色油状液体。Step 1: Dissolve A13-1 (10 g, 59.82 mmol), 1,3-chlorobromopropane (28.25 g, 179.5 mmol) in acetonitrile (120 mL), and add Cs 2 CO 3 (38.88 g, 119.6 mmol). The reaction solution was reacted at 80° C. for 16 hours. The reaction solution was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran=1/1) to obtain the desired product A13-2 (5.4 g, yield: 40%) as a yellow oily liquid.
LC-MS[M+1]+＝226.2LC-MS [M+1] + = 226.2
步骤二：A13-2(5.4g,23.97mmol)溶解在二氯甲烷(50mL)中，在0℃下加入SOCl2(11.4g,95.9mmol)，反应液在室温下搅拌3小时。混合物旋干后进行柱层析分离(石油醚/四氢呋喃＝1/1)，得到所需的产物A13-3(3.0g,产率：27.5％)，为黄色固体。Step 2: A13-2 (5.4g, 23.97mmol) was dissolved in dichloromethane (50mL), and SOCl 2 (11.4g, 95.9mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 3 hours. The mixture was spin-dried and separated by column chromatography (petroleum ether/tetrahydrofuran=1/1) to obtain the desired product A13-3 (3.0 g, yield: 27.5%) as a yellow solid.
LC-MS[M+1]+＝244.2LC-MS [M+1] + = 244.2
步骤三：在室温下向A13-3(3.0g,12.3mmol)的四氢呋喃(20mL)溶液中滴加甲基溴化镁(123mL,123mmol,1M in THF)。上述混合液在室温下搅拌4小时。将反应液缓慢倒入冰的氯化铵水溶液(100mL)中，用乙酸乙酯(100mL*3)萃取，合并的有机相用饱和食盐水(300mL)洗涤并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/四氢呋喃＝1/1)，得到所需的产物A13-4(1.1g,产率：26.76％)，为淡黄色油状物。Step 3: Add methylmagnesium bromide (123 mL, 123 mmol, 1M in THF) dropwise to a solution of A13-3 (3.0 g, 12.3 mmol) in tetrahydrofuran (20 mL) at room temperature. The above mixture was stirred at room temperature for 4 hours. The reaction solution was slowly poured into iced ammonium chloride aqueous solution (100mL), extracted with ethyl acetate (100mL*3), the combined organic phase was washed with saturated brine (300mL) and dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran=1/1) to obtain the desired product A13-4 (1.1 g, yield: 26.76%) as a pale yellow oil.
LC-MS[M+1]+＝244.2 LC-MS [M+1] + = 244.2
步骤六:在室温下向A13-4(800mg,3.28mmol)和苯酚(1.54g,16.4mmol)的1,2-二氯乙烷(10mL)溶液中加入三氟化硼乙醚溶液(2.98g,9.85mmol)。上述混合液在100℃至室温下搅拌3小时。将反应液用水淬灭(20mL)，用二氯甲烷(20mL*3)萃取，合并的有机相用饱和食盐水(60mL)洗涤并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/四氢呋喃＝1/1)，得到所需的产物A13-5(340mg,产率：22.1％)，为黄色油状物。LC-MS[M+1]+＝320.3Step 6: Add boron trifluoride ether solution (2.98g, 9.85 mmol). The above mixture was stirred at 100° C. to room temperature for 3 hours. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL*3), the combined organic phase was washed with saturated brine (60 mL), dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated and subjected to column chromatography Separation (petroleum ether/tetrahydrofuran=1/1) gave the desired product A13-5 (340 mg, yield: 22.1%) as a yellow oil. LC-MS [M+1] + = 320.3
后面三步反应参考中间体I-A2的合成路线，用A13-5代替I-A1，经过三步反应合成中间体A13。LC-MS[M+1]+＝328.1Refer to the synthetic route of intermediate I-A2 for the following three-step reactions, replace I-A1 with A13-5, and synthesize intermediate A13 through three-step reactions. LC-MS [M+1] + = 328.1
中间体A14的合成：7-氯-1-(2-氯乙基)-5-(2-(4-乙炔苯基)丙烷-2-基)-1H-苯并[d][1,2,3]三唑
Synthesis of Intermediate A14: 7-Chloro-1-(2-chloroethyl)-5-(2-(4-ethynylphenyl)propan-2-yl)-1H-benzo[d][1,2 ,3] triazole
参考中间体I-A2的合成路线，用I-A21代替I-A1，经过三步反应合成中间体A14。Refer to the synthetic route of intermediate I-A2, replace I-A1 with I-A21, and synthesize intermediate A14 through three-step reactions.
LC-MS[M+1]+＝358.1LC-MS [M+1] + = 358.1
中间体A16的合成：2-(2-氯乙氧基)-3-氟-5-(2-(4-乙炔苯基)丙烷-2-基)苯甲腈
Synthesis of Intermediate A16: 2-(2-Chloroethoxy)-3-fluoro-5-(2-(4-ethynylphenyl)propan-2-yl)benzonitrile
参考中间体I-A2的合成路线，用I-A24代替I-A1，经过三步反应合成中间体A16。Refer to the synthetic route of intermediate I-A2, replace I-A1 with I-A24, and synthesize intermediate A16 through three-step reactions.
LC-MS[M+1]+＝342.1LC-MS [M+1] + = 342.1
按照上面中间体A13的合成方法合成中间体A19；按照中间体I-A29的合成方法合成中间体A21。
Synthesize intermediate A19 according to the synthesis method of intermediate A13 above; synthesize intermediate A21 according to the synthesis method of intermediate I-A29.
中间体A23的合成：3-(2-氯乙基)-6-(2-(4-乙炔基苯基)丙烷-2-基)-3H-咪唑并[4,5-b]吡啶
Synthesis of Intermediate A23: 3-(2-Chloroethyl)-6-(2-(4-ethynylphenyl)propan-2-yl)-3H-imidazo[4,5-b]pyridine
步骤一：将原料A23-1(10g,46.17mmol)溶解在DMF(100mL)，加入A23-2(2.82g,46.17mmol)和DIEA(11.91g,92.35mmol)，在25℃下反应2小 时。将反应混合物投入到饱和食盐水中(200mL)，用乙酸乙酯萃取(200mL*2)，合并有机相用无水硫酸钠干燥后浓缩。浓缩后得到粗产物A23-3(11.7g)，为黄色固体。Step 1: Dissolve raw material A23-1 (10g, 46.17mmol) in DMF (100mL), add A23-2 (2.82g, 46.17mmol) and DIEA (11.91g, 92.35mmol), react at 25°C for 2 hours hour. The reaction mixture was poured into saturated brine (200 mL), extracted with ethyl acetate (200 mL*2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. The crude product A23-3 (11.7 g) was obtained after concentration as a yellow solid.
LC-MS[M-1]-＝242.1LC-MS[M-1] - = 242.1
步骤二：室温下将A23-3(11.7g,48.51mmol)，还原铁粉(13.55g,242.5mmol)，NH4Cl(15.57g,291.04mmol)溶解于乙醇(150mL)和水(50mL)中。混合物在85℃下搅拌4小时。反应混合投入到水中(200mL)后并用乙酸乙酯(200mL*3)萃取。有机相用饱和食盐水(600mL)洗并用无水硫酸钠干燥并过滤。滤液浓缩后得到产物A23-4(7.7g)，为黄色固体。Step 2: Dissolve A23-3 (11.7g, 48.51mmol), reduced iron powder (13.55g, 242.5mmol), NH 4 Cl (15.57g, 291.04mmol) in ethanol (150mL) and water (50mL) at room temperature . The mixture was stirred at 85°C for 4 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL*3). The organic phase was washed with saturated brine (600 mL), dried over anhydrous sodium sulfate and filtered. The product A23-4 (7.7 g) was obtained after concentration of the filtrate as a yellow solid.
LC-MS[M+1]+＝212.2LC-MS [M+1] + = 212.2
步骤三：将化合物A23-4(4.3g,20.36mmol)溶解于原甲酸三乙酯中(40mL)中，室温下加入TsOH(350.3mg,2.4mmol)，升至130℃反应16小时后。LC-MS检测，原料反应完全，有产物生成。浓缩后，经柱层析分离(PE/EA＝1/4)得到产物A23-5(3.8g,产率：67.25)，黄色油状液体。Step 3: Dissolve compound A23-4 (4.3g, 20.36mmol) in triethyl orthoformate (40mL), add TsOH (350.3mg, 2.4mmol) at room temperature, and react at 130°C for 16 hours. LC-MS detection showed that the reaction of the raw materials was complete and the product was formed. After concentration, it was separated by column chromatography (PE/EA=1/4) to obtain the product A23-5 (3.8 g, yield: 67.25) as a yellow oily liquid.
LC-MS[M+1]+＝222.1LC-MS [M+1] + = 222.1
步骤四：将A23-5(3.7g,16.7mmol)溶解于四氢呋喃(30mL)中在0℃下滴加到氮气保护的甲基溴化镁(100mL,1M的四氢呋喃溶液)中，滴加完后室温反应2小时。反应混合物缓慢的加入到0℃下的饱和氯化铵溶液中，并用乙酸乙酯(150mL*3)萃取。有机相用饱和食盐水洗(450mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝2/3)，得到所需的产物A23-6(2.1g,产率：56.75％)，为黄色油状液体。Step 4: Dissolve A23-5 (3.7g, 16.7mmol) in tetrahydrofuran (30mL) and add dropwise to methylmagnesium bromide (100mL, 1M solution in tetrahydrofuran) under nitrogen protection at 0°C. After the dropwise addition React at room temperature for 2 hours. The reaction mixture was slowly added to saturated ammonium chloride solution at 0°C, and extracted with ethyl acetate (150 mL*3). The organic phase was washed with saturated brine (450 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=2/3) to obtain the desired product A23-6 (2.1 g, yield: 56.75%) as a yellow oily liquid.
1H NMR(400MHz,Chloroform-d)δ8.53(s,1H),8.17(s,1H),8.13(s,1H),4.46(s,2H),3.92(s,2H),1.64(s,6H).LC-MS[M+1]+＝222.2 1 H NMR (400MHz, Chloroform-d) δ8.53(s,1H),8.17(s,1H),8.13(s,1H),4.46(s,2H),3.92(s,2H),1.64(s ,6H).LC-MS[M+1] + ＝222.2
步骤五：将A23-6(1.9g,8.59mmol)，苯酚(4.04g,42.94mmol)溶解于二氯甲烷(30mL)中，在室温氮气保护下滴加三氟化硼乙醚溶液(6.85mL,47％)，滴加完后自然升温至90℃反应2小时。TLC检测反应完全,反应混合物浓缩后进行柱层 析分离A23-8(2.8g,产率：87.7％)，为黄色油状液体。Step 5: Dissolve A23-6 (1.9g, 8.59mmol), phenol (4.04g, 42.94mmol) in dichloromethane (30mL), add boron trifluoride ether solution (6.85mL, 47%), after the dropwise addition, the temperature was naturally raised to 90° C. for 2 hours. TLC detects that the reaction is complete, and the reaction mixture is concentrated and subjected to column chromatography A23-8 (2.8 g, yield: 87.7%) was isolated by analysis as a yellow oily liquid.
1H NMR(400MHz,Methanol-d4)δ9.47(s,1H),8.49(s,1H),8.17(s,1H),7.10–7.04(m,2H),6.73–6.67(m,2H),4.63(s,2H),3.98(s,3H),1.75(s,6H).LC-MS[M+1]+＝298.1 1 H NMR (400MHz, Methanol-d 4 )δ9.47(s,1H),8.49(s,1H),8.17(s,1H),7.10–7.04(m,2H),6.73–6.67(m,2H ),4.63(s,2H),3.98(s,3H),1.75(s,6H).LC-MS[M+1] + ＝298.1
步骤六:在室温下A23-8(800mg,2.69mmol)溶解在DCM(10mL)中，在室温下滴加SOCl2(1.92g,16.14mmol)，滴加完成后混合物在45℃下反应16小时。LC-MS检测原料反应完全，混合物浓缩后加入DCM(10mL)，依次用饱和碳酸氢钠(10mL)和饱和实验室(10mL)清洗，有机相用无水硫酸钠干燥后浓缩经柱层析(PE/THF＝1/1)得到产物A23-9(510mg,产率：34％)，为黄色油状液体。Step 6: A23-8 (800mg, 2.69mmol) was dissolved in DCM (10mL) at room temperature, and SOCl 2 (1.92g, 16.14mmol) was added dropwise at room temperature. After the addition was completed, the mixture was reacted at 45°C for 16 hours . LC-MS detected that the reaction of the raw material was complete. After the mixture was concentrated, DCM (10mL) was added, washed with saturated sodium bicarbonate (10mL) and saturated laboratory (10mL) successively, and the organic phase was dried with anhydrous sodium sulfate and concentrated by column chromatography ( PE/THF=1/1) to obtain the product A23-9 (510 mg, yield: 34%) as a yellow oily liquid.
LC-MS[M+1]+＝316.2LC-MS [M+1] + = 316.2
参考中间体I-A2的合成路线用中间体A23-9代替中间体I-A1，经过三步反应合成中间体A23.LCMS[M+H]+＝324.1m/zReferring to the synthetic route of intermediate I-A2, intermediate A23-9 was used to replace intermediate I-A1, and intermediate A23 was synthesized through three-step reactions. LCMS[M+H] + =324.1m/z
中间体A34的合成：4-(2-(1-(2-氯乙烷)-7-甲基-1H-吲唑-5-基)丙烷-2-基)苯酚
Synthesis of Intermediate A34: 4-(2-(1-(2-Chloroethane)-7-methyl-1H-indazol-5-yl)propan-2-yl)phenol
步骤一：将A34-1(2g,9.48mmol)溶解在N,N-二甲基甲酰胺(20mL)，加入1-溴-2-氯乙烷(4.08g,28.43mmol)，碳酸钾(1.96g,14.21mmol)，75℃搅拌3小时。反应液用乙酸乙酯萃取两次(100mL*2)，合并有机相用饱和食盐水洗涤三次(50mL*3)，用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝6/1)纯化得到中间体A34-2(830mg,产率：31.89％)，为黄色固体。Step 1: Dissolve A34-1 (2g, 9.48mmol) in N,N-dimethylformamide (20mL), add 1-bromo-2-chloroethane (4.08g, 28.43mmol), potassium carbonate (1.96 g, 14.21 mmol), stirred at 75°C for 3 hours. The reaction solution was extracted twice with ethyl acetate (100mL*2), the combined organic phase was washed three times with saturated brine (50mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was subjected to column chromatography (petroleum Ether/tetrahydrofuran=6/1) was purified to obtain intermediate A34-2 (830 mg, yield: 31.89%) as a yellow solid.
1H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.81(s,1H),7.29(s,1H),4.85(d,J＝6.0Hz,2H),4.02(d,J＝6.7Hz,2H),2.68(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.07(s,1H),7.81(s,1H),7.29(s,1H),4.85(d,J=6.0Hz,2H),4.02(d, J＝6.7Hz,2H),2.68(s,3H).
LC-MS[M+1]+＝273.10LC-MS [M+1] + = 273.10
步骤二：将A34-2(510mg,1.86mmol)溶解在乙醇(6mL)和N,N-二甲基甲酰胺(2mL)，加入TEA(565.96mg,5.59mmol)和Pd(dppf)Cl2(135.16mg,186.43μmol)，CO气体置换，85℃反应过夜16小时。过滤，滤液浓缩得到粗品，经柱层析(石油醚/四氢呋喃＝6/1)纯化得到A34-3(400mg,产率：76.42％)，为白色固体。Step 2: Dissolve A34-2 (510mg, 1.86mmol) in ethanol (6mL) and N,N-dimethylformamide (2mL), add TEA (565.96mg, 5.59mmol) and Pd(dppf)Cl 2 ( 135.16mg, 186.43μmol), replaced with CO gas, and reacted at 85°C overnight for 16 hours. After filtration, the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether/tetrahydrofuran=6/1) to obtain A34-3 (400 mg, yield: 76.42%) as a white solid.
1H NMR(400MHz,Acetonitrile-d3)δ8.29(s,1H),8.14(s,1H),7.75(s,1H),5.03–4.76(m,2H),4.32(q,J＝7.3,6.3Hz,2H),4.11–3.93(m,2H),2.74(s,3H),1.34(d,J＝11.7Hz,3H). 1 H NMR (400MHz, Acetonitrile-d 3 )δ8.29(s,1H),8.14(s,1H),7.75(s,1H),5.03–4.76(m,2H),4.32(q,J=7.3 ,6.3Hz,2H),4.11–3.93(m,2H),2.74(s,3H),1.34(d,J=11.7Hz,3H).
LC-MS[M+1]+＝267.10LC-MS [M+1] + = 267.10
步骤三：将A34-3(250mg,989.33μmol)溶解在四氢呋喃(5mL)中，氮气置换，40℃预热反应液，滴加MeMgBr(1M,3.96mL)，保持30℃反应10分钟。在0℃下将反应液缓慢到入到饱和氯化铵水溶液(50mL)中，加入乙酸乙酯萃取两次(30mL*2)，合并有机相用饱和食盐水洗涤一次(30mL)，用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝3/1)纯化得到中间体A34-4(310mg,产率：69.74％)，为无色油状物。Step 3: Dissolve A34-3 (250 mg, 989.33 μmol) in tetrahydrofuran (5 mL), replace with nitrogen, preheat the reaction solution at 40°C, add MeMgBr (1M, 3.96mL) dropwise, and keep at 30°C for 10 minutes. Slowly pour the reaction solution into saturated aqueous ammonium chloride solution (50 mL) at 0°C, add ethyl acetate to extract twice (30 mL*2), combine the organic phases and wash once with saturated brine (30 mL), wash with anhydrous Dry over sodium sulfate, filter, and concentrate to obtain a crude product, which is purified by column chromatography (petroleum ether/tetrahydrofuran=3/1) to obtain intermediate A34-4 (310 mg, yield: 69.74%) as a colorless oil.
1H NMR(400MHz,Acetonitrile-d3)δ7.95(s,1H),7.63(s,1H),7.28(s,1H),4.85(d,J＝6.0Hz,2H),3.99(d,J＝5.8Hz,2H),2.70(s,3H),1.50(s,6H). 1 H NMR (400MHz, Acetonitrile-d 3 )δ7.95(s,1H),7.63(s,1H),7.28(s,1H),4.85(d,J=6.0Hz,2H),3.99(d, J＝5.8Hz, 2H), 2.70(s, 3H), 1.50(s, 6H).
LC-MS[M+1]+＝253.10LC-MS [M+1] + = 253.10
步骤四：将A34-4(520mg,2.06mmol)溶解在二氯甲烷(10mL)中，加入苯酚(968.15mg,10.29mmol)，氮气置换，在0℃下滴入三氟化硼-乙醚溶液(1.86g,6.17mmol,1.64mL,47％purity)，室温25℃在下反应4小时。将反应液缓慢倒入到20mL水中，用乙酸乙酯萃取两次(20mL*2)，合并有机相用饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤，滤液浓缩，混合物经柱层析分离柱层析(石油醚/四氢呋喃＝3/1)得到中间体A34(510mg,产率53.80％)，为白色固体。Step 4: Dissolve A34-4 (520mg, 2.06mmol) in dichloromethane (10mL), add phenol (968.15mg, 10.29mmol), replace with nitrogen, drop boron trifluoride-ether solution at 0°C ( 1.86g, 6.17mmol, 1.64mL, 47%purity), react at room temperature 25°C for 4 hours. The reaction solution was slowly poured into 20 mL of water, extracted twice with ethyl acetate (20 mL*2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the mixture was passed through the column layer Separation column chromatography (petroleum ether/tetrahydrofuran=3/1) gave intermediate A34 (510 mg, yield 53.80%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.01(s,1H),7.44(s,1H),7.05–6.94(m,2H),6.84(s,1H),6.72–6.55(m,2H),4.79(s,2H),4.01(s,2H),2.57(s,3H),1.59(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ9.13(s,1H),8.01(s,1H),7.44(s,1H),7.05–6.94(m,2H),6.84(s,1H), 6.72–6.55(m,2H),4.79(s,2H),4.01(s,2H),2.57(s,3H),1.59(s,6H).
中间体A35的合成：4-(2-(1-(2-氯乙烷)-7-氟-1H-吲唑-5-基)丙烷-2-基)苯酚
Synthesis of Intermediate A35: 4-(2-(1-(2-Chloroethane)-7-fluoro-1H-indazol-5-yl)propan-2-yl)phenol
步骤一：将A35-1(4g,18.60mmol)溶于N,N-二甲基甲酰胺(80mL)中，加入碳酸钾(7.71g,55.81mmol)和1-溴-2-氯乙烷(8.00g,55.81mmol)，75℃搅拌3小时。反应液用乙酸乙酯萃取两次(100mL*2)，合并有机相用饱和食盐水洗涤三次(50mL*3)，用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝6/1)纯化得到中间体A35-2(3.6g,产率：53.10％)，为白色固体。LC-MS[M+1]+＝279.10Step 1: Dissolve A35-1 (4g, 18.60mmol) in N,N-dimethylformamide (80mL), add potassium carbonate (7.71g, 55.81mmol) and 1-bromo-2-chloroethane ( 8.00g, 55.81mmol), stirred at 75°C for 3 hours. The reaction solution was extracted twice with ethyl acetate (100mL*2), the combined organic phase was washed three times with saturated brine (50mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was subjected to column chromatography (petroleum Ether/tetrahydrofuran=6/1) was purified to obtain intermediate A35-2 (3.6 g, yield: 53.10%) as a white solid. LC-MS [M+1] + = 279.10
步骤二：将A35-2(3.6g,12.97mmol)溶解在甲醇(40mL)中，加入TEA(3.94g,38.92mmol)和Pd(dppf)Cl2(941.33mg,1.30mmol)，CO气体置换完全，75℃反应过夜16小时。过滤，滤液浓缩得到粗品，经柱层析(石油醚/四氢呋喃＝6/1)纯化得到A35-3(3.2g,产率：95.15％)，为白色固体。LC-MS[M+1]+＝257.00Step 2: Dissolve A35-2 (3.6g, 12.97mmol) in methanol (40mL), add TEA (3.94g, 38.92mmol) and Pd(dppf)Cl 2 (941.33mg, 1.30mmol), CO gas replacement is complete , react overnight at 75°C for 16 hours. After filtration, the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether/tetrahydrofuran=6/1) to obtain A35-3 (3.2 g, yield: 95.15%) as a white solid. LC-MS [M+1] + = 257.00
步骤三：将A35-3(1g,3.90mmol)溶解在四氢呋喃(10mL)中，氮气置换，30℃预热反应液，滴加甲基溴化镁(1M,15.58mL)，保持30℃反应10分钟。在0℃下将反应液缓慢到入到饱和氯化铵水溶液(50mL)中，加入乙酸乙酯萃取两次(30mL*2)，合并有机相用饱和食盐水洗涤一次(30mL)，用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝3/1)纯化得到中间体A35-4(630mg,产率：61.73％)为无色油状物。1H NMR(400MHz,Chloroform-d)δ7.98(s,1H),7.56(s,1H),7.25(s,1H),4.81(d,J＝11.0Hz,2H),3.93(d,J＝10.7Hz,2H),1.62(s,6H).Step 3: Dissolve A35-3 (1g, 3.90mmol) in tetrahydrofuran (10mL), replace with nitrogen, preheat the reaction solution at 30°C, add methylmagnesium bromide (1M, 15.58mL) dropwise, and keep at 30°C for 10 minute. Slowly pour the reaction solution into saturated aqueous ammonium chloride solution (50 mL) at 0°C, add ethyl acetate to extract twice (30 mL*2), combine the organic phases and wash once with saturated brine (30 mL), wash with anhydrous Dry over sodium sulfate, filter, and concentrate to obtain a crude product, which is purified by column chromatography (petroleum ether/tetrahydrofuran=3/1) to obtain intermediate A35-4 (630 mg, yield: 61.73%) as a colorless oil. 1 H NMR (400MHz, Chloroform-d) δ7.98(s,1H),7.56(s,1H),7.25(s,1H),4.81(d,J=11.0Hz,2H),3.93(d,J =10.7Hz,2H),1.62(s,6H).
LC-MS[M+1]+＝257.00 LC-MS [M+1] + = 257.00
步骤四：将A35-4(600mg,2.34mmol)溶解在DCM(10mL)中，加入苯酚(1.10g,11.69mmol)，氮气置换，在0℃下滴入三氟化硼-乙醚溶液(2.11g,7.01mmol,1.87mL,47％purity)，15℃在下反应4小时。将反应液缓慢倒入到20mL水中，用乙酸乙酯萃取两次(20mL*2)，合并有机相用饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤，滤液浓缩，混合物经柱层析分离柱层析(石油醚/四氢呋喃＝3/1)得到中间体A35(550mg,产率：65.76％)，为白色固体。Step 4: Dissolve A35-4 (600mg, 2.34mmol) in DCM (10mL), add phenol (1.10g, 11.69mmol), replace with nitrogen, drop boron trifluoride-ether solution (2.11g , 7.01mmol, 1.87mL, 47%purity), reacted at 15°C for 4 hours. The reaction solution was slowly poured into 20 mL of water, extracted twice with ethyl acetate (20 mL*2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the mixture was passed through the column layer Separation column chromatography (petroleum ether/tetrahydrofuran=3/1) gave intermediate A35 (550 mg, yield: 65.76%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.13(s,1H),7.45(s,1H),7.00(t,J＝7.5Hz,2H),6.88(d,J＝12.9Hz,1H),6.68–6.59(m,2H),4.72(s,2H),4.02(s,2H),1.61(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ9.19(s, 1H), 8.13(s, 1H), 7.45(s, 1H), 7.00(t, J=7.5Hz, 2H), 6.88(d, J＝12.9Hz,1H),6.68–6.59(m,2H),4.72(s,2H),4.02(s,2H),1.61(s,6H).
LC-MS[M+1]+＝333.10LC-MS [M+1] + = 333.10
参照上面中间体A35的合成方法合成中间体A53，A54，A55，A56。参照A35合成方法再进行一步反应合成A60。

Intermediates A53, A54, A55, and A56 were synthesized referring to the synthesis method of intermediate A35 above. Refer to the synthesis method of A35 and carry out a further reaction to synthesize A60.

中间体A37的合成：4-(2-(3-(2-氯乙基)-3H-[1,2,3]三唑[4,5-b]吡啶-6-基)丙烷-2-基)苯酚
Synthesis of Intermediate A37: 4-(2-(3-(2-Chloroethyl)-3H-[1,2,3]triazol[4,5-b]pyridin-6-yl)propane-2- base) phenol
步骤一：将原料A37-1(10g,46.17mmol)溶解在DMF(100mL)，加入2-羟基乙胺(2.82g,46.17mmol)和DIEA(11.91g,92.35mmol)，在25℃下反应2小时，TLC检测发现反应完全。将反应混合物投入到饱和食盐水中(200mL)，用乙酸乙酯萃取(200mL*2)，合并有机相用无水硫酸钠干燥后浓缩。浓缩后得到粗产物A37-3(11.7g)为黄色固体。Step 1: Dissolve raw material A37-1 (10g, 46.17mmol) in DMF (100mL), add 2-hydroxyethylamine (2.82g, 46.17mmol) and DIEA (11.91g, 92.35mmol), and react at 25°C for 2 Hours, TLC detection found that the reaction was complete. The reaction mixture was poured into saturated brine (200 mL), extracted with ethyl acetate (200 mL*2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. The crude product A37-3 (11.7 g) was obtained as a yellow solid after concentration.
LC-MS[M-1]-＝242.1LC-MS [M-1] - = 242.1
步骤二：室温下将A37-3(11.7g,48.51mmol)，还原铁粉(13.55g,242.5mmol)，NH4Cl(15.57g,291.04mmol)溶解于乙醇(150mL)和水(50mL)中。混合物在85℃下搅拌4小时。反应混合投入到水中(200mL)后并用乙酸乙酯(200mL*3)萃取。有机相用饱和食盐水(600mL)洗并用无水硫酸钠干燥并过滤。滤液浓缩后得到所需的产物A37-4(7.7g)，为黄色固体。Step 2: A37-3 (11.7g, 48.51mmol), reduced iron powder (13.55g, 242.5mmol), NH4Cl (15.57g, 291.04mmol) were dissolved in ethanol (150mL) and water (50mL) at room temperature. The mixture was stirred at 85°C for 4 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL*3). The organic phase was washed with saturated brine (600 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the desired product A37-4 (7.7 g) as a yellow solid.
LC-MS[M+1]+＝212.2 LC-MS[M+1]+=212.2
步骤三：将化合物A37-4(3g,14.20mmol)溶解于AcOH(30mL)中，降至0℃分批加入NaNO2(1.27g,18.46mmol)固体，升至30℃反应2小时后。浓缩除去大部分AcOH后，用饱和Na2CO3调节pH＝8，用乙酸乙酯(40mL*3)萃取三次，合并有机相，浓缩后得到粗产物A37-5(3g)，为棕色固体。Step 3: Compound A37-4 (3g, 14.20mmol) was dissolved in AcOH (30mL), and NaNO2 (1.27g, 18.46mmol) was added in batches as a solid at 0°C, raised to 30°C for 2 hours. After concentration to remove most of AcOH, the pH was adjusted to 8 with saturated Na2CO3, extracted three times with ethyl acetate (40 mL*3), the organic phases were combined and concentrated to give the crude product A37-5 (3 g) as a brown solid.
LC-MS[M+1]+＝223.2LC-MS[M+1]+=223.2
步骤四：将A37-5(2g,9mmol)溶解于四氢呋喃(20mL)中在0℃下滴加到氮气保护的甲基溴化镁(54mL,1M的四氢呋喃溶液)中，滴加完后室温反应2小时。TLC检测反应完全。反应混合物缓慢的加入到0℃下的饱和氯化铵溶液中，并用乙酸乙酯(100mL*3)萃取。有机相用饱和食盐水洗(300mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(PE/EA＝2/3)，得到所需的产物A37-6(750mg,产率：35.6％)，为黄色油状液体。Step 4: Dissolve A37-5 (2g, 9mmol) in tetrahydrofuran (20mL) and add dropwise to methylmagnesium bromide (54mL, 1M solution in tetrahydrofuran) under nitrogen protection at 0°C, and react at room temperature after the dropwise addition 2 hours. TLC detects that the reaction is complete. The reaction mixture was slowly added to saturated ammonium chloride solution at 0°C, and extracted with ethyl acetate (100 mL*3). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (PE/EA=2/3) to obtain the desired product A37-6 (750 mg, yield: 35.6%) as a yellow oily liquid.
1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.34(s,1H),4.84(s,2H),4.19(s,2H),1.65(s,6H).LC-MS[M+1]+＝223.11H NMR (400MHz, Chloroform-d) δ8.77(s,1H),8.34(s,1H),4.84(s,2H),4.19(s,2H),1.65(s,6H).LC-MS[ M+1]+=223.1
步骤五：将A37-6(750mg,3.37mmol)，苯酚(1.59g,16.87mmol)溶解于二氯甲烷(10mL)中，在室温氮气保护下滴加三氟化硼乙醚溶液(2.69mL,47％)，滴加完后自然升温至90℃反应2小时。反应混合物浓缩后进行柱层析分离(PE/THF＝2/1)得到A37-8(1.0g,产率：71％)，为黄色油状液体。Step 5: Dissolve A37-6 (750mg, 3.37mmol), phenol (1.59g, 16.87mmol) in dichloromethane (10mL), add boron trifluoride ether solution (2.69mL, 47 %), after the dropwise addition, the temperature was naturally raised to 90° C. for 2 hours. The reaction mixture was concentrated and separated by column chromatography (PE/THF=2/1) to obtain A37-8 (1.0 g, yield: 71%) as a yellow oily liquid.
LC-MS[M+1]+＝299.2LC-MS [M+1]+=299.2
步骤六:在室温下向A37-8(300mg,1.01mmol)溶解在DCM(4mL)中，在室温下滴加SOCl2(718mg,6.06mmol)，滴加完成后，混合物在45℃下反应16小时。混合物浓缩后加入DCM(5mL)，依次用饱和碳酸氢钠(10mL)和饱和实验室(10mL)清洗，有机相用无水硫酸钠干燥后浓缩经柱层析得到产物(PE/THF＝1/1),得到A37(100mg,产率：30％)为黄色油状液体。Step 6: A37-8 (300mg, 1.01mmol) was dissolved in DCM (4mL) at room temperature, and SOCl2 (718mg, 6.06mmol) was added dropwise at room temperature. After the addition was completed, the mixture was reacted at 45°C for 16 hours . After the mixture was concentrated, DCM (5mL) was added, washed successively with saturated sodium bicarbonate (10mL) and saturated laboratory (10mL), the organic phase was dried over anhydrous sodium sulfate, concentrated and the product was obtained by column chromatography (PE/THF=1/ 1), A37 (100 mg, yield: 30%) was obtained as a yellow oily liquid.
1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.46(s,1H),8.40(s,1H),7.04(d,J＝10.0Hz,2H),6.70–6.64(m,2H),5.00(s,2H),4.22(s,2H),1.70(s,6H).LC-MS[M+1]+＝317.21H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.46(s,1H),8.40(s,1H),7.04(d,J＝10.0Hz,2H),6.70–6.64(m, 2H), 5.00(s, 2H), 4.22(s, 2H), 1.70(s, 6H).LC-MS[M+1]+=317.2
中间体A39的合成：4-(2-(1-(2-氯乙烷)-7-甲氧基-1H-吲唑-5-基)丙烷-2-基)苯酚
Synthesis of Intermediate A39: 4-(2-(1-(2-Chloroethane)-7-methoxy-1H-indazol-5-yl)propan-2-yl)phenol
步骤一：将A39-1(40g,291.59mmol)和醋酸(46mL)加入到甲醇(230mL)中，降温至0℃，缓慢滴加Br2(46.60g,291.59mmol)，加毕升温至25℃搅拌反应2小时。加入乙酸乙酯(200mL),过滤,滤饼用乙酸乙酯(30mL)洗涤,真空减压浓缩至干得A39-2(55.00g,粗品)的醋酸盐，类白色固体。Step 1: Add A39-1 (40g, 291.59mmol) and acetic acid (46mL) to methanol (230mL), cool down to 0°C, slowly add Br 2 (46.60g, 291.59mmol) dropwise, and heat up to 25°C after addition The reaction was stirred for 2 hours. Ethyl acetate (200 mL) was added, filtered, the filter cake was washed with ethyl acetate (30 mL), and concentrated to dryness under reduced pressure in vacuo to obtain the acetate salt of A39-2 (55.00 g, crude product) as an off-white solid.
LC-MS[M+1]+＝216.08LC-MS [M+1] + = 216.08
步骤二：将A39-2(20g,92.56mmol)加入到AcOH(210mL)中，降温至0℃，缓慢滴加NaNO2(12.77g,185.12mmol)的水溶液(5mL),加毕缓慢升温至25℃搅拌反应16小时，反应液浓缩至干，加入乙酸乙酯(200mL)，分别用碳酸氢钠溶液(200mL)，饱和食盐水洗涤(100mL)，有机相分离并浓缩至干，残余物经柱层析纯化(EA/PE＝0至40％)得A39-3(5.80g,产率：24.84％)，为黄色固体产物。Step 2: Add A39-2 (20g, 92.56mmol) into AcOH (210mL), cool down to 0°C, slowly add NaNO 2 (12.77g, 185.12mmol) aqueous solution (5mL), and slowly heat up to 25 Stir the reaction at ℃ for 16 hours, concentrate the reaction solution to dryness, add ethyl acetate (200 mL), wash with sodium bicarbonate solution (200 mL), and saturated brine (100 mL), respectively, separate the organic phase and concentrate to dryness, and the residue is passed through a column Purification by chromatography (EA/PE=0 to 40%) gave A39-3 (5.80 g, yield: 24.84%) as a yellow solid product.
LC-MS[M+1]+＝227.06LC-MS [M+1] + = 227.06
步骤三：将A39-3(19g,83.68mmol)，1-溴-2-氯-乙烷(24.00g,167.36mmol)，Cs2CO3(68.16g,209.20mmol)依次加入到DMF(10mL)中，反应在25℃下搅拌反应1小时，反应液过滤，滤液直接浓缩至干，残余物经柱层析纯化(乙酸乙酯/石油醚＝0至25％)得A39-4(17.00g,产率：63.15％)，为白色固体产物。Step 3: Add A39-3 (19g, 83.68mmol), 1-bromo-2-chloro-ethane (24.00g, 167.36mmol), Cs 2 CO 3 (68.16g, 209.20mmol) to DMF (10mL) in sequence , the reaction was stirred at 25°C for 1 hour, the reaction solution was filtered, the filtrate was directly concentrated to dryness, and the residue was purified by column chromatography (ethyl acetate/petroleum ether=0 to 25%) to obtain A39-4 (17.00g, Yield: 63.15%) as a white solid product.
步骤四：将A39-4(8.4g,29.01mmol)，Pd(dppf)Cl2(2.11g,2.90mmol)，三乙胺(29.30g,290.10mmol)依次加入到甲醇(200mL)中，一氧化碳气体置换3次，将反应液升温至90℃搅拌反应16小时，将反应液冷却至室温，真空减压浓缩至干，残余物经柱层析纯化(乙酸乙酯/石油醚＝0至20％)得A39-5(5.50g,产率：63.50％)，为黄色固体产物。 Step 4: Add A39-4 (8.4g, 29.01mmol), Pd(dppf)Cl 2 (2.11g, 2.90mmol), triethylamine (29.30g, 290.10mmol) to methanol (200mL) in turn, and carbon monoxide gas Replaced 3 times, heated the reaction solution to 90°C and stirred for 16 hours, cooled the reaction solution to room temperature, concentrated to dryness under reduced pressure in vacuo, and purified the residue by column chromatography (ethyl acetate/petroleum ether=0 to 20%) A39-5 (5.50 g, yield: 63.50%) was obtained as a yellow solid product.
LC-MS[M+1]+＝269.10LC-MS [M+1] + = 269.10
步骤五：将A39-5(268.7mg,1.00mmol)加入THF(4mL)中，氮气置换3次，降温至0℃，滴加MeMgBr(1M,4.00mL)，加毕升温至25℃搅拌反应1小时，在0℃下将反应液缓慢到入到饱和氯化铵水溶液中，加入乙酸乙酯(5mL)萃取两次，合并有机相用无水硫酸钠干燥，过滤浓缩得到粗品，粗品经柱层析(PE:EA＝1：0～5：1)得到产物A39-6(220mg,产率：90.22％)，为白色固体。Step 5: Add A39-5 (268.7mg, 1.00mmol) into THF (4mL), replace with nitrogen 3 times, cool down to 0°C, add MeMgBr (1M, 4.00mL) dropwise, heat up to 25°C and stir for reaction 1 hours, slowly pour the reaction solution into saturated aqueous ammonium chloride solution at 0°C, add ethyl acetate (5mL) to extract twice, combine the organic phases and dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is passed through the column layer Analysis (PE:EA=1:0～5:1) gave the product A39-6 (220 mg, yield: 90.22%) as a white solid.
步骤六：将A39-6(4.8g,17.86mmol)和苯酚(3.36g,35.72mmol)溶解在DCM(80mL)，氮气置换，在0℃下滴加BF3.Et2O(16.11g,53.58mmol,14.26mL,47％purity)，滴加完毕后，升高室温25℃反应3小时。将反应液倒入到20mL水中，用乙酸乙酯萃取两次(300mL*2)，有机相用饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤，滤液浓缩，混合物经柱层析分离(PE/THF＝1/0～5/1)得到产物A39(3.90g,产率：56.99％)，为白色固体。Step 6: Dissolve A39-6 (4.8g, 17.86mmol) and phenol (3.36g, 35.72mmol) in DCM (80mL), replace with nitrogen, add BF 3 .Et 2 O (16.11g, 53.58 mmol, 14.26mL, 47%purity), after the dropwise addition was completed, the room temperature was raised to 25°C for 3 hours. The reaction solution was poured into 20 mL of water, extracted twice with ethyl acetate (300 mL*2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the mixture was separated by column chromatography (PE/THF=1/0～5/1) The product A39 (3.90 g, yield: 56.99%) was obtained as a white solid.
1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.14(s,1H),7.00(s,2H),6.62(s,2H),6.51(s,1H),4.79(s,2H),3.97(s,2H),3.76(s,3H),1.60(s,6H)。LC-MS[M+1]+＝344.10 1 H NMR (400MHz,DMSO-d 6 )δ7.95(s,1H),7.14(s,1H),7.00(s,2H),6.62(s,2H),6.51(s,1H),4.79( s,2H), 3.97(s,2H), 3.76(s,3H), 1.60(s,6H). LC-MS [M+1] + = 344.10
中间体A44的合成：4-(2-(3-氯-1-(2-氯乙烷)-7-氟-1H-吲唑-5-基)丙烷-2-基)苯酚
Synthesis of Intermediate A44: 4-(2-(3-Chloro-1-(2-chloroethane)-7-fluoro-1H-indazol-5-yl)propan-2-yl)phenol
步骤一：将A44-1(2.5g,11.63mmol)溶解于N,N-二甲基甲酰胺(20mL)中，加入N-氯代丁二酰亚胺(1.71g,12.79mmol)，反应在25℃下搅拌反应1小时。将反应液直接浓缩，经柱层析(乙酸乙酯/石油醚＝0～50％)纯化得A44-2(1.90g,6.85mmol,收率：58.96％)，性状为白色固体。 Step 1: Dissolve A44-1 (2.5g, 11.63mmol) in N,N-dimethylformamide (20mL), add N-chlorosuccinimide (1.71g, 12.79mmol), and react in The reaction was stirred at 25°C for 1 hour. The reaction solution was directly concentrated, and purified by column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain A44-2 (1.90 g, 6.85 mmol, yield: 58.96%), which was a white solid.
LC-MS[M+1]+＝248.82LC-MS [M+1] + = 248.82
步骤二：将A44-2(1.9g,7.62mmol)，Pd(dppf)Cl2(552.18mg,761.62μmol)和三乙胺(15.41g,152.32mmol)依次加入到无水乙醇(50mL)中，一氧化碳置换3次后，反应升温至90℃搅拌反应5小时。将反应液冷却至室温并浓缩，经柱层析(乙酸乙酯/石油醚＝0～50％)纯化得A44-3(1.70g,6.31mmol,82.79％yield,90％purity)，性状为黄色固体。Step 2: A44-2 (1.9g, 7.62mmol), Pd(dppf)Cl 2 (552.18mg, 761.62μmol) and triethylamine (15.41g, 152.32mmol) were sequentially added to absolute ethanol (50mL), After replacing carbon monoxide three times, the temperature of the reaction was raised to 90° C. and the reaction was stirred for 5 hours. The reaction solution was cooled to room temperature and concentrated, and purified by column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain A44-3 (1.70g, 6.31mmol, 82.79% yield, 90% purity), which was yellow solid.
步骤三：将A44-3(1.7g,7.01mmol)，1-溴-2-氯乙烷(2.01g,14.01mmol)，碳酸铯(6.85g,21.02mmol)依次加入到N,N-二甲基甲酰胺(5mL)中，反应在25℃下搅拌反应1小时，将反应液直接浓缩，经柱层析(乙酸乙酯/石油醚＝0～10％)纯化得A44-4(1.80g,5.31mmol,75.78％yield,90％purity)，为黄色固体产物。Step 3: Add A44-3 (1.7g, 7.01mmol), 1-bromo-2-chloroethane (2.01g, 14.01mmol), cesium carbonate (6.85g, 21.02mmol) to N,N-dimethyl In methyl formamide (5mL), the reaction was stirred at 25°C for 1 hour, the reaction solution was directly concentrated, and purified by column chromatography (ethyl acetate/petroleum ether=0～10%) to obtain A44-4 (1.80g, 5.31 mmol, 75.78% yield, 90% purity), as a yellow solid product.
LC-MS[M+1]+＝304.10LC-MS [M+1] + = 304.10
步骤四：将A44-4(1.6g,5.24mmol)溶解于四氢呋喃(16mL)中，氮气置换3次，升温至35℃后滴加甲基溴化镁(1M,20.97mL)，加毕搅拌反应1小时。将反应液倒入冰氯化铵(20mL)中，乙酸乙酯(20mL*3)萃取,有机相合并并浓缩，经柱层析(乙酸乙酯/石油醚＝0～50％)纯化得A44-5(1.40g,4.33mmol,82.53％yield,90％purity)，为黄色固体产物。Step 4: Dissolve A44-4 (1.6g, 5.24mmol) in tetrahydrofuran (16mL), replace with nitrogen 3 times, add methylmagnesium bromide (1M, 20.97mL) dropwise after heating up to 35°C, and stir the reaction after adding 1 hour. The reaction solution was poured into glacial ammonium chloride (20mL), extracted with ethyl acetate (20mL*3), the organic phases were combined and concentrated, and purified by column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain A44 -5 (1.40 g, 4.33 mmol, 82.53% yield, 90% purity), a yellow solid product.
LC-MS[M+1]+＝291.10LC-MS [M+1] + = 291.10
步骤五：依次将A44-5(1.46g,5.00mmol)，苯酚(1.88g,20.00mmol)加入到二氯甲烷(20mL)中，氮气置换3次，体系降温至-60℃，缓慢滴加三氟化硼(2.13g,15.00mmol)，加毕自然升温至25℃，反应在25℃下搅拌1小时。加入甲醇(3mL)淬灭反应,反应液直接浓缩，经柱层析(乙酸乙酯/石油醚＝0～50％)纯化得A44(1.40g,3.62mmol,收率：72.42％)为无色油状物。Step 5: Add A44-5 (1.46g, 5.00mmol) and phenol (1.88g, 20.00mmol) into dichloromethane (20mL) in turn, replace with nitrogen for 3 times, cool the system down to -60°C, and slowly add three Boron fluoride (2.13g, 15.00mmol) was naturally heated to 25°C after the addition, and the reaction was stirred at 25°C for 1 hour. The reaction was quenched by adding methanol (3 mL), the reaction solution was directly concentrated, and purified by column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain A44 (1.40 g, 3.62 mmol, yield: 72.42%) as colorless Oil.
1H NMR(400MHz,DMSO-d6)δ7.27(d,J＝1.4Hz,1H),7.10-6.92(m,2H),6.75-6.56(m,1H),4.69(t,J＝5.6Hz,2H),4.02(t,J＝5.4Hz,2H),1.62(s,4H). 1 H NMR (400MHz, DMSO-d 6 )δ7.27(d, J=1.4Hz, 1H), 7.10-6.92(m, 2H), 6.75-6.56(m, 1H), 4.69(t, J=5.6 Hz, 2H), 4.02(t, J=5.4Hz, 2H), 1.62(s, 4H).
LC-MS[M+1]+＝368.70 LC-MS [M+1] + = 368.70
中间体A51的合成：3-氯-2-(2-氯乙氧基)-5-(1-(4-乙炔基苯基)-1-羟乙基)苯甲腈
Synthesis of Intermediate A51: 3-Chloro-2-(2-chloroethoxy)-5-(1-(4-ethynylphenyl)-1-hydroxyethyl)benzonitrile
步骤一：0℃下将A51-1(20g,146.90mmol)，A51-2(1.01g,7.34mmol,HCl)，A51-3(28.94g,146.90mmol)加入到甲苯(700mL)，0℃下反应4小时，将反应液倒入饱和氯化铵水溶液中，加入DCM(400mL*3)萃取，合并有机相。有机相用无水硫酸钠干燥后浓缩，柱层析(石油醚：乙酸乙酯＝3:1)纯化得目标产物A51-4(16.80g,粗品)，性状为白色固体。Step 1: Add A51-1 (20g, 146.90mmol), A51-2 (1.01g, 7.34mmol, HCl), A51-3 (28.94g, 146.90mmol) to toluene (700mL) at 0°C, After reacting for 4 hours, the reaction solution was poured into a saturated ammonium chloride aqueous solution, and DCM (400 mL*3) was added for extraction, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product A51-4 (16.80 g, crude product) as a white solid.
LC-MS[M+1]+＝170.9LC-MS [M+1] + = 170.9
步骤二：将A51-4(16.8g,98.48mmol)溶于DCM(200mL)，N2保护，10℃下加入NIS(44.31g,196.96mmol)，10℃下搅拌16小时，将反应液旋干，用DCM(60mL)打浆一次，用乙酸乙酯(60mL)打浆一次，用(300mL)打浆一次，过滤得到目标产物A51-5(17.80g,产率：60.96％)，性状为白色固体。Step 2: Dissolve A51-4 (16.8g, 98.48mmol) in DCM (200mL), protect with N 2 , add NIS (44.31g, 196.96mmol) at 10°C, stir at 10°C for 16 hours, spin the reaction solution to dryness , beating once with DCM (60mL), once with ethyl acetate (60mL), once with (300mL), and filtered to obtain the target product A51-5 (17.80g, yield: 60.96%), which is a white solid.
LC-MS[M+1]+＝296.8LC-MS [M+1] + = 296.8
步骤三：将A51-5(16.6g,55.99mmol)，A51-6(16.06g,111.98mmol,9.32mL)，Cs2CO3(36.39g,111.98mmol)加入到DMF(159.66mL)，70℃下搅拌16小时，将反应液倒入水(500mL)中，加入乙酸乙酯萃取(300mL*3)，合并有机相，饱和食盐水洗涤(300mL*3)，拌样，经柱层析(石油醚：乙酸乙酯＝5:1)纯化得目标产物A51-7(15.90g,产率：79.11％)，性状为白色固体。Step 3: A51-5 (16.6g, 55.99mmol), A51-6 (16.06g, 111.98mmol, 9.32mL), Cs 2 CO 3 (36.39g, 111.98mmol) were added to DMF (159.66mL), 70°C Stir for 16 hours, pour the reaction solution into water (500mL), add ethyl acetate for extraction (300mL*3), combine the organic phases, wash with saturated brine (300mL*3), mix the sample, and perform column chromatography (petroleum Ether: ethyl acetate = 5:1) to obtain the target product A51-7 (15.90 g, yield: 79.11%), which is a white solid.
1H NMR(400MHz,Chloroform-d)δ8.24(s,1H),7.94(s,1H),4.30(s,2H),3.91(s,2H),2.55(s,3H). 1 H NMR (400MHz, Chloroform-d) δ8.24(s,1H),7.94(s,1H),4.30(s,2H),3.91(s,2H),2.55(s,3H).
步骤四：将A51-7(15.9g,44.29mmol)，CuCN(6.22g,66.44mmol)加入到NMP(200mL)，160℃下搅拌3小时，将反应液倒入水(1000mL)中，加入乙酸乙酯萃取(300mL*3)，有机相合并，用饱和食盐水洗涤(500mL*3)，拌 样，柱层析(石油醚：乙酸乙酯＝3:1)得目标产物A51-8(6.50g,产率：56.86％)，性状为白色固体。Step 4: Add A51-7 (15.9g, 44.29mmol), CuCN (6.22g, 66.44mmol) to NMP (200mL), stir at 160°C for 3 hours, pour the reaction solution into water (1000mL), add acetic acid Ethyl ester extraction (300mL*3), the organic phases were combined, washed with saturated brine (500mL*3), stirred Then, column chromatography (petroleum ether: ethyl acetate = 3:1) gave the target product A51-8 (6.50 g, yield: 56.86%), which was a white solid.
步骤五：将A51-9(7.13g,30.22mmol)溶于THF(200mL)，干冰浴至-77℃，N2保护，滴加n-Butyllithium(2.5M,13.02mL)，滴加完毕后，搅拌1小时，再次滴加溶有A51-8(6.00g,23.25mmol)的THF(60mL)溶液，滴加完毕后，搅拌2小时，将氯化铵水溶液倒入反应液中，加入乙酸乙酯(300mL)萃取，分层，有机相用饱和食盐水(200mL)洗涤3次，无水硫酸钠干燥，浓缩，柱层析(PE：EA＝6:1)得目标产物A51-10(7.40g,产率：76.68％)，性状为黄色油状物。Step 5: Dissolve A51-9 (7.13g, 30.22mmol) in THF (200mL), put in a dry ice bath to -77°C, protect with N2 , add n-Butyllithium (2.5M, 13.02mL) dropwise, after the dropwise addition, Stir for 1 hour, add dropwise a solution of A51-8 (6.00g, 23.25mmol) in THF (60mL) again, after the dropwise addition, stir for 2 hours, pour ammonium chloride aqueous solution into the reaction solution, add ethyl acetate (300mL) extraction, separated, the organic phase was washed 3 times with saturated brine (200mL), dried over anhydrous sodium sulfate, concentrated, column chromatography (PE:EA=6:1) to obtain the target product A51-10 (7.40g , Yield: 76.68%), the property is yellow oil.
LC-MS[M+23]+＝437.9LC-MS [M+23] + = 437.9
步骤六：将A51-10(2g,4.82mmol)，A51-11(4.73g,48.18mmol,6.81mL)，DIPEA(9.34g,72.27mmol,11.94mL)，CuI(91.76mg,481.80μmol)，Pd(pph3)2Cl2(352.20mg,481.80μmol)加入至THF(15mL)，N2保护，封管下80℃搅拌5小时，将反应液拌样，柱层析(石油醚：乙酸乙酯＝4:1)得目标产物A51-12(1.50g,产率：72.00％)，性状为黄色油状物。Step 6: A51-10 (2g, 4.82mmol), A51-11 (4.73g, 48.18mmol, 6.81mL), DIPEA (9.34g, 72.27mmol, 11.94mL), CuI (91.76mg, 481.80μmol), Pd (pph 3 ) 2 Cl 2 (352.20mg, 481.80μmol) was added to THF (15mL), protected by N 2 , stirred at 80°C for 5 hours under sealed tube, the reaction solution was mixed, and column chromatography (petroleum ether: ethyl acetate =4:1) to obtain the target product A51-12 (1.50 g, yield: 72.00%), which was a yellow oil.
1H NMR(400MHz,Chloroform-d)δ7.60(s,1H),7.50(s,1H),7.43(s,2H),7.32(s,2H),4.42–4.38(m,2H),3.87–3.83(m,2H),1.90(s,3H),0.23(s,9H) 1 H NMR (400MHz, Chloroform-d) δ7.60(s,1H),7.50(s,1H),7.43(s,2H),7.32(s,2H),4.42–4.38(m,2H),3.87 –3.83(m,2H),1.90(s,3H),0.23(s,9H)
步骤七：将A51-12(1.5g,3.47mmol)溶于MeOH(20mL)，加入KF(2.02g,34.69mmol)，40℃下搅拌2小时，将反应液浓缩后柱层析(二氧化硅，石油醚：乙酸乙酯＝6:1)得目标产物A51(1.00g,产率：80.02％)，性状为黄色油状物。Step 7: Dissolve A51-12 (1.5g, 3.47mmol) in MeOH (20mL), add KF (2.02g, 34.69mmol), stir at 40°C for 2 hours, concentrate the reaction solution and perform column chromatography (silica , petroleum ether: ethyl acetate=6:1) to obtain the target product A51 (1.00 g, yield: 80.02%), which was a yellow oil.
1H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.52(s,1H),7.49–7.44(m,2H),7.35(s,2H),4.39(s,2H),3.87(s,2H),3.08(s,1H),1.91(s,3H). 1 H NMR (400MHz, Chloroform-d) δ7.64(s,1H),7.52(s,1H),7.49–7.44(m,2H),7.35(s,2H),4.39(s,2H),3.87 (s,2H),3.08(s,1H),1.91(s,3H).
参考A34的合成方法合成中间体A36，A40，A41，A42，A46，A47，A48，A49，A50，A57，A58。Synthesize intermediates A36, A40, A41, A42, A46, A47, A48, A49, A50, A57, A58 with reference to the synthesis method of A34.
参考A44的合成方法合成中间体A43，A45。


