WO2021180160A1 - 一种双官能化合物及其制备方法和用途 - Google Patents

一种双官能化合物及其制备方法和用途 Download PDF

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WO2021180160A1
WO2021180160A1 PCT/CN2021/080167 CN2021080167W WO2021180160A1 WO 2021180160 A1 WO2021180160 A1 WO 2021180160A1 CN 2021080167 W CN2021080167 W CN 2021080167W WO 2021180160 A1 WO2021180160 A1 WO 2021180160A1
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halogen
optionally substituted
alkyl
cyano
hydrogen
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PCT/CN2021/080167
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French (fr)
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童友之
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苏州开拓药业股份有限公司
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Priority to EP21768133.7A priority Critical patent/EP4119546A1/en
Publication of WO2021180160A1 publication Critical patent/WO2021180160A1/zh
Priority to US17/942,094 priority patent/US20230054270A1/en

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Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a bifunctional compound and a preparation method and application thereof, wherein the bifunctional compound comprises a binding part that is bound to E3 ubiquitin ligase; a target protein binding part that is bound to androgen receptor; and E3 The linking part where the ubiquitin ligase binding part and the target protein binding part are connected.
  • the bifunctional compound of the present application enables the androgen receptor to be positioned adjacent to the ubiquitin ligase to achieve degradation or inhibition of the androgen receptor.
  • Androgen receptor belongs to the family of nuclear hormone receptors activated by androgens. In the absence of androgens, AR is bound by heat shock protein 90 (Hsp90) in the cytosol. When androgen binds to AR, its conformation changes to release AR from Hsp90 and expose the nuclear localization signal (NLS). The latter enables the transfer of AR into the nucleus, and AR acts as a transcription factor to promote the expression of genes responsible for male sex characteristics. AR deficiency can lead to androgen insensitivity syndrome.
  • Hsp90 heat shock protein 90
  • NLS nuclear localization signal
  • AR is responsible for the development of male sex characteristics, it is also a well-documented oncogene in certain forms of cancer, such as prostate cancer.
  • One commonly measured target gene for AR activity is the secreted prostate specific antigen (PSA) protein.
  • PSA prostate specific antigen
  • Current treatment options for prostate cancer include two options. The first strategy relies on the reduction of androgens, while the second strategy aims to inhibit AR function.
  • An alternative approach for the treatment of prostate cancer involves the elimination of the AR protein. Because AR is a key driver of tumorigenesis in many forms of prostate cancer, its elimination will result in a therapeutically beneficial response.
  • the present invention provides a bifunctional compound whose function is to recruit endogenous proteins to E3 ubiquitin ligase for degradation.
  • the present invention provides bifunctional compounds or proteolytic targeted chimeric (PROTAC) compounds, which are used as modulators of targeted ubiquitination and degradation of androgen receptor (AR).
  • the present invention provides a method of using an effective amount of a compound as described herein for the treatment or amelioration of disease conditions (including cancer, for example, prostate cancer and Kennedy's disease).
  • the present invention provides compounds that function to recruit endogenous proteins (eg, AR proteins) to E3 ubiquitin ligase for ubiquitination and degradation.
  • endogenous proteins eg, AR proteins
  • ABM has a structure of formula (IV), where Indicates the connection point of the connection part:
  • Z 1 is selected from: hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by one or more halogens, and C 1-4 alkane optionally substituted by one or more halogens Oxy;
  • X is selected from: halogen, hydroxyl, cyano and C 1-4 alkoxy optionally substituted by one or more halogens;
  • Y 1 and Y 2 are each independently selected from: O, S;
  • R 1, R 2 are each independently selected from: H, halogen, optionally substituted by halogen, C 1-6 alkoxy substituted C 1-6 alkyl or C 1-6 alkoxy, or R 1, R 2 Together with the atoms to which they are attached, a 3- to 8-membered ring containing 0 to 2 heteroatoms is formed;
  • W 1 is selected from: chemical bond, C 6-10 aryl, 5-10 membered heteroaryl, bi C 6-10 aryl or bi 5-10 membered heteroaryl, each of which is optionally substituted by 1-10 R W1 replace;
  • Each R W1 is independently selected from: H, halo, cyano, hydroxyl, amine, -COOR W11 , -CONR W11 R W12 , optionally substituted by halogen, hydroxyl, cyano, C 1-6 alkoxy C 1-6 alkyl or C 1-6 alkoxy, C 3-6 cycloalkyl, C 4-6 cycloheteroalkyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R W11 And R W12 are each independently selected from: hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl optionally substituted by halogen;
  • L is the chemical linking part connecting ABM and ULM;
  • ULM is hydroxycerebroside E3 ubiquitin ligase binding part (CLM) or VHLE3 ligase binding part (VLM).
  • the bifunctional compound is a bifunctional compound of the following formula I, and salts, polymorphs, and prodrugs thereof:
  • ABM is the androgen receptor (AR) binding part
  • L is the chemical linking part connecting ABM and ULM
  • ULM is the E3 ligase binding part, for example, hydroxycerebroside E3 ubiquitin ligase binding part (CLM) or VHLE3 Ligase binding part (VLM).
  • CLM hydroxycerebroside E3 ubiquitin ligase binding part
  • VLM VHLE3 Ligase binding part
  • the ABM has a structure of formula (IV), wherein Indicates the connection point of the connection part:
  • Z 1 is selected from: hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by one or more halogens, and C 1-4 alkane optionally substituted by one or more halogens Oxy;
  • X is selected from: halogen, hydroxyl, cyano and C 1-4 alkoxy optionally substituted by one or more halogens;
  • Y 1 and Y 2 are each independently selected from: O, S;
  • R 1, R 2 are each independently selected from: hydrogen, halogen, optionally substituted by halogen, C 1-6 alkoxy substituted C 1-6 alkyl or C 1-6 alkoxy, or R 1, R 2 Together with the atoms to which they are attached, a 3- to 8-membered ring containing 0 to 2 heteroatoms is formed;
  • W 1 is selected from: chemical bond, C 6-10 aryl, 5-10 membered heteroaryl, bi C 6-10 aryl or bi 5-10 membered heteroaryl, each of which is optionally substituted by 1-10 R W1 replace;
  • Each R W1 is independently selected from: hydrogen, halo, cyano, hydroxy, amino, optionally substituted with halo, hydroxy, cyano, C 1-6 alkoxy C 1-6 alkyl group or a C 1 -6 alkoxy, C 3-6 cycloalkyl, C 4-6 cycloheteroalkyl, C 6-10 aryl or 5-10 membered heteroaryl.
  • Z 1 is selected from halogen, cyano, methyl, CH 2 F, CHF 2 , CF 3 , methoxy, and CF 3 O;
  • X is selected from: halogen, hydroxyl, cyano, C 1-3 alkoxy and CF 3 O;
  • Y 1 and Y 2 are each independently selected from: O, S;
  • R 1 and R 2 are each independently selected from: C 1-6 alkyl or C 1-6 alkoxy optionally substituted by halogen, C 1-6 alkoxy, or R 1 , R 2 together with them Atoms of together form a C 3-6 cycloalkyl group;
  • W 1 is selected from: chemical bond, C 6-10 aryl group, 5-10 membered heteroaryl group, bi-C 6-10 aryl group or bi-C 6-10 membered heteroaryl group, each of which is optionally substituted by 1, 2 or 3 R W1 replaced; and
  • Each R W1 is independently selected from: hydrogen, halo, cyano, C 1-6 alkyl or C 1-6 alkoxy optionally substituted by halogen, hydroxy, cyano.
  • W 1 is selected from the group consisting of: chemical bond, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, each of which is optionally substituted with 1, 2, or 3 R W1 ; and
  • Each R W1 is independently selected from: hydrogen, halo, cyano, C 1-6 alkyl or C 1-6 alkoxy optionally substituted by halogen, hydroxyl, cyano, -COOR W11 , -CONR W11 R W12 ; R W11 and R W12 are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen.
  • Z 1 is selected from halogen, cyano, methyl, CH 2 F, CHF 2 , CF 3 , methoxy, and CF 3 O;
  • X is selected from: halogen, hydroxyl, cyano, C 1-3 alkoxy and CF 3 O;
  • Y 1 and Y 2 are each independently selected from: O, S;
  • R 1 and R 2 are each independently selected from: C 1-6 alkyl or C 1-6 alkoxy optionally substituted by halogen, C 1-6 alkoxy, or R 1 , R 2 together with them Atoms of together form a C 3-6 cycloalkyl group;
  • W 1 is selected from: chemical bond, C 6-10 aryl group, 5-10 membered heteroaryl group, bi-C 6-10 aryl group or bi-C 6-10 membered heteroaryl group, each of which is optionally substituted by 1, 2 or 3 R W1 replaced; and
  • Each R W1 is independently selected from: hydrogen, halo, cyano, C 1-6 alkyl or C 1-6 alkoxy optionally substituted by halogen, hydroxyl, cyano, -COOR W11 , -CONR W11 R W12 ; R W11 and R W12 are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen.
  • Z 1 is selected from: halogen, cyano, methyl, CH 2 F, CHF 2 , CF 3 , methoxy, and CF 3 O;
  • X is selected from: halogen
  • Y 1 and Y 2 are each independently selected from: O, S;
  • R 1 and R 2 are each independently selected from: methyl, or R 1 and R 2 together with the atoms to which they are attached form a C 3-6 cycloalkyl group;
  • W 1 is selected from: chemical bond, Each of which is optionally substituted with 1, 2, or 3 R W1 ;
  • Each R W1 is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl or C 1-3 alkoxy optionally substituted by halogen.
  • Z 1 is selected from: halogen, cyano, methyl, CH 2 F, CHF 2 , CF 3 , methoxy, and CF 3 O;
  • X is selected from: halogen
  • Y 1 and Y 2 are each independently selected from: O, S;
  • R 1 and R 2 are each independently selected from: methyl, or R 1 and R 2 together with the atoms to which they are attached form a C 3-6 cycloalkyl group;
  • W 1 is selected from: chemical bond, Each of which is optionally substituted with 1, 2, or 3 R W1 ;
  • Each R W1 is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl or C 1-3 alkoxy optionally substituted by halogen, -COOR W11 , -CONR W11 R W12 ; R W11 And R W12 are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen.
  • Z 1 is selected from: CF 3 ;
  • X is selected from: F;
  • Y 1 and Y 2 are each independently selected from: O, S;
  • R 1 and R 2 are each independently selected from: methyl, or R 1 and R 2 together with the atoms to which they are attached form a C 3-4 cycloalkyl group;
  • W 1 is selected from: chemical bond, Each of which is optionally substituted with 1, 2, or 3 R W1 ;
  • Each R W1 is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl optionally substituted with F, or C 1-3 alkoxy.
  • Z 1 is selected from: CF 3 ;
  • X is selected from: F;
  • Y 1 and Y 2 are each independently selected from: O, S;
  • R 1 and R 2 are each independently selected from: methyl, or R 1 and R 2 together with the atoms to which they are attached form a C 3-4 cycloalkyl group;
  • W 1 is selected from: chemical bond, Each of which is optionally substituted with 1, 2, or 3 R W1 ;
  • Each R W1 is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl or C 1-3 alkoxy optionally substituted by F, -CONH 2 , -COOC 1-3 alkyl.
  • ABM is selected from the following compound fragments, wherein Indicates the connection point of the connection part:
  • ABM is selected from the following compound fragments, wherein Indicates the connection point of the connection part:
  • the present invention provides a bifunctional compound with the structure of formula (II), and salts, polymorphs and prodrugs thereof:
  • ABM is the androgen receptor (AR) binding part
  • L is the chemical linking part connecting ABM and CLM
  • CLM is the hydroxycerebroside E3 ubiquitin ligase binding part.
  • ABM is defined as above.
  • the CLM comprises a chemical group derived from an imide, thioimide, amide, or thioamide, which is bound to the hydroxycerebroside E3 ubiquitin ligase.
  • CLM is a phthalimide group or an analog thereof.
  • CLM is a structural fragment represented by formula (V) or a stereoisomer thereof, wherein Indicates the connection point of the connection part:
  • Each T is independently selected from: O or S;
  • G is selected from: hydrogen, C 1-6 alkyl or hydroxyl
  • Q 1 , Q 2 , Q 3 and Q 4 are independently selected from: CR' or N;
  • A is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or halogen;
  • R 11 is selected from: halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy optionally substituted by halogen, C 3-6 cycloalkyl, -CONR'R", -OR', or -NR'R";
  • R'and R" are each independently selected from: hydrogen, halogen, amine, cyano, C 1-6 alkyl or C 1-6 alkoxy optionally substituted by halogen, C 3-6 cycloalkyl.
  • Each T is independently selected from: O or S;
  • G is selected from: hydrogen, or C 1-6 alkyl
  • Q 1 , Q 2 , Q 3 and Q 4 are independently selected from: CH;
  • A is selected from: hydrogen, C 1-6 alkyl or halogen
  • R 11 is selected from: halogen, cyano, -CF 3 , OCF 3 , methyl, -CONR'R", -OR', or -NR'R";
  • R'and R" are each independently selected from: hydrogen, halogen, cyano, amine, -CF 3 , OCF 3 or methyl.
  • CLM is a structural fragment represented by formula (V)-1 or a stereoisomer thereof, wherein Indicates the connection point of the connection part::
  • A is selected from: hydrogen or C 1-6 alkyl.
  • CLM is a structural fragment represented by formula (V)-2 or (V)-3 or a stereoisomer thereof, wherein Indicates the connection point of the connection part:
  • CLM is a fragment of thalidomide, lenalidomide, pomalidomide, or an analog thereof.
  • linking group (L) is selected from the group represented by the following general structure:
  • m, n, o, p, q and t are each independently selected from: 0, 1, 2, 3, 4, 5, 6, provided that when the number is zero, there is no NO or OO bond,
  • Each R 31 is independently selected from the group hydrogen, methyl or ethyl, and Cy is selected from C 6-10 aryl, C 3-6 heteroaryl, C 3-6 cycloalkyl, C 3-6 heterocycloalkane Base, preferably Each of which is optionally substituted with 1, 2, or 3 R Cy ; and
  • Each R Cy is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl or C 1-3 alkoxy optionally substituted by halogen.
  • linking group (L) is selected from the group represented by the following general structure:
  • m, n, o, p, and q are each independently selected from: 0, 1, 2, 3, 4, 5, 6, provided that when the number is zero, there is no NO or OO bond, and each R 31 is independently selected from the group hydrogen, methyl or ethyl, Cy is selected from C 3-6 aryl, C 3-6 heteroaryl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, Preferred Each of which is optionally substituted with 1, 2, or 3 R Cy ; and
  • Each R Cy is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl or C 1-3 alkoxy optionally substituted by halogen.
  • the linking group (L) is selected from the group:
  • the linking group (L) is selected from the group:
  • the present invention provides compounds having the structure of formula (III), and salts, polymorphs and prodrugs thereof:
  • ABM is as defined above;
  • VLM is a structural fragment represented by formula (VI) or its stereoisomers:
  • Y 3 is NR Y3 R Y4 , OR Y3 , SR Y3 ,
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano ;
  • R Y3 and R Y4 are independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano , C 1-6 alkyl-CO- optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl-CO- optionally substituted by halogen, hydroxy, cyano; or R Y3 , R 21 and the carbon atom and nitrogen atom to which they are attached together form an optionally substituted 5-6 membered heterocycloalkyl group;
  • X Y3 is O or S
  • R 23 and R 24 are each independently selected from: H, C 1-6 alkyl optionally substituted by halogen, hydroxy, and cyano;
  • W 2 is C 6-10 aryl or 5-10 membered heteroaryl
  • R 25 is hydrogen, halogen, cyano, hydroxy, nitro, C1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C1-6 alkoxy optionally substituted by halogen, hydroxy, cyano Group, NR25aR25b, CONR25aR25b, C6-10 aryl, 6-10 membered heteroaryl, thienyl, or Wherein R 25a and R 25b are each independently selected from: H, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano; R 27 is H, halogen, optionally halogen, hydroxy, cyano A substituted C 1-6 alkyl group, and Xa is S, O or NR 28 ; R 28 is hydrogen, a C 1-6 alkyl group optionally substituted by halogen; the C6-10 aryl group, 6-10 member Heteroaryl and thienyl are optionally substituted by one or more C 1-6 alkyl groups selected from hydrogen, hal
  • R 26 is hydrogen, halo, cyano, hydroxy, nitro, optionally substituted with halogen, hydroxy, cyano-substituted C 1-6 alkyl, optionally substituted by halogen, hydroxy, cyano, C 1-6 Alkoxy;
  • the present invention provides compounds having the structure of formula (III), and salts, polymorphs and prodrugs thereof:
  • ABM is the AR binding part
  • L is the chemical linking part connecting ABM and VLM
  • VLM is the VHLE3 ligase binding part.
  • the VLM comprises a hydroxyprolyl moiety.
  • ABM is defined as above;
  • VLM is a structural fragment represented by formula (VI) or its stereoisomers:
  • Y 3 is NR Y3 R Y4 , OR Y3 , SR Y3 ;
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano ;
  • R Y3 and R Y4 are independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano , C 1-6 alkyl-CO- optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl-CO- optionally substituted by halogen, hydroxy, cyano; or R Y3 , R 21 and the carbon atom and nitrogen atom to which they are attached together form an optionally substituted 5-6 membered heterocycloalkyl group;
  • R 23 and R 24 are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, and cyano;
  • W 2 is C 6-10 aryl or 5-10 membered heteroaryl
  • R 25 is hydrogen, halo, cyano, hydroxy, nitro, optionally substituted with halogen, hydroxy, cyano-substituted C 1-6 alkyl, optionally substituted by halogen, hydroxy, cyano, C 1-6 Alkoxy, NR 25a R 25b , CONR 25a R 25b , C 6-10 aryl, or Wherein R 25a and R 25b are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano; R 27 is hydrogen, halogen, optionally halogen, hydroxy, cyano Substituted C 1-6 alkyl, and Xa is S or O;
  • R 26 is hydrogen, halo, cyano, hydroxy, nitro, optionally substituted with halogen, hydroxy, cyano-substituted C 1-6 alkyl, optionally substituted by halogen, hydroxy, cyano, C 1-6 Alkoxy;
  • Y 3 is NR Y3 R Y4 , OR Y3 ;
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl
  • R Y3 and R Y4 are independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano -CO-; or R Y3 , R 21 and the carbon atom and nitrogen atom to which they are attached together form an optionally substituted 5-6 membered heterocycloalkyl group;
  • R 23 and R 24 are each independently selected from: hydrogen, C 1-6 alkyl
  • W 2 is phenyl
  • R 25 is hydrogen, halogen, C 1-6 alkyl, CONR 25a R 25b , or Wherein R 25a and R 25b are each independently selected from: hydrogen, C 1-6 alkyl; R 27 is hydrogen, C 1-6 alkyl, and Xa is S;
  • R 26 is hydrogen, C 1-6 alkyl.
  • Y 3 is NR Y3 R Y4 , OR Y3 ;
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl
  • R Y3 and R Y4 are independently selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl-CO- optionally substituted by halogen, hydroxyl, cyano ; or R Y3 , R 21 and these The attached carbon atom and the nitrogen atom together form an optionally substituted 5-membered heterocycloalkyl group;
  • R 23 and R 24 are each independently selected from: hydrogen, C 1-6 alkyl
  • W 2 is phenyl
  • R 25 is CONR 25a R 25b , or Wherein R 25a and R 25b are each independently selected from: hydrogen, C 1-6 alkyl; R 27 is C 1-6 alkyl, and Xa is S;
  • R 26 is hydrogen
  • Y 3 is
  • R Y3 is selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, and C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano;
  • X Y3 is O or S.
  • the VLM is selected from the following structural fragments or stereoisomers thereof, wherein Indicates the connection point of the connection part:
  • VLM is a structural fragment represented by formula (VI)-1 or a stereoisomer thereof:
  • Y 3 , R 21 , R 23 and R 25 are as defined above.
  • VLM is a structural fragment represented by formula (VI)-2 or a stereoisomer thereof:
  • Y 5 is NR Y5 , O;
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano ;
  • R Y5 is hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano, optionally halogen, Hydroxy, cyano substituted C 1-6 alkyl-CO-, optionally halogen, hydroxy, cyano substituted C 3-6 cycloalkyl-CO-; or R Y5 , R 21 and their connected The carbon atom and the nitrogen atom together form an optionally substituted 5-6 membered heterocycloalkyl group;
  • R 23 and R 24 are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, and cyano;
  • W 2 is C 6-10 aryl or 5-10 membered heteroaryl
  • R 25 is hydrogen, halo, cyano, hydroxy, nitro, optionally substituted with halogen, hydroxy, cyano-substituted C 1-6 alkyl, optionally substituted by halogen, hydroxy, cyano, C 1-6 Alkoxy, NR 25a R 25b , CONR 25a R 25b , C 6-10 aryl, or Wherein R 25a and R 25b are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano; R 27 is hydrogen, halogen, optionally halogen, hydroxy, cyano Substituted C 1-6 alkyl, and Xa is S or O;
  • R 26 is hydrogen, halo, cyano, hydroxy, nitro, optionally substituted with halogen, hydroxy, cyano-substituted C 1-6 alkyl, optionally substituted by halogen, hydroxy, cyano, C 1-6 Alkoxy.
  • VLM is a structural fragment represented by formula (VI)-2 or a stereoisomer thereof:
  • Y 5 is NR Y5 , O;
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano ;
  • R Y5 is hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano, C 3-6 cycloalkyl optionally substituted by halogen, hydroxy, cyano, optionally halogen, Hydroxy, cyano substituted C 1-6 alkyl-CO-, optionally halogen, hydroxy, cyano substituted C 3-6 cycloalkyl-CO-; or R Y5 , R 21 and their connected The carbon atom and the nitrogen atom together form an optionally substituted 5-6 membered heterocycloalkyl group;
  • R 23 and R 24 are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, and cyano;
  • W 2 is a 5-6 membered heteroaryl group
  • R 25 is hydrogen, halo, cyano, hydroxy, nitro, optionally substituted with halogen, hydroxy, cyano-substituted C 1-6 alkyl, optionally substituted by halogen, hydroxy, cyano, C 1-6 Alkoxy, NR 25a R 25b , CONR 25a R 25b , C 6-10 aryl, 6-10 membered heteroaryl, thienyl, or Wherein R 25a and R 25b are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted by halogen, hydroxy, cyano; R 27 is H, halogen, optionally halogen, hydroxy, cyano A substituted C 1-6 alkyl group, and Xa is S, O or NR 28 ; R 28 is hydrogen, a C 1-6 alkyl group optionally substituted by halogen; the C6-10 aryl group, 6-10 member Heteroaryl and thienyl are optionally selected from hydrogen, halogen, C
  • R 26 is hydrogen, halo, cyano, hydroxy, nitro, optionally substituted with halogen, hydroxy, cyano-substituted C 1-6 alkyl, optionally substituted by halogen, hydroxy, cyano, C 1-6 Alkoxy.
  • Y 5 is NR Y5 , O;
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl
  • R Y5 is hydrogen, C 1-6 alkyl; or R Y5 , R 21 and the carbon atom and nitrogen atom to which they are attached together form an optionally substituted 5-membered heterocycloalkyl group;
  • R 23 and R 24 are each independently selected from: hydrogen, C 1-6 alkyl
  • W 2 is phenyl
  • R 25 is CONR 25a R 25b , or Wherein R 25a and R 25b are each independently selected from: hydrogen, C 1-6 alkyl; R 27 is C 1-6 alkyl, and Xa is S;
  • R 26 is hydrogen
  • R 21 is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, sec-butyl, tert-butyl, n-pentyl Group, isopentyl or neopentyl.
  • Y 5 is NR Y5 , O;
  • R 21 is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or neopentyl;
  • R 22 is selected from: hydrogen
  • R Y5 is hydrogen, C 1-6 alkyl
  • R 23 and R 24 are each independently selected from: hydrogen, C 1-6 alkyl
  • R 25 is Wherein R 27 is a C 1-3 alkyl group, and Xa is S;
  • R 26 is hydrogen
  • Y 5 is NR Y5 , O;
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl
  • R Y5 is hydrogen, C 1-6 alkyl; or R Y5 , R 21 and the carbon atom and nitrogen atom to which they are attached together form an optionally substituted 5-membered heterocycloalkyl group;
  • R 23 and R 24 are each independently selected from: hydrogen, C 1-6 alkyl
  • W 2 is oxazolyl or thiazolyl
  • R 25 is hydrogen
  • R 26 is hydrogen
  • Y 5 is NR Y5 , O
  • R 21 is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or neopentyl;
  • R 22 is selected from: hydrogen
  • R Y5 is hydrogen, C 1-6 alkyl
  • R 23 and R 24 are each independently selected from: hydrogen, C 1-6 alkyl
  • W 2 is oxazolyl or thiazolyl
  • R 25 is hydrogen
  • R 26 is hydrogen
  • the VLM is selected from the following structural fragments or stereoisomers thereof, wherein Indicates the connection point of the connection part:
  • VLM is a structural fragment represented by formula (VI)-3 or a stereoisomer thereof:
  • Y 5 , R 21 , R 23 and R 25 are as defined above.
  • VLM is a structural fragment represented by formula (VI)-4 or (VI)-5 or a stereoisomer thereof:
  • R 21 , R 22 , and Xa are as defined above; R 27a and R 27b are each independently selected from: hydrogen, C 1-6 alkyl.
  • the VLM is selected from the following structural fragments or stereoisomers thereof, wherein Indicates the connection point of the connection part:
  • VLM is a structural fragment represented by formula (VI)-5 or a stereoisomer thereof:
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl
  • R 27a and R 27b are each independently selected from: H, 5-6 membered heteroaryl, preferably H, thiazolyl.
  • the VLM is selected from the following structural fragments or stereoisomers thereof, wherein Indicates the connection point of the connection part:
  • VLM is a structural fragment represented by formula (VI)-61 or a stereoisomer thereof:
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl
  • R 29 is C1-6 alkyl optionally substituted with halogen.
  • the VLM is selected from the following structural fragments or stereoisomers thereof, wherein Indicates the connection point of the connection part:
  • VLM is a structural fragment represented by formula (VI)-71 or formula (VI)-81 or a stereoisomer thereof:
  • R 21 and R 22 are independently selected from: hydrogen, C 1-6 alkyl
  • R 25 is phenyl, pyridyl, pyrimidinyl, thienyl, or R 27 is a C 1-6 alkyl group, and Xa is S, O or NR 28 ; R 28 is a C 1-6 alkyl group; the phenyl, pyridyl, pyrimidinyl, and thienyl groups are optionally substituted by one or more Substitution with a group selected from halogen, C 1-6 alkyl, -CONHC 1-6 alkyl;
  • X V is S, O or NR 29 ; R 29 is hydrogen, C 1-6 alkyl; W is CH.
  • the VLM is selected from the following structural fragments or stereoisomers thereof, wherein Indicates the connection point of the connection part:
  • linking group (L) is selected from groups represented by the following general structure:
  • each R 31 is independently selected from the group hydrogen, methyl, ethyl, or benzyl
  • Cy is selected from C 6-10 aryl, C 3-6 heteroaryl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, preferably Each of which is optionally substituted with 1, 2, or 3 R Cy ;
  • Each R Cy is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl or C 1-3 alkoxy optionally substituted by halogen.
  • linking group (L) is selected from groups represented by the following general structure:
  • n, o, p and q are each independently selected from: 0, 1, 2, 3, 4, 5, 6, provided that when the number is zero, there is no NO or OO bond, and each R 31 is independently selected from the group hydrogen, methyl, ethyl, or benzyl, Cy is selected from C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, preferably Each of which is optionally substituted with 1, 2, or 3 R Cy ; and
  • Each R Cy is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl or C 1-3 alkoxy optionally substituted by halogen.
  • Cy is selected from C 6-10 aryl, C 3-6 heteroaryl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, preferably phenyl, pyridine Group, triazolyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, oxopiperazinyl, tetrahydropyridyl, oxodihydropyridyl, more preferred Each of which is optionally substituted with 1, 2, or 3 R Cy ; and
  • Each R Cy is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl optionally substituted by halogen.
  • the linking group (L) is selected from the following groups:
  • m, n and o are each independently selected from: 1, 2, 3, 4, 5, 6, q is selected from: 1, Cy is selected from C 6-10 aryl, C 3-6 heteroaryl, C 3 -6 cycloalkyl, C 3-6 heterocycloalkyl, preferably phenyl, pyridyl, triazolyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, oxopiperazinyl , Tetrahydropyridyl, oxodihydropyridyl, more preferred Each of which is optionally substituted with 1, 2, or 3 R Cy ; and
  • Each R Cy is independently selected from: hydrogen, halo, cyano, C 1-3 alkyl optionally substituted by halogen.
  • the linking group (L) is selected from the group:
  • the linking group (L) is selected from the group:
  • compositions comprising an effective amount of the bifunctional compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier of the present invention includes ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances (e.g., phosphate, glycine, sorbic acid, potassium sorbate), partial fatty acids of saturated plants Glyceride mixture, water, salt or electrolyte.
  • buffer substances e.g., phosphate, glycine, sorbic acid, potassium sorbate
  • partial fatty acids of saturated plants Glyceride mixture water, salt or electrolyte.
  • the active compound is prepared with a carrier that protects the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a carrier that protects the compound against rapid elimination from the body
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. The methods used to prepare such formulations will be obvious to those skilled in the art.
  • the liposome suspension can also be a pharmaceutically acceptable carrier, and the liposome formulation can be prepared as follows: appropriate lipids (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachidonic phospholipid Acylcholine and cholesterol) are dissolved in an inorganic solvent and then evaporated, leaving a thin film of dry lipid on the surface of the container. The aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to detach the lipid material from the sides of the container, and the lipid aggregates are dispersed, thereby forming a liposome suspension.
  • appropriate lipids such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachidonic phospholipid Acylcholine and cholesterol
  • the composition further comprises at least one other biologically active agent.
  • the bioactive agent is an anticancer agent.
  • Another aspect of the present invention provides a therapeutic composition comprising an effective amount of at least two different compounds of the present invention.
  • Another aspect of the present invention provides a method for recruiting endogenous proteins to E3 ubiquitin ligase for degradation in a subject in need thereof, the method comprising administering the compound of the present invention.
  • Another aspect of the present invention provides a method of degrading or inhibiting the androgen receptor in a subject in need thereof, the method comprising administering the compound of the present invention.
  • Another aspect of the present invention provides a method for treating a disease or condition in a subject, which comprises the following steps: administering a composition to a subject in need, the composition comprising a pharmaceutically acceptable carrier and an effective The amount of the compound of the present invention.
  • the disease or condition is acne, hirsutism, enlarged sebaceous glands, alopecia, asthma, multiple sclerosis, cancer, Kenney's disease, ciliary disease, cleft palate, diabetes, heart disease , High blood pressure, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome (Angelman syndrome), Canavandisease, celiac disease, summer horse -Charcot-Marie-Toothdisease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter's syndrome, neurofibromatosis, phenylketonuria Syndrome, polycystic kidney disease (PKD1) or 4 (PKD2), Prader-Willisyndrome, sickle cell disease, Tay-Sachsdisease, Turner syndrome Disease (Turnersyndrome).
  • PDD1 or 4 polycystic kidney disease
  • the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma; bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, Cancer of the ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, especially Burkitt's lymphoma (Burkitt's lymphoma) and non-Hodgkin's lymphoma (Non-Hodgkin's lymphoma); benign and malignant melanomas ; Myeloproliferative diseases; Sarcoma, including Ewing's sarcoma (Ewing' ssarcoma), hemangioendothelioma, Kaposi's sarcoma (Kaposi' ssarcoma), liposarcoma, sarcoma, peripheral neuroepithelioma, synovial sarcom
  • the disease or condition is cancer, acne, hirsutism, enlarged sebaceous glands, alopecia, or Kennedy's disease.
  • the disease or condition is prostate cancer, acne or hair loss.
  • the instructions provide a therapeutic composition
  • a therapeutic composition comprising an effective amount of a compound according to the invention or a salt form thereof and a pharmaceutically acceptable carrier.
  • the therapeutic composition regulates protein degradation in a patient or subject, and can be used to treat or ameliorate disease states or conditions regulated by the degraded protein.
  • the therapeutic composition according to the present invention can be used to achieve degradation and/or inhibition of the protein of interest in order to treat or ameliorate diseases, such as cancer.
  • hydrocarbyl shall refer to compounds that contain carbon and hydrogen and can be fully saturated, partially unsaturated or aromatic and include aryl, alkyl, alkenyl and alkynyl groups.
  • alkyl in its context shall refer to a linear, branched or cyclic fully saturated hydrocarbon group or alkyl group which may be optionally substituted, preferably C 1 -C 10 , more preferably C 1 -C 6 , or C 1 -C 3 alkyl.
  • alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl Group, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, cyclohexyl and so on.
  • alkynyl refers to a straight, branched or cyclic C 2 -C 10 (preferably C 2 -C 6 ) hydrocarbon group containing at least one C ⁇ C bond.
  • alkylene when used refers to a -(CH 2 ) n -group that may be optionally substituted (n is generally an integer of 0-6).
  • the alkylene group is preferably substituted by a C 1 -C 6 alkyl group (including cyclopropyl or tert-butyl) on one or more methylene groups, and may be substituted by one or more halo groups (preferably 1 To 3 halo groups) or one or two hydroxy groups or C 1-6 alkyloxy groups.
  • unsubstituted shall refer to replacement by hydrogen atoms only.
  • substituents can be: hydroxyl, thiol, carboxyl, cyano, nitro, halogen (preferably 1, 2 or 3 halogens, especially on alkyl groups, especially methyl groups, such as trifluoromethyl) , Alkyl (preferably C 1 -C 10 , more preferably, C 1 -C 6 ), haloalkyl, aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy Group (preferably C 1 -C 6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C 1 -C 6 alkyl or aryl), acyl (preferably C 1 -C 6 acyl) , C
  • aryl refers to a substituted or unsubstituted C6-C16 aromatic group having a single ring (such as phenyl) or a condensed ring (such as naphthyl, anthryl, phenanthryl, etc.), preferably C6-C10 Aromatic group.
  • heteroaryl refers to a 5-16 membered aromatic group containing at least one heteroatom (such as N, O or S), preferably a 5-10 membered aromatic group, and may refer to optionally substituted quinoline Morpholine, optionally substituted indole, optionally substituted indoleazine, optionally substituted azaindoleazine, optionally substituted benzimidazole, benzodiazole, benzo Furan, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably substituted by methyl), optionally substituted diazole, optionally substituted Triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably substituted by methyl and/or thiol), optionally substituted An isothiazole, an optionally substituted triazole, an optionally substituted pyridine (2-pyridine,
  • aralkyl and heteroarylalkyl refer to groups containing aryl or heteroaryl, respectively, as well as alkyl and/or heteroalkyl and/or carbocyclic and/or hetero Cycloalkyl ring system.
  • heterocyclyl refers to a 3-10 membered ring group containing at least one heteroatom (such as N, O or S), preferably a 3-6 membered ring group, and can be aromatic (heteroaryl) or non-aromatic Family.
  • azetidinyl benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazole Group, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolane, ethylene urea, 1,3-dioxolane Alkyl, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl , Isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolidinyl, morpholinyl, naphthyridinyl, oxazolidinyl, ox
  • cycloalkyl refers to a C 3 -C 20 monocyclic or polycyclic alkyl group, preferably a C 3 -C 15 monocyclic or polycyclic alkyl group, most preferably a C 3 -C 10 monocyclic or polycyclic alkyl group
  • Alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Heterocycloalkyl refers to a 3-20 membered monocyclic or polycyclic alkyl group, preferably a 3-15 membered monocyclic or polycyclic alkyl group, most preferably a 3-10 membered monocyclic or polycyclic alkyl group, , Wherein at least one ring carbon atom in its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S or P.
  • Halogen refers to F, Cl, Br, I.
  • pharmaceutically acceptable salt is used to describe the salt form of one or more of the compounds described herein, which is provided to increase the solubility of the compound in the gastric juice of the patient's gastrointestinal tract in order to promote the dissolution and biological activity of the compound.
  • Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids where applicable. Suitable salts include those derived from alkali metals (e.g., potassium and sodium), alkaline earth metals (e.g., calcium, magnesium, and ammonium salts), and many other acids and bases well known in the pharmaceutical arts.
  • the acid used in the preparation of the pharmaceutically acceptable acid addition salt suitable for the present invention is an acid that forms a non-toxic acid addition salt, that is, a salt containing a pharmacologically acceptable anion, such as hydrochloride, hydrobromic acid Salt, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, tartrate, hydrogen tartrate Salt, succinate, maleate, fumarate, gluconate, glucarate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate Acid salts, p-toluenesulfonate and pamoate salts, as well as many other salts.
  • a pharmacologically acceptable anion such as hydrochloride, hydrobromic acid Salt, hydroiodide, nitrate, sulfate, bisulfate,
  • the term "effective” can mean, but is not limited to, the amount/dosage of the active pharmaceutical ingredient, which when used in the context of its intended use, achieves or is sufficient to prevent the condition in subjects in need of such treatment or receiving such treatment , Disease or disease state, inhibit its occurrence, improve, delay or treat its symptoms (to a certain extent, it is preferable to completely relieve the symptoms).
  • pharmaceutically acceptable carrier may mean any and all solvents, dispersion media, coatings, antibacterial and antibacterial, etc. compatible with drug administration.
  • the term “compound” refers to any specific compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (to Enantiomers) and other stereoisomers (diastereomers), as well as their pharmaceutically acceptable salts and derivatives (including prodrug forms).
  • the term compound generally refers to not only a single compound, but also other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures), as well as the disclosed compounds Specific enantiomers or enantiomers enriched mixtures.
  • the term also refers to the prodrug form of the compound in this context, which has been modified to facilitate the administration and delivery of the compound to the active site.
  • Figure 1 shows the results of the degradation experiment of the compound of the present invention on the AR protein of LNCaP cells
  • Figure 2 is the PK/PD experimental result of the compound of the present invention on transplanted tumors in LNCaP mice;
  • Figure 3 is the result of the compound of the present invention inhibiting the growth of sebaceous gland spots in female golden hamsters
  • Figure 4 shows the effect of the compound of the present invention and its control drug on the body weight of golden hamsters on the 21st day after administration;
  • Figure 5 is a graph showing the effect of the compound of the present invention and its control drug on the body weight of C57BL/6 mice after administration;
  • Figure 6 is a comparison of the results of the degradation experiment of the compound A279 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells;
  • Figure 7 is a comparison of the experimental results of the degradation of the AR protein of LNCaP cells by the compound A283-A286 of the present invention and the positive compound ARD-69;
  • Figure 8 is a comparison of the results of the degradation experiment of the compound A288 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells;
  • Figure 9 is a comparison of the results of the degradation experiment of the compound A307 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells;
  • Figure 10 is a comparison of the results of the degradation experiment of the compound A308 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells;
  • Figure 11 is a comparison of the results of the degradation experiment of the compound A309-A313 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells;
  • Figure 12 is a comparison of the results of the degradation experiment of the compounds A314, A315, A317 and A318 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells;
  • Figure 13 is a comparison of the results of the degradation experiment of the compounds A320-A324 and A318 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells;
  • Figure 14 is a comparison of the results of the degradation experiment of the compounds A340 and A318 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells;
  • Figure 15 is a comparison of the experimental results of the degradation of the AR protein of LNCaP cells by the compounds A347-A351 and A318 of the present invention and the positive compound ARD-69;
  • Figure 16 is a comparison of the results of the degradation experiment of the compounds A352-A354 and A318 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells;
  • Figure 17 is a comparison of the results of the degradation experiment of the compounds A357-A358 and A318 of the present invention and the positive compound ARD-69 on the AR protein of LNCaP cells.
  • Examples A2-A45 adopt the similar operation as that of Example A1, and synthesize with the corresponding reagents.
  • Examples A47-A142 were synthesized using the same operation as that of Example A1 and the corresponding reagents.

Abstract

本发明涉及一种双官能化合物及其制备方法和用途，其中双官能化合物包含结合到E3泛素连接酶结合部分；结合到雄激素受体的靶蛋白结合部分；和将E3泛素连接酶结合部分和靶蛋白结合部分连接的连接部分。本申请双官能化合物使雄激素受体邻近泛素连接酶定位，以实现雄激素受体的降解或抑制。

Description

一种双官能化合物及其制备方法和用途
本申请要求于2020年3月11日提交中国专利局、申请号为202010165789.1、发明名称为“一种双官能化合物及其制备方法和用途”，2020年12月29日提交中国专利局、申请号为202011593015.5、发明名称为“一种双官能化合物及其制备方法和用途”，2021年3月5日提交中国专利局、申请号为202110246427.X、发明名称为“一种双官能化合物及其制备方法和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物领域，具体涉及一种双官能化合物及其制备方法和用途，其中双官能化合物包含结合到E3泛素连接酶结合部分；结合到雄激素受体的靶蛋白结合部分；和将E3泛素连接酶结合部分和靶蛋白结合部分连接的连接部分。本申请双官能化合物使雄激素受体邻近泛素连接酶定位，以实现雄激素受体的降解或抑制。
背景技术
雄激素受体(AR)属于被雄激素活化的细胞核激素受体家族。在没有雄激素存在下，AR被胞质溶胶中的热休克蛋白90(Hsp90)结合。当雄激素结合AR时，它的构象变成从Hsp90释放AR并暴露核定位信号(NLS)。后者能使AR转移进细胞核中，AR作为转录因子起作用以促进负责雄性性别特征的基因表达。AR缺乏会导致雄激素不敏感综合征。
尽管AR负责雄性性别特征的发育，它也是某些形式的癌症中充分记载的癌基因，例如前列腺癌。AR活性的一种通常测量的靶基因是分泌的前列腺特异性抗原(PSA)蛋白。前列腺癌的当前治疗方案包括两种方案。第一个方案依赖于雄激素的减少，而第二个策略目标在于抑制AR功能。尽管开发了有效的靶向疗法，大多数患者发生抗药性，且疾病持续进展。用于治疗前列腺癌的一个替代方案包括消除AR蛋白。因为AR是许多形式的前列腺癌中的肿瘤发生的关键驱动器，它的消除将会导致治疗上有益的应答。
本领域中继续需要与异常AR调节或活性有关的疾病和病症(例如，癌症、前列腺癌和肯尼迪氏病的有效治疗。
发明内容
本发明提供一种双官能化合物，其作用是将内源蛋白质募集到E3泛素连接酶进行降解。具体地，本发明提供了双功能化合物或蛋白酶解靶向嵌合(PROTAC)化合物，其用作雄激素受体(AR)的靶向泛素化和降解的调节剂。另外，本发明提供了使用有效量的如本文中所述的化合物用于治疗或改善疾病状况(包括癌症，例如，前列腺癌和肯尼迪氏病)的方法。
在一个方面，本发明提供了起将内源性蛋白(例如，AR蛋白)募集至E3泛素连接酶用于泛素化和降解的作用的化合物。
在某些实施方案中，式(I)所示的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药：
ABM-L-ULM(I)，
其中ABM具有式(IV)结构，其中
Figure PCTCN2021080167-appb-000001
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000002
Z 1选自：氢、卤素、氰基、任选地被一个或更多个卤素所取代的C 1-4烷基和任选地被一个或更多个卤素所取代的C 1-4烷氧基；
X选自：卤素、羟基、氰基和任选地被一个或更多个卤素所取代的C 1-4烷氧基；
Y 1、Y 2各自独立地选自：O、S；
R 1、R 2各自独立地选自：H、卤素、任选被卤素、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，或R 1、R 2连同它们所连接的原子一起形成含有0到2个杂原子的3到8元环；
W 1选自：化学键，C 6-10芳基，5-10元杂芳基、联C 6-10芳基或联5-10元杂芳基，各自任选地被1-10个R W1取代；
每个R W1独立地选自：H、卤基、氰基、羟基、胺基、-COOR W11、-CONR W11R W12、任选被卤素、羟基、氰基、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，C 3-6环烷基、C 4-6环杂烷基、C 6-10芳基或5-10元杂芳基；R W11和R W12各自独立地选自：氢、任选被卤素取代的C 1-6烷基或C 3-6环烷基；
L是连接ABM和ULM的化学连接部分；
ULM是羟脑苷脂E3泛素连接酶结合部分(CLM)或VHLE3连接酶结合部分(VLM)。
在某些实施方案中，双官能化合物为下述式I结构的双官能化合物，及其盐、多晶型物和前药：
ABM-L-ULM    (I)，
其中ABM是雄激素受体(AR)结合部分，L是连接ABM和ULM的化学连接部分，ULM是E3连接酶结合部分，例如，羟脑苷脂E3泛素连接酶结合部分(CLM)或VHLE3连接酶结合部分(VLM)。
所述ABM具有式(IV)结构，其中
Figure PCTCN2021080167-appb-000003
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000004
其中：
Z 1选自：氢、卤素、氰基、任选地被一个或更多个卤素所取代的C 1-4烷基和任选地被一个或更多个卤素所取代的C 1-4烷氧基；
X选自：卤素、羟基、氰基和任选地被一个或更多个卤素所取代的C 1-4烷氧基；
Y 1、Y 2各自独立地选自：O、S；
R 1、R 2各自独立地选自：氢、卤素、任选被卤素、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，或R 1、R 2连同它们所连接的原子一起形成含有0到2个杂原子的3到8元环；
W 1选自：化学键，C 6-10芳基，5-10元杂芳基、联C 6-10芳基或联5-10元杂芳基，各自任选地被1-10个R W1取代；
每个R W1独立地选自：氢、卤基、氰基、羟基、胺基、任选被卤素、羟基、氰基、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，C 3-6环烷基、C 4-6环杂烷基、C 6-10芳基或5-10元杂芳基。
在某些实施方案中，Z 1选自卤素、氰基、甲基、CH 2F、CHF 2、CF 3、甲氧基和CF 3O；
X选自：卤素、羟基、氰基、C 1-3烷氧基和CF 3O；
Y 1、Y 2各自独立地选自：O、S；
R 1、R 2各自独立地选自：任选被卤素、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，或R 1、R 2连同它们所连接的原子一起形成C 3-6环烷基；
W 1选自：化学键，C 6-10芳基，5-10元杂芳基、联C 6-10芳基或联5-10元杂芳基，各自任选地被1、2或3个R W1取代；并且
每个R W1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C 1-6烷基或C 1-6烷氧基。
在本发明的某些实施方案中，W 1选自：化学键、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基，各自任选地被1、2或3个R W1取代；并且
每个R W1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C 1-6烷基或C 1-6烷氧基、-COOR W11、-CONR W11R W12；R W11和R W12各自独立地选自：氢、任选被卤素取代的C 1-6烷基。
在某些实施方案中，Z 1选自卤素、氰基、甲基、CH 2F、CHF 2、CF 3、甲氧基和CF 3O；
X选自：卤素、羟基、氰基、C 1-3烷氧基和CF 3O；
Y 1、Y 2各自独立地选自：O、S；
R 1、R 2各自独立地选自：任选被卤素、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，或R 1、R 2连同它们所连接的原子一起形成C 3-6环烷基；
W 1选自：化学键，C 6-10芳基，5-10元杂芳基、联C 6-10芳基或联5-10元杂芳基，各自任选地被1、2或3个R W1取代；并且
每个R W1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的 C 1-6烷基或C 1-6烷氧基、-COOR W11、-CONR W11R W12；R W11和R W12各自独立地选自：氢、任选被卤素取代的C 1-6烷基。
在某些实施方案中，Z 1选自：卤素、氰基、甲基、CH 2F、CHF 2、CF 3、甲氧基和CF 3O；
X选自：卤素；
Y 1、Y 2各自独立地选自：O、S；
R 1、R 2各自独立地选自：甲基，或R 1、R 2连同它们所连接的原子一起形成C 3-6环烷基；
W 1选自：化学键，
Figure PCTCN2021080167-appb-000005
Figure PCTCN2021080167-appb-000006
其各自任选地被1、2或3个R W1取代；并且
每个R W1独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基。
在某些实施方案中，Z 1选自：卤素、氰基、甲基、CH 2F、CHF 2、CF 3、甲氧基和CF 3O；
X选自：卤素；
Y 1、Y 2各自独立地选自：O、S；
R 1、R 2各自独立地选自：甲基，或R 1、R 2连同它们所连接的原子一起形成C 3-6环烷基；
W 1选自：化学键，
Figure PCTCN2021080167-appb-000007
Figure PCTCN2021080167-appb-000008
其各自任选地被1、2或3个R W1取代；并且
每个R W1独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基、-COOR W11、-CONR W11R W12；R W11和R W12各自独立地选自：氢、 任选被卤素取代的C 1-6烷基。
在某些实施方案中，Z 1选自：CF 3；
X选自：F；
Y 1、Y 2各自独立地选自：O、S；
R 1、R 2各自独立地选自：甲基，或R 1、R 2连同它们所连接的原子一起形成C 3-4环烷基；
W 1选自：化学键，
Figure PCTCN2021080167-appb-000009
其各自任选地被1、2或3个R W1取代；并且
每个R W1独立地选自：氢、卤基、氰基、任选被F取代的C 1-3烷基或C 1-3烷氧基。
在某些实施方案中，Z 1选自：CF 3；
X选自：F；
Y 1、Y 2各自独立地选自：O、S；
R 1、R 2各自独立地选自：甲基，或R 1、R 2连同它们所连接的原子一起形成C 3-4环烷基；
W 1选自：化学键，
Figure PCTCN2021080167-appb-000010
其各自任选地被1、2或3个R W1取代；并且
每个R W1独立地选自：氢、卤基、氰基、任选被F取代的C 1-3烷基或C 1-3烷氧基、-CONH 2、-COOC 1-3烷基。
在某些实施方案中，ABM选自如下化合物片段，其中
Figure PCTCN2021080167-appb-000011
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000012
在某些实施方案中，ABM选自如下化合物片段，其中
Figure PCTCN2021080167-appb-000013
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000014
Figure PCTCN2021080167-appb-000015
在第一种方案中，本发明提供一种具有式(II)结构的双官能化合物，及其盐、多晶型物和前药：
ABM-L-CLM(II)，
其中ABM是雄激素受体(AR)结合部分，L是连接ABM和CLM的化学连接部分，CLM是羟脑苷脂E3泛素连接酶结合部分。
其中，ABM定义如上。
在某些实施方案中，CLM包含衍生自酰亚胺、硫代酰亚胺、酰胺或硫代酰胺的化学基团，其结合到羟脑苷脂E3泛素连接酶。
在某些实施方案中，CLM是邻苯二酰亚胺基或其类似物。
在某些实施方案中，CLM为式(V)所示结构片段或其立体异构体，其中
Figure PCTCN2021080167-appb-000016
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000017
其中
W选自：CH 2、CHR 11、C＝O、NH或-N-C 1-6烷基；
每个T独立地选自：O或S；
G选自：氢、C 1-6烷基或羟基；
Q 1、Q 2、Q 3和Q 4独立地选自：CR′或N；
A选自：氢、C 1-6烷基、C 3-6环烷基、或卤素；
R 11选自：卤素、氰基、任选被卤素取代的C 1-6烷基或C 1-6烷氧基、C 3-6环烷基、-CONR′R″、-OR′、或-NR′R″；
R′和R″各自独立地选自：氢、卤素、胺基、氰基、任选被卤素取代的C 1-6烷基或C 1-6烷氧基、C 3-6环烷基。
在某些实施方案中，W选自：CH 2、CHR 11或C＝O；
每个T独立地选自：O或S；
G选自：氢、或C 1-6烷基；
Q 1、Q 2、Q 3和Q 4独立地选自：CH；
A选自：氢、C 1-6烷基或卤素；
R 11选自：卤素、氰基、-CF 3、OCF 3、甲基、-CONR′R″、-OR′、或-NR′R″；
R′和R″各自独立地选自：氢、卤素、氰基、胺基、-CF 3、OCF 3或甲基。
在某些实施方案中，CLM为式(V)-1所示结构片段或其立体异构体，其中
Figure PCTCN2021080167-appb-000018
表示连接部分的连接点：：
Figure PCTCN2021080167-appb-000019
其中：
W选自：CH 2或C＝O；
A选自：氢或C 1-6烷基。
在某些实施方案中，CLM为式(V)-2或(V)-3所示结构片段或其立体异构体，其中
Figure PCTCN2021080167-appb-000020
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000021
在某些实施方案中，CLM是沙立度胺、来那度胺、泊马度胺或其类似物的片段。
Figure PCTCN2021080167-appb-000022
在本发明的方案中，连接基团(L)选自如下通式结构表示的基团：
-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
-(CH 2) m-CO-N(R 31)-；
-O-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-Cy-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-C≡C-Cy-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-O-(CH 2) n-N(R 31)-；
-C≡C-(Cy) p-CO-(CH 2) o-O-；
-O-(Cy) p-CO-(CH 2) o-O-；
-O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
-(CH 2) m-CO-Cy-CO-(CH 2) o-O-；
-(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
-(Cy) q-(CH 2) m-CO-N(R 31)-；
-(Cy) q-O-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(Cy) q-Cy-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(Cy) q-C≡C-Cy-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(Cy) q-O-(CH 2) n-N(R 31)-；
-(Cy) q-(Cy) q-C≡C-(Cy) p-CO-(CH 2) o-O-；
-(Cy) q-O-(Cy) p-CO-(CH 2) o-O-；
-(Cy) q-O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
-(Cy) q-(CH 2) m-CO-Cy-CO-(CH 2) o-O-；
-(CH 2) m-O-(CH 2) n-CO-N(R 31)-(CH 2) o-N(R 31)-CO-(CH 2) t-O-；
-CO-N(R 31)-(CH 2) m-N(R 31)-(CH 2) n-CO-N(R 31)-；
-(Cy) q-O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) t-O-；
其中m、n、o、p、q和t各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R 31独立地选自基团氢、 甲基或乙基，Cy选自C 6-10芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选
Figure PCTCN2021080167-appb-000023
其各自任选地被1、2或3个R Cy取代；并且
每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基。
在优选的本发明的方案中，连接基团(L)选自如下通式结构表示的基团：
-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
-(CH 2) m-CO-N(R 31)-；
-O-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-Cy-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-C≡C-Cy-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-O-(CH 2) n-N(R 31)-；
-C≡C-(Cy) p-CO-(CH 2) o-O-；
-O-(Cy) p-CO-(CH 2) o-O-；
-O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
-(CH 2) m-CO-Cy-CO-(CH 2) o-O-；
-(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
-(Cy) q-(CH 2) m-CO-N(R 31)-；
-(Cy) q-O-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(Cy) q-Cy-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(Cy) q-C≡C-Cy-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
-(Cy) q-O-(CH 2) n-N(R 31)-；
-(Cy) q-(Cy) q-C≡C-(Cy) p-CO-(CH 2) o-O-；
-(Cy) q-O-(Cy) p-CO-(CH 2) o-O-；
-(Cy) q-O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
-(Cy) q-(CH 2) m-CO-Cy-CO-(CH 2) o-O-；
其中m、n、o、p和q各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R 31独立地选自基团氢、甲基或乙基，Cy选自C 3-6芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选
Figure PCTCN2021080167-appb-000024
其各自任选地被1、2或3个R Cy取代；并且
每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基。
在某些实施方案中，连接基团(L)选自基团：
Figure PCTCN2021080167-appb-000025
Figure PCTCN2021080167-appb-000026
Figure PCTCN2021080167-appb-000027
在某些实施方案中，连接基团(L)选自基团：
Figure PCTCN2021080167-appb-000028
在本发明第二种方案中，本发明提供了具有式(III)结构的化合物，及其盐、多晶型物和前药：
ABM-L-VLM(III)，
其中，ABM如定义如上；
VLM为式(VI)所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000029
Y 3是NR Y3R Y4、OR Y3、SR Y3、
Figure PCTCN2021080167-appb-000030
R 21和R 22独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基；
R Y3和R Y4独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、任选地被卤素、羟基、氰基取代的C 1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y3、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
X Y3是O或S；
R 23、R 24各自独立地选自：H、任选地被卤素、羟基、氰基取代的C 1-6烷基；
W 2是C 6-10芳基或5-10元杂芳基；
R 25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，6-10元杂芳基，噻吩基，或
Figure PCTCN2021080167-appb-000031
其中R 25a、R 25b各自独立地选自：H、任选地被卤素、羟基、氰基取代的C 1-6烷基；R 27 是H、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基，且Xa是S、O或NR 28；R 28是氢、任选地被卤素取代的C 1-6烷基；所述C6-10芳基、6-10元杂芳基、噻吩基任选被一个或更多个选自氢、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、-CONHC 1-6烷基、-COOC 1-6烷基的基团取代；
R 26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基；
“---”是连接基团L与上述结构式中任意一个H原子去掉后的基团相连。
在优选的本发明第二种方案中，本发明提供了具有式(III)结构的化合物，及其盐、多晶型物和前药：
ABM-L-VLM(III)，
其中ABM是AR结合部分，L是连接ABM和VLM化学连接部分，VLM是VHLE3连接酶结合部分。在某些实施方案中，所述VLM包含羟基脯氨酰基部分。
其中，ABM定义如上；
VLM为式(VI)所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000032
其中，
Y 3是NR Y3R Y4、OR Y3、SR Y3；
R 21和R 22独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基；
R Y3和R Y4独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、任选地被卤素、羟基、氰基取代的C 1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y3、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R 23、R 24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；
W 2是C 6-10芳基或5-10元杂芳基；
R 25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基，NR 25aR 25b，CONR 25aR 25b，C 6-10芳基，或
Figure PCTCN2021080167-appb-000033
其中R 25a、R 25b各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；R 27是氢、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基，且Xa是S或O；
R 26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基；
“---”是连接基团L与上述结构式中任意一个氢原子去掉后的基团相连。
在某些实施方案中，Y 3是NR Y3R Y4、OR Y3；
R 21和R 22独立地选自：氢、C 1-6烷基；
R Y3和R Y4独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y3、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R 23、R 24各自独立地选自：氢、C 1-6烷基；
W 2是苯基；
R 25是氢，卤素，C 1-6烷基，CONR 25aR 25b，或
Figure PCTCN2021080167-appb-000034
其中R 25a、R 25b各自独立地选自：氢、C 1-6烷基；R 27是氢、C 1-6烷基，且Xa是S；
R 26是氢，C 1-6烷基。
在某些实施方案中，Y 3是NR Y3R Y4、OR Y3；
R 21和R 22独立地选自：氢、C 1-6烷基；
R Y3和R Y4独立地选自：氢、C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y3、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
R 23、R 24各自独立地选自：氢、C 1-6烷基；
W 2是苯基；
R 25是CONR 25aR 25b，或
Figure PCTCN2021080167-appb-000035
其中R 25a、R 25b各自独立地选自：氢、C 1-6烷基；R 27是C 1-6烷基，且Xa是S；
R 26是氢。
在某些实施方案中，Y 3是
Figure PCTCN2021080167-appb-000036
R Y3选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基；
X Y3是O或S。
在某些实施方案中，其中Y 3是
Figure PCTCN2021080167-appb-000037
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
Figure PCTCN2021080167-appb-000038