Refer to the synthetic method of A44 to synthesize intermediates A43 and A45.


中间体A61的合成：4-(1-(1-(2-氯乙基)-7-氟-1H-吲唑-5-基)乙烯基)苯酚
Synthesis of Intermediate A61: 4-(1-(1-(2-Chloroethyl)-7-fluoro-1H-indazol-5-yl)vinyl)phenol
步骤一：将A61-1(5g,23.25mmol)，1-溴-2-氯-乙烷(10.00g,69.76mmol,5.81mL)，Cs2CO3(11.34g,34.88mmol)加入到DMF(47.68mL)，N2保护，20℃下搅拌3小时，LCMS监测反应完成，将反应液倒入水中，加入EA萃取(50mL)，有机相用饱和食盐水洗涤3次(50mL x3)，有机相浓缩，柱层析纯化得目标产物A61-2(2.70g,产率：41.84％)，性状为白色固体。Step 1: Add A61-1 (5g, 23.25mmol), 1-bromo-2-chloro-ethane (10.00g, 69.76mmol, 5.81mL), Cs 2 CO 3 (11.34g, 34.88mmol) into DMF ( 47.68mL), N 2 protection, stirred at 20°C for 3 hours, LCMS monitored the completion of the reaction, poured the reaction solution into water, added EA for extraction (50mL), washed the organic phase with saturated brine 3 times (50mL x3), and the organic phase Concentrate and purify by column chromatography to obtain the target product A61-2 (2.70 g, yield: 41.84%), which is a white solid.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝2.3Hz,1H),7.83(d,J＝1.5Hz,1H),7.47(dd,J＝11.4,1.5Hz,1H),4.76(t,J＝5.6Hz,2H),4.03(t,J＝5.6Hz,2H).LC-MS[M+1]+＝278.9 1 H NMR (400MHz, DMSO-d 6 ) δ8.17(d, J=2.3Hz, 1H), 7.83(d, J=1.5Hz, 1H), 7.47(dd, J=11.4, 1.5Hz, 1H) , 4.76(t, J=5.6Hz, 2H), 4.03(t, J=5.6Hz, 2H).LC-MS[M+1] + ＝278.9
步骤二：将A61-2(2.5g,9.55mmol)，三丁基(1-乙氧基乙烯)锡(6.90g,19.10mmol,6.45mL)，Pd(dppf)Cl2(763.91mg,954.88μmol)加入到dioxane(25mL)，N2保护，90℃下搅拌16小时，冷却至室温，加入2M HCl搅拌，TLC监测反应完成，将反应液倒入氟化钾水(100mL)溶液中，搅拌，过滤，EA(500mL)萃取，分层，用饱和食盐水洗涤有机相3次(100mL x3)，有机相浓缩，柱层析(石油醚：乙酸乙酯＝5:1)纯化得目标产物A61-3(2.00g,产率：87.03％)，性状为白 色固体。Step 2: Add A61-2 (2.5g, 9.55mmol), tributyl(1-ethoxyethylene) tin (6.90g, 19.10mmol, 6.45mL), Pd(dppf)Cl 2 (763.91mg, 954.88μmol ) was added to dioxane (25mL), under N2 protection, stirred at 90°C for 16 hours, cooled to room temperature, added 2M HCl and stirred, TLC monitored the completion of the reaction, poured the reaction solution into potassium fluoride water (100mL) solution, stirred, Filter, extract with EA (500mL), separate layers, wash the organic phase 3 times with saturated brine (100mL x3), concentrate the organic phase, and purify by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product A61- 3 (2.00g, yield: 87.03%), the character is white color solid.
LC-MS[M+1]+＝241.0LC-MS [M+1] + = 241.0
步骤三：将A61-3(1.85g,7.69mmol)溶于THF(5mL)，0℃下滴加进4-(2-四氢-2H-吡喃氧代)苯基溴化镁溶液(0.5M,61.50mL)，0℃下搅拌1小时，LCMS监测反应完成，将反应液倒入水中，加入EA，分层，有机相浓缩，柱层析纯化得目标产物A61-4(2.70g,产率：83.85％)性状为无色油状物。Step 3: Dissolve A61-3 (1.85g, 7.69mmol) in THF (5mL), and add dropwise into 4-(2-tetrahydro-2H-pyranyloxy)phenylmagnesium bromide solution (0.5 M, 61.50mL), stirred at 0°C for 1 hour, LCMS monitored the completion of the reaction, poured the reaction solution into water, added EA, separated layers, concentrated the organic phase, and purified by column chromatography to obtain the target product A61-4 (2.70g, produced Yield: 83.85%) is a colorless oil.
LC-MS[M+1]+＝419.1LC-MS [M+1] + = 419.1
步骤四：将A61-4(2.6g,6.21mmol)加入到冰乙酸(15mL)和H2O(15mL)的混合溶液中，40℃下搅拌1小时，LC-MS监测反应完成，加入EA萃取EA(500mL x 2)，有机相浓缩，柱层析纯化得目标产物A61(1.70g,产率：86.47％)，性状为白色固体。Step 4: Add A61-4 (2.6g, 6.21mmol) into a mixed solution of glacial acetic acid (15mL) and H 2 O (15mL), stir at 40°C for 1 hour, LC-MS monitors the completion of the reaction, add EA to extract EA (500mL x 2), the organic phase was concentrated, and purified by column chromatography to obtain the target product A61 (1.70g, yield: 86.47%), which was a white solid.
1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.18(d,J＝2.0Hz,1H),7.43(s,1H),7.13(dd,J＝17.8,11.3Hz,3H),6.74(d,J＝8.5Hz,2H),5.34(d,J＝9.2Hz,2H),4.78(t,J＝5.5Hz,2H),4.05(t,J＝5.3Hz,2H). 1 H NMR (400MHz, DMSO-d6) δ9.57(s, 1H), 8.18(d, J=2.0Hz, 1H), 7.43(s, 1H), 7.13(dd, J=17.8, 11.3Hz, 3H ), 6.74(d, J=8.5Hz, 2H), 5.34(d, J=9.2Hz, 2H), 4.78(t, J=5.5Hz, 2H), 4.05(t, J=5.3Hz, 2H).
LC-MS[M+1]+＝317.0LC-MS [M+1] + = 317.0
参考A61的合成方法合成中间体A62，A63，A64，A65。Synthesize intermediates A62, A63, A64, A65 with reference to the synthesis method of A61.
参考A61合成方法，再经过一步反应合成A66。

Referring to the synthesis method of A61, A66 was synthesized through a one-step reaction.