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000039
在某些实施方案中，VLM为式(VI)-1所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000040
其中，Y 3，R 21，R 23，R 25定义如上。
在某些实施方案中，VLM为式(VI)-2所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000041
其中，
Y 5是NR Y5、O；
R 21和R 22独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基；
R Y5是氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、任选地被卤素、羟基、氰基取代的C 1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y5、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R 23、R 24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；
W 2是C 6-10芳基或5-10元杂芳基；
R 25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基，NR 25aR 25b，CONR 25aR 25b，C 6-10芳基，或
Figure PCTCN2021080167-appb-000042
其中R 25a、R 25b各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；R 27是氢、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基，且Xa是S或O；
R 26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基。
在某些实施方案中，VLM为式(VI)-2所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000043
Y 5是NR Y5、O；
R 21和R 22独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基；
R Y5是氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、任选地被卤素、羟基、氰基取代的C 1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y5、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R 23、R 24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；
W 2是5-6元杂芳基；
R 25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基，NR 25aR 25b，CONR 25aR 25b，C 6-10芳基，6-10元杂芳基，噻吩基，或
Figure PCTCN2021080167-appb-000044
其中R 25a、R 25b 各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；R 27是H、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基，且Xa是S、O或NR 28；R 28是氢、任选地被卤素取代的C 1-6烷基；所述C6-10芳基、6-10元杂芳基、噻吩基任选被一个或更多个选自氢、卤素、任选地被卤素取代的C 1-6烷基、任选地被卤素取代的C 3-6环烷基、-CONHC 1-6烷基、-COOC 1-6烷基的基团取代；
R 26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基。
在某些实施方案中，Y 5是NR Y5、O；
R 21和R 22独立地选自：氢、C 1-6烷基；
R Y5是氢、C 1-6烷基；或R Y5、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
R 23、R 24各自独立地选自：氢、C 1-6烷基；
W 2是苯基；
R 25是CONR 25aR 25b，或
Figure PCTCN2021080167-appb-000045
其中R 25a、R 25b各自独立地选自：氢、C 1-6烷基；R 27是C 1-6烷基，且Xa是S；
R 26是氢。
在本发明的某些实施方案中，R 21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基。
在某些实施方案中，Y 5是NR Y5、O；
R 21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基；
R 22选自：氢；
R Y5是氢、C 1-6烷基；
R 23、R 24各自独立地选自：氢、C 1-6烷基；
W 2是
Figure PCTCN2021080167-appb-000046
R 25是
Figure PCTCN2021080167-appb-000047
其中R 27是C 1-3烷基，且Xa是S；
R 26是氢。
在某些实施方案中，Y 5是NR Y5、O；
R 21和R 22独立地选自：氢、C 1-6烷基；
R Y5是氢、C 1-6烷基；或R Y5、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
R 23、R 24各自独立地选自：氢、C 1-6烷基；
W 2是噁唑基或噻唑基；
R 25是氢；
R 26是氢。
在某些实施方案中，其中Y 5是NR Y5、O；
R 21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基；
R 22选自：氢；
R Y5是氢、C 1-6烷基；
R 23、R 24各自独立地选自：氢、C 1-6烷基；
W 2是噁唑基或噻唑基；
R 25是氢；
R 26是氢。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
Figure PCTCN2021080167-appb-000048
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000049
在某些实施方案中，VLM为式(VI)-3所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000050
其中，Y 5，R 21，R 23，R 25定义如上。
在另一个实施方案中，VLM为式(VI)-4或(VI)-5所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000051
其中，R 21，R 22，Xa定义如上；R 27a，R 27b各自独立地选自：氢、C 1-6烷基。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
Figure PCTCN2021080167-appb-000052
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000053
在某些实施方案中，VLM为式(VI)-5所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000054
R 21和R 22独立地选自：氢、C 1-6烷基；
R 27a，R 27b各自独立地选自：H、5-6元杂芳基，优选H、噻唑基。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
Figure PCTCN2021080167-appb-000055
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000056
在某些实施方案中，VLM为式(VI)-61所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000057
R 21和R 22独立地选自：氢、C 1-6烷基；
R 29是任选地被卤素取代的C1-6烷基。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
Figure PCTCN2021080167-appb-000058
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000059
在某些实施方案中，VLM为式(VI)-71或式(VI)-81所示结构片段或其立体异构体：
Figure PCTCN2021080167-appb-000060
R 21和R 22独立地选自：氢、C 1-6烷基；
R 25是苯基，吡啶基，嘧啶基，噻吩基，或
Figure PCTCN2021080167-appb-000061
R 27是C 1-6烷基，且Xa是S、O或NR 28；R 28是C 1-6烷基；所述苯基、吡啶基、嘧啶基、噻吩基任选被一个或更多个选自卤素、C 1-6烷基、-CONHC 1-6烷基的基团取代；
X V是S、O或NR 29；R 29是氢、C 1-6烷基；W是CH。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
Figure PCTCN2021080167-appb-000062
表示连接部分的连接点：
Figure PCTCN2021080167-appb-000063
Figure PCTCN2021080167-appb-000064
在某些实施方案中，连接基团(L)选自如下通式结构表示的基团：
-(CH 2) m-CO-N(R 31)-(CH 2) n-CO-；
-O-(CH 2) m-O-(CH 2) n-CO-；
-O-(CH 2) m-CO-；
-C≡C-(Cy) p-(CH 2) m-CO-；
-CO-N(R 31)-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-CO-(Cy) p-(CH 2) n-CO-；
-O-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-N(R 31)-CO-(CH 2) m-O-(CH 2) n-CO-；
-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
-(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
-C≡C-(CH 2) m-CO-；
-(CH 2) m-CO-N(R 31)-(CH 2) n-(Cy) p-CO-；
-C≡C-(Cy) p-(CH 2) m-N(R 31)-CO-；
-(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-CO-；
-(Cy) q-C≡C-(Cy) p-(CH 2) m-CO-；
-(Cy) q-CO-N(R 31)-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-(Cy) q-CO-(Cy) p-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-(Cy) q-N(R 31)-CO-(CH 2) m-O-(CH 2) n-CO-；
-(Cy) q-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
-(Cy) q-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
-(Cy) q-(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
-(Cy) q-C≡C-(CH 2) m-CO-；
-(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-(Cy) p-CO-；
-(Cy) q-C≡C-(Cy) p-(CH 2) m-N(R 31)-CO-；
-O-(CH 2) m-O-(CH 2) n-；
-CH＝CH-CO-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-N(R 31)-CO-；
-(Cy) q-O-(Cy) p-(CH 2) m-N(R 31)-CO-；
-(Cy) q-N(R 31)-CO-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-(Cy) p-CO-；
-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-O-(CH 2) t-CO-；
-O-(Cy) q-CO-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
-O-(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-(Cy) q-CO-；
-O-(CH 2) m-O-(CH 2) n-(Cy) q-CO-；
其中m、n、o、p、q和t各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个-CH 2-中的一个或两个氢原子可以被氟原子替代，各个R 31独立地选自基团氢、甲基、乙基、或苄基，Cy选自C 6-10芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选
Figure PCTCN2021080167-appb-000065
Figure PCTCN2021080167-appb-000066
Figure PCTCN2021080167-appb-000067
其各自任选地被1、2或3个R Cy取代；并且
每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基。
在某些实施方案中，连接基团(L)选自如下通式结构表示的基团：
-(CH 2) m-CO-N(R 31)-(CH 2) n-CO-；
-O-(CH 2) m-O-(CH 2) n-CO-；
-O-(CH 2) m-CO-；
-C≡C-(Cy) p-(CH 2) m-CO-；
-CO-N(R 31)-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-CO-(Cy) p-(CH 2) n-CO-；
-O-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-N(R 31)-CO-(CH 2) m-O-(CH 2) n-CO-；
-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
-(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
-C≡C-(CH 2) m-CO-；
-(CH 2) m-CO-N(R 31)-(CH 2) n-(Cy) p-CO-；
-C≡C-(Cy) p-(CH 2) m-N(R 31)-CO-；
-(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-CO-；
-(Cy) q-C≡C-(Cy) p-(CH 2) m-CO-；
-(Cy) q-CO-N(R 31)-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-(Cy) q-CO-(Cy) p-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-(Cy) q-N(R 31)-CO-(CH 2) m-O-(CH 2) n-CO-；
-(Cy) q-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
-(Cy) q-(CH 2) m-(Cy) p-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
-(Cy) q-(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
-(Cy) q-C≡C-(CH 2) m-CO-；
-(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-(Cy) p-CO-；
-(Cy) q-C≡C-(Cy) p-(CH 2) m-N(R 31)-CO-；
其中m、n、o、p和q各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R 31独立地选自基团氢、甲基、乙基、或苄基，Cy选自C 3-6环烷基,C 3-6杂环烷基，优选
Figure PCTCN2021080167-appb-000068
Figure PCTCN2021080167-appb-000069
Figure PCTCN2021080167-appb-000070
其各自任选地被1、2或3个R Cy取代；并且
每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基。
在本发明的某些实施方案中，Cy选自C 6-10芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选苯基、吡啶基、三唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、氧代哌嗪基、四氢吡啶基、氧代二氢吡啶基，进一步优选
Figure PCTCN2021080167-appb-000071
Figure PCTCN2021080167-appb-000072
其各自任选地被1、2或3个R Cy取代；并且
每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基。
在某些实施方案中，连接基团(L)选自如下基团：
-O-(CH 2) m-O-(CH 2) n-CO-；
-O-(CH 2) m-CO-；
-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
-(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
-(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
-(Cy) q-O-(CH 2) m-CO-；
-(Cy) q-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
-O-(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-(Cy) q-CO-；
-O-(CH 2) m-O-(CH 2) n-(Cy) q-CO-；
其中m、n和o各自独立地选自：1、2、3、4、5、6，q选自：1，Cy选自C 6-10芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选苯基、吡啶基、三唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、氧代哌嗪基、四氢吡啶基、氧代二氢吡啶基，进一步优选
Figure PCTCN2021080167-appb-000073
Figure PCTCN2021080167-appb-000074
Figure PCTCN2021080167-appb-000075
其各自任选地被1、2或3个R Cy取代；并且
每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基。 在某些实施方案中，连接基团(L)选自基团：
Figure PCTCN2021080167-appb-000076
Figure PCTCN2021080167-appb-000077
Figure PCTCN2021080167-appb-000078
在某些实施方案中，连接基团(L)选自基团：
Figure PCTCN2021080167-appb-000079
Figure PCTCN2021080167-appb-000080
Figure PCTCN2021080167-appb-000081
Figure PCTCN2021080167-appb-000082
本发明具体化合物如下：
Figure PCTCN2021080167-appb-000083
Figure PCTCN2021080167-appb-000084
Figure PCTCN2021080167-appb-000085
Figure PCTCN2021080167-appb-000086
Figure PCTCN2021080167-appb-000087
Figure PCTCN2021080167-appb-000088
Figure PCTCN2021080167-appb-000089
Figure PCTCN2021080167-appb-000090
Figure PCTCN2021080167-appb-000091
Figure PCTCN2021080167-appb-000092
Figure PCTCN2021080167-appb-000093
Figure PCTCN2021080167-appb-000094
Figure PCTCN2021080167-appb-000095
Figure PCTCN2021080167-appb-000096
Figure PCTCN2021080167-appb-000097
Figure PCTCN2021080167-appb-000098
Figure PCTCN2021080167-appb-000099
Figure PCTCN2021080167-appb-000100
Figure PCTCN2021080167-appb-000101
Figure PCTCN2021080167-appb-000102
Figure PCTCN2021080167-appb-000103
Figure PCTCN2021080167-appb-000104
Figure PCTCN2021080167-appb-000105
Figure PCTCN2021080167-appb-000106
Figure PCTCN2021080167-appb-000107
Figure PCTCN2021080167-appb-000108
Figure PCTCN2021080167-appb-000109
Figure PCTCN2021080167-appb-000110
Figure PCTCN2021080167-appb-000111
Figure PCTCN2021080167-appb-000112
Figure PCTCN2021080167-appb-000113
Figure PCTCN2021080167-appb-000114
Figure PCTCN2021080167-appb-000115
Figure PCTCN2021080167-appb-000116
Figure PCTCN2021080167-appb-000117
Figure PCTCN2021080167-appb-000118
Figure PCTCN2021080167-appb-000119
Figure PCTCN2021080167-appb-000120
Figure PCTCN2021080167-appb-000121
Figure PCTCN2021080167-appb-000122
Figure PCTCN2021080167-appb-000123
Figure PCTCN2021080167-appb-000124
Figure PCTCN2021080167-appb-000125
Figure PCTCN2021080167-appb-000126
Figure PCTCN2021080167-appb-000127
Figure PCTCN2021080167-appb-000128
Figure PCTCN2021080167-appb-000129
Figure PCTCN2021080167-appb-000130
Figure PCTCN2021080167-appb-000131
Figure PCTCN2021080167-appb-000132
Figure PCTCN2021080167-appb-000133
Figure PCTCN2021080167-appb-000134
Figure PCTCN2021080167-appb-000135
Figure PCTCN2021080167-appb-000136
Figure PCTCN2021080167-appb-000137
Figure PCTCN2021080167-appb-000138
Figure PCTCN2021080167-appb-000139
Figure PCTCN2021080167-appb-000140
Figure PCTCN2021080167-appb-000141
Figure PCTCN2021080167-appb-000142
Figure PCTCN2021080167-appb-000143
Figure PCTCN2021080167-appb-000144
Figure PCTCN2021080167-appb-000145
Figure PCTCN2021080167-appb-000146
Figure PCTCN2021080167-appb-000147
Figure PCTCN2021080167-appb-000148
Figure PCTCN2021080167-appb-000149
Figure PCTCN2021080167-appb-000150
Figure PCTCN2021080167-appb-000151
Figure PCTCN2021080167-appb-000152
Figure PCTCN2021080167-appb-000153
Figure PCTCN2021080167-appb-000154
Figure PCTCN2021080167-appb-000155
本发明的另一方面提供一种组合物，其包含有效量的本发明双官能化合物和药学上可接受的载体。
本发明的药学上可接受的载体包括离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白质、缓冲物质(例如磷酸盐、甘氨酸、山梨酸、山梨酸钾)、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质。
在一个实施方案中，使用保护化合物以免从身体快速排除的载体制备活性化合物，例如控释型配制物，包括植入物和微囊封递送系统。可以使用可生物降解的生物相容性聚合物，例如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯以及聚乳酸。用于制备此类配制物的方法对于所属领域的技术人 员来说是显而易见的。
脂质体悬浮液也可以是药学上可接受的载体，脂质体配制物可以如下制备：将适当脂质(例如硬脂酰基磷脂酰基乙醇胺、硬脂酰基磷脂酰基胆碱、花生四烯酰基磷脂酰基胆碱和胆固醇)溶解于无机溶剂中，然后蒸发，在容器表面上留下干燥脂质的薄膜。然后将活性化合物的水溶液引入容器中。然后用手旋转容器以使脂质材料脱离容器的侧面，并且分散脂质聚集体，从而形成脂质体悬浮液。
在本发明的方案中，组合物进一步包含至少一种其它生物活性剂。
在本发明的方案中，生物活性剂是抗癌剂。
本发明的另一个方面提供一种治疗组合物，其包含有效量的至少两种不同的本发明所述的化合物。
本发明的另一个方面提供一种在需要其的受试者中将内源蛋白质募集到E3泛素连接酶进行降解的方法，所述方法包括给予本发明所述的化合物。
本发明的另一个方面提供一种在需要其的受试者中将雄激素受体降解或抑制的方法，所述方法包括给予本发明所述的化合物。
本发明的另一方面提供了一种治疗受试者的疾病或病症的方法，其包含以下步骤：向有需要的受试者施用组合物，所述组合物包含药学上可接受的载体和有效量的本发明所述的化合物。
在某些实施方案中，所述疾病或病症是痤疮、多毛症、皮脂腺增大、脱发、哮喘、多发性硬化症、癌症、肯尼亚病(Kenney′ sdisease)、纤毛病、腭裂、糖尿病、心脏病、高血压、发炎性肠病、智力迟钝、情绪障碍、肥胖症、屈光不正、不育症、安格尔曼综合症(Angelmansyndrome)、卡纳万疾病 (Canavandisease)、腹腔病、夏-马-图三氏病(Charcot-Marie-Toothdisease)、囊肿性纤维化、杜氏肌营养不良(Duchennemusculardystrophy)、血色病、血友病、克氏综合症(Klinefelter′ ssyndrome)、神经纤维瘤、苯丙酮尿症、多囊性肾病(PKDl)或4(PKD2)、普拉德-威利综合症(Prader-Willisyndrome)、镰状细胞病、泰伊-萨克斯二氏病(Tay-Sachsdisease)、特纳综合症(Turnersyndrome)。其中所述癌症是鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌瘤；膀胱、肠道、乳房、子宫颈、结肠、食道、头、肾脏、肝脏、肺、颈、卵巢、胰腺、前列腺和胃的癌症；白血病；良性和恶性淋巴瘤，尤其伯基特氏淋巴瘤(Burkitt′ slymphoma)和非霍奇金淋巴瘤(Non-Hodgkin′ slymphoma)；良性和恶性黑色素瘤；骨髓增生性疾病；肉瘤，包括尤文氏肉瘤(Ewing′ ssarcoma)、血管内皮瘤、卡波西肉瘤(Kaposi′ ssarcoma)、脂肪肉瘤、肌肉瘤、末梢神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、寡突神经胶质细胞瘤、室管膜瘤、神经胶母细胞瘤、神经母细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和许旺细胞瘤(Schwannomas)；肠道癌、乳癌、前列腺癌、子宫颈癌、子宫癌、肺癌、卵巢癌、睾丸癌、甲状腺癌、星形细胞瘤、食道癌、胰脏癌、胃癌、肝癌、结肠癌、黑色素瘤；癌肉瘤、霍奇金氏疾病、维尔姆斯瘤或畸胎癌。
在本发明的方案中，所述疾病或病症是癌症、痤疮、多毛症、皮脂腺增大、脱发、或肯尼迪病。
在本发明的方案中，所述疾病或病症是前列腺癌、痤疮或脱发。
在另一方面，说明书提供了治疗组合物，其包含有效量的如本发明所述化合物或其盐形式和药学上可接受的载体。治疗组合物调节患者或受试者中的蛋 白质降解，并且能够用于治疗或改善通过降解的蛋白质调节的疾病状态或病状。在某些实施方案中，如本发明所述的治疗组合物能够用于实现所关注蛋白质的降解和/或抑制，以便治疗或改善疾病，例如癌症。
定义
除非另外定义，否则本文所用的术语具有与本领域所属领域的普通技术人员通常所理解相同的含义。说明书中所用的术语仅用于描述特定实施方案并且不希望限制本发明。
术语“烃基”应指含有碳和氢并且可以是完全饱和、部分不饱和或芳香族并且包括芳基、烷基、烯基和炔基的化合物。
术语“烷基”在其上下文内应该指可以任选地被取代的直链、支链链或环状完全饱和烃基或烷基，优选C 1-C 10，更优选C 1-C 6，或者C 1-C 3烷基。烷基实例是甲基、乙基、正丁基、仲丁基、正己基、正庚基、正辛基、正壬基、正癸基、异丙基、2-甲基丙基、环丙基、环丙基甲基、环丁基、环戊基、环戊基乙基、环己基乙基和环己基等等。
术语“烯基”是指含有至少一个C＝C键的直链、支链链或环状C 2-C 10(优选C 2-C 6)烃基。
术语“炔基”是指含有至少一个C≡C键的直链、支链链或环状C 2-C 10(优选C 2-C 6)烃基。
术语“亚烷基”在使用时是指可以任选地被取代的-(CH 2) n-基团(n一般是整数0-6)。被取代时，亚烷基优选地在一个或多个亚甲基上被C 1-C 6烷基(包括环丙基或叔丁基)取代，而且可以被一个或多个卤基(优选1到3个卤基)或一个或两个羟基或C 1-6烷基氧基。
术语“未被取代”应该指仅被氢原子取代。
术语“被取代”或“任选地被取代”指分子任一处的碳(或氮)位置处独立地存在一个或多个取代基，优选1-5个取代基，最优选1-3个取代基，取代基可以为：羟基、硫醇、羧基、氰基、硝基、卤素(优选地，1、2或3个卤素，尤其在烷基上，尤其甲基，例如三氟甲基)、烷基(优选C 1-C 10，更优选地，C 1-C 6)、卤代烷基、芳基(尤其苯基和被取代的苯基，例如苯甲基或苯甲酰基)、烷氧基(优选C 1-C 6烷基或芳基，包括苯基和被取代的苯基)、硫醚(C 1-C 6烷基或芳基)、酰基(优选C 1-C 6酰基)、C 1-C 6烷基胺、C 1-C 6二烷基胺，被一或两个C 1-C 6烷基取代的酰胺基(包括任选地被一个或两个C 1-C 6烷基取代的甲酰胺)、羧基、C 1-C 6酯等。
术语“芳基”是指具有单环(例如苯基)或稠环(例如萘基、蒽基、菲基等)的被取代或未被取代的C6-C16芳香族基团，优选C6-C10芳香族基团。
术语“杂芳基”是指含有至少一个杂原子(例如N、O或S)的5-16元芳香族基团，优选5-10元芳香族基团，可以指任选地被取代的喹啉、任选地被取代的吲哚、任选地被取代的吲哚嗪、任选地被取代的氮杂吲哚嗪、任选地被取代的苯并咪唑、苯并二唑、苯并呋喃、任选地被取代的咪唑、任选地被取代的异噁唑、任选地被取代的噁唑(优选被甲基取代)、任选地被取代的二唑、任选地被取代的三唑、四唑、任选地被取代的苯并呋喃、任选地被取代的噻吩、任选地被取代的噻唑(优选被甲基和/或硫醇取代)、任选地被取代的异噻唑、任选地被取代的三唑、任选地被取代的吡啶(2-吡啶、3-吡啶或4-吡啶)。
术语“芳烷基”和“杂芳基烷基”是指分别包含芳基或杂芳基的基团，以及符合上述定义的烷基和/或杂烷基和/或碳环和/或杂环烷基环系统。
术语“杂环基”是指含有至少一个杂原子(例如N、O或S)的3-10元环基，优选3-6元环基，且可以是芳香族(杂芳基)或非芳香族。其包括：氮杂环丁烷基、苯并咪唑基、1，4-苯并二噁烷基、1，3-苯并间二氧杂环戊烯基、苯并噁唑基、苯并噻唑基、苯并噻吩基、二氢咪唑基、二氢吡喃基、二氢呋喃基、二噁烷基、二氧杂环戊烷基、亚乙基脲、1，3-二氧杂环戊烷、1，3-二噁烷、1，4-二噁烷、呋喃基、高哌啶基、咪唑基、咪唑啉基、咪唑啶基、吲哚啉基、吲哚基、异喹啉基、异噻唑啶基、异噻唑基、异噁唑啶基、异噁唑基、吗啉基、萘啶基、噁唑啶基、噁唑基、吡啶酮、2-吡咯烷酮、吡啶、哌嗪基、N-甲基哌嗪基、哌啶基、邻苯二甲酰亚胺、丁二酰亚胺、吡嗪基、吡唑啉基、吡啶基、嘧啶基、吡咯啶基、吡咯啉基、吡咯基、喹啉基、四氢呋喃基、四氢吡喃基、四氢喹啉、噻唑啶基、噻唑基、噻吩基、四氢噻吩、噁烷、氧杂环丁烷基、氧硫杂环戊烷基、噻烷等等。
术语“环烷基”是指C 3-C 20的单环或多环烷基，优选C 3-C 15的单环或多环烷基，最优选C 3-C 10的单环或多环烷基，包括环丙基、环丁基、环戊基、环己基、环庚基等。
“杂环烷基”是指3-20元的单环或多环烷基，优选3-15元的单环或多环烷基，最优选3-10元的单环或多环烷基，，其中其环状结构中的至少一个环碳原子被选自由N、O、S或P组成的组的杂原子置换。
“卤素”是指F、Cl、Br、I。
术语“药学上可接受的盐”用于描述本文所述的一种或多种化合物的盐形式，提供其是为了增加化合物在患者胃肠道的胃汁液中的溶解度以便促进化合物的溶解和生物利用度。药学上可接受的盐在适用时包括衍生自药学上可接受 的无机或有机碱和酸的盐。适合的盐包括衍生自碱金属(例如钾和钠)、碱土金属(例如钙、镁和铵盐)以及药学领域中众所周知的许多其它酸和碱的盐。
制备适用于本发明的药学上可接受的酸加成盐所用的酸是形成无毒酸加成盐的酸，即，含有药理学上可接受的阴离子的盐，例如盐酸盐、氢溴酸盐、氢碘化物、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、酒石酸盐、酒石酸氢盐、丁二酸盐、顺丁烯二酸盐、反丁烯二酸盐、葡糖酸盐、葡糖二酸盐、苯甲酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐盐，以及多种其它盐。
术语“有效”可以意指但不限于活性医药成分的量/剂量，当在其预定用途的背景下使用时，其在需要此类治疗或接受此类治疗的受试者中实现或足以预防病状、病症或疾病状态，抑制其发生，改善、延迟或治疗其症状(在一定程度上，优选完全缓解症状)。
术语“药学上可接受的载体”可以意指与药物施用兼容的任何和所有溶剂、分散介质、包衣、抗细菌和抗等。
除非另外指明，术语“化合物”是指本文公开的任何特定化合物并且包括互变异构体、区位异构体、几何异构体，以及适用时，立体异构体，包括光学异构体(对映异构体)和其它立体异构体(非对映异构体)，以及其药学上可接受的盐和衍生物(包括前药形式)。其在上下文中使用时，术语化合物通常不仅指单一化合物，而且可以包括其它化合物，例如立体异构体、区位异构体和/或光学异构体(包括外消旋混合物)，以及所公开化合物的特定对映异构体或对映异构体增浓混合物。所述术语在上下文中还指化合物的前药形式，其已经修饰以促进化合物施用和递送到活性部位。
附图说明
本发明附图示出了本发明的若干实施方案，且与说明书一起用于解释本发明的原理。附图仅出于图示本发明的实施方案的目的并且不被解释为限制本发明。结合展示本发明的说明性实施方案的附图，从以下详细描述中将显而易知本发明的其它目标、特点和优点，其中：
图1为本发明化合物对LNCaP细胞AR蛋白的降解实验结果；
图2为本发明化合物对LNCaP小鼠移植瘤的PK/PD实验结果；
图3为本发明化合物对雌性金黄地鼠皮脂腺斑生长的抑制结果；
图4为本发明化合物及其对照药给药后第21天对金黄地鼠体重的影响作用；
图5为本发明化合物及其对照药给药后对C57BL/6小鼠体重的影响图；
图6为本发明化合物A279与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图7为本发明化合物A283-A286与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图8为本发明化合物A288与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图9为本发明化合物A307与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图10为本发明化合物A308与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图11为本发明化合物A309-A313与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图12为本发明化合物A314、A315、A317和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图13为本发明化合物A320-A324和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图14为本发明化合物A340和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图15为本发明化合物A347-A351和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图16为本发明化合物A352-A354和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图17为本发明化合物A357-A358和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比。
具体实施方式
下面将结合附图以及进一步的详细说明来举例说明本发明。需要指出的是，以下说明仅仅是对本发明要求保护的技术方案的举例说明，并非对这些技术方案的任何限制。本发明的保护范围以所附权利要求书记载的内容为准。
一、制备实施例
ABM-L-CLM的合成
实施例A1
Figure PCTCN2021080167-appb-000156
将1-1(2g,10mmol)，TMSCN(3g,30mmol)，ZnCl 2(136mg,1mmol)依次加入到50ml丙酮中，室温反应1h，反应结束后，100ml水洗，100mlEA萃取，50ml饱和食盐水洗涤，无水硫酸钠干燥，旋干得2.3g产物1-2，产率88％，产品不经纯化直接用于下一步。
Figure PCTCN2021080167-appb-000157
将1-2(2.3g,8.8mmol)，1-3(4.3g,17.6mmol)依次加入到10mlDMF中，室温反应过夜，反应结束后，加入20ml甲醇，20ml6NHCl，90℃反应1h，反应结束用50ml水洗，50mlEA萃取，20ml饱和食盐水洗涤，无水硫酸钠干燥，旋干上层析柱PE:EA＝5:1-2:1得到400mg产物1-4，产率9.2％。
Figure PCTCN2021080167-appb-000158
将1-4(300mg,0.6mmol)，1-5(112mg,0.6mmol)，HATU(456mg,1.2mmol)，三乙胺(0.2ml,1.2mmol)依次加入到10mlDCM中，室温搅拌一小时，反应结束后，用50ml水洗涤，50mlDCM萃取，20ml饱和食盐水洗涤，无水硫酸钠干燥，旋蒸，上厚制备板DCM:MeOH＝15:1，得到150mg产物1-6，产率37％。
Figure PCTCN2021080167-appb-000159
将1-6(150mg)加入大2mlTHF中，冷却至0℃，通入HCl气体，0℃反应2h，反应结束后，用饱和碳酸氢钠溶液调节pH＝8，20mlEA萃取，10ml饱和食盐水洗涤，无水硫酸钠干燥，旋干得到80mg产物1-7，产率63％。
Figure PCTCN2021080167-appb-000160
将1-7(80mg，0.14mmol)，2(46mg，0.14mmol)，HATU(106mg，0.28mmol)，三乙胺(28mg，0.28mmol)依次加入到5mlDMF中，室温搅拌一小时，反应结束后，用20ml水洗涤，20mlEA萃取，20ml饱和食盐水洗涤，无水硫酸钠干燥，旋蒸，上后制备板DCM:MeOH＝10:1,得到50mg，再HPLC制备得25mg白色固体A1，纯度97.5％，收率20％。
LCMS([M+H] +):878.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.39–8.21(m,2H),7.99(t,J＝5.7Hz,1H),7.82(dd,J＝13.9,6.6Hz,2H),7.50(d,J＝7.2Hz,1H),7.37(s,3H),7.32(d,J＝8.4Hz,2H),5.13(dd,J＝12.9,5.4Hz,1H),4.77(s,2H),3.15(d,J＝5.9Hz,2H),3.05(d,J＝5.9Hz,2H),3.01–2.83(m,1H),2.62(dd,J＝18.9,11.2Hz,3H),2.13(t,J＝7.4Hz,2H),2.03(dd,J＝25.3,10.3Hz,2H),1.85(dd,J＝15.2,7.4Hz,2H),1.50(d,J＝4.2Hz,6H),1.43(s,4H).
实施例A2-A45采用与实施例A1相似的操作，用与之相对应的试剂合成。
实施例A2
Figure PCTCN2021080167-appb-000161
LCMS([M+H] +):820.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.53(d,J＝2.4Hz,1H),8.33–8.23(m, 2H),7.87(t,J＝5.6Hz,1H),7.82(dd,J＝8.3,2.5Hz,1H),7.59–7.52(m,1H),7.45(t,J＝9.8Hz,1H),7.11(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.58(t,J＝5.9Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.31(s,2H),3.09(dd,J＝12.4,6.3Hz,2H),2.96–2.70(m,4H),2.62–2.53(m,2H),2.15(t,J＝7.4Hz,2H),2.10–1.90(m,4H),1.53(s,6H),1.47(d,J＝7.3Hz,2H).
实施例A3
Figure PCTCN2021080167-appb-000162
LCMS([M+H] +):854.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.54(t,J＝5.4Hz,1H),8.30–8.22(m,2H),8.02(t,J＝5.7Hz,1H),7.81(dd,J＝8.4,7.4Hz,1H),7.75(t,J＝8.0Hz,1H),7.52(dd,J＝10.6,1.8Hz,1H),7.49(d,J＝7.2Hz,1H),7.37(m,2H),5.12(dd,J＝12.9,5.4Hz,1H),4.78(s,2H),3.27(d,J＝5.5Hz,2H),3.19(d,J＝5.7Hz,2H),2.95–2.83(m,1H),2.63–2.51(m,2H),2.06–1.96(m,1H),1.55(d,J＝1.7Hz,6H),1.52(m,4H).
实施例A4
Figure PCTCN2021080167-appb-000163
LCMS([M+H] +):750.3
1HNMR(400MHz,DMSO-d6)δ11.18(s,1H),9.80(s,1H),8.54(d,J＝2.4Hz,1H),8.45(d,J＝8.4Hz,1H),8.32–8.25(m,2H),7.83(m,2H),7.63(d,J＝7.3Hz,1H),7.52(d,J＝8.2Hz,1H),5.15(dd,J＝12.8,5.3Hz,1H),2.97–2.81(m,4H),2.58(m,4H),2.08(m,2H),1.52(s,6H).
实施例A5
Figure PCTCN2021080167-appb-000164
LCMS([M+H] +):835.3
1HNMR(400MHz,DMSOd6)δ11.12(s,1H),8.63(t,J＝5.6Hz,1H),8.26(s,2H),8.02(d,J＝5.8Hz,1H),7.98(d,J＝8.4Hz,2H),7.79(t,J＝7.9Hz,1H),7.52(d,J＝8.2Hz,2H),7.46(d,J＝7.2Hz,1H),7.36(d,J＝8.5Hz,1H),5.14–5.07(m,1H),4.76(s,2H),3.27(d,J＝6.0Hz,2H),3.17(t,J＝6.4Hz,2H),2.89–2.81(m,1H),2.62–2.49(m,2H),1.99(t,J＝7.6Hz,1H),1.51(d,J＝2.3Hz,10H).
实施例A6
Figure PCTCN2021080167-appb-000165
LCMS([M+H] +):851.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.52(d,J＝2.4Hz,1H),8.33–8.23(m,2H),8.07(t,J＝5.6Hz,1H),7.92(t,J＝5.4Hz,1H),7.85–7.75(m,2H),7.47(dd,J＝11.8,7.8Hz,2H),7.39(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.3Hz,1H),4.77(s,2H),3.24–3.17(m,2H),3.17–3.11(m,2H),2.81–2.74(m,2H),2.13(t,J＝7.4Hz,2H),2.06–1.86(m,6H),1.52(s,6H).
实施例A7
Figure PCTCN2021080167-appb-000166
LCMS([M+H] +):605.2
1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.53(d,J＝2.4Hz,1H),8.32–8.20(m, 3H),7.82(dd,J＝8.3,2.5Hz,1H),7.49(d,J＝8.3Hz,1H),4.56(dd,J＝18.0,7.9Hz,1H),2.88–2.80(m,2H),2.77–2.68(m,1H),2.47(d,J＝3.3Hz,1H),2.23(t,J＝7.4Hz,2H),2.00–1.89(m,4H),1.53(s,6H).
实施例A8
Figure PCTCN2021080167-appb-000167
LCMS([M+H] +):799.2
1HNMR(400MHz,DMSO-d6)δ11.14(s,1H),8.33(t,J＝5.7Hz,1H),8.29–8.22(m,2H),7.74(dd,J＝8.4,7.4Hz,1H),7.47(d,J＝7.2Hz,1H),7.42(dd,J＝11.7,2.0Hz,1H),7.39–7.32(m,2H),7.21(d,J＝8.8Hz,1H),5.12(dd,J＝12.8,5.4Hz,1H),4.84(s,2H),4.20(t,J＝5.4Hz,2H),3.60(d,J＝3.2Hz,2H),2.95–2.84(m,1H),2.60(d,J＝18.0Hz,1H),2.08–1.92(m,2H),1.52(s,6H).
实施例A9
Figure PCTCN2021080167-appb-000168
LCMS([M+H] +):808.3
1HNMR(400MHz,DMSOd6)δ11.14(s,1H),8.68(t,J＝5.3Hz,1H),8.29(d,J＝5.2Hz,2H),8.20(t,J＝5.6Hz,1H),8.00–7.95(m,2H),7.77–7.72(m,1H),7.56–7.51(m,2H),7.45(dd,J＝7.2,2.7Hz,1H),7.37(d,J＝8.6Hz,1H),5.18–5.07(m,2H),4.80(s,2H),3.39(d,J＝7.8Hz,2H),2.87(d,J＝17.1Hz,2H),2.64–2.52(m,2H),2.06–1.98(m,1H),1.54(d,J＝2.0Hz,6H).
实施例A10
Figure PCTCN2021080167-appb-000169
LCMS([M+H] +):879.3
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.51(d,J＝2.3Hz,1H),8.25(s,2H),7.97(t,J＝5.6Hz,1H),7.86–7.75(m,3H),7.46(t,J＝7.7Hz,2H),7.36(d,J＝8.5Hz,1H),5.10(dd,J＝12.9,5.4Hz,1H),4.75(s,2H),3.18–3.09(m,2H),3.06–2.98(m,2H),2.93–2.82(m,1H),2.78(s,2H),2.56(t,J＝13.3Hz,1H),2.13(s,2H),2.06(s,1H),2.04–1.98(m,1H),1.92(dt,J＝14.7,7.5Hz,2H),1.51(s,6H),1.40(s,4H).
实施例A11
Figure PCTCN2021080167-appb-000170
LCMS([M+H] +):793.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.52(d,J＝2.3Hz,1H),8.33–8.24(m,2H),8.13(t,J＝5.4Hz,1H),7.80(dd,J＝8.2,2.4Hz,1H),7.61–7.53(m,1H),7.44(d,J＝8.3Hz,1H),7.19(d,J＝8.7Hz,1H),7.02(d,J＝7.0Hz,1H),6.75(t,J＝6.0Hz,1H),5.05(dd,J＝12.8,5.3Hz,1H),3.40-3.38(m,2H),3.26-3.25(m,2H),2.92–2.74(m,3H),2.59-2.55(m,2H),2.15(t,J＝7.3Hz,2H),2.01–1.88(m,3H),1.53(s,6H).
实施例A12
Figure PCTCN2021080167-appb-000171
LCMS([M+H] +):852.2
1HNMR(400MHz,DMSO-d6)11.17–11.10(m,1H),8.36–8.23(m,2H),8.17–8.05(m,1H),8.05–7.90(m,1H),7.86–7.75(m,1H),7.64–7.54(m,2H),7.53–7.47(m,1H),7.41(q,J＝8.3Hz,3H),5.20–5.05(m,1H),4.86–4.69(m,2H),4.65–4.50(m,2H),4.04–3.90(m,2H),3.30–3.17(m,4H),2.59(ddd,J＝23.2,12.6,4.2Hz,2H),2.06–1.94(m,2H),1.57–1.47(m,6H).
实施例A13
Figure PCTCN2021080167-appb-000172
LCMS([M+H] +):820.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.33–8.22(m,2H),7.86(d,J＝5.4Hz,1H),7.55(t,J＝7.8Hz,1H),7.34(dd,J＝21.9,8.2Hz,4H),7.10(d,J＝8.6Hz,1H),7.00(d,J＝7.0Hz,1H),6.56(d,J＝6.0Hz,1H),5.04(dd,J＝12.6,5.2Hz,1H),3.30(s,2H),3.09(d,J＝5.8Hz,2H),2.93–2.80(m,1H),2.60(dd,J＝20.9,12.9Hz,3H),2.12(t,J＝7.2Hz,2H),2.08–1.94(m,2H),1.91–1.76(m,2H),1.53(dd,J＝24.3,5.8Hz,10H).
实施例A14
Figure PCTCN2021080167-appb-000173
LCMS([M+H] +):896.2
1HNMR(400MHz,DMSO-d6)δ11.15(s,1H),8.27(s,2H),8.00(t,J＝5.6Hz,1H),7.86(t,J＝5.3Hz,1H),7.81(t,J＝7.9Hz,1H),7.50–7.46(m,2H),7.40–7.30(m,2H),7.21(d,J＝7.8Hz,1H),5.12(dd,J＝12.9,5.3Hz,1H),4.77(s,2H),3.14(d,J＝5.7Hz,2H),3.03(d,J＝5.6Hz,2H),2.92–2.86(m,1H),2.68–2.55(m,3H),2.13(t,J＝7.3Hz,2H),2.07–1.93(m,2H),1.8 7–1.76(m,2H),1.52(s,6H),1.41(m,4H).
实施例A15
Figure PCTCN2021080167-appb-000174
LCMS([M+H] +):865.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.53(d,J＝2.4Hz,1H),8.36–8.20(m,2H),8.11–7.96(m,1H),7.91–7.74(m,3H),7.49(t,J＝7.8Hz,2H),7.40(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.79(s,2H),3.16(dd,J＝12.9,6.6Hz,2H),3.07(dd,J＝12.2,6.1Hz,2H),2.96–2.73(m,4H),2.66–2.52(m,2H),2.15(t,J＝7.3Hz,2H),2.10–1.90(m,4H),1.67–1.44(m,6H).
实施例A16
Figure PCTCN2021080167-appb-000175
LCMS([M+H] +):835.2
1HNMR(400MHz,DMSO-d6)δ11.15(s,1H),8.81(d,J＝8.4Hz,1H),8.61(t,J＝5.6Hz,1H),8.28(s,2H),7.99–7.94(m,2H),7.85(dd,J＝8.5,7.3Hz,1H),7.60(d,J＝7.2Hz,1H),7.55–7.50(m,2H),5.16(dd,J＝13.0,5.4Hz,1H),3.41–3.36(m,2H),3.28(s,2H),2.89(td,J＝17.3,16.0,5.4Hz,1H),2.67–2.53(m,4H),2.10–1.95(m,2H),1.59(s,4H),1.54(d,J＝2.1Hz,6H).
实施例A17
Figure PCTCN2021080167-appb-000176
LCMS([M+H] +):851.2
1HNMR(400MHz,)δ11.13(s,1H),8.52(d,J＝2.4Hz,1H),8.28(s,3H),8.10–7.71(m,3H),7.43(ddd,J＝10.6,7.1,3.0Hz,3H),5.13(dd,J＝12.9,5.3Hz,1H),4.72(s,2H),3.19(dt,J＝11.2,5.7Hz,4H),2.96–2.72(m,4H),2.70–2.53(m,2H),2.16(t,J＝7.4Hz,2H),2.08(s,4H),1.53(s,6H).
实施例A18
Figure PCTCN2021080167-appb-000177
LCMS([M+H] +):877.2
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.55(s,1H),8.28(d,J＝5.1Hz,2H),7.86–7.74(m,2H),7.48(dd,J＝16.4,7.7Hz,2H),7.36(d,J＝8.5Hz,1H),5.21(s,2H),5.15–5.07(m,1H),3.58(s,2H),3.46(d,J＝12.7Hz,6H),2.93–2.83(m,3H),2.60(d,J＝17.2Hz,2H),2.45(s,2H),2.05–1.93(m,3H),1.55(s,6H).
实施例A19
Figure PCTCN2021080167-appb-000178
LCMS([M+H] +):851.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.52(d,J＝2.4Hz,1H),8.31–8.23(m,2H),7.97(t,J＝5.7Hz,1H),7.88(t,J＝5.6Hz,1H),7.83–7.79(m,2H),7.48(t,J＝8.1Hz,2H),7.38(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.3Hz,1H),4.77(s,2H),3.14(dd,J＝12.1,6.1Hz,2H),3.04(dd,J＝10.2,4.9Hz,4H),2.96–2.80(m,2H),2.56–2.54(m,2H),2.04–1.99(m,2H),1.52(s,6H),1.40–1.39(m,2H).
实施例A20
Figure PCTCN2021080167-appb-000179
LCMS([M+H] +):837.2
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.52(d,J＝2.4Hz,1H),8.31–8.24(m,2H),8.06(t,J＝5.4Hz,1H),7.98(t,J＝5.4Hz,1H),7.84–7.76(m,2H),7.51–7.43(m,2H),7.39(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.77(s,2H),3.22–3.10(m,4H),3.06–2.99(m,2H),2.94–2.81(m,2H),2.56–2.54(m,3H),2.03–1.99(m,3H),1.52(s,6H).
实施例A21
Figure PCTCN2021080167-appb-000180
LCMS([M+H] +):915.2
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.66(d,J＝2.4Hz,1H),8.33–8.21(m,3H),8.12(d,J＝8.8Hz,4H),7.95(dd,J＝8.5,2.5Hz,1H),7.78(dd,J＝8.4,7.4Hz,1H),7.47(d,J＝7.2Hz,1H),7.38(d,J＝8.5Hz,1H),7.09(d,J＝8.9Hz,2H),5.10(dd,J＝12.9,5.4Hz,1H),4.77(s,2H),4.54(s,2H),3.27(m,4H),2.92–2.83(m,1H),2.62–2.51(m,2H),2.06–1.96(m,1H),1.58(s,6H).
实施例A22
Figure PCTCN2021080167-appb-000181
LCMS([M+H] +):857.3
1HNMR(400MHz,DMSO-d6)δ11.15(s,1H),8.33–8.19(m,3H),7.84–7.74(m,3H),7.69(d,J＝8.8Hz,2H),7.51–7.44(m,3H),7.41(d,J＝8.5Hz,1H),7.07(d,J＝8.8Hz,2H),5.12(dd,J＝12.8,5.5Hz,1H),4.83(s,2H),4.11(t,J＝5.4Hz,2H),3.60–3.58(m,2H),2.95–287(m,1H),2.62–2.54(m,2H),2.10–1.94(m,2H),1.56(d,J＝2.8Hz,6H).
实施例A23
Figure PCTCN2021080167-appb-000182
LCMS([M+H] +):858.3
1HNMR(400MHz,DMSO-d6)δ11.14(s,1H),8.66(d,J＝2.4Hz,1H),8.34–8.20(m,3H),8.14–8.07(m,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.77(dd,J＝8.3,7.4Hz,1H),7.47(d,J＝7.2Hz,1H),7.41(d,J＝8.5Hz,1H),7.09(d,J＝8.9Hz,2H),5.11(dd,J＝12.8,5.4Hz,1H),4.83(s,2H),4.14(t,J＝5.4Hz,2H),3.64–3.55(m,2H),2.90(ddd,J＝16.3,13.8,5.1Hz,1H),2.66–2.51(m,2H),2.03(dd,J＝10.2,5.2Hz,1H),1.59(s,6H).
实施例A24
Figure PCTCN2021080167-appb-000183
LCMS([M+H] +):849.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.43(d,J＝2.4Hz,1H),8.31–8.24(m,2H),8.12(m,1H),7.99(m,1H),7.80–7.70(m,2H),7.48(d,J＝7.3Hz,1H),7.43(d,J＝8.4Hz,1H),7.35(d,J＝8.6Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.74(s,2H),3.02–2.90(m,4H),2.90–2.83(m,1H),2.63–2.55(m,2H),2.14–2.06(m,1H),2.03–1.99(m,1H),1.69–1.64(m,1H),1.47(s,6H),1.33–1.24(m,2H).
实施例A25
Figure PCTCN2021080167-appb-000184
LCMS([M+H] +):862.3
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.43(s,1H),8.30–8.22(m,2H),8.04(t,J＝5.8Hz,1H),7.87(m,1H),7.81–7.75(m,1H),7.72(dt,J＝8.4,2.7Hz,1H),7.49(d,J＝7.2Hz,1H),7.41(d,J＝8.4Hz,1H),7.36(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.3Hz,1H),4.74(s,2H),3.06–2.82(m,5H),2.58(dd,J＝16.6,8.4Hz,3H),2.13(dd,J＝15.3,8.0Hz,1H),2.03–1.99(m,1H),1.67(m,1H),1.47(s,6H),1.39–1.27(m,3H).
实施例A26
Figure PCTCN2021080167-appb-000185
LCMS([M+H] +):877.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.43(d,J＝2.3Hz,1H),8.30–8.22(m,2H),8.02(t,J＝5.7Hz,1H),7.92(t,J＝5.6Hz,1H),7.82–7.76(m,1H),7.76–7.71(m,1H),7.48(d,J＝7.2Hz,1H),7.42(d,J＝8.4Hz,1H),7.37(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.75(s,2H),3.06(dd,J＝12.5,6.3Hz,2H),2.95–2.85(m,3H),2.63–2.52(m,3H),2.12(dd,J＝15.4,8.1Hz,1H),2.05–1.98(m,1H),1.69–1.65(m,1H),1.49(s,6H),1.32–1.27(m,3 H),1.23–1.22(m,2H).
实施例A27
Figure PCTCN2021080167-appb-000186
LCMS([M+H] +):872.3
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.27(d,J＝4.6Hz,2H),7.83(q,J＝8.1,7.4Hz,2H),7.57(d,J＝8.0Hz,2H),7.51(d,J＝7.3Hz,1H),7.42(t,J＝7.1Hz,3H),5.11(dd,J＝12.6,5.4Hz,1H),4.78(s,2H),3.28(d,J＝6.4Hz,3H),2.87(t,J＝14.3Hz,1H),2.74–2.62(m,3H),2.40(t,J＝6.3Hz,2H),2.24(s,2H),2.09–2.00(m,1H),1.92–1.80(m,2H),1.60(d,J＝12.1Hz,2H),1.52(s,6H).
实施例A28
Figure PCTCN2021080167-appb-000187
LCMS([M+H] +):877.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.47(s,1H),8.31–8.24(m,2H),8.20(t,J＝5.1Hz,1H),7.98(t,J＝5.7Hz,1H),7.82–7.77(m,2H),7.63(d,J＝8.3Hz,1H),7.49(d,J＝7.2Hz,1H),7.38(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.3Hz,1H),4.77(s,2H),3.18–3.11(m,2H),3.08(d,J＝5.8Hz,2H),2.93–2.83(m,1H),2.62–2.51(m,3H),2.23–2.17(m,1H),2.06–1.99(m,1H),1.52(s,6H),1.47–1.36(m,6H).
实施例A29
Figure PCTCN2021080167-appb-000188
LCMS([M+H] +):849.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.47(s,1H),8.33–8.24(m,3H),8.12(m,1H),7.82–7.76(m,2H),7.63(d,J＝8.3Hz,1H),7.48(d,J＝7.2Hz,1H),7.38(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.5Hz,1H),4.77(s,2H),3.20(s,4H),2.95–2.84(m,1H),2.61–2.54(m,3H),2.22–2.15(m,1H),2.06–1.98(m,1H),1.52(s,6H),1.40–1.38(m,2H).
实施例A30
Figure PCTCN2021080167-appb-000189
LCMS([M+H] +):863.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.47(d,J＝2.3Hz,1H),8.31–8.25(m,2H),8.27–8.23(m,1H),8.01(t,J＝5.6Hz,1H),7.84–7.76(m,2H),7.63(d,J＝8.4Hz,1H),7.49(d,J＝7.2Hz,1H),7.39(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.77(s,2H),3.20–3.06(m,4H),2.94–2.82(m,1H),2.63–2.52(m,3H),2.23–2.16(m,1H),2.05–1.99(m,1H),1.62–1.55(m,2H),1.52(s,6H),1.43–1.38(m,2H).
实施例A31
Figure PCTCN2021080167-appb-000190
LCMS([M+H] +):814.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.65(d,J＝2.5Hz,1H),8.29(q,J＝8.4Hz,2H),8.12(d,J＝8.8Hz,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.60–7.54(m,1H),7.14(dd,J＝13.8,8.8Hz,3H),7.03(d,J＝7.0Hz,1H),6.78(t,J＝5.8Hz,1H),5.06(dd,J＝12.9,5.5Hz,1H),4.17(t,J＝5.8Hz,2H),3.53(d,J＝6.0Hz,2H),2.88(dd,J＝22.5,8.8Hz,1H),2.63–2.52(m,3H),2.13–2.05(m,2H),1.58(s,6H).
实施例A32
Figure PCTCN2021080167-appb-000191
LCMS([M+H] +):842.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.66(d,J＝2.4Hz,1H),8.30(q,J＝8.5Hz,2H),8.12(dd,J＝8.8,2.4Hz,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.62–7.56(m,1H),7.15–7.00(m,4H),6.59(t,J＝5.8Hz,1H),5.06(dd,J＝12.8,5.3Hz,1H),4.08(t,J＝6.3Hz,2H),2.95–2.83(m,1H),2.64–2.51(m,3H),2.21–1.95(m,2H),1.86–1.76(m,2H),1.67(dd,J＝14.4,7.0Hz,2H),1.59(s,6H),1.54(d,J＝6.9Hz,2H).
实施例A33
Figure PCTCN2021080167-appb-000192
LCMS([M+H] +):912.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.27(d,J＝4.2Hz,2H),7.77(dd,J＝8.5,7.3Hz,1H),7.57(d,J＝8.0Hz,2H),7.47–7.39(m,3H),7.32(d,J＝8.6Hz,1H),5.21–5.06(m,3H),4.34(d,J＝12.1Hz,1H),3.84(s,1H),3.04(t,J＝12.7Hz,2H),2.96–2.82(m,2H),2.78(s,1H),2.68–2.52(m,4H),2.39(s,1H),2.14–1.56(m,9H),1.51(d,J＝1.9Hz,7H).
实施例A34
Figure PCTCN2021080167-appb-000193
LCMS([M+H] +):885.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.77(d,J＝2.0Hz,1H),8.65(m,1H),8.27(m,6H),8.07(dd,J＝8.5,2.4Hz,1H),7.96(d,J＝8.4Hz,2H),7.81–7.74(m,1H),7.43(dd,J＝22.6,7.9Hz,2H),7.29–7.02(m,1H),5.09(m,1H),4.81(m,2H),3.39(m,4H),2.95–2.82(m,2H),2.08–1.93(m,2H),1.61(s,6H).
实施例A35
Figure PCTCN2021080167-appb-000194
LCMS([M+H] +):876.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.67(d,J＝2.5Hz,1H),8.34–8.23(m,3H),8.17(d,J＝8.5Hz,1H),8.06–7.92(m,3H),7.75(dd,J＝8.5,7.3Hz,1H),7.47(d,J＝7.2Hz,1H),7.39(d,J＝8.5Hz,1H),7.33(t,J＝8.8Hz,1H),5.09(dd,J＝12.9,5.4Hz,1H),4.83(s,2H),4.22(t,J＝5.5Hz,2H),3.61(t,J＝5.7Hz,2H),2.88(ddd,J＝17.4,14.0,5.3Hz,1H),2.57(td,J＝13.9,3.9Hz,2H),2.01(ddd,J＝14.8,6.5,2.3Hz,1H),1.59(s,6H).
实施例A36
Figure PCTCN2021080167-appb-000195
LCMS([M+H] +):883.3
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.71(d,J＝2.4Hz,1H),8.51(d,J＝2.3Hz,1H),8.45(dd,J＝8.9,2.4Hz,1H),8.32–8.23(m,4H),8.03(dd,J＝8.5,2.5Hz,1H),7.76(dd,J＝8.5,7.3Hz,1H),7.48–7.38(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),4.83(s,2H),4.33(t,J＝5.5Hz,2H),3.63(q,J＝5.6Hz,2H),2.87(ddd,J＝17.3,14.0,5.5Hz,1H),2.63–2.51(m,2H),1.59(s,6H).
实施例A37
Figure PCTCN2021080167-appb-000196
LCMS([M+H] +):898.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.67(m,1H),8.29(m,2H),8.13(d,J＝8.1Hz,3H),7.96(d,J＝7.9Hz,1H),7.79(t,J＝7.6Hz,1H),7.47(d,J＝6.6Hz,1H),7.37(d,J＝8.4Hz,1H),7.16(d,J＝7.9Hz,2H),5.23(m,2H),5.11(m,1H),4.79(m,1H),3.79(m,3H),2.88(m,1H),2.66–2.51(m,4H),2.05(m,3H),1.78(m,1H),1.59(s,6H).
实施例A38
Figure PCTCN2021080167-appb-000197
LCMS([M+H] +):858.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.65(d,J＝2.5Hz,1H),8.48(t,J＝5.6Hz,1H),8.29(q,J＝8.5Hz,2H),8.11(d,J＝8.9Hz,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.84(d,J＝8.3Hz,1H),7.46(d,J＝2.2Hz,1H),7.39(dd,J＝8.3,2.3Hz,1H),7.07(d,J＝8.9Hz,2H),5.11(dd,J＝12.8,5.4Hz,1H),4.78(s,2H),4.13(t,J＝5.5Hz,2H),3.61–3.52(m,2H),2.93–2.80(m,1H),2.57(dd,J＝21.7,6.7Hz,2H),2.08–1.97(m,1H),1.58(s,6H).
实施例A39
Figure PCTCN2021080167-appb-000198
LCMS([M+H] +):894.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(s,1H),8.32–8.25(m,3H),8.16(dd,J＝11.9,1.9Hz,1H),7.84(m,2H),7.75(m,1H),7.47(d,J＝7.2Hz,1H),7.38(dd,J＝16.1,8.8Hz,2H),5.08(m,1H),4.83(s,2H),4.24(m,2H),3.62(m,2H),2.88(m,1H),2.62–2.51(m,2H),2.03(m,1H),1.61(brs,6H).
实施例A40
Figure PCTCN2021080167-appb-000199
LCMS([M+H] +):894.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(s,1H),8.51(t,J＝5.7Hz,1H),8.32–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.89–7.80(m,3H),7.45(d,J＝2.2Hz,1H),7.42–7.32(m,2H),5.10(m,J＝12.9,5.4Hz,1H),4.78(s,2H),4.23(m,2H),3.59(m,2H),2.88(m,1H),2.63–2.51(m,2H),2.06–1.97(m,1H),1.61(s,6H).
实施例A41
Figure PCTCN2021080167-appb-000200
LCMS([M+H] +):893.2
1HNMR(400MHz,DMSO-d6)δ11.09(s,1H),8.63(s,1H),8.38(t,J＝5.8Hz,1H),8.2 9(s,2H),8.17(d,J＝11.9Hz,1H),7.87(d,J＝13.8Hz,1H),7.76(d,J＝8.0Hz,1H),7.61–7.56(m,1H),7.24–7.17(m,2H),7.02(d,J＝6.9Hz,1H),6.75(s,1H),5.05(dd,J＝13.0,5.4Hz,1H),4.70(s,2H),3.43(s,2H),3.39(d,J＝4.8Hz,2H),2.88(s,1H),2.00(d,J＝7.6Hz,3H),1.62(s,6H).
实施例A42
Figure PCTCN2021080167-appb-000201
LCMS([M+H] +):934.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.64(s,1H),8.28(d,J＝3.3Hz,2H),8.17(dd,J＝11.8,1.9Hz,1H),7.86(dd,J＝12.4,9.9Hz,3H),7.48(dd,J＝16.3,5.5Hz,2H),7.36(dd,J＝8.3,2.3Hz,1H),5.18(s,2H),5.12(dd,J＝12.9,5.4Hz,1H),4.83(s,1H),3.78(d,J＝54.3Hz,2H),3.41(s,2H),2.87(d,J＝11.5Hz,1H),2.61(dd,J＝31.3,14.5Hz,2H),2.12–1.94(m,4H),1.81(s,1H),1.61(s,6H).
实施例A43
Figure PCTCN2021080167-appb-000202
LCMS([M+H] +):934.3
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.64(s,1H),8.28(s,2H),8.17(dd,J＝11.8,1.9Hz,1H),7.86(t,J＝9.8Hz,2H),7.82–7.76(m,1H),7.48(dd,J＝17.1,8.1Hz,2H),7.37(d,J＝8.7Hz,1H),5.23(s,2H),5.10(dd,J＝12.8,5.4Hz,1H),4.83(s,1H),3.86(s,2H),3.40(s,2H),2.88(d,J＝11.3Hz,1H),2.70–2.56(m,2H),2.06–1.91(m,4H),1.81(s,1H),1.61(s,6H).
实施例A44
Figure PCTCN2021080167-appb-000203
LCMS([M+H] +):884.3
1HNMR(400MHz,DMSO-d6)δ11.09(s,1H),8.66(s,1H),8.32-8.26(m,2H),8.15-8.12(m,3H),7.96(d,J＝8.3Hz,1H),7.78(t,J＝7.9Hz,1H),7.46(d,J＝7.3Hz,1H),7.39(d,J＝8.5Hz,2H),7.16–7.09(m,2H),5.30–5.00(m,4H),3.88–3.58(m,4H),2.93-2.86(m,1H),2.61–2.54(m,2H),2.32-2.27(m,1H),2.19–2.13(m,1H),2.04-2.03(m,1H),1.58(s,6H).
实施例A45
Figure PCTCN2021080167-appb-000204
LCMS([M+H] +):911.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.76(d,J＝2.4Hz,1H),8.32–8.24(m,5H),8.06(dd,J＝8.4,2.4Hz,1H),7.80–7.76(m,1H),7.61(d,J＝8.3Hz,2H),7.46(d,J＝7.2Hz,1H),7.37(d,J＝8.7Hz,1H),5.22(s,2H),5.10(dd,J＝12.8,5.4Hz,1H),3.55(m,7H),2.89(t,J＝12.8Hz,1H),2.67-2.54(m,2H),2.04–1.99(m,1H),1.60(s,6H).
实施例A46
Figure PCTCN2021080167-appb-000205
将中间体46-1(5.85g,0.03mol)，化合物46-2(5.4g,0.06mol)，TBAC(4.17g,0.015mol),依次加入到120mlDCM中，冷却至0℃后滴加60ml33％ 的NaOH溶液，室温反应过夜，反应结束后，200ml水洗，200mlDCM萃取，100ml饱和食盐水洗涤，无水硫酸钠干燥，旋干得粗品，柱层析PE:EA＝2:1-1:1得到4.08g无色油状中间体46-3，产率66.7％.
Figure PCTCN2021080167-appb-000206
将中间体46-3(4.08g,0.02mmol)，TsCl(5.72g,0.03mol)，三乙胺(4.04g,0.04mol)，DMAP(244mg,0.002mol)依次加入到100mlDCM中，室温反应一小时，反应结束后，100ml水洗，100mlDCM萃取，100ml饱和食盐水洗涤，无水硫酸钠干燥，旋干上层析柱PE:EA＝20:1-10:1得到6g无色液体46-4,产率83.7％.
Figure PCTCN2021080167-appb-000207
将中间体46-5(5.02g,0.029mol)，化合物46-6(4.83g,0.035mol)，Pd(dppf)Cl 2(2.12g,0.0029mol)，Na 2CO 3(6.15g,0.058mol)加入到150ml二氧六环和50ml水中，N2保护下，90℃搅拌过夜，反应结束后过滤，用100ml水洗涤，200mlEA萃取2次，饱和食盐水100ml洗涤，无水硫酸钠干燥，旋干上层析柱DCM:MeOH＝100:1-50:1-20:1得到5.5g棕色固体中间体46-7，产率92.6％。
Figure PCTCN2021080167-appb-000208
将中间体46-7(1.19g,9.6mmol)，中间体46-4(4.13g,11.52mmol)和碳酸钾(2.65g,19.2mmol)加入到20mlDMF中，100℃反应2小时，反应结束后，用100ml水洗涤，100mlEA萃取2次，饱和食盐水100ml洗涤2次，无水硫酸钠干燥，旋干上层析柱PE:EA＝5:1-2:1得到2g浅棕色油状物中间体46-8，产率56％.
Figure PCTCN2021080167-appb-000209
将中间体46-8(2.01g,5.4mmol)，TMSCN(2.68g,27.0mmol)，ZnCl2(147mg,1.08mmol)依次加入到20ml的丙酮中，室温反应1小时，反应结束后，100ml水洗，100mlEA萃取，100ml饱和食盐水洗涤，无水硫酸钠干燥，旋干得到2.2g棕色油状物46-9，产率92.8％.
Figure PCTCN2021080167-appb-000210
将中间体46-9(2.2g,5mmol)，化合物46-10(2.46g,10mmol)加入到20mlDMF中，室温搅拌过夜，加入20ml二氧六环和20ml6N的盐酸，90℃搅拌1小时，反应结束后，100ml水洗涤，100mlEA萃取2次，饱和食盐水洗涤，无水硫酸钠干燥，旋干上层析柱PE:EA＝5:1-2:1得到1.2g浅棕色中间体46-11，产率38％
Figure PCTCN2021080167-appb-000211
将46-11(140mg，0.22mmol)，46-12(103mg，0.22mmol)，HATU(167mg，0.44mmol)，三乙胺(66mg，0.66mmol)依次加入到10mlDCM中，室温搅拌一小时，反应结束后，用20ml水洗涤，20mlDCM萃取，20ml饱和食盐水洗涤，无水硫酸钠干燥，旋蒸，上后制备板DCM:MeOH＝10:1,得到100mg，再上制备柱得到60mg白色固体A46，纯度98％，产率26％
LCMS([M+H] +):1043.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.7Hz,1H),8.68–8.57(m,2H),8.30(q,J ＝8.5Hz,2H),8.10(dd,J＝8.7,4.1Hz,3H),7.95(dd,J＝8.5,2.4Hz,1H),7.47–7.36(m,5H),7.06(d,J＝8.9Hz,2H),5.17(d,J＝3.5Hz,1H),4.58(d,J＝9.6Hz,1H),4.50–4.33(m,3H),4.27(dd,J＝15.8,5.6Hz,1H),4.09(t,J＝6.2Hz,2H),3.96(s,2H),3.70–3.54(m,4H),2.44(d,J＝7.2Hz,3H),2.07(dd,J＝12.4,8.3Hz,1H),1.95–1.80(m,3H),1.75(dd,J＝13.9,6.2Hz,2H),1.59(s,6H),0.94(d,J＝6.9Hz,9H).
实施例A47-A142采用与实施例A1相似的操作，用与之相对应的试剂合成。
实施例A47
Figure PCTCN2021080167-appb-000212
LCMS([M+H] +):1020.2
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59–8.50(m,2H),8.32–8.24(m,2H),7.82(ddd,J＝14.0,13.5,7.5Hz,3H),7.42(dt,J＝16.1,8.3Hz,5H),5.13(d,J＝3.5Hz,1H),4.54(d,J＝9.4Hz,1H),4.43(dd,J＝15.7,7.2Hz,2H),4.34(s,1H),4.21(dd,J＝15.9,5.4Hz,1H),3.71–3.59(m,2H),3.01(dd,J＝13.1,6.3Hz,2H),2.83–2.74(m,2H),2.44(s,3H),2.29–2.20(m,1H),2.13(q,J＝7.7Hz,3H),1.92(dd,J＝14.8,7.9Hz,3H),1.53(s,6H),1.51–1.34(m,4H),1.28–1.17(m,3H),0.92(d,J＝7.9Hz,9H).
实施例A48
Figure PCTCN2021080167-appb-000213
LCMS([M+H] +):971.2
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝5.3Hz,1H),8.66(d,J＝2.3Hz,1H),8.60(t,J＝6.1Hz,1H),8.29(q,J＝8.7Hz,2H),8.13(d,J＝8.9Hz,3H),7.98–7.89(m,2H),7.45–7.31(m,4H),7.10(d,J＝8.9Hz,2H),5.16(d,J＝3.5Hz,1H),4.79–4.69(m,2H),4.60(d,J＝9.4Hz,1H),4.48–4.33(m,3H),4.25(dd,J＝15.9,5.4Hz,1H),3.65(dd,J＝23.5,8.8Hz,2H),2.44(d,J＝6.2Hz,3H),1.99(ddd,J＝31.9,16.9,10.7Hz,3H),1.58(s,6H),0.93(d,J＝10.6Hz,9H).
实施例A49
Figure PCTCN2021080167-appb-000214
LCMS([M+H] +):999.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.8Hz,1H),8.65(d,J＝2.4Hz,1H),8.56(t,J＝6.0Hz,1H),8.29(q,J＝8.5Hz,2H),8.09(dd,J＝17.2,8.8Hz,3H),7.99(d,J＝9.3Hz,1H),7.94(dd,J＝8.5,2.5Hz,1H),7.40(q,J＝8.4Hz,4H),7.07(d,J＝8.9Hz,2H),5.14(d,J＝3.5Hz,1H),4.57(d,J＝9.4Hz,1H),4.47–4.39(m,2H),4.36(s,1H),4.21(dd,J＝15.9,5.5Hz,1H),4.05(d,J＝2.2Hz,2H),3.67(s,2H),2.47–2.31(m,5H),2.07–1.87(m,4H),1.58(s,6H),0.93(d,J＝7.7Hz,9H).