中间体A67的合成：4-(1-(1-(2-氯乙基)-7-氟-1H-苯并[d][1,2,3]三唑-5-基)乙烯基)苯酚
Synthesis of Intermediate A67: 4-(1-(1-(2-Chloroethyl)-7-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)ethenyl) phenol
步骤一：将A67-1(10.0g，42mmol)溶于EtOH(150mL)中，分批加入氨基丙醇(5.13g，84mmol)，反应液室温搅拌反应16小时。LC-MS检测发现原料反应完全，将反应液倒入H2O(600mL)中，边加边搅拌，加完后乙酸乙酯(200mL x3)萃取，饱和食盐水洗涤，无水硫酸钠干燥旋蒸除溶剂，得到化合物A67-2(12g,粗品)为棕色粘稠油状物。Step 1: Dissolve A67-1 (10.0 g, 42 mmol) in EtOH (150 mL), add aminopropanol (5.13 g, 84 mmol) in batches, and stir the reaction solution at room temperature for 16 hours. LC-MS detection found that the reaction of the raw materials was complete, and the reaction solution was poured into H 2 O (600mL), stirred while adding, extracted with ethyl acetate (200mL x3), washed with saturated brine, dried over anhydrous sodium sulfate, and spun The solvent was distilled off to obtain compound A67-2 (12 g, crude product) as a brown viscous oil.
LC-MS[M+1]+＝279.0LC-MS [M+1] + = 279.0
步骤二：将A67-2(12g,43.00mmol)加入EtOH(200mL)和饱和NH4Cl溶液(20mL)混合溶剂中，再加入铁粉(24.01g,430.01mmol)，升温至90℃，搅拌反应16小时。LC-MS检测反应原料完全，反应液加入大量乙酸乙酯(500mL)中稀释后用过硅藻土过滤，滤液旋蒸除溶剂，柱层析分离(石油醚/乙酸乙酯＝55％)，得到化合物A67-3(10.50g,42.16mmol,产率：98.03％)为棕黑色固体。Step 2: Add A67-2 (12g, 43.00mmol) into the mixed solvent of EtOH (200mL) and saturated NH 4 Cl solution (20mL), then add iron powder (24.01g, 430.01mmol), heat up to 90°C, and stir the reaction 16 hours. LC-MS detected that the reaction raw materials were complete, and the reaction solution was diluted by adding a large amount of ethyl acetate (500 mL) and then filtered through diatomaceous earth. The filtrate was rotary evaporated to remove the solvent, and separated by column chromatography (petroleum ether/ethyl acetate=55%). Compound A67-3 (10.50 g, 42.16 mmol, yield: 98.03%) was obtained as a brown-black solid.
LC-MS[M+1]+＝249.0LC-MS [M+1] + = 249.0
步骤三：化合物A67-3(10.4g,41.75mmol)加入醋酸(100mL)与ACN(10mL)中，搅拌降温至-5℃。滴加NaNO2溶液(3.17g,45.93mmol)再继续反应2小时，LC-MS检测发现原料反应完全，反应液倒入水(500mL)中，乙酸乙酯(100 mL x 3)萃取，饱和食盐水洗涤，无水硫酸钠干燥，柱层析分离(石油醚/乙酸乙酯＝60％)，得到化合物A67-4(7.00g,粗品)为红棕色固体油状混合物。Step 3: Compound A67-3 (10.4 g, 41.75 mmol) was added into acetic acid (100 mL) and ACN (10 mL), stirred and cooled to -5°C. NaNO solution (3.17g, 45.93mmol) was added dropwise and the reaction was continued for 2 hours, and the LC-MS detection found that the raw material had reacted completely, and the reaction solution was poured into water (500mL), ethyl acetate (100 mL x 3) extraction, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (petroleum ether/ethyl acetate=60%) to obtain compound A67-4 (7.00g, crude product) as a reddish-brown solid oily mixture .
LC-MS[M+1]+＝260.0LC-MS [M+1] + = 260.0
步骤四：将化合物A67-4(6g,23.07mmol)溶于DCM(50mL)中，加入SOCl2(8.23g,69.21mmol)，再加入DMF(催化量加2～3滴)，升温至45℃搅拌反应12小时。LC-MS检测发现反应完全，反应液旋蒸除去溶剂，柱层析分离(乙酸乙酯/石油醚＝25-40％)，得到化合物A67-5(4.0g,14.36mmol，产率：62.25％)为棕色固体。1H NMR(400MHz,Methanol-d4)δ8.04(d,J＝1.3Hz,1H),7.50(dd,J＝10.1,1.4Hz,1H),5.22–5.05(m,2H),4.10(t,J＝5.9,0.6Hz,2H).Step 4: Dissolve compound A67-4 (6g, 23.07mmol) in DCM (50mL), add SOCl 2 (8.23g, 69.21mmol), then add DMF (add 2-3 drops of catalytic amount), heat up to 45°C The reaction was stirred for 12 hours. LC-MS detection found that the reaction was complete, the reaction solution was rotary evaporated to remove the solvent, and separated by column chromatography (ethyl acetate/petroleum ether=25-40%) to obtain compound A67-5 (4.0g, 14.36mmol, yield: 62.25%) ) is a brown solid. 1 H NMR (400MHz, Methanol-d 4 ) δ8.04 (d, J = 1.3Hz, 1H), 7.50 (dd, J = 10.1, 1.4Hz, 1H), 5.22–5.05 (m, 2H), 4.10 ( t,J=5.9,0.6Hz,2H).
LC-MS[M+1]+＝278.0LC-MS [M+1] + = 278.0
步骤五：将A67-5(700mg,2.51mmol)溶解在dioxane(10mL)中，加入三丁基(1-乙氧基乙烯)锡(1.82g,5.03mmol)和Pd(dppf)Cl2(182.39mg,251.34μmol)，氮气保护，90℃下反应12小时。LC-MS显示中间态生成。降温至常温25℃，加入2.2N HCl(10mL)，继续反应2小时。LC-MS显示原料基本反应完全。反应液加KF溶液淬灭，乙酸乙酯(50mL x 3)萃取，饱和食盐水(200mL)洗涤，无水硫酸钠干燥，减压浓缩。经柱层析(石油醚/乙酸乙酯＝5/1)分离纯化得到目标产物A67-6(500mg,产率：74.09％)为白色固体。Step 5: Dissolve A67-5 (700mg, 2.51mmol) in dioxane (10mL), add tributyl(1-ethoxyethylene)tin (1.82g, 5.03mmol) and Pd(dppf)Cl 2 (182.39 mg, 251.34μmol), under nitrogen protection, react at 90°C for 12 hours. LC-MS showed intermediate state formation. Cool down to room temperature 25°C, add 2.2N HCl (10 mL), and continue the reaction for 2 hours. LC-MS showed that the starting material was almost completely reacted. The reaction solution was quenched with KF solution, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target product A67-6 (500 mg, yield: 74.09%) was separated and purified by column chromatography (petroleum ether/ethyl acetate=5/1) as a white solid.
LC-MS[M+1]+＝242.1LC-MS [M+1] + = 242.1
步骤六：将化合物A67-6(500mg,2.07mmol)溶于THF(10mL)中，0℃下滴加进4-(2-四氢-2H-吡喃氧代)苯基溴化镁溶液(0.5M,16.55mL)中。0℃搅拌反应1小时。LC-MS检测发现反应完全，反应液倒入水中(30mL)淬灭，乙酸乙酯萃取(30mL x 3)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压浓缩，柱层析(乙酸乙酯/石油醚＝0-100％)得到化合物A67-7(868mg，2.07mmol，产率：99.91％)为淡黄色油状物。Step 6: Compound A67-6 (500mg, 2.07mmol) was dissolved in THF (10mL), and added dropwise into 4-(2-tetrahydro-2H-pyranyloxy)phenylmagnesium bromide solution at 0°C ( 0.5M, 16.55mL). The reaction was stirred at 0°C for 1 hour. LC-MS detection found that the reaction was complete, the reaction solution was poured into water (30mL) to quench, extracted with ethyl acetate (30mL x 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (Ethyl acetate/petroleum ether=0-100%) gave compound A67-7 (868 mg, 2.07 mmol, yield: 99.91%) as a light yellow oil.
LC-MS[M+1]+＝420.3LC-MS [M+1] + = 420.3
步骤七：将化合物A67-7(800mg,1.91mmol)溶于AcOH(1mL)和H2O(0.3mL)中，25℃搅拌反应2小时。LC-MS检测发现原料反应完全，反应液减压浓缩，柱层析(石油醚/乙酸乙酯＝3/1)得到化合物A67(567mg,1.79mmol,产率：93.7％) 为黄色油状物。Step 7: Compound A67-7 (800 mg, 1.91 mmol) was dissolved in AcOH (1 mL) and H 2 O (0.3 mL), and stirred at 25° C. for 2 hours. LC-MS detection found that the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and column chromatography (petroleum ether/ethyl acetate=3/1) gave compound A67 (567mg, 1.79mmol, yield: 93.7%) For the yellow oil.
LC-MS[M+1]+＝318.1LC-MS [M+1] + = 318.1
中间体A68的合成：(1-(2-氯乙基)-7-氟-1H-吲唑-5-基)(4-羟基苯基)甲酮
Synthesis of Intermediate A68: (1-(2-Chloroethyl)-7-fluoro-1H-indazol-5-yl)(4-hydroxyphenyl)methanone
步骤一：将A68-1(2g,7.79mmol)加入到四氢呋喃(16mL)和水(4mL)中，随后加入氢氧化锂(373.26mg,15.58mmol)，在25℃下搅拌反应16h。反应结束后，向反应液中加入少量冰水(20mL)，用4M盐酸调节酸碱度(pH＝3)，待固体析出后过滤得A68-2(1.99g,7.37mmol,产率：94.54％)，性状为白色固体。Step 1: Add A68-1 (2g, 7.79mmol) into tetrahydrofuran (16mL) and water (4mL), then add lithium hydroxide (373.26mg, 15.58mmol), and stir the reaction at 25°C for 16h. After the reaction was completed, a small amount of ice water (20 mL) was added to the reaction solution, and the pH was adjusted with 4M hydrochloric acid (pH=3). After the solid precipitated, it was filtered to obtain A68-2 (1.99 g, 7.37 mmol, yield: 94.54%). Appearance is white solid.
LC-MS[M+1]+＝242.9LC-MS [M+1] + = 242.9
步骤二：将A68-2(1.9g,7.83mmol)、甲氧基甲基胺(478.32mg,7.83mmol)加入到N,N-二甲基甲酰胺(30mL)中，随后再加入三乙胺(2.38g,23.49mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(5.95g,15.66mmol)，体系在25℃下反应2小时。反应结束后加入水(20mL)和乙酸乙酯(200mL)，用饱和氯化钠(200mL x 3)洗涤，无水硫酸钠干燥，有机相浓缩至干，经柱层析(乙酸乙酯/石油醚＝0至20％)纯化得A68-3(2.00g,6.30mmol,产率：80.46％)，性状为浅黄色油状物。Step 2: Add A68-2 (1.9g, 7.83mmol), methoxymethylamine (478.32mg, 7.83mmol) to N,N-dimethylformamide (30mL), and then add triethylamine (2.38g, 23.49mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.95g, 15.66mmol), the system was The reaction was carried out at 25°C for 2 hours. After the reaction, add water (20mL) and ethyl acetate (200mL), wash with saturated sodium chloride (200mL x 3), dry over anhydrous sodium sulfate, and concentrate the organic phase to dryness. ether=0 to 20%) to obtain A68-3 (2.00 g, 6.30 mmol, yield: 80.46%) as a pale yellow oil.
LC-MS[M+1]+＝286.10LC-MS [M+1] + = 286.10
步骤三：将A68-3(2.2g,7.70mmol)溶于四氢呋喃(20mL)中，升温至35℃， 缓慢滴加4-(2-四氢-2H-吡喃氧代)苯基溴化镁溶液(0.5M,9.24mmol)，加毕体系搅拌反应1小时。反应结束后，将混合物冷却至室温，倒入饱和氯化铵溶液中，加入乙酸乙酯(300mL x 3)萃取，有机相浓缩至干。经柱层析(乙酸乙酯/石油醚＝0至30％)纯化得A68-4(2.84g,6.34mmol,产率：82.34％)，性状为淡黄色油状物。1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.2Hz,1H),8.05–7.96(m,1H),7.74(d,J＝8.9Hz,2H),7.57(dd,J＝12.7,1.2Hz,1H),7.15(d,J＝8.9Hz,2H),5.61(d,J＝3.4Hz,1H),4.84(t,J＝5.6Hz,2H),4.08(t,J＝5.4Hz,2H),2.09–0.58(m,8H).LC-MS[M+1]+＝403.2Step 3: Dissolve A68-3 (2.2g, 7.70mmol) in tetrahydrofuran (20mL), heat up to 35°C, 4-(2-Tetrahydro-2H-pyranyloxy)phenylmagnesium bromide solution (0.5M, 9.24mmol) was slowly added dropwise, and the system was stirred and reacted for 1 hour after the addition. After the reaction, the mixture was cooled to room temperature, poured into saturated ammonium chloride solution, added ethyl acetate (300mL x 3) for extraction, and the organic phase was concentrated to dryness. Purified by column chromatography (ethyl acetate/petroleum ether = 0 to 30%) to obtain A68-4 (2.84 g, 6.34 mmol, yield: 82.34%) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d 6 )δ8.39(d, J=2.2Hz, 1H), 8.05–7.96(m, 1H), 7.74(d, J=8.9Hz, 2H), 7.57(dd, J=12.7,1.2Hz,1H),7.15(d,J=8.9Hz,2H),5.61(d,J=3.4Hz,1H),4.84(t,J=5.6Hz,2H),4.08(t, J＝5.4Hz, 2H), 2.09–0.58(m, 8H).LC-MS[M+1] + ＝403.2
步骤四：将A68-4(1g,2.48mmol)溶于1,4-二氧六环(1mL)，氮气置换3次，在25℃下滴加盐酸(181.02mg,4.96mmol)，搅拌反应1小时。反应完毕后将反应液浓缩，加入乙酸乙酯(50mL)，用饱和碳酸氢钠(50mL x 2)和饱和氯化钠(50mL x 2)洗涤，无水硫酸钠干燥，有机相浓缩至干，经柱层析(乙酸乙酯/石油醚＝0至40％)纯化得A68(769.00mg,2.17mmol,产率：87.48％)，性状为白色固体。Step 4: Dissolve A68-4 (1g, 2.48mmol) in 1,4-dioxane (1mL), replace with nitrogen three times, add hydrochloric acid (181.02mg, 4.96mmol) dropwise at 25°C, and stir for reaction 1 Hour. After the reaction was completed, the reaction solution was concentrated, ethyl acetate (50 mL) was added, washed with saturated sodium bicarbonate (50 mL x 2) and saturated sodium chloride (50 mL x 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness. Purified by column chromatography (ethyl acetate/petroleum ether = 0 to 40%) to obtain A68 (769.00 mg, 2.17 mmol, yield: 87.48%) as a white solid.
LC-MS[M+1]+＝319.2LC-MS [M+1] + = 319.2
中间体A69的合成：4-((1-(2-氯乙基)-7-氟-1H-吲唑-5-基)硫代)苯酚
Synthesis of Intermediate A69: 4-((1-(2-Chloroethyl)-7-fluoro-1H-indazol-5-yl)thio)phenol
步骤一：将A69-1(5g,23.25mmol)，1-溴-2-氯-乙烷(10.00g,69.76mmol,5.81mL)，Cs2CO3(11.34g,34.88mmol)加入到DMF(47.68mL)，N2保护，20℃下搅拌3小时。LCMS监测反应完成。将反应液倒入水中，EA(200mL)萃取，有机相用饱和食盐水洗涤(300mL*3)，有机相浓缩，柱层析(石油醚：乙酸乙酯＝5:1)纯化得目标产物A69-2(2.70g,产率：41.84％)，性状为白色固体。Step 1: A69-1 (5g, 23.25mmol), 1-bromo-2-chloro-ethane (10.00g, 69.76mmol, 5.81mL), Cs 2 CO 3 (11.34g, 34.88mmol) were added to DMF ( 47.68mL), under N 2 protection, stirred at 20°C for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was poured into water, extracted with EA (200mL), the organic phase was washed with saturated brine (300mL*3), the organic phase was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product A69 -2 (2.70g, yield: 41.84%), the property is a white solid.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝2.3Hz,1H),7.83(d,J＝1.5Hz,1H),7.47(dd,J＝11.4,1.5Hz,1H),4.76(t,J＝5.6Hz,2H),4.03(t,J＝5.6Hz,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.17(d, J=2.3Hz, 1H), 7.83(d, J=1.5Hz, 1H), 7.47(dd, J=11.4, 1.5Hz, 1H) ,4.76(t,J=5.6Hz,2H),4.03(t,J=5.6Hz,2H).
LC-MS[M+1]+＝279.0LC-MS [M+1] + = 279.0
步骤二：将A69-2(1g,3.60mmol)，对甲氧基苯硫酚(757.80mg,5.41mmol)，DIPEA(931.39mg,7.21mmol)，Pd2(dba)3(329.96mg,360.33μmol)，Xantphos (208.50mg,360.33μmol)加入到dioxane(15mL)，N2保护，100℃下搅拌8小时。LCMS监测反应完成。有机相浓缩，柱层析(石油醚：乙酸乙酯＝5:1)纯化得目标产物A69-3(700.00mg,产率：57.68％)，性状为黄色固体。Step 2: A69-2 (1g, 3.60mmol), p-methoxythiophenol (757.80mg, 5.41mmol), DIPEA (931.39mg, 7.21mmol), Pd 2 (dba) 3 (329.96mg, 360.33μmol ), Xantphos (208.50 mg, 360.33 μmol) was added to dioxane (15 mL), N 2 protected, and stirred at 100° C. for 8 hours. LCMS monitored the completion of the reaction. The organic phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product A69-3 (700.00 mg, yield: 57.68%) as a yellow solid.
LC-MS[M+1]+＝337.0LC-MS [M+1] + = 337.0
步骤三：将A69-3(480mg,1.43mmol)溶于DCM(6mL)，滴加BBr3(1.79g,7.13mmol)，N2保护，0℃下搅拌1小时。LCMS监测反应完成。将反应液倒入水中，DCM(20Ml)萃取，有机相用饱和食盐水洗涤(30mL*3)，有机相浓缩，柱层析(石油醚：乙酸乙酯＝5:1)纯化得目标产物A69(330.00mg,产率：71.74％)，性状为黄色油状物。1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.11(d,J＝2.3Hz,1H),7.35(d,J＝1.4Hz,1H),7.32–7.27(m,2H),7.06(dd,J＝12.3,1.4Hz,1H),6.82–6.76(m,2H),4.73(t,J＝5.7Hz,2H),4.01(t,J＝5.4Hz,2H).Step 3: Dissolve A69-3 (480 mg, 1.43 mmol) in DCM (6 mL), add BBr 3 (1.79 g, 7.13 mmol) dropwise, protect with N 2 , and stir at 0°C for 1 hour. LCMS monitored the completion of the reaction. The reaction solution was poured into water, extracted with DCM (20Ml), the organic phase was washed with saturated brine (30mL*3), the organic phase was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product A69 (330.00mg, Yield: 71.74%), the property is yellow oil. 1 H NMR (400MHz, DMSO-d 6 )δ9.83(s, 1H), 8.11(d, J=2.3Hz, 1H), 7.35(d, J=1.4Hz, 1H), 7.32–7.27(m, 2H), 7.06(dd, J=12.3, 1.4Hz, 1H), 6.82–6.76(m, 2H), 4.73(t, J=5.7Hz, 2H), 4.01(t, J=5.4Hz, 2H).
LC-MS[M+1]+＝323.0LC-MS [M+1] + = 323.0
中间体I-B1的合成：噻吩，1,1,2,3,4,5-六氢-1-亚氨基-1-氧化物
Synthesis of intermediate I-B1: thiophene, 1,1,2,3,4,5-hexahydro-1-imino-1-oxide
步骤一：向反应瓶中依次加入甲醇(5mL)，四氢噻吩(0.20mL,2.27mmol)，氨基甲酸铵(177.1mg,2.27mmol)和醋酸碘苯(1826.6mg,5.67mmol)，在25℃下敞口搅拌1小时，反应完全后，反应液加压浓缩，通过柱层析(0-7％甲醇/二氯甲烷)纯化得到黄色液体I-B1(200mg,1.68mmol,73.98％)。Step 1: Add methanol (5mL), tetrahydrothiophene (0.20mL, 2.27mmol), ammonium carbamate (177.1mg, 2.27mmol) and iodobenzene acetate (1826.6mg, 5.67mmol) to the reaction flask in sequence, at 25°C After the reaction was complete, the reaction solution was concentrated under pressure and purified by column chromatography (0-7% methanol/dichloromethane) to obtain a yellow liquid I-B1 (200mg, 1.68mmol, 73.98%).
1H NMR(400MHz,Chloroform-d)δ3.22-3.12(m,4H),2.36-2.22(m 4H). 1 H NMR (400MHz, Chloroform-d) δ3.22-3.12 (m, 4H), 2.36-2.22 (m 4H).
中间体I-B2的合成：1λ4-噻吩-1-亚胺-1-氧化物
Synthesis of intermediate I-B2: 1λ 4 -thiophene-1-imine-1-oxide
参考中间体I-B1的合成方法，用三甲烯化硫代替四氢噻吩，进行一步反应得到 中间体I-B2。With reference to the synthetic method of intermediate I-B1, replace tetrahydrothiophene with sulfur trimethene, and carry out a one-step reaction to obtain Intermediate I-B2.
1H NMR(400MHz,Chloroform-d)δ4.21-4.03(m,4H),2.29-2.06(m,2H). 1 H NMR (400MHz, Chloroform-d) δ4.21-4.03 (m, 4H), 2.29-2.06 (m, 2H).
中间体I-B3的合成：1λ4-硫吡喃-1-亚胺-六氢-1-氧化物
Synthesis of intermediate I-B3: 1λ 4 -thiopyran-1-imine-hexahydro-1-oxide
参考中间体I-B1的合成方法，用硫化环戊烷代替四氢噻吩，进行一步反应得到中间体I-B3。Refer to the synthesis method of intermediate I-B1, replace tetrahydrothiophene with cyclopentane sulfide, and perform a one-step reaction to obtain intermediate I-B3.
1H NMR(400MHz,Chloroform-d)δ3.12-2.88(m,4H),2.17-1.99(m,4H),1.69-1.49(m,2H). 1 H NMR (400MHz, Chloroform-d) δ3.12-2.88 (m, 4H), 2.17-1.99 (m, 4H), 1.69-1.49 (m, 2H).
中间体I-B4的合成：2H-4λ4-1,4-氧硫辛-4-亚胺-4-氧化物
Synthesis of Intermediate I-B4: 2H-4λ 4 -1,4-Oxythione-4-imine-4-oxide
参考中间体I-B1的合成方法，用1,4-噻恶烷代替四氢噻吩，进行一步反应得到中间体I-B4。Refer to the synthesis method of intermediate I-B1, replace tetrahydrothiophene with 1,4-thioxane, and perform a one-step reaction to obtain intermediate I-B4.
1H NMR(400MHz,Chloroform-d)δ4.31(brs,1H),4.17-3.86(m,4H),3.12(t,J＝5.2Hz,4H). 1 H NMR (400MHz, Chloroform-d) δ 4.31 (brs, 1H), 4.17-3.86 (m, 4H), 3.12 (t, J=5.2Hz, 4H).
中间体I-B5的合成：1λ4-硫吗啉-4-羧酸-1-亚氨基-1,1-二甲基乙酯-1-氧化物
Synthesis of intermediate I-B5: 1λ 4 -thiomorpholine-4-carboxylic acid-1-imino-1,1-dimethylethyl ester-1-oxide
步骤一：向反应瓶中依次加入二氯甲烷(10mL)，硫吗啉(0.18mL,1.94mmol)，三乙胺(0.81mL,5.82mmol)和Boc2O(634.5mg,2.91mmol)，在25℃下搅拌12小时，反应完全后，反应液加压浓缩，通过柱层析(0-8％乙酸乙酯/石油醚)纯化得到白色固 体I-B5-1(370mg,1.82mmol,93.90％)。Step 1: Add dichloromethane (10mL), thiomorpholine (0.18mL, 1.94mmol), triethylamine (0.81mL, 5.82mmol) and Boc 2 O (634.5mg, 2.91mmol) to the reaction flask successively, in Stir at 25°C for 12 hours. After the reaction is complete, the reaction solution is concentrated under pressure and purified by column chromatography (0-8% ethyl acetate/petroleum ether) to obtain a white solid Body I-B5-1 (370 mg, 1.82 mmol, 93.90%).
1H NMR(400MHz,Chloroform-d)δ3.80-3.60(m,4H),2.72-2.49(m,4H),1.49(s,9H). 1 H NMR (400MHz, Chloroform-d) δ3.80-3.60 (m, 4H), 2.72-2.49 (m, 4H), 1.49 (s, 9H).
步骤二：参考中间体I-B1的合成方法，用中间体I-B5-1代替四氢噻吩，进行一步反应得到中间体I-B5。Step 2: Refer to the synthesis method of intermediate I-B1, replace tetrahydrothiophene with intermediate I-B5-1, and perform a one-step reaction to obtain intermediate I-B5.
1H NMR(400MHz,Chloroform-d)δ5.18(s,1H),4.09-3.92(m,2H),3.91-3.78(m,2H),3.15-2.98(m,4H),1.49(s,9H). 1 H NMR (400MHz, Chloroform-d) δ5.18(s,1H),4.09-3.92(m,2H),3.91-3.78(m,2H),3.15-2.98(m,4H),1.49(s, 9H).
中间体I-B6的合成：(S)-N-(1-亚氨基-1-氧化三氢-1H-1λ6-噻吩-3-基)-2-甲基丙烷-2-亚硫酰胺
Synthesis of intermediate I-B6: (S)-N-(1-imino-1-oxytrihydro-1H- 1λ6 -thiophen-3-yl)-2-methylpropane-2-thionamide
步骤一：向反应瓶中依次加入噻吩-3-酮(2g,19.58mmol)，(R)-叔丁亚磺酰胺(2.61g,21.54mmol)和无水四氢呋喃(40mL)，最后加入钛酸四乙脂(8.21mL,39.15mmol)。黄色反应液在65℃下敞口搅拌2小时，然后降温到0℃，滴加到配好的硼氢化钠/四氢呋喃中(1.48g n溶解于40mL)，继续搅拌2小时。缓慢滴加甲醇(20mL)淬灭反应液后，减压浓缩，残留物用乙酸乙酯(60mL)稀释过滤，滤液再用饱和食盐水(40mL)洗涤，干燥，减压浓缩，通过柱层析(0-40％乙酸乙酯/石油醚)纯化得到黄色固体I-B6-1(2.75g,13.26mmol,67.75％)。Step 1: Add thiophen-3-one (2g, 19.58mmol), (R)-tert-butylsulfinamide (2.61g, 21.54mmol) and anhydrous tetrahydrofuran (40mL) to the reaction flask in sequence, and finally add tetratitanate Ethyl ester (8.21 mL, 39.15 mmol). The yellow reaction solution was stirred at 65 °C for 2 hours, then cooled to 0 °C, added dropwise to the prepared sodium borohydride/tetrahydrofuran (1.48 g n dissolved in 40 mL), and continued to stir for 2 hours. Slowly add methanol (20mL) to quench the reaction solution, concentrate under reduced pressure, the residue is diluted with ethyl acetate (60mL) and filtered, the filtrate is washed with saturated brine (40mL), dried, concentrated under reduced pressure, and passed through column chromatography Purification (0-40% ethyl acetate/petroleum ether) gave I-B6-1 (2.75 g, 13.26 mmol, 67.75%) as a yellow solid.
步骤二：参考中间体I-B1的合成方法，用中间体I-B6-1代替四氢噻吩，进行一步反应得到中间体I-B6。Step 2: Refer to the synthesis method of intermediate I-B1, replace tetrahydrothiophene with intermediate I-B6-1, and perform a one-step reaction to obtain intermediate I-B6.
中间体I-B7的合成：(S)-N-(1-亚氨基-1-氧化六氢-1λ6-硫吡喃-4-基)-2-甲基丙烷-2-亚硫酰胺
Synthesis of intermediate I-B7: (S)-N-(1-imino-1-oxyhexahydro- 1λ6 -thiopyran-4-yl)-2-methylpropane-2-sulfinamide
参考中间体I-B6的合成方法，用四氢噻喃-4-酮代替噻吩-3-酮，进行两步反应得到中间体I-B7。Refer to the synthesis method of intermediate I-B6, replace thiophen-3-one with tetrahydrothiopyran-4-one, and perform two-step reaction to obtain intermediate I-B7.
中间体I-B8的合成：4-(氯甲基)-2-(甲硫基)噁唑
Synthesis of Intermediate I-B8: 4-(Chloromethyl)-2-(methylthio)oxazole
步骤一：将I-B8-1(1g,4.55mmol)溶于EtOH(15mL)，然后加入MeSNa(530.94mg,6.82mmol,90％purity)，在氮气保护下升温至80℃反应2小时，LC-MS结果表明原料反应完全，将以上反应液浓缩后加入水(10mL)和乙酸乙酯(10mL*3)萃取，有机相用饱和食盐水洗涤，然后用无水硫酸钠干燥、浓缩后得到I-B8-2(0.566g,收率：62.56％)为黄色固体Step 1: Dissolve I-B8-1 (1g, 4.55mmol) in EtOH (15mL), then add MeSNa (530.94mg, 6.82mmol, 90%purity), heat up to 80°C under nitrogen protection for 2 hours, LC -MS results show that the raw material has reacted completely. After the above reaction solution is concentrated, water (10mL) and ethyl acetate (10mL*3) are added for extraction. The organic phase is washed with saturated brine, then dried with anhydrous sodium sulfate, and concentrated to obtain I -B8-2 (0.566g, yield: 62.56%) is a yellow solid
LC-MS[M+1]+＝174.19LC-MS [M+1] + = 174.19
步骤二：将I-B8-2(0.436g,2.33mmol)溶于THF(16mL)和EtOH(4mL)中，然后加入NaBH4(88.10mg,2.33mmol)，氮气置换3次，在氮气保护下升温至60℃，搅拌反应4小时。将反应液降温至0℃，加入饱和氯化铵水溶液淬灭，将反应液PH调为中性，浓缩后，加入水(2mL)和乙酸乙酯(10mL*2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩。通过TLC板纯化(乙酸乙酯)最终得到I-B8-3(0.234g,收率：66.44％)，为黄色油状物。Step 2: Dissolve I-B8-2 (0.436g, 2.33mmol) in THF (16mL) and EtOH (4mL), then add NaBH 4 (88.10mg, 2.33mmol), nitrogen replacement 3 times, under nitrogen protection The temperature was raised to 60°C, and the reaction was stirred for 4 hours. Cool the reaction solution to 0°C, add saturated ammonium chloride aqueous solution to quench, adjust the pH of the reaction solution to neutral, concentrate, add water (2mL) and ethyl acetate (10mL*2) for extraction, and use saturated salt for the organic phase Washed with water, dried over anhydrous sodium sulfate, concentrated. Purification by TLC plate (ethyl acetate) finally gave I-B8-3 (0.234 g, yield: 66.44%) as a yellow oil.
LC-MS[M+1]+＝146.18LC-MS [M+1] + = 146.18
步骤三：往I-B8-3(130mg,895.44μmol)中加入SOCl2(106.53mg,895.44μmol)，然后升温至80℃回流0.5小时。TLC点板(PE：EA＝1：3)，反应完全，浓缩，加入乙腈溶解后再次浓缩得到中间体I-B8(130mg，粗品)。Step 3: Add SOCl 2 (106.53 mg, 895.44 μmol) to I-B8-3 (130 mg, 895.44 μmol), then raise the temperature to 80° C. and reflux for 0.5 hours. TLC spot plate (PE:EA=1:3), the reaction was complete, concentrated, added acetonitrile to dissolve and concentrated again to obtain intermediate I-B8 (130mg, crude product).
中间体I-B9的合成：4-(氯甲基)-5-(甲硫基)噁唑
Synthesis of Intermediate I-B9: 4-(Chloromethyl)-5-(methylthio)oxazole
步骤一：将I-B9-1(5g,35.43mmol)溶于乙腈(50mL)，加入NBS(9.46g,53.14mmol)和AIBN(581.79mg,3.54mmol)。反应在85℃反应16小时。反应液浓缩后过柱纯化(石油醚/乙酸乙酯＝5/1)得到I-B9-2(1.6g,产率：18.47％)，为黄色油状液体。1H-NMR(400MHz,Chloroform-d)δ8.25(s,1H),4.40(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H).LC-MS[M+H]+＝220.0/222.0Step 1: Dissolve I-B9-1 (5g, 35.43mmol) in acetonitrile (50mL), add NBS (9.46g, 53.14mmol) and AIBN (581.79mg, 3.54mmol). The reaction was carried out at 85°C for 16 hours. The reaction solution was concentrated and purified by column (petroleum ether/ethyl acetate=5/1) to obtain I-B9-2 (1.6 g, yield: 18.47%) as a yellow oily liquid. 1H-NMR (400MHz, Chloroform-d) δ8.25(s,1H),4.40(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H).LC-MS[M+H ] + ＝220.0/222.0
步骤二：将I-B9-2(1.6g,7.27mmol)溶解于乙醇(8mL)中，加入甲硫醇钠(611.63mg,8.73mmol)。混合物在80℃下反应2小时。反应液浓缩后过柱(石油醚/乙酸乙酯＝5/1)得到I-B9-3(1.1g,产率：76.76％)，为黄色固体。Step 2: Dissolve I-B9-2 (1.6g, 7.27mmol) in ethanol (8mL), and add sodium methylthiolate (611.63mg, 8.73mmol). The mixture was reacted at 80°C for 2 hours. The reaction solution was concentrated and passed through a column (petroleum ether/ethyl acetate=5/1) to obtain I-B9-3 (1.1 g, yield: 76.76%) as a yellow solid.
1H-NMR(400MHz,Chloroform-d)δ8.18(s,1H),4.38(q,J＝7.1Hz,2H),2.71(s,3H),1.38(t,J＝7.1Hz,3H).LC-MS[M+H]+＝187.9 1 H-NMR (400MHz, Chloroform-d) δ8.18(s, 1H), 4.38(q, J=7.1Hz, 2H), 2.71(s, 3H), 1.38(t, J=7.1Hz, 3H) .LC-MS [M+H] + = 187.9
步骤三：将I-B9-3(0.6g,3.20mmol)溶在乙醇中，加入NaBH4(242.48mg,6.41mmol)。将混合物加热到70℃反应两个小时。反应液慢慢倒入100mL水中，加入乙酸乙酯(50mL)。水相用乙酸乙酯萃取三遍，合并有机相后用饱和食盐水洗涤2次，用无水硫酸钠干燥后浓缩得到I-B9-4(450mg,2.76mmol,收率：86.08％)，为无色油状液体直接用于下一步。Step 3: Dissolve I-B9-3 (0.6g, 3.20mmol) in ethanol, and add NaBH 4 (242.48mg, 6.41mmol). The mixture was heated to 70°C for two hours. The reaction solution was slowly poured into 100 mL of water, and ethyl acetate (50 mL) was added. The aqueous phase was extracted three times with ethyl acetate, the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain I-B9-4 (450mg, 2.76mmol, yield: 86.08%), as The colorless oily liquid was used directly in the next step.
步骤四：将I-B9-4(450mg,3.10mmol)溶在二氯甲烷(9.55mL)中之后加入SOCl2(737.52mg,6.20mmol,449.71μL)。反应在40℃下反应2小时。LCMS检测反应完成。混合物浓缩之后得到I-B9(400mg,2.08mmol,收率：67.04％)，为无色油状液体直接用于下一步。MS(ESI)m/z＝164[M+H]+ Step 4: Dissolve I-B9-4 (450 mg, 3.10 mmol) in dichloromethane (9.55 mL) and add SOCl 2 (737.52 mg, 6.20 mmol, 449.71 μL). The reaction was carried out at 40°C for 2 hours. LCMS detected that the reaction was complete. After the mixture was concentrated, I-B9 (400 mg, 2.08 mmol, yield: 67.04%) was obtained as a colorless oily liquid, which was directly used in the next step. MS(ESI)m/z=164[M+H] +
中间体I-B10的合成：2-氯-6-(氯甲基)吡嗪
Synthesis of Intermediate I-B10: 2-Chloro-6-(chloromethyl)pyrazine
将原料I-B10-1(1g,7.78mmol)溶解在乙腈(15mL)中，然后加入AIBN和NCS，升温至85℃搅拌反应16小时，浓缩。浓缩后的混合物使用柱层析(石油醚/乙酸乙酯＝4/1)得到产物I-B10(1.21g,产率：71.81％)，为黄色油状液体。LC-MS[M+1]+＝163The raw material I-B10-1 (1 g, 7.78 mmol) was dissolved in acetonitrile (15 mL), then AIBN and NCS were added, the temperature was raised to 85° C., the reaction was stirred for 16 hours, and concentrated. The concentrated mixture was subjected to column chromatography (petroleum ether/ethyl acetate=4/1) to obtain product I-B10 (1.21 g, yield: 71.81%) as a yellow oily liquid. LC-MS[M+1] + =163
中间体B11的合成：1-亚胺-4-(吡啶-2-基)-1λ6-硫代吗啡啉-1-氧代
Synthesis of intermediate B11: 1-imino-4-(pyridin-2-yl)-1λ 6 -thiomorpholine-1-oxo
步骤一：将B11-1(200mg,2.06mmol,177.30μL)，硫代吗啡啉(637.67mg,6.18mmol,621.51μL)溶于DMA(5mL)，60℃下搅拌4小时，LCMS监测反应完成，加水(30mL)和乙酸乙酯萃取(20mL*3)，饱和食盐水(20mL*3)洗涤有机相，有机相拌样，经正相柱(石油醚:乙酸乙酯＝15:1)纯化得目标产物B11-2(90.00mg，产率：24.24％)，性状为透明油状物。Step 1: Dissolve B11-1 (200mg, 2.06mmol, 177.30μL) and thiomorpholine (637.67mg, 6.18mmol, 621.51μL) in DMA (5mL), stir at 60°C for 4 hours, and monitor the completion of the reaction by LCMS. Add water (30mL) and ethyl acetate to extract (20mL*3), wash the organic phase with saturated brine (20mL*3), mix the organic phase, and purify by normal phase column (petroleum ether:ethyl acetate=15:1) to obtain The target product B11-2 (90.00 mg, yield: 24.24%) is a transparent oil.
LC-MS[M+1]+＝181.1LC-MS [M+1] + = 181.1
步骤二：将B11-2(90mg,499.25μmol)，[acetoxy(phenyl)-iodanyl]acetate(402.02mg,1.25mmol)，NH2COONH4(42.84mg,549.18μmol)加入到MeOH(2mL)中，反应室温搅拌2小时，LCMS监测完成，将反应液拌样，经正相柱(石油醚:乙酸乙酯＝0:1)纯化得目标产物B11(40.00mg，产率：37.92％)，性状为白色固体。Step 2: Add B11-2 (90mg, 499.25μmol), [acetoxy(phenyl)-iodanyl]acetate (402.02mg, 1.25mmol), NH 2 COONH 4 (42.84mg, 549.18μmol) into MeOH (2mL), The reaction was stirred at room temperature for 2 hours, and the LCMS monitoring was completed. The reaction solution was mixed and purified by a normal phase column (petroleum ether: ethyl acetate = 0:1) to obtain the target product B11 (40.00mg, yield: 37.92%), the properties are white solid.
LC-MS[M+1]+＝212.1LC-MS [M+1] + = 212.1
中间体B12的合成：6-亚胺基-2-氧-6λ4-硫代螺[3.3]庚烷-6-氧代
Synthesis of intermediate B12: 6-imino-2-oxo-6λ 4 -thiospiro[3.3]heptane-6-oxo
参考中间体I-B1的合成方法，进行一步反应得到中间体B12。Referring to the synthesis method of intermediate I-B1, a one-step reaction was carried out to obtain intermediate B12.
中间体B14的合成：苄基2-亚胺基-2λ6-硫代-6-氮杂螺[3.3]庚烷-6-碳酰氧基-2-氧代
Synthesis of Intermediate B14: Benzyl 2-imino-2λ 6 -thio-6-azaspiro[3.3]heptane-6-carbonyloxy-2-oxo
步骤一：将B14-1(800mg,3.16mmol)溶于四氢呋喃(2mL)中，0℃加入HBr水溶液(532.34mg,3.16mmol,1mL,48％purity)，反应1小时。加入饱和NaHCO3水溶液，调节pH＝8,用甲基叔丁基醚(10mL*3)萃取，饱和食盐水(10mL*3)洗，无水硫酸钠干燥，过滤，减压浓缩得目标产物B14-2(1.0g,crude)，为白色固体。LC-MS[M+23]+＝334.10Step 1: Dissolve B14-1 (800 mg, 3.16 mmol) in tetrahydrofuran (2 mL), add HBr aqueous solution (532.34 mg, 3.16 mmol, 1 mL, 48% purity) at 0°C, and react for 1 hour. Add saturated NaHCO 3 aqueous solution, adjust pH=8, extract with methyl tert-butyl ether (10mL*3), wash with saturated brine (10mL*3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the target product B14 -2 (1.0 g, crude), as a white solid. LC-MS [M+23] + = 334.10
步骤二：将B14-2(1.0g,2.99mmol)和CBr4(1.59g,4.79mmol)溶于二氯甲烷(20mL)，0℃加入PPh3(1.26g,4.79mmol),温度升到室温20℃继续反应12小时。将反应液减压浓缩，经柱层析(乙酸乙酯/石油醚＝0-30％)得到目标产物B14-3(700mg,产率：53.02％)为白色固体。Step 2: Dissolve B14-2 (1.0g, 2.99mmol) and CBr 4 (1.59g, 4.79mmol) in dichloromethane (20mL), add PPh 3 (1.26g, 4.79mmol) at 0°C, and raise the temperature to room temperature The reaction was continued for 12 hours at 20°C. The reaction solution was concentrated under reduced pressure, and the target product B14-3 (700 mg, yield: 53.02%) was obtained as a white solid through column chromatography (ethyl acetate/petroleum ether = 0-30%).
1H NMR(400MHz,Chloroform-d)δ7.72(d,J＝8.2Hz,2H),7.38(d,J＝7.5Hz,2H),δ3.58(d,J＝0.9Hz,4H),3.52(d,J＝1.1Hz,4H),2.46(s,3H). 1 H NMR (400MHz, Chloroform-d) δ7.72(d, J=8.2Hz, 2H), 7.38(d, J=7.5Hz, 2H), δ3.58(d, J=0.9Hz, 4H), 3.52(d, J=1.1Hz, 4H), 2.46(s, 3H).
步骤三：化合物B14-3(700mg,1.76mmol)溶于乙腈(20mL)和水(2mL)，加入Na2S(343.90mg,4.41mmol),50℃搅拌3小时。反应液减压浓缩，加水(30mL)，用乙酸乙酯(10mL*3)萃取，无水硫酸钠干燥，过滤，减压浓缩得目标产物B14-4(300mg,crude)为白色固体。LC-MS[M+1]+＝270.10Step 3: Compound B14-3 (700mg, 1.76mmol) was dissolved in acetonitrile (20mL) and water (2mL), Na 2 S (343.90mg, 4.41mmol) was added, and stirred at 50°C for 3 hours. The reaction solution was concentrated under reduced pressure, added with water (30 mL), extracted with ethyl acetate (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product B14-4 (300 mg, crude) as a white solid. LC-MS [M+1] + = 270.10
步骤四：将B14-4(240mg,890.93μmol)溶于甲醇(5mL)中，再加入镁粉(129.95mg,5.35mmol)，室温20℃反应3小时。反应液过滤得到目标产物B14-5(102.63mg,crude)，为无色甲醇溶液，直接用于下步反应。LC-MS[M+1]+＝116.10 Step 4: Dissolve B14-4 (240 mg, 890.93 μmol) in methanol (5 mL), then add magnesium powder (129.95 mg, 5.35 mmol), and react at room temperature 20° C. for 3 hours. The reaction solution was filtered to obtain the target product B14-5 (102.63 mg, crude) as a colorless methanol solution, which was directly used in the next reaction. LC-MS [M+1] + = 116.10
步骤五：将化合物B14-5(102.63mg,890.91μmol)溶于甲醇(20mL),20℃加入CbzCl(222.03mg,890.91μmol)和三乙胺(450.76mg,4.45mmol)，反应12小时。反应液直接减压浓缩，经柱层析(乙酸乙酯/石油醚＝0-16％)得到目标产物B14-6(220mg,crude)，为无色油状物。LC-MS[M+1]+＝250.10Step 5: Dissolve compound B14-5 (102.63 mg, 890.91 μmol) in methanol (20 mL), add CbzCl (222.03 mg, 890.91 μmol) and triethylamine (450.76 mg, 4.45 mmol) at 20°C, and react for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the target product B14-6 (220 mg, crude) was obtained as a colorless oil by column chromatography (ethyl acetate/petroleum ether=0-16%). LC-MS [M+1] + = 250.10
步骤六：将B14-6(220mg,882.37μmol)溶于甲醇(5mL)中，加入氨基甲酸胺(68.89mg,882.37μmol)和醋酸碘苯(284.21mg,882.37μmol)，室温20℃反应1小时。反应液减压浓缩，经柱层析(乙酸乙酯/石油醚＝0-100％)得到目标产物B14(180.00mg,产率：58.21％)，为无色油状物。LC-MS[M+1]+＝281.20Step 6: Dissolve B14-6 (220 mg, 882.37 μmol) in methanol (5 mL), add amine carbamate (68.89 mg, 882.37 μmol) and iodobenzene acetate (284.21 mg, 882.37 μmol), and react at room temperature 20°C for 1 hour . The reaction solution was concentrated under reduced pressure, and the target product B14 (180.00 mg, yield: 58.21%) was obtained as a colorless oil by column chromatography (ethyl acetate/petroleum ether = 0-100%). LC-MS [M+1] + = 281.20
中间体B15的合成：5-亚胺基-2-甲基-4,5,6,7-四氢-2H-5λ4-硫代吡喃[4,3-c]吡唑-5-氧代
Synthesis of intermediate B15: 5-imino-2-methyl-4,5,6,7-tetrahydro-2H-5λ 4 -thiopyrano[4,3-c]pyrazole-5-oxo generation
步骤六：化合物B15-1(5.0g，43.04mmol)溶于溶剂甲苯(40mL)中，加入B15-2(8.25g，47.34mmol)。20℃下搅拌反应18小时。将反应液浓缩得到中间体B15-3(6.0g,粗品)，为黄色油状物。LC-MS[M-1]-＝143.0Step 6: Compound B15-1 (5.0 g, 43.04 mmol) was dissolved in solvent toluene (40 mL), and B15-2 (8.25 g, 47.34 mmol) was added. The reaction was stirred at 20°C for 18 hours. The reaction solution was concentrated to obtain intermediate B15-3 (6.0 g, crude product) as a yellow oil. LC-MS[M-1] - = 143.0
步骤七：化合物B15-3(6g，粗品)溶于溶剂EtOH(60mL)中，加入水合肼(7.02g，175.17mmol)。90℃搅拌反应12小时。旋蒸除溶剂得到中间体B15-4(8.00g,粗品)，为淡黄色固体。LC-MS[M+1]+＝141.1Step 7: Compound B15-3 (6 g, crude product) was dissolved in solvent EtOH (60 mL), and hydrazine hydrate (7.02 g, 175.17 mmol) was added. The reaction was stirred at 90°C for 12 hours. The solvent was removed by rotary evaporation to obtain intermediate B15-4 (8.00 g, crude product) as a pale yellow solid. LC-MS [M+1] + = 141.1
步骤八：B15-4(4g，28.53mmol)溶于溶剂DMF(40mL)中，加入t-BuOK(3.51g，31.38mmol)，反应液搅拌均匀。0℃下加入MeI(4.05g，28.53mmol)，加完升温至20℃搅拌反应16小时。反应液倒入200mL水中淬灭，乙酸乙酯(40mL*3)萃取，饱和食盐水(30mL*3)洗涤，无水硫酸钠干 燥，柱层析分离(石油醚/四氢呋喃＝2/1)，得到中间体B15-5(2.00g，粗品)为淡黄色油状物。LC-MS[M+1]+＝155.1Step 8: B15-4 (4 g, 28.53 mmol) was dissolved in the solvent DMF (40 mL), t-BuOK (3.51 g, 31.38 mmol) was added, and the reaction solution was stirred evenly. MeI (4.05 g, 28.53 mmol) was added at 0°C, and after the addition, the temperature was raised to 20°C and the reaction was stirred for 16 hours. The reaction solution was quenched by pouring into 200mL water, extracted with ethyl acetate (40mL*3), washed with saturated brine (30mL*3), dried over anhydrous sodium sulfate Drying and separation by column chromatography (petroleum ether/tetrahydrofuran=2/1) gave intermediate B15-5 (2.00 g, crude product) as a pale yellow oil. LC-MS [M+1] + = 155.1
步骤九：B15-5(1.9g，粗品)溶于溶剂MeOH(20mL)中，加入NH2COONH4(2.11g，27.10mmol)和(Diacetoxyiodo)benzene(11.11g,34.49mmol)。30℃下搅拌反应16小时。旋蒸除溶剂，柱层析分离(甲醇/四氢呋喃＝3/17)，得到粗品1.70g。取400mg粗品进行Prep-HPLC制备的中间体B15(50.00mg)为白色固体。1H NMR(400MHz,DMSO-d6)δ7.44(s,1H),4.10(s,2H),3.78(s,1H),3.72(s,3H),3.21(ddt,J＝25.7,13.9,6.5Hz,2H),2.96(t,J＝6.4Hz,2H).Step 9: B15-5 (1.9 g, crude product) was dissolved in the solvent MeOH (20 mL), and NH 2 COONH 4 (2.11 g, 27.10 mmol) and (Diacetoxyiodo)benzene (11.11 g, 34.49 mmol) were added. The reaction was stirred at 30°C for 16 hours. The solvent was removed by rotary evaporation and separated by column chromatography (methanol/tetrahydrofuran=3/17) to obtain 1.70 g of crude product. Intermediate B15 (50.00 mg) prepared by Prep-HPLC from 400 mg of crude product was a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ7.44(s,1H),4.10(s,2H),3.78(s,1H),3.72(s,3H),3.21(ddt,J=25.7,13.9 ,6.5Hz,2H),2.96(t,J=6.4Hz,2H).
LC-MS[M+1]+＝186.10LC-MS [M+1] + = 186.10
参考以上的合成方法合成中间体B13
Synthesize intermediate B13 with reference to the above synthetic method
实施例1：化合物I-1的合成：Embodiment 1: the synthesis of compound 1-1:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-((二甲基(氧代)-λ6-亚砜基)氨基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((dimethyl(oxo)-λ 6 -sulfoxide)amino)pyrimidine-4- Base) methoxy) phenyl) prop-2-yl) benzonitrile
步骤一：在室温下向I-A1(1.5g,4.28mmol)和中间体I-1-1(698mg,4.28mmol,1.0eq)的40mL乙腈溶液中加入碳酸铯(2.79g,8.57mmol，2.0eq)。混合溶液在40℃下搅拌两小时。TLC检测发现反应完全。反应液过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝4/1)得到产物I-1-2(0.8g,产率：39％)。 Step 1: Add cesium carbonate (2.79g, 8.57mmol, 2.0 eq). The mixed solution was stirred at 40°C for two hours. TLC detection found that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=4/1) to obtain the product I-1-2 (0.8 g, yield: 39%).
步骤二：在室温下，向反应瓶中依次加入甲苯(1mL)，I-1-2(20mg,0.04mmol)，二甲基亚磺酰亚胺(4.69mg,5.50mmol)，醋酸钯(0.94mg,0.004mmol)，2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(3.91mg,0.008mmol)和碳酸铯(20.50mg,0.063mmol)。氮气置换三次，然后升温到100℃，搅拌12小时。反应完全后，过滤，滤液通过HPLC制备得到白色固体化合物I-1(5mg，产率：22.34％)。Step 2: At room temperature, add toluene (1mL), I-1-2 (20mg, 0.04mmol), dimethylsulfinimide (4.69mg, 5.50mmol), palladium acetate (0.94 mg, 0.004mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (3.91mg, 0.008mmol) and cesium carbonate (20.50mg, 0.063mmol). Nitrogen was replaced three times, then the temperature was raised to 100° C., and stirred for 12 hours. After the reaction was complete, it was filtered, and the filtrate was prepared by HPLC to obtain compound I-1 (5 mg, yield: 22.34%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.63(d,J＝2.4Hz,1H),7.57(d,J＝2.4Hz,1H),7.19(t,J＝8.4Hz,2H),6.98–6.91(m,2H),6.66(d,J＝8.4Hz,1H),5.04(s,2H),4.45–4.37(m,2H),3.99–3.92(m,2H),3.39(s,6H),1.24(s,6H). 1 H NMR (400MHz, DMSO-d6) δ8.45(s, 1H), 7.63(d, J=2.4Hz, 1H), 7.57(d, J=2.4Hz, 1H), 7.19(t, J=8.4 Hz,2H),6.98–6.91(m,2H),6.66(d,J＝8.4Hz,1H),5.04(s,2H),4.45–4.37(m,2H),3.99–3.92(m,2H) ,3.39(s,6H),1.24(s,6H).
LCMS[M+H]+＝533.1LCMS [M+H] + = 533.1
实施例2：化合物I-2的合成：Embodiment 2: the synthesis of compound 1-2:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-((1-氧代四氢-1λ6-噻吩-1-亚基)胺基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxotetrahydro-1λ 6 -thiophene-1-ylidene)amino)pyrimidine -4-yl)methoxy)phenyl)propan-2-yl)benzonitrile
在室温下，向反应瓶中依次加入甲苯(1mL)，中间体I-1-2(60mg,0.088mmol)，中间体I-B1(21.0mg,0.176mmol)，醋酸钯(1.98mg,0.009mmol)，2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(8.22mg,0.018mmol)和碳酸铯(43.05mg,0.132mmol)。氮气置换三次，然后升温到100℃，搅拌12小时。反应完全后，过滤，滤液通过HPLC(甲酸体系)制备得到白色固体化合物I-2(5mg，产率：10.14％)。At room temperature, successively add toluene (1mL), intermediate I-1-2 (60mg, 0.088mmol), intermediate I-B1 (21.0mg, 0.176mmol), palladium acetate (1.98mg, 0.009mmol) into the reaction flask ), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (8.22mg, 0.018mmol) and cesium carbonate (43.05mg, 0.132mmol). Nitrogen was replaced three times, then the temperature was raised to 100° C., and stirred for 12 hours. After the reaction was complete, it was filtered, and the filtrate was prepared by HPLC (formic acid system) to obtain white solid compound I-2 (5 mg, yield: 10.14%).
1H NMR(400MHz,DMSO-d6)δ8.51-8.40(m,1H),7.70-7.54(m,2H),7.23-7.13(m,2H),7.00-6.97(m,3H),5.03(s,2H),4.49-4.36(m,2H),3.99-3.91(m,2H),2.29-1.98(m,4H),1.71-1.57(m,4H),1.24(s,6H). 1 H NMR (400MHz, DMSO-d6) δ8.51-8.40 (m, 1H), 7.70-7.54 (m, 2H), 7.23-7.13 (m, 2H), 7.00-6.97 (m, 3H), 5.03 ( s,2H),4.49-4.36(m,2H),3.99-3.91(m,2H),2.29-1.98(m,4H),1.71-1.57(m,4H),1.24(s,6H).
LCMS[M+H]+＝559.1LCMS [M+H] + = 559.1
按照上面化合物I-1和化合物I-2的合成方法或参考文献分别合成下列化合物：
Synthesize the following compounds respectively according to the synthetic method of above compound 1-1 and compound 1-2 or references:
实施例3：化合物I-3的合成：Embodiment 3: the synthesis of compound 1-3:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((4-氧代-1,4λ6-氧代-4-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((4-oxo-1,4λ 6 -oxo-4-ylidene)amino)pyrimidin-4-yl )methoxy)phenyl)propan-2-yl)benzonitrile
参考化合物I-1的合成方法，用中间体I-B4代替二甲基亚磺酰亚胺，进行一步反应得到化合物I-3。 Referring to the synthesis method of compound I-1, intermediate I-B4 was used instead of dimethylsulfinimide, and compound I-3 was obtained by one-step reaction.
1H NMR(400MHz,MeOD-d4)δ8.45(s,1H),7.54-7.45(m,2H),7.25–7.13(m,2H),7.11–7.02(m,1H),6.99–6.87(m,2H),5.08(s,2H),4.47–4.37(m,2H),4.22–4.12(m,2H),4.07–3.98(m,2H),3.92–3.87(m,2H),3.87–3.79(m,2H),3.62-3.49(m,2H),1.66(s,6H). 1 H NMR (400MHz, MeOD-d4) δ8.45 (s, 1H), 7.54-7.45 (m, 2H), 7.25-7.13 (m, 2H), 7.11-7.02 (m, 1H), 6.99-6.87 ( m,2H),5.08(s,2H),4.47–4.37(m,2H),4.22–4.12(m,2H),4.07–3.98(m,2H),3.92–3.87(m,2H),3.87– 3.79(m,2H),3.62-3.49(m,2H),1.66(s,6H).
LCMS[M+H]+＝575.1LCMS [M+H] + = 575.1
实施例4：化合物I-4的合成：Embodiment 4: the synthesis of compound 1-4:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-((1-氧化-1λ6-噻乙烷-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxidation-1λ 6 -thioethane-1-ylidene)amino)pyrimidine-4 -yl)methoxy)phenyl)propan-2-yl)benzonitrile
参考化合物I-1的合成方法，用中间体I-B2代替二甲基亚磺酰亚胺，进行一步反应得到化合物I-4。Referring to the synthesis method of compound I-1, intermediate I-B2 was used instead of dimethylsulfinimide, and compound I-4 was obtained by one-step reaction.
1H NMR(400MHz,MeOD-d4)δ8.43(d,J＝5.2Hz,1H),7.48(dd,J＝16.0,2.4Hz,2H),7.21–7.11(m,2H),7.07(d,J＝5.2Hz,1H),6.96–6.83(m,2H),5.05(s,2H),4.44–4.23(m,6H),3.88(t,J＝5.6Hz,2H),2.53-2.32(m,2H),1.64(s,6H). 1 H NMR (400MHz, MeOD-d4) δ8.43(d, J=5.2Hz, 1H), 7.48(dd, J=16.0, 2.4Hz, 2H), 7.21–7.11(m, 2H), 7.07(d ,J=5.2Hz,1H),6.96–6.83(m,2H),5.05(s,2H),4.44–4.23(m,6H),3.88(t,J=5.6Hz,2H),2.53-2.32( m,2H),1.64(s,6H).
LCMS[M+H]+＝545.1LCMS[M+H] + = 545.1
实施例5：化合物I-5的合成：Embodiment 5: the synthesis of compound 1-5:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-((1-氧化三氢-2H-1λ6-硫吡喃-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxytrihydro-2H-1λ 6 -thiopyran-1-ylidene)amino )pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile
参考化合物I-1的合成方法，用中间体I-B3代替二甲基亚磺酰亚胺，进行一步反应得到化合物I-5。 Referring to the synthesis method of compound I-1, intermediate I-B3 was used instead of dimethylsulfinimide, and compound I-5 was obtained by one-step reaction.
LCMS[M+H]+＝573.1LCMS [M+H] + = 573.1
实施例6：化合物I-6的合成：Embodiment 6: the synthesis of compound 1-6:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-((1-氧代-1λ6-硫代吗啡啉-1-亚基)胺基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯腈
3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxo-1λ 6 -thiomorpholin-1-ylidene)amino) pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile
步骤一：在室温下，向反应瓶中依次加入甲苯(1mL)，I-1-2(50mg,0.105mmol)，中间体I-B5(24.60mg,0.105mmol),醋酸钯(2.36mg,0.01mmol)，2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(9.79mg,0.021mmol)和碳酸铯(51.25mg,0.157mmol)。氮气置换三次，然后升温到100℃，搅拌12小时。反应完全后，过滤，滤液减压浓缩，残留物通过柱层析法纯化(0-4％甲醇/二氯甲烷)得到黄色油状中间体I-6-1(40mg，产率：56.47％)。Step 1: At room temperature, add toluene (1mL), I-1-2 (50mg, 0.105mmol), intermediate I-B5 (24.60mg, 0.105mmol), palladium acetate (2.36mg, 0.01 mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (9.79 mg, 0.021 mmol) and cesium carbonate (51.25 mg, 0.157 mmol). Nitrogen was replaced three times, then the temperature was raised to 100° C., and stirred for 12 hours. After the reaction was complete, it was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (0-4% methanol/dichloromethane) to obtain yellow oily intermediate I-6-1 (40 mg, yield: 56.47%).
LCMS[M+H-Boc]+＝574.1LCMS [M+H-Boc] + = 574.1
步骤二：向反应瓶中依次加入中间体I-6-1(40mg,0.06mmol)，二氯甲烷(1mL)和盐酸/二氧六环溶液(1mL)，25℃下搅拌12小时，反应完全后减压浓缩，通过HPLC制备(甲酸体系)得到白色固体化合物I-6(30mg,产率：82.81％)。Step 2: Add intermediate I-6-1 (40mg, 0.06mmol), dichloromethane (1mL) and hydrochloric acid/dioxane solution (1mL) to the reaction flask in sequence, stir at 25°C for 12 hours, and the reaction is complete After concentrated under reduced pressure, it was prepared by HPLC (formic acid system) to obtain white solid compound I-6 (30 mg, yield: 82.81%).
1H NMR(400MHz,MeOD-d4)δ8.45(d,J＝5.2Hz,1H),7.50(dd,J＝18.0,2.4Hz,2H),7.19(d,J＝8.8Hz,2H),7.10(s,1H),6.95(d,J＝8.8Hz,2H),5.08(s,2H),4.46–4.36(m,2H),3.90(t,J＝5.6Hz,2H),3.87–3.76(m,2H),3.54–3.37(m,4H),3.36-3.32(m,2H),1.67(s,6H). 1 H NMR (400MHz, MeOD-d4) δ8.45 (d, J = 5.2Hz, 1H), 7.50 (dd, J = 18.0, 2.4Hz, 2H), 7.19 (d, J = 8.8Hz, 2H), 7.10(s,1H),6.95(d,J=8.8Hz,2H),5.08(s,2H),4.46–4.36(m,2H),3.90(t,J=5.6Hz,2H),3.87–3.76 (m,2H),3.54–3.37(m,4H),3.36-3.32(m,2H),1.67(s,6H).
LCMS[M+H]+＝574.1LCMS[M+H] + = 574.1
实施例7：化合物I-7的合成： Embodiment 7: the synthesis of compound 1-7:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((4-甲基-1-氧化-1λ6-硫吗啉-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((4-methyl-1-oxidation-1λ 6 -thiomorpholine-1-ylidene)amino)pyrimidine- 4-yl)methoxy)phenyl)propan-2-yl)benzonitrile
步骤一：在室温下，向反应瓶中加入乙腈(1mL)，化合物I-6(40mg,0.07mmol)，碳酸钾(19.2mg,0.14mmol)和碘甲烷(4.36uL,0.070mmol)，25℃下搅拌12小时，反应完全后，减压浓缩，残留物进行柱层析分离(0-5％甲醇/二氯甲烷)得到白色固体化合物I-7(10mg,产率：24.27％)。Step 1: Add acetonitrile (1 mL), compound I-6 (40 mg, 0.07 mmol), potassium carbonate (19.2 mg, 0.14 mmol) and iodomethane (4.36 uL, 0.070 mmol) to the reaction flask at room temperature, 25 °C After the reaction was complete, it was concentrated under reduced pressure, and the residue was subjected to column chromatography (0-5% methanol/dichloromethane) to obtain white solid compound I-7 (10 mg, yield: 24.27%).
1H NMR(400MHz,MEOD-D4)δ8.45(s,1H),7.50(dd,J＝17.2,2.0Hz,2H),7.18(d,J＝8.8Hz,2H),7.10(s,1H),6.95(d,J＝8.8Hz,2H),5.08(s,2H),4.42(t,J＝5.6Hz,2H),3.90(t,J＝5.6Hz,2H),3.85-3.74(m,2H),3.64–3.51(m,2H),3.14-2.94(m,4H),2.45(s,3H),1.66(s,6H). 1 H NMR (400MHz, MEOD-D4) δ8.45(s, 1H), 7.50(dd, J=17.2, 2.0Hz, 2H), 7.18(d, J=8.8Hz, 2H), 7.10(s, 1H ), 6.95(d, J=8.8Hz, 2H), 5.08(s, 2H), 4.42(t, J=5.6Hz, 2H), 3.90(t, J=5.6Hz, 2H), 3.85-3.74(m ,2H),3.64–3.51(m,2H),3.14-2.94(m,4H),2.45(s,3H),1.66(s,6H).
LCMS[M+H]+＝588.1LCMS[M+H] + = 588.1
实施例8：化合物I-8的合成：Embodiment 8: the synthesis of compound 1-8:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((5-((1-氧化三氢-1λ6-噻吩-1-亚基)氨基)噻唑-2-基)甲氧基)苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((5-((1-oxytrihydro-1λ 6 -thiophene-1-ylidene)amino)thiazole-2 -yl)methoxy)phenyl)propan-2-yl)benzonitrile
步骤一：参考化合物I-1的合成步骤，用中间体I-8-1代替中间体I-1-1，得到中间体I-8-2。Step 1: Referring to the synthesis procedure of compound I-1, intermediate I-8-1 is used instead of intermediate I-1-1 to obtain intermediate I-8-2.
步骤二：在室温下，向反应瓶中依次加入甲苯(1mL)，中间体I-8-2(50mg, 0.095mmol)，中间体I-B1(16.99mg,0.14mmol)，Pd2(dba)3(17.40mg,0.019mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(21.99mg,0.038mmol)和碳酸铯(46.43mg,0.143mmol)。氮气置换三次，然后升温到100℃，搅拌12小时。反应完全后，过滤，滤液减压浓缩后，通过柱层析法(0-80％乙酸乙酯/石油醚)纯化得到黄色固体化合物I-8(40mg，产率：74.57％)。Step 2: At room temperature, add toluene (1mL) successively to the reaction flask, intermediate I-8-2 (50mg, 0.095mmol), intermediate I-B1 (16.99mg, 0.14mmol), Pd 2 (dba) 3 (17.40mg, 0.019mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxa Anthracene (21.99 mg, 0.038 mmol) and cesium carbonate (46.43 mg, 0.143 mmol). Nitrogen was replaced three times, then the temperature was raised to 100° C., and stirred for 12 hours. After the reaction was complete, it was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (0-80% ethyl acetate/petroleum ether) to obtain compound I-8 (40 mg, yield: 74.57%) as a yellow solid.
1H NMR(400MHz,MEOD-D4)δ7.51(d,J＝2.4Hz,1H),7.46(d,J＝2.4Hz,1H),7.17(d,J＝8.4Hz,2H),6.96(d,J＝8.4Hz,2H),6.71(d,J＝8.4Hz,1H),5.20(s,2H),4.42(t,J＝5.6Hz,2H),3.89(t,J＝5.6Hz,2H),3.46–3.36(m,2H),3.26-3.18(m,2H),2.40–2.18(m,4H),1.66(s,6H). 1 H NMR (400MHz, MEOD-D4) δ7.51(d, J=2.4Hz, 1H), 7.46(d, J=2.4Hz, 1H), 7.17(d, J=8.4Hz, 2H), 6.96( d,J=8.4Hz,2H),6.71(d,J=8.4Hz,1H),5.20(s,2H),4.42(t,J=5.6Hz,2H),3.89(t,J=5.6Hz, 2H),3.46–3.36(m,2H),3.26-3.18(m,2H),2.40–2.18(m,4H),1.66(s,6H).
LCMS[M+H]+＝564.1LCMS[M+H] + = 564.1
实施例9：化合物I-9的合成：Embodiment 9: the synthesis of compound 1-9:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(2-羟乙基)-1-氧化-1λ6-硫吗啉-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-hydroxyethyl)-1-oxide-1λ 6 -thiomorpholine-1-ylidene )amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile
步骤一：在室温下，向反应瓶中加入乙腈(1mL)，化合物I-6(40mg,0.07mmol)，碳酸钾(19.2mg,0.14mmol)和2-溴乙醇(7.42uL,0.10mmol)，80℃下搅拌48小时，反应完全后，减压浓缩，残留物进行柱层析分离(0-5％甲醇/二氯甲烷)得到白色固体化合物I-9(12mg,产率：27.86％)。Step 1: Add acetonitrile (1 mL), compound I-6 (40 mg, 0.07 mmol), potassium carbonate (19.2 mg, 0.14 mmol) and 2-bromoethanol (7.42 uL, 0.10 mmol) to the reaction flask at room temperature, Stirring at 80°C for 48 hours, after the reaction was complete, concentrated under reduced pressure, and the residue was subjected to column chromatography (0-5% methanol/dichloromethane) to obtain white solid compound I-9 (12 mg, yield: 27.86%).
1H NMR(400MHz,MEOD-D4)δ8.44(s,1H),7.50(dd,J＝2.0&15.6Hz,2H),7.18(d,J＝8.8Hz,2H),7.07(d,J＝4.4Hz,1H),6.95(d,J＝8.8Hz,2H),5.07(s,2H),4.42(t,J＝5.2Hz,2H),3.90(t,J＝5.2Hz,2H),3.82-3.73(m,2H),3.66(t,J＝5.2Hz,2H),3.60–3.47(m,2H),3.19-3.12(m,2H),3.11–2.98(m,2H),2.69(t,J＝5.2Hz,2H),1.66(s,6H).LCMS[M+H]+＝618.1 1 H NMR (400MHz, MEOD-D4) δ8.44(s, 1H), 7.50(dd, J＝2.0&15.6Hz, 2H), 7.18(d, J＝8.8Hz, 2H), 7.07(d, J =4.4Hz,1H),6.95(d,J=8.8Hz,2H),5.07(s,2H),4.42(t,J=5.2Hz,2H),3.90(t,J=5.2Hz,2H), 3.82-3.73(m,2H),3.66(t,J＝5.2Hz,2H),3.60-3.47(m,2H),3.19-3.12(m,2H),3.11-2.98(m,2H),2.69( t,J=5.2Hz,2H),1.66(s,6H).LCMS[M+H] + ＝618.1
实施例10：化合物I-10的合成： Embodiment 10: the synthesis of compound 1-10:
5-(2-(4-((2-((3-氨基-1-氧化三氢-1λ6-噻吩-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)-3-氯-2-(2-氯乙氧基)苯甲腈
5-(2-(4-((2-((3-Amino-1-oxytrihydro-1λ 6 -thiophen-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propane -2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile
参考化合物I-6的合成方法，用中间体I-B6代替中间体I-B5，进行两步反应得到化合物I-10。Referring to the synthetic method of compound I-6, intermediate I-B6 was used instead of intermediate I-B5, and two-step reaction was carried out to obtain compound I-10.
1H NMR(400MHz,MeOD-d4)δ8.46(d,J＝5.2Hz,1H),7.49(dt,J＝13.6,6.8Hz,2H),7.18(d,J＝8.8Hz,2H),7.10(d,J＝5.2Hz,1H),6.95(d,J＝8.8Hz,2H),5.08(s,2H),4.42(t,J＝5.6Hz,2H),3.98-3.84(m,4H),3.81–3.69(m,1H),3.52–3.39(m,2H),2.62–2.53(m,1H),2.09-1.99(m,1H),1.66(s,6H). 1 H NMR (400MHz, MeOD-d4) δ8.46 (d, J = 5.2Hz, 1H), 7.49 (dt, J = 13.6, 6.8Hz, 2H), 7.18 (d, J = 8.8Hz, 2H), 7.10(d, J=5.2Hz, 1H), 6.95(d, J=8.8Hz, 2H), 5.08(s, 2H), 4.42(t, J=5.6Hz, 2H), 3.98-3.84(m, 4H ),3.81–3.69(m,1H),3.52–3.39(m,2H),2.62–2.53(m,1H),2.09-1.99(m,1H),1.66(s,6H).
LCMS[M+H]+＝574.1LCMS[M+H] + = 574.1
实施例11：化合物I-11的合成：Embodiment 11: the synthesis of compound I-11:
5-(2-(4-((2-((4-氨基-1-氧化三氢-2H-1λ6-硫吡喃-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)-3-氯-2-(2-氯乙氧基)苯甲腈
5-(2-(4-((2-((4-Amino-1-oxytrihydro-2H-1λ 6 -thiopyran-1-ylidene)amino)pyrimidin-4-yl)methoxy) Phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile
参考化合物I-6的合成方法，用中间体I-B7代替中间体I-B5，进行两步反应得 到化合物I-11。With reference to the synthetic method of compound I-6, intermediate I-B7 is used to replace intermediate I-B5, and a two-step reaction is carried out to obtain to compound 1-11.
产物I-11-A(顺式或反式)：1H NMR(400MHz,MeOD-d4)δ8.47(d,J＝5.2Hz,1H),7.57-7.39(m,3H),7.25–7.08(m,4H),6.96(d,J＝8.8Hz,2H),5.08(s,2H),4.58(s,2H),4.42(t,J＝5.6Hz,2H),4.08(d,J＝12.0Hz,2H),3.96–3.85(m,2H),3.48(t,J＝13.6Hz,3H),2.34(d,J＝13.6Hz,2H),2.22–2.13(m,2H),1.66(s,6H).Product I-11-A (cis or trans): 1 H NMR (400MHz, MeOD-d4) δ8.47 (d, J=5.2Hz, 1H), 7.57-7.39 (m, 3H), 7.25–7.08 (m,4H),6.96(d,J=8.8Hz,2H),5.08(s,2H),4.58(s,2H),4.42(t,J=5.6Hz,2H),4.08(d,J= 12.0Hz, 2H), 3.96–3.85(m, 2H), 3.48(t, J＝13.6Hz, 3H), 2.34(d, J＝13.6Hz, 2H), 2.22–2.13(m, 2H), 1.66( s,6H).
产物I-11-B(反式或顺式)：1H NMR(400MHz,MeOD-d4)δ8.43(d,J＝5.2Hz,1H),7.56–7.38(m,3H),7.29–7.06(m,4H),6.94(d,J＝8.8Hz,2H),5.07(s,2H),4.58(s,2H),4.42(t,J＝5.6Hz,2H),3.89(t,J＝5.6Hz,3H),3.55(t,J＝13.5Hz,2H),2.38(d,J＝13.7Hz,2H),2.25(d,J＝8.8Hz,2H),1.66(s,6H).Product I-11-B (trans or cis): 1 H NMR (400MHz, MeOD-d4) δ8.43 (d, J=5.2Hz, 1H), 7.56–7.38 (m, 3H), 7.29–7.06 (m,4H),6.94(d,J=8.8Hz,2H),5.07(s,2H),4.58(s,2H),4.42(t,J=5.6Hz,2H),3.89(t,J= 5.6Hz, 3H), 3.55(t, J=13.5Hz, 2H), 2.38(d, J=13.7Hz, 2H), 2.25(d, J=8.8Hz, 2H), 1.66(s, 6H).
LCMS[M+1]+＝588.1LCMS[M+1] + =588.1
实施例12：化合物I-12的合成：Embodiment 12: the synthesis of compound 1-12:
3-氯-2-(2-羟基乙氧基)-5-(2-(4-((2-((1-氧化-1λ6-硫吗啉-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-hydroxyethoxy)-5-(2-(4-((2-((1-oxidation-1λ 6 -thiomorpholine-1-ylidene)amino)pyrimidine-4 -yl)methoxy)phenyl)propan-2-yl)benzonitrile
步骤一：在室温下，依次向反应瓶中加入二甲基亚砜(1mL)，中间体I-6-1(100mg,0.15mmol)，四丁基氟化铵(0.005mL,0.015mmol)和甲酸钠(25.20mg,0.37mmol)，反应液在110℃下搅拌两小时。然后冷却到25℃，加入氢氧化钠水溶液(0.024mL,0.296mmol，12.5M)，搅拌12小时。反应完全后，反应液用水(10mL)和二氯甲烷(5mL*3)萃取，合并后的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩后，通过柱层析法(0-5％甲醇/二氯甲烷)纯化得到白色固体I-12-1(50mg,产率：51.41％)。 Step 1: Add dimethylsulfoxide (1mL), intermediate I-6-1 (100mg, 0.15mmol), tetrabutylammonium fluoride (0.005mL, 0.015mmol) and Sodium formate (25.20mg, 0.37mmol), the reaction solution was stirred at 110°C for two hours. Then cooled to 25°C, added aqueous sodium hydroxide solution (0.024mL, 0.296mmol, 12.5M), and stirred for 12 hours. After the reaction was complete, the reaction solution was extracted with water (10 mL) and dichloromethane (5 mL*3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, it was purified by column chromatography (0-5% methanol/dichloromethane) to obtain white solid I-12-1 (50 mg, yield: 51.41%).
步骤二：在室温下，向反应瓶中依次加入二氯甲烷(1mL)，中间体I-12-1(50mg,0.076mmol)和三氟乙酸(1mL)，反应液在25℃下搅拌12小时。反应完全后，减压浓缩得到的残留物用饱和碳酸氢钠溶液调节pH到8，然后用二氯甲烷(10mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后先通过柱层析法(0-10％甲醇/二氯甲烷)纯化，再通过制备级厚硅胶板纯化(甲醇/二氯甲烷＝1/10)得到化合物I-12(15mg，产率：35.40％)。Step 2: Add dichloromethane (1mL), intermediate I-12-1 (50mg, 0.076mmol) and trifluoroacetic acid (1mL) to the reaction flask in turn at room temperature, and stir the reaction solution at 25°C for 12 hours . After the reaction was complete, the residue obtained by concentrating under reduced pressure was adjusted to pH 8 with saturated sodium bicarbonate solution, then extracted with dichloromethane (10mL*3), the combined organic phases were washed with saturated brine (10mL), anhydrous sulfuric acid Sodium-dried, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (0-10% methanol/dichloromethane), and then purified by preparative grade thick silica gel plate (methanol/dichloromethane=1/10) to obtain the compound I-12 (15 mg, yield: 35.40%).
1H NMR(400MHz,MeOD-d4)δ8.43(d,J＝5.2Hz,1H),7.48(dd,J＝17.6,2.4Hz,2H),7.19–7.15(m,2H),7.07(d,J＝5.2Hz,1H),7.01–6.91(m,2H),5.07(s,2H),4.24(t,J＝4.8Hz,2H),3.91(t,J＝4.8Hz,2H),3.84–3.71(m,2H),3.52–3.32(m,4H),3.21(ddd,J＝14.0,8.8,2.8Hz,2H),1.65(s,6H). 1 H NMR (400MHz, MeOD-d4) δ8.43(d, J=5.2Hz, 1H), 7.48(dd, J=17.6, 2.4Hz, 2H), 7.19–7.15(m, 2H), 7.07(d ,J=5.2Hz,1H),7.01–6.91(m,2H),5.07(s,2H),4.24(t,J=4.8Hz,2H),3.91(t,J=4.8Hz,2H),3.84 –3.71(m,2H),3.52–3.32(m,4H),3.21(ddd,J＝14.0,8.8,2.8Hz,2H),1.65(s,6H).
LCMS[M+H]+＝556.1LCMS[M+H] + = 556.1
实施例13：化合物I-13的合成：Embodiment 13: the synthesis of compound 1-13:
1-((4-((4-(2-(7-氯-1-(2-氯乙基)-1H-吲唑-5-基)丙烷-2-基)苯氧基)甲基)嘧啶-2-基)亚氨基)四氢-1H-1λ6-噻吩-1-氧代
1-((4-((4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl) Pyrimidin-2-yl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxo
步骤一：将中间体I-A3(300mg,0.859mmol)，中间体I-1-1(150mg,0.920mmol)和碳酸铯(560mg,1.72mmol)溶解于乙腈(5mL)中，将其在室温下反应3小时后。将反应混合物浓缩后进行柱层析分离(石油醚/乙酸乙酯＝3/1)得到产物I-13-1(300mg,产率：62％)，为黄色油状。Step 1: Dissolve Intermediate I-A3 (300mg, 0.859mmol), Intermediate I-1-1 (150mg, 0.920mmol) and cesium carbonate (560mg, 1.72mmol) in acetonitrile (5mL), and place it at room temperature After 3 hours of reaction. The reaction mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain the product I-13-1 (300 mg, yield: 62%) as a yellow oil.
LCMS[M+1]+＝474.9LCMS[M+1] + =474.9
步骤二：将中间体I-13-1(50mg,0.105mmol)，中间体I-B1(63mg,0.525mmol)、 碳酸铯(103mg,0.315mmol)和t-BuXPhos Pd G3(8mg,0.009mmol)溶解于二氧六环(1mL)中，将其在100℃下用微波反应1小时后。将反应混合物浓缩后进行HPLC分离得到产物化合物I-13(20mg,产率：17％)，为白色固体。Step 2: Intermediate I-13-1 (50mg, 0.105mmol), Intermediate I-B1 (63mg, 0.525mmol), Cesium carbonate (103 mg, 0.315 mmol) and t-BuXPhos Pd G3 (8 mg, 0.009 mmol) were dissolved in dioxane (1 mL), which were reacted by microwave at 100° C. for 1 hour. The reaction mixture was concentrated and separated by HPLC to obtain the product compound I-13 (20 mg, yield: 17%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.47(d,J＝4.0Hz,1H),7.98(s,1H),7.55(s,1H),7.15-7.12(m,3H),7.07(d,J＝4.0Hz,1H),6.87-6.83(m,2H),5.05-5.02(m,4H),3.92(t,J＝8.0Hz,2H),3.73-3.66(m,2H),3.44-3.38(m,2H),2.39-2.26(m,4H),1.69(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.47(d, J=4.0Hz, 1H), 7.98(s, 1H), 7.55(s, 1H), 7.15-7.12(m, 3H), 7.07(d ,J=4.0Hz,1H),6.87-6.83(m,2H),5.05-5.02(m,4H),3.92(t,J=8.0Hz,2H),3.73-3.66(m,2H),3.44- 3.38(m,2H),2.39-2.26(m,4H),1.69(s,6H).
LCMS[M+1]+＝558.2LCMS[M+1] + =558.2
实施例14：化合物I-14的合成：Embodiment 14: the synthesis of compound I-14:
1-((4-((4-(2-(7-氯-2-(2-氯乙基)-2H-吲唑-5-基)丙烷-2-基)苯氧基)甲基)嘧啶-2-基)亚氨基)四氢-1H-1λ6-噻吩-1-氧代
1-((4-((4-(2-(7-chloro-2-(2-chloroethyl)-2H-indazol-5-yl)propan-2-yl)phenoxy)methyl) Pyrimidin-2-yl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxo
参考化合物I-13的合成步骤，用中间体I-A5代替中间体I-A3，经过两步合成化合物I-14。Referring to the synthesis steps of compound I-13, intermediate I-A5 was used instead of intermediate I-A3, and compound I-14 was synthesized in two steps.
1H NMR(400MHz,Chloroform-d)δ8.47(d,J＝4.0Hz,1H),8.03(s,1H),7.52(s,1H),7.16-7.12(m,2H),7.06(d,J＝8.0Hz,1H),7.04(s,1H),6.86-6.83(m,2H),5.05(s,2H),4.74(t,J＝8.0Hz,2H),4.04(t,J＝8.0Hz,2H),3.73-3.66(m,2H),3.44-3.37(m,2H),2.39-2.23(m,4H),1.67(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.47(d, J=4.0Hz, 1H), 8.03(s, 1H), 7.52(s, 1H), 7.16-7.12(m, 2H), 7.06(d ,J=8.0Hz,1H),7.04(s,1H),6.86-6.83(m,2H),5.05(s,2H),4.74(t,J=8.0Hz,2H),4.04(t,J= 8.0Hz,2H),3.73-3.66(m,2H),3.44-3.37(m,2H),2.39-2.23(m,4H),1.67(s,6H).
LCMS[M+1]+＝558.2LCMS[M+1] + =558.2
实施例15：化合物I-15的合成：Embodiment 15: the synthesis of compound 1-15:
1-(2-氯乙基)-5-(2-(4-((2-((1-氧代四氢-1λ6-噻吩-1-亚基)胺基)嘧啶-4-基)甲氧基)苯基) 丙烷-2-基)-1H-吲唑-7-甲腈
1-(2-chloroethyl)-5-(2-(4-((2-((1-oxotetrahydro-1λ 6 -thiophene-1-ylidene)amino)pyrimidin-4-yl) Methoxy)phenyl) Propan-2-yl)-1H-indazole-7-carbonitrile
参考化合物I-13的合成步骤，用中间体I-A10代替中间体I-A3，经过两步合成化合物I-15。Referring to the synthesis steps of compound I-13, intermediate I-A10 was used instead of intermediate I-A3, and compound I-15 was synthesized in two steps.
1H NMR(400MHz,Chloroform-d)δ8.52–8.41(m,1H),8.07(s,1H),7.94–7.85(m,1H),7.60–7.51(m,1H),7.15–7.07(m,2H),7.07–6.99(m,1H),6.85(d,J＝9.9Hz,2H),5.04(s,2H),5.00(t,J＝6.1Hz,2H),4.05–3.95(m,2H),3.71-3.64(m,2H),3.42-3.35(m,2H),2.37-2.23(m,4H),1.70(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.52–8.41(m,1H),8.07(s,1H),7.94–7.85(m,1H),7.60–7.51(m,1H),7.15–7.07( m,2H),7.07–6.99(m,1H),6.85(d,J＝9.9Hz,2H),5.04(s,2H),5.00(t,J＝6.1Hz,2H),4.05–3.95(m ,2H),3.71-3.64(m,2H),3.42-3.35(m,2H),2.37-2.23(m,4H),1.70(s,6H).
LC-MS[M+1]+＝549.2LC-MS [M+1] + = 549.2
实施例16：化合物I-16的合成：Embodiment 16: the synthesis of compound 1-16:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((4-(甲胺基)-1-氧化三氢-2H-1λ6-硫吡喃-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((4-(methylamino)-1-oxytrihydro-2H-1λ 6 -thiopyran-1- Subunit) amino) pyrimidin-4-yl) methoxy) phenyl) propan-2-yl) benzonitrile
步骤一：在0℃下，将中间体I-11-1(100mg,0.144mmol)溶解在N,N-二甲基乙酰胺(1mL)中，然后加入氢化钠(11.55mg,0.289mmol)，继续搅拌0.5小时，然后 加入碘甲烷(0.027mL,0.433mmol)，室温下，继续搅拌12小时。反应完全后，反应液用水(20mL)和乙酸乙酯(10mL*3)萃取，合并的有机相用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后通过柱层析法纯化得到黄色油状物I-16-1(80mg,产率：78.42％)。Step 1: Intermediate I-11-1 (100mg, 0.144mmol) was dissolved in N,N-dimethylacetamide (1mL) at 0°C, and then sodium hydride (11.55mg, 0.289mmol) was added, Stirring was continued for 0.5 hours, then Iodomethane (0.027 mL, 0.433 mmol) was added and stirring was continued for 12 hours at room temperature. After the reaction was complete, the reaction solution was extracted with water (20 mL) and ethyl acetate (10 mL*3), the combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and passed through the column layer Purification by analytical method gave yellow oil I-16-1 (80 mg, yield: 78.42%).
LCMS[M+H]+＝706.1LCMS[M+H] + =706.1
步骤二：向反应瓶中依次加入二氯甲烷(1mL)，中间体I-16-1(80mg,0.113mmol)和三氟乙酸(1mL)，25℃下搅拌12小时。反应完全后，减压浓缩，用饱和碳酸氢钠水溶液调节pH到8,然后用二氯甲烷(10mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后通过柱层析法(0-10％甲醇/二氯甲烷)纯化得到白色固体化合物I-16(30mg，产率：43.98％)。Step 2: Add dichloromethane (1 mL), intermediate I-16-1 (80 mg, 0.113 mmol) and trifluoroacetic acid (1 mL) to the reaction flask in sequence, and stir at 25° C. for 12 hours. After the reaction was complete, concentrate under reduced pressure, adjust the pH to 8 with saturated aqueous sodium bicarbonate, then extract with dichloromethane (10 mL*3), wash the combined organic phase with saturated brine (10 mL), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (0-10% methanol/dichloromethane) to obtain white solid compound I-16 (30 mg, yield: 43.98%).
1H NMR(400MHz,DMSO-d6)δ8.47-8.42(m,1H),7.54-7.43(m,2H),7.18(dd,J＝8.8,2.0Hz,2H),7.12-7.06(m,1H)6.95(dd,J＝8.8,4.0Hz,2H),5.07(d,J＝2.4Hz,2H),4.42(t,J＝5.6Hz,2H),4.06(d,J＝14.0Hz,1H),3.93–3.85(m,2H),3.67–3.37(m,4H),262(s,3H),2.48-2.36(m,2H),2.24-1.99(m,2H)，1.66(s,6H). 1 H NMR (400MHz, DMSO-d6) δ8.47-8.42(m, 1H), 7.54-7.43(m, 2H), 7.18(dd, J=8.8, 2.0Hz, 2H), 7.12-7.06(m, 1H)6.95(dd,J=8.8,4.0Hz,2H),5.07(d,J=2.4Hz,2H),4.42(t,J=5.6Hz,2H),4.06(d,J=14.0Hz,1H ),3.93–3.85(m,2H),3.67–3.37(m,4H),262(s,3H),2.48-2.36(m,2H),2.24-1.99(m,2H),1.66(s,6H ).
LCMS[M+H]+＝602.1LCMS[M+H] + = 602.1
实施例17：化合物I-17的合成：Embodiment 17: the synthesis of compound 1-17:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((4-((2-羟乙基)氨基)-1-氧化三氢-2H-1λ6-硫吡喃-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((4-((2-hydroxyethyl)amino)-1-oxytrihydro-2H-1λ 6 -sulfur pyran-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile
参考化合物I-9的合成方法，用化合物I-11代替化合物I-6，进行一步反应得到化合物I-17。Referring to the synthetic method of compound I-9, compound I-11 was used instead of compound I-6, and compound I-17 was obtained by one-step reaction.
1H NMR(400MHz,MEOD-D4)δ8.44(dd,J＝9.2,5.2Hz,1H),7.58–7.40(m,2H),7.25–7.13(m,2H),7.08(dd,J＝9.2,5.2Hz,1H),7.01–6.90(m,2H),5.07(d,J＝2.0Hz,2H),4.58(s,1H),4.42(t,J＝5.6Hz,2H),4.03(d,J＝14.4Hz,1H),3.96–3.78(m,3H), 3.73(q,J＝7.2,6.4Hz,2H),3.57(t,J＝12.0Hz,1H),3.44(d,J＝12.8Hz,1H),3.17(s,1H),2.93(t,J＝5.6Hz,2H),2.37(s,2H),2.24–2.04(m,2H),1.66(s,6H). 1 H NMR (400MHz, MEOD-D4) δ8.44 (dd, J = 9.2, 5.2 Hz, 1H), 7.58-7.40 (m, 2H), 7.25-7.13 (m, 2H), 7.08 (dd, J = 9.2,5.2Hz,1H),7.01–6.90(m,2H),5.07(d,J=2.0Hz,2H),4.58(s,1H),4.42(t,J=5.6Hz,2H),4.03( d,J＝14.4Hz,1H),3.96–3.78(m,3H), 3.73(q,J=7.2,6.4Hz,2H),3.57(t,J=12.0Hz,1H),3.44(d,J=12.8Hz,1H),3.17(s,1H),2.93(t,J =5.6Hz, 2H), 2.37(s, 2H), 2.24–2.04(m, 2H), 1.66(s, 6H).
LCMS[M+1]+＝632.1LCMS[M+1] + =632.1
按照上面的合成方法或参考文献分别合成下列化合物：Synthesize the following compounds respectively according to the above synthetic method or references:
如终产物需脱除N-Boc保护基团，可任选如下条件进行脱除：1)4N HCl/1,4-二氧六环/甲醇(1/1)液，室温或加热搅拌直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物；2)三氟乙酸/二氯甲烷(1/10)溶液室温反应直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物。