实施例A50
Figure PCTCN2021080167-appb-000215
LCMS([M+H] +):985.1
1HNMR(400MHz,DMSO-d6)δ8.94(s,1H),8.60(t,J＝6.0Hz,1H),8.27(d,J＝4.5Hz, 2H),7.80(d,J＝9.7Hz,1H),7.55(d,J＝8.5Hz,2H),7.41(s,5H),5.15(d,J＝3.4Hz,1H),4.51(d,J＝9.7Hz,1H),4.44(t,J＝8.2Hz,1H),4.35(d,J＝5.8Hz,2H),4.30(d,J＝5.9Hz,1H),3.70–3.57(m,2H),3.04(d,J＝16.2Hz,1H),2.95(d,J＝16.0Hz,1H),2.74(s,3H),2.44(s,3H),2.35(d,J＝12.3Hz,2H),2.06(dd,J＝13.7,6.8Hz,1H),1.90(ddd,J＝12.8,8.9,4.4Hz,3H),1.51(s,7H),0.95(s,9H).
实施例A51
Figure PCTCN2021080167-appb-000216
LCMS([M+H] +):1043.2
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝1.8Hz,1H),8.98–8.95(m,1H),8.63(t,J＝6.0Hz,1H),8.57(d,J＝2.0Hz,1H),8.33–8.25(m,2H),8.19(s,1H),7.72(d,J＝8.7Hz,2H),7.46–7.34(m,5H),7.07(d,J＝8.8Hz,2H),5.20(d,J＝3.3Hz,1H),4.56(d,J＝9.7Hz,1H),4.45(t,J＝8.3Hz,1H),4.41–4.35(m,2H),4.27(d,J＝5.4Hz,1H),4.07(t,J＝6.2Hz,2H),3.93(s,2H),3.66–3.62(m,2H),3.57–3.54(m,2H),2.42(s,3H),2.11–2.03(m,1H),2.00–1.99(m,1H),1.94–1.87(m,1H),1.83–1.81(m,2H),1.77–1.69(m,2H),1.60(d,J＝2.6Hz,6H),0.94(s,9H).
实施例A52
Figure PCTCN2021080167-appb-000217
LCMS([M+H] +):1013.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.8Hz,1H),8.65(d,J＝2.4Hz,1H),8.56(t,J＝5.8Hz,1H),8.29(q,J＝8.5Hz,2H),8.11(d,J＝8.8Hz,3H),7.96–7.89(m,2H),7.40(q,J＝ 8.4Hz,4H),7.07(d,J＝8.9Hz,2H),5.13(d,J＝3.5Hz,1H),4.57(d,J＝9.3Hz,1H),4.48–4.39(m,2H),4.36(s,1H),4.21(dd,J＝15.9,5.5Hz,1H),4.06(t,J＝5.7Hz,2H),3.73–3.62(m,2H),2.44(d,J＝3.5Hz,3H),2.41–2.32(m,1H),2.23(dd,J＝14.0,6.9Hz,1H),2.04(dd,J＝19.1,6.1Hz,1H),1.95–1.86(m,1H),1.78–1.63(m,4H),1.58(s,6H),0.95(s,9H).
实施例A53
Figure PCTCN2021080167-appb-000218
LCMS([M+H] +):1054.3
1HNMR(400MHz,DMSO-d6):8.91(s,1H),8.69(s,1H),8.10(d,J＝12Hz2H),7.96-7.87(m,4H),7.83(d,J＝8Hz2H),7.44-7.41(t,1H),7.34-7.36(t,4H),6.81(s,1H),6.37-6.39(d,J＝8Hz1H),4.72-4.76(t,1H),4.55-4.61(t,3H),4.33-4.38(m,1H),4.08-4.13(m,1H),3.62-3.65(m,1H),3.45-3.49(m,2H),2.42-2.49(m,5H),2.15-2.33(m,4H),1.61-1.67(m,10H),1.38-1.44(m,2H),0.97(s,9H).
实施例A54
Figure PCTCN2021080167-appb-000219
LCMS([M+H] +):1085.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.7Hz,1H),8.66–8.58(m,2H),8.29(q,J＝8.5Hz,2H),8.10(dd,J＝8.7,1.9Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.46–7.37(m,5H),7.06(d,J＝8.9Hz,2H),5.27(s,1H),4.44(ddd,J＝32.8,16.1,7.3Hz,3H),4.28(dd,J＝15.7,5.8Hz,1H),4.09(t,J＝6.2Hz,2H),3.94(t,J＝7.4Hz,3H),3.84(dd,J＝11.7,4.1Hz,1H),3.55(t,J＝6.2Hz,2H),2.44(d,J＝5.8Hz,3H),2.26(dd,J＝13.6,7.8Hz,1H),2.12(ddd,J＝13.7,9.0,4.9H z,1H),1.98(d,J＝13.4Hz,3H),1.82(dd,J＝14.0,6.2Hz,2H),1.78–1.69(m,2H),1.58(s,6H),1.35(s,1H),0.94(d,J＝8.2Hz,9H).
实施例A55
Figure PCTCN2021080167-appb-000220
LCMS([M+H] +):1061.3
1HNMR(400MHz,DMSO-d6)δ8.97–(m,1H),8.67(d,J＝2.3Hz,1H),8.60(t,J＝6.0Hz,1H),8.34–8.24(m,2H),8.17(d,J＝8.5Hz,1H),8.03–7.93(m,3H),7.45–7.35(m,5H),7.29(t,J＝8.6Hz,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.5Hz,1H),4.49–4.34(m,3H),4.28–4.23(m,1H),4.17(t,J＝6.2Hz,2H),3.96(d,J＝1.7Hz,2H),3.70–3.53(m,5H),2.44–2.42(m,3H),2.09–2.04(m,1H),1.93–1.83(m,3H),1.77–1.72(m,2H),1.58(s,6H),0.94–0.92(m,9H)
实施例A56
Figure PCTCN2021080167-appb-000221
LCMS([M+H] +):1081.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.95(m,1H),8.75(d,J＝2.4Hz,1H),8.62–8.43(m,3H),8.33–8.20(m,5H),8.4–8.00(m,3H),7.45–7.35(m,4H),5.19–5.12(m,1H),4.54(dd,J＝9.3,2.6Hz,1H),4.50–4.33(m,4H),4.29–4.20(m,1H),3.70–3.63(m,2H),2.89(m,1H),2.79–2.57(m,4H),2.43(s,3H),2.34–2.18(m,3H),2.04(m,1H),1.99–1.86(m,2H),1.82(m,1H),1.59(s,6H),0.94(d,J＝4.8Hz,9H).
实施例A57
Figure PCTCN2021080167-appb-000222
LCMS([M+H] +):1068.2
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝8.2Hz,1H),8.70(d,J＝2.0Hz,1H),8.59(t,J＝6.1Hz,1H),8.50(d,J＝2.2Hz,1H),8.46(d,J＝8.9Hz,1H),8.27(dd,J＝17.1,7.1Hz,3H),8.02(dd,J＝8.5,2.3Hz,1H),7.44–7.35(m,6H),5.15(d,J＝3.4Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.38(m,2H),4.36(d,J＝6.0Hz,4H),4.27(t,J＝6.1Hz,3H),3.96(d,J＝3.2Hz,2H),3.69–3.62(m,2H),3.59(t,J＝6.2Hz,5H),2.43(d,J＝6.7Hz,3H),2.03(dd,J＝22.7,10.5Hz,2H),1.88(d,J＝8.0Hz,6H),1.80–1.73(m,2H),1.58(s,6H),0.93(d,J＝7.9Hz,9H).
实施例A58
Figure PCTCN2021080167-appb-000223
LCMS([M+H] +):1081.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.2Hz,1H),8.75(d,J＝2.5Hz,1H),8.59(t,J＝6.2Hz,1H),8.47(d,J＝9.5Hz,1H),8.30(q,J＝8.5Hz,2H),8.21(dd,J＝18.2,8.4Hz,3H),8.05(dd,J＝8.4,2.5Hz,1H),7.49(d,J＝8.2Hz,2H),7.44(d,J＝8.2Hz,2H),7.37(d,J＝8.3Hz,2H),5.32(t,J＝4.7Hz,1H),5.14(d,J＝3.4Hz,1H),4.56(d,J＝9.5Hz,1H),4.44(dd,J＝16.8,8.7Hz,2H),4.35(s,1H),4.21(dd,J＝15.9,5.5Hz,1H),3.64(dd,J＝23.6,8.3Hz,4H),2.65(d,J＝12.2Hz,3H),2.44(d,J＝8.5Hz,5H),2.28(d,J＝15.5Hz,1H),2.00(dd,J＝14.8,7.2Hz,3H),1.91(dd,J＝17.3,8.6Hz,1H),1.60(s,6H),1.45(s,1H),0.95(s,8H).
实施例A59
Figure PCTCN2021080167-appb-000224
LCMS([M+H] +):1080.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.76(d,J＝2.3Hz,1H),8.60–8.54(m,2H),8.34–8.23(m,5H),8.06(dd,J＝8.5,2.4Hz,1H),8.01(d,J＝8.5Hz,2H),7.72(d,J＝9.3Hz,1H),7.41(q,J＝8.4Hz,4H),5.14(m,1H),4.52(m,1H),4.44(m,2H),4.36(m,1H),4.22(m,1H),3.69–3.61(m,2H),3.16(m,2H),2.45(s,3H),2.36(m,1H),2.07–1.99(m,1H),1.90(m,1H),1.80(m,3H),1.69(m,1H),1.61(s,6H),1.31(m,4H),0.93(m,,9H).
实施例A60
Figure PCTCN2021080167-appb-000225
LCMS([M+H] +):1074.3
1HNMR(400MHz,DMSO-d6)δ9.25(t,J＝6.0Hz,1H),8.98(s,1H),8.76(d,J＝2.4Hz,1H),8.58(t,J＝6.0Hz,1H),8.31–8.26(m,5H),8.06(dd,J＝8.5,2.6Hz,3H),7.91(d,J＝9.1Hz,1H),7.85(d,J＝8.2Hz,2H),7.45–7.39(m,6H),5.15(d,J＝3.6Hz,1H),4.77(d,J＝9.1Hz,1H),4.56(d,J＝5.8Hz,2H),4.49–4.35(m,3H),4.24(dd,J＝15.9,5.5Hz,1H),3.73(d,J＝3.1Hz,2H),2.44(s,3H),2.06–1.88(m,2H),1.60(s,6H),1.03(s,9H).
实施例A61
Figure PCTCN2021080167-appb-000226
LCMS([M+H] +):1135.3
1HNMR(400MHz,DMSO-d6):8.99(s,1H),8.76(s,1H),8.56(s,1H),8.21-8.31(m,5H),8.05(d,J＝8Hz1H),7.73-7.76(d,J＝12Hz1H),7.55(d,J＝8Hz2H),7.38-7.43(m,4H),5.14(s,1H),4.36-4.54(m,5H),4.21-4.24(m,1H),3.64(m,3H),3.06(s,2H),2.86(s,2H),2.45(s,3H),2.35(s,1H),2.02-2.14(m,4H),1.68-1.90(m,5H),1.58-1.60(m,6H),1.44-1.48(m,4H),0.94(s,9H).
实施例A62
Figure PCTCN2021080167-appb-000227
LCMS([M+H] +):1111.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝9.9Hz,2H),8.60(t,J＝5.8Hz,1H),8.49(d,J＝1.8Hz,1H),8.27(d,J＝12.3Hz,2H),7.50(d,J＝8.5Hz,2H),7.46–7.35(m,5H),7.05(d,J＝8.7Hz,2H),5.17(s,1H),4.57(d,J＝9.6Hz,1H),4.50–4.33(m,3H),4.26(m,1H),4.09(m,2H),3.95(m,2H),3.69–3.54(m,5H),2.44(m,3H),2.00(m,3H),1.89–1.79(m,2H),1.80–1.70(m,2H),1.64(d,J＝7.1Hz,6H),1.24(m,2H),0.95(s,9H).
实施例A63
Figure PCTCN2021080167-appb-000228
LCMS([M+H] +):1061.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.8Hz,1H),8.60(s,2H),8.29(d,J＝12.7Hz,2H),8.11(d,J＝11.7Hz,1H),7.96(d,J＝7.9Hz,2H),7.40(d,J＝7.7Hz,5H),7.09(d,J＝8.7Hz,2H),5.17(d,J＝3.1Hz,1H),4.57(d,J＝9.5Hz,1H),4.50–4.32(m,3H),4.26(dd,J＝15.7,5.4Hz,1H),4.09(t,J＝5.9Hz,2H),3.96(s,2H),3.70–3.51(m,4H),2.43(d,J＝7.2Hz,3H),2.07(t,J＝9.8Hz,1H),1.96–1.79(m,3H),1.79–1.69(m,2H),1.61(s,6H),0.94(s,9H).
实施例A64
Figure PCTCN2021080167-appb-000229
LCMS([M+H] +):1054.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝7.5Hz,1H),8.67(d,J＝2.4Hz,1H),8.55(t,J＝6.0Hz,1H),8.29(q,J＝8.5Hz,2H),8.16–8.05(m,3H),8.01–7.93(m,2H),7.39(q,J＝8.3Hz,4H),6.99(dd,J＝30.6,8.8Hz,2H),5.17–5.09(m,1H),4.55(d,J＝9.4Hz,1H),4.47–4.38(m,2H),4.34(s,1H),4.31–4.16(m,3H),4.07–3.96(m,2H),3.66(dt,J＝16.6,7.2Hz,2H),3.13–2.99(m,2H),2.43(d,J＝6.5Hz,3H),2.36–2.26(m,1H),2.25–2.14(m,1H),2.02(d,J＝7.7Hz,1H),1.89(ddd,J＝40.5,20.4,16.0Hz,4H),1.58(s,6H),0.93(d,J＝9.0Hz,9H).
实施例A65
Figure PCTCN2021080167-appb-000230
LCMS([M+H] +):1068.4
1HNMR(400MHz,DMSO-d6):8.95(s,1H),8.74-8.77(d,J＝12Hz1H),8.62-8.66(m,2H),8.26-8.33(m,2H),8.04-8.10(m,3H),7.96-7.94(d,J＝8Hz1H),7.39-7.47(m,4H),6.99-7.01(d,J＝8Hz2H),5.16(s,1H),4.19-4.59(m,6H),3.62-3.68(m,2H),2.76-2.82(m,2H),2.61(s,1H),2.44(m,4H),2.27-2.35(m,3H),1.92-2.05(m,4H),2.02-2.14(m,4H),1.74-1.80(m,2H),1.59(s,6H),1.23(s,1H),0.97(s,9H).
实施例A66
Figure PCTCN2021080167-appb-000231
LCMS([M+H] +):1057.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.1Hz,1H),8.65(d,J＝2.3Hz,1H),8.47(t,J＝5.9Hz,1H),8.33–8.24(m,2H),8.10(t,J＝9.1Hz,3H),7.94(dd,J＝8.5,2.4Hz,1H),7.39(s,4H),7.06(t,J＝9.9Hz,2H),5.15(dd,J＝11.0,3.5Hz,1H),5.06(s,1H),4.33(dt,J＝14.5,8.1Hz,4H),4.23(d,J＝12.2Hz,1H),4.09(t,J＝6.2Hz,2H),3.62(dd,J＝10.6,4.3Hz,1H),3.53(dt,J＝12.1,6.0Hz,2H),3.03–2.92(m,3H),2.43(d,J＝5.8Hz,3H),2.07–1.98(m,1H),1.94–1.78(m,3H),1.71(dd,J＝14.2,6.3Hz,2H),1.58(s,6H),1.08–0.88(m,9H).
实施例A67
Figure PCTCN2021080167-appb-000232
LCMS([M+H] +):1146.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.96(m,1H),8.69(d,J＝2.4,1H),8.59(t,J＝5.9Hz,1H),8.32–8.24(m,2H),8.17–8.12(m,3H),8.00(dd,J＝8.5,2.5Hz,1H),7.39–7.18(m,12H),5.15(d,J＝3.5Hz,1H),4.92(s,2H),4.51(d,J＝9.6Hz,1H),4.44(t,J＝8.2Hz,1H),4.40–4.34(m,2H),4.26(dd,J＝15.9,5.7Hz,1H),3.85(s,2H),3.65–3.57(m,2H),3.42(m,2H),2.41(s,3H),2.25(m,2H),2.08–2.02(m,1H),1.92–1.87(m,1H),1.84–1.78(m,2H),1.56(s,6H),0.86(s,9H).
实施例A68
Figure PCTCN2021080167-appb-000233
LCMS([M+H] +):1042.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.58(d,J＝2.6Hz,2H),8.30(q,J＝8.6Hz,2H),8.04–7.95(m,3H),7.85(t,J＝7.8Hz,2H),7.40(d,J＝2.7Hz,4H),6.77(d,J＝8.9Hz,2H),5.33(m,1H),5.16(m,1H),4.57(m,1H),4.45(m,3H),4.41–4.34(m,2H),4.26(m,2H),4.244.04(m,2H),3.66(m,2H),3.60(m,2H),2.45(s,3H),2.04–1.99(m,2H),1.58(s,6H),1.53–1.43(m,4H),0.91(d,J＝11.8Hz,9H).
实施例A69
Figure PCTCN2021080167-appb-000234
LCMS([M+H] +):1067.4
1HNMR(400MHz,DMSO-d6)δ8.99–8.94(m,1H),8.70(d,J＝2.4Hz,1H),8.59(t,J＝5.6Hz,1H),8.32–8.26(m,2H),8.17(d,J＝8.3Hz,1H),8.08(d,J＝7.2Hz,2H),7.99(d,J＝8.2Hz,1H),7.78(d,J＝9.2Hz,1H),7.41–7.38(m,6H),5.15(d,J＝3.4Hz,1H),4.51(d,J＝9.6Hz,1H),4.45–4.36(m,3H),4.30–4.25(m,1H),3.66(m,2H),3.60(m,2H),2.82(m,6H),2.54(m,4H),2.45(m,3H),2.09–1.83(m,4H),1.59(s,6H),0.94(m,9H).
实施例A70
Figure PCTCN2021080167-appb-000235
LCMS([M+H] +):1079.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝10.8Hz,1H),8.66–8.57(m,2H),8.33–8.26(m,2H),8.16(dd,J＝11.9,1.8Hz,1H),7.83(d,J＝10.6Hz,2H),7.46–7.31(m,6H),5.17(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.33(m,3H),4.32–4.16(m,3H),4.01–3.90(m,2H),3.63(ddd,J＝27.9,11.5,4.8Hz,4H),2.44(d,J＝7.4Hz,3H),2.07(dd,J＝12.5,7.3Hz,1H),1.95–1.83(m,3H),1.76(dd,J＝14.0,6.1Hz,2H),1.61(s,6H),0.94(d,J＝7.0Hz,9H).
实施例A71
Figure PCTCN2021080167-appb-000236
LCMS([M+H] +):1015.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.92(m,1H),8.63–8.60(m,2H),8.32–8.26(m,2H),8.13–8.03(m,3H),7.93(dd,J＝8.5,2.5Hz,1H),7.51(d,J＝9.5Hz,1H),7.40(dd,J＝19.6,8.4Hz,4H),7.15(d,J＝8.9Hz,2H),5.17(d,J＝3.6Hz,1H),4.61(d,J＝9.6Hz,1H),4.48–4.39(m,2H),4.36(m,1H),4.29–4.21(m,3H),4.07(s,2H),3.89–3.88(m,2H),3.71–3.66(m,1H),3.63–3.60(m,1H),2.39(s,3H),2.10–1.87(m,2H),1.57(s,6H),0.96(s,9H).
实施例A72
Figure PCTCN2021080167-appb-000237
LCMS([M+H] +):1047.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.67(d,J＝2.5Hz,1H),8.59(t,J＝6.0Hz,1H),8.32–8.25(m,2H),8.15(d,J＝8.5Hz,1H),7.97(dt,J＝8.5,2.3Hz,3H),7.45(d,J＝9.5Hz,1H),7.38(d,J＝1.7Hz,4H),7.36–7.31(m,1H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.5Hz,1H),4.46(t,J＝8.2Hz,1H),4.38(dd,J＝15.8,6.0Hz,2H),4.29(d,J＝5.7Hz,1H),4.24(t,J＝6.4Hz,2H),3.98(d,J＝1.5Hz,2H),3.70–3.59(m,4H),2.42(s,3H),2.11–2.03(m,3H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.58(s,6H),0.94(s,9H).
实施例A73
Figure PCTCN2021080167-appb-000238
LCMS([M+H] +):1058.3
1HNMR(400MHz,DMSO-d6):8.96(s,1H),8.65-8.66(d,J＝4Hz1H),8.60-8.61(m,1H),8.27-8.31(m,2H),8.09-8.11(m,3H),7.93-7.96(m,1H),7.37-7.44(m,5H),7.04-7.06(d,J＝8Hz2H),5.16-5.17(d,J＝4Hz1H),4.56-4.58(d,J＝8Hz2H),4.36-4.44(m,5H),4.24-4.28(m,2H),4.04-4.07(m,2H),3.94(s,2H),3.60-3.68(m,3H),3.51-3.54(m,3H),2.45(s,3H),2.0-2.07(m,6H),1.77-1.79(m,3H),1.63-1.65(m,3H),1.53-1.58(m,3H),1.24(s,6),0.95(s,9H).
实施例A74
Figure PCTCN2021080167-appb-000239
LCMS([M+H] +):1129.2
1HNMR(400MHz,DMSO-d6)δ8.99(t,J＝3.0Hz,1H),8.95(m,1H),8.60(t,J＝6.0Hz,1H),8.53(d,J＝2.1Hz,1H),8.32–8.24(m,2H),7.40(m,6H),7.32(m,2H),5.16(m,1H),4.57(m,1H),4.46(m,1H),4.39(m,2H),4.26(m,1H),4.18(m,2H),3.97(m,2H),3.71–3.62(m,2H),3.58(m,2H),2.44(s,3H),2.10–1.93(m,2H),1.92–1.84(m,2H),1.76(m,2H),1.64(d,J＝7.1Hz,6H),0.95(s,9H).
实施例A75
Figure PCTCN2021080167-appb-000240
LCMS([M+H] +):1136.3
1HNMR(400MHz,DMSO-d6)δ9.02(d,J＝1.9Hz,1H),8.95(m,1H),8.60(t,J＝6.0Hz,1H),8.56(d,J＝2.1Hz,1H),8.31–8.24(m,2H),7.91(d,J＝2.2Hz,1H),7.88–7.81(m,1H),7.46–7.37(m,6H),5.17(d,J＝3.5Hz,1H),4.57(m,1H),4.46(m,1H),4.39(m,2H),4.32–4.24(m,3H),3.97(m,2H),3.71–3.63(m,2H),3.60(m,2H),2.44(m,3H),2.11–2.03(m,1H),1.91(m,3H),1.79(m,2H),1.64(d,J＝7.7Hz,6H),0.94(d,J＝7.0Hz,9H).
实施例A76
Figure PCTCN2021080167-appb-000241
LCMS([M+H] +):1059.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝8.3Hz,1H),8.65(d,J＝2.4Hz,1H),8.58(t,J＝6.0Hz,1H),8.29(q,J＝8.5Hz,2H),8.09(dd,J＝8.8,2.3Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.48–7.35(m,5H),7.08(t,J＝10.5Hz,2H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.38(dd,J＝15.9,6.3Hz,2H),4.31–4.16(m,3H),3.97(d,J＝15.2Hz,2H),3.82(dd,J＝8.8,4.3Hz,2H),3.72–3.58(m,6H),2.43(d,J＝8.5Hz,3H),2.11–1.85(m,3H),1.58(s,6H),0.93(d,J＝8.2Hz,9H).
实施例A77
Figure PCTCN2021080167-appb-000242
LCMS([M+H] +):1097.3
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝15.1Hz,1H),8.66(s,1H),8.60(t,J＝5.9Hz,1H),8.27(s,2H),8.22(dd,J＝11.8,1.9Hz,1H),7.78–7.70(m,2H),7.45–7.34(m,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.32(m,4H),4.25(dd,J＝12.5,6.3Hz,2H),3.94(s,2H),3.65(dd,J＝12.9,9.3Hz,2H),3.55(t,J＝6.3Hz,2H),2.43(d,J＝10.2Hz,3H),2.10–1.86(m,4H),1.78(ddd,J＝19.5,13.8,7.0Hz,4H),1.61(s,6H),0.92(d,J＝8.4Hz,9H).
实施例A78
Figure PCTCN2021080167-appb-000243
LCMS([M+H] +):1086.3
1HNMR(400MHz,DMSO-d6):8.95(s,1H),8.66(s,1H),8.59-8.62(m,1H),8.29-8.30(m,5H),8.20-8.23(m,1H),7.40-7.43(m,6H),5.16-5.17(d,J＝4Hz1H),4.56-4.57(d,J＝8Hz1H),4.36-4.44(m,2H),4.29-4.31(m,2H),4.24-4.28(m,3H),3.97(s,2H),3.58-3.67(m,5H),2.43(s,3H),1.99-2.06(m,2H),1.89-1.92(m,4H),1.77-1.79(m,2H),1.62(s,6H),0.94(s,9H).
实施例A79
Figure PCTCN2021080167-appb-000244
LCMS([M+H] +):1147.3
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝2.1Hz,1H),8.94(s,1H),8.60(t,J＝6.0Hz,1H),8.57(d,J＝2.2Hz,1H),8.28(s,2H),7.46–7.31(m,7H),5.15(d,J＝3.6Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.32(m,3H),4.29–4.21(m,3H),3.95(s,2H),3.70–3.59(m,2H),3.56(t,J＝6.3Hz,2H),2.42(s,3H),2.06(dd,J＝13.1,7.7Hz,1H),1.90(ddd,J＝13.1,8.8,4.5Hz,1H),1.85–1.72(m,4H),1.63(d,J＝7.5Hz,6H),0.94(s,9H).
实施例A80
Figure PCTCN2021080167-appb-000245
LCMS([M+H] +):1066.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.95(m,1H),8.66(d,J＝2.5Hz,1H),8.56(t,J＝6.0Hz,1H),8.34–8.24(m,2H),8.22–8.06(m,5H),7.95(dd,J＝8.5,2.5Hz,1H),7.39(q,J＝8.4Hz,4H),7.18(d,J＝8.9Hz,2H),5.21(s,2H),5.17(d,J＝3.5Hz,1H),4.67–4.50(m,3H),4.47–4.39(m,2H),4.36(s,1H),4.21(dd,J＝15.8,5.5Hz,1H),3.66–3.65(m,2H),2.98–2.92(m,1H),2.83–2.73(m,1H),2.43(s,3H),2.08–2.00(m,1H),1.90–1.87(m,1H),1.58(s,6H),0.87(s,9H).
实施例A81
Figure PCTCN2021080167-appb-000246
LCMS([M+H] +):1080.1
1HNMR(400MHz,DMSO-d6)δ8.97–8.96(m,1H),8.66(d,J＝2.5Hz,1H),8.56(t,J＝6.0Hz,1H),8.34–8.23(m,3H),8.13(d,J＝9.0Hz,3H),8.03–7.92(m,2H),7.40(q,J＝8.4Hz,4H),7.19(d,J＝9.0Hz,2H),5.23(m,2H),5.14(d,J＝3.6Hz,1H),4.54(d,J＝9.3Hz,1H),4.45–4.36(m,5H),4.21(dd,J＝15.9,5.5Hz,1H),3.70–3.61(m,2H),2.44–2.43(m,3H),2.33–2.17(m,2H),2.07–2.04(m,3H),1.93–1.87(m,1H),1.58(s,6H),0.93(s,9H).
实施例A82
Figure PCTCN2021080167-appb-000247
LCMS([M+H] +):1033.3
1HNMR(400MHz,DMSO-d6):8.95(s,1H),8.68(s,1H),8.57-8.60(m,1H),8.26-8.32(m,2H),8.15-8.17(d,J＝8Hz1H),7.97-8.02(m,3H),7.34-7.40(m,6H),5.16(s,1H),4.57-4.60(d,J＝12Hz1H),4.22-4.35(m,6H),4.05-4.09(m,1H),3.9-3.92(m,2H),3.61-3.70(m,3H),2.43(s,3H),1.88-2.06(m,4H),1.6(s,6H),1.77-1.79(m,2H),1.62(s,6H),0.94(s,9H).
实施例A83
Figure PCTCN2021080167-appb-000248
LCMS([M+H] +):1077.3
1HNMR(400MHz,DMSO-d6)δ9.00–8.97(m,1H),8.71(d,J＝2.3Hz,1H),8.61(t,J＝6.0Hz,1H),8.35–8.29(m,2H),8.25(d,J＝2.2Hz,1H),8.21(d,J＝8.5Hz,1H),8.13(dd,J＝8.7,2.2Hz,1H),8.01(dd,J＝8.5,2.5Hz,1H),7.48–7.38(m,5H),7.30(d,J＝8.9Hz,1H),5.18(d,J＝3.5Hz,1H),4.60(d,J＝9.6Hz,1H),4.52–4.36(m,3H),4.29(dd,J＝15.8,5.8Hz,1H),4.22(t,J＝6.2Hz,2H),4.04–3.92(m,2H),3.72–3.60(m,4H),2.47–2.45(m,3H),2.14–1.98(m,1H),1.97–1.87(m,3H),1.83–1.78(m,2H),1.61(s,6H),0.97(s,9H).
实施例A84
Figure PCTCN2021080167-appb-000249
LCMS([M+H] +):1111.3
1HNMR(400MHz,DMSO-d6):δ8.94(s,1H),8.73–8.68(m,1H),8.58(t,J＝6.0Hz,1H),8.39(d,J＝5.9Hz,2H),8.34–8.20(m,3H),8.01(dd,J＝8.5,2.5Hz,1H),7.46–7.33(m,6H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.51–4.20(m,6H),3.95(d,J＝1.7Hz,2H),3.72–3.59(m,2H),3.57(t,J＝6.3Hz,2H),2.42(s,3H),2.14–1.67(m,6H),1.59(s,6H),0.94(s,9H).
实施例A85
Figure PCTCN2021080167-appb-000250
LCMS([M+H] +):1077.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.69(t,J＝7.4Hz,1H),8.63–8.56(m,1H),8.30(s,2H),8.17(t,J＝8.4Hz,1H),8.08–7.93(m,3H),7.47(d,J＝9.6Hz,1H),7.41(s,4H),7.33(q,J＝8.3Hz,1H),5.17(t,J＝10.1Hz,1H),4.59(t,J＝9.3Hz,1H),4.48(q,J＝8.1Hz,1H),4.44–4.35(m,2H),4.31(s,3H),4.02(s,2H),3.92–3.79(m,2H),3.70(s,6H),2.45(s,3H),2.14–2.04(m,1H),1.93(tt,J＝15.1,7.6Hz,1H),1.61(s,6H),0.96(d,J＝7.7Hz,9H).
实施例A86
Figure PCTCN2021080167-appb-000251
LCMS([M+H] +):1053.3
1HNMR(400MHz,DMSO-d6)δ8.99–8.98(m,1H),8.70(d,J＝2.5Hz,1H),8.59(t,J＝6.1Hz,1H),8.34–8.24(m,2H),8.16(d,J＝8.5Hz,1H),8.10(d,J＝8.3Hz,2H),7.99(dd,J＝8.5,2.5Hz,1H),7.78(d,J＝9.6Hz,1H),7.49–7.37(m,6H),5.14(d,J＝3.4Hz,1H),4.49(d,J＝9.7Hz,1H),4.46–4.33(m,3H),4.27(dd,J＝15.7,5.7Hz,1H),3.69–3.52(m,6H),2.99(dd,J＝41.9,16.1Hz,2H),2.52(m,3H),2.46–2.44(m,6H),2.06–1.85(m,2H),1.59(s,6H),0.94(s,9H).
实施例A87
Figure PCTCN2021080167-appb-000252
LCMS([M+H] +)：1070.3
1HNMR(400MHz,DMSO-d6)δ8.92(s,1H),8.66(s,1H),8.59(t,J＝6.2Hz,1H),8.28(s,2H),8.22(d,J＝11.7Hz,1H),7.73(d,J＝9.3Hz,2H),7.45–7.33(m,5H),4.57(d,J＝9.6Hz,1H),4.40(t,J＝17.8Hz,5H),4.24–4.19(m,1H),4.04(s,2H),3.85(s,2H),3.66(s,2H),2.42(d,J＝16.6Hz,4H),2.08–1.96(m,3H),1.61(s,6H),0.91(d,J＝8.9Hz,8H).
实施例A88
Figure PCTCN2021080167-appb-000253
LCMS([M+H] +):1028.3
1HNMR(400MHz,DMSO-d6)δ8.89(s,1H),8.54(dd,J＝11.8,5.8Hz,2H),8.22(s,2H),8.13(dd,J＝9.7,1.9Hz,1H),7.48(d,J＝9.0Hz,1H),7.32(d,J＝10.3Hz,7H),5.09(d,J＝3.5Hz,1H),4.51(d,J＝9.6Hz,1H),4.39(t,J＝8.2Hz,1H),4.32(dd,J＝15.8,6.2Hz,2H),4.20(dd,J＝15.7,5.7Hz,1H),4.11(t,J＝6.2Hz,2H),3.93–3.83(m,2H),3.57(ddd,J＝26.4,11.6,4.9Hz,4H),2.37(s,3H),2.04–1.95(m,1H),1.88–1.74(m,3H),1.70(dd,J＝13.9,6.1Hz,2H),1.54(s,6H),0.88(s,9H).
实施例A89
Figure PCTCN2021080167-appb-000254
LCMS([M+H] +):1093.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.63(s,1H),8.60(t,J＝6.0Hz,1H),8.28(s,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.86–7.80(m,2H),7.39(s,6H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.39(m,1H),4.37(d,J＝6.1Hz,2H),4.26(dd,J＝15.8,5.7Hz,1H),4.15(t,J＝6.4Hz,2H),3.95(d,J＝1.7Hz,2H),3.66(dt,J＝21.8,7.3Hz,2H),3.53(t,J＝6.3Hz,2H),2.43(s,3H),2.09–2.03(m,1H),1.90(ddd,J＝19.8,10.0,5.6Hz,1H),1.86(s,2H),1.69–1.63(m,2H),1.61(s,6H),1.54(dd,J＝15.0,8.0Hz,2H),0.95(s,9H).
实施例A90
Figure PCTCN2021080167-appb-000255
LCMS([M+H] +):1095.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.95(m,1H),8.62(s,1H),8.58(t,J＝6.0Hz,1H),8.31–8.26(m,2H),8.15(dd,J＝11.9,1.9Hz,1H),7.85–7.81(m,2H),7.46–7.30(m,6H),5.15(d,J＝3.6Hz,1H),4.57(d,J＝9.6Hz,1H),4.47–4.36(m,3H),4.32–4.23(m,3H),4.03–3.95(m,2H),3.87-3.82(m,2H),3.69–3.63(m,6H),2.44-2.42(m,3H),2.09-2.04(m,1H),1.90(ddd,J＝12.9,8.8,4.5Hz,1H),1.61-1.55(m,6H),0.94-0.92(m,9H).
实施例A91
Figure PCTCN2021080167-appb-000256
LCMS([M+H] +):1051.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.63(s,1H),8.59(t,J＝6.0Hz,1H),8.29(s,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.87–7.79(m,2H),7.47(t,J＝6.9Hz,1H),7.40(d,J＝4.2Hz,5H),5.16(s,1H),4.59(d,J＝9.6Hz,1H),4.49–4.39(m,2H),4.38–4.33(m,3H),4.24(dd,J＝15.9,5.5Hz,1H),4.10(s,2H),3.96–3.88(m,2H),3.69(dd,J＝10.6,3.8Hz,1H),3.63(d,J＝10.9Hz,1H),2.43(s,3H),2.10–2.02(m,1H),1.92(ddd,J＝12.9,8.8,4.5Hz,1H),1.62(s,6H),0.94(s,9H).
实施例A92
Figure PCTCN2021080167-appb-000257
LCMS([M+H] +):1083.2
1HNMR(400MHz,DMSO-d6)δ8.95(m,2H),8.61(t,J＝6.0Hz,1H),8.48(d,J＝2.2Hz,1H),8.30–8.24(m,2H),7.49(m,3H),7.39(m,4H),7.14(d,J＝8.8Hz,2H),5.16(m,1H),4.61(m,1H),4.45(m,2H),4.41–4.34(m,2H),4.26–4.22(m,2H),4.08(m,2H),3.88(m,2H),3.71–3.67(m,1H),3.63(m,1H),2.39(s,3H),2.04(m,1H),1.94–1.88(m,1H),1.63(d,J＝7.0Hz,6H),0.95(d,J＝7.6Hz,9H).
实施例A93
Figure PCTCN2021080167-appb-000258
LCMS([M+H] +):1127.2
1HNMR(400MHz,DMSO-d6)δ8.99–8.93(m,2H),8.58(t,J＝5.9Hz,1H),8.49(d,J＝2.2Hz,1H),8.31–8.23(m,2H),7.50(d,J＝8.6Hz,2H),7.45(d,J＝9.6Hz,1H),7.47–7.36(m,5H),7.07(t,J＝10.6Hz,2H),5.15(d,J＝3.6Hz,1H),4.57(d,J＝9.6Hz,1H),4.45(t,J＝8.1Hz,1H),4.38(dd,J＝15.8,6.2Hz,2H),4.25(dd,J＝15.7,5.7Hz,1H),4.20(dd,J＝9.9,5.2Hz,2H),3.98(d,J＝15.7Hz,2H),3.87–3.79(m,2H),3.71–3.58(m,6H),2.43(d,J＝7.2Hz,3H),2.06(dd,J＝13.5,7.1Hz,1H),1.90(ddd,J＝12.9,8.8,4.4Hz,1H),1.63(d,J＝7.0Hz,6H),0.93(d,J＝7.0Hz,9H).
实施例A94
Figure PCTCN2021080167-appb-000259
LCMS([M+H] +):1079.3
1HNMR(400MHz,DMSO-d6)δ8.98-8.95(m,1H),8.66(s,1H),8.59(t,J＝6.0Hz,1H),8.31–8.26(m,2H),8.17(dd,J＝10.2,1.8Hz,1H),7.59(t,J＝8.5Hz,1H),7.43–7.37(m,5H),7.01–6.94(m,2H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.45(t,J＝8.3Hz,1H),4.41-4.36(m,2H),4.26(dd,J＝15.7,5.6Hz,1H),4.11(t,J＝6.2Hz,2H),4.00–3.90(m,2H),3.69-3.60(m,2H),3.56(t,J＝6.2Hz,2H),2.45-2.43(m,3H),2.09–2.04(m,1H),1.94–1.88(m,1H),1.87–1.81(m,2H),1.76-1.71(m,2H),1.62(s,6H),0.94-0.92(d,J＝6.4Hz,9H).
实施例A95
Figure PCTCN2021080167-appb-000260
LCMS([M+H] +)：1129.2
1HNMR(400MHz,DMSO-d6)δ9.02(s,1H),8.95(s,1H),8.60(s,1H),8.55(s,2H),8.28(s,2H),7.45–7.32(m,6H),6.92(dd,J＝25.4,10.3Hz,2H),4.56(d,J＝9.5Hz,1H),4.48–4.34(m,3H),4.26(dd,J＝15.6,5.3Hz,1H),4.09(d,J＝6.2Hz,2H),3.96(s,2H),3.64(d,J＝13.8Hz,2H),3.56(d,J＝6.1Hz,2H),2.44(d,J＝6.4Hz,3H),2.02(dd,J＝20.8,7.9Hz,2H),1.83(d,J＝7.6Hz,2H),1.74(d,J＝7.0Hz,2H),1.63(d,J＝7.9Hz,6H),0.94(s,9H).
实施例A96
Figure PCTCN2021080167-appb-000261
LCMS([M+H] +):1116.2
1HNMR(400MHz,DMSO-d6)δ8.97-8.95(m,1H),8.63(s,1H),8.56(t,J＝6.0Hz,1H),8.30-8.26(m,3H),8.16(dd,J＝11.8,1.9Hz,1H),8.00(d,J＝9.3Hz,1H),7.90–7.81(m,2H),7.57(t,J＝8.8Hz,1H),7.39(q,J＝8.4Hz,4H),5.32-5.30(m,2H),4.54(d,J＝9.3Hz,1H),4.40-4.35(m,5H),4.24-4.18(m,1H),3.65(d,J＝10.2Hz,2H),2.43(d,J＝3.7Hz,3H),2.33–2.16(m,2H),2.09–2.00(m,3H),1.90(ddd,J＝12.9,8.6,4.6Hz,1H),1.61-1.55(m,6H),0.930.92(m,9H).
实施例A97
Figure PCTCN2021080167-appb-000262
LCMS([M+H] +)：1111.3
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝11.5Hz,1H),8.66(s,1H),8.59(t,J＝5.7Hz,1H),8.27(s,2H),8.22(dd,J＝11.8,1.9Hz,1H),7.74(d,J＝9.3Hz,3H),7.44–7.33(m,5H),5.16(d,J＝3.5Hz,1H),4.55(d,J＝9.7Hz,1H),4.43(dd,J＝16.8,8.4Hz,2H),4.37(d,J＝6.6Hz,2H),4.22(t,J＝6.2Hz,2H),3.93(s,2H),3.65(d,J＝3.3Hz,2H),3.51(d,J＝2.6Hz,2H),2.43(d,J＝9.7Hz,3H),2.09–1.97(m,2H),1.78–1.71(m,2H),1.67–1.50(m,10H),0.92(d,J＝7.5Hz,9H).
实施例A98
Figure PCTCN2021080167-appb-000263
LCMS([M+H] +):1044.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.65–8.55(m,3H),8.32–8.23(m,2H),8.19(dd,J＝9.5,2.4Hz,1H),8.02(d,J＝8.5Hz,1H),7.95(dd,J＝8.5,2.2Hz,1H),7.39(d,J＝9.9Hz,5H),6.51(d,J＝9.5Hz,1H),5.16(d,J＝3.4Hz,1H),4.55(d,J＝9.5Hz,1H),4.43(dd,J＝15.3,7.2Hz,1H),4.36(dd,J＝15.4,6.2Hz,2H),4.25(dd,J＝15.7,5.6Hz,1H),4.04(t,J＝6.8Hz,2H),3.99–3.86(m,2H),3.64(dt,J＝20.6,7.2Hz,2H),3.51(t,J＝6.2Hz,2H),2.43(s,3H),2.06(dd,J＝13.1,7.1Hz,1H),1.94–1.85(m,1H),1.83–1.71(m,2H),1.58(d,J＝16.3Hz,8H),0.90(d,J＝7.9Hz,9H).
实施例A99
Figure PCTCN2021080167-appb-000264
LCMS([M+H] +):1113.3
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝12.2Hz,1H),8.66(s,1H),8.59(t,J＝5.9Hz,1H),8.29(d,J＝11.9Hz,2H),8.21(dd,J＝11.8,1.7Hz,1H),7.74(t,J＝7.6Hz,2H),7.45–7.33(m,5H),5.16(m,1H),4.56(m,1H),4.41(m,5H),4.24(m,1H),3.94(m,2H),3.83–3.74(m,2H),3.71–3.57(m,6H),2.43(m,3H),2.06(m,1H),1.95–1.86(m,1H),1.60(s,6H),0.92(d,J＝8.3Hz,9H).
实施例A100
Figure PCTCN2021080167-appb-000265
LCMS([M+H] +):1044.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝11.6Hz,1H),8.92(d,J＝2.4Hz,1H),8.70(d,J＝2.4Hz,1H),8.60(t,J＝6.0Hz,1H),8.41(dd,J＝8.7,2.5Hz,1H),8.33–8.25(m,2H),8.19–8.15(m,1H),8.00(dd,J＝8.5,2.5Hz,1H),7.44–7.35(m,5H),6.92(d,J＝8.7Hz,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.32(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),4.00–3.89(m,2H),3.65(dt,J＝21.3,7.3Hz,2H),3.56(t,J＝6.4Hz,2H),2.43(d,J＝8.5Hz,3H),2.11–2.02(m,1H),1.91(ddd,J＝12.9,8.9,4.3Hz,1H),1.83(dd,J＝14.5,6.3Hz,2H),1.76–1.67(m,2H),1.58(s,6H),0.92(d,J＝7.0Hz,9H).
实施例A101
Figure PCTCN2021080167-appb-000266
LCMS([M+H] +):1178.3
1HNMR(400MHz,DMSO-d6)δ9.00(d,J＝9.1Hz,1H),8.96(s,1H),8.59(dd,J＝15.5,9.3Hz,2H),8.31–8.25(m,2H),7.40(s,9H),5.16(d,J＝3.5Hz,1H),4.58(d,J＝9.6Hz,1H),4.46(t,J＝8.2Hz,1H),4.39(dd,J＝15.7,6.0Hz,2H),4.27(dd,J＝15.7,5.7Hz,1H),4.17(t,J＝6.2Hz,2H),4.00–3.92(m,2H),3.64(ddd,J＝26.2,11.7,5.0Hz,4H),2.44(s,3H),1.95–1.83(m,3H),1.80–1.72(m,2H),1.63(d,J＝9.8Hz,6H),0.95(s,9H).
实施例A102
Figure PCTCN2021080167-appb-000267
LCMS([M+H] +)：1049.4
1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.62(s,1H),8.31–8.24(m,2H),8.15(dd,J＝11.9,1.9Hz,1H),8.01(d,J＝8.3Hz,1H),7.85(d,J＝10.8Hz,2H),7.36(t,J＝8.7Hz,1H),4.67–4.55(m,1H),4.19(t,J＝6.3Hz,2H),3.93(s,2H),3.56(td,J＝9.3,3.1Hz,2H),2.74(ddd,J＝18.8,13.5,5.5Hz,1H),2.11–1.91(m,2H),1.90–1.83(m,2H),1.76(dd,J＝14.2,6.3Hz,2H),1.61(s,6H).
实施例A103
Figure PCTCN2021080167-appb-000268
LCMS([M+H] +):1178.2
1HNMR(400MHz,DMSO-d6)δ9.00(s,1H),8.77(d,J＝2.3Hz,1H),8.65(t,J＝6.0Hz,1H),8.34(s,3H),8.10(dd,J＝8.5,2.5Hz,1H),8.03–7.95(m,2H),7.45(d,J＝2.3Hz,5H),5.20(d,J＝3.5Hz,1H),4.61(d,J＝9.6Hz,1H),4.54–4.39(m,3H),4.35–4.24(m,3H),4.04–3.93(m,2H),3.76–3.55(m,4H),2.48(s,3H),2.15–2.07(m,1H),1.95(ddd,J＝22.9,11.6,7.2Hz,1H),1.90–1.76(m,4H),1.64(s,6H),1.29(s,2H),0.99(s,9H).
实施例A104
Figure PCTCN2021080167-appb-000269
LCMS([M+H] +)：1104.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝21.9Hz,1H),8.62(dt,J＝12.1,6.9Hz,3H),8.32–8.25(m,2H),8.16(dd,J＝11.8,1.9Hz,1H),7.86–7.78(m,2H),7.44(d,J＝8.3Hz,2H),7.37(dd,J＝11.7,8.8Hz,3H),5.15(s,1H),4.57(d,J＝9.5Hz,2H),4.50–4.41(m,2H),4.37(s,1H),4.22(dd,J＝15.9,5.3Hz,1H),3.67(dt,J＝21.4,7.5Hz,2H),2.76(d,J＝32.2Hz,2H),2.61(dd,J＝11.8,6.0Hz,1H),2.43(s,3H),2.41–2.24(m,4H),2.02(dd,J＝12.9,5.6Hz,4H),1.94–1.88(m,1H),1.78(dd,J＝21.9,9.1Hz,2H),1.62(s,6H),0.96(d,J＝6.4Hz,9H).
实施例A105
Figure PCTCN2021080167-appb-000270
LCMS([M+H] +):1098.3
1HNMR(400MHz,DMSO-d6)δ8.97-8.97(m,1H),8.77(d,J＝2.4Hz,1H),8.55(t,J＝6.0Hz,1H),8.42(s,1H),8.33-8.26(m,3H),8091–8.04(m,3H),7.75-7.71(m,2H),7.40(q,J＝8.4Hz,4H),5.13(d,J＝3.5Hz,1H),4.51(d,J＝9.3Hz,1H),4.46–4.39(m,2H),4.35(s,1H),4.22(dd,J＝15.8,5.4Hz,1H),3.69-3.61(m,2H),3.14(t,J＝6.1Hz,2H),2.44(s,3H),2.38-2.33(m,1H),2.07–2.00(m,1H),1.94–1.86(m,1H),1.80(d,J＝11.2Hz,3H),1.69(d,J＝10.8Hz,1H),1.60-1.58(m,6H),1.51(s,1H),1.38–1.28(m,2H),1.05–0.88(m,11H).
实施例A106
Figure PCTCN2021080167-appb-000271
LCMS([M+H] +):1035.3
1HNMR(400MHz,MeOD)δ8.87(s,1H),8.13–8.05(m,2H),8.01(d,J＝8.4Hz,1H),7.54(dd,J＝9.1,2.7Hz,1H),7.50–7.39(m,4H),6.90(m,1H),4.72(s,1H),4.64–4.50(m,3H),4.37(m,1H),4.08–3.94(m,2H),3.89(m,1H),3.82(m,1H),3.63(m,6H),2.66–2.58(m,4H),2.53–2.45(m,5H),2.30–2.22(m,1H),2.11(m,1H),1.72(m,4H),1.56(dd,J＝5.6,4.9Hz,6H),1.05(d,J＝9.6Hz,9H).
实施例A107
Figure PCTCN2021080167-appb-000272
LCMS([M+H] +):1080.3
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝3.3Hz,1H),8.62(s,1H),8.58(t,J＝6.2Hz,1H),8.28(d,J＝3.2Hz,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.85(d,J＝10.9Hz,2H),7.46–7.33(m,5H),5.38(s,1H),4.68(d,J＝7.9Hz,1H),4.51(t,J＝8.3Hz,1H),4.40(dd,J＝15.8,6.3Hz,1H),4.27(dd,J＝15.8,5.7Hz,1H),4.19(t,J＝6.3Hz,2H),4.12(s,2H),3.96(d,J＝12.1Hz,1H),3.90(d,J＝7.9Hz,1H),3.75(dd,J＝12.2,4.0Hz,1H),3.54(t,J＝6.3Hz,2H),2.44(s,3H),2.27(d,J＝7.6Hz,1H),2.16–2.08(m,1H),2.04–1.95(m,1H),1.89–1.79(m,2H),1.74–1.66(m,2H),1.61(s,6H),0.89(d,J＝10.4Hz,9H).
实施例A108
Figure PCTCN2021080167-appb-000273
LCMS([M+H] +):1143.3
1HNMR(400MHz,DMSO-d6)δ8.99(d,J＝2.0Hz,1H),8.97(s,1H),8.52(d,J＝2.1Hz,1H),8.44(d,J＝7.7Hz,1H),8.30–8.24(m,2H),7.48–7.30(m,8H),5.14(m,1H),4.90(m,1H),4.56(m,1H),4.47(m,1H),4.29(m,1H),4.19(m,2H),4.01–3.88(m,2H),3.65–3.53(m,4H),2.45(s,3H),2.11–2.03(m,1H),1.93–1.83(m,2H),1.82–1.71(m,3H),1.63(d,J＝7.2Hz,6H),1.36(d,J＝7.0Hz,3H),0.94(s,9H).
实施例A109
Figure PCTCN2021080167-appb-000274
LCMS([M+H] +):1143.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.63(s,1H),8.44(d,J＝7.7Hz,1H),8.28(s,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.57(d,J＝9.3Hz,1H),7.40(dt,J＝16.2,8.3Hz,8H),5.13(d,J＝3.5Hz,1H),4.89(dd,J＝14.3,7.2Hz,1H),4.56(d,J＝9.6Hz,1H),4.45(dd,J＝15.3,7.1Hz,1H),4.27(d,J＝17.5Hz,1H),4.19(s,2H),3.96(d,J＝1.3Hz,2H),3.59(d,J＝6.1Hz,4H),2.45(s,3H),2.05(dd,J＝20.1,11.5Hz,1H),1.86(dd,J＝13.7,6.2Hz,2H),1.77(dd,J＝13.1,7.7Hz,3H),1.61(s,6H),1.37(d,J＝7.0Hz,2H),0.94(s,9H).
实施例A110
Figure PCTCN2021080167-appb-000275
LCMS([M+H] +)：1093.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.62(s,1H),8.43(d,J＝7.7Hz,1H),8.31–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.85(d,J＝11.0Hz,2H),7.38(dt,J＝23.4,6.5Hz,6H),5.13(d,J＝3.5Hz,1H),4.93–4.87(m,1H),4.54(d,J＝9.6Hz,1H),4.45(t,J＝8.1Hz,1H),4.28(s,1H),4.20(t,J＝6.3Hz,2H),3.96(t,J＝8.8Hz,2H),3.57(t,J＝6.2Hz,4H),2.45(s,3H),2.10–1.95(m,3H),1.91–1.83(m,2H),1.81–1.71(m,3H),1.61(s,6H),1.36(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A111
Figure PCTCN2021080167-appb-000276
LCMS([M+H] +):1062.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,2H),8.97-8.95(m,1H),8.59(t,J＝5.9Hz,1H),8.31–8.23(m,3H),8.14(dd,J＝12.6,1.9Hz,1H),7.42–7.32(m,6H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.41-4.36(m,2H),4.26(dd,J＝15.9,5.6Hz,1H),4.20(t,J＝6.2Hz,2H),4.00–3.90(m,2H),3.66-3.55(m,4H),2.44-2.42(m,3H),2.11–2.02(m,1H),2.00–1.83(m,4H),1.76-1.72(m,2H),1.62(s,6H),0.93-0.92(m,9H).
实施例A112
Figure PCTCN2021080167-appb-000277
LCMS([M+H] +)：1107.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.62(s,1H),8.42(d,J＝7.7Hz,1H),8.28(d,J＝3.3Hz,2H),8.15(dd,J＝11.9,1.9Hz,1H),7.85(d,J＝10.5Hz,2H),7.42(d,J＝8.3Hz,2H),7.39–7.30(m,4H),5.13(s,1H),4.94–4.84(m,1H),4.54(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.28(s,1H),4.17(t,J＝6.4Hz,2H),3.98–3.86(m,2H),3.64–3.48(m,4H),2.44(s,3H),2.10–2.02(m,1H),1.81(ddd,J＝17.4,11.1,5.4Hz,3H),1.66(dd,J＝14.1,7.2Hz,2H),1.60(s,6H),1.57–1.50(m,2H),1.35(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A113
Figure PCTCN2021080167-appb-000278
LCMS([M+H] +):1125.2
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.71(d,J＝2.4Hz,1H),8.47–8.40(m,3H),8.34–8.23(m,3H),8.01(dd,J＝8.5,2.5Hz,1H),7.45-7.41(m,3H),7.37–7.33(m,3H),5.14(d,J＝3.5Hz,1H),4.95–4.86(m,1H),4.54(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.28-4.24(m,3H),3.98–3.88(m,2H),3.59–3.55(m,4H),2.45(s,3H),2.10–2.02(m,1H),1.88-1.83(m,2H),1.77-1.74(m,3H),1.58(s,6H),1.36(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A114
Figure PCTCN2021080167-appb-000279
LCMS([M+H] +):1050.3
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝2.0Hz,1H),8.57(d,J＝2.1Hz,1H),8.52(t,J＝6.0Hz,1H),8.31–8.23(m,2H),7.43–7.33(m,3H),7.32–7.22(m,4H),7.17(dd,J＝11.1,4.3Hz,1H),5.14(m,1H),4.56(m,1H),4.43(m,1H),4.35(m,2H),4.30–4.17(m,3H),3.98–3.87(m,2H),3.69–3.53(m,4H),2.01(m,1H),1.83(m,5H),1.63(d,J＝7.6Hz,6H),0.93(d,J＝11.3Hz,9H).
实施例A115
Figure PCTCN2021080167-appb-000280
LCMS([M+H] +):1161.2
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝2.0Hz,1H),8.97(s,1H),8.57(d,J＝2.1Hz,1H),8.43(d,J＝7.7Hz,1H),8.31–8.23(m,2H),7.47–7.41(m,2H),7.36(m,5H),5.13(m,1H),4.90(m,1H),4.54(d,J＝9.6Hz,1H),4.45(m,1H),4.26(m,3H),3.99–3.87(m,2H),3.57(m,4H),2.45(s,3H),2.09–2.00(m,1H),1.78(m,5H),1.63(d,J＝7.6Hz,6H),1.37(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A116
Figure PCTCN2021080167-appb-000281
LCMS([M+H] +):1093.3
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝1.9Hz,1H),8.58(m,2H),8.31–8.23(m,2H),7.90(s,1H),7.80(m,2H),7.42–7.32(m,5H),7.27(s,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.27(m,3H),3.99–3.88(m,2H),3.70–3.53(m,4H),2.07–1.99(m,1H),1.93–1.70(m,5H),1.63(d,J＝7.7Hz,6H),0.93(d,J＝11.4Hz,9H).
实施例A117
Figure PCTCN2021080167-appb-000282
LCMS([M+H] +)：1039.3
1HNMR(400MHz,DMSO-d6)δ8.59(dd,J＝13.7,7.7Hz,2H),8.32–8.25(m,2H),8.15(dd,J＝11.9,1.9Hz,1H),7.91(s,1H),7.88–7.81(m,2H),7.79(t,J＝6.4Hz,2H),7.40–7.31(m,4H),7.28(s,1H),5.15(s,1H),4.56(d,J＝9.6Hz,1H),4.46–4.32(m,3H),4.25(dd,J＝15.7,5.6Hz,1H),4.16(t,J＝6.4Hz,2H),3.99–3.89(m,2H),3.68–3.58(m,2H),3.52(t,J＝6.3Hz,2H),2.06–1.95(m,2H),1.92–1.78(m,3H),1.69–1.58(m,7H),1.53(dd,J＝15.1,8.0Hz,2H),0.93(d,J＝10.3Hz,9H).
实施例A118
Figure PCTCN2021080167-appb-000283
LCMS([M+H] +)：996.3
1HNMR(400MHz,DMSO-d6)δ8.62(s,1H),8.51(t,J＝6.0Hz,1H),8.32–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.88–7.81(m,2H),7.39–7.23(m,6H),7.22–7.15(m,1H),5.14(s,1H),4.56(d,J＝9.6Hz,1H),4.43(t,J＝8.2Hz,1H),4.33(dd,J＝15.2,6.2Hz,2H),4.19(dt,J＝13.2,6.1Hz,3H),3.98–3.87(m,2H),3.69–3.57(m,2H),3.52(t,J＝6.3Hz,2H),2.07–1.95(m,2H),1.92–1.80(m,3H),1.70–1.49(m,10H),0.93(d,J＝10.6Hz,9H).
实施例A119
Figure PCTCN2021080167-appb-000284
LCMS([M+H] +)：1025.3
1HNMR(400MHz,DMSO-d6)δ8.62(s,1H),8.59(t,J＝6.0Hz,1H),8.32–8.25(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.91(s,1H),7.88–7.82(m,2H),7.79(d,J＝8.3Hz,2H),7.37(dd,J＝18.8,9.2Hz,4H),7.28(s,1H),5.15(s,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.30–4.17(m,3H),4.02–3.89(m,2H),3.70–3.61(m,2H),3.57(t,J＝6.3Hz,2H),2.02(dt,J＝14.4,9.8Hz,2H),1.92–1.82(m,3H),1.75(dd,J＝14.4,6.3Hz,2H),1.61(s,6H),0.93(d,J＝11.2Hz,9H).
实施例A120
Figure PCTCN2021080167-appb-000285
LCMS([M+H] +)：982.4
1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.51(t,J＝6.0Hz,1H),8.31–8.25(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.89–7.81(m,2H),7.37(dd,J＝16.6,9.1Hz,2H),7.32–7.23(m,4H),7.21–7.15(m,1H),5.14(d,J＝3.2Hz,1H),4.56(d,J＝9.6Hz,1H),4.43(t,J＝8.3Hz,1H),4.34(dd,J＝15.3,6.4Hz,2H),4.25–4.17(m,3H),4.00–3.91(m,2H),3.62(ddd,J＝23.4,11.7,5.1Hz,4H),2.03(dd,J＝15.2,10.1Hz,1H),1.92–1.82(m,3H),1.75(dd,J＝14.2,6.4Hz,2H),1.61(s,6H),0.93(d,J＝10.8Hz,9H).
实施例A121
Figure PCTCN2021080167-appb-000286
LCMS([M+H] +):1014.3
1HNMR(400MHz,DMSO-d6)δ8.71(d,J＝2.4Hz,1H),8.53(t,J＝6.0Hz,1H),8.45–8.38(m,2H),8.33-8.24(m,3H),8.01(dd,J＝8.5,2.5Hz,1H),7.40(dd,J＝17.2,9.6Hz,2H),7.33–7.23(m,4H),7.19-7.15(m,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.43(t,J＝8.2Hz,1H),4.35-4.31(m,2H),4.27-4.18(m,3H),4.00–3.88(m,2H),3.68-3.55(m,4H),2.07-2.01(m,1H),1.93–1.82(m,3H),1.78-1.73(m,2H),1.58(s,6H),0.94-0.91(m,9H).
实施例A122
Figure PCTCN2021080167-appb-000287
LCMS([M+H] +):1057.3
1HNMR(400MHz,DMSO-d6)δ8.70(d,J＝2.4Hz,1H),8.59(t,J＝6.0Hz,1H),8.41(m,2H),8.34–8.22(m,3H),8.01(dd,J＝8.5,2.4Hz,1H),7.91(s,1H),7.83-7.78(m,2H),7.45–7.32(m,4H),7.28(s,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.30–4.22(m,3H),4.00–3.90(m,2H),3.69–3.54(m,4H),2.07–1.99(m,1H),1.93–1.81(m,3H),1.80–1.70(m,2H),1.58(s,6H),0.93(d,J＝11.2Hz,9H).
实施例A123
Figure PCTCN2021080167-appb-000288
LCMS([M+H] +):1065.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.64(s,1H),8.43(d,J＝7.7Hz,1H),8.29(d,J＝3.5Hz,2H),8.17(dd,J＝11.9,1.8Hz,1H),7.88(d,J＝4.2Hz,2H),7.86(s,1H),7.50–7.22(m,7H),5.14(d,J＝3.5Hz,1H),4.95–4.86(m,1H),4.56(d,J＝9.5Hz,1H),4.45(t,J＝8.1Hz,1H),4.40–4.33(m,2H),4.29(s,1H),4.07(d,J＝17.5Hz,2H),3.93(d,J＝4.0Hz,2H),3.66–3.56(m,2H),2.45(s,3H),2.14–1.96(m,1H),1.78(ddd,J＝13.0,8.8,4.4Hz,1H),1.62(s,6H),1.37(d,J＝7.0Hz,1H),1.24(s,1H),0.94(s,9H).
实施例A124
Figure PCTCN2021080167-appb-000289
LCMS([M+H] +):1111.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.67(s,1H),8.44(d,J＝7.7Hz,1H),8.28–8.22(m,3H),7.80-7.76(m,2H),7.43(d,J＝8.2Hz,2H),7.37–7.33(m,3H),5.14(d,J＝3.4Hz,1H),4.90(t,J＝7.2Hz,1H),4.54(d,J＝9.6Hz,1H),4.44(t,J＝8.2Hz,1H),4.28(t,J＝5.9Hz,3H),3.94–3.87(m,2H),3.62-3.54(m,4H),2.45(s,3H),2.08–2.03(m,1H),1.83–1.73(m,5H),1.61(s,6H),1.37(d,J＝7.0Hz,3H),0.92(s,9H).