If the final product needs to remove the N-Boc protecting group, the following conditions can be selected for removal: 1) 4N HCl/1,4-dioxane/methanol (1/1) solution, room temperature or heating and stirring until the reaction Complete, the reaction solution was concentrated and separated by preparative HPLC to obtain the target product; 2) trifluoroacetic acid/dichloromethane (1/10) solution was reacted at room temperature until the reaction was completed, and the reaction solution was concentrated and separated by preparative HPLC to obtain the target product.


实施例19：化合物I-56的合成：Embodiment 19: the synthesis of compound 1-56:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((6-((2-羟乙基)氨基)-2-((1-氧代四氢-1λ6-噻吩-1-亚基)胺 基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((6-((2-hydroxyethyl)amino)-2-((1-oxotetrahydro-1λ 6 -thiophen-1-ylidene)amine Base) pyrimidin-4-yl) methoxy) phenyl) propan-2-yl) benzonitrile
步骤一：将甲硫醇钠(1.04g,14.78mmol)的水溶液(12.5mL)滴加到中间体I-56-1(3g,14.49mmol)的甲苯(75mL)溶液中，室温下反应12小时。反应液用乙酸乙酯(20mL*2)萃取，合并有机相，用饱和食盐水清洗(20mL*2)，有机相用无水硫酸钠干燥，旋干过柱(石油醚/乙酸乙酯＝8/1)得到粗品I-56-2(1.2g,产率：37.9％)，为白色固体。Step 1: Add an aqueous solution (12.5 mL) of sodium methyl mercaptide (1.04 g, 14.78 mmol) dropwise to a solution of intermediate I-56-1 (3 g, 14.49 mmol) in toluene (75 mL), and react at room temperature for 12 hours . The reaction solution was extracted with ethyl acetate (20mL*2), the organic phases were combined, washed with saturated brine (20mL*2), the organic phase was dried with anhydrous sodium sulfate, spin-dried and passed through the column (petroleum ether/ethyl acetate=8 /1) The crude product I-56-2 (1.2 g, yield: 37.9%) was obtained as a white solid.
LC-MS[M+1]-＝219.00LC-MS[M+1] - = 219.00
步骤二：室温下，将中间体I-56-2(1.2g,5.49mmol)和中间体I-B1(687mg,5.76mmol)溶解于无水二氧六环(10mL)中，然后加入Cs2CO3(4.47g,13.72mmol),t-BuXPhos Pd G3(397mg,0.5mmol)。加完后，吹入氮气保护，然后用微波在100℃,反应1小时。将反应液过滤。滤液旋干过柱(石油醚/乙酸乙酯＝0/1)得到中间体I-56-3(800mg,产率：48.50％)，为淡橙色油状液体。Step 2: Dissolve Intermediate I-56-2 (1.2g, 5.49mmol) and Intermediate I-B1 (687mg, 5.76mmol) in anhydrous dioxane (10mL) at room temperature, and then add Cs 2 CO3 (4.47 g, 13.72 mmol), t-BuXPhos Pd G3 (397 mg, 0.5 mmol). After the addition, nitrogen protection was blown in, and then microwave was used at 100°C for 1 hour of reaction. The reaction solution was filtered. The filtrate was spin-dried and passed through the column (petroleum ether/ethyl acetate=0/1) to obtain intermediate I-56-3 (800 mg, yield: 48.50%) as a light orange oily liquid.
LC-MS[M+1]+＝302.10LC-MS [M+1] + = 302.10
步骤三：将I-56-3(800mg,2.65mmol)溶解于无水乙醇(10mL)中，再加入硼氢化钠(301.27mg,7.96mmol)，室温下搅拌4小时，再在70℃下搅拌反应4小时。将反应液浓缩后进行柱层析分离(二氯甲烷/甲醇＝10/1)，得到所需的产物(I-56-4,700mg,产率：96.5％)，为橙色油状液体。Step 3: Dissolve I-56-3 (800mg, 2.65mmol) in absolute ethanol (10mL), then add sodium borohydride (301.27mg, 7.96mmol), stir at room temperature for 4 hours, and then stir at 70°C React for 4 hours. The reaction solution was concentrated and separated by column chromatography (dichloromethane/methanol=10/1) to obtain the desired product (I-56-4, 700 mg, yield: 96.5%) as an orange oily liquid.
LC-MS[M+1]+＝274.10 LC-MS [M+1] + = 274.10
步骤四：在0℃下向I-56-4(300mg,1.1mmol)的二氯甲烷溶液(10mL)中滴加二氯亚砜(391.67mg,3.29mmol)，在0℃下反应30分钟，再在室温下反应30分钟。反应混合物缓慢的加入到饱和碳酸氢钠溶液中，并用二氯甲烷(10mL*3)萃取。有机相用饱和食盐水洗(20mL)，然后用无水硫酸钠干燥并过滤。将滤液浓缩后得到粗品I-56-5(320mg,产率：93.7％)，为橙色油状液体。Step 4: Add thionyl chloride (391.67 mg, 3.29 mmol) dropwise to a solution of I-56-4 (300 mg, 1.1 mmol) in dichloromethane (10 mL) at 0°C, and react at 0°C for 30 minutes, Then react at room temperature for 30 minutes. The reaction mixture was slowly added to saturated sodium bicarbonate solution, and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product I-56-5 (320 mg, yield: 93.7%) as an orange oily liquid.
LC-MS[M+1]+＝292.1LC-MS [M+1] + = 292.1
步骤五：在室温下向I-56-5(320mg,1.1mmol)和中间体I-A1(384.06mg,1.1mmol,1.0eq)的乙腈溶液(10mL)中加入碳酸铯(1.07g,3.3mmol，3.0eq)。混合溶液在40℃下搅拌1小时。反应液过滤，将滤液浓缩后得到产物I-56-6(600mg,产率：90.4％)，为淡黄色油状。Step 5: Add cesium carbonate (1.07g, 3.3mmol) to a solution of I-56-5 (320mg, 1.1mmol) and intermediate I-A1 (384.06mg, 1.1mmol, 1.0eq) in acetonitrile (10mL) at room temperature , 3.0eq). The mixed solution was stirred at 40°C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to obtain the product I-56-6 (600 mg, yield: 90.4%) as a pale yellow oil.
步骤六：在0℃下向I-56-6(600mg,0.99mmol)的二氯甲烷溶液(6mL)中滴加间氯过氧苯甲酸(216mg,0.94mmol，0.95eq)的二氯甲烷溶液(2mL)。混合溶液在0℃下搅拌30分钟。TLC检测发现反应完全。反应液用饱和碳酸氢钠溶液(10mL)淬灭，用二氯甲烷(20mL)萃取两遍，混合的有机相用饱和食盐水(20mL)洗涤，干燥过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝0/1)得到产物I-56-7(500mg,产率：81.2％)，为白色固体。Step 6: Add m-chloroperoxybenzoic acid (216mg, 0.94mmol, 0.95eq) in dichloromethane solution (6mL) dropwise at 0°C (2 mL). The mixed solution was stirred at 0°C for 30 minutes. TLC detection found that the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution (10mL), extracted twice with dichloromethane (20mL), the mixed organic phase was washed with saturated brine (20mL), dried and filtered, and the filtrate was concentrated and separated by column chromatography (Petroleum ether/ethyl acetate=0/1) gave the product I-56-7 (500 mg, yield: 81.2%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ7.79(s,1H),7.43(d,J＝2.3Hz,1H),7.32(d,J＝2.3Hz,1H),7.14–7.06(m,2H),6.93–6.85(m,2H),5.10(s,2H),4.41(t,J＝6.2Hz,2H),3.86(t,J＝6.2Hz,2H),3.75–3.56(m,2H),3.45–3.32(m,2H),2.89(s,3H),2.43–2.19(m,4H),1.63(s,6H). 1 H NMR (400MHz, Chloroform-d) δ7.79(s, 1H), 7.43(d, J=2.3Hz, 1H), 7.32(d, J=2.3Hz, 1H), 7.14–7.06(m, 2H ),6.93–6.85(m,2H),5.10(s,2H),4.41(t,J＝6.2Hz,2H),3.86(t,J＝6.2Hz,2H),3.75–3.56(m,2H) ,3.45–3.32(m,2H),2.89(s,3H),2.43–2.19(m,4H),1.63(s,6H).
LC-MS[M+1]+＝621.30LC-MS [M+1] + = 621.30
步骤七：室温条件下，向I-56-7(60mg,0.096mmol)和2-氨基乙基-1-羟基盐酸盐(47.17mg,0.772mmol)的NMP(3mL)溶液中加入碳酸钠(143.23mg,1.35mmol)，然后150℃微波反应1小时。LC-MS检测发现反应完全。用乙酸乙酯(20mL)萃取两遍，混合的有机相用饱和食盐水(20mL)洗涤，干燥过滤，将滤液浓缩后进行制备HPLC(TFA)制备，得到化合物I-56(4.99mg,产率：8.4％)，为白色固体。Step 7: At room temperature, add sodium carbonate ( 143.23mg, 1.35mmol), then microwave reaction at 150°C for 1 hour. LC-MS detection found that the reaction was complete. Extracted twice with ethyl acetate (20mL), the mixed organic phase was washed with saturated brine (20mL), dried and filtered, and the filtrate was concentrated and prepared by preparative HPLC (TFA) to obtain compound I-56 (4.99mg, yield : 8.4%), as a white solid.
1H NMR(400MHz,Methanol-d4)δ7.49(d,J＝2.3Hz,1H),7.42(d,J＝2.3Hz,1H), 7.21–7.16(m,2H),6.97–6.91(m,2H),6.35(s,1H),4.96(d,J＝0.8Hz,2H),4.43–4.35(m,2H),3.90–3.83(m,2H),3.82–3.69(m,4H),3.62–3.45(m,4H),2.47–2.03(m,4H),1.64(s,6H).1H NMR (400MHz, Methanol-d4) δ7.49(d, J=2.3Hz, 1H), 7.42(d, J=2.3Hz, 1H), 7.21–7.16(m,2H),6.97–6.91(m,2H),6.35(s,1H),4.96(d,J＝0.8Hz,2H),4.43–4.35(m,2H),3.90–3.83( m,2H),3.82–3.69(m,4H),3.62–3.45(m,4H),2.47–2.03(m,4H),1.64(s,6H).
LC-MS[M+1]+＝618.40LC-MS [M+1] + = 618.40
按照上面的合成方法或参考文献分别合成下列化合物：Synthesize the following compounds respectively according to the above synthetic method or references:
如终产物需脱除N-Boc保护基团，可任选如下条件进行脱除：1)4N HCl/1,4-二氧六环/甲醇(1/1)液，室温或加热搅拌直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物；2)三氟乙酸/二氯甲烷(1/10)溶液室温反应直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物。

If the final product needs to remove the N-Boc protecting group, the following conditions can be selected for removal: 1) 4N HCl/1,4-dioxane/methanol (1/1) solution, room temperature or heating and stirring until the reaction Complete, the reaction solution was concentrated and separated by preparative HPLC to obtain the target product; 2) trifluoroacetic acid/dichloromethane (1/10) solution was reacted at room temperature until the reaction was completed, and the reaction solution was concentrated and separated by preparative HPLC to obtain the target product.

实施例20：化合物I-66的合成：Example 20: Synthesis of Compound 1-66:
1-(2-氯乙基)-5-(2-(4-((5-氟-2-((1-氧代四氢-1λ6-噻吩-1-亚基)氨基)嘧啶-4-基)甲氧基)苯基)丙基-2-基)-1H-吲唑-7-氰基
1-(2-chloroethyl)-5-(2-(4-((5-fluoro-2-((1-oxotetrahydro-1λ 6 -thiophene-1-ylidene)amino)pyrimidine-4 -yl)methoxy)phenyl)propyl-2-yl)-1H-indazole-7-cyano
步骤一：在-78℃下向I-66-1(500mg,2.99mmol)，Fe(acac)2(211mg,0.60mmol)和NMP(356mg,3.60mmol)的THF(17mL)溶液中滴入甲基溴化镁的THF溶液(4.20mL,4.20mmol)。上述混合液在-78℃下搅拌2小时。TLC检测反应完全。将反应液用水淬灭(30mL)中，用乙酸乙酯(30mL*3)萃取，合并的有机相用饱和食盐水(30mL)洗涤并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝10/1)，得到所需的产物I-66-2(400mg,产率：92％)，为淡黄色固体。Step 1: Add formazan to a solution of I-66-1 (500mg, 2.99mmol), Fe(acac) 2 (211mg, 0.60mmol) and NMP (356mg, 3.60mmol) in THF (17mL) at -78°C Magnesium bromide in THF (4.20 mL, 4.20 mmol). The above mixture was stirred at -78°C for 2 hours. TLC detects that the reaction is complete. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (30 mL*3), the combined organic phase was washed with saturated brine (30 mL), dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated and subjected to column chromatography Analysis and separation (petroleum ether/ethyl acetate=10/1) gave the desired product I-66-2 (400 mg, yield: 92%) as a pale yellow solid.
LC-MS[M+1]+＝147.0LC-MS [M+1] + = 147.0
步骤二：在室温下向I-66-2(1.0g,6.82mmol)的二氧六环(20mL)溶液中加入二氧化硒(3.0g,27.3mmol)。混合溶液在108℃下搅拌36小时。LCMS检测发现反应完全。将反应液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝4/1)得到产物I-66-3(410mg,产率：37％)，为棕色油状物。Step 2: To a solution of I-66-2 (1.0 g, 6.82 mmol) in dioxane (20 mL) was added selenium dioxide (3.0 g, 27.3 mmol) at room temperature. The mixed solution was stirred at 108°C for 36 hours. LCMS detection found that the reaction was complete. The reaction solution was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=4/1) to obtain the product I-66-3 (410 mg, yield: 37%) as a brown oil.
LC-MS[M+1]+＝161.00LC-MS [M+1] + = 161.00
步骤三：在室温下向I-66-3(400mg,2.49mmol)的甲醇(20mL)溶液中加入醋酸硼氢化钠(1.6g,7.48mmol)。混合溶液在25℃下搅拌2小时。LCMS检测发现反应完全。将反应液用水淬灭(30mL)中，用乙酸乙酯(30mL*3)萃取，合并的有机 相用饱和食盐水(30mL)洗涤并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝3/1)，得到所需的产物I-66-4(200mg,产率：49％)，为无色油状物。Step 3: To a solution of I-66-3 (400 mg, 2.49 mmol) in methanol (20 mL) was added sodium acetate borohydride (1.6 g, 7.48 mmol) at room temperature. The mixed solution was stirred at 25°C for 2 hours. LCMS detection found that the reaction was complete. The reaction solution was quenched with water (30mL), extracted with ethyl acetate (30mL*3), and the combined organic The phase was washed with saturated brine (30 mL) and dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain the desired product I-66-4 (200mg, Yield: 49%), as a colorless oil.
LC-MS[M+1]+＝163.10LC-MS [M+1] + = 163.10
步骤四：在0℃下向I-66-4(100mg,0.62mmol)和三乙胺(125mg,1.23mmol)的二氯甲烷(5mL)溶液中滴入MsCl(86mg,0.74mmol)。上述混合液在0℃-室温下搅拌2小时。TLC检测反应完全。将反应液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝3/1)得到产物I-66-5(80mg,产率：38％)，为棕色油状物。Step 4: To a solution of I-66-4 (100 mg, 0.62 mmol) and triethylamine (125 mg, 1.23 mmol) in dichloromethane (5 mL) was added dropwise MsCl (86 mg, 0.74 mmol) at 0°C. The above mixture was stirred at 0°C-room temperature for 2 hours. TLC detects that the reaction is complete. The reaction solution was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain the product I-66-5 (80 mg, yield: 38%) as a brown oil.
LC-MS[M+1]+＝240.90LC-MS [M+1] + = 240.90
步骤五：在室温下向I-66-5(80mg,0.23mmol)和中间体I-A10(79mg,0.23mmol)的乙腈(3mL)溶液中加入碳酸铯(76mg,0.23mmol)。上述混合液在室温下搅拌2小时。TLC检测反应完全。将反应液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝3/1)得到产物I-66-6(75mg,产率：66％)，为无色油状物。Step 5: To a solution of I-66-5 (80 mg, 0.23 mmol) and intermediate I-A10 (79 mg, 0.23 mmol) in acetonitrile (3 mL) was added cesium carbonate (76 mg, 0.23 mmol) at room temperature. The above mixture was stirred at room temperature for 2 hours. TLC detects that the reaction is complete. The reaction solution was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain the product I-66-6 (75 mg, yield: 66%) as a colorless oil.
LC-MS[M+1]+＝484.30LC-MS [M+1] + = 484.30
步骤六：在室温下向I-66-6(70mg,0.14mmol)，中间体I-B1(24mg,0.20mmol)和碳酸铯(47mg,0.14mmol)的二氧六环(3mL)溶液中加入t-Buxphos Pd G3(8mg,0.014mmol)。混合溶液用氮气置换三次，用微波在100℃下搅拌1小时。LCMS检测发现反应完全。将反应液浓缩后用HPLC制备得到化合物I-66(10mg,产率：12％)，为白色固体。Step 6: To a solution of I-66-6 (70mg, 0.14mmol), intermediate I-B1 (24mg, 0.20mmol) and cesium carbonate (47mg, 0.14mmol) in dioxane (3mL) was added at room temperature t-Buxphos Pd G3 (8 mg, 0.014 mmol). The mixed solution was replaced with nitrogen three times and stirred at 100° C. for 1 hour by microwave. LCMS detection found that the reaction was complete. The reaction solution was concentrated and prepared by HPLC to obtain compound I-66 (10 mg, yield: 12%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.35(s,2H)，8.09(s,1H)，7.89(d,J＝1.6Hz,1H)，7.55(d,J＝1.6Hz,1H)，7.13–7.09(m,2H)，6.92–6.88(m,2H)，5.15(s，2H)，5.02(t,J＝6.0Hz,2H)4.01(t,J＝6.0Hz,2H)3.65–3.58(m,2H)，3.36–3.29(m,2H)，2.36–2.20(m,4H)，1.71(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.35(s, 2H), 8.09(s, 1H), 7.89(d, J=1.6Hz, 1H), 7.55(d, J=1.6Hz, 1H), 7.13–7.09(m,2H), 6.92–6.88(m,2H), 5.15(s,2H), 5.02(t,J=6.0Hz,2H)4.01(t,J=6.0Hz,2H)3.65–3.58 (m,2H), 3.36–3.29(m,2H), 2.36–2.20(m,4H), 1.71(s,6H).
LC-MS[M+1]+＝567.50LC-MS [M+1] + = 567.50
按照上面的合成方法或参考文献分别合成下列化合物：


Synthesize the following compounds respectively according to the above synthetic method or references:


实施例21：化合物187的合成：Example 21: Synthesis of Compound 187:
((4-((4-(2-(1-(2-氯乙基)-7-甲基-1H-吲唑-5-基)丙烷-2-基)苯氧基)甲基)嘧啶-2-基)亚氨基)二甲基-λ6-亚磺酰
((4-((4-(2-(1-(2-chloroethyl)-7-methyl-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidine -2-yl)imino)dimethyl-λ 6 -sulfinyl
步骤一：将A34(200mg,608.21μmol)溶解在乙腈(10mL)，加入I-1-1(297.42mg,1.82mmol)，碳酸铯(296.50mg,912.31μmol)，在25℃反应6小时。将反应液倒入到10mL水中，用乙酸乙酯萃取两次(20mL*2)，合并有机相用饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤，浓缩得到粗品，粗品经过柱层析(石油醚/四氢呋喃＝3/1)得到化合物187-1(250mg,产率：63.32％)，为无色油状物。Step 1: Dissolve A34 (200 mg, 608.21 μmol) in acetonitrile (10 mL), add I-1-1 (297.42 mg, 1.82 mmol), cesium carbonate (296.50 mg, 912.31 μmol), and react at 25° C. for 6 hours. The reaction solution was poured into 10 mL of water, extracted twice with ethyl acetate (20 mL*2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was passed through the column layer Analysis (petroleum ether/tetrahydrofuran=3/1) gave compound 187-1 (250 mg, yield: 63.32%) as a colorless oil.
LC-MS[M+1]+＝455.30LC-MS [M+1] + = 455.30
步骤二：将187-1(240mg,528.18μmol)溶解在1,4-二氧六环(5.0mL)中，加入碳酸铯(120.16mg,369.73μmol)，t-BuxphosPdG3(41.94mg,52.82μmol)，二甲基亚磺酰亚胺(147.60mg,1.58mmol)，氮气置换，在100℃微波反应1小时。浓缩得到粗品，粗品加2mL乙腈，过滤，经Prep-HPLC(250*20.0mml.D.S-5μm,12nm.ACN/H2O(0.05％FA)＝0％～95％)纯化并冻干得到产物187(120.0mg,产率：43.20％)，冻干为淡黄色固体。Step 2: Dissolve 187-1 (240mg, 528.18μmol) in 1,4-dioxane (5.0mL), add cesium carbonate (120.16mg, 369.73μmol), t-BuxphosPdG3 (41.94mg, 52.82μmol) , dimethylsulfinimide (147.60mg, 1.58mmol), replaced with nitrogen, reacted with microwave at 100°C for 1 hour. Concentrate to obtain the crude product, which is added with 2 mL of acetonitrile, filtered, purified by Prep-HPLC (250*20.0 mml.DS-5 μm, 12 nm. ACN/H 2 O (0.05% FA) = 0% to 95%) and lyophilized to obtain the product 187 (120.0 mg, yield: 43.20%), lyophilized to pale yellow solid.
1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.02(s,1H),7.46(s,1H),7.24–7.05(m,2H),6.90(s,1H),6.86(d,J＝11.3Hz,3H),4.98(s,2H),4.78(s,2H),4.01(s,2H),3.35(s,6H),2.56(s,3H),1.61(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.41(s,1H),8.02(s,1H),7.46(s,1H),7.24–7.05(m,2H),6.90(s,1H), 6.86(d, J=11.3Hz, 3H), 4.98(s, 2H), 4.78(s, 2H), 4.01(s, 2H), 3.35(s, 6H), 2.56(s, 3H), 1.61(s ,6H).
LC-MS[M+1]+＝512.30LC-MS [M+1] + = 512.30
实施例22：化合物188的合成：Example 22: Synthesis of Compound 188:
((4-((4-(2-(1-(2-氯乙基)-7-氟-1H-吲唑-5-基)丙烷-2-基)苯氧基)甲基)嘧啶-2-基)亚氨基)二甲基-λ6-亚磺酰
((4-((4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidine- 2-yl)imino)dimethyl-λ 6 -sulfinyl
步骤一：将A35(200mg,600.96μmol)溶解在乙腈(5mL)中，加入I-1-1(200mg,600.96μmol)和碳酸铯(292.97mg,901.45μmol)，在15℃反应5小时。将反应液倒入到10mL水中，用乙酸乙酯萃取两次(20mL*2)，合并有机相用饱和食盐水洗 涤(10mL)，无水硫酸钠干燥，过滤，浓缩得到粗品，粗品经过柱层析(石油醚/四氢呋喃＝3/1)得到化合物188-1(130mg,产率：33.91％)，为无色油状物。Step 1: Dissolve A35 (200 mg, 600.96 μmol) in acetonitrile (5 mL), add I-1-1 (200 mg, 600.96 μmol) and cesium carbonate (292.97 mg, 901.45 μmol), and react at 15°C for 5 hours. Pour the reaction solution into 10 mL of water, extract twice with ethyl acetate (20 mL*2), combine the organic phases and wash with saturated brine Wash (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product, which is subjected to column chromatography (petroleum ether/tetrahydrofuran=3/1) to obtain compound 188-1 (130 mg, yield: 33.91%) as a colorless Oil.
LC-MS[M+1]+＝459.30LC-MS [M+1] + = 459.30
步骤二：将188-1(100mg,217.70μmol)溶解在1,4-二氧六环(5mL)中，加入二甲基亚磺酰亚胺(60.84mg,653.11μmol)，碳酸铯(70.75mg,217.70μmol)，t-BuxphosPdG3(17.29mg,21.77μmol)，氮气置换，在100℃微波反应1小时。浓缩得到粗品，粗品加2mL乙腈，过滤，经Prep-HPLC(250*20.0mml.D.S-5μm,12nm.ACN/H2O(0.05％FA)＝0％～95％)纯化并冻干得到产物188(40.00mg,产率：34.89％)，冻干为淡黄色固体。Step 2: Dissolve 188-1 (100mg, 217.70μmol) in 1,4-dioxane (5mL), add dimethylsulfinimide (60.84mg, 653.11μmol), cesium carbonate (70.75mg , 217.70μmol), t-BuxphosPdG3 (17.29mg, 21.77μmol), nitrogen replacement, microwave reaction at 100°C for 1 hour. Concentrate to obtain the crude product, which is added with 2 mL of acetonitrile, filtered, purified by Prep-HPLC (250*20.0 mml.DS-5 μm, 12 nm. ACN/H 2 O (0.05% FA) = 0% to 95%) and lyophilized to obtain the product 188 (40.00 mg, yield: 34.89%), lyophilized to pale yellow solid.
1H NMR(400MHz,Acetonitrile-d3)δ8.37(s,1H),8.00(s,1H),7.50(s,1H),7.15(s,2H),6.92(s,1H),6.84(d,J＝13.3Hz,2H),4.98(s,2H),4.73(d,J＝5.8Hz,2H),3.97(d,J＝6.5Hz,2H),3.28(s,6H),1.66(s,6H). 1 H NMR (400MHz,Acetonitrile-d 3 )δ8.37(s,1H),8.00(s,1H),7.50(s,1H),7.15(s,2H),6.92(s,1H),6.84( d,J=13.3Hz,2H),4.98(s,2H),4.73(d,J=5.8Hz,2H),3.97(d,J=6.5Hz,2H),3.28(s,6H),1.66( s,6H).
LC-MS[M+1]+＝516.10LC-MS [M+1] + = 516.10
按照上面的合成方法或参考文献分别合成下列化合物：









Synthesize the following compounds respectively according to the above synthetic method or references:









实施例23：化合物I-73的合成：Example 23: Synthesis of Compound I-73:
1-(5-氯-7-(2-(4-((2-((1-1-氧代四氢-1λ6-噻吩-1-亚基)胺基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)-3,4-二氢异喹啉-2(1H)-基)丙基-2-烯-1-酮
1-(5-chloro-7-(2-(4-((2-((1-1-oxotetrahydro-1λ 6 -thiophene-1-ylidene)amino)pyrimidin-4-yl)methyl Oxy)phenyl)propan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propyl-2-en-1-one
步骤一：0℃下向I-73-1(30g,197.18mmol)和吡啶(93.58g,1183mmol)的二氯甲烷(350mL)中，滴加三光气(14.63g,49.29mmol)的二氯甲烷(50mL)溶液。反应液在0-25℃反应2小时。将反应液缓慢倒入饱和氯化铵水溶液(200mL)与水(400mL)的混合液中，用DCM(200mL*2)萃取，有机相用无水硫酸钠干燥后浓缩，得到油状液体，将该油状液体加入到石油醚(200mL)中，析出白色固体。过滤得到产物I-73-2(33g,产率：50.7％)，为白色固体。Step 1: To I-73-1 (30g, 197.18mmol) and pyridine (93.58g, 1183mmol) in dichloromethane (350mL) at 0°C, add triphosgene (14.63g, 49.29mmol) in dichloromethane dropwise (50 mL) solution. The reaction solution was reacted at 0-25°C for 2 hours. The reaction solution was slowly poured into a mixture of saturated aqueous ammonium chloride solution (200mL) and water (400mL), extracted with DCM (200mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain an oily liquid. The oily liquid was added to petroleum ether (200 mL), and a white solid was precipitated. The product I-73-2 (33 g, yield: 50.7%) was obtained by filtration as a white solid.
LC-MS[M+23]+＝353.20LC-MS [M+23] + = 353.20
步骤二：室温下，向I-73-2(33g,99.91mmol)的THF(350mL)中，滴加I-73-3(19.99g,99.91mmol)的THF(50mL)溶液。反应液室温搅拌16小时。反应液旋干，缓慢加入石油醚(200mL)，搅拌10分钟，然后过滤，滤饼干燥得到所需的产物(I-73-4,35g,产率：86.14％)，为白色固体。Step 2: Add I-73-3 (19.99 g, 99.91 mmol) in THF (50 mL) dropwise to I-73-2 (33 g, 99.91 mmol) in THF (350 mL) at room temperature. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was spin-dried, petroleum ether (200 mL) was slowly added, stirred for 10 minutes, then filtered, and the filter cake was dried to obtain the desired product (I-73-4, 35 g, yield: 86.14%) as a white solid.
LC-MS[M+1]+＝400.30LC-MS [M+1] + = 400.30
步骤三：0℃下向氮气保护的I-73-4(34.0g,89.90mmol)的DCM(200mL)中，滴加TfOH(121.42g,809.06mmol)，室温反应1小时。反应液倒入冰水中，用二氯甲 烷(200mL*3)萃取。有机相用饱和食盐水(200mL)洗并用无水硫酸钠干燥，过滤，将滤液浓缩后进行柱层析分离(二氯甲烷/乙酸乙酯＝1/1)，得到所需的产物I-73-5(14.5g,产率：71.35％)，为白色固体。Step 3: Add TfOH (121.42 g, 809.06 mmol) dropwise to I-73-4 (34.0 g, 89.90 mmol) in DCM (200 mL) protected by nitrogen at 0° C., and react at room temperature for 1 hour. The reaction solution was poured into ice water, dichloromethane Alkanes (200mL*3) extraction. The organic phase was washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (dichloromethane/ethyl acetate=1/1) to obtain the desired product I-73 -5 (14.5 g, yield: 71.35%), as a white solid.
LC-MS[M+1]+＝226.10LC-MS [M+1] + = 226.10
步骤四：在-78℃下向I-73-5(3.0g,13.27mmol)的四氢呋喃(40mL)溶液中滴加n-BuLi(2.55g,39.81mmol,16mL)，反应液在-78℃下搅拌1小时，然后加入干冰(1.75g,39.81mmol)，缓慢升至室温，反应4小时。加水(100mL)淬灭，用乙酸乙酯(30mL*3)萃取，水相用0.5N HCl调节pH到4，大量固体产生，过滤，滤饼冻干得所需的产物I-73-6(1.2g,产率：47.30％)，为白色固体。Step 4: Add n-BuLi (2.55g, 39.81mmol, 16mL) dropwise to a solution of I-73-5 (3.0g, 13.27mmol) in tetrahydrofuran (40mL) at -78°C, and the reaction solution was kept at -78°C Stir for 1 hour, then add dry ice (1.75 g, 39.81 mmol), slowly warm to room temperature, and react for 4 hours. Add water (100mL) to quench, and extract with ethyl acetate (30mL*3), adjust the pH to 4 with 0.5N HCl in the aqueous phase, a large amount of solids are produced, filter, and freeze-dry the filter cake to obtain the desired product I-73-6( 1.2 g, yield: 47.30%), as a white solid.
LC-MS[M+1]+＝192.00LC-MS[M+1]+=192.00
步骤五：向I-73-6(1.2g,6.28mmol)的TfOH(10mL)溶液中加入I-73-7(4.95g,25.11mmol)。上述混合液在80℃搅拌12小时。将反应液倒入水(30mL)中，用乙酸乙酯(20mL*3)萃取，合并的有机相用饱和食盐水(30mL)洗涤并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(二氯甲烷/甲醇＝10/1)，得到所需的产物I-73-8(1.10g,产率：35.73％)，为白色固体。Step 5: Add I-73-7 (4.95 g, 25.11 mmol) to a solution of I-73-6 (1.2 g, 6.28 mmol) in TfOH (10 mL). The above mixture was stirred at 80°C for 12 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and subjected to column chromatography Analysis and separation (dichloromethane/methanol=10/1) gave the desired product I-73-8 (1.10 g, yield: 35.73%) as a white solid.
LC-MS[M+1]+＝225.90LC-MS[M+1]+=225.90
步骤六：在室温下向I-73-8(1.1g,4.88mmol)的甲醇溶液(10mL)中加入SOCl2(1.16g,9.75mmol)。反应液在80℃下搅拌2小时。反应液直接浓缩后进行柱层析分离(石油醚/乙酸乙酯＝1/1)得到产物I-73-9(600mg,产率：41.08％)，为白色固体。Step 6: To a methanol solution (10 mL) of I-73-8 (1.1 g, 4.88 mmol) was added SOCl 2 (1.16 g, 9.75 mmol) at room temperature. The reaction solution was stirred at 80° C. for 2 hours. The reaction solution was directly concentrated and separated by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the product I-73-9 (600 mg, yield: 41.08%) as a white solid.
LC-MS[M+1]+＝240.00LC-MS [M+1] + = 240.00
步骤七：室温下，将I-73-9(500mg,2.09mmol)的THF(10mL)溶液中滴加MeMgBr(746.32mg,6.26mmol)，上述混合液在60℃反应3小时。LCMS显示反应完成。反应液将反应液缓慢倒入0℃下的饱和氯化铵水溶液(10mL)中，用乙酸乙酯(15mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，并用无水硫酸钠干燥并过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝2/1)，得到所需的产物(I-73-10，400mg,产率：79.99％)，为白色固体。Step 7: At room temperature, MeMgBr (746.32 mg, 6.26 mmol) was added dropwise to a solution of I-73-9 (500 mg, 2.09 mmol) in THF (10 mL), and the above mixture was reacted at 60° C. for 3 hours. LCMS showed the reaction was complete. Reaction solution The reaction solution was slowly poured into saturated aqueous ammonium chloride solution (10mL) at 0°C, extracted with ethyl acetate (15mL*3), the combined organic phases were washed with saturated brine (10mL), and washed with anhydrous sulfuric acid Sodium-dried and filtered, the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=2/1) to obtain the desired product (I-73-10, 400mg, yield: 79.99%) as white solid.
LC-MS[M+1]+＝240.10LC-MS [M+1] + = 240.10
步骤八：室温下，将I-73-10(250mg,1.04mmol)，苯酚(294.47mg,3.13mmol) 溶于DCM(3mL)中,在-78℃氮气保护下滴加BF3(282.90mg,4.17mmol)，滴加完后自然升温至室温25℃反应12小时。LCMS显示反应完成。反应液倒入水(20mL)中，并用二氯甲烷(10mL*3)萃取。有机相用饱和食盐水洗(30mL)，并用无水硫酸钠干燥并过滤。将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝2/1)，得到所需的产物(I-73-11，180mg,产率：54.65％)，为无色油状。Step 8: At room temperature, mix I-73-10 (250mg, 1.04mmol), phenol (294.47mg, 3.13mmol) Dissolve in DCM (3 mL), add BF 3 (282.90 mg, 4.17 mmol) dropwise under nitrogen protection at -78°C, and then naturally warm to room temperature 25°C for 12 hours after the addition. LCMS showed the reaction was complete. The reaction solution was poured into water (20 mL), and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=2/1) to obtain the desired product (I-73-11, 180 mg, yield: 54.65%) as a colorless oil.
LC-MS[M+1]+＝316.30LC-MS [M+1] + = 316.30
步骤九：室温下，将I-73-11(180mg,0.57mmol)溶于THF(2mL),加入BH3(39.42mg,2.85mmol)，在60℃反应12小时。反应液浓缩，得到粗产品(I-73-12，170mg,产率：98.8％)，为白色固体。Step 9: Dissolve I-73-11 (180 mg, 0.57 mmol) in THF (2 mL) at room temperature, add BH 3 (39.42 mg, 2.85 mmol), and react at 60°C for 12 hours. The reaction solution was concentrated to obtain a crude product (I-73-12, 170 mg, yield: 98.8%) as a white solid.
LC-MS[M+1]+＝302.30LC-MS [M+1] + = 302.30
步骤十：室温下，将I-73-12(160mg,0.53mmol)溶于HCl/MeOH(4mL),室温搅拌5分钟，旋干，再溶于DCM(8mL)，然后加入三乙胺(160.59mg,1.59mmol)和Boc2O(347.10mg,1.59mmol)，在25℃反应12小时。反应液浓缩，过柱(石油醚/乙酸乙酯＝5/1)得到产品(I-73-13，55mg,产率：25.8％)，为无色油状。Step 10: At room temperature, dissolve I-73-12 (160mg, 0.53mmol) in HCl/MeOH (4mL), stir at room temperature for 5 minutes, spin dry, then dissolve in DCM (8mL), then add triethylamine (160.59 mg, 1.59mmol) and Boc 2 O (347.10mg, 1.59mmol), react at 25°C for 12 hours. The reaction solution was concentrated and passed through a column (petroleum ether/ethyl acetate=5/1) to obtain the product (I-73-13, 55 mg, yield: 25.8%) as a colorless oil.
LC-MS[M-56+1]+＝346.30LC-MS [M-56+1] + = 346.30
步骤十一：室温下，将I-73-16(4.0g,23.18mmol)溶于二氧六环(20mL)中，然后加入中间体I-B1(2.76g,23.18mmol),Cs2CO3(15.10g,46.36mmol)和t-BuXPhos Pd G3(1.84g,2.32mmol)，在氮气保护下加热升温至80℃反应2.5小时。反应液浓缩，过滤，用乙酸乙酯洗涤滤饼，过柱得到产品(I-73-17，3.10g,产率：41.94％)，为黄色固体。Step 11: Dissolve I-73-16 (4.0g, 23.18mmol) in dioxane (20mL) at room temperature, then add intermediate I-B1 (2.76g, 23.18mmol), Cs 2 CO 3 (15.10g, 46.36mmol) and t-BuXPhos Pd G3 (1.84g, 2.32mmol), heated to 80°C for 2.5 hours under the protection of nitrogen. The reaction solution was concentrated, filtered, the filter cake was washed with ethyl acetate, and passed through a column to obtain the product (I-73-17, 3.10 g, yield: 41.94%) as a yellow solid.
LC-MS[M+1]+＝256.10LC-MS [M+1] + = 256.10
步骤十二：室温下，将I-73-17(3.0g,11.75mmol)溶于THF(15mL)和EtOH(15mL)中,然后降温至0℃，分批加入NaBH4(666.82mg,17.63mmol),然后0℃反应0.5小时。然后补加NaBH4(666.82mg,17.63mmol),0℃反应0.5小时。TLC(EA/MeOH＝10/1)显示原料基本反应完，加入水(3mL)，然后加入无水硫酸镁干燥，过滤，浓缩。过柱(DCM/MeOH＝10/1)得到产品(I-73-18，1.47g,产率：50.64％)，为黄色油状固体。Step 12: Dissolve I-73-17 (3.0g, 11.75mmol) in THF (15mL) and EtOH (15mL) at room temperature, then cool down to 0°C, add NaBH 4 (666.82mg, 17.63mmol) in batches ), and react at 0°C for 0.5 hours. Then NaBH 4 (666.82mg, 17.63mmol) was added and reacted at 0°C for 0.5 hours. TLC (EA/MeOH=10/1) showed that the starting material was almost completely reacted, and water (3 mL) was added, then anhydrous magnesium sulfate was added to dry, filtered, and concentrated. The product (I-73-18, 1.47 g, yield: 50.64%) was obtained by column (DCM/MeOH=10/1) as a yellow oily solid.
LC-MS[M+1]+＝228.60 LC-MS [M+1] + = 228.60
步骤十三：室温下，将I-73-18(300.0mg,1.32mmol)和DIEA(667.82mg,6.60mmol)溶于DCM(5mL)中,0℃下加入甲磺酰氯(302.40mg,2.64mmol),然后0℃反应1小时。反应液直接旋干用TLC(石油醚/乙酸乙酯＝10/1)得到产品(I-73-19，310.00mg,产率：69.22％)为淡橙色油状。Step 13: Dissolve I-73-18 (300.0mg, 1.32mmol) and DIEA (667.82mg, 6.60mmol) in DCM (5mL) at room temperature, add methanesulfonyl chloride (302.40mg, 2.64mmol) at 0°C ), and react at 0°C for 1 hour. The reaction solution was directly spin-dried and TLC (petroleum ether/ethyl acetate=10/1) was used to obtain the product (I-73-19, 310.00 mg, yield: 69.22%) as a light orange oil.
LC-MS[M+1]+＝306.8LC-MS [M+1] + = 306.8
步骤十四：室温下，将I-73-13(50.0mg,0.124mmol)溶于ACN(2mL)中,然后加入Cs2CO3(40.43mg,0.124mmol)和I-73-19(151.96mg,0.498mmol)室温下反应12小时。反应液直接旋干过柱子(石油醚/乙酸乙酯＝0～100％)得到产品(I-73-14，45.00mg,产率：53.27％)，为无色油状。Step Fourteen: Dissolve I-73-13 (50.0mg, 0.124mmol) in ACN (2mL) at room temperature, then add Cs 2 CO 3 (40.43mg, 0.124mmol) and I-73-19 (151.96mg , 0.498mmol) at room temperature for 12 hours. The reaction solution was directly spin-dried and passed through the column (petroleum ether/ethyl acetate = 0-100%) to obtain the product (I-73-14, 45.00 mg, yield: 53.27%) as a colorless oil.
LC-MS[M+2]+＝611.70LC-MS [M+2] + = 611.70
步骤十五：室温下，将I-73-14(45.0mg,0.073mmol)溶于DCM(2.5mL)中,然后加入TFA(0.5mL),室温反应0.5小时。反应液用饱和碳酸氢钠调节pH到7，然后用二氯甲烷(10mL*2)萃取，饱和食盐水洗，有机相用硫酸钠干燥，旋干，得目标产物(I-73-15，24.00mg,产率：63.8％)，为无色油状。Step 15: Dissolve I-73-14 (45.0 mg, 0.073 mmol) in DCM (2.5 mL) at room temperature, then add TFA (0.5 mL) and react at room temperature for 0.5 hours. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate, then extracted with dichloromethane (10mL*2), washed with saturated brine, the organic phase was dried with sodium sulfate, and spin-dried to obtain the target product (I-73-15, 24.00mg , Yield: 63.8%), as a colorless oil.
LC-MS[M+2]+＝512.50LC-MS [M+2] + = 512.50
步骤十六：室温下，将I-73-15(24.0mg,0.047mmol)溶于DCM(3mL)中,然后在0℃加入DIEA(18.21mg,0.141mmol)和I-73-20(17.77mg,0.141mmol)在0℃,反应0.5小时。反应液用二氯甲烷(10mL*2)萃取，饱和食盐水洗，有机相用硫酸钠干燥，旋干，用甲醇和DMF溶解用HPLC制备得到产品化合物I-73(3.00mg,产率：11.3％)，为白色固体。Step 16: Dissolve I-73-15 (24.0mg, 0.047mmol) in DCM (3mL) at room temperature, then add DIEA (18.21mg, 0.141mmol) and I-73-20 (17.77mg , 0.141mmol) at 0°C for 0.5 hours. The reaction solution was extracted with dichloromethane (10mL*2), washed with saturated brine, the organic phase was dried with sodium sulfate, spin-dried, dissolved in methanol and DMF and prepared by HPLC to obtain the product compound I-73 (3.00mg, yield: 11.3% ), as a white solid.
1H NMR(400MHz,Acetonitrile-d3)δ8.38(d,J＝5.1Hz,1H),7.16–7.11(m,2H),7.03(m,2H),6.94(d,J＝5.1Hz,1H),6.89–6.85(m,2H),6.80–6.63(m,1H),6.14(dd,J＝15.6,2.0Hz,1H),,5.65(dd,J＝10.3,1.9Hz,1H),4.99(s,2H),4.64(s,2H),3.78(t,J＝6.1Hz,2H),3.59–3.49(m,2H),3.27–3.20(m,2H),2.86–2.74(m,2H),2.30–2.19(m,2H),2.11–2.09(m,2H),1.59(s,6H).1H NMR (400MHz, Acetonitrile-d3) δ8.38 (d, J = 5.1Hz, 1H), 7.16–7.11 (m, 2H), 7.03 (m, 2H), 6.94 (d, J = 5.1Hz, 1H) ,6.89–6.85(m,2H),6.80–6.63(m,1H),6.14(dd,J＝15.6,2.0Hz,1H),,5.65(dd,J＝10.3,1.9Hz,1H),4.99( s,2H),4.64(s,2H),3.78(t,J＝6.1Hz,2H),3.59–3.49(m,2H),3.27–3.20(m,2H),2.86–2.74(m,2H) ,2.30–2.19(m,2H),2.11–2.09(m,2H),1.59(s,6H).
LC-MS[M+1]+＝565.50LC-MS [M+1] + = 565.50
实施例24：化合物I-74的合成： Example 24: Synthesis of Compound 1-74:
4-丙烯酰基-7-(2-(4-((2-((1-氧代四氢-1λ6-噻吩-1-亚基)胺基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-5-氰基
4-acryloyl-7-(2-(4-((2-((1-oxotetrahydro-1λ 6 -thiophen-1-ylidene)amino)pyrimidin-4-yl)methoxy)benzene Base) propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-cyano
步骤一：将I-74-1(5.0g,29.91mmol)溶解于DCM(100mL)和DMF(10mL)中，在0℃下，分批加入NBS(6.92g,38.88mmol)。该反应液在30℃下，搅拌2小时后，加入H2O(50mL)，水层用DCM(100mL)萃取三次，合并有机相，干燥，浓缩，通过SGC(石油醚/乙酸乙酯＝3/1)纯化得到所需产物(I-74-2，2.50g,8.10mmol,产率：27.09％)，为棕色固体。Step 1: I-74-1 (5.0 g, 29.91 mmol) was dissolved in DCM (100 mL) and DMF (10 mL), and NBS (6.92 g, 38.88 mmol) was added in portions at 0°C. After the reaction solution was stirred at 30°C for 2 hours, H 2 O (50 mL) was added, the aqueous layer was extracted three times with DCM (100 mL), the organic phases were combined, dried, concentrated, passed through SGC (petroleum ether/ethyl acetate=3 /1) Purification gave the desired product (I-74-2, 2.50 g, 8.10 mmol, yield: 27.09%) as a brown solid.
LC-MS[M+1]+＝245.9LC-MS [M+1] + = 245.9
步骤二：将I-74-2(2.3g,9.35mmol)和K2CO3(6.45g,46.74mmol)溶解于DMF(140mL)中，加入1,2-二溴乙烷(4.39g,23.37mmol)。该反应液在80℃下搅拌18小时后，浓缩，过柱(石油醚/乙酸乙酯＝5/1)纯化得到所需产物(I-74-3，1.10g,3.84mmol,产率：41.09％)，为淡黄色固体。Step 2: Dissolve I-74-2 (2.3g, 9.35mmol) and K 2 CO 3 (6.45g, 46.74mmol) in DMF (140mL), add 1,2-dibromoethane (4.39g, 23.37 mmol). The reaction solution was stirred at 80°C for 18 hours, concentrated, and purified by column (petroleum ether/ethyl acetate=5/1) to obtain the desired product (I-74-3, 1.10g, 3.84mmol, yield: 41.09 %), as light yellow solid.
LC-MS[M+1]+＝272.0LC-MS [M+1] + = 272.0
步骤三：将I-74-3(200mg,916.56μmol)，DMAP(55.99mg,458.28μmol)和DIEA(278.24mg,2.75mmol,383.51μL)溶解于二氧六环(5mL)中，加入(Boc)2O(400.08mg,1.83mmol)，该反应液在30℃下，搅拌18小时后，浓缩，通过制备TLC(石油醚/乙酸乙酯＝5/1)纯化得到所需产物(I-74-4，150.00mg,447.66μmol,收率：48.84％),为白色固体。 Step 3: Dissolve I-74-3 (200mg, 916.56μmol), DMAP (55.99mg, 458.28μmol) and DIEA (278.24mg, 2.75mmol, 383.51μL) in dioxane (5mL), add (Boc ) 2 O (400.08mg, 1.83mmol), the reaction solution was stirred at 30°C for 18 hours, concentrated, and purified by preparative TLC (petroleum ether/ethyl acetate=5/1) to obtain the desired product (I-74 -4, 150.00 mg, 447.66 μmol, yield: 48.84%), is a white solid.
LC-MS[M+1]+＝319.1LC-MS [M+1] + = 319.1
步骤四：在30℃下，向MeMgBr(1M,2.01mL)中滴入I-74-4(40mg,125.66μmol)的THF(1mL)溶液，该反应液在30℃下，反应1小时后，TLC检测原料已经全部反应；在0℃下用饱和NH4Cl溶液(5mL)淬灭后，用乙酸乙酯(20mL)萃取两次，合并有机相干燥浓缩后得到所需产物(I-74-5，40.00mg,125.64μmol,收率：99.99％)，为白色固体。Step 4: Add a THF (1 mL) solution of I-74-4 (40 mg, 125.66 μmol) dropwise into MeMgBr (1M, 2.01 mL) at 30° C., and react the reaction solution for 1 hour at 30° C. It was detected by TLC that all the raw materials had reacted; quenched with saturated NH 4 Cl solution (5 mL) at 0°C, extracted twice with ethyl acetate (20 mL), combined the organic phases, dried and concentrated to obtain the desired product (I-74- 5, 40.00 mg, 125.64 μmol, yield: 99.99%), as a white solid.
LC-MS[M+1]+＝,319.20LC-MS[M+1] + ＝,319.20
步骤五：将I-74-5(40mg,125.64μmol)和苯酚(23.65mg,251.28μmol)溶解在无水DCM(1mL)中，在-78℃下加入BF3·Et2O(53.50mg,376.92μmol)，该反应液自然升温至0℃后搅拌3小时后；在0℃下，用饱和NaHCO3(5mL)淬灭后，用DCM(20mL)萃取三次，合并有机相浓缩，然后用制备TLC(石油醚/乙酸乙酯＝3/1)得到所需产物(I-74-6，15.00mg,48.41μmol,收率：38.53％)，为白色固体。Step 5: Dissolve I-74-5 (40mg, 125.64μmol) and phenol (23.65mg, 251.28μmol) in anhydrous DCM (1mL), add BF 3 ·Et 2 O (53.50mg, 376.92μmol), the reaction solution was naturally warmed to 0°C and stirred for 3 hours; at 0°C, quenched with saturated NaHCO 3 (5mL), extracted three times with DCM (20mL), combined the organic phases and concentrated, and then prepared TLC (petroleum ether/ethyl acetate=3/1) gave the desired product (I-74-6, 15.00 mg, 48.41 μmol, yield: 38.53%) as a white solid.
LC-MS[M+1]+＝295.1LC-MS [M+1] + = 295.1
步骤六：将I-74-6(35mg,118.91μmol)和I-73-19(145.24mg,475.63μmol)溶解于ACN(1mL)和DMF(0.3mL)中，加入Cs2CO3(232.58mg,713.44μmol)；该反应液在45℃下反应18小时后加入H2O(15mL)，水相通过乙酸乙酯(30mL)萃取三次，合并有机相浓缩后，用制备TLC(石油醚/乙酸乙酯＝0：1)纯化得到所需产物(I-74-7，45.00mg,60.76μmol,收率：51.10％)，为白色固体。Step 6: Dissolve I-74-6 (35mg, 118.91μmol) and I-73-19 (145.24mg, 475.63μmol) in ACN (1mL) and DMF (0.3mL), add Cs 2 CO 3 (232.58mg ,713.44μmol); the reaction solution was reacted at 45°C for 18 hours, then H 2 O (15mL) was added, the aqueous phase was extracted three times with ethyl acetate (30mL), the combined organic phases were concentrated, and then preparative TLC (petroleum ether/acetic acid Ethyl ester=0:1) Purification gave the desired product (I-74-7, 45.00 mg, 60.76 μmol, yield: 51.10%) as a white solid.
LC-MS[M+1]+＝504.2LC-MS [M+1] + = 504.2
步骤七：将I-74-7(40mg,79.43μmol)，DMAP(1.94mg,15.89μmol)和DIEA(102.65mg,794.26μmol)溶解于DCM(1mL)中，在0℃下加入丙烯酸酐I-73-20(20.03mg,158.85μmol)，该反应液在30℃下，反应18小时后，用MeOH(2mL)淬灭后，加入H2O(10mL)，该混合液用乙酸乙酯(30mL)萃取三次，合并有机相，浓缩后，通过制备HPLC纯化得到所化合物I-74(1.61mg,2.89μmol,收率：3.63％)，为白色固体.Step 7: Dissolve I-74-7 (40 mg, 79.43 μmol), DMAP (1.94 mg, 15.89 μmol) and DIEA (102.65 mg, 794.26 μmol) in DCM (1 mL), add acrylic anhydride I- 73-20 (20.03mg, 158.85μmol), the reaction solution was reacted at 30°C for 18 hours, quenched with MeOH (2mL), added H 2 O (10mL), the mixture was washed with ethyl acetate (30mL ) was extracted three times, the organic phases were combined, concentrated, and purified by preparative HPLC to obtain the compound I-74 (1.61 mg, 2.89 μmol, yield: 3.63%) as a white solid.
1H NMR(400MHz,MeCN-d6)δ8.38(d,J＝4.8Hz,1H),7.16-7.13(m,3H),6.97-6.87(m,4H),6.35-6.30(m,2H),5.82(d,J＝10.8Hz,1H),5.00(s,2H),4.25(s,2H),3.58-3.51(m,2H),3.28-3.17(m,4H),2.16-2.07(m,4H),1.60(s,6H). 1 H NMR (400MHz, MeCN-d6) δ8.38 (d, J = 4.8Hz, 1H), 7.16-7.13 (m, 3H), 6.97-6.87 (m, 4H), 6.35-6.30 (m, 2H) ,5.82(d,J＝10.8Hz,1H),5.00(s,2H),4.25(s,2H),3.58-3.51(m,2H),3.28-3.17(m,4H),2.16-2.07(m ,4H),1.60(s,6H).
LC-MS[M+1]+＝558.4LC-MS [M+1] + = 558.4
按照上面的合成方法或参考文献分别合成下列化合物：
Synthesize the following compounds respectively according to the above synthetic method or references:
实施例25：化合物I-77的合成：Example 25: Synthesis of Compound 1-77:
1-(2-氯乙基)-5-(2-(4-((2-((1-氧代四氢-1λ6-噻吩-1-亚基)胺基)嘧啶-4-基)氧基)苯基)丙烷-2-基)-1H-吲唑-7-氰基
1-(2-chloroethyl)-5-(2-(4-((2-((1-oxotetrahydro-1λ 6 -thiophene-1-ylidene)amino)pyrimidin-4-yl) Oxy)phenyl)propan-2-yl)-1H-indazol-7-cyano
步骤一：在室温下向中间体I-A10(60mg,0.17mmol)和2，4-二氯嘧啶(26.3mg,0.17mmol,1.0eq)的DMF溶液(2mL)中加入碳酸铯(57.53mg,0.17mmol，1.0eq)。混合溶液在50℃下搅拌1小时。LCMS检测发现反应完全。反应液过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝1/1)得到产物I-77-1(70mg,产率：87.6％)，为无 色液体。Step 1: Add cesium carbonate (57.53mg, 0.17 mmol, 1.0 eq). The mixed solution was stirred at 50°C for 1 hour. LCMS detection found that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the product I-77-1 (70 mg, yield: 87.6%), which was free colored liquid.
LC-MS[M+1]+＝452.2LC-MS [M+1] + = 452.2
步骤二：室温下，将I-77-1(70.0mg,0.155mmol)和中间体I-B1(18.44mg,0.155mmol)溶解于无水二氧六环(2mL)中，然后加入Cs2CO3(50.42mg,0.155mmol),t-BuXPhos Pd G3(12.3mg,0.016mmol)。加完后，吹入氮气保护，然后用微波在100℃,反应1小时。LCMS检测到目标产物的MS。反应混合物旋干后用HPLC制备得到化合物I-77(23.92mg,产率：29.0％)，为白色固体。Step 2: Dissolve I-77-1 (70.0mg, 0.155mmol) and intermediate I-B1 (18.44mg, 0.155mmol) in anhydrous dioxane (2mL) at room temperature, then add Cs 2 CO 3 (50.42 mg, 0.155 mmol), t-BuX Phos Pd G3 (12.3 mg, 0.016 mmol). After the addition, nitrogen protection was blown in, and then microwave was used at 100°C for 1 hour of reaction. LCMS detected MS of the target product. The reaction mixture was spin-dried and prepared by HPLC to obtain compound I-77 (23.92 mg, yield: 29.0%) as a white solid.
1H NMR(400MHz,MeOD-d4)δ8.25(d,J＝5.8Hz,1H),8.21(s,1H),8.11(d,J＝1.8Hz,1H),7.66(d,J＝1.8Hz,1H),7.33-7.31(m,2H),7.10–7.06(m,2H),6.52(d,J＝5.8Hz,1H),5.05(t,J＝6.1Hz,2H),4.03(t,J＝5.9Hz,2H),3.47–3.35(m,2H),2.97–2.81(m,2H),2.17–1.97(m,4H),1.76(s,6H).1H NMR (400MHz, MeOD-d4) δ8.25(d, J＝5.8Hz, 1H), 8.21(s, 1H), 8.11(d, J＝1.8Hz, 1H), 7.66(d, J＝1.8Hz ,1H),7.33-7.31(m,2H),7.10–7.06(m,2H),6.52(d,J＝5.8Hz,1H),5.05(t,J＝6.1Hz,2H),4.03(t, J＝5.9Hz, 2H), 3.47–3.35(m, 2H), 2.97–2.81(m, 2H), 2.17–1.97(m, 4H), 1.76(s, 6H).
LC-MS[M+1]+＝535.40LC-MS [M+1] + = 535.40
实施例26：化合物I-78的合成：Example 26: Synthesis of Compound 1-78:
1-(2-氯乙基)-5-(2-(4-((5-((1-氧代四氢-1λ6-噻吩-1-亚基)胺基)嘧啶-2-基)氧基)苯基)丙烷-2-基)-1H-吲唑-7-氰基
1-(2-Chloroethyl)-5-(2-(4-((5-((1-oxotetrahydro-1λ 6 -thiophene-1-ylidene)amino)pyrimidin-2-yl) Oxy)phenyl)propan-2-yl)-1H-indazol-7-cyano
步骤一：在室温下向中间体I-A10(60mg,0.18mmol)和2-氯-5-溴嘧啶(41mg,0.21mmol)的DMF(1.5mL)溶液中加入碳酸铯(69mg,0.21mmol)。混合溶液在50℃下搅拌1小时。LCMS检测发现反应完全。将反应液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝3/1)得到产物(I-78-1,70mg,产率：79.8％)，为无色油状物。Step 1: To intermediate I-A10 (60 mg, 0.18 mmol) and 2-chloro-5-bromopyrimidine (41 mg, 0.21 mmol) in DMF (1.5 mL) was added cesium carbonate (69 mg, 0.21 mmol) at room temperature . The mixed solution was stirred at 50°C for 1 hour. LCMS detection found that the reaction was complete. The reaction solution was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain the product (I-78-1, 70 mg, yield: 79.8%) as a colorless oil.
LC-MS[M+1]+＝496.20 LC-MS [M+1] + = 496.20
步骤二：在室温下向I-78-1(70mg,0.14mmol)，中间体I-B1(24mg,0.20mmol)和碳酸铯(55mg,0.17mmol)的二氧六环(2mL)溶液中加入t-Buxphos Pd G3(11mg,0.014mmol)。混合溶液用氮气置换三次，用微波在100℃下搅拌1小时。LCMS检测发现反应完全。将反应液浓缩后用HPLC制备得到化合物I-78(10mg,产率：13％)，为白色固体。Step 2: To a solution of I-78-1 (70mg, 0.14mmol), intermediate I-B1 (24mg, 0.20mmol) and cesium carbonate (55mg, 0.17mmol) in dioxane (2mL) was added at room temperature t-Buxphos Pd G3 (11 mg, 0.014 mmol). The mixed solution was replaced with nitrogen three times and stirred at 100° C. for 1 hour by microwave. LCMS detection found that the reaction was complete. The reaction solution was concentrated and prepared by HPLC to obtain compound I-78 (10 mg, yield: 13%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.31(s,2H),8.10(s,1H),7.92(d,J＝2.0Hz,1H),7.65(d,J＝1.6Hz,1H),7.24–7.22(m,2H),7.14–7.10(m,2H),5.03(t,J＝6.0Hz,2H),4.01(t,J＝6.0Hz,2H),3.39–3.32(m,2H),3.22–3.15(m,2H),2.38–2.25(m,4H),1.76(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.31(s, 2H), 8.10(s, 1H), 7.92(d, J=2.0Hz, 1H), 7.65(d, J=1.6Hz, 1H), 7.24–7.22(m,2H),7.14–7.10(m,2H),5.03(t,J=6.0Hz,2H),4.01(t,J=6.0Hz,2H),3.39–3.32(m,2H) ,3.22–3.15(m,2H),2.38–2.25(m,4H),1.76(s,6H).
LC-MS[M+1]+＝535.3LC-MS [M+1]+=535.3
按照上面的合成方法或参考文献分别合成下列化合物：
Synthesize the following compounds respectively according to the above synthetic method or references:
实施例27：化合物I-79的合成：Example 27: Synthesis of Compound 1-79:
1-((4-((4-(2-(1-(2-氯乙基)-1H-吡唑[3,4-b]吡啶-5-基)丙-2-基)苯氧基)甲基)嘧啶-2-基)亚胺基)-4-(丙-2-炔-1-基)-1λ6-硫代吗啡啉-1-氧代
1-((4-((4-(2-(1-(2-chloroethyl)-1H-pyrazol[3,4-b]pyridin-5-yl)propan-2-yl)phenoxy )methyl)pyrimidin-2-yl)imino)-4-(prop-2-yn-1-yl)-1λ 6 -thiomorpholine-1-oxo
步骤一：将I-A22(0.35g,1.11mmol)，I-1-1(361.32mg,2.22mmol)和Cs2CO3(541.66mg,1.66mmol)加入ACN(3.5mL)中，40℃搅拌反应4小时。LC-MS检测发现产物。将反应液进行柱层析分离(石油醚/四氢呋喃＝4/1)，得到所需的产物I-79-1(340.00mg,产率：67.97％)，为淡黄色油状物。Step 1: Add I-A22 (0.35g, 1.11mmol), I-1-1 (361.32mg, 2.22mmol) and Cs 2 CO 3 (541.66mg, 1.66mmol) into ACN (3.5mL), stir at 40°C React for 4 hours. The product was found by LC-MS detection. The reaction solution was subjected to column chromatography (petroleum ether/tetrahydrofuran=4/1) to obtain the desired product I-79-1 (340.00 mg, yield: 67.97%) as a pale yellow oil.
1H NMR(400MHz,DMSO-d6)δ8.75(d,J＝5.1Hz,1H),8.30(d,J＝2.3Hz,1H),8.11(s,1H),8.09(d,J＝2.2Hz,1H),7.59(d,J＝5.1Hz,1H),7.16(d,J＝9.0Hz,2H),6.93(d,J＝9.0Hz,2H),5.17(s,2H),4.69(d,J＝5.9Hz,2H),4.07(t,J＝5.8Hz,2H),1.68(s,6H). 1 H NMR (400MHz, DMSO-d6) δ8.75(d, J=5.1Hz, 1H), 8.30(d, J=2.3Hz, 1H), 8.11(s, 1H), 8.09(d, J=2.2 Hz,1H),7.59(d,J=5.1Hz,1H),7.16(d,J=9.0Hz,2H),6.93(d,J=9.0Hz,2H),5.17(s,2H),4.69( d,J=5.9Hz,2H),4.07(t,J=5.8Hz,2H),1.68(s,6H).
LC-MS[M+1]+＝442.1LC-MS [M+1] + = 442.1
步骤二：化合物I-79-1(0.3g,678.21μmol)，I-B5(206.59mg,881.67μmol)，Cs2CO3(220.97mg,678.21μmol)和t-BuXphos Pd G3(53.85mg,67.82μmol)加入溶剂dioxane(15mL)中，氮气置换，90℃微波反应1小时。LC-MS检测发现反应完全，柱层析分离(石油醚/四氢呋喃＝9/1)得到化合物I-79-2(220.00mg,产率：34.46％)，为黄色油状物。Step 2: Compound I-79-1 (0.3g, 678.21μmol), I-B5 (206.59mg, 881.67μmol), Cs 2 CO 3 (220.97mg, 678.21μmol) and t-BuXphos Pd G 3 (53.85mg, 67.82 μmol) was added to the solvent dioxane (15 mL), replaced with nitrogen, and reacted with microwave at 90° C. for 1 hour. LC-MS detection showed that the reaction was complete, and column chromatography separation (petroleum ether/tetrahydrofuran=9/1) gave compound I-79-2 (220.00 mg, yield: 34.46%) as a yellow oil.
LC-MS[M+1]+＝640.6LC-MS [M+1] + = 640.6
步骤三：室温下将I-79-2(0.2g,312.41μmol)溶于DCM(6mL)中，然后加入TFA(1.5mL)。室温搅拌5小时后用碳酸氢钠溶液将反应液pH调至中性，二氯甲烷萃取(20mL*3)，饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除溶剂得到中间体I-79-3(150mg，粗品)，为黄色油状物。 Step 3: I-79-2 (0.2 g, 312.41 μmol) was dissolved in DCM (6 mL) at room temperature, then TFA (1.5 mL) was added. After stirring at room temperature for 5 hours, the pH of the reaction solution was adjusted to neutral with sodium bicarbonate solution, extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain intermediate I-79 -3 (150 mg, crude product), as a yellow oil.
LC-MS[M+1]+＝540.40LC-MS [M+1] + = 540.40
步骤四：I-79-3(80mg,148.13μmol)，3-溴乙炔(52.86mg，444.38μmol)和K2CO3(102.36mg，740.63μmol)加入溶剂乙腈(8mL)中，室温条件下搅拌反应12小时。LC-MS检测显示反应完全，反应液浓缩，过滤，进行制备HPLC制备，得到化合物I-79(10.12mg，产率：11.11％)为淡黄色固体。Step 4: Add I-79-3 (80 mg, 148.13 μmol), 3-bromoacetylene (52.86 mg, 444.38 μmol) and K 2 CO 3 (102.36 mg, 740.63 μmol) into the solvent acetonitrile (8 mL), and stir at room temperature React for 12 hours. LC-MS detection showed that the reaction was complete. The reaction solution was concentrated, filtered, and prepared by preparative HPLC to obtain compound I-79 (10.12 mg, yield: 11.11%) as a light yellow solid.
1H NMR(400MHz,Acetonitrile-d3)δ8.37(d,J＝5.1Hz,1H),8.30(d,J＝2.2Hz,1H),8.06(d,J＝2.3Hz,1H),7.99(s,1H),7.17(d,J＝9.0Hz,2H),6.94(d,J＝5.1Hz,1H),6.88(d,J＝9.0Hz,2H),4.99(s,2H),4.72(t,J＝5.9Hz,2H),4.05(t,J＝5.9Hz,2H),3.71–3.62(m,2H),3.46–3.38(m,4H),3.04–2.96(m,2H),2.91(ddd,J＝12.2,8.4,3.2Hz,2H),2.53(t,J＝2.4Hz,1H),1.71(s,6H). 1 H NMR (400MHz, Acetonitrile-d3) δ8.37(d, J=5.1Hz, 1H), 8.30(d, J=2.2Hz, 1H), 8.06(d, J=2.3Hz, 1H), 7.99( s,1H),7.17(d,J=9.0Hz,2H),6.94(d,J=5.1Hz,1H),6.88(d,J=9.0Hz,2H),4.99(s,2H),4.72( t,J=5.9Hz,2H),4.05(t,J=5.9Hz,2H),3.71–3.62(m,2H),3.46–3.38(m,4H),3.04–2.96(m,2H),2.91 (ddd,J=12.2,8.4,3.2Hz,2H),2.53(t,J=2.4Hz,1H),1.71(s,6H).
LC-MS[M+1]+＝578.20LC-MS [M+1] + = 578.20
按照上面的化合物I-79合成方法分别合成下列化合物：








Synthesize the following compounds respectively according to the synthetic method of compound I-79 above:








实施例30：化合物I-103的合成：Example 30: Synthesis of Compound 1-103:
1-(2-氯乙基)-5-(2-(4-((2-((1-氧代-λ6-亚砜基)氨基)嘧啶-4-基)甲氧基)苯基)丙-2-基)-1H-吲唑-7-氰基
1-(2-chloroethyl)-5-(2-(4-((2-((1-oxo-λ 6 -sulfoxide)amino)pyrimidin-4-yl)methoxy)phenyl )propan-2-yl)-1H-indazol-7-cyano
在室温下向I-15-1(60mg,0.128mmol)，I-B2(27.06mg,0.257mmol)和碳酸铯(41.92mg,0.128mmol)的二氧六环(2mL)溶液中加入t-Buxphos Pd G3(10.18mg,0.013mmol)。混合溶液用氮气置换三次，用微波在100℃下搅拌1小时。将反应液浓缩后用HPLC制备得到化合物I-103(14.16mg,产率：20.6％)，为白色固体。To a solution of I-15-1 (60 mg, 0.128 mmol), I-B2 (27.06 mg, 0.257 mmol) and cesium carbonate (41.92 mg, 0.128 mmol) in dioxane (2 mL) was added t-Buxphos at room temperature PdG3 (10.18 mg, 0.013 mmol). The mixed solution was replaced with nitrogen three times and stirred at 100° C. for 1 hour by microwave. The reaction solution was concentrated and prepared by HPLC to obtain compound I-103 (14.16 mg, yield: 20.6%) as a white solid.
1H NMR(400MHz,Methanol-d4)δ8.42(d,J＝5.2Hz,1H),8.16(s,1H),8.03(d,J＝1.7Hz,1H),7.58(d,J＝1.7Hz,1H),7.23–7.12(m,2H),7.06(d,J＝5.2Hz,1H),6.90(d,J＝6.7Hz,2H),5.03(s,2H),4.98(t,J＝5.9Hz,2H),4.41–4.27(m,4H),4.01(t,J＝5.9Hz,2H),2.45–2.26(m,2H),1.71(s,6H). 1 H NMR (400MHz, Methanol-d4) δ8.42(d, J=5.2Hz, 1H), 8.16(s, 1H), 8.03(d, J=1.7Hz, 1H), 7.58(d, J=1.7 Hz,1H),7.23–7.12(m,2H),7.06(d,J=5.2Hz,1H),6.90(d,J=6.7Hz,2H),5.03(s,2H),4.98(t,J ＝5.9Hz, 2H), 4.41–4.27(m, 4H), 4.01(t, J＝5.9Hz, 2H), 2.45–2.26(m, 2H), 1.71(s, 6H).
LC-MS[M+1]+＝535.3LC-MS [M+1] + = 535.3
实施例31：化合物I-104的合成：Example 31: Synthesis of Compound 1-104:
2-(2-氯乙氧基)-3-氟-5-(2-(4-((2-((1-氧代-λ6-亚砜基)氨基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯甲腈
2-(2-Chloroethoxy)-3-fluoro-5-(2-(4-((2-((1-oxo-λ 6 -sulfoxide)amino)pyrimidin-4-yl)methyl Oxy)phenyl)propan-2-yl)benzonitrile
步骤一：在室温下向中间体I-A24(150mg,0.449mmol)和中间体I-1-1(73.25mg,0.449mmol,1.0eq)的ACN溶液(2mL)中加入碳酸铯(146.05mg,0.449mmol，1.0eq)。混合溶液在40℃下搅拌1小时。反应液过滤，将滤液浓缩后进行柱层析分离(石油醚/乙酸乙酯＝1/1)得到I-104-1(120mg,产率：52.21％)，为无色液体。Step 1: Add cesium carbonate (146.05 mg, 0.449 mmol, 1.0 eq). The mixed solution was stirred at 40°C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain I-104-1 (120 mg, yield: 52.21%) as a colorless liquid.
LC-MS[M+1]+＝460.20LC-MS[M+1]+=460.20
步骤二：室温下将I-104-1(120.0mg,0.261mmol)和中间体I-B1(31.07mg,0.261mmol)溶解于无水二氧六环(2mL)中，然后加入Cs2CO3(84.72mg,0.261mmol),t-BuXPhos Pd G3(20.70mg,0.026mmol)。加完后，吹入氮气保护，然后用微波，在100℃下，反应1小时。反应混合物旋干后用制备HPLC制备得到化合物I-104(14.74mg,产率：10.2％)，为白色固体。Step 2: Dissolve I-104-1 (120.0mg, 0.261mmol) and intermediate I-B1 (31.07mg, 0.261mmol) in anhydrous dioxane (2mL) at room temperature, then add Cs 2 CO 3 (84.72 mg, 0.261 mmol), t-BuXPhos Pd G3 (20.70 mg, 0.026 mmol). After the addition, nitrogen protection was blown in, and then microwave was used to react for 1 hour at 100°C. The reaction mixture was spin-dried and prepared by preparative HPLC to obtain compound I-104 (14.74 mg, yield: 10.2%) as a white solid.
1H NMR(400MHz,Methanol-d4)δ8.41(d,J＝5.2Hz,1H),7.34–7.21(m,2H),7.21–7.10(m,2H),7.03(s,1H),6.99–6.85(m,2H),5.04(s,2H),4.53–4.39(m,2H),3.96–3.76(m,2H),3.63(m,2H),3.36(m,2H),2.36–2.14(m,4H),1.62(s,6H). 1 H NMR (400MHz, Methanol-d4) δ8.41 (d, J = 5.2Hz, 1H), 7.34–7.21 (m, 2H), 7.21–7.10 (m, 2H), 7.03 (s, 1H), 6.99 –6.85(m,2H),5.04(s,2H),4.53–4.39(m,2H),3.96–3.76(m,2H),3.63(m,2H),3.36(m,2H),2.36–2.14 (m,4H),1.62(s,6H).
LC-MS[M+1]+＝544.50LC-MS[M+1]+=544.50
实施例33：化合物I-18的合成：Example 33: Synthesis of Compound 1-18:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-((1-氧化-1λ6-硫吗啉-1-亚基)氨基)嘧啶-5-基)乙炔基)苯基)丙烷-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxidation-1λ 6 -thiomorpholine-1-ylidene)amino)pyrimidine-5 -yl)ethynyl)phenyl)propan-2-yl)benzonitrile
步骤一：在氮气保护的条件下，依次向反应瓶中加入无水四氢呋喃(2mL)，中间体I-A2(50mg,0.140mmol)，中间体I-18-1(33.66mg,0.140mmol)，三乙胺(0.039mL,0.280mmol)，二三苯基膦二氯化钯(9.83mg,0.014mmol)和碘化亚铜(5.32mg,0.028mmol)，反应液在25℃下搅拌6小时。反应完全后，反应液减压浓缩，残留物通过柱层析法(0-20％乙酸乙酯/石油醚)纯化得到黄色固体I-18-2(55mg,产率：83.71％)。Step 1: Under the condition of nitrogen protection, add anhydrous tetrahydrofuran (2mL), intermediate I-A2 (50mg, 0.140mmol), intermediate I-18-1 (33.66mg, 0.140mmol) to the reaction flask in sequence, Triethylamine (0.039mL, 0.280mmol), ditriphenylphosphinepalladium dichloride (9.83mg, 0.014mmol) and cuprous iodide (5.32mg, 0.028mmol), the reaction solution was stirred at 25°C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (0-20% ethyl acetate/petroleum ether) to obtain a yellow solid I-18-2 (55 mg, yield: 83.71%).
LCMS[M+H]+＝470.1LCMS[M+H] + = 470.1
步骤二、三：参考化合物I-6的合成方法，用中间体I-18-2代替中间体I-1-2，进行两步反应得到化合物I-18。Steps 2 and 3: Refer to the synthesis method of compound I-6, replace intermediate I-1-2 with intermediate I-18-2, and perform two-step reaction to obtain compound I-18.
1H NMR(400MHz,Chloroform-d)δ8.70-8.55(m,2H),7.46(d,J＝8.4Hz,2H),7.42(d,J＝2.4Hz,1H),7.33(d,J＝2.4Hz,1H),7.17(d,J＝8.4Hz,2H),4.43(t,J＝6.0Hz,2H),3.88(t,J＝6.0Hz,2H),3.67-3.41(m,8H),1.67(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.70-8.55 (m, 2H), 7.46 (d, J = 8.4Hz, 2H), 7.42 (d, J = 2.4Hz, 1H), 7.33 (d, J =2.4Hz, 1H), 7.17(d, J=8.4Hz, 2H), 4.43(t, J=6.0Hz, 2H), 3.88(t, J=6.0Hz, 2H), 3.67-3.41(m, 8H ),1.67(s,6H).
LCMS[M+H]+＝568.1LCMS[M+H] + = 568.1
实施例34：化合物I-19的合成：Example 34: Synthesis of Compound 1-19:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-((1-氧化三氢-1λ6-噻吩-1-亚基)氨基)嘧啶-4-基)乙炔基)苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxytrihydro-1λ 6 -thiophene-1-ylidene)amino)pyrimidine-4 -yl)ethynyl)phenyl)prop-2-yl)benzonitrile
参考化合物I-18的合成方法，用中间体I-19-1代替中间体I-18-1，中间体I-B1代替中间体I-B5，进行两步反应得到化合物I-19。Referring to the synthesis method of compound I-18, intermediate I-19-1 was used instead of intermediate I-18-1, intermediate I-B1 was used instead of intermediate I-B5, and compound I-19 was obtained by two-step reaction.
1H NMR(400MHz,MeOD-d4)δ8.49(brs,1H),7.63–7.50(m,4H),7.33(d,J＝8.4Hz,2H),7.09(brs,1H),4.44(t,J＝5.6Hz,2H),3.90(t,J＝5.6Hz,2H),3.78–3.61(m,2H),3.45–3.41(m,2H),2.42–2.21(m,4H),1.71(s,6H).1H NMR (400MHz, MeOD-d4) δ8.49(brs,1H),7.63–7.50(m,4H),7.33(d,J＝8.4Hz,2H),7.09(brs,1H),4.44(t, J＝5.6Hz, 2H), 3.90(t, J＝5.6Hz, 2H), 3.78–3.61(m, 2H), 3.45–3.41(m, 2H), 2.42–2.21(m, 4H), 1.71(s ,6H).
LCMS[M+H]+＝553.1LCMS [M+H] + = 553.1
实施例35：化合物I-20的合成：Example 35: Synthesis of Compound 1-20:
2-(2-氯乙氧基)-5-(2-(4-((2-((1-氧化四氢-1λ6-噻吩-1-亚基)氨基)嘧啶-5-基)乙炔基)苯基)丙烷-2-基)间苯二腈
2-(2-Chloroethoxy)-5-(2-(4-((2-((1-oxytetrahydro-1λ 6 -thiophene-1-ylidene)amino)pyrimidin-5-yl)acetylene Base) phenyl) propan-2-yl) isophthalonitrile
步骤一：将中间体I-A12(100mg,0.29mmol)和中间体I-20-1(68mg,0.35mmol)，Pd(PPh3)4(35mg,0.03mmol),碘化亚铜(6mg,0.03mmol)，N,N-二异丙基乙胺(748mg,5.8mmol)，加入到乙腈(2ml)中。混合物在75℃氮气保护下搅拌16小时，TLC检测反应完全。反应混合物浓缩，使用柱层析纯化得到产物I-20-2(64mg, 产率：48.5％)，为黄色油状液体。Step 1: Intermediate I-A12 (100mg, 0.29mmol) and intermediate I-20-1 (68mg, 0.35mmol), Pd(PPh 3 ) 4 (35mg, 0.03mmol), cuprous iodide (6mg, 0.03mmol), N,N-diisopropylethylamine (748mg, 5.8mmol), was added to acetonitrile (2ml). The mixture was stirred at 75°C under nitrogen protection for 16 hours, and the reaction was complete as detected by TLC. The reaction mixture was concentrated and purified using column chromatography to obtain product I-20-2 (64 mg, Yield: 48.5%) as a yellow oily liquid.
LC-MS[M+1]+＝461.1LC-MS [M+1]+=461.1
步骤二：将中间体I-20-2(64mg,0.14mmol)和中间体I-B1(25mg,0.21mmol)，t-Buxphos Pd G3(11mg,0.014mmol),碳酸铯(137mg,0.42mmol)，加入到1,4-二氧六环(2mL)中。混合物用氮气置换气3次，在微波反应器中100℃反应1小时。LC-MS检测反应完全。反应混合物浓缩，HPLC分离纯化得到化合物I-20(2.5mg,产率：3.3％)，为白色固体。Step 2: Intermediate I-20-2 (64mg, 0.14mmol) and intermediate I-B1 (25mg, 0.21mmol), t-Buxphos Pd G3 (11mg, 0.014mmol), cesium carbonate (137mg, 0.42mmol) , was added to 1,4-dioxane (2 mL). The mixture was replaced with nitrogen three times, and reacted in a microwave reactor at 100°C for 1 hour. LC-MS detected that the reaction was complete. The reaction mixture was concentrated, separated and purified by HPLC to obtain compound I-20 (2.5 mg, yield: 3.3%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.60(s,2H),7.61(s,2H),7.47(d,J＝7.3Hz,2H),7.15(d,J＝8.2Hz,2H),4.68(s,2H),3.88(t,J＝5.7Hz,2H),3.68(d,J＝13.8Hz,2H),3.42(d,J＝10.6Hz,2H),2.32(d,J＝40.0Hz,4H),1.68(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.60(s, 2H), 7.61(s, 2H), 7.47(d, J=7.3Hz, 2H), 7.15(d, J=8.2Hz, 2H), 4.68(s, 2H), 3.88(t, J=5.7Hz, 2H), 3.68(d, J=13.8Hz, 2H), 3.42(d, J=10.6Hz, 2H), 2.32(d, J=40.0 Hz,4H),1.68(s,6H).
LC-MS[M+1]+＝544.1LC-MS[M+1]+=544.1
实施例36：化合物I-21的合成：Example 36: Synthesis of Compound 1-21:
2-(2-氯乙氧基)-3-甲氧基-5-(2-(4-((2-((1-氧代四氢-1λ6-噻吩-1-亚基)胺基)嘧啶-5-基)乙炔基)苯基)丙烷-2-基)苯腈
2-(2-Chloroethoxy)-3-methoxy-5-(2-(4-((2-((1-oxotetrahydro-1λ 6 -thiophene-1-ylidene)amino )pyrimidin-5-yl)ethynyl)phenyl)propan-2-yl)benzonitrile
步骤一：室温下，将中间体I-A11(128.0mg,0.36mmol)和中间体I-20-1(70mg,0.36mmol)溶解于无水四氢呋喃(2mL)中，然后加入DIEA(465.3mg,3.6mmol),Pd(PPh3)4(42mg,0.036mmol)和CuI(6.9mg,0.036mmol)。加完后，吹入氮气保护，并慢慢升温到80℃，搅拌12小时。反应混合物旋干过柱(石油醚/乙酸乙酯＝3/1)得到所需的产物I-21-1(12mg,产率：28％)，为淡黄色油状。Step 1: Dissolve Intermediate I-A11 (128.0mg, 0.36mmol) and Intermediate I-20-1 (70mg, 0.36mmol) in anhydrous THF (2mL) at room temperature, then add DIEA (465.3mg, 3.6 mmol), Pd(PPh 3 ) 4 (42 mg, 0.036 mmol) and CuI (6.9 mg, 0.036 mmol). After the addition was complete, nitrogen protection was blown in, and the temperature was slowly raised to 80° C., and stirred for 12 hours. The reaction mixture was spin-dried and passed through a column (petroleum ether/ethyl acetate=3/1) to obtain the desired product I-21-1 (12 mg, yield: 28%) as a pale yellow oil.
LCMS[M+1]+＝466.10LCMS[M+1] + =466.10
步骤二：室温下，将中间体I-21-1(100.0mg,0.214mmol)和中间体I-B1 (25.56mg,0.214mmol)溶解于无水二氧六环(4mL)中，然后加入Cs2CO3(209.59mg,0.643mmol)和t-BuXPhos Pd G3(17mg,0.0214mmol)。加完后，吹入氮气保护,然后用微波在100℃反应1小时。反应混合物旋干过柱(PE/THF＝3/1)得无色油状产品,冻干，得到所需的产物化合物I-21(51.01mg,产率：43.3％)，为白色固体。Step 2: At room temperature, intermediate I-21-1 (100.0mg, 0.214mmol) and intermediate I-B1 (25.56 mg, 0.214 mmol) was dissolved in anhydrous dioxane (4 mL), then Cs 2 CO 3 (209.59 mg, 0.643 mmol) and t-BuXPhos Pd G3 (17 mg, 0.0214 mmol) were added. After the addition, nitrogen protection was blown in, and then reacted at 100° C. for 1 hour by microwave. The reaction mixture was spin-dried and passed through a column (PE/THF=3/1) to obtain a colorless oily product, which was lyophilized to obtain the desired product Compound I-21 (51.01 mg, yield: 43.3%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.58(s,2H),7.43(d,J＝8.6Hz,2H),7.17(d,J＝8.6Hz,2H),7.05(d,J＝2.2Hz,1H),6.81(d,J＝2.2Hz,1H),4.40–4.33(t,J＝6.3Hz,2H),3.81–3.78(t,J＝6.3Hz,2H),3.74(s,3H),3.71–3.64(m,2H),3.42–3.37(m,2H),2.41–2.23(m,4H),1.65(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.58(s, 2H), 7.43(d, J=8.6Hz, 2H), 7.17(d, J=8.6Hz, 2H), 7.05(d, J=2.2 Hz,1H),6.81(d,J=2.2Hz,1H),4.40–4.33(t,J=6.3Hz,2H),3.81–3.78(t,J=6.3Hz,2H),3.74(s,3H ),3.71–3.64(m,2H),3.42–3.37(m,2H),2.41–2.23(m,4H),1.65(s,6H).
LCMS[M+1]+＝549.16LCMS[M+1] + =549.16
实施例37：化合物I-22的合成：Example 37: Synthesis of Compound 1-22:
1-((5-((4-(2-(7-氯-1-(2-氯乙基)-1H-吲唑-5-基)丙烷-2-基)苯基)乙炔基)嘧啶-2-基)亚氨基)四氢-1H-1λ6-噻吩-1-氧代
1-((5-((4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)propan-2-yl)phenyl)ethynyl)pyrimidine -2-yl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxo
步骤一：将中间体I-A4(90mg,0.252mmol)，DIEA(4.2g,41.6mmol)，中间体I-20-1(49mg,0.252mmol)，CuI(10mg,0.05mmol)和Pd(PPh3)4(29mg,0.025mmol)溶解于THF(2mL)中，将其在80℃下用微波反应1.5小时后。将反应混合物浓缩后进行柱层析分离(石油醚/乙酸乙酯＝5/1)得到产物I-22-1(40mg,产率：34％)，为黄色固体。Step 1: Intermediate I-A4 (90mg, 0.252mmol), DIEA (4.2g, 41.6mmol), Intermediate I-20-1 (49mg, 0.252mmol), CuI (10mg, 0.05mmol) and Pd(PPh 3 ) 4 (29mg, 0.025mmol) was dissolved in THF (2mL), and reacted with microwave at 80°C for 1.5 hours. The reaction mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the product I-22-1 (40 mg, yield: 34%) as a yellow solid.
LCMS[M+1]+＝469.1LCMS[M+1] + =469.1
步骤二：将中间体I-22-1(40mg,0.085mmol)，中间体I-B1(51mg,0.426mmol)，碳酸铯(83mg,0.255mmol)和t-BuXPhos Pd G3(8mg,0.009mmol)溶解于二氧六 环(1mL)中，将其在100℃下用微波反应1小时后。将反应混合物浓缩后用HPLC分离得到产物化合物I-22(20mg,产率：43％)，为白色固体。Step 2: Intermediate I-22-1 (40mg, 0.085mmol), Intermediate I-B1 (51mg, 0.426mmol), cesium carbonate (83mg, 0.255mmol) and t-BuXPhos Pd G3 (8mg, 0.009mmol) dissolved in dioxane ring (1 mL), which was microwaved at 100°C for 1 hour. The reaction mixture was concentrated and separated by HPLC to obtain the product compound I-22 (20 mg, yield: 43%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.60(s,2H),7.99(s,1H),7.56(s,1H),7.45-7.42(m,2H),7.23-7.21(m,2H),7.11(s,1H),5.04(t,J＝8.0Hz,2H),3.92(t,J＝8.0Hz,2H),3.73-3.66(m,2H),3.46-3.39(m,2H),2.41-2.24(m,4H),1.72(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.60(s,2H),7.99(s,1H),7.56(s,1H),7.45-7.42(m,2H),7.23-7.21(m,2H) ,7.11(s,1H),5.04(t,J=8.0Hz,2H),3.92(t,J=8.0Hz,2H),3.73-3.66(m,2H),3.46-3.39(m,2H), 2.41-2.24(m,4H),1.72(s,6H).
LCMS[M+1]+＝552.2LCMS[M+1] + =552.2
实施例38：化合物I-27的合成：Example 38: Synthesis of Compound 1-27:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((3-((1-氧化-1λ6-硫吗啉-1-亚基)氨基)吡嗪-2-基)乙炔基)苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((3-((1-oxidation-1λ 6 -thiomorpholine-1-ylidene)amino)pyrazine- 2-yl)ethynyl)phenyl)prop-2-yl)benzonitrile
步骤一：参考化合物I-18的合成方法，用中间体I-27-1代替中间体I-18-1，进行一步反应得到中间体I-27-2。Step 1: Refer to the synthesis method of compound I-18, replace intermediate I-18-1 with intermediate I-27-1, and perform a one-step reaction to obtain intermediate I-27-2.
LCMS[M+H]+＝470.2LCMS [M+H] + = 470.2
步骤二：在室温下，向反应瓶中依次加入甲苯(1.5mL)，中间体I-27-2(50mg,0.11mmol)，中间体I-B5(37.26mg,0.16mmol),Pd2(dba)3(9.73mg,0.011mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(12.29mg,0.021mmol)和碳酸铯(51.91mg,0.159mmol)。氮气置换三次，然后升温到100℃，搅拌12小时。反应完全后，过滤，滤液减压浓缩后，通过柱层析法(0-8％甲醇/二氯甲烷)纯化得到黄色油状物I-27-3(50mg，产率：70.54％)。Step 2: Add toluene (1.5mL), intermediate I-27-2 (50mg, 0.11mmol), intermediate I-B5 (37.26mg, 0.16mmol), Pd 2 (dba ) 3 (9.73 mg, 0.011 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (12.29 mg, 0.021 mmol) and cesium carbonate (51.91 mg, 0.159 mmol). Nitrogen was replaced three times, then the temperature was raised to 100° C., and stirred for 12 hours. After the reaction was complete, it was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (0-8% methanol/dichloromethane) to obtain yellow oil I-27-3 (50 mg, yield: 70.54%).
LCMS[M+H]+＝668.1LCMS[M+H] + = 668.1
步骤三：向反应瓶中依次加入二氯甲烷(1mL)，中间体I-27-3(50mg,0.075 mmol)和三氟乙酸(1mL)，25℃下搅拌12小时。反应完全后，减压浓缩，用饱和碳酸氢钠水溶液调节pH到8,然后用二氯甲烷(10mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后通过柱层析法(甲醇/二氯甲烷＝1/10)纯化得到白色固体化合物I-27(12mg，产率：28.23％)。Step 3: Add dichloromethane (1mL) successively to the reaction flask, intermediate I-27-3 (50mg, 0.075 mmol) and trifluoroacetic acid (1 mL), stirred at 25°C for 12 hours. After the reaction was complete, concentrate under reduced pressure, adjust the pH to 8 with saturated aqueous sodium bicarbonate, then extract with dichloromethane (10 mL*3), wash the combined organic phase with saturated brine (10 mL), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (methanol/dichloromethane=1/10) to obtain white solid compound I-27 (12 mg, yield: 28.23%).
1H NMR(400MHz,MEOD-D4)δ8.07(d,J＝2.8Hz,1H),7.99(d,J＝2.8Hz,1H),7.55(td,J＝6.8,2.4Hz,4H),7.36–7.27(m,2H),4.44(t,J＝5.6Hz,2H),3.90(t,J＝5.6Hz,2H),3.86–3.72(m,2H),3.40(ddd,J＝16.8,12.4,3.6Hz,4H),3.29–3.22(m,2H),1.71(s,6H). 1 H NMR (400MHz, MEOD-D4) δ8.07 (d, J = 2.8Hz, 1H), 7.99 (d, J = 2.8Hz, 1H), 7.55 (td, J = 6.8, 2.4Hz, 4H), 7.36–7.27(m,2H),4.44(t,J=5.6Hz,2H),3.90(t,J=5.6Hz,2H),3.86–3.72(m,2H),3.40(ddd,J=16.8, 12.4,3.6Hz,4H),3.29–3.22(m,2H),1.71(s,6H).
LCMS[M+H]+＝568.1LCMS[M+H] + = 568.1
按照上面化合物I-18～22以及化合物I-27的合成方法或参考文献分别合成下列化合物：Synthesize the following compounds respectively according to the synthetic method of above compound I-18～22 and compound I-27 or references:
如终产物需脱除N-Boc保护基团，可任选如下条件进行脱除：1)4N HCl/1,4-二氧六环/甲醇(1/1)液，室温或加热搅拌直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物；2)三氟乙酸/二氯甲烷(1/10)溶液室温反应直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物。