实施例A125
Figure PCTCN2021080167-appb-000290
LCMS([M+H] +):977.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.55(t,J＝6.1Hz,1H),8.50(d,J＝1.1Hz,1H),8.30–8.21(m,2H),8.12(dd,J＝9.5,1.9Hz,1H),7.90(d,J＝9.4Hz,1H),7.40(q,J＝8.4Hz,4H),5.12(d,J＝3.6Hz,1H),4.55(d,J＝9.4Hz,1H),4.47–4.38(m,2H),4.35(s,1H),4.21(dd,J＝15.9,5.5Hz,1H),3.66(d,J＝4.1Hz,2H),3.39(s,2H),2.58(t,J＝6.5Hz,2H),2.44(s,3H),2.35(dt,J＝14.1,7.1Hz,1H),2.19(dt,J＝14.0,7.0Hz,1H),2.02(dd,J＝17.4,9.7Hz,1H),1.94–1.86(m,1H),1.67(dd,J＝14.4,7.4Hz,2H),1.60(d,J＝6.7Hz,8H),0.93(d,J＝8.7Hz,9H).
实施例A126
Figure PCTCN2021080167-appb-000291
LCMS([M+H] +):1058.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.95(d,J＝2.2Hz,1H),8.70(d,J＝2.1Hz,1H),8.49–8.40(m,2H),8.29(q,J＝8.5Hz,2H),8.19(d,J＝8.5Hz,1H),8.01(dd,J＝8.5,2.5Hz,1H),7.38(dt,J＝19.1,9.5Hz,5H),6.97(d,J＝8.8Hz,1H),5.13(d,J＝3.5Hz,1H),4.95–4.85(m,1H),4.54(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.38(t,J＝6.5Hz,2H),4.28(s,1H),4.00–3.87(m,2H),3.64–3.51(m,4H),2.45(s,3H),2.11–1.94(m,2H),1.87–1.69(m,5H),1.59(s,6H),1.37(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A127
Figure PCTCN2021080167-appb-000292
LCMS([M+H] +):990.3
1HNMR(400MHz,DMSO-d6)δ8.94(d,J＝2.4Hz,1H),8.70(d,J＝2.3Hz,1H),8.59(t,J＝6.0Hz,1H),8.44(dd,J＝8.7,2.5Hz,1H),8.29(q,J＝8.5Hz,2H),8.18(d,J＝8.5Hz,1H),8.00(dd,J＝8.5,2.5Hz,1H),7.91(s,1H),7.80(t,J＝9.7Hz,2H),7.37(dd,J＝12.0,9.0Hz,3H),7.28(s,1H),6.96(d,J＝8.8Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,5H),4.26(dd,J＝16.1,5.7Hz,1H),4.01–3.89(m,2H),3.70–3.51(m,4H),2.09–2.01(m,1H),1.93–1.79(m,3H),1.73(dd,J＝14.4,6.3Hz,2H),1.58(s,6H),0.92(d,J＝10.7Hz,9H).
实施例A128
Figure PCTCN2021080167-appb-000293
LCMS([M+H] +):947.3
1HNMR(400MHz,DMSO-d6)δ8.94(d,J＝2.3Hz,1H),8.70(d,J＝2.4Hz,1H),8.52(t,J＝6.0Hz,1H),8.44(dd,J＝8.7,2.5Hz,1H),8.29(q,J＝8.5Hz,2H),8.19(d,J＝8.6Hz,1H),8.00(dd,J＝8.5,2.5Hz,1H),7.38(d,J＝9.6Hz,1H),7.33–7.23(m,4H),7.18(t,J＝6.7Hz,1H),6.96(d,J＝8.7Hz,1H),5.14(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.43(t,J＝8.3Hz,1H),4.40–4.31(m,4H),4.21(dd,J＝15.5,5.6Hz,1H),4.00–3.87(m,2H),3.62(ddd,J＝27.3,11.7,5.1Hz,4H),2.03(dd,J＝20.1,12.9Hz,1H),1.92–1.79(m,3H),1.73(dd,J＝14.4,6.2Hz,2H),1.59(s,6H),0.92(d,J＝11.0Hz,9H).
实施例A129
Figure PCTCN2021080167-appb-000294
LCMS([M+H] +):997.3
1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.57(t,J＝6.0Hz,1H),8.32–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.91–7.82(m,3H),7.79(t,J＝6.5Hz,2H),7.47(d,J＝9.5Hz,1H),7.43–7.33(m,3H),7.27(s,1H),5.15(d,J＝3.6Hz,1H),4.57(d,J＝9.5Hz,1H),4.46–4.37(m,2H),4.37–4.31(m,3H),4.25(dd,J＝15.9,5.5Hz,1H),4.07(d,J＝19.9Hz,2H),3.95–3.87(m,2H),3.65(dt,J＝22.5,7.3Hz,2H),2.06–1.99(m,1H),1.88(ddd,J＝13.0,8.8,4.5Hz,1H),1.61(s,6H),0.93(d,J＝12.7Hz,9H).
实施例A130
Figure PCTCN2021080167-appb-000295
LCMS([M+H] +):954.3
1HNMR(400MHz,DMSO-d6)δ8.66–8.60(m,1H),8.51(t,J＝6.0Hz,1H),8.33–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.92–7.81(m,2H),7.47(d,J＝9.5Hz,1H),7.40(t,J＝9.0Hz,1H),7.34–7.14(m,5H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.44(dd,J＝13.9,5.7Hz,1H),4.39–4.31(m,4H),4.19(dd,J＝15.6,5.6Hz,1H),4.11–4.02(m,2H),3.95–3.87(m,2H),3.65(dt,J＝23.5,7.4Hz,2H),2.09–1.99(m,1H),1.88(ddd,J＝12.9,8.7,4.5Hz,1H),1.61(s,6H),0.92(d,J＝11.6Hz,9H).
实施例A131
Figure PCTCN2021080167-appb-000296
LCMS([M+H] +):1075.3
1HNMR(400MHz,DMSO-d6)δ8.62(d,J＝0.9Hz,1H),8.59(t,J＝6.0Hz,1H),8.32–8.24(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.91(s,1H),7.80(dd,J＝12.8,8.3Hz,2H),7.59–7.53(m,1H),7.44–7.32(m,5H),7.28(s,1H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.26(dd,J＝15.9,5.6Hz,1H),4.18(t,J＝6.2Hz,2H),4.01–3.89(m,2H),3.67(dd,J＝10.7,3.7Hz,1H),3.59(dd,J＝15.2,8.9Hz,3H),2.06(dd,J＝15.0,6.3Hz,1H),1.92–1.81(m,3H),1.80–1.71(m,2H),1.60(s,6H),0.93(d,J＝10.4Hz,9H).
实施例A132
Figure PCTCN2021080167-appb-000297
LCMS([M+H] +):1032.3
1HNMR(400MHz,DMSO-d6)δ8.64–8.60(m,1H),8.52(t,J＝6.0Hz,1H),8.32–8.25(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.58–7.53(m,1H),7.39(dd,J＝6.5,3.8Hz,3H),7.32–7.23(m,4H),7.20–7.13(m,1H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.44(t,J＝8.2Hz,1H),4.34(dd,J＝15.4,6.3Hz,2H),4.24–4.14(m,3H),4.03–3.87(m,2H),3.62(ddd,J＝22.7,11.6,5.1Hz,4H),2.09–2.00(m,1H),1.88(tt,J＝12.2,5.9Hz,3H),1.76(dd,J＝14.2,6.2Hz,2H),1.61(s,6H),0.93(d,J＝10.7Hz,9H).
实施例A133
Figure PCTCN2021080167-appb-000298
LCMS([M+H] +):1071.3
1HNMR(400MHz,DMSO-d6)δ8.99–8.90(m,1H),8.52(t,J＝8.4Hz,1H),8.31–8.24(m,2H),7.55(d,J＝8.4Hz,1H),7.42(dq,J＝10.9,8.4Hz,7H),7.27(d,J＝7.8Hz,1H),5.26–5.11(m,2H),4.57(d,J＝9.2Hz,1H),4.46(t,J＝8.3Hz,1H),4.28(s,1H),3.84(d,J＝46.3Hz,1H),3.58(dd,J＝22.1,10.4Hz,3H),3.24(d,J＝10.2Hz,1H),3.06(d,J＝9.7Hz,1H),2.97–2.76(m,3H),2.44(d,J＝5.4Hz,3H),2.02(dd,J＝15.9,8.5Hz,1H),1.76(s,3H),1.52(s,6H),1.49–1.41(m,1H),1.36(d,J＝12.3Hz,3H),1.17(d,J＝27.1Hz,2H),0.96(d,J＝5.8Hz,9H).
实施例A134
Figure PCTCN2021080167-appb-000299
LCMS([M+H] +):1040.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.58(t,J＝6.0Hz,1H),8.54(d,J＝2.4Hz,1H),8.44(t,J＝5.9Hz,1H),8.33–8.23(m,2H),7.91(d,J＝9.1Hz,1H),7.87–7.77(m,3H),7.48(d,J＝8.3Hz,1H),7.44–7.36(m,4H),7.33(d,J＝8.2Hz,2H),5.15(d,J＝3.5Hz,1H),4.76(d,J＝9.1Hz,1H),4.48–4.17(m,6H),3.73(s,2H),2.85(dd,J＝19.4,11.8Hz,2H),2.44(d,J＝4.5Hz,3H),2.26(t,J＝7.3Hz,2H),2.11–1.91(m,4H),1.53(s,6H),1.01(d,J＝11.4Hz,9H).
实施例A135
Figure PCTCN2021080167-appb-000300
LCMS([M+H] +):1032.3
1HNMR(400MHz,DMSO-d6)δ8.99-8.97(m,1H),8.65-8.58(m,2H),8.33–8.22(m,2H),7.89(s,1H),7.77(s,1H),7.45–7.34(m,6H),6.80(s,1H),5.20(d,J＝3.2Hz,1H),4.56(d,J＝9.5Hz,1H),4.51–4.32(m,4H),4.30–4.19(m,2H),3.99–3.90(m,2H),3.69–3.58(m,2H),3.55–3.47(m,3H),2.90–2.67(m,5H),2.45–2.41(m,4H),2.10-2.05(m,1H),1.90(td,J＝8.6,4.2Hz,1H),1.62(s,2H),1.54(s,6H),0.95-0.93(m,9H).
实施例A136
Figure PCTCN2021080167-appb-000301
LCMS([M+H] +):1176.3
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝1.8Hz,1H),8.63(brs,1H),8.51(m,1H),8.32–8.24(m,2H),8.16(dd,J＝11.9,1.8Hz,1H),7.84(m,2H),7.48–7.37(m,5H),7.27(dd,J＝9.2,2.5Hz,1H),5.26–5.17(m,1H),5.14(m,1H),4.72(m,1H),4.58(m,1H),4.46(m,1H),4.29(m,1H),3.83(m,1H),3.74–3.41(m,3H),3.22(m,2H),2.96–2.83(m,2H),2.45(d,J＝5.5Hz,3H),2.04(m,1H),2.00–1.88(m,2H),1.83–1.73(m,1H),1.61(s,6H),1.53–1.43(m,1H),1.40–1.31(m,2H),1.21(m,2H),0.96(d,J＝6.5Hz,9H).
实施例A137
Figure PCTCN2021080167-appb-000302
LCMS([M+H] +):906.4
1HNMR(400MHz,DMSO-d6)δ8.63(brs,1H),8.31–8.25(m,2H),8.16(dd,J＝11.9,1.8Hz,1H),7.90–7.81(m,3H),7.41–7.28(m,2H),5.12(d,J＝3.5Hz,1H),4.54(d,J＝9.6Hz,1H),4.32(m,2H),4.19(m,2H),3.92(m,2H),3.63(m,1H),3.60–3.52(m,3H),2.55(d,J＝8.0Hz,3H),1.97(m,1H),1.83(m,3H),1.79–1.70(m,2H),1.61(s,6H),0.91(d,J＝15.4Hz,9H).
实施例A138
Figure PCTCN2021080167-appb-000303
LCMS([M+H] +):1062.2
1HNMR(400MHz,DMSO-d6)δ12.45(s,1H),8.94(d,J＝7.6Hz,1H),8.62(s,1H),8.34–8.23(m,2H),8.15(dd,J＝11.9,1.8Hz,1H),7.84(d,J＝10.8Hz,2H),7.55(s,2H),7.39–7.29(m,2H),7.23(brs,1H),5.28(d,J＝3.7Hz,1H),5.21(t,J＝7.8Hz,1H),4.60(d,J＝9.6Hz,1H),4.53(brs,1H),4.17(m,2H),4.04–3.86(m,3H),3.76–3.68(m,1H),3.55(m,2H),2.45(s,3H),2.24(m,2H),1.84(m,2H),1.78–1.67(m,2H),1.60(s,6H),0.89(d,J＝27.7Hz,9H).
实施例A139
Figure PCTCN2021080167-appb-000304
LCMS([M+H] +):1114.3
1HNMR(400MHz,DMSO-d6)δ9.12(s,1H),8.98(s,1H),8.57(d,J＝7.9Hz,1H),8.26(s,2H),8.21(s,1H),7.63(s,1H),7.58(d,J＝8.0Hz,1H),7.44(d,J＝6.8Hz,3H),7.37(d,J＝7.7Hz,2H),7.20(s,1H),5.23(s,2H),5.16(d,J＝3.4Hz,1H),4.57(d,J＝9.2Hz,1H),4.44(t,J＝8.2Hz,1H),4.28(s,1H),3.58(s,2H),3.23–2.93(m,6H),2.66(s,2H),2.45(d,J＝6.9Hz,3H),2.19–1.93(m,6H),1.72(s,3H),1.52(s,6H),1.37(d,J＝10.2Hz,2H),0.97(d,J＝5.3Hz,9H).
实施例A140
Figure PCTCN2021080167-appb-000305
LCMS([M+H] +):1046.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59–8.50(m,2H),8.33–8.22(m,2H),7.84–7.75(m,2H),7.70(d,J＝9.3Hz,1H),7.47(d,J＝8.3Hz,1H),7.40(q,J＝8.4Hz,4H),5.12(d,J＝3.4Hz,1H),4.50(d,J＝9.3Hz,1H),4.43(dd,J＝15.3,7.0Hz,2H),4.34(s,1H),4.21(dd,J＝15.9,5.4Hz,1H),3.64(dt,J＝18.7,7.4Hz,2H),2.90(t,J＝6.1Hz,2H),2.84–2.75(m,2H),2.44(s,3H),2.31(t,J＝11.9Hz,1H),2.16(t,J＝7.3Hz,2H),2.06–1.85(m,4H),1.81–1.61(m,5H),1.53(s,6H),1.31(dd,J＝23.9,11.4Hz,4H),0.91(d,J＝9.5Hz,9H).
实施例A141
Figure PCTCN2021080167-appb-000306
LCMS([M+H] +):1034.3
1HNMR(400MHz,DMSO-d6)δ8.99-8.97(m,1H),8.60(t,J＝5.9Hz,1H),8.56(s,1H),8.32–8.24(m,2H),7.85(d,J＝8.0Hz,1H),7.50(d,J＝8.2Hz,1H),7.42-7.39(m,5H),5.17(d,J＝3.3Hz,1H),4.56(d,J＝9.5Hz,1H),4.44(t,J＝8.4Hz,1H),4.35(m,2H),4.25(dd,J＝15.5,5.7Hz,1H),3.94(s,2H),3.67–3.59(m,2H),3.51(m,2H),2.49-2.43(m,3H),2.06-1.87(m,9H),1.61(s,5H),1.52(s,6H),1.23(s,3H),0.95-0.93(m,9H).
实施例A142
Figure PCTCN2021080167-appb-000307
LCMS([M+H] +):1063.3
1HNMR(400MHz,DMSO-d6)δ8.98-8.95(m,1H),8.62(s,1H),8.45-8.39(m,1H),8.31-8.28(m,2H),8.16(d,J＝11.9Hz,1H),7.867.81(m,2H),7.42–7.33(m,5H),5.19–5.05(m,1H),4.78–4.41(m,1H),4.48–4.23(m,4H),4.19–3.64(m,4H),3.67–3.41(m,6H),2.44–2.41(m,3H),2.04–2.01(m,2H),1.93–1.81(m,5H),1.73–1.61(m,9H).
以下实施例A143-A362中A155,A156,A179,A180,A181,A182,A187-A195,A197,A199,A200采用与实施例A1相似的操作，用与之相对应的试剂合成；其余采用与实施例A46相似的操作，用与之相对应的试剂合成。
实施例A143
Figure PCTCN2021080167-appb-000308
LCMS([M+H] +):1149.4
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝7.4Hz,1H),8.60(t,J＝5.9Hz,1H),8.50(d,J＝2.5Hz,1H),8.32–8.24(m,2H),8.15(d,J＝8.9Hz,1H),7.93(dd,J＝8.9,2.6Hz,1H),7.46–7.32(m,5H),5.18(d,J＝2.6Hz,1H),4.57(d,J＝9.6Hz,1H),4.50–4.32(m,3H),4.25(dd,J＝15.8,5.6Hz,1H),3.98–3.87(m,4H),3.65(dt,J＝22.0,7.2Hz,2H),3.52(t,J＝5.5Hz,2H),3.28(d,J＝8.2Hz,2H),2.86–2.75(m,2H),2.47–2.39(m,5H),2.10–2.01(m,1H),1.98–1.85(m,1H),1.56(t,J＝10.2Hz,10H),0.94(d,J＝7.6Hz,9H).
实施例A144
Figure PCTCN2021080167-appb-000309
LCMS([M+H] +):1147.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.69(s,1H),8.45(d,J＝7.6Hz,1H),8.29(s,3H),7.80(d,J＝9.2Hz,2H),7.44(d,J＝8.3Hz,3H),7.37(d,J＝8.3Hz,2H),5.15(d,J＝3.5Hz,3H),4.91(p,J＝6.9Hz,1H),4.71–4.42(m,4H),4.26(d,J＝19.1Hz,1H),4.07(s,4H),3.65–3.42(m,2H),2.46(s,3H),2.09– 1.99(m,1H),1.82–1.72(m,1H),1.62(s,6H),1.37(d,J＝7.0Hz,3H),0.94(s,9H).
实施例A145
Figure PCTCN2021080167-appb-000310
LCMS([M+H] +):1047.4
1HNMR(400MHz,DMSO-d6)δ8.97(m,1H),8.67(d,J＝2.4Hz,1H),8.57(s,1H),8.33–8.26(m,2H),8.17(d,J＝8.5Hz,1H),8.05–7.94(m,3H),7.46–7.34(m,4H),7.30(t,J＝8.7Hz,1H),5.08–4.96(m,1H),4.55–4.51(m,1H),4.43–4.32(m,2H),4.25(dd,J＝15.8,5.6Hz,1H),4.19–4.11(m,2H),3.64(d,J＝10.4Hz,1H),3.58–3.52(m,1H),3.44(dd,J＝14.8,6.2Hz,4H),3.19–3.09(m,1H),2.64(m,1H),2.43(d,J＝6.4Hz,4H),2.10–1.74(m,5H),1.67(dt,J＝13.9,6.8Hz,2H),1.58(s,6H),0.90(d,J＝5.8Hz,9H).
实施例A146
Figure PCTCN2021080167-appb-000311
LCMS([M+H] +):1171.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.64(s,2H),8.29(s,2H),8.21(dd,J＝9.7,1.8Hz,1H),7.56(d,J＝9.1Hz,1H),7.39(d,J＝8.1Hz,7H),5.30(d,J＝18.9Hz,1H),4.58–4.34(m,3H),4.34–4.24(m,1H),4.18(s,2H),3.97(s,3H),3.89–3.79(m,1H),3.57(s,2H),2.44(s,3H),2.27(dd,J＝13.7,7.6Hz,1H), 2.12(ddd,J＝13.8,9.3,4.9Hz,1H),2.01(s,3H),1.85(dd,J＝14.0,6.4Hz,2H),1.79–1.70(m,2H),1.61(s,6H),0.95(d,J＝8.5Hz,9H).
实施例A147
Figure PCTCN2021080167-appb-000312
LCMS([M+H] +):1097.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.64(s,2H),8.29(s,2H),8.18(dd,J＝11.8,1.5Hz,1H),7.84(s,2H),7.51(d,J＝9.5Hz,1H),7.40(s,5H),5.20–4.97(m,2H),4.58(d,J＝9.5Hz,1H),4.41(d,J＝36.4Hz,7H),4.01(s,2H),3.67(d,J＝4.9Hz,4H),2.43(s,3H),2.11–2.00(m,3H),1.91(ddd,J＝12.9,8.8,4.4Hz,1H),1.61(s,6H),0.94(d,J＝7.1Hz,9H).
实施例A148
Figure PCTCN2021080167-appb-000313
LCMS([M+H] +):1086.4
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝12.0Hz,2H),8.71(s,1H),8.64(s,1H),8.43(d,J＝8.5Hz,1H),8.30(d,J＝6.2Hz,2H),8.19(d,J＝8.5Hz,1H),8.01(d,J＝7.8Hz,1H),7.47–7.36(m,5H),6.94(d,J＝8.6Hz,1H),5.28(s,1H),4.40(ddd,J＝32.5,21.3,6.8Hz,6H),3.94(d,J＝12.2Hz,3H),3.85(s,1H),3.55(s,2H),2.43(s,3H),2.32–2.19(m,1H),2.13(s,1H),1.99(d,J＝15.0Hz,3H),1.83(d,J＝7.0Hz,2H),1.72(s,2H),1.59(s,6H),0.95(s,9H).
实施例A149
Figure PCTCN2021080167-appb-000314
LCMS([M+H] +):1128.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.67(s,1H),8.45(d,J＝7.7Hz,1H),8.32–8.20(m,3H),7.83–7.73(m,2H),7.39(dt,J＝27.3,8.6Hz,5H),5.18–4.85(m,3H),4.59–4.34(m,4H),4.26(d,J＝17.8Hz,1H),4.04–3.90(m,2H),3.57(ddd,J＝60.5,30.4,8.4Hz,4H),2.45(s,3H),2.08–1.96(m,3H),1.81–1.72(m,1H),1.61(s,6H),1.42(dd,J＝41.5,7.0Hz,3H),0.93(s,9H).
实施例A150
Figure PCTCN2021080167-appb-000315
LCMS([M+H] +):1115.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.64(m,2H),8.29(s,2H),8.19(dd,J＝11.8,1.8Hz,1H),7.87(t,J＝8.6Hz,2H),7.57(d,J＝8.2Hz,1H),7.41(m,6H),5.17(m,2H),4.59(m,)1H),4.49–4.42(m,2H),4.38(m,2H),4.30–4.24(m,1H),4.10(m,2H),4.03–3.86(m,2H),3.66(m,2H),2.44(s,3H),2.05(m,1H),1.96–1.85(m,1H),1.62(s,6H),0.94(d,J＝7.5Hz,9H).
实施例A151
Figure PCTCN2021080167-appb-000316
LCMS([M+H] +):1121.3
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝7.2Hz,1H),8.63(s,2H),8.30(d,J＝11.6Hz,2H),8.17(d,J＝11.9Hz,1H),7.84(d,J＝10.4Hz,2H),7.50–7.30(m,6H),5.28(m,1H),4.45(m,3H),4.28(m,1H),4.19(m,2H),4.01–3.90(m,3H),3.84(m,1H),3.56(m,2H),2.44(d,J＝5.5Hz,3H),2.27(m,1H),2.12(m,1H),1.99(d,J＝14.4Hz,3H),1.93–1.82(m,2H),1.75(m,2H),1.61(s,6H),0.95(d,J＝8.7Hz,9H).
实施例A152
Figure PCTCN2021080167-appb-000317
LCMS([M+H] +):1139.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.2Hz,1H),8.62(dd,J＝17.8,11.9Hz,2H),8.32–8.19(m,3H),7.74(t,J＝7.5Hz,2H),7.47–7.31(m,5H),5.27(s,1H),4.44(ddd,J＝22.0,16.5,7.4Hz,3H),4.27(dd,J＝11.4,5.7Hz,3H),3.99–3.89(m,3H),3.83(dd,J＝11.7,4.1Hz,1H),3.54(t,J＝5.5Hz,2H),2.43(d,J＝7.7Hz,3H),2.26(dd,J＝13.7,7.9Hz,1H),2.12(ddd,J＝13.6,8.9,4.8Hz,1H),2.00(s,3H),1.77(ddd,J＝19.6,14.0,7.1Hz,4H),1.61(s,6H),0.93(d,J＝9.9Hz,9H).
实施例A153
Figure PCTCN2021080167-appb-000318
LCMS([M+H] +):1152.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.67(s,1H),8.47(d,J＝7.6Hz,1H),8.33–8.18(m,3H),7.78(t,J＝7.5Hz,2H),7.39(dt,J＝14.2,7.2Hz,5H),5.17(d,J＝22.5Hz,1H),4.96–4.84(m,1H),4.53–4.39(m,2H),4.27(t,J＝6.0Hz,2H),4.00–3.85(m,3H),3.76(dd,J＝11.7,3.8Hz,1H),3.54(t,J＝5.1Hz,2H),2.45(s,3H),2.26(dd,J＝13.4,7.5Hz,1H),2.05–1.92(m,4H),1.77(ddd,J＝19.4,13.5,6.9Hz,4H),1.61(s,6H),1.42(dd,J＝38.8,6.9Hz,3H),0.94(s,9H).
实施例A154
Figure PCTCN2021080167-appb-000319
LCMS([M+H] +):1165.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.6Hz,1H),8.6 3–8.58(m,2H),8.34–8.25(m,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.57(dd,J＝18.1,9.0Hz,2H),7.50–7.36(m,6H),5.33–5.01(m,3H),4.64–4.32(m,6H),4.25(dd,J＝15.7,5.5Hz,1H),4.15–4.04(m,2H),4.04–3.81(m,2H),3.69–3060(m 2H),2.44(d,J＝3.2Hz,3H),2.10–2.03(m,1H),1.90(ddd,J＝12.9,8.7,4.4Hz,1H),1.61(s,6H),0.93(d,J＝7.0Hz,9H).
实施例A155
Figure PCTCN2021080167-appb-000320
LCMS([M+H] +):944.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(d,J＝0.9Hz,1H),8.49(t,J＝5.6Hz,1H),8.29(d,J＝3.2Hz,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.86(d,J＝8.3Hz,1H),7.58(d,J＝9.2Hz,1H),7.47(d,J＝2.2Hz,1H),7.43–7.34(m,3H),5.11(dd,J＝12.9,5.4Hz,1H),4.78(s,2H),4.24(t,J＝5.5Hz,2H),3.59(dd,J＝11.0,5.5Hz,2H),2.88(ddd,J＝17.3,14.0,5.3Hz,1H),2.70–2.51(m,2H),2.10–1.97(m,1H),1.61(s,6H).
实施例A156
Figure PCTCN2021080167-appb-000321
LCMS([M+H] +):944.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(d,J＝0.9Hz,1H),8.49(t,J＝5.6Hz,1H),8.29(d,J＝3.2Hz,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.86(d,J＝8.3Hz,1H),7.58(d,J＝9.2Hz,1H),7.47(d,J＝2.2Hz,1H),7.43–7.34(m,3H),5.11(dd,J＝12.9,5.4Hz,1H),4.78(s,2H),4.24(t,J＝5.5Hz,2H),3.59(dd,J＝11.0,5.5Hz,2H),2.88(ddd,J＝17.3,14.0,5.3Hz,1H),2.70–2.51(m,2H),2.10–1.97(m,1H),1.61(s,6H).
实施例A157
Figure PCTCN2021080167-appb-000322
LCMS([M+H] +):1111.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.71(s,1H),8.61(s,1H),8.29(t,J＝7.9Hz,2H),8.03(d,J＝7.4Hz,1H),7.69(d,J＝8.2Hz,1H),7.56(d,J＝8.6Hz,1H),7.37(d,J＝25.5Hz,7H),5.17(s,1H),4.58(d,J＝9.4Hz,1H),4.51–4.32(m,3H),4.29(d,J＝4.8Hz,1H),4.17(s,2H),3.97(s,2H),3.75–3.50(m,4H),2.43(s,3H),2.08(s,2H),1.98–1.68(m,5H),1.59(s,6H),0.95(s,9H).
实施例A158
Figure PCTCN2021080167-appb-000323
LCMS([M+H] +):1061.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.0Hz,1H),8.73(d,J＝2.1Hz,1H),8.60(t,J＝5.9Hz,1H),8.34–8.25(m,2H),7.97(dd,J＝18.2,8.8Hz,3H),7.47–7.34(m,5H),7.00–6.90(m,2H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.5Hz,1H),4.49–4.32(m,3H),4.26(dd,J＝15.7,5.6Hz,1H),4.10(t,J＝6.3Hz,2H),4.01–3.89(m,2H),3.71–3.52(m,4H),2.43(d,J＝7.2Hz,3H),2.07(dd,J＝12.2,7.9Hz,1H),2.01–1.89(m,1H),1.88–1.79(m,2H),1.74(dd,J＝14.1,6.3Hz,2H),1.59(s,6H),0.93(s,9H).
实施例A159
Figure PCTCN2021080167-appb-000324
LCMS([M+H] +):1097.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.64(s,2H),8.28(s,2H),8.17(dd,J＝11.9,1.8Hz,1H),7.84(s,2H),7.48(t,J＝9.0Hz,1H),7.40(d,J＝1.4Hz,5H),5.16(d,J＝3.5Hz,1H),5.08–4.84(m,1H),4.58(d,J＝8.2Hz,1H),4.50–4.33(m,3H),4.29(s,3H),4.06(s,2H),3.88–3.59(m,4H),2.44(s,3H),2.24–2.10(m,2H),2.10(s,1H),1.91(ddd,J＝12.9,8.8,4.4Hz,1H),1.62(s,6H),0.95(s,9H).
实施例A160
Figure PCTCN2021080167-appb-000325
LCMS([M+H] +):1012.3
1HNMR(400MHz,DMSO-d6)δ12.19(d,J＝61.4Hz,1H),8.73(s,1H),8.63(s,1H),8.29(s,2H),8.16(d,J＝10.5Hz,1H),7.93–7.77(m,2H),7.35(dd,J＝18.8,9.2Hz,2H),7.25(s,1H),5.20(d,J＝3.6Hz,1H),5.06(t,J＝7.8Hz,1H),4.57(d,J＝9.5Hz,1H),4.43(d,J＝31.3Hz,1H),4.19(t,J＝6.2Hz,2H),3.96(s,2H),3.85(d,J＝6.4Hz,1H),3.68–3.51(m,4H),2.47(s,3H),2.15(d,J＝4.4Hz,2H),1.85(d,J＝7.7Hz,2H),1.79–1.69(m,2H),1.62(s,6H),0.89(s,9H).
实施例A161
Figure PCTCN2021080167-appb-000326
LCMS([M+H] +):1035.3
1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.28(s,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.85(d,J＝10.6Hz,2H),7.41(dd,J＝37.5,4.4Hz,7H),6.90(s,1H), 5.61(dd,J＝27.6,5.7Hz,1H),5.42–5.30(m,1H),5.00–4.83(m,1H),4.64(dt,J＝15.2,6.8Hz,1H),4.51(d,J＝9.5Hz,1H),4.26(d,J＝29.6Hz,1H),4.23(s,2H),3.95(s,2H),3.58(d,J＝6.8Hz,6H),2.87(ddd,J＝13.2,8.4,4.9Hz,1H),1.95–1.80(m,3H),1.76(dd,J＝14.0,6.1Hz,2H),1.61(s,6H),0.97(s,3H),0.68(s,6H).
实施例A162
Figure PCTCN2021080167-appb-000327
LCMS([M+H] +):1115.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.64(s,2H),8.28(s,2H),8.17(dd,J＝11.9,1.8Hz,1H),7.86(d,J＝10.5Hz,2H),7.59(d,J＝9.4Hz,1H),7.40(d,J＝2.9Hz,5H),5.16(d,J＝3.5Hz,1H),4.58(d,J＝9.5Hz,1H),4.44(dt,J＝14.1,7.1Hz,2H),4.39(d,J＝11.9Hz,4H),4.25(dd,J＝15.7,5.5Hz,1H),4.14(s,2H),3.93(t,J＝13.5Hz,2H),3.66(dt,J＝20.8,7.3Hz,2H),2.44(s,3H),2.08(s,2H),1.96–1.86(m,1H),1.62(s,6H),0.93(d,J＝7.3Hz,9H).