If the final product needs to remove the N-Boc protecting group, the following conditions can be selected for removal: 1) 4N HCl/1,4-dioxane/methanol (1/1) solution, room temperature or heating and stirring until the reaction Complete, the reaction solution was concentrated and separated by preparative HPLC to obtain the target product; 2) trifluoroacetic acid/dichloromethane (1/10) solution was reacted at room temperature until the reaction was completed, and the reaction solution was concentrated and separated by preparative HPLC to obtain the target product.


按照上面化合物I-18～22以及化合物I-27的合成方法或参考文献分别合成下列化合物：Synthesize the following compounds respectively according to the synthetic method of above compound I-18～22 and compound I-27 or references:
如终产物需脱除N-Boc保护基团，可任选如下条件进行脱除：1)4N HCl/1,4-二氧六环/甲醇(1/1)液，室温或加热搅拌直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物；2)三氟乙酸/二氯甲烷(1/10)溶液室温反应直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物。





If the final product needs to remove the N-Boc protecting group, the following conditions can be selected for removal: 1) 4N HCl/1,4-dioxane/methanol (1/1) solution, room temperature or heating and stirring until the reaction Complete, the reaction solution was concentrated and separated by preparative HPLC to obtain the target product; 2) trifluoroacetic acid/dichloromethane (1/10) solution was reacted at room temperature until the reaction was completed, and the reaction solution was concentrated and separated by preparative HPLC to obtain the target product.





实施例39：化合物I-28的合成：Example 39: Synthesis of Compound 1-28:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((3-((1-氧化三氢-1λ6-噻吩-1-亚基)氨基)吡嗪-2-基)乙炔基) 苯基)丙-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((3-((1-oxytrihydro-1λ 6 -thiophene-1-ylidene)amino)pyrazine- 2-yl)ethynyl) phenyl)propan-2-yl)benzonitrile
参考化合物I-27的合成方法，用中间体I-B1代替中间体I-B5，进行一步反应得到化合物I-28。Referring to the synthetic method of compound I-27, intermediate I-B1 was used to replace intermediate I-B5, and a one-step reaction was carried out to obtain compound I-28.
1H NMR(400MHz,MeOD-d4)δ8.10(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),7.62–7.48(m,4H),7.30(d,J＝8.4Hz,2H),4.43(t,J＝5.6Hz,2H),3.90(t,J＝5.6Hz,2H),3.77–3.63(m,2H),3.51–3.37(m,2H),2.43–2.18(m,4H),1.70(s,6H). 1 H NMR (400MHz, MeOD-d4) δ8.10 (d, J = 2.4Hz, 1H), 7.99 (d, J = 2.4Hz, 1H), 7.62–7.48 (m, 4H), 7.30 (d, J =8.4Hz,2H),4.43(t,J=5.6Hz,2H),3.90(t,J=5.6Hz,2H),3.77–3.63(m,2H),3.51–3.37(m,2H),2.43 –2.18(m,4H),1.70(s,6H).
LCMS[M+H]+＝553.1LCMS [M+H] + = 553.1
实施例40：化合物I-106的合成：Example 40: Synthesis of Compound 1-106:
3-氯-2-(2-氯乙氧基)-5-(2-(4-((3-((二甲基(氧)-1λ6-磺酰亚基)氨基)吡嗪-2-基)乙炔基)苯基)丙基-2-基)苯甲腈
3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((3-((dimethyl(oxy)-1λ 6 -sulfonyl)amino)pyrazine-2 -yl)ethynyl)phenyl)propyl-2-yl)benzonitrile
步骤一：室温下，将二甲基亚磺酰亚胺(502mg,5.391mmol)和I-106-1(730mg,4.9mmol)溶解于无水二氧六环(15mL)中，然后加入Cs2CO3(3.19g,9.8mmol)，t-BuXPhos Pd G3(350mg,0.49mmol)。加完后，吹入氮气保护，然后用微波在100℃,反应1小时。将反应液过滤。将滤液浓缩后进行柱层析分离(四氢呋喃/石油醚＝2/1)，得到所需的产物I-106-2(350mg,产率：34.7％)，为黄色固体。Step 1: Dissolve dimethylsulfinimide (502mg, 5.391mmol) and I-106-1 (730mg, 4.9mmol) in anhydrous dioxane (15mL) at room temperature, then add Cs 2 CO3 (3.19 g, 9.8 mmol), t-BuXPhos Pd G3 (350 mg, 0.49 mmol). After the addition, nitrogen protection was blown in, and then microwave was used at 100°C for 1 hour of reaction. The reaction solution was filtered. The filtrate was concentrated and separated by column chromatography (tetrahydrofuran/petroleum ether=2/1) to obtain the desired product I-106-2 (350 mg, yield: 34.7%) as a yellow solid.
步骤二：室温下将I-106-2(11.5mg,0.05mmol)和中间体I-A2(20mg,0.05mmol)溶解于乙腈(1mL)中，然后加入Cs2CO3(45mg,0.14mmol),XPhos Pd G2(6mg,0.005mmol)。加完后，吹入氮气保护,然后用微波在100℃，反应1小时。将反应液过滤。将滤液浓缩后将滤液浓缩后进行制备HPLC(甲酸)制备得到化合物I-106 (4.57mg,产率：12.42％)，为白色固体。Step 2: Dissolve I-106-2 (11.5mg, 0.05mmol) and intermediate I-A2 (20mg, 0.05mmol) in acetonitrile (1mL) at room temperature, then add Cs 2 CO 3 (45mg, 0.14mmol) , XPhos Pd G2 (6 mg, 0.005 mmol). After the addition, nitrogen protection was blown in, and then the reaction was carried out at 100°C by microwave for 1 hour. The reaction solution was filtered. After the filtrate was concentrated, preparative HPLC (formic acid) was carried out after the filtrate was concentrated to prepare compound I-106 (4.57mg, Yield: 12.42%), as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.05(d,J＝2.6Hz,1H),8.03(d,J＝2.7Hz,1H),7.57–7.52(m,2H),7.40(d,J＝2.4Hz,1H),7.33(d,J＝2.4Hz,1H),7.19–7.14(m,2H),4.41(t,J＝6.2Hz,2H),3.86(t,J＝6.2Hz,2H),3.42(s,6H),1.65(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.05 (d, J = 2.6Hz, 1H), 8.03 (d, J = 2.7Hz, 1H), 7.57–7.52 (m, 2H), 7.40 (d, J =2.4Hz,1H),7.33(d,J=2.4Hz,1H),7.19–7.14(m,2H),4.41(t,J=6.2Hz,2H),3.86(t,J=6.2Hz,2H ),3.42(s,6H),1.65(s,6H).
LC-MS[M+1]+＝527.40LC-MS [M+1] + = 527.40
实施例47：化合物1的合成:Embodiment 47: the synthesis of compound 1:
N-(5-((4-(2-(3-氯-4-(2-氯乙氧基)-5-氰基苯基)丙烷-2-基)苯基)乙炔基)嘧啶-2-基)甲磺酰胺
N-(5-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)ethynyl)pyrimidine-2 -yl)methanesulfonamide
将中间体I-A2(2.3g,5.3mmol)和1-1(1.3g,5.3mmol)，Pd(PPh3)4(613mg,6.4mmol)，碘化亚铜(101mg,0.53mmol)，N,N-二异丙基乙胺(13.7g,106mmol)，加入到四氢呋喃(13ml)中。混合物在80℃氮气保护下搅拌16小时，TLC检测反应完全。反应混合物投入到水中(20mL)，使用乙酸乙酯萃取(20mL*3)，有机相用饱和食盐水洗后经无水硫酸钠干燥后浓缩，使用柱层析纯化得到粗产物，粗产物经制备高效液相分离得到化合物1(253mg,产率：7.4％)，为白色固体。Intermediate I-A2 (2.3g, 5.3mmol) and 1-1 (1.3g, 5.3mmol), Pd(PPh 3 ) 4 (613mg, 6.4mmol), cuprous iodide (101mg, 0.53mmol), N , N-diisopropylethylamine (13.7g, 106mmol), was added to tetrahydrofuran (13ml). The mixture was stirred at 80° C. under nitrogen protection for 16 hours, and the reaction was complete as detected by TLC. The reaction mixture was poured into water (20mL), extracted with ethyl acetate (20mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a crude product, which was prepared by high-efficiency Liquid phase separation gave compound 1 (253 mg, yield: 7.4%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.74(s,2H),7.50(d,J＝7.7Hz,2H),7.43(s,1H),7.34(d,J＝2.3Hz,1H),7.20(d,J＝8.2Hz,2H),4.44(t,J＝6.3Hz,2H),3.88(t,J＝6.2Hz,2H),3.49(s,3H),1.68(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.74(s, 2H), 7.50(d, J=7.7Hz, 2H), 7.43(s, 1H), 7.34(d, J=2.3Hz, 1H), 7.20(d, J=8.2Hz, 2H), 4.44(t, J=6.3Hz, 2H), 3.88(t, J=6.2Hz, 2H), 3.49(s, 3H), 1.68(s, 6H).
LC-MS[M+1]+＝529.1LC-MS [M+1] + = 529.1
实施例48：化合物2的合成:Embodiment 48: the synthesis of compound 2:
N-(4-((4-(2-(3-氯-4-(2-氯乙氧基)-5-氰基苯基)丙烷-2-基)苯基)乙炔)嘧啶-2-基)甲磺酰胺
N-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)acetylene)pyrimidine-2- base) methanesulfonamide
步骤一：将2-1(0.5g,3.8mmol)溶解在无水四氢呋喃(10mL)中，0℃加入NaH(0.34g,8.5mmol)，搅拌30分钟后，0℃下加入甲磺酰氯(0.88g,7.6mmol)。在室温下反应1小时，将反应液倒入冷水，用乙酸乙酯(50mL)萃取除去杂质。水相用DCM/iPrOH(3/1，30mL*3)萃取，浓缩得目标产物2-2(139mg，产率：17.4％)，为黄色固体。Step 1: Dissolve 2-1 (0.5g, 3.8mmol) in anhydrous tetrahydrofuran (10mL), add NaH (0.34g, 8.5mmol) at 0°C, stir for 30 minutes, then add methanesulfonyl chloride (0.88 g, 7.6 mmol). After reacting at room temperature for 1 hour, the reaction solution was poured into cold water, and extracted with ethyl acetate (50 mL) to remove impurities. The aqueous phase was extracted with DCM/iPrOH (3/1, 30 mL*3) and concentrated to obtain the target product 2-2 (139 mg, yield: 17.4%) as a yellow solid.
1HNMR(400MHz,Methanol-d4)δ8.45(d,J＝5.3Hz,1H),7.13(d,J＝5.3Hz,1H),3.36(s,3H). 1 H NMR (400MHz, Methanol-d4) δ8.45 (d, J = 5.3Hz, 1H), 7.13 (d, J = 5.3Hz, 1H), 3.36 (s, 3H).
步骤二：室温下，将中间体2-2(116.0mg,0.56mmol)和中间体I-A2(200mg,0.56mmol)溶解于无水四氢呋喃(5mL)中，然后加入DIEA(724mg,5.6mmol)，Pd(PPh3)4(97mg,0.08mmol)，CuI(96mg,0.5mmol)。加完后，氮气保护，并慢慢升温到70℃,搅拌15小时，停止反应。LCMS检测到目标产物的MS。反应液旋干过柱(石油醚/四氢呋喃＝3/1)得棕色油状粗品180mg，经制备液相分离得到化合物2(13mg，产率：4.4％)，为白色固体。Step 2: Dissolve Intermediate 2-2 (116.0mg, 0.56mmol) and Intermediate I-A2 (200mg, 0.56mmol) in anhydrous THF (5mL) at room temperature, then add DIEA (724mg, 5.6mmol) , Pd(PPh 3 ) 4 (97 mg, 0.08 mmol), CuI (96 mg, 0.5 mmol). After the addition, nitrogen protection was used, and the temperature was slowly raised to 70° C., stirred for 15 hours, and the reaction was stopped. LCMS detected MS of the target product. The reaction solution was spin-dried and passed through a column (petroleum ether/tetrahydrofuran=3/1) to obtain 180 mg of a brown oily crude product, which was separated by preparative liquid phase to obtain compound 2 (13 mg, yield: 4.4%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ7.57(d,J＝8.1Hz,2H),7.42(s,1H),7.34(s,1H),7.22(d,J＝8.2Hz,4H),4.44(t,J＝6.4Hz,2H),3.88(t,J＝6.4Hz,2H),3.50(s,3H),1.68(s,6H). 1 H NMR (400MHz, Chloroform-d) δ7.57(d, J=8.1Hz, 2H), 7.42(s, 1H), 7.34(s, 1H), 7.22(d, J=8.2Hz, 4H), 4.44(t, J=6.4Hz, 2H), 3.88(t, J=6.4Hz, 2H), 3.50(s, 3H), 1.68(s, 6H).
LCMS[M+1]+＝528.9LCMS[M+1] + =528.9
实施例49：化合物3的合成:Embodiment 49: the synthesis of compound 3:
N-(3-((4-(2-(3-氯-4-(2-氯乙氧基)-5-氰基苯基)丙烷-2-基)苯基)乙炔)吡嗪-2-基)甲磺酰胺
N-(3-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)ethynyl)pyrazine-2 -yl)methanesulfonamide
步骤一：将3-1(5g,38.6mmol)溶解在无水四氢呋喃(50mL)中，0℃加入TEA(7.5g,74.1mmol)。然后加入甲磺酰氯(6.6g,57.6mmol)。在0℃下反应4小时。反应液旋干过柱(石油醚/乙酸乙酯＝1/1)得中间体3-2(4.3g,产率：39.1％)，为白色固体。Step 1: 3-1 (5 g, 38.6 mmol) was dissolved in anhydrous THF (50 mL), and TEA (7.5 g, 74.1 mmol) was added at 0°C. Methanesulfonyl chloride (6.6 g, 57.6 mmol) was then added. The reaction was carried out at 0°C for 4 hours. The reaction solution was spin-dried and passed through a column (petroleum ether/ethyl acetate=1/1) to obtain intermediate 3-2 (4.3 g, yield: 39.1%) as a white solid.
LC-MS[M+1]+＝285.9LC-MS [M+1] + = 285.9
步骤二：室温下，3-2(2.2g,7.7mmol)溶解于无水甲醇(50mL)中，然后加入K2CO3(2g,14.5mmol)。加完后，慢慢升温到60℃，搅拌1小时。过滤掉K2CO3，滤液旋干过柱(DCM/MeOH＝0-10％)得中间体3-3(1g,产率：62.9％)，为淡黄色固体。Step 2: 3-2 (2.2g, 7.7mmol) was dissolved in anhydrous methanol (50mL) at room temperature, and then K 2 CO 3 (2g, 14.5mmol) was added. After the addition, the temperature was slowly raised to 60°C and stirred for 1 hour. K 2 CO 3 was filtered off, and the filtrate was spin-dried and passed through a column (DCM/MeOH=0-10%) to obtain intermediate 3-3 (1 g, yield: 62.9%) as a pale yellow solid.
LC-MS[M+1]+＝207.8LC-MS [M+1] + = 207.8
步骤三：室温下，将中间体3-3(240.0mg,1.16mmol)和中间体I-A2(414.1mg,1.16mmol)溶解于无水四氢呋喃(5mL)中，然后加入DIEA(1.5g,11.6mmol),Pd(PPh3)4(134mg,0.12mmol),CuI(22.1mg,0.12mmol)。加完后，氮气保护，并慢慢升温到80℃,搅拌12小时。反应混合物旋干过柱(石油醚/四氢呋喃＝3/1)得棕色油状粗品400mg,经HPLC制备得到化合物3(36mg,产率：5.9％)，为白色固体。Step 3: Dissolve Intermediate 3-3 (240.0mg, 1.16mmol) and Intermediate I-A2 (414.1mg, 1.16mmol) in anhydrous THF (5mL) at room temperature, then add DIEA (1.5g, 11.6 mmol), Pd(PPh 3 ) 4 (134 mg, 0.12 mmol), CuI (22.1 mg, 0.12 mmol). After the addition was complete, the mixture was protected under nitrogen, and the temperature was slowly raised to 80° C., and stirred for 12 hours. The reaction mixture was spin-dried and passed through a column (petroleum ether/tetrahydrofuran=3/1) to obtain 400 mg of a brown oily crude product, which was prepared by HPLC to obtain compound 3 (36 mg, yield: 5.9%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.59(d,J＝2.6Hz,1H),8.40(d,J＝2.6Hz,1H),7.51(s,1H),7.48(d,J＝1.5Hz,2H),7.37(d,J＝2.3Hz,1H),7.26–7.25(m,1H),6.81(s,1H),4.41(t,J＝6.4Hz,2H),3.86(t,J＝6.4Hz,2H),3.54(s,3H),1.71(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.59(d, J=2.6Hz, 1H), 8.40(d, J=2.6Hz, 1H), 7.51(s, 1H), 7.48(d, J=1.5 Hz,2H),7.37(d,J=2.3Hz,1H),7.26–7.25(m,1H),6.81(s,1H),4.41(t,J=6.4Hz,2H),3.86(t,J =6.4Hz,2H),3.54(s,3H),1.71(s,6H).
LC-MS[M+1]+＝529.1LC-MS [M+1] + = 529.1
按照上面的化合物1到化合物3的合成方法或参考文献分别合成下列化合物：
Synthesize the following compounds respectively according to the synthetic method of above compound 1 to compound 3 or references:
实施例50：化合物10的合成:Embodiment 50: the synthesis of compound 10:
N-(5-((4-(2-(3-氯-4-(2-氯乙氧基)-5-氰基)丙烷-2-基)苯基)乙炔基)嘧啶-4-基)甲烷磺酰胺
N-(5-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyano)propan-2-yl)phenyl)ethynyl)pyrimidin-4-yl ) Methanesulfonamide
步骤一：将I-A2(100mg,279.13μmol)和10-1(100.67mg,418.69μmol)溶解在乙腈(1.5mL)中，加入三乙胺(141.22mg,1.40mmol),CuI(5.32mg,27.91μmol)和Pd(PPh3)2Cl2(19.59mg,27.91μmol)。混合物氮气置换气3次，在25℃下反应16小时。将反应液过滤浓缩后过柱(石油醚/乙酸乙酯＝0-15％)分离得到产物10-2(75.00mg,产率：57.07％)，为无色油状物。Step 1: Dissolve I-A2 (100mg, 279.13μmol) and 10-1 (100.67mg, 418.69μmol) in acetonitrile (1.5mL), add triethylamine (141.22mg, 1.40mmol), CuI (5.32mg, 27.91 μmol) and Pd(PPh 3 ) 2 Cl 2 (19.59 mg, 27.91 μmol). The mixture was replaced with nitrogen three times, and reacted at 25° C. for 16 hours. The reaction solution was concentrated by filtration and then separated by column (petroleum ether/ethyl acetate=0-15%) to obtain product 10-2 (75.00 mg, yield: 57.07%) as a colorless oil.
LC-MS[M+1]+＝470.20LC-MS [M+1] + = 470.20
步骤二：室温下，将10-2(50mg,106.21μmol)和甲磺酰胺(15mg,157.69μmol)溶于二氧六环(2mL)，加入DIEA(68.63mg,531.04μmol)和t-BuXphos Pd G3(8.43mg,10.62μmol)，混合物氮气置换气3次，在100℃下微波反应1小时。将反 应液旋干，制备HPLC制备纯化得到目标产物化合物10(4.24mg,产率：7.39％)，为白色固体。Step 2: Dissolve 10-2 (50mg, 106.21μmol) and methanesulfonamide (15mg, 157.69μmol) in dioxane (2mL) at room temperature, add DIEA (68.63mg, 531.04μmol) and t-BuXphos Pd G3 (8.43 mg, 10.62 μmol), the mixture was replaced with nitrogen three times, and microwaved at 100° C. for 1 hour. will reverse The solution was spin-dried and purified by preparative HPLC to obtain the target compound 10 (4.24 mg, yield: 7.39%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ9.08(s,1H),9.02(s,1H),7.51–7.43(m,3H),7.35(d,J＝2.3Hz,1H),7.26(s,1H),7.23(s,1H),6.62(s,1H),4.42(t,J＝6.1Hz,2H),3.86(t,J＝6.2Hz,2H),3.62(s,3H),1.70(s,6H). 1 H NMR (400MHz, Chloroform-d) δ9.08(s, 1H), 9.02(s, 1H), 7.51–7.43(m, 3H), 7.35(d, J=2.3Hz, 1H), 7.26(s ,1H),7.23(s,1H),6.62(s,1H),4.42(t,J=6.1Hz,2H),3.86(t,J=6.2Hz,2H),3.62(s,3H),1.70 (s,6H).
LC-MS[M+1]+＝529.30LC-MS [M+1] + = 529.30
实施例51：化合物14的合成:Embodiment 51: the synthesis of compound 14:
N-(3-((4-(2-(7-氯-1-(2-氯乙基)-1H-吲唑-5-基)丙烷-2-基)苯基)乙炔基)吡嗪-2-基)甲磺酰胺
N-(3-((4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)propan-2-yl)phenyl)ethynyl)pyrazine -2-yl)methanesulfonamide
将中间体I-A4(100mg,0.280mmol)，DIEA(362mg,2.80mmol)，中间体3-3(76mg,0.364mmol)，CuI(6mg,0.028mmol)和Pd(PPh3)4(32mg,0.028mmol)溶解于THF(3mL)中，将其在80℃下用微波反应2小时后。将反应混合物浓缩后进行HPLC分离得到产物N-(3-((4-(2-(7-氯-1-(2-氯乙基)-1H-吲唑-5-基)丙烷-2-基)苯基)乙炔基)吡嗪-2-基)甲磺酰胺(化合物14，25mg,产率：17％)，为白色固体。Intermediate I-A4 (100mg, 0.280mmol), DIEA (362mg, 2.80mmol), Intermediate 3-3 (76mg, 0.364mmol), CuI (6mg, 0.028mmol) and Pd(PPh 3 ) 4 (32mg, 0.028 mmol) was dissolved in THF (3 mL), and reacted with microwave at 80° C. for 2 hours. The reaction mixture was concentrated and separated by HPLC to obtain the product N-(3-((4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)propane-2- yl)phenyl)ethynyl)pyrazin-2-yl)methanesulfonamide (compound 14, 25 mg, yield: 17%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.59(s,1H),8.41(d,J＝4.0Hz,1H),8.01(s,1H),7.61(d,J＝4.0Hz,1H),7.50-7.46(m,2H),7.34-7.31(m,2H),7.21(d,J＝4.0Hz,1H),6.81(s,1H),5.05(t,J＝8.0Hz,2H),3.93(t,J＝8.0Hz,2H),3.55(s,3H),1.78(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.59(s, 1H), 8.41(d, J=4.0Hz, 1H), 8.01(s, 1H), 7.61(d, J=4.0Hz, 1H), 7.50-7.46(m,2H),7.34-7.31(m,2H),7.21(d,J=4.0Hz,1H),6.81(s,1H),5.05(t,J=8.0Hz,2H),3.93 (t,J=8.0Hz,2H),3.55(s,3H),1.78(s,6H).
LC-MS[M+1]+＝527.9LC-MS [M+1] + = 527.9
实施例52：化合物15的合成:Embodiment 52: the synthesis of compound 15:
N-(3-((4-(2-(4-(2-氯乙氧基)-3-氰基-5-甲氧基苯基)丙烷-2-基)苯基)乙炔基)吡嗪-2-基)甲磺酰胺
N-(3-((4-(2-(4-(2-chloroethoxy)-3-cyano-5-methoxyphenyl)propan-2-yl)phenyl)ethynyl)pyridine Azin-2-yl)methanesulfonamide
室温下，将化合物3-3(100.0mg,0.48mmol)和化合物I-A11(170.4mg,0.48mmol)溶解于无水四氢呋喃(4mL)中，然后加入DIEA(620mg,4.8mmol),Pd(PPh3)4(57.8mg,0.05mmol),CuI(9.5mg,0.05mmol)。加完后，氮气保护，并慢慢升温到80℃,搅拌12小时。反应混合物旋干过柱(石油醚/四氢呋喃＝4/1)得粗品220mg为橙色固体，制备HPLC纯化得到化合物15(40.67mg,产率：16.08％)，为白色固体。At room temperature, compound 3-3 (100.0 mg, 0.48 mmol) and compound I-A11 (170.4 mg, 0.48 mmol) were dissolved in anhydrous tetrahydrofuran (4 mL), and then DIEA (620 mg, 4.8 mmol), Pd (PPh 3 ) 4 (57.8 mg, 0.05 mmol), CuI (9.5 mg, 0.05 mmol). After the addition was complete, the mixture was protected under nitrogen, and the temperature was slowly raised to 80° C., and stirred for 12 hours. The reaction mixture was spin-dried and passed through a column (petroleum ether/tetrahydrofuran=4/1) to obtain 220 mg of the crude product as an orange solid, which was purified by preparative HPLC to obtain Compound 15 (40.67 mg, yield: 16.08%) as a white solid.
1H NMR(400MHz,Chloroform-d)δ8.59(d,J＝2.4Hz,1H),8.40(d,J＝2.8Hz,1H),7.51(d,J＝14.4Hz,2H),7.30(d,J＝17.2Hz,2H),6.83(s,J＝9.2Hz,2H),4.39(t,J＝6.4Hz,2H),3.82(t,J＝6.4Hz,2H),3.75(s,3H),3.54(s,3H),1.71(s,6H). 1 H NMR (400MHz, Chloroform-d) δ8.59(d, J=2.4Hz, 1H), 8.40(d, J=2.8Hz, 1H), 7.51(d, J=14.4Hz, 2H), 7.30( d, J=17.2Hz, 2H), 6.83(s, J=9.2Hz, 2H), 4.39(t, J=6.4Hz, 2H), 3.82(t, J=6.4Hz, 2H), 3.75(s, 3H), 3.54(s,3H), 1.71(s,6H).
LC-MS[M+1]+＝525.20LC-MS [M+1] + = 525.20
按照上面的合成方法或参考文献分别合成下列化合物：



Synthesize the following compounds respectively according to the above synthetic method or references:



实施例55：化合物217的合成:Embodiment 55: the synthesis of compound 217:
((4-((4-(2-(1-(2-氯乙烷)-7-甲氧基-1H-吲唑-5-基)丙烷-2-基)苯氧基)甲基)嘧啶-2-基)亚胺基)二甲基-λ6-亚磺亚胺
((4-((4-(2-(1-(2-chloroethane)-7-methoxy-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl) pyrimidin-2-yl)imino)dimethyl-λ 6 -sulfoximine
步骤一：将A39(1g,2.90mmol)溶解在ACN(15mL)中，加入I-1-1(945.41mg,5.80mmol)，Cs2CO3(1.41g,4.35mmol)在30℃下搅拌3小时。LC-MS显示原料反应完全，将反应液浓缩得到粗品，粗品经柱层析分离(PE/THF＝1/0～1/1)得到产物217-2(800.00mg,产率：58.52％)为黄色油状物。Step 1: Dissolve A39 (1g, 2.90mmol) in ACN (15mL), add I-1-1 (945.41mg, 5.80mmol), Cs 2 CO 3 (1.41g, 4.35mmol) and stir at 30°C for 3 Hour. LC-MS showed that the reaction of the raw materials was complete, and the reaction solution was concentrated to obtain a crude product, which was separated by column chromatography (PE/THF=1/0～1/1) to obtain the product 217-2 (800.00 mg, yield: 58.52%) as Yellow oil.
LC-MS[M+1]+＝471.1LC-MS [M+1] + = 471.1
步骤二：将217-2(150mg,318.22μmol)和二甲基亚磺酰亚胺(59.28mg,636.43μmol)溶解在dioxane(2mL)中，加入Cs2CO3(206.84mg,636.43μmol)，t-Buxphos Pd G3(28.64mg,31.82μmol)，在氮气保护下微波100℃反应1小时。LC-MS显示原料反应完全，向反应液中加入20mL水，用乙酸乙酯萃取两次(100mLx2)，无水硫酸钠干燥，过滤，有机相浓缩，送prep-HPLC反相柱层析(250*20.0mml.D.S-5μm,12nm.0.05％TFA,ACN/H2O＝0％～95％)纯化得到产物217(46.00mg,产率：26.01％),为白色固体。Step 2: Dissolve 217-2 (150 mg, 318.22 μmol) and dimethylsulfinimide (59.28 mg, 636.43 μmol) in dioxane (2 mL), add Cs 2 CO 3 (206.84 mg, 636.43 μmol), t-Buxphos Pd G3 (28.64 mg, 31.82 μmol) was reacted in microwave at 100° C. for 1 hour under the protection of nitrogen. LC-MS showed that the reaction of the raw material was complete, and 20 mL of water was added to the reaction solution, extracted twice with ethyl acetate (100 mLx2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated, and sent to prep-HPLC reverse phase column chromatography (250 *20.0mml.DS-5μm, 12nm.0.05%TFA, ACN/H 2 O=0%～95%) was purified to obtain the product 217 (46.00mg, yield: 26.01%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.76(s,1H),4.89(s,2H),4.31(dd, J＝12.5,7.3Hz,2H),4.05(s,2H),2.71(s,3H),1.31(d,J＝6.6Hz,3H). 1 H NMR (400MHz,DMSO-d 6 )δ7.85(s,1H),7.76(s,1H),4.89(s,2H),4.31(dd, J=12.5,7.3Hz,2H),4.05(s,2H),2.71(s,3H),1.31(d,J=6.6Hz,3H).
LC-MS[M+H]+＝528.05LC-MS [M+H] + = 528.05
实施例56：化合物274的合成:Embodiment 56: the synthesis of compound 274:
1-((4-(4-(2-(1-(2-氯乙基)-7-氟-1H-吲唑-5-基)丙-2-基)苯氧基)甲基)嘧啶-2-基)亚氨基)-1λ6-硫代吗啉-1-氧化物
1-((4-(4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)prop-2-yl)phenoxy)methyl)pyrimidine -2-yl)imino)-1λ 6 -thiomorpholine-1-oxide
步骤一：将A35(80mg,228.06μmol)溶解在DMF(5mL)中，加入I-1-1(74.35mg,456.11μmol)和Cs2CO3(222.92mg,684.17μmol)，在50℃下搅拌反应2小时。LC-MS显示目标产物生成。反应液加水(5mL)稀释，乙酸乙酯(5mL x 3)萃取，饱和食盐水(15mL x 2)洗涤，无水硫酸钠干燥，减压浓缩。经柱层析(石油醚/乙酸乙酯＝10/1)分离纯化得到目标产物274-2(100.00mg,产率：80.97％)为黄色胶状物。Step 1: Dissolve A35 (80mg, 228.06μmol) in DMF (5mL), add I-1-1 (74.35mg, 456.11μmol) and Cs 2 CO 3 (222.92mg, 684.17μmol), and stir at 50°C React for 2 hours. LC-MS showed formation of the target product. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 3), washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After separation and purification by column chromatography (petroleum ether/ethyl acetate=10/1), the target product 274-2 (100.00 mg, yield: 80.97%) was obtained as a yellow gum.
LC-MS[M+1]+＝477.20LC-MS [M+1] + = 477.20
步骤二：将274-2(100mg,217.70μmol)溶解在dioxane(2mL)中，加入I-B5(51.01mg,217.70μmol)，Cs2CO3(70.93mg,217.70μmol)和t-BuXphos Pd G3(17.33mg,21.77μmol)，氮气保护，在100℃下微波反应1小时。LC-MS显示有目标产物生成。反应液加水淬灭(3mL)，乙酸乙酯萃取(3mL x 3)，饱和食盐水洗涤(10mL)，无水硫酸钠干燥，减压浓缩，得到274-3(120.00mg,crude)为黄色油状物。Step 2: Dissolve 274-2 (100mg, 217.70μmol) in dioxane (2mL), add I-B5 (51.01mg, 217.70μmol), Cs 2 CO 3 (70.93mg, 217.70μmol) and t-BuXphos Pd G3 (17.33mg, 21.77μmol), nitrogen protection, microwave reaction at 100°C for 1 hour. LC-MS showed that the target product was formed. The reaction solution was quenched with water (3 mL), extracted with ethyl acetate (3 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 274-3 (120.00 mg, crude) as a yellow oil thing.
LC-MS[M+1]+＝657.40LC-MS [M+1] + = 657.40
步骤三：将274-3(120mg,182.59μmol)溶解在TFA(1mL)和DCM(4mL)中，在25℃下反应1小时。LC-MS显示原料反应完全。反应液直接减压浓缩， 经Pre-HPLC(YMC-PACK ODS-A,250x20mml.D.S-5um,12nm AA12S05-2520WT,Ser.No.114ZB00083)(FA)制备，冻干得到目标产物274(13.75mg，产率：13.27％)为红色固体。Step 3: 274-3 (120 mg, 182.59 μmol) was dissolved in TFA (1 mL) and DCM (4 mL), and reacted at 25° C. for 1 hour. LC-MS showed complete reaction of starting material. The reaction solution was directly concentrated under reduced pressure, Prepared by Pre-HPLC (YMC-PACK ODS-A, 250x20mml.DS-5um, 12nm AA12S05-2520WT, Ser.No.114ZB00083) (FA), lyophilized to obtain the target product 274 (13.75mg, yield: 13.27%) It is a red solid.
1H NMR(400MHz,Methanol-d4)δ8.49(d,J＝5.2Hz,1H),8.04(d,J＝2.2Hz,1H),7.52(d,J＝1.1Hz,1H),7.19-7.16(m,3H),6.92-6.90(m,2H),6.82(dd,J＝14.2,1.2Hz,1H),5.09(s,2H),4.78(t,J＝5.9Hz,2H),4.13-4.09(m,2H),3.96(t,J＝5.8Hz,2H),3.90-3.67(m,6H),1.69(s,6H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.49(d, J=5.2Hz, 1H), 8.04(d, J=2.2Hz, 1H), 7.52(d, J=1.1Hz, 1H), 7.19 -7.16(m,3H),6.92-6.90(m,2H),6.82(dd,J=14.2,1.2Hz,1H),5.09(s,2H),4.78(t,J=5.9Hz,2H), 4.13-4.09(m,2H),3.96(t,J=5.8Hz,2H),3.90-3.67(m,6H),1.69(s,6H).
LC-MS[M+1]+＝557.30LC-MS [M+1] + = 557.30
实施例57：化合物275的合成:Embodiment 57: the synthesis of compound 275:
1-((4-(4-(2-(1-(2-氯乙基)-7-氟-1H-吲唑-5-基)丙-2-基)苯氧基)甲基)嘧啶-2-基)亚氨基)-4-(2,2-二氟乙基)-1λ6-硫代吗啉-1-氧化物
1-((4-(4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)prop-2-yl)phenoxy)methyl)pyrimidine -2-yl)imino)-4-(2,2-difluoroethyl)-1λ 6 -thiomorpholine-1-oxide
步骤一：将化合物274(100mg,179.51μmol)和275-1(206.73mg,1.08mmol)溶解在DMA(5mL)中，加入Cs2CO3(175.02mg,538.52μmol)，在60℃下反应12小时。LC-MS显示反应完成，经Prep-HPLC(0.05％NH3.H2O)H2O-ACN)(Waters Xbridge Prep C18OBD 5um 19mm*250mm)纯化并冻干得到产物275(17.83mg,产率：15.35％)为白色固体。Step 1: Dissolve compound 274 (100mg, 179.51μmol) and 275-1 (206.73mg, 1.08mmol) in DMA (5mL), add Cs 2 CO 3 (175.02mg, 538.52μmol) and react at 60°C for 12 Hour. LC-MS showed that the reaction was complete, purified by Prep-HPLC (0.05% NH 3 .H 2 O)H 2 O-ACN) (Waters Xbridge Prep C18OBD 5um 19mm*250mm) and lyophilized to give product 275 (17.83mg, yield : 15.35%) is a white solid.
1H NMR(400MHz,Methanol-d4)δ8.41(d,J＝5.2Hz,1H),8.02(d,J＝2.3Hz,1H),7.51(d,J＝1.2Hz,1H),7.17-7.13(m,2H),7.06(d,J＝5.2Hz,1H),6.89-6.85(m,2H),6.81(dd,J＝14.2,1.4Hz,1H),6.22-5.90(m,1H),5.04(s,2H),4.75(t,J＝6.0Hz,2H),4.31(td,J＝14.3,3.7Hz,2H),4.19-4.08(m,2H),3.94(t,J＝5.8Hz,2H),3.84-3.71(m,4H),3.53-3.46(m,2H),1.67(s,6H). 1 H NMR (400MHz, Methanol-d 4 )δ8.41(d, J=5.2Hz, 1H), 8.02(d, J=2.3Hz, 1H), 7.51(d, J=1.2Hz, 1H), 7.17 -7.13(m,2H),7.06(d,J=5.2Hz,1H),6.89-6.85(m,2H),6.81(dd,J=14.2,1.4Hz,1H),6.22-5.90(m,1H ),5.04(s,2H),4.75(t,J=6.0Hz,2H),4.31(td,J=14.3,3.7Hz,2H),4.19-4.08(m,2H),3.94(t,J= 5.8Hz, 2H), 3.84-3.71(m, 4H), 3.53-3.46(m, 2H), 1.67(s, 6H).
LC-MS[M+44+1]+＝665.30 LC-MS [M+44+1] + = 665.30
实施例58：化合物278的合成:Embodiment 58: the synthesis of compound 278:
(4-((4-(2-(1-(2-氯乙基)-7-氟-1H-吲唑-5-基)丙-2-基)-3-氟苯氧基)甲基)嘧啶-2-基)亚氨基)二甲基-λ6-磺胺酮
(4-((4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)prop-2-yl)-3-fluorophenoxy)methyl )pyrimidin-2-yl)imino)dimethyl-λ 6 -sulfazone
步骤一：化合物A54(0.11g,313.58μmol)，I-1-1(56.23mg,344.94μmol)和Cs2CO3(203.83mg,627.16μmol)加入ACN(2mL)中，40℃搅拌反应2小时，LC-MS显示原料反应完全，浓缩反应液，柱层析分离(四氢呋喃/石油醚＝20-30％),得到化合物278-2(140.00mg,293.30μmol,产率：93.53％)为淡黄色油状物。Step 1: Compound A54 (0.11g, 313.58μmol), I-1-1 (56.23mg, 344.94μmol) and Cs 2 CO 3 (203.83mg, 627.16μmol) were added to ACN (2mL), stirred at 40°C for 2 hours , LC-MS showed that the reaction of the raw materials was complete, the reaction solution was concentrated, and separated by column chromatography (tetrahydrofuran/petroleum ether=20-30%) to obtain compound 278-2 (140.00 mg, 293.30 μmol, yield: 93.53%) as light yellow Oil.
LC-MS[M+1]+＝477.1LC-MS [M+1] + = 477.1
步骤二：化合物278-2(100mg,，209.50μmol),二甲基亚磺酰亚胺(58.54mg，628.49μmol)溶于dioxane(2mL),加入碳酸铯(68.26mg,209.50μmol)和t-BuXphos Pd G3(16.64mg，20.95μmol)，反应用氮气保护，然后在微波条件下100℃搅拌1小时。LCMS检测反应完全。反应液用乙酸乙酯萃取(15mL*3)，饱和NaCl(20mL)洗，无水硫酸钠干燥，过滤，浓缩旋干，通过prep-HPLC(FA)(YMC-PACK ODS-A,250x20mml.D.S-5um,12nm AA12S05-2520WT,Ser.No.114ZB00083)纯化得到278(39.28mg,73.56μmol,产率：35.11％)，黄色固体。Step 2: Compound 278-2 (100mg, 209.50μmol), dimethylsulfinimide (58.54mg, 628.49μmol) was dissolved in dioxane (2mL), cesium carbonate (68.26mg, 209.50μmol) and t- BuXphos Pd G3 (16.64mg, 20.95μmol), the reaction was protected with nitrogen, and then stirred at 100°C for 1 hour under microwave conditions. LCMS detected that the reaction was complete. The reaction solution was extracted with ethyl acetate (15mL*3), washed with saturated NaCl (20mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried, passed through prep-HPLC (FA) (YMC-PACK ODS-A, 250x20mmml.D.S -5um, 12nm AA12S05-2520WT, Ser.No.114ZB00083) was purified to obtain 278 (39.28mg, 73.56μmol, yield: 35.11%), a yellow solid.
1H NMR(400MHz,DMSO-d6)δ8.42(d,J＝5.0Hz,1H),8.11(d,J＝2.3Hz,1H),7.44–7.38(m,1H),7.38(d,J＝1.3Hz,1H),6.93–6.87(m,2H),6.84(dd,J＝8.6,2.6Hz,1H),6.74(dd,J＝13.7,2.7Hz,1H),5.03(s,2H),4.72(t,J＝5.7Hz,2H),4.02(t,J＝5.6Hz,2H),3.35(s,6H),1.63(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ8.42(d, J=5.0Hz, 1H), 8.11(d, J=2.3Hz, 1H), 7.44–7.38(m, 1H), 7.38(d, J＝1.3Hz, 1H), 6.93–6.87(m, 2H), 6.84(dd, J＝8.6, 2.6Hz, 1H), 6.74(dd, J＝13.7, 2.7Hz, 1H), 5.03(s, 2H ), 4.72(t, J=5.7Hz, 2H), 4.02(t, J=5.6Hz, 2H), 3.35(s, 6H), 1.63(s, 6H).
LC-MS[M+1]+＝534.2LC-MS [M+1] + = 534.2
实施例59：化合物282的合成:Embodiment 59: the synthesis of compound 282:
1-((4-(4-(2-(7-氯-1-(2-氯乙基)-1H-吲唑-5-基)丙-2-基)苯氧基)甲基)嘧啶-2-基)亚氨基)-1λ6-硫代吗啉-1-氧化物
1-((4-(4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)prop-2-yl)phenoxy)methyl)pyrimidine -2-yl)imino)-1λ 6 -thiomorpholine-1-oxide
步骤一：将I-A3(280mg,801.71μmol)，I-1-1(261.36mg,1.60mmol)溶解在ACN(3mL)中，加入Cs2CO3(390.83mg,1.20mmol)，反应液在45℃下搅拌3小时。TLC显示原料反应完全，将反应液浓缩得到粗品，经柱层析纯化(四氢呋喃/石油醚＝0～20％)得到产物282-2(280.00mg,产率：66.06％)为黄色油状物。Step 1: Dissolve I-A3 (280mg, 801.71μmol), I-1-1 (261.36mg, 1.60mmol) in ACN (3mL), add Cs 2 CO 3 (390.83mg, 1.20mmol), and the reaction solution was Stir at 45°C for 3 hours. TLC showed that the reaction of the raw material was complete, and the reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (THF/petroleum ether = 0-20%) to obtain the product 282-2 (280.00 mg, yield: 66.06%) as a yellow oil.
LC-MS[M+1]+＝475.80LC-MS [M+1] + = 475.80
步骤二：将282-2(230mg,483.40μmol)溶解在1,4-二氧六环(2mL)中，加入I-B5(226.54mg,966.80μmol)，Cs2CO3(157.10mg,483.40μmol)，t-BuXphos Pd G3(39.08mg,48.34μmol)，氮气保护，在微波100℃下反应1小时。TLC显示原料反应完全，将反应液浓缩得到粗品，粗品经柱层析分离(石油醚/四氢呋喃＝1/0～1/1)得到产物282-3(300.00mg,产率：87.52％)为黄色油状物。Step 2: Dissolve 282-2 (230mg, 483.40μmol) in 1,4-dioxane (2mL), add I-B5 (226.54mg, 966.80μmol), Cs 2 CO 3 (157.10mg, 483.40μmol ), t-BuXphos Pd G3 (39.08 mg, 48.34 μmol), under nitrogen protection, reacted under microwave at 100°C for 1 hour. TLC showed that the reaction of the raw material was complete, and the reaction solution was concentrated to obtain a crude product, which was separated by column chromatography (petroleum ether/tetrahydrofuran=1/0～1/1) to obtain the product 282-3 (300.00 mg, yield: 87.52%) as yellow Oil.
1H NMR(400MHz,Acetonitrile-d3)δ8.38(s,1H),8.01(s,1H),7.66(s,1H),7.14(t,J＝12.4Hz,3H),6.96(s,1H),6.88(d,J＝5.2Hz,2H),4.99(s,4H),4.08(m,2H),3.65(d,J＝17.8Hz,6H),3.31(t,J＝12.9Hz,2H),1.66(s,6H),1.42(s,9H). 1 H NMR (400MHz, Acetonitrile-d 3 )δ8.38(s,1H),8.01(s,1H),7.66(s,1H),7.14(t,J=12.4Hz,3H),6.96(s, 1H), 6.88(d, J=5.2Hz, 2H), 4.99(s, 4H), 4.08(m, 2H), 3.65(d, J=17.8Hz, 6H), 3.31(t, J=12.9Hz, 2H), 1.66(s,6H), 1.42(s,9H).
步骤三：将282-3(60mg,89.07μmol)溶解在二氯甲烷(3mL),加入TFA(1mL)，在30℃下搅拌3小时。将反应液浓缩得到粗品，加入乙腈(2mL)过滤，滤液送Prep-HPLC反相柱层析(250*20.0mml.D.S-5μm,12nm.0.05％NH3.H2O,ACN/H2O＝0％～95％)纯化得到282(12.00mg,产率：22.79％)为白色固体。Step 3: Dissolve 282-3 (60 mg, 89.07 μmol) in dichloromethane (3 mL), add TFA (1 mL), and stir at 30° C. for 3 hours. Concentrate the reaction solution to obtain the crude product, add acetonitrile (2mL) to filter, and send the filtrate to Prep-HPLC reverse phase column chromatography (250*20.0mml.DS-5μm, 12nm.0.05%NH 3.H 2 O, ACN/H 2 O =0%～95%) to obtain 282 (12.00 mg, yield: 22.79%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.16(s,1H),7.64(s,1H),7.13(d,J＝12.8Hz,3H),6.96-6.83(m,3H),4.97(d,J＝9.8Hz,4H),4.00(s,2H),3.57(d,J＝14.9Hz,2H),3.21(s,2H),3.12(d,J＝14.7Hz,2H),2.94(dd,J＝12.3Hz,2H),1.63(s,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.39(s, 1H), 8.16(s, 1H), 7.64(s, 1H), 7.13(d, J=12.8Hz, 3H), 6.96-6.83( m,3H),4.97(d,J=9.8Hz,4H),4.00(s,2H),3.57(d,J=14.9Hz,2H),3.21(s,2H),3.12(d,J=14.7 Hz,2H),2.94(dd,J=12.3Hz,2H),1.63(s,6H).
LCMS[M+1]+＝573.2 LCMS[M+1] + =573.2
实施例60：化合物285的合成:Embodiment 60: the synthesis of compound 285:
(4-((4-(2-(2-(1-(2-氯乙基)-7-氟-1H-苯并[d][1,2,3]三唑-5-基)丙-2-基)苯氧基)甲基)嘧啶-2-基)亚氨基)二甲基-λ6--磺胺酮
(4-((4-(2-(2-(1-(2-chloroethyl)-7-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propane -2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)dimethyl-λ 6 --sulfanilone
步骤一：将化合物A38(0.23g,689.06μmol),I-1-1(224.64mg,1.38mmol)和Cs2CO3(224.50mg,689.06μmol)加入ACN(3mL)中，35℃搅拌反应2小时，LC-MS检测原料反应完全，反应液过滤，旋蒸除溶剂，柱层析分离(四氢呋喃/石油醚＝20-50％),得到化合物285-2(220.00mg,477.92μmol,产率：69.36％)为淡黄色油状物。Step 1: Compound A38 (0.23g, 689.06μmol), I-1-1 (224.64mg, 1.38mmol) and Cs 2 CO 3 (224.50mg, 689.06μmol) were added to ACN (3mL), stirred at 35°C for reaction 2 After hours, LC-MS detected that the reaction of the raw materials was complete, the reaction solution was filtered, the solvent was removed by rotary evaporation, and the column chromatography (tetrahydrofuran/petroleum ether=20-50%) was obtained to obtain compound 285-2 (220.00 mg, 477.92 μmol, yield: 69.36%) as pale yellow oil.
LC-MS[M+1]+＝460.20LC-MS [M+1] + = 460.20
步骤二：将化合物285-2(0.09g,195.51μmol)，二甲基亚磺酰亚胺(36.42mg,391.02μmol)，Cs2CO3(63.54mg,195.51μmol)和t-BuXphos Pd G3(15.52mg,19.55μmol)加入溶剂Dioxane(1.5mL)中，氮气保护，微波95℃反应1小时。LC-MS显示原料反应完全，反应液过滤，浓缩，乙腈溶解，进行prep.HPLC(250*20.0mml.D.S-5μm,12nm.ACN/H2O(0.05％FA)＝0％～95％)制备，得到化合物285(10.94mg,20.90μmol,产率10.69％)为白色固体。Step 2: Compound 285-2 (0.09g, 195.51μmol), dimethylsulfinimide (36.42mg, 391.02μmol), Cs 2 CO 3 (63.54mg, 195.51μmol) and t-BuXphos Pd G3 ( 15.52mg, 19.55μmol) was added to the solvent Dioxane (1.5mL), protected by nitrogen, and reacted in microwave at 95°C for 1 hour. LC-MS showed that the reaction of the raw material was complete. The reaction solution was filtered, concentrated, dissolved in acetonitrile, and prep.HPLC (250*20.0mml.DS-5μm, 12nm.ACN/H 2 O (0.05%FA)=0%～95%) Preparation, compound 285 (10.94 mg, 20.90 μmol, yield 10.69%) was obtained as a white solid.
1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝5.0Hz,1H),7.76(d,J＝1.2Hz,1H),7.15(d,J＝10.4Hz,2H),7.06(d,J＝12.1Hz,1H),6.90(s,1H),6.88(d,J＝4.2Hz,2H),5.02(t,J＝5.6Hz,2H),4.99(s,2H),4.13(t,J＝5.6Hz,2H),3.29(s,6H),1.66(s,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.40(d, J=5.0Hz, 1H), 7.76(d, J=1.2Hz, 1H), 7.15(d, J=10.4Hz, 2H), 7.06 (d, J=12.1Hz, 1H), 6.90(s, 1H), 6.88(d, J=4.2Hz, 2H), 5.02(t, J=5.6Hz, 2H), 4.99(s, 2H), 4.13 (t,J=5.6Hz,2H),3.29(s,6H),1.66(s,6H).
LC-MS[M+1]+＝517.30LC-MS [M+1] + = 517.30
实施例61：化合物298的合成:Embodiment 61: the synthesis of compound 298:
N-(5-((4-(2-(1-(2-氯乙基)-7-氟-1H-吲唑-5-基)丙-2-基)苯基)乙炔基)嘧啶-2-基)-N-(2-羟乙基)甲磺酰胺
N-(5-((4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)prop-2-yl)phenyl)ethynyl)pyrimidine- 2-yl)-N-(2-hydroxyethyl)methanesulfonamide
步骤一：依次将A59(500mg,1.47mmol)、1-1(479.41mg,1.91mmol)、碘化亚铜(27.94mg,146.70μmol)、三乙胺(1.48g,14.67mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(132.03mg,146.70μmol)加入到N,N-二甲基甲酰胺(10mL)中，氮气保护，微波100℃反应1小时。反应结束后，加入水(10ml)和乙酸乙酯(100ml)，用饱和氯化钠(100×3)洗涤，无水硫酸钠干燥，有机相浓缩至干，经combiFlash纯化得298-2(219.00mg,406.35μmol,产率：27.70％)为黄色固体。Step 1: A59 (500mg, 1.47mmol), 1-1 (479.41mg, 1.91mmol), cuprous iodide (27.94mg, 146.70μmol), triethylamine (1.48g, 14.67mmol) and [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (132.03 mg, 146.70 μmol) was added to N,N-dimethylformamide (10 mL), under nitrogen protection, Microwave at 100°C for 1 hour. After the reaction was completed, water (10ml) and ethyl acetate (100ml) were added, washed with saturated sodium chloride (100×3), dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness, purified by combiFlash to give 298-2 (219.00 mg, 406.35 μmol, yield: 27.70%) as a yellow solid.
LC-MS[M+1]+＝511.8LC-MS [M+1] + = 511.8
步骤二：依次将298-2(100mg,195.31μmol)、298-3(24.25mg,390.63μmol)和氰基亚甲基三正丁基膦(94.28mg,390.63μmol)加入到四氢呋喃(5mL)中，氮气保护，微波100℃反应1小时。反应液经Prep-HPLC(250*20.0mml.D.S-5μm,12nm.ACN/H2O(0.05％FA)＝0％～95％)纯化得298(11.53mg,19.70μmol,产率：10.09％)为白色固体。Step 2: Add 298-2 (100mg, 195.31μmol), 298-3 (24.25mg, 390.63μmol) and cyanomethylenetri-n-butylphosphine (94.28mg, 390.63μmol) to tetrahydrofuran (5mL) in sequence , under nitrogen protection, microwave at 100°C for 1 hour. The reaction solution was purified by Prep-HPLC (250*20.0mml.DS-5μm, 12nm.ACN/H 2 O (0.05%FA)=0%～95%) to obtain 298 (11.53mg, 19.70μmol, yield: 10.09% ) is a white solid.
1H NMR(400MHz,DMSO-d6)δ8.87(s,2H),8.19(s,1H),7.52(d,J＝4.4Hz,2H),7.50(s,1H),7.33(d,J＝8.6Hz,2H),6.96(d,J＝14.1Hz,1H),4.93(s,1H),4.76(t,J＝5.7Hz,2H),4.12(t,J＝6.3Hz,2H),4.06(s,2H),3.57(s,2H),3.55(s,3H),1.71(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ8.87(s, 2H), 8.19(s, 1H), 7.52(d, J=4.4Hz, 2H), 7.50(s, 1H), 7.33(d, J＝8.6Hz, 2H), 6.96(d, J＝14.1Hz, 1H), 4.93(s, 1H), 4.76(t, J＝5.7Hz, 2H), 4.12(t, J＝6.3Hz, 2H) ,4.06(s,2H),3.57(s,2H),3.55(s,3H),1.71(s,6H).
LC-MS[M+1]+＝555.8LC-MS [M+1] + = 555.8
对照化合物AA：按照专利(WO2020081999,化合物编号A109)的方法合成对照化合物：N-(4-((4-(2-(3-氯-4-(2-氯乙氧基)-5-氰基苯基)丙烷-2-基)苯氧基)甲基)嘧啶-2-基)甲磺酰胺
Reference compound AA: Synthesized according to the method of the patent (WO2020081999, compound number A109): N-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyano phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide
测试例一：LNCaP细胞(AR阳性)PSA荧光素酶报告基因实验Test Example 1: LNCaP Cell (AR Positive) PSA Luciferase Reporter Gene Experiment
通过荧光素酶报告基因检测系统对细胞内AR转录活性水平进行测定。PSA(6.1kb)-Luc荧光素酶报告基因载体含有数个AR结合序列(androgen response element,ARE),可在雄激素的刺激下受AR结合调控，启动荧光素酶报告基因的表达(Cleutjens,K.B.J.M.,van der Korput,H.A.G.M.,van Eekelen,C.C.E.M.,van Rooij,H.C.J.,Faber,P.W.,and Trapman,J.(1997).An Androgen Response Element in a Far Upstream Enhancer Region Is Essential for High,Androgen-Regulated Activity of the Prostate-Specific Antigen Promoter.Mol.Endocrinol.11,148–161；Ueda,T.,Bruchovsky,N.,and Sadar,M.D.(2002).Activation of the N-terminus of the androgen receptor by interleukin-6via MAPK and STAT3signal transduction pathways cells.J.Biol.Chem.277,7076–7085)。通过对ATP的定量来测定细胞活力，细胞活力信号用于归一化实验结果，控制细胞数量或细胞状态造成的误差。The level of AR transcriptional activity in cells was measured by a luciferase reporter gene detection system. PSA (6.1kb)-Luc luciferase reporter gene vector contains several AR binding sequences (androgen response element, ARE), which can be regulated by AR binding under the stimulation of androgen, and start the expression of luciferase reporter gene (Cleutjens, K.B.J.M., van der Korput, H.A.G.M., van Eekelen, C.C.E.M., van Rooij, H.C.J., Faber, P.W., and Trapman, J. (1997). An Androgen Response Element in a Far Upstream Enhancer Region Is Essent ial for High, Androgen-Regulated Activity of the Prostate-Specific Antigen Promoter.Mol.Endocrinol.11,148–161; Ueda,T.,Bruchovsky,N.,and Sadar,M.D.(2002).Activation of the N-terminus of the androgen receptor by interleukin-6via MAPK and STAT3 signal transduction pathways cells. J. Biol. Chem. 277, 7076–7085). Cell viability is determined by quantifying ATP, and the cell viability signal is used to normalize experimental results to control errors caused by cell number or cell state.
第一步：瞬时转染构建好的报告基因载体PSA(6.1kb)-Luc进入LNCaP细胞(购自南京科佰生物科技有限公司)。以每孔10000个细胞密度接种细胞到96孔板，每孔体积80μL，置于37℃，5％二氧化碳培养箱培养过夜。Step 1: Transiently transfect the constructed reporter gene vector PSA (6.1 kb)-Luc into LNCaP cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.). Cells were seeded into a 96-well plate at a density of 10,000 cells per well, with a volume of 80 μL per well, and placed in a 5% carbon dioxide incubator at 37°C for overnight cultivation.
第二步：过夜培养24h，待细胞完全贴壁后，加入化合物处理细胞。待测化合物预先用DMSO进行3倍浓度稀释，共设置8个浓度梯度；每孔分别加入10μL含相应浓度待测化合物或DMSO对照的培养液，每个浓度设置3个重复，所有测试孔中DMSO的终浓度均为0.5％。化合物处理1小时后，每孔加入10μL含DHT(双氢睾酮dihydrotestosterone)的培养液，DHT终浓度为1nM；无DHT处理对照组加入10μL含对照溶剂的培养液，置于37℃，5％二氧化碳培养箱继续培养24小时。设置重复板，分别检测报告基因活性和细胞活力。The second step: culture overnight for 24 hours, after the cells are completely adhered to the wall, add compounds to treat the cells. The compound to be tested was diluted 3 times with DMSO in advance, and a total of 8 concentration gradients were set up; 10 μL of culture solution containing the corresponding concentration of the compound to be tested or DMSO control was added to each well, and each concentration was set for 3 replicates. DMSO in all test wells The final concentration is 0.5%. After compound treatment for 1 hour, add 10 μL of culture solution containing DHT (dihydrotestosterone) to each well, and the final concentration of DHT is 1 nM; add 10 μL of culture solution containing control solvent to the control group without DHT treatment, place at 37 ° C, 5% carbon dioxide The incubator continued to cultivate for 24 hours. Set up duplicate plates to test reporter gene activity and cell viability separately.
第三步：ONE-GloTMLuciferase Assay System(Promega，E6120)检测样品中的萤光素酶报告基因活性。每孔加入50μL ONE-GloTMReagent混匀，在室温下振荡孵育3分钟，检测萤火虫萤光素酶(Fluc)的活性。在另一块重复板中，每孔加入50μL CellTiter-Luminescent Cell Viability Assay(Promega，G7572)试剂，混匀，室温振荡孵育10分钟，检测细胞活力发光信号。使用多功能酶标仪(EnVision,PerkinElmer)读取信号。信号比值为报告基因信号值/细胞活力信号值。抑制百分率 (％)通过以下公式计算获得：Step 3: ONE-Glo TM Luciferase Assay System (Promega, E6120) detects the activity of the luciferase reporter gene in the sample. Add 50 μL ONE-Glo ™ Reagent to each well, mix well, shake and incubate at room temperature for 3 minutes, and detect firefly luciferase (Fluc) activity. In another duplicate plate, add 50 μL CellTiter- Luminescent Cell Viability Assay (Promega, G7572) reagent was mixed evenly, and incubated with shaking at room temperature for 10 minutes to detect the cell viability luminescent signal. Signals were read using a multifunctional microplate reader (EnVision, PerkinElmer). The signal ratio is reporter gene signal value/cell viability signal value. Inhibition percentage (%) is calculated by the following formula:
抑制百分率(DHT-dependent，％)＝(1-(化合物处理组信号比值-无DHT处理组信号比值)/(DMSO处理组信号值信号比值-无DHT处理组信号比值))*100，IC50值采用GraphPad Prism软件计算求得，结果如表1所示。Inhibition percentage (DHT-dependent, %)=(1-(signal ratio of compound treatment group-signal ratio of no DHT treatment group)/(signal ratio of DMSO treatment group-signal ratio of no DHT treatment group))*100, IC 50 The values were calculated using GraphPad Prism software, and the results are shown in Table 1.
测试例二：LNCaP细胞(AR阳性)增殖抑制活性测试Test Example 2: Proliferation Inhibitory Activity Test of LNCaP Cells (AR Positive)
通过CellTiter-Glo发光法细胞活力检测试剂盒对细胞内ATP进行定量测定来检测细胞活力。Cell viability was detected by quantitative determination of intracellular ATP by CellTiter-Glo Luminescent Cell Viability Assay Kit.
第一步：在96孔板中接种LNCaP细胞(购自南京科佰生物科技有限公司)，以每孔1000个细胞密度接种细胞到96孔板，每孔培养基体积90μL，置于37℃，5％二氧化碳培养箱培养过夜。Step 1: Inoculate LNCaP cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) in a 96-well plate, inoculate the cells into a 96-well plate at a density of 1000 cells per well, and place the culture medium in each well at a volume of 90 μL at 37°C. Cultivate overnight in a 5% carbon dioxide incubator.
第二步：过夜培养24h，待细胞完全贴壁后，加入化合物处理细胞。待测化合物进行3倍稀释，共设置8个浓度梯度；每孔分别加入5μL含相应浓度的待测化合物或DMSO对照的培养液，每个浓度设置3个重复，所有测试孔中DMSO的终浓度均为0.5％。化合物处理1小时后，除无DHT处理组外，每孔加入5μL含DHT(双氢睾酮dihydrotestosterone)的培养液，DHT终浓度为0.2nM。置于37℃，5％二氧化碳培养箱继续培养4天。The second step: culture overnight for 24 hours, after the cells are completely adhered to the wall, add compounds to treat the cells. The compound to be tested was diluted 3-fold, and a total of 8 concentration gradients were set; 5 μL of culture solution containing the compound to be tested or DMSO control at the corresponding concentration was added to each well, and each concentration was set for 3 replicates. The final concentration of DMSO in all test wells was Both are 0.5%. After compound treatment for 1 hour, 5 μL of culture solution containing DHT (dihydrotestosterone) was added to each well except the DHT-treated group, and the final concentration of DHT was 0.2 nM. Place in a 37°C, 5% carbon dioxide incubator to continue culturing for 4 days.
第三步：CellTiter-Glo Luminescent Cell Viability Assay试剂盒(Promega，G7570)检测细胞活力。每孔加入50ul CellTiter-Glo，混匀，室温孵育10分钟。使用多功能酶标仪(EnVision,PerkinElmer)读取信号。抑制百分率(％)通过以下公式计算获得：The third step: CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7570) detects cell viability. Add 50ul CellTiter-Glo to each well, mix well, and incubate at room temperature for 10 minutes. Signals were read using a multifunctional microplate reader (EnVision, PerkinElmer). Inhibition percentage (%) is calculated by the following formula:
抑制百分率(DHT依赖部分％)＝(1-(有DHT刺激的化合物处理组信号值-无DHT刺激的DMSO处理组信号值)/(有DHT刺激的DMSO处理组信号值-无DHT刺激的DMSO处理组信号值))*100；Inhibition percentage (DHT dependent part %)=(1-(signal value of compound treatment group with DHT stimulation-signal value of DMSO treatment group without DHT stimulation)/(signal value of DMSO treatment group with DHT stimulation-DMSO without DHT stimulation Processing group signal value))*100;
IC50值采用GraphPad Prism软件计算求得，结果如表1所示。 IC50 values were calculated using GraphPad Prism software, and the results are shown in Table 1.
表1：LNCaP细胞PSA-Luc报告基因抑制活性和细胞增殖抑制活性


Table 1: PSA-Luc reporter gene inhibitory activity and cell proliferation inhibitory activity of LNCaP cells


实验结果表明，该系列化合物对表达AR蛋白的前列腺癌细胞LNCaP有着良好的增殖抑制活性。The experimental results show that the series of compounds have good growth inhibitory activity on prostate cancer cell LNCaP expressing AR protein.
测试例三：22Rv1(AR阳性/AR-V7阳性)细胞增殖抑制实验测试Test Example 3: 22Rv1 (AR Positive/AR-V7 Positive) Cell Proliferation Inhibition Experimental Test
通过CellTiter-Glo发光法细胞活力检测试剂盒对细胞内ATP进行定量测定来检测细胞活力。Cell viability was detected by quantitative determination of intracellular ATP by CellTiter-Glo Luminescent Cell Viability Assay Kit.
第一步：在384孔板中接种22Rv1细胞(购自南京科佰生物科技有限公司)，以每孔1500个细胞密度接种细胞到384孔板，每孔培养基体积40μL，置于37℃，5％二氧化碳培养箱培养过夜。Step 1: Inoculate 22Rv1 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) in a 384-well plate, inoculate the cells into a 384-well plate at a density of 1500 cells per well, and place the culture medium in each well at a volume of 40 μL at 37°C. Cultivate overnight in a 5% carbon dioxide incubator.
第二步：过夜培养24h，待细胞完全贴壁后，加入化合物处理细胞。待测化合物进行3倍稀释，共设置10个浓度梯度；待测化合物用Mosquito仪器加样，每孔分别加入100nL的含相应浓度待测化合物或DMSO对照，每个浓度设置3个重复，DMSO的终浓度控制在0.2％。置于37℃，5％二氧化碳培养箱培养4天。The second step: culture overnight for 24 hours, after the cells are completely adhered to the wall, add compounds to treat the cells. The compound to be tested was diluted 3 times, and a total of 10 concentration gradients were set; the compound to be tested was loaded with a Mosquito instrument, and 100 nL of the compound to be tested or DMSO control containing the corresponding concentration was added to each well, and each concentration was set for 3 replicates. The final concentration was controlled at 0.2%. Placed in a 37°C, 5% carbon dioxide incubator for 4 days.
第三步：CellTiter-Glo Luminescent Cell Viability Assay试剂盒(Promega，G7570)检测细胞活力。每孔加入20μL CellTiter-Glo，混匀，室温孵育10分钟。使用多功能酶标仪(EnVision,PerkinElmer)读取信号。抑制百分率(％)通过以下公式计算获得：The third step: CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7570) detects cell viability. Add 20 μL CellTiter-Glo to each well, mix well, and incubate at room temperature for 10 minutes. Signals were read using a multifunctional microplate reader (EnVision, PerkinElmer). Inhibition percentage (%) is calculated by the following formula:
抑制百分率(％)＝(1-化合物处理组信号值/DMSO处理组信号值)*100。Inhibition percentage (%)=(1-signal value of compound treatment group/signal value of DMSO treatment group)*100.
IC50值采用GraphPad Prism软件计算求得，结果如表2所示。 表2-1：22Rv1细胞增殖抑制活性

 IC50 values were calculated using GraphPad Prism software, and the results are shown in Table 2. Table 2-1: 22Rv1 cell proliferation inhibitory activity

其中，字母A代表IC50小于5μM；字母B代表IC50为5μM至10μM；字母C代表IC50大于10μM。Among them, the letter A indicates that the IC 50 is less than 5 μM; the letter B indicates that the IC 50 is from 5 μM to 10 μM; the letter C indicates that the IC 50 is greater than 10 μM.
实验结果表明，该系列化合物对同时表达AR及AR-V7蛋白的前列腺癌细胞22Rv1有着良好的增殖抑制活性。Experimental results show that the series of compounds have good growth inhibitory activity on prostate cancer cell 22Rv1 expressing both AR and AR-V7 proteins.
测试例四：DU145细胞(AR阴性)增殖抑制活性测试Test example 4: DU145 cell (AR negative) proliferation inhibitory activity test
通过CellTiter-Glo发光法细胞活力检测试剂盒对细胞内ATP进行定量测定来检测细胞活力。Cell viability was detected by quantitative determination of intracellular ATP by CellTiter-Glo Luminescent Cell Viability Assay Kit.
第一步：在96孔板中接种DU145细胞(购自南京科佰生物科技有限公司)，以每孔1500个细胞密度接种细胞到96孔板，每孔体积95μL，置于37℃，5％二氧化碳培养箱培养过夜。Step 1: Inoculate DU145 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) in a 96-well plate, inoculate the cells into a 96-well plate at a density of 1500 cells per well, with a volume of 95 μL per well, place at 37°C, 5% Cultivate overnight in a carbon dioxide incubator.
第二步：过夜培养24h，待细胞完全贴壁后，加入化合物处理细胞。待测化合物进行3倍稀释，共设置9个浓度梯度；每孔分别加入5μL含相应浓度的待测化合物或DMSO对照的培养液，每个浓度设置3个重复，DMSO的终浓度控制在0.5％。置于37℃，5％二氧化碳培养箱培养4天。The second step: culture overnight for 24 hours, after the cells are completely adhered to the wall, add compounds to treat the cells. The compound to be tested was diluted 3 times, and a total of 9 concentration gradients were set up; 5 μL of culture solution containing the compound to be tested or DMSO control at the corresponding concentration was added to each well, and each concentration was set for 3 replicates, and the final concentration of DMSO was controlled at 0.5%. . Placed in a 37°C, 5% carbon dioxide incubator for 4 days.
第三步：CellTiter-Glo Luminescent Cell Viability Assay试剂盒(Promega，G7570)检测细胞活力。每孔加入50μL CellTiter-Glo，混匀，室温孵育10分钟。使用多功能酶标仪(EnVision,PerkinElmer)读取信号。抑制百分率(％)通过以下公式计算获 得：Step 3: Cell Titer-Glo Luminescent Cell Viability Assay kit (Promega, G7570) was used to detect cell viability. Add 50 μL CellTiter-Glo to each well, mix well, and incubate at room temperature for 10 minutes. Signals were read using a multifunctional microplate reader (EnVision, PerkinElmer). Inhibition percentage (%) is calculated by the following formula to obtain have to:
抑制百分率(％)＝(1-化合物处理组信号值/DMSO处理组信号值)*100。Inhibition percentage (%)=(1-signal value of compound treatment group/signal value of DMSO treatment group)*100.
IC50值采用GraphPad Prism软件计算求得，结果如表3所示。 IC50 values were calculated using GraphPad Prism software, and the results are shown in Table 3.
表3：DU145细胞增殖抑制活性
Table 3: DU145 cell proliferation inhibitory activity
其中，字母A代表IC50小于5μM；字母B代表IC50为5μM至10μM；字母C代表IC50大于10μM。Among them, the letter A indicates that the IC 50 is less than 5 μM; the letter B indicates that the IC 50 is from 5 μM to 10 μM; the letter C indicates that the IC 50 is greater than 10 μM.
实验结果表明，该系列化合物对不表达AR蛋白的前列腺癌细胞DU145(阴性对照细胞)具有良好的选择性，增殖抑制IC50均大于10μM。Experimental results show that the series of compounds have good selectivity to prostate cancer cell DU145 (negative control cell) that does not express AR protein, and the IC 50 of inhibition of proliferation is greater than 10 μM.
测试例五：PC3细胞(AR阴性)增殖抑制活性测试Test Example 5: PC3 cell (AR negative) proliferation inhibitory activity test
通过CellTiter-Glo发光法细胞活力检测试剂盒对细胞内ATP进行定量测定来检测细胞活力。Cell viability was detected by quantitative determination of intracellular ATP by CellTiter-Glo Luminescent Cell Viability Assay Kit.
第一步：在384孔板中接种PC3细胞(购自南京科佰生物科技有限公司)，以每孔1000个细胞密度接种细胞到384孔板，每孔体积40μL，置于37℃，5％二氧化碳培养箱培养过夜。Step 1: Inoculate PC3 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) in a 384-well plate, inoculate cells into a 384-well plate at a density of 1,000 cells per well, with a volume of 40 μL per well, place at 37°C, 5% Cultivate overnight in a carbon dioxide incubator.
第二步：过夜培养24h，待细胞完全贴壁后，加入化合物处理细胞。待测化合物进行3倍稀释，共设置10个浓度梯度；待测化合物用Mosquito仪器加样，每孔分别加入100nL的含相应浓度待测化合物或DMSO对照，每个浓度设置3个重复，DMSO的终浓度控制在0.2％。置于37℃，5％二氧化碳培养箱培养4天。The second step: culture overnight for 24 hours, after the cells are completely adhered to the wall, add compounds to treat the cells. The compound to be tested was diluted 3 times, and a total of 10 concentration gradients were set; the compound to be tested was loaded with a Mosquito instrument, and 100 nL of the compound to be tested or DMSO control containing the corresponding concentration was added to each well, and each concentration was set for 3 replicates. The final concentration was controlled at 0.2%. Placed in a 37°C, 5% carbon dioxide incubator for 4 days.
第三步：CellTiter-Glo Luminescent Cell Viability Assay试剂盒(Promega，G7570) 检测细胞活力。每孔加入20μL CellTiter-Glo，混匀，室温孵育10分钟。使用多功能酶标仪(EnVision,PerkinElmer)读取信号。抑制百分率(％)通过以下公式计算获得：Step 3: CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, G7570) Check cell viability. Add 20 μL CellTiter-Glo to each well, mix well, and incubate at room temperature for 10 minutes. Signals were read using a multifunctional microplate reader (EnVision, PerkinElmer). Inhibition percentage (%) is calculated by the following formula:
抑制百分率(％)＝(1-化合物处理组信号值/DMSO处理组信号值)*100。Inhibition percentage (%)=(1-signal value of compound treatment group/signal value of DMSO treatment group)*100.
IC50值采用GraphPad Prism软件计算求得，结果如表4所示。 IC50 values were calculated using GraphPad Prism software, and the results are shown in Table 4.
表4：PC3细胞增殖抑制活性

Table 4: PC3 cell proliferation inhibitory activity

其中，字母A代表IC50小于5μM；字母B代表IC50为5μM至20μM；字母C代表IC50大于20μM。Among them, the letter A indicates that the IC 50 is less than 5 μM; the letter B indicates that the IC 50 is from 5 μM to 20 μM; the letter C indicates that the IC 50 is greater than 20 μM.
实验结果表明，该系列化合物对不表达AR蛋白的前列腺癌细胞PC3(阴性对照细胞)具有良好的选择性，大部分化合物增殖抑制IC50大于20μM。The experimental results showed that this series of compounds had good selectivity to prostate cancer cells PC3 (negative control cells) not expressing AR protein, and most of the compounds inhibited proliferation with IC 50 greater than 20 μM.
测试例六：VCaP(AR阳性/AR-V7阳性)细胞增殖抑制活性测试Test Example 6: VCaP (AR Positive/AR-V7 Positive) Cell Proliferation Inhibitory Activity Test
通过CellTiter-Glo发光法细胞活力检测试剂盒对细胞内ATP进行定量测定来检测细胞活力。Cell viability was detected by quantitative determination of intracellular ATP by CellTiter-Glo Luminescent Cell Viability Assay Kit.
第一步：在384孔板中接种VCaP细胞(购自南京科佰生物科技有限公司)，以每孔1800个细胞密度接种细胞到384孔板，每孔体积40μL，置于37℃，5％二氧化碳培养箱培养48h。Step 1: Inoculate VCaP cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) in a 384-well plate, inoculate the cells into a 384-well plate at a density of 1800 cells per well, with a volume of 40 μL per well, place at 37°C, 5% Cultivate in a carbon dioxide incubator for 48 hours.
第二步：化合物处理细胞。待测化合物进行3倍稀释，共设置10个浓度梯度；待测化合物用Mosquito仪器加样，每孔分别加入100nL的含相应浓度待测化合物或DMSO对照，每个浓度设置3个重复，DMSO的终浓度控制在0.2％。置于37℃、5％二氧化碳培养箱培养6天。Second step: compound treatment of cells. The compound to be tested was diluted 3 times, and a total of 10 concentration gradients were set; the compound to be tested was loaded with a Mosquito instrument, and 100 nL of the compound to be tested or DMSO control containing the corresponding concentration was added to each well, and each concentration was set for 3 replicates. The final concentration was controlled at 0.2%. Placed in a 37°C, 5% carbon dioxide incubator for 6 days.
第三步：CellTiter-Glo Luminescent Cell Viability Assay试剂盒(Promega，G7570)检测细胞活力。每孔加入20μL CellTiter-Glo，混匀，室温孵育10分钟。使用多功能酶标仪(EnVision,PerkinElmer)读取信号。抑制百分率(％)通过以下公式计算获得：The third step: CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7570) detects cell viability. Add 20 μL CellTiter-Glo to each well, mix well, and incubate at room temperature for 10 minutes. Signals were read using a multifunctional microplate reader (EnVision, PerkinElmer). Inhibition percentage (%) is calculated by the following formula:
抑制百分率(％)＝(1-化合物处理组信号值/DMSO处理组信号值)*100。Inhibition percentage (%)=(1-signal value of compound treatment group/signal value of DMSO treatment group)*100.
IC50值采用GraphPad Prism软件计算求得。 IC50 values were calculated using GraphPad Prism software.
测试例七：RT-qPCR方法检测22Rv1细胞中AR或AR-V7靶基因表达Test Example 7: Detection of AR or AR-V7 Target Gene Expression in 22Rv1 Cells by RT-qPCR
通过实时荧光定量PCR法检测化合物对AR或AR-V7靶基因的影响。用相对定量标准曲线法分析化合物处理组样品相对于未处理参照组样品AR或AR-V7相关靶 基因表达量的变化。The effects of compounds on AR or AR-V7 target genes were detected by real-time fluorescent quantitative PCR. Relative quantitative standard curve analysis of compound treatment group samples relative to untreated reference group samples AR or AR-V7 related targets Changes in gene expression.
第一步：在12孔细胞培养板中接种22Rv1细胞(购自南京科佰生物科技有限公司)，以每孔200000个细胞密度接种细胞到12孔板，每孔培养基体积1mL，置于37℃，5％二氧化碳培养箱培养48h。The first step: Inoculate 22Rv1 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) in a 12-well cell culture plate, inoculate the cells into a 12-well plate at a density of 200,000 cells per well, with a medium volume of 1 mL per well, and place at 37 Cultivate for 48 hours in a 5% carbon dioxide incubator.
第二步：化合物处理细胞。待测化合物进行4倍稀释，共设置4个浓度梯度；每孔分别加入一定体积的DMSO或者待测化合物，DMSO的终浓度控制在0.5％。置于37℃，5％二氧化碳培养箱培养48h。Second step: compound treatment of cells. The compound to be tested was diluted 4 times, and a total of 4 concentration gradients were set; a certain volume of DMSO or the compound to be tested was added to each well, and the final concentration of DMSO was controlled at 0.5%. Placed in a 37°C, 5% carbon dioxide incubator for 48 hours.
第三步：实时荧光定量PCR。RNeasy Mini Kit试剂盒(QIAGEN，74104)提取样品RNA。Maxima First Strand cDNA Synthesis Kit for RT-qPCR试剂盒(Thermo Scientific，K1416-2)反转RNA为cDNA。使用PowerUpTMSYBRTMGreen Master Mix试剂盒(Applied Biosystems，A25743)进行实时荧光定量PCR工作，384孔板每孔加入10μL工作液，混匀，1000rpm离心1min。参照PowerUpTMSYBRTMGreen Master Mix试剂盒说明书，使用qPCR仪(QuantStudio 5Real-Time PCR Instrument,appliedbiosysterms)读取信号。The third step: real-time fluorescent quantitative PCR. RNeasy Mini Kit kit (QIAGEN, 74104) was used to extract sample RNA. Maxima First Strand cDNA Synthesis Kit for RT-qPCR kit (Thermo Scientific, K1416-2) reversed RNA to cDNA. Real-time fluorescent quantitative PCR was performed using the PowerUp ™ SYBR ™ Green Master Mix kit (Applied Biosystems, A25743). 10 μL of working solution was added to each well of a 384-well plate, mixed evenly, and centrifuged at 1000 rpm for 1 min. Referring to the instructions of the PowerUp ™ SYBR ™ Green Master Mix kit, the signal was read using a qPCR instrument (QuantStudio 5 Real-Time PCR Instrument, appliedbiosysterms).
以GAPDH作为内参基因，利用算术公式2^(-ΔΔCT)来获取化合物处理组样品与未处理参照组样品相对定量结果。Using GAPDH as an internal reference gene, the arithmetic formula 2^(-ΔΔCT) was used to obtain the relative quantitative results of the compound-treated group samples and the untreated reference group samples.
测试例八：VCaP去势抵抗前列腺癌小鼠模型Test Example 8: VCaP castration-resistant prostate cancer mouse model
将5x 10^6个VCaP细胞皮下接种于6-8周龄CB-17SCID雄性小鼠右后背，接种后待肿瘤平均体积达到～100mm3时，对小鼠执行去势手术，当肿瘤开始恢复生长至～100mm3时，进行随机分组给药，并一周两次监测记录肿瘤体积与小鼠体重。5x 10^6 VCaP cells were subcutaneously inoculated on the right back of 6-8 week old CB-17SCID male mice. After inoculation, when the average volume of the tumor reached ~100mm3, the mice were castrated. When the tumor began to recover When the tumor size reached ~100mm3, administration was performed in random groups, and the tumor volume and body weight of the mice were monitored and recorded twice a week.
测试例九：化合物药代动力学实验Test Example 9: Compound Pharmacokinetic Experiment
本发明化合物对药代动力学测定。本申请采用以下方法测定本申请的化合物药代动力学参数。Pharmacokinetic determination of compounds of the present invention. The application adopts the following methods to determine the pharmacokinetic parameters of the compounds of the application.
研究使用的健康雄性成年小鼠，每组动物单次灌胃给药5-100mg/Kg。禁食从给药前10小时至给药后4小时。给药后不同时间点后采血，并测定化合物血浆含量(LC-MS/MS)。血浆浓度-时间关系用专业软件分析(winnonlin)，计算化合物的药代动力学参数。数据表明，本发明化合物具有良好的药代动力学性质。 For the healthy male adult mice used in the study, each group of animals was given 5-100mg/Kg by intragastric administration. Fasting from 10 hours before administration to 4 hours after administration. Blood was collected at different time points after administration, and the plasma content of the compound was determined (LC-MS/MS). The plasma concentration-time relationship was analyzed with professional software (winnonlin), and the pharmacokinetic parameters of the compound were calculated. The data show that the compounds of the invention have good pharmacokinetic properties.