实施例A163
Figure PCTCN2021080167-appb-000328
LCMS([M+H] +):1115.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.7Hz,1H),8.64(s,1H),8.58(t,J＝5.9Hz,1H),8.28(m,2H),8.18(dd,J＝11.8,1.8Hz,1H),7.86(t,J＝9.1Hz,2H),7.51(d,J＝9.5Hz,1H),7.46(d,J＝8.6Hz,1H),7.41(d,J＝9.3Hz,4H), 5.15(m,1H),4.59(m,2H),4.47–4.41(m,2H),4.37(m,2H),4.25(m,2H),4.00(m,2H),3.75(m,2H),3.70–3.62(m,2H),2.43(s,3H),2.05(m,2H),2.02–1.97(m,2H),1.62(s,6H),0.93(s,9H).
实施例A164
Figure PCTCN2021080167-appb-000329
LCMS([M+H] +):1085.4
1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.34–8.26(m,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.62–7.54(m,1H),7.51–7.30(m,8H),6.94(d,J＝32.8Hz,1H),5.61(dd,J＝28.0,5.7Hz,1H),5.40–5.31(m,1H),4.97(dd,J＝23.3,6.4Hz,1H),4.64(dt,J＝15.1,6.9Hz,1H),4.52(d,J＝9.5Hz,1H),4.30(s,1H),4.19(t,J＝6.0Hz,2H),4.00–3.84(m,2H),3.64–3.49(m,7H),2.87(ddd,J＝13.2,8.4,5.0Hz,1H),1.95–1.69(m,5H),1.61(s,6H),0.97(s,2H),0.68(s,7H).
实施例A165
Figure PCTCN2021080167-appb-000330
LCMS([M+H] +):1062.3
1HNMR(400MHz,DMSO-d6)δ12.31–12.05(m,1H),8.73(d,J＝10.2Hz,1H),8.62(s,1H),8.34–8.24(m,2H),8.19(dd,J＝9.7,1.7Hz,1H),7.55(d,J＝9.1Hz,1H),7.43–7.29(m,3H),7.25(d,J＝5.5Hz,1H),5.20(d,J＝3.7Hz,1H),5.06(t,J＝7.7Hz,1H),4.57(d,J＝9.5Hz,1H),4.49–4.33(m,1H),4.17(t,J＝6.1Hz,2H),4.01–3.90(m,2H),3.82(dt,J＝34.8,17.4Hz,1H),3.68–3.52(m, 3H),2.48–2.39(m,3H),2.25–2.10(m,2H),1.83(dd,J＝13.7,6.3Hz,2H),1.78–1.68(m,2H),1.61(s,6H),0.95–0.80(m,9H).
实施例A166
Figure PCTCN2021080167-appb-000331
LCMS([M+H] +):1147.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.0Hz,1H),8.66–8.56(m,2H),8.28(s,2H),8.20(d,J＝9.7Hz,1H),7.57(d,J＝8.2Hz,1H),7.49(d,J＝9.5Hz,1H),7.40(d,J＝4.2Hz,5H),5.15(d,J＝3.4Hz,1H),5.03(s,1H),4.92(s,1H),4.57(d,J＝9.5Hz,1H),4.49–4.33(m,3H),4.25(dd,J＝15.6,5.7Hz,3H),4.05(d,J＝9.5Hz,2H),3.88–3.58(m,5H),2.44(d,J＝4.7Hz,3H),2.22–1.86(m,6H),1.61(s,6H),0.94(s,9H).
实施例A167
Figure PCTCN2021080167-appb-000332
LCMS([M+H] +):1165.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.63(s,1H),8.58(t,J＝6.0Hz,1H),8.28(s,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.59(d,J＝8.6Hz,1H),7.55–7.44(m,3H),7.39(s,4H),5.14(d,J＝2.5Hz,1H),4.59(dd,J＝16.1,11.3Hz,3H),4.49–4.31(m,3H),4.25(dd,J＝15.8,5.6Hz,1H),4.01(s,2H),3.75(t,J＝6.2Hz,2H),3.70–3.57(m,2H),2.44(d,J＝4.1Hz,5H),2.07–2.00(m,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.61(s,6H),0.91(d,J＝6.4Hz,9H).
实施例A168
Figure PCTCN2021080167-appb-000333
LCMS([M+H] +):1165.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.66–8.56(m,2H),8.29(d,J＝3.4Hz,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.59(dd,J＝13.2,9.3Hz,2H),7.46–7.33(m,6H),5.15(d,J＝3.4Hz,1H),4.58(d,J＝9.5Hz,1H),4.50–4.32(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),4.15(s,2H),3.93(t,J＝13.7Hz,2H),3.71–3.57(m,2H),2.60–2.52(m,1H),2.43(s,5H),2.05(d,J＝8.6Hz,1H),1.91(ddd,J＝13.0,8.9,4.5Hz,1H),1.61(s,6H),0.93(d,J＝6.1Hz,9H).
实施例A169
Figure PCTCN2021080167-appb-000334
LCMS([M+H] +):1079.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.96(m,1H),8.66(d,J＝2.2Hz,1H),8.59(t,J＝5.9Hz,1H),8.32–8.26(m,2H),8.13(d,J＝8.7Hz,3H),7.96(dd,J＝8.5,2.4Hz,1H),7.54(d,J＝8.8Hz,1H),7.45–7.35(m,4H),7.14(d,J＝8.8Hz,2H),5.32–4.96(m,3H),4.58(d,J＝9.4Hz,1H),4.48–4.32(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),4.15–4.04(m,2H),4.02–3.87(m,2H),3.70–3.61(m,2H),2.43(s,3H),2.07–2.04(m,1H),1.96–1.86(m,1H),1.58(s,6H),0.94(d,J＝6.9Hz,9H).
实施例A170
Figure PCTCN2021080167-appb-000335
LCMS([M+H] +):1020.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.66(d,J＝2.3Hz,1H),8.59(t,J＝5.9Hz,1H),8.36(t,J＝5.5Hz,1H),8.33–8.23(m,2H),7.96(dd,J＝8.3,2.4Hz,1H),7.79(d,J＝8.3Hz,1H),7.51(d,J＝15.4Hz,1H),7.46–7.35(m,5H),7.14(d,J＝15.4Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.40–4.34(m,2H),4.29–4.24(m,1H),3.98–3.86(m,2H),3.68–3.59(m,2H),3.50(t,J＝6.0Hz,2H),3.26–3.18(m,2H),2.44(s,3H),2.06–2.01(m,1H),1.95–1.86(m,1H),1.59–1.56(m,10H),0.93(d,J＝6.8Hz,9H).
实施例A171
Figure PCTCN2021080167-appb-000336
LCMS([M+H] +):1061.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝6.8Hz,1H),8.66(d,J＝2.3Hz,1H),8.59(t,J＝5.9Hz,1H),8.29(q,J＝8.5Hz,2H),8.11(d,J＝8.7Hz,3H),7.95(dd,J＝8.5,2.3Hz,1H),7.48(d,J＝9.5Hz,1H),7.45–7.36(m,4H),7.09(d,J＝8.8Hz,2H),5.16(d,J＝3.4Hz,1H),4.95(dd,J＝47.5,6.7Hz,1H),4.57(d,J＝9.5Hz,1H),4.50–4.33(m,3H),4.25(dd,J＝15.8,5.6Hz,1H),4.18(t,J＝6.1Hz,2H),4.11–3.99(m,2H),3.88–3.58(m,4H),2.44(d,J＝4.4Hz,3H), 2.15(d,J＝6.1Hz,1H),2.10(d,J＝7.6Hz,2H),1.91(ddd,J＝13.0,8.9,4.4Hz,1H),1.58(s,6H),0.94(s,9H).
实施例A172
Figure PCTCN2021080167-appb-000337
LCMS([M+H] +):1116.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.88(m,1H),8.63(s,1H),8.44(dd,J＝51.5,8.1Hz,1H),8.33–8.23(m,2H),8.16(d,J＝11.9Hz,1H),8.07–7.93(m,1H),7.81(dt,J＝12.1,10.3Hz,2H),7.49–7.28(m,4H),7.26–7.14(m,1H),6.22(d,J＝9.7Hz,1H),5.36–4.89(m,2H),4.50–3.39(m,7H),3.20(m,2H),2.69–2.54(m,2H),2.46–2.36(m,3H),2.34–2.11(m,4H),2.05–1.73(m,4H),1.62(s,7H),0.96(dd,J＝6.5,2.9Hz,3H),0.78(dd,J＝12.0,6.7Hz,3H).
实施例A173
Figure PCTCN2021080167-appb-000338
LCMS([M+H] +):1038.3
1HNMR(400MHz,DMSO-d6)δ9.00–8.86(m,1H),8.59(m,1H),8.46(m,1H),8.30–8.27(m,2H),7.91–7.87(m,1H),7.69–7.54(m,1H),7.49–7.33(m,4H),6.25–6.16(m,1H),5.32–5.09(m,2H),4.40–4.20(m,2H),3.94–3.49(m, 5H),3.05–2.81(m,5H),2.46–2.43(m,3H),2.27–2.18(m,4H),1.99(m,1H),1.79(m,3H),1.55–1.45(m,8H),0.97–0.73(m,6H).
实施例A174
Figure PCTCN2021080167-appb-000339
LCMS([M+H] +):1081.4
1HNMR(400MHz,DMSO-d6)δ8.97–8.59(m,3H),7.41–7.29(m,8H),6.25–6.21(m,2H),5.11–5.07(m,3H),4.39–4.20(m,5H),3.85–3.73(m,4H),2.67–2.56(m,5H),2.43(s,6H),2.29–2.23(m,3H),2.19–2.16(m,7H),2.00–1.97(m,3H),1.81–1.78(m,2H),0.97–0.93(m,6H),0.78(dd,J＝14.2,6.8Hz,6H).
实施例A175
Figure PCTCN2021080167-appb-000340
LCMS([M+H] +):1079.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.66(d,J＝2.2Hz,1H),8.59(t,J＝5.9Hz,1H),8.29(q,J＝8.5Hz,2H),8.12(d,J＝8.8Hz,3H),7.95(dd,J＝8.5,2.4Hz,1H),7.59(d,J＝9.5Hz,1H),7.39(q,J＝8.3Hz,4H),7.10(d,J＝8.8Hz,2H),5.16(d,J＝3.4Hz,1H),4.57(d,J＝9.5Hz,1H),4.49–4.33(m,3H),4.31–4.20(m,3H),4.12(d,J＝16.6Hz,2H),3.91(t,J＝13.3Hz,2H),3.66(dt,J＝21.0,7.1Hz,2H),2.52(d,J＝7.6Hz,1H),2.43(s,4H),2.06(dd,J＝12.9,6.9Hz,1H),1.96–1.86(m,1H),1.58(s,6H),0.93(d,J＝7.0Hz,9H).
实施例A176
Figure PCTCN2021080167-appb-000341
LCMS([M+H] +):1037.1
1HNMR(400MHz,DMSO-d6)δ9.02–8.87(m,1H),8.61(d,J＝133.7Hz,1H),8.32–8.22(m,2H),7.66–7.25(m,8H),6.28–6.14(m,1H),5.38–4.87(m,2H),4.33(ddd,J＝58.1,32.8,20.0Hz,2H),3.96–3.49(m,4H),3.24–2.65(m,6H),2.47–2.41(m,3H),2.33–2.09(m,4H),2.00(d,J＝7.5Hz,1H),1.78(s,3H),1.52(s,8H),0.84(ddd,J＝32.0,22.1,6.4Hz,6H).
实施例A177
Figure PCTCN2021080167-appb-000342
LCMS([M+H] +):1158.4
1HNMR(400MHz,DMSO-d6)δ9.00–8.84(m,1H),8.63(s,1H),8.41(dd,J＝59.3,8.0Hz,1H),8.29(d,J＝11.9Hz,2H),8.20–8.12(m,1H),7.83(t,J＝10.7Hz,3H),7.50–7.25(m,5H),6.22(d,J＝9.8Hz,1H),5.37–5.03(m,2H),4.50–4.23(m,2H),4.14–4.02(m,2H),3.88–3.69(m,1H),3.49(m,2H),3.10–2.87(m,2H),2.68–2.52(m,2H),2.45(d,J＝3.3Hz,3H),2.35–2.13(m,4H),2.00(m,1H),1.89–1.65(m,3H),1.61(s,6H),1.41–1.25(m,4H),1.20(m,1H),1.00–0.94(m,2H),0.78(dd,J＝12.6,6.7Hz,3H).
实施例A178
Figure PCTCN2021080167-appb-000343
LCMS([M+H] +):1142.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.77(m,0.5H),8.63(s,1H),8.44(m,0.5H),8.30–8.28(m,2H),8.17(d,J＝11.7Hz,1H),7.87–7.83(m,2H),7.51–7.32(m,5H),6.25–6.16(m,1H),5.33–4.72(m,4H),4.48–4.16(m,2H),4.01–3.38(m,6H),2.95–2.84(m,2H),2.45–2.44(m,3H),2.28–2.17(m,4H),2.05–1.75(m,4H),1.61(s,7H),1.03–0.69(m,6H).
实施例A179
Figure PCTCN2021080167-appb-000344
LCMS([M+H] +):984.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(s,1H),8.31–8.27(m,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.81–7.77(m,1H),7.60–7.58(m,1H),7.49–7.45(m,3H),7.37(d,J＝8.7Hz,1H),5.23(s,2H),5.11(dd,J＝12.9,5.4Hz,1H),4.91(m,1H),3.85(s,1H),3.72(s,1H),3.43–3.38(m,2H),2.94–2.85(m,1H),2.62–2.54(m,2H),2.08(m,1H),2.02–1.99(m,2H),1.81(m,1H),1.61(s,7H).
实施例A180
Figure PCTCN2021080167-appb-000345
LCMS([M+H] +):984.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.64(s,1H),8.32–8.29(m,2H),8.21(dd,J＝9.7,1.7Hz,1H),7.85(d,J＝8.3Hz,1H),7.60(d,J＝8.5Hz,1H),7.50–7.46(m,3H),7.37(dd,J＝8.3,2.2Hz,1H),5.19(s,2H),5.13(dd,J＝12.9,5.3Hz,1H),4.92(m,1H),3.87(s,1H),3.73(s,1H),3.43–3.39(m,2H),2.97–2.84(m,1H),2.63–2.56(m,2H),2.08(s,1H),2.04–2.00(m,2H),1.78(m,1H),1.62(s,7H).
实施例A181
Figure PCTCN2021080167-appb-000346
LCMS([M+H] +):943.2
1HNMR(400MHz,DMSO-d6)δ11.08(s,1H),8.63(s,1H),8.47(t,J＝5.5Hz,1H),8.32–8.26(m,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.62–7.55(m,2H),7.47(d,J＝2.4Hz,1H),7.38(dd,J＝8.6,2.3Hz,1H),7.21(d,J＝8.6Hz,1H),7.03(d,J＝7.0Hz,1H),6.79(t,J＝5.9Hz,1H),5.05(m,1H),4.69(m,2H),3.49–3.37(m,4H),2.88(m,1H),2.64–2.51(m,2H),2.00(m 1H),1.61(s,6H).
实施例A182
Figure PCTCN2021080167-appb-000347
LCMS([M+H] +):911.2
1HNMR(400MHz,DMSO-d6)δ11.09(s,1H),8.67(s,1H),8.41(s,1H),8.29(s,2H),8.23(dd,J＝11.8,1.8Hz,1H),7.76(d,J＝9.5Hz,2H),7.64–7.54(m,1H),7.20(d,J＝8.6Hz,1H),7.03(d,J＝7.0Hz,1H),6.77(s,1H),5.05(s,1H),4.71(s, 2H),3.54–3.35(m,4H),2.98–2.80(m,1H),2.57(s,2H),2.07–1.94(m,1H),1.62(s,6H).
实施例A183
Figure PCTCN2021080167-appb-000348
LCMS([M+H] +):1192.3
1HNMR(400MHz,DMSO-d6)δ8.99(d,J＝4.1Hz,1H),8.79(s,1H),8.62(s,1H),8.45(d,J＝5.1Hz,1H),8.28(s,2H),8.23–8.16(m,1H),7.62–7.29(m,7H),6.28–6.16(m,1H),5.41–4.74(m,5H),4.47–4.24(m,2H),4.01–3.64(m,4H),3.62–3.35(m,4H),2.89(d,J＝22.1Hz,3H),2.46(d,J＝3.8Hz,3H),2.38–2.11(m,5H),2.05–1.75(m,5H),1.61(s,8H),1.02–0.67(m,7H).
实施例A184
Figure PCTCN2021080167-appb-000349
LCMS([M+H] +):1080.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.2Hz,1H),8.28(d,J＝4.8Hz,2H),7.85(s,2H),7.55(d,J＝8.2Hz,2H),7.41(dt,J＝17.3,11.0Hz,6H),6.23(d,J＝10.8Hz,1H),5.24–5.10(m,2H),4.34(dd,J＝28.4,19.6Hz,3H),3.80(dd,J＝40.6,9.2Hz,3H),3.14(s,4H),2.64(s,5H),2.46(s,4H),2.19(d,J＝8.8Hz,9H),2.06–1.95(m,3H),1.80(s,4H),1.61(s,3H),1.52(s,6H),1.02–0.71(m,9H).
实施例A185
Figure PCTCN2021080167-appb-000350
LCMS([M+H] +):1005.4
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝9.6Hz,1H),8.68–8.56(m,2H),8.09(d,J＝8.8Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.84(dd,J＝8.4,1.6Hz,1H),7.53(dd,J＝8.4,6.4Hz,1H),7.46–7.36(m,5H),7.05(d,J＝8.9Hz,2H),5.16(s,1H),4.57(m,1H),4.49–4.33(m,3H),4.26(m,,1H),4.13(m,3H),4.08(m,2H),4.01–3.89(m,2H),3.70–3.53(m,4H),2.43(d,J＝7.2Hz,3H),2.11–2.03(m,1H),1.95–1.79(m,3H),1.74(m,2H),1.56(s,6H),0.93(d,J＝6.9Hz,9H).
实施例A186
Figure PCTCN2021080167-appb-000351
LCMS([M+H] +):1185.4
1HNMR(400MHz,DMSO-d6)δ9.00–8.93(m,1H),8.64(s,1H),8.29(d,J＝3.6Hz,2H),8.17(dd,J＝11.8,1.8Hz,1H),7.85(t,J＝11.1Hz,2H),7.49–7.27(m,5H),6.23(d,J＝12.4Hz,1H),5.21(d,J＝7.4Hz,1H),5.10(s,1H),4.65(d,J＝36.0Hz,1H),4.36(s,1H),4.28(s,1H),3.76(d,J＝9.7Hz,1H),3.59–3.43(m,2H),3.34–3.12(m,10H),2.70–2.54(m,3H),2.46(s,3H),2.20(d,J＝10.2Hz, 3H),2.13–1.96(m,3H),1.92–1.68(m,3H),1.62(s,6H),1.24(s,1H),0.97(t,J＝6.2Hz,2H),0.82–0.71(m,3H).
实施例A187
Figure PCTCN2021080167-appb-000352
LCMS([M+H] +):860.2
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.22(d,J＝2.8Hz,1H),7.92–7.70(m,5H),7.47(dd,J＝25.9,7.8Hz,2H),7.29(dd,J＝8.7,2.8Hz,1H),7.05(d,J＝7.3Hz,2H),6.43(s,1H),5.40–5.09(m,4H),4.77(,1H),4.10–3.89(m,5H),2.94–2.86(m,2H),2.67–2.57(m,2H),2.03(m,2H),1.68(s,6H).
实施例A188
Figure PCTCN2021080167-appb-000353
LCMS([M+H] +):860.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.23(d,J＝2.7Hz,1H),7.92–7.86(m,3H),7.75(d,J＝8.7Hz,2H),7.49(s,1H),7.37(m,1H),7.29(dd,J＝8.7,2.9Hz,1H),7.05(d,J＝8.6Hz,2H),6.45(s,1H),5.55–4.99(m,4H),4.77(s,1H),4.20–4.03(m,4H),3.89–3.73(m,4H),2.88(m,1H),2.61(m,2H),2.03–1.99(m,2H),1.69(s,6H).
实施例A189
Figure PCTCN2021080167-appb-000354
LCMS([M+H] +):951.8
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.68(s,1H),8.32–8.20(m,3H),7.82(dd,J＝11.7,8.7Hz,3H),7.46(d,J＝2.2Hz,1H),7.36(dd,J＝8.3,2.3Hz,1H),5.23–5.06(m,3H),4.57(s,1H),3.84(s,1H),3.72(s,1H),3.35(s,2H),2.97–2.82(m,1H),2.57(dd,J＝19.9,10.6Hz,2H),2.03(d,J＝5.7Hz,2H),1.95(s,1H),1.83(s,1H),1.61(s,6H).
实施例A190
Figure PCTCN2021080167-appb-000355
LCMS([M+H] +):912.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.66(s,1H),8.28(s,2H),8.25–8.17(m,2H),7.77(dd,J＝16.9,8.6Hz,3H),7.47(d,J＝7.2Hz,1H),7.40(d,J＝8.5Hz,1H),5.10(dd,J＝12.9,5.4Hz,1H),4.81(s,2H),4.31(t,J＝5.3Hz,2H),3.57(d,J＝3.9Hz,2H),2.96–2.79(m,1H),2.55(dd,J＝20.2,10.7Hz,2H),2.03(dd,J＝14.8,9.7Hz,1H),1.61(s,6H).
实施例A191
Figure PCTCN2021080167-appb-000356
LCMS([M+H] +):951.8
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.68(s,1H),8.31–8.21(m,3H),7.79(dd,J＝14.1,8.7Hz,3H),7.45(d,J＝7.2Hz,1H),7.36(d,J＝8.6Hz,1H),5.23(s,2H),5.11(dd,J＝12.9,5.4Hz,1H),4.57(s,1H),3.77(d,J＝48.3Hz,2H),3.34(s,2H),2.88(dd,J＝17.4,5.6Hz,1H),2.57(dd,J＝19.5,10.4Hz,2H),2.07–2.01(m,2H),1.95(s,1H),1.86(s,1H),1.68(d,J＝8.4Hz,1H),1.61(s,6H).
实施例A192
Figure PCTCN2021080167-appb-000357
LCMS([M+H] +):912.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.66(s,1H),8.44(t,J＝5.6Hz,1H),8.29(d,J＝11.3Hz,2H),8.25–8.19(m,1H),7.85(d,J＝8.3Hz,1H),7.81–7.71(m,2H),7.46(d,J＝2.2Hz,1H),7.39(dd,J＝8.3,2.3Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.76(s,2H),4.30(t,J＝5.5Hz,2H),3.55(q,J＝5.5Hz,2H),2.88(ddd,J＝17.5,14.3,5.5Hz,1H),2.64–2.51(m,2H),2.04(dd,J＝9.0,3.7Hz,1H),1.61(s,6H).
实施例A193
Figure PCTCN2021080167-appb-000358
LCMS([M+H] +):856.2
1HNMR(400MHz,DMSO-d6)δ11.16(s,1H),8.69(s,1H),8.35(t,J＝5.6Hz,1H),8.23(dd,J＝11.9,1.9Hz,1H),7.91(t,J＝8.7Hz,3H),7.86–7.78(m,1H),7.61–7.51(m,2H),7.44(m,2H),5.14(m,1H),4.90(m,2H),4.30(m,2H),4.20(d,J＝2.5Hz,3H),3.75–3.62(m,2H),3.00–2.89(m,1H),2.69–2.58(m,2H),2.13–2.04(m,1H),1.66(d,J＝2.9Hz,6H).
实施例A194
Figure PCTCN2021080167-appb-000359
LCMS([M+H] +):896.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.64(s,1H),8.17(dd,J＝11.9,1.8Hz,1H),7.94–7.74(m,4H),7.50(ddd,J＝13.8,9.0,4.2Hz,3H),7.36(dd,J＝8.3,2.3Hz,1H),5.25–5.07(m,3H),4.89–4.74(m,1H),4.14(d,J＝2.6Hz,3H),3.92–3.81(m,1H),3.73(d,J＝12.7Hz,1H),3.40(dd,J＝21.0,6.7Hz,2H),2.89(ddd,J＝17.4,14.5,5.4Hz,1H),2.65–2.51(m,2H),2.08(s,1H),2.07–1.95(m,2H),1.81(d,J＝8.2Hz,1H),1.61(t,J＝11.2Hz,7H).
实施例A195
Figure PCTCN2021080167-appb-000360
LCMS([M+H] +):896.2
1HNMR(400MHz,DMSO-d6)δ11.16(s,1H),8.69(s,1H),8.23(dd,J＝11.9,1.8Hz,1H),7.87(dt,J＝15.8,9.5Hz,4H),7.55(ddd,J＝19.1,11.5,6.8Hz,3H),7.42(d,J＝8.6Hz,1H),5.28(s,2H),5.16(dd,J＝12.9,5.4Hz,1H),4.88(d,J＝3.4Hz,1H),4.19(d,J＝2.5Hz,3H),3.92(d,J＝13.0Hz,1H),3.78(d,J＝13.7Hz,1H),3.52–3.38(m,2H),2.95(ddd,J＝17.4,13.9,5.4Hz,1H),2.69–2.56(m,2H),2.11(dt,J＝11.1,9.1Hz,3H),1.88(d,J＝7.9Hz,1H),1.68(dd,J＝22.4,6.0Hz,7H).
实施例A196
Figure PCTCN2021080167-appb-000361
LCMS([M+H] +):1091.4
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝10.7Hz,1H),8.66–8.57(m,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.86(dd,J＝8.4,1.6Hz,1H),7.57–7.48(m,2H),7.45–7.33(m,7H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.32(m,3H),4.26(dd,J＝15.7,5.6Hz,1H),4.17(t,J＝6.2Hz,2H),4.14(d,J＝2.6Hz,3H),4.01–3.89(m,2H),3.63(ddd,J＝27.0,11.6,5.0Hz,4H),2.44(d,J＝7.1Hz,3H),2.11–2.03(m,1H),1.89(tdd,J＝17.0,11.5,5.2Hz,3H),1.79–1.71(m,2H),1.59(d,J＝5.6Hz,6H),0.93(d,J＝6.5Hz,9H).
实施例A197
Figure PCTCN2021080167-appb-000362
LCMS([M+H] +):856.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(s,1H),8.51(s,1H),8.16(dd,J＝11.9,1.9Hz,1H),7.89–7.80(m,4H),7.51(dd,J＝8.4,6.4Hz,1H),7.46(d,J＝2.2Hz,1H),7.42–7.33(m,2H),5.11(m,1H),4.78(m,2H),4.23(m,2H),4.14(d,J＝2.6Hz,3H),3.60(m,2H),2.88(m,1H),2.64–2.51(m,2H),2.04(m,1H),1.59(d,J＝3.2Hz,6H).
实施例A198
Figure PCTCN2021080167-appb-000363
LCMS([M+H] +):976.3
1HNMR(400MHz,DMSO-d6)δ12.13(s,1H),8.72(s,1H),8.65(d,J＝2.3Hz,1H),8.29(d,J＝7.1Hz,2H),8.10(d,J＝8.7Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.32(d,J＝9.6Hz,1H),7.25(s,1H),7.07(d,J＝8.9Hz,2H),5.21(d,J＝3.6Hz,1H),5.05(t,J＝7.8Hz,1H),4.57(d,J＝9.6Hz,1H),4.45(s,1H),4.08(t,J＝ 6.2Hz,2H),3.95(d,J＝2.1Hz,2H),3.84(dd,J＝10.7,4.3Hz,1H),3.63(d,J＝9.2Hz,1H),3.55(t,J＝6.3Hz,2H),2.46(s,3H),2.26–2.11(m,2H),1.86–1.77(m,2H),1.77–1.68(m,2H),1.58(s,6H),0.88(s,9H).
实施例A199
Figure PCTCN2021080167-appb-000364
LCMS([M+H] +):820.2
1HNMR(400MHz,DMSO-d6)δ11.15(s,1H),8.65(s,1H),8.24(s,1H),8.11(d,J＝8.4Hz,3H),7.95(d,J＝7.8Hz,1H),7.85(d,J＝8.2Hz,1H),7.76(t,J＝7.8Hz,1H),7.59–7.36(m,3H),7.09(d,J＝8.4Hz,2H),5.11(dd,J＝12.6,5.1Hz,1H),4.83(s,2H),4.14(s,5H),3.60(d,J＝4.4Hz,2H),2.90(t,J＝13.2Hz,1H),2.60(d,J＝18.5Hz,2H),2.04(dd,J＝14.0,7.3Hz,1H),1.57(s,6H).
实施例A200
Figure PCTCN2021080167-appb-000365
LCMS([M+H] +):820.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.66(d,J＝2.4Hz,1H),8.50(t,J＝5.6Hz,1H),8.12(d,J＝8.8Hz,3H),7.96(dd,J＝8.5,2.5Hz,1H),7.86(d,J＝8.3Hz,2H),7.54(dd,J＝8.4,6.4Hz,1H),7.47(d,J＝2.2Hz,1H),7.40(dd,J＝8.3,2.3Hz,1H),7.08(d,J＝8.9Hz,2H),5.12(dd,J＝12.9,5.4Hz,1H),4.79(s,2H),4.13(t,J＝4.6Hz,5H),3.57(dd,J＝11.0,5.5Hz,2H),2.88(ddd,J＝17.0,13.9,5.2Hz,1H),2.58(dd,J＝21.5,6.6Hz,2H),2.04(dd,J＝10.6,5.3Hz,1H),1.57(s,6H).
实施例A201
Figure PCTCN2021080167-appb-000366
LCMS([M+H] +):955.3
1HNMR(400MHz,DMSO-d6)δ11.89(s,1H),8.65(d,J＝2.3Hz,1H),8.29(d,J＝6.9Hz,2H),8.10(d,J＝8.7Hz,3H),7.93(dd,J＝8.4,2.4Hz,1H),7.69(d,J＝6.8Hz,2H),7.45(s,1H),7.34(d,J＝9.6Hz,3H),7.18–7.02(m,3H),5.22(s,1H),5.08(s,1H),4.57(d,J＝9.4Hz,1H),4.48(s,1H),4.08(t,J＝6.0Hz,2H),3.95(s,2H),3.86(d,J＝7.6Hz,1H),3.64(d,J＝10.9Hz,1H),3.55(s,1H),2.20(d,J＝27.5Hz,2H),2.04–1.93(m,1H),1.81(d,J＝7.6Hz,2H),1.76–1.68(m,2H),1.58(s,6H),0.90(d,J＝27.2Hz,9H).
实施例A202
Figure PCTCN2021080167-appb-000367
LCMS([M+H] +):1041.3
1HNMR(400MHz,DMSO-d6)δ12.07(d,J＝149.8Hz,1H),8.63(s,1H),8.28(s,2H),8.23–8.16(m,1H),7.65(dd,J＝35.7,7.4Hz,2H),7.54(t,J＝7.2Hz,1H),7.48–7.22(m,6H),7.15(dt,J＝25.3,7.4Hz,1H),5.21(d,J＝3.5Hz,1H),5.13–5.02(m,1H),4.58(d,J＝9.5Hz,1H),4.48(s,1H),4.17(t,J＝6.0Hz,2H),4.02–3.82(m,3H),3.64(d,J＝9.6Hz,1H),3.56(t,J＝6.2Hz,2H),2.28–2.19(m,1H),2.18–2.10(m,1H),1.89–1.79(m,2H),1.79–1.69(m,2H),1.60(s,6H),0.96–0.81(m,9H).
实施例A203
Figure PCTCN2021080167-appb-000368
LCMS([M+H] +):962.3
1HNMR(400MHz,DMSO-d6)δ12.60–12.02(m,1H),8.96–8.81(m,1H),8.65(d,J＝2.2Hz,1H),8.29(q,J＝8.5Hz,2H),8.08(t,J＝