Claims (112)

  1. 下式1-I所示的化合物： The compound shown in following formula 1-I:
    或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
    其中：in:
    环A和环B各自独立为环烷基、杂环基、芳基或杂芳基；Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
    环C为键、环烷基、杂环基、芳基或杂芳基；Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
    X为C、N、O或S；X is C, N, O or S;
    R1和R2各自独立地为不存在、H、卤素、氰基、羟基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基或-NRaRa；R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
    前提是当X为C时，R1和R2各自独立地为不存在、H、卤素、氰基、羟基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基或-NRaRa，或者R1和R2与X一起形成任选取代的 provided that when X is C, R and R are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, Optionally substituted alkoxy or -NR a R a , or R 1 and R 2 together with X form optionally substituted
    R3和R4各自独立地为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烷氧基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、-(CH2)rNRaRa或-ORb；R and R are each independently H, halogen, cyano, oxo , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally Substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b ;
    Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-、-NRa-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a - or -(CH 2 ) r -NR a -CO-;
    R5为H、任选取代的烷基、任选取代的烯基或任选取代的炔基； R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Z2为**-Y1-Y2-*，其中Y1为键、任选取代的烷基、任选取代的烯基或任选取代的炔基，Y2为键、O、NH或S，“*”表示Z2与环A的连接点，“**”表示Z2与环C的连接点；Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y 2 is a bond, O, NH or S, "*" indicates the connection point between Z 2 and ring A, "**" indicates the connection point between Z 2 and ring C;
    R6为N＝S(O)RcRd或-(CH2)sS(O)(＝NRe)Rf；R 6 is N=S(O)R c R d or -(CH 2 ) s S(O)(=NR e )R f ;
    R7各自独立地为卤素、氰基、任选取代的烷基、任选取代的烯基、任选取代的炔基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg；Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g ;
    Ra各自独立为H、任选取代的烷基、任选取代的烯基、任选取代的炔基或-CORb；each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
    Rb为H、任选取代的烷基、任选取代的烯基或任选取代的炔基； R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rc和Rd各自独立选自任选取代的烷基、任选取代的烯基、任选取代的炔基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -NR a R a ; or R c , R d together with the S atom to which they are attached Forming an optionally substituted 4-10 membered heterocyclyl;
    Re为H、氰基、任选取代的烷基、任选取代的烯基或任选取代的炔基；R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rf为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rg各自独立为H、-SO2Rf、任选取代的烷基、任选取代的烯基或任选取代的炔基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基；Each R g is independently H, -SO 2 R f , optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R g together with the N atoms to which they are attached form an optionally Substituted 4-10 membered heterocyclic group;
    r为0、1、2或3；r is 0, 1, 2 or 3;
    s为0、1、2或3；且s is 0, 1, 2 or 3; and
    m、n和p各自独立为0、1、2或3。m, n and p are each independently 0, 1, 2 or 3.
  2. 如权利要求1所述的化合物或其药学上可接受的盐，其中环C为环烷基、杂环基、芳基或杂芳基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl.
  3. 如权利要求1所述的化合物或其药学上可接受的盐，其中：The compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein:
    环A为6-14元芳基或5-10元杂芳基，优选选自苯基、萘基、噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、吡咯基、三唑基、三嗪基、咪唑基、吡唑基、吡咯基、吡啶基、嘧啶基或吡嗪基；和/或Ring A is 6-14 membered aryl or 5-10 membered heteroaryl, preferably selected from phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazolyl, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl or pyrazinyl; and/or
    环B为6-14元芳基或5-10元杂芳基，优选选自苯基、萘基、噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、吡咯基、三唑基、三嗪基、吡啶酮基、苯并吗啉基、吲唑基、二氢苯并恶嗪基、吡唑并吡啶基、苯并三唑基、苯并咪唑基、吡啶并吗啉基、四氢异喹啉基、咪唑并吡啶基、吡啶并吗啉基、苯并吲哚基、苯并异二唑基、吲哚基、喹啉基、异喹啉基、喹唑啉基、喹噁啉基、十氢异喹啉基、二氢吲哚基、八氢吲哚基或八氢异吲哚基；和/或Ring B is 6-14 membered aryl or 5-10 membered heteroaryl, preferably selected from phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, Pyrazinyl, pyridazinyl, furyl, pyrrolyl, triazolyl, triazinyl, pyridonyl, benzomorpholinyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridyl, Benzotriazolyl, benzimidazolyl, pyridomorpholinyl, tetrahydroisoquinolinyl, imidazopyridinyl, pyridomorpholinyl, benzindolyl, benzisodiazolyl, indole yl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, decahydroisoquinolyl, dihydroindolyl, octahydroindolyl or octahydroisoindolyl; and/or
    环C为键、6-14元芳基或5-10元杂芳基，优选选自苯基、萘基、嘧啶基、吡嗪基、吡啶基、哌啶基、哌嗪基、吗啉基、噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、哒嗪基、呋喃基、吡咯基、三唑基或三嗪基。Ring C is a bond, 6-14 membered aryl or 5-10 membered heteroaryl, preferably selected from phenyl, naphthyl, pyrimidinyl, pyrazinyl, pyridyl, piperidinyl, piperazinyl, morpholinyl , thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridazinyl, furyl, pyrrolyl, triazolyl or triazinyl.
  4. 如权利要求1-3中任一项所述的化合物或其药学上可接受的盐，其中环A为苯基。The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-3, wherein ring A is phenyl.
  5. 如权利要求1-3中任一项所述的化合物或其药学上可接受的盐，其中环B选自苯基、吡啶基、吡啶酮基、吲唑基、二氢苯并恶嗪基、苯并吗啉基、吡啶并吗啉基、苯并咪唑基、吡唑并吡啶基或苯并三唑基。The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-3, wherein ring B is selected from phenyl, pyridyl, pyridonyl, indazolyl, dihydrobenzoxazinyl, Benzmorpholinyl, pyridomorpholinyl, benzimidazolyl, pyrazolopyridinyl or benzotriazolyl.
  6. 如权利要求3所述的化合物或其药学上可接受的盐，其中环C为6-14元芳基或5-10元杂芳基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 3, wherein ring C is 6-14 membered aryl or 5-10 membered heteroaryl.
  7. 如权利要求3所述的化合物或其药学上可接受的盐，其中环C为嘧啶基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein ring C is pyrimidinyl.
  8. 如权利要求1-7中任一项所述的化合物或其药学上可接受的盐，其中X为C，R1和R2各自独立为H、羟基或任选取代的烷基。The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7, wherein X is C, and R 1 and R 2 are each independently H, hydroxyl or optionally substituted alkyl.
  9. 如权利要求8所述的化合物或其药学上可接受的盐，其中R1和R2各自独立地为任选取代的烷基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 8, wherein R 1 and R 2 are each independently an optionally substituted alkyl group, and the optionally substituted alkyl group is optionally replaced by one or more Substituents independently selected from halogen, hydroxy, cyano and -NR a R a are substituted.
  10. 如权利要求8所述的化合物或其药学上可接受的盐，其中R1和R2中的一者为任选取代的烷基，另一者为H或羟基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 8, wherein one of R and R is optionally substituted alkyl, the other is H or hydroxyl, and the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NR a R a .
  11. 如权利要求1-10中任一项所述的化合物或其药学上可接受的盐，其中R3和R4各自独立地为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb。The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-10 , wherein R and R are each independently H, halogen, cyano, oxo, optionally substituted alkyl, Optionally substituted alkenyl, optionally substituted alkynyl , -( CH2 ) rNRaRa , or -ORb .
  12. 如权利要求1-10中任一项所述的化合物或其药学上可接受的盐，其中各R3独立为H、卤素、任选取代的烷基、任选取代的烷氧基或-ORb。The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein each R is independently H, halogen, optionally substituted alkyl, optionally substituted alkoxy or -OR b .
  13. 如权利要求1-10中任一项所述的化合物或其药学上可接受的盐，其中各R4独立为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的烯基或-CORb，Rb为H、任选取代的烷基、任选取代的烯基、任选取代的炔基，其中所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基、烷氧基或-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-10, wherein each R is independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted Alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH 2 ) r NR a R a or -OR b , where each R a is independently H, optionally substituted alkenyl or -COR b , R b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkyne and optionally substituted cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, alkoxy, or -NR a R a .
  14. 如权利要求1-13中任一项所述的化合物或其药学上可接受的盐，其中Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-或-NRa-。The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-13, wherein Z is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 - or -NR a -.
  15. 如权利要求1-13中任一项所述的化合物或其药学上可接受的盐，其中Z1为键、-O-、-CO-、或-NRa-，其中Ra为H或任选取代的烷基。The compound or pharmaceutically acceptable salt thereof as any one of claims 1-13, wherein Z is a bond, -O-, -CO-, or -NR a -, wherein R a is H or any Choose a substituted alkyl group.
  16. 如权利要求1-15中任一项所述的化合物或其药学上可接受的盐，其中R5为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，所述任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-15, wherein R is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, said optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR a R a .
  17. 如权利要求1所述的化合物或其药学上可接受的盐，其中Z1为键或-O-，R5为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein Z 1 is a bond or -O-, R 5 is an optionally substituted C 1 -C 4 alkyl, and the optionally substituted C 1 -C4alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NRaRa .
  18. 如权利要求1所述的化合物或其药学上可接受的盐，其中Z1为-CO-，R5为任选取代的C2-C4烯基，所述任选取代的C2-C4烯基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein Z 1 is -CO-, R 5 is optionally substituted C 2 -C 4 alkenyl, and said optionally substituted C 2 -C 4 alkenyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, or -NR a R a .
  19. 如权利要求1所述的化合物或其药学上可接受的盐，其中Y1为键，Y2为O、NH或S。The compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein Y 1 is a bond, and Y 2 is O, NH or S.
  20. 如权利要求1所述的化合物或其药学上可接受的盐，其中Y1为任选取代的烷基、任选取代的烯基或任选取代的炔基，Y2为键或O，所述任选取代的烷基、任选取代的烯基或任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基、烷基或氧代的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein Y is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y is a bond or O, and The optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, alkyl or oxo.
  21. 如权利要求20所述的化合物或其药学上可接受的盐，其中Y1为C1-C4烷基或C2-C4炔基，Y2为键或O。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 20, wherein Y 1 is C 1 -C 4 alkyl or C 2 -C 4 alkynyl, and Y 2 is a bond or O.
  22. 如权利要求1所述的化合物或其药学上可接受的盐，其中R6为-N＝S(O)RcRd。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 is -N=S(O)R c R d .
  23. 如权利要求1所述的化合物或其药学上可接受的盐，其中R6为-N＝S(O)RcRd，Rc和Rd各自独立选自任选取代的烷基或-NRaRa，其中Ra各自独立为H或任选取代的烷基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R 6 is -N=S(O)R c R d , R c and R d are each independently selected from optionally substituted alkyl or - NR a R a , wherein each R a is independently H or optionally substituted alkyl.
  24. 如权利要求23所述的化合物或其药学上可接受的盐，其中R6为-N＝S(O)RcRd，Rc和Rd各自独立选自任选取代的C1-C4烷基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 23, wherein R 6 is -N═S(O)R c R d , and R c and R d are each independently selected from optionally substituted C 1 -C 4 alkyl.
  25. 如权利要求23或24所述的化合物或其药学上可接受的盐，其中R6为-N＝S(O)RcRd，Rc和Rd各自独立地为任选取代的甲基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 23 or 24, wherein R 6 is -N=S(O) RcRd , Rc and Rd are each independently optionally substituted methyl .
  26. 如权利要求23或24所述的化合物或其药学上可接受的盐，其中R6为 The compound or pharmaceutically acceptable salt thereof as claimed in claim 23 or 24, wherein R is
  27. 如权利要求1所述的化合物或其药学上可接受的盐，其中R6为-N＝S(O)RcRd，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述任选取代的4-10元杂环基任选地被一个或多个Rh取代，其中Rh选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，Rg为任选取代的烷基或任选取代的环烷基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R 6 is -N=S(O)R c R d , R c , R d together with the S atom they are connected to form an optional substitution A 4-10 membered heterocyclic group, the optionally substituted 4-10 membered heterocyclic group is optionally substituted by one or more Rh , wherein Rh is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkyne and optionally substituted cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, and -OR b , wherein R b is optionally substituted alkyl, optionally substituted The alkenyl or optionally substituted alkynyl, R g is an optionally substituted alkyl or an optionally substituted cycloalkyl.
  28. 如权利要求27所述的化合物或其药学上可接受的盐，其中R6选自下组： The compound or pharmaceutically acceptable salt thereof as claimed in claim 27, wherein R is selected from the group consisting of:
    其各自任选地被一个或多个Rh取代。Each of which is optionally substituted with one or more Rh .
  29. 如权利要求27所述的化合物或其药学上可接受的盐，其中R6选自下组： The compound or pharmaceutically acceptable salt thereof as claimed in claim 27, wherein R is selected from the group consisting of:
  30. 如权利要求26-29中任一项所述的化合物或其药学上可接受的盐，其中环C为杂芳基。The compound according to any one of claims 26-29, or a pharmaceutically acceptable salt thereof, wherein ring C is heteroaryl.
  31. 如权利要求1所述的化合物或其药学上可接受的盐，其中R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein each R 7 is independently halogen, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f or -NR g R g .
  32. 如权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物具有下式： The compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound has the following formula:
    其中in
    V1和V2各自独立地为N或CH；V and V are each independently N or CH;
    环C为键、芳基或杂芳基；Ring C is a bond, aryl or heteroaryl;
    Z1为键、-O-、-CO-或-(CH2)r-NRa-CO；Z 1 is a bond, -O-, -CO- or -(CH 2 ) r -NR a -CO;
    Z2为**-Y1-Y2-*，其中Y1为键、任选取代的烷基或任选取代的炔基，Y2为键或O；Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl or optionally substituted alkynyl, and Y 2 is a bond or O;
    R1和R2各自独立地为羟基或任选取代的烷基；或者R and R are each independently hydroxyl or optionally substituted alkyl; or
    R1和R2与其所连接的碳原子一起形成任选取代的 R and R together with the carbon atom to which they are attached form an optionally substituted
    R3为H、卤素、-ORb或任选取代的烷基；R 3 is H, halogen, -OR b or optionally substituted alkyl;
    R4各自独立地为卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb； Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRaRa or -ORb ;
    R5为任选取代的烷基或任选取代的烯基； R is optionally substituted alkyl or optionally substituted alkenyl;
    R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg；Ra各自独立为H、任选取代的烷基或-CORb；Each R 7 is independently halogen, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f , or -NR g R g ; each R a is independently H, any Select substituted alkyl or -COR b ;
    Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rc和Rd各自独立选自任选取代的烷基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
    Rf为任选取代的烷基； R is optionally substituted alkyl;
    Rg各自独立为H、-SO2Rf或任选取代的烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基；且Each R g is independently H, -SO 2 R f or optionally substituted alkyl; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
    r、s、m、n和p各自独立为0、1或2。r, s, m, n and p are each independently 0, 1 or 2.
  33. 如权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物具有下式： The compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound has the following formula:
    其中in
    V3为N或CH；V 3 is N or CH;
    环C为键、芳基或杂芳基；Ring C is a bond, aryl or heteroaryl;
    环D为杂环基或杂芳基；Ring D is heterocyclyl or heteroaryl;
    Z1为键、-O-、-CO-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -CO- or -(CH 2 ) r -NR a -CO-;
    Z2为**-Y1-Y2-*，其中Y1为键、任选取代的烷基或任选取代的炔基，Y2为键或O；Z 2 is **-Y 1 -Y 2 -*, wherein Y 1 is a bond, optionally substituted alkyl or optionally substituted alkynyl, and Y 2 is a bond or O;
    R1和R2各自独立地为羟基或任选取代的烷基；或者R and R are each independently hydroxyl or optionally substituted alkyl; or
    R1和R2与其所连接的碳原子一起形成任选取代的 R and R together with the carbon atom to which they are attached form an optionally substituted
    R3为H、卤素、任选取代的烷基或任选取代的烷氧基； R is H, halogen, optionally substituted alkyl or optionally substituted alkoxy;
    R4各自独立地为卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb； Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRaRa or -ORb ;
    R5为H、任选取代的烷基或任选取代的烯基； R is H, optionally substituted alkyl or optionally substituted alkenyl;
    R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg； Each R7 is independently halogen, cyano , optionally substituted alkyl, -ORa , -S(O) Rf , -SO2Rf , or -NRgRg ;
    Ra各自独立为H、任选取代的烷基或-CORb；each R a is independently H, optionally substituted alkyl, or -COR b ;
    Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rc和Rd各自独立选自任选取代的烷基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
    Rf为任选取代的烷基； R is optionally substituted alkyl;
    Rg各自独立为H、-SO2Rf或任选取代的烷基；或者两个Rg与它们所连接的N原子一起形成任选取代的4-10元杂环基；且Each R g is independently H, -SO 2 R f or optionally substituted alkyl; or two R g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
    r、s、m、n和p各自独立为0、1或2。r, s, m, n and p are each independently 0, 1 or 2.
  34. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中所述环C为芳基或杂芳基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein the ring C is aryl or heteroaryl.
  35. 如权利要求34所述的化合物或其药学上可接受的盐，其中环C为6-14元芳基或5-10元杂芳基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 34, wherein ring C is 6-14 membered aryl or 5-10 membered heteroaryl.
  36. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中所述Z1为键、-O-或-CO-。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein said Z 1 is a bond, -O- or -CO-.
  37. 如权利要求32-36中任一项所述的化合物或其药学上可接受的盐，其中所述R3为H或任选取代的烷基。The compound according to any one of claims 32-36, or a pharmaceutically acceptable salt thereof, wherein said R 3 is H or optionally substituted alkyl.
  38. 如权利要求32所述的化合物或其药学上可接受的盐，其中为苯基、吡啶基或吡啶酮基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 32, wherein is phenyl, pyridyl or pyridonyl.
  39. 如权利要求33所述的化合物或其药学上可接受的盐，其中选自： The compound or pharmaceutically acceptable salt thereof as claimed in claim 33, wherein selected from:
  40. 如权利要求33所述的化合物或其药学上可接受的盐，其中所述环D被1、2或3个R9取代，R9为H、卤素或任选取代的烷基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 33, wherein the ring D is substituted by 1, 2 or 3 R 9 , and R 9 is H, halogen or optionally substituted alkyl.
  41. 如权利要求40所述的化合物或其药学上可接受的盐，其中R9选自H、F、Cl、CH3或CF3。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 40, wherein R 9 is selected from H, F, Cl, CH 3 or CF 3 .
  42. 如权利要求33或39所述的化合物或其药学上可接受的盐，其中通过环D上的饱和N原子与-Z1R5连接。The compound or pharmaceutically acceptable salt thereof as claimed in claim 33 or 39, wherein Attachment to -Z 1 R 5 is through a saturated N atom on ring D.
  43. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中各R3独立为H、氟、氯、任选取代的C1-C4烷基或任选取代的C1-C4烷氧基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein each R 3 is independently H, fluorine, chlorine, optionally substituted C 1 -C 4 alkyl or optionally substituted C 1 - C 4 alkoxy.
  44. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中各R3独立为任选取代的C1-C4烷基或任选取代的C1-C4烷氧基，所述任选取代的C1-C4烷基或任选取代的C1-C4烷氧基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein each R 3 is independently optionally substituted C 1 -C 4 alkyl or optionally substituted C 1 -C 4 alkoxy, The optionally substituted C 1 -C 4 alkyl or optionally substituted C 1 -C 4 alkoxy is optionally selected from one or more independently selected from halogen, hydroxyl, cyano and -NR a R a of substituents.
  45. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中各R3独立地选自卤素、C1-C4烷基或C1-C4烷氧基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein each R 3 is independently selected from halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  46. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中各R3独立地选自为氟、氯、甲基或甲氧基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein each R 3 is independently selected from fluorine, chlorine, methyl or methoxy.
  47. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中Rc和Rd各自独立地为C1-C4烷基或-NH-(C1-C4烷基)。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein R c and R d are each independently C 1 -C 4 alkyl or -NH-(C 1 -C 4 alkyl).
  48. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中Rc和Rd各自独立地为任选取代的甲基。The compound according to claim 32 or 33, or a pharmaceutically acceptable salt thereof, wherein R c and R d are each independently optionally substituted methyl.
  49. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中Rc和Rd均为甲基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein both R c and R d are methyl.
  50. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中Rc和Rd与它们所连接的S原子一起形成任选地被一个或多个Rh取代的4-10元杂环基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein R c and R d together with the S atom they are connected to form a 4-10 member optionally substituted by one or more R h heterocyclyl.
  51. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中Rc和Rd与它们所连接的S原子一起形成任选地被一个或多个Rh取代的4-10元杂环基，其中Rh选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，Rg为任选取代的烷基或任选取代的环烷基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein R c and R d together with the S atom they are connected to form a 4-10 member optionally substituted by one or more R h Heterocyclyl, wherein R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -NR a R a , -C(O)R g , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or optionally substituted alkyl, the The optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen, hydroxy, cyano and -OR b is substituted with a substituent, wherein R b is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and R g is optionally substituted alkyl or optionally substituted cycloalkyl.
  52. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中Rc和Rd与它们所连接的S原子一起形成的4-10元杂环基选自下组： The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein the 4-10 membered heterocyclic group formed by R c and R d together with the S atom they are connected to is selected from the following group:
    其各自任选地被一个或多个Rh取代，其中Rh选自任选取代的C1-C4烷基、任选取代的C2-C4炔基、任选取代的C3-C6环烷基、任选取代的4-9元杂环基、-NRaRa、-C(O)Rg、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的C1-C4烷基，上述任选取代的C1-C4烷基、任选取代的C2-C4炔基和任选取代的C3-C6环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，Rg为任选取代的C1-C4烷基或任选取代的C2-C4环烷基。Each of which is optionally substituted by one or more Rh , wherein Rh is selected from optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 - C 6 Cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a R a , -C(O) R g , -C(O)NR a R a , -S(O) R f or -SO 2 R f , wherein R a is independently H or optionally substituted C 1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, and -OR b , wherein R b is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, R g is optionally substituted C 1 -C 4 alkyl or optionally substituted C 2 -C 4 cycloalkyl.
  53. 如权利要求52所述的化合物或其药学上可接受的盐，其中Rh选自下组：任选地被一个或多个独立地选自羟基、卤素、氰基或-O(C2-C4炔基)的取代基取代的C1-C4烷基、C2-C4炔基、C3-C6环烷基、任选被一个或多个C1-C4烷基取代的4-9元杂环基、-NH2、-NH(C1-C4烷基)、-C(O)-(C1-C4烷基)、-C(O)-(C2-C4环烷基)、-C(O)NH2和-SO2(C1-C4烷基)，其中-NH(C1-C4烷基)和-C(O)-(C1-C4烷基)中的C1-C4烷基任选地被一个或多个卤素或羟基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 52, wherein Rh is selected from the group consisting of optionally one or more independently selected from hydroxyl, halogen, cyano or -O(C 2 - C 4 alkynyl) substituted C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, optionally substituted by one or more C 1 -C 4 alkyl 4-9 membered heterocyclyl, -NH 2 , -NH(C 1 -C 4 alkyl), -C(O)-(C 1 -C 4 alkyl), -C(O)-(C 2 -C 4 cycloalkyl), -C(O)NH 2 and -SO 2 (C 1 -C 4 alkyl), where -NH(C 1 -C 4 alkyl) and -C(O)-(C C 1 -C 4 alkyl in 1 -C 4 alkyl) is optionally substituted by one or more halogen or hydroxy.
  54. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基选自下组： The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein R c , R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group selected from the following group:
  55. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中Z2为-O-、C2-C4炔基或**-(任选取代的C1-C4烷基)-O-*、其中所述任选取代的C1-C4烷基任选地被一个或多个选自羟基、C1-C4烷基或氧代的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein Z 2 is -O-, C 2 -C 4 alkynyl or **-(optionally substituted C 1- C 4 alkyl )-O-*, wherein the optionally substituted C 1- C 4 alkyl is optionally substituted by one or more substituents selected from hydroxyl, C 1-C 4 alkyl or oxo.
  56. 如权利要求32或33所述的化合物或其药学上可接受的盐，其中环C为苯基、吡啶基、嘧啶基、吡嗪基、噻唑基或噁唑基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 32 or 33, wherein ring C is phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl.
  57. 下式2-I所示的化合物： The compound shown in following formula 2-I:
    或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof,
    其中：in:
    环A和环B各自独立为环烷基、杂环基、芳基或杂芳基；Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;
    环C为键、环烷基、杂环基、芳基或杂芳基；Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;
    X为C、N、O或S；X is C, N, O or S;
    R1和R2各自独立地为不存在、H、卤素、氰基、羟基、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的烷氧基或-NRaRa；R and R are each independently absent, H, halogen, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy , or -NR a R a ;
    R3和R4各自独立地为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb；R 3 and R 4 are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH 2 ) r NR a R a or -OR b ;
    Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-、-NRa-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 -, -NR a - or -(CH 2 ) r -NR a -CO-;
    R5为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    R6为-N＝S(O)RcRd、-(CH2)sS(O)(＝NRe)Rf或-NRa-SO2Rg；R 6 is -N=S(O)R c R d , -(CH 2 ) s S(O)(=NR e )R f or -NR a -SO 2 R g ;
    R7各自独立地为卤素、氰基、任选取代的烷基、任选取代的烯基、任选取代的炔基、-ORa、-S(O)Rf、-SO2Rf或-NRhRh；Each R 7 is independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a , -S(O)R f , -SO 2 R f , or -NR h R h ;
    Ra各自独立为H、任选取代的烷基、任选取代的烯基、任选取代的炔基或-CORb；each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR ;
    Rb为H、任选取代的烷基、任选取代的烯基或任选取代的炔基； R is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rc和Rd各自独立选自任选取代的烷基、任选取代的烯基、任选取代的炔基、-ORa或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR a or -NR a R a ; or R c , R d are connected to them The S atoms together form an optionally substituted 4-10 membered heterocyclic group;
    Re为H、氰基、任选取代的烷基、任选取代的烯基或任选取代的炔基；R is H, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rf为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rg选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的4-10元杂环基或-NRhRh；R g is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-10 membered heterocyclyl, or -NR h R h ;
    Rh各自独立为H、任选取代的烷基、任选取代的烯基或任选取代的炔基；或者两个Rh与它们所连接的N原子一起形成任选取代的4-10元杂环基；R h are each independently H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered Heterocyclyl;
    r为0、1、2或3；r is 0, 1, 2 or 3;
    s为0、1、2或3；且s is 0, 1, 2 or 3; and
    m、n和p各自独立为0、1、2或3。m, n and p are each independently 0, 1, 2 or 3.
  58. 如权利要求57所述的化合物或其药学上可接受的盐，其中所述Z1为键、-O-、-S-、-CO-、-S(O)-、-SO2-或-NRa-。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein said Z 1 is a bond, -O-, -S-, -CO-, -S(O)-, -SO 2 - or - NR a -.
  59. 如权利要求56-58中任一项所述的化合物或其药学上可接受的盐，其中所述R6为-N＝S(O)RcRd或-NRa-SO2Rg。The compound according to any one of claims 56-58 or a pharmaceutically acceptable salt thereof, wherein said R 6 is -N═S(O)R c R d or -NR a -SO 2 R g .
  60. 如权利要求57所述的化合物或其药学上可接受的盐，其中环A为6-14元芳基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein ring A is a 6-14 membered aryl group.
  61. 如权利要求58所述的化合物或其药学上可接受的盐，其中环A为苯基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 58, wherein ring A is phenyl.
  62. 如权利要求57所述的化合物或其药学上可接受的盐，其中环A为5-10元杂芳基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein ring A is a 5-10 membered heteroaryl group.
  63. 如权利要求62所述的化合物或其药学上可接受的盐，其中环A为吡啶基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 62, wherein ring A is pyridyl.
  64. 如权利要求57所述的化合物或其药学上可接受的盐，其中环B为5-10元杂环基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein ring B is a 5-10 membered heterocyclic group.
  65. 如权利要求64所述的化合物或其药学上可接受的盐，其中环B为吡啶酮基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 64, wherein ring B is pyridinonyl.
  66. 如权利要求57所述的化合物或其药学上可接受的盐，其中环B为6-14元芳基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein ring B is a 6-14 membered aryl group.
  67. 如权利要求66所述的化合物或其药学上可接受的盐，其中环B为苯基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 66, wherein ring B is phenyl.
  68. 如权利要求57所述的化合物或其药学上可接受的盐，其中环B为6-14元杂芳基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein ring B is a 6-14 membered heteroaryl group.
  69. 如权利要求68所述的化合物或其药学上可接受的盐，其中环B选自吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基、吡啶酮基、苯并吗啉基、吲唑基、二氢苯并恶嗪基、吡唑并吡啶基、苯并三唑基、苯并咪唑基、吡啶并吗啉基、四氢异喹啉基、咪唑并吡啶基、吡啶并吗啉基、苯并异二唑基、吲哚基、喹啉基、异喹啉基、喹唑啉基、喹噁啉基、十氢异喹啉基、二氢吲哚基、八氢吲哚基或八氢异吲哚基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 68, wherein ring B is selected from pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, pyridonyl, benzomorpholinyl, Indazolyl, dihydrobenzoxazinyl, pyrazolopyridyl, benzotriazolyl, benzimidazolyl, pyridomorpholinyl, tetrahydroisoquinolinyl, imidazopyridinyl, pyridomorph Linyl, benzisodiazolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, decahydroisoquinolinyl, dihydroindolyl, octahydroindoline base or octahydroisoindolyl.
  70. 如权利要求57所述的化合物或其药学上可接受的盐，其中环C为6-14元杂芳基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein ring C is a 6-14 membered heteroaryl group.
  71. 如权利要求70所述的化合物或其药学上可接受的盐，其中环C选自吡啶基、嘧啶基或吡嗪基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 70, wherein ring C is selected from pyridyl, pyrimidyl or pyrazinyl.
  72. 如权利要求57所述的化合物或其药学上可接受的盐，其中X为C，R1和R2各自独立为H、羟基或任选取代的烷基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 57, wherein X is C, and R 1 and R 2 are each independently H, hydroxyl or optionally substituted alkyl.
  73. 如权利要求72所述的化合物或其药学上可接受的盐，其中R1和R2各自独立地为任选取代的烷基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 72, wherein R 1 and R 2 are each independently an optionally substituted alkyl group, and the optionally substituted alkyl group is optionally replaced by one or more Substituents independently selected from halogen, hydroxy, cyano and -NR a R a are substituted.
  74. 如权利要求72所述的化合物或其药学上可接受的盐，其中R1和R2中的一者为任选取代的烷基，另一者为H或羟基，所述任选取代的烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 72, wherein one of R and R is optionally substituted alkyl, the other is H or hydroxyl, and the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NR a R a .
  75. 如权利要求57所述的化合物或其药学上可接受的盐，其中各R3独立为H、卤素、氰基、任选取代的烷基或ORb。The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently H, halogen, cyano, optionally substituted alkyl or OR b .
  76. 如权利要求57所述的化合物或其药学上可接受的盐，其中各R4独立为H、卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb，其中Ra各自独立为H、任选取代的烯基或-CORb，Rb为H、任选取代的烷基、任选取代的烯基、任选取代的炔基，其中所述任选取代的烷基、任选取代的烯基和任选取代的炔基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 57, wherein each R is independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH 2 ) r NR a R a or -OR b , wherein R a is each independently H, optionally substituted alkenyl or -COR b , R b is H, optionally substituted alkyl, Optionally substituted alkenyl, optionally substituted alkynyl, wherein the optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl are optionally selected from one or more independently selected from halogen , hydroxyl, cyano or -NR a R a substituent substitution.
  77. 如权利要求57所述的化合物或其药学上可接受的盐，其中Z1为键、-O-、-CO-、-NRa-或-(CH2)r-NRa-CO-，其中Ra为H或任选取代的烷基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein Z 1 is a bond, -O-, -CO-, -NR a - or -(CH 2 ) r -NR a -CO-, wherein R a is H or optionally substituted alkyl.
  78. 如权利要求57所述的化合物或其药学上可接受的盐，其中Z1为键、-O-、-CO-或-NRa-，其中Ra为H或任选取代的烷基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein Z 1 is a bond, -O-, -CO- or -NR a -, wherein R a is H or optionally substituted alkyl.
  79. 如权利要求57所述的化合物或其药学上可接受的盐，其中R5为任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基，所述任选取代的C1-C4烷基、任选取代的C2-C4烯基或任选取代的C2-C4炔基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。The compound or pharmaceutically acceptable salt thereof as claimed in claim 57, wherein R 5 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl, said optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl optionally replaced by one or Multiple substituents independently selected from halogen, hydroxyl, cyano or -NR a R a are substituted.
  80. 如权利要求57所述的化合物或其药学上可接受的盐，其中Z1为键，R5为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein Z 1 is a bond, R 5 is an optionally substituted C 1 -C 4 alkyl, and the optionally substituted C 1 -C 4 alkane is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR a R a .
  81. 如权利要求57所述的化合物或其药学上可接受的盐，其中Z1为-O-，R5为任选取代的C1-C4烷基，所述任选取代的C1-C4烷基任选地被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein Z 1 is -O-, R 5 is an optionally substituted C 1 -C 4 alkyl, and the optionally substituted C 1 -C 4 Alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR a R a .
  82. 如权利要求57所述的化合物或其药学上可接受的盐，其中R6为-N＝S(O)RcRd，Rc和Rd各自独立选自任选取代的烷基、-ORa或-NRaRa，其中Ra各自独立为H、任选取代的烷基或任选取代的炔基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein R 6 is -N=S(O)R c R d , and R c and R d are each independently selected from optionally substituted alkyl, - OR a or -NR a R a , wherein each R a is independently H, optionally substituted alkyl, or optionally substituted alkynyl.
  83. 如权利要求57所述的化合物或其药学上可接受的盐，其中R6为 The compound or pharmaceutically acceptable salt thereof as claimed in claim 57, wherein R is
  84. 如权利要求57所述的化合物或其药学上可接受的盐，其中R6为-N＝S(O)RcRd，Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基，所述任选取代的4-10元杂环基任选地被一个或多个Ri取代，其中Ri各自独立地选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的4-9元杂环基、-C(O)Rj、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，其中Rj为任选取代的烷基或任选取代的环烷基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein R 6 is -N=S(O)R c R d , R c , R d together with the S atom they are connected to form an optional substitution A 4-10 membered heterocyclic group, the optionally substituted 4-10 membered heterocyclic group is optionally substituted by one or more R i , wherein each R i is independently selected from optionally substituted alkyl, any Optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -C(O)R j , -NR a R a , -C( O) NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or an optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkene , optionally substituted alkynyl, and optionally substituted cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -OR b , wherein R b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein R j is optionally substituted alkyl or optionally substituted cycloalkyl.
  85. 如权利要求84所述的化合物或其药学上可接受的盐，其中R6选自下组： The compound or a pharmaceutically acceptable salt thereof as claimed in claim 84, wherein R is selected from the group consisting of:
    其各自任选地被一个或多个Ri取代。Each of which is optionally substituted with one or more R i .
  86. 如权利要求84或85所述的化合物或其药学上可接受的盐，其中R6选自下组： The compound or pharmaceutically acceptable salt thereof as claimed in claim 84 or 85, wherein R is selected from the group consisting of:
  87. 如权利要求82-86中任一项所述的化合物或其药学上可接受的盐，其中环C为杂芳基。The compound according to any one of claims 82-86, or a pharmaceutically acceptable salt thereof, wherein ring C is heteroaryl.
  88. [根据细则26改正 29.03.2023]
    如权利要求57所述的化合物或其药学上可接受的盐，其中R6为-NRa-SO2Rg，Ra为H或任选取代的烷基，Rg为任选取代的烷基、任选取代的4-10元杂环基或-NRhRh。    [Correction 29.03.2023 under Rule 26]
    The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein R 6 is -NR a -SO 2 R g , R a is H or optionally substituted alkyl, R g is optionally substituted alkyl group, an optionally substituted 4-10 membered heterocyclic group or -NR h R h .
  89. 如权利要求88所述的化合物或其药学上可接受的盐，其中Ra为H或任选被一个或多个独立地选自卤素、羟基或氰基的取代基取代的烷基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 88, wherein R a is H or alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl or cyano.
  90. 如权利要求88所述的化合物或其药学上可接受的盐，其中Rg为任选被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代的烷基，其中Ra独立地选自氢或烷基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 88, wherein R g is an alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano or -NR a R a group, wherein R a is independently selected from hydrogen or alkyl.
  91. 如权利要求88所述的化合物或其药学上可接受的盐，其中Rg为任选被一个或多个独立地选自卤素、羟基、氰基或-NRaRa的取代基取代的4-10元杂环基，其中Ra独立地选自氢或烷基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 88, wherein R g is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano or -NR a R a -10 membered heterocyclyl, wherein R a is independently selected from hydrogen or alkyl.
  92. 如权利要求88所述的化合物或其药学上可接受的盐，其中Rg为-NRhRh，其中Rh各自独立地为氢或任选被一个或多个独立地选自卤素、羟基或氰基的取代基取代的烷基，或者两个Rh与它们所连接的N原子一起形成任选取代的4-10元杂环基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 88, wherein R g is -NR h R h , wherein R h is each independently hydrogen or is optionally selected from one or more independently selected from halogen, hydroxyl Or an alkyl group substituted by a substituent of a cyano group, or two Rh together with the N atoms to which they are attached form an optionally substituted 4-10 membered heterocyclic group.
  93. 如权利要求57所述的化合物或其药学上可接受的盐，其中R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRgRg。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 57, wherein each R 7 is independently halogen, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f or -NR g R g .
  94. 如权利要求57所述的化合物或其药学上可接受的盐，其中所述化合物具有下式： The compound or pharmaceutically acceptable salt thereof as claimed in claim 57, wherein said compound has the following formula:
    其中in
    V1和V2各自独立地为N或CH；V and V are each independently N or CH;
    环C为键、芳基或杂芳基；Ring C is a bond, aryl or heteroaryl;
    Z1为键、-O-、-CO-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -CO- or -(CH 2 ) r -NR a -CO-;
    R1和R2各自独立地为羟基或任选取代的烷基；R and R are each independently hydroxyl or optionally substituted alkyl;
    R3为H、ORb或任选取代的烷基；R 3 is H, OR b or optionally substituted alkyl;
    R4各自独立地为卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb； Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRaRa or -ORb ;
    R5为任选取代的烷基或任选取代的烯基； R is optionally substituted alkyl or optionally substituted alkenyl;
    R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRhRh；Ra各自独立为H、任选取代的烷基或-CORb；Each R 7 is independently halogen, cyano, optionally substituted alkyl, -OR a , -S(O)R f , -SO 2 R f or -NR h R h ; each R a is independently H, any Select substituted alkyl or -COR b ;
    Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rc和Rd各自独立选自任选取代的烷基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
    Rf为任选取代的烷基； R is optionally substituted alkyl;
    Rh各自独立为H、-SO2Rf或任选取代的烷基；或者两个Rh与它们所连接的N原子一起形成任选取代的4-10元杂环基；且Each R h is independently H, -SO 2 R f or an optionally substituted alkyl group; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
    r、s、m、n和p各自独立为0、1或2。r, s, m, n and p are each independently 0, 1 or 2.
  95. 如权利要求57所述的化合物或其药学上可接受的盐，其中所述化合物具有下式： The compound or pharmaceutically acceptable salt thereof as claimed in claim 57, wherein said compound has the following formula:
    其中in
    V3为N或CH；V 3 is N or CH;
    环C为键、芳基或杂芳基；Ring C is a bond, aryl or heteroaryl;
    环D为杂环基或杂芳基；Ring D is heterocyclyl or heteroaryl;
    Z1为键、-O-、-CO-或-(CH2)r-NRa-CO-；Z 1 is a bond, -O-, -CO- or -(CH 2 ) r -NR a -CO-;
    R1和R2各自独立地为羟基或任选取代的烷基；R and R are each independently hydroxyl or optionally substituted alkyl;
    R3为H、ORb或任选取代的烷基；R 3 is H, OR b or optionally substituted alkyl;
    R4各自独立地为卤素、氰基、氧代、任选取代的烷基、任选取代的烯基、任选取代的炔基、-(CH2)rNRaRa或-ORb； Each R4 is independently halogen, cyano, oxo, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, -( CH2 ) rNRaRa or -ORb ;
    R5为任选取代的烷基或任选取代的烯基； R is optionally substituted alkyl or optionally substituted alkenyl;
    R7各自独立地为卤素、氰基、任选取代的烷基、-ORa、-S(O)Rf、-SO2Rf或-NRhRh；Each R 7 is independently halogen, cyano , optionally substituted alkyl, -ORa , -S(O) Rf , -SO2Rf , or -NRhRh ;
    Ra各自独立为H、任选取代的烷基或-CORb；each R a is independently H, optionally substituted alkyl, or -COR b ;
    Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基； R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
    Rc和Rd各自独立选自任选取代的烷基或-NRaRa；或者Rc、Rd与它们所连接的S原子一起形成任选取代的4-10元杂环基；R c and R d are each independently selected from optionally substituted alkyl or -NR a R a ; or R c and R d together with the S atom they are connected to form an optionally substituted 4-10 membered heterocyclic group;
    Rf为任选取代的烷基； R is optionally substituted alkyl;
    Rh各自独立为H、-SO2Rf或任选取代的烷基；或者两个Rh与它们所连接的N原子一起形成任选取代的4-10元杂环基；且Each R h is independently H, -SO 2 R f or an optionally substituted alkyl group; or two R h together with the N atoms to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and
    r、s、m、n和p各自独立为0、1或2。r, s, m, n and p are each independently 0, 1 or 2.
  96. 如权利要求94或95所述的化合物或其药学上可接受的盐，其中环C为芳基或杂芳基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 94 or 95, wherein ring C is aryl or heteroaryl.
  97. 如权利要求94或95所述的化合物或其药学上可接受的盐，其中环C为6-14元芳基或6-14元杂芳基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 94 or 95, wherein ring C is 6-14 membered aryl or 6-14 membered heteroaryl.
  98. 如权利要求94-96中任一项所述的化合物或其药学上可接受的盐，其中Z1为键、-O-或-CO-。The compound according to any one of claims 94-96, or a pharmaceutically acceptable salt thereof, wherein Z 1 is a bond, -O- or -CO-.
  99. 如权利要求94所述的化合物或其药学上可接受的盐，其中为苯基、吡啶基或吡啶酮基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 94, wherein is phenyl, pyridyl or pyridonyl.
  100. 如权利要求95所述的化合物或其药学上可接受的盐，其中选自： The compound or pharmaceutically acceptable salt thereof as claimed in claim 95, wherein selected from:
  101. 如权利要求95所述的化合物或其药学上可接受的盐，其中，所述环D被1、2或3个R9取代，所述R9为H、卤素或任选取代的烷基。The compound or a pharmaceutically acceptable salt thereof as claimed in claim 95, wherein the ring D is substituted by 1, 2 or 3 R 9 , and the R 9 is H, halogen or optionally substituted alkyl.
  102. 如权利要求95或100所述的化合物或其药学上可接受的盐，其中通过环D上的饱和N原子与-Z1R5连接。The compound or pharmaceutically acceptable salt thereof as claimed in claim 95 or 100, wherein Attachment to -Z 1 R 5 is through a saturated N atom on ring D.
  103. 如权利要求94或95所述的化合物或其药学上可接受的盐，其中Rc和Rd各自独立地为C1-C4烷基或-NH-(C1-C4烷基)。The compound according to claim 94 or 95, or a pharmaceutically acceptable salt thereof, wherein R c and R d are each independently C 1 -C 4 alkyl or -NH-(C 1 -C 4 alkyl).
  104. 如权利要求94或95所述的化合物或其药学上可接受的盐，其中Rc和Rd与它们所连接的S原子一起形成任选地被一个或多个Ri取代的4-10元杂环基，其中Ri各自独立地选自任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的4-9元杂环基、-C(O)Rj-、-NRaRa、-C(O)NRaRa、-S(O)Rf或-SO2Rf，其中Ra各自独立为H或任选取代的烷基，所述任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的环烷基任选地被一个或多个独立地选自卤素、羟基、氰基和-ORb的取代基取代，其中Rb为任选取代的烷基、任选取代的烯基或任选取代的炔基，其中Rj为任选取代的烷基或任选取代的环烷基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 94 or 95, wherein R c and R d together with the S atom they are connected to form a 4-10 member optionally substituted by one or more R i Heterocyclyl, wherein R i are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered hetero Cyclic group, -C(O)Rj-, -NR a R a , -C(O)NR a R a , -S(O)R f or -SO 2 R f , wherein R a is each independently H or any Optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally selected from one or more independently selected from halogen, Substituent substitution of hydroxy, cyano and -OR b , wherein R b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein R j is optionally substituted alkyl or any Choose a substituted cycloalkyl group.
  105. 如权利要求94或95所述的化合物或其药学上可接受的盐，其中环C为苯基、吡啶基、嘧啶基或吡嗪基。The compound or pharmaceutically acceptable salt thereof as claimed in claim 94 or 95, wherein ring C is phenyl, pyridyl, pyrimidyl or pyrazinyl.
  106. 如权利要求1-105中任一项所述的化合物或其药学上可接受的盐，其中所述化合物选自下组： The compound or pharmaceutically acceptable salt thereof as any one of claims 1-105, wherein the compound is selected from the group consisting of:
  107. 一种药物组合物，其含有治疗或预防有效量的如权利要求1-106中任一项所述的化合物或其药学上可接受的盐，以及药学上可接受的载体。A pharmaceutical composition, which contains a therapeutically or preventively effective amount of the compound according to any one of claims 1-106 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  108. 如权利要求1-106中任一项所述的化合物或其药学上可接受的盐或者如权利要求107所述的药物组合物在制备用于治疗或预防雄激素受体介导的疾病的药物中的用途。The compound as described in any one of claims 1-106 or pharmaceutically acceptable salt thereof or the pharmaceutical composition as described in claim 107 is used in the preparation of the medicine for treating or preventing the disease mediated by androgen receptor use in .
  109. 如权利要求108所述的用途，其中所述雄激素受体介导的疾病包括：前列腺癌、乳腺癌、卵巢癌、膀胱癌、胶质母细胞瘤、黑色素瘤、肾细胞癌、套细胞淋巴瘤、胰腺癌、肝细胞癌、子宫内膜癌、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、年龄相关性黄斑变性和其组合；优选地，所述疾病为前列腺癌，更优选为原发性/局限性前列腺癌、局部晚期前列腺癌、复发性前列腺癌、转移性前列腺癌、晚期前列腺癌或转移性去势抵抗性前列腺癌或激素敏感性前列腺癌。The use according to claim 108, wherein the androgen receptor-mediated diseases include: prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma tumors, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration, and combinations thereof; Preferably, the disease is prostate cancer, more preferably primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer or metastatic castration-resistant prostate cancer or Hormone-sensitive prostate cancer.
  110. 如权利要求1-106中任一项所述的化合物或其药学上可接受的盐或者如权利要求107所述的药物组合物在制备用于治疗或预防雄激素受体变异体介导的疾病的药物中的用途。The compound according to any one of claims 1-106 or the pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 107 is used for the treatment or prevention of diseases mediated by androgen receptor variants use in medicines.
  111. 如权利要求110所述的用途，其中所述雄激素受体变异体为AR剪切体变异体。The use of claim 110, wherein the androgen receptor variant is an AR splice variant.
  112. 如权利要求111所述的用途，其中所述雄激素受体变异体为AR-V7。The use of claim 111, wherein the androgen receptor variant is AR-V7.
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WO2020198710A1 (en) * 2019-03-28 2020-10-01 Essa Pharma, Inc. Pharmaceutical compositions and combinations comprising inhibitors of the androgen receptor and uses thereof
WO2021138392A1 (en) * 2019-12-30 2021-07-08 Tyra Biosciences, Inc. Aminopyrimidine compounds

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CN105732614A (en) * 2014-12-09 2016-07-06 中国科学院广州生物医药与健康研究院 Sulfonamide aryl acetylene compound and use thereof
WO2020198710A1 (en) * 2019-03-28 2020-10-01 Essa Pharma, Inc. Pharmaceutical compositions and combinations comprising inhibitors of the androgen receptor and uses thereof
WO2021138392A1 (en) * 2019-12-30 2021-07-08 Tyra Biosciences, Inc. Aminopyrimidine compounds

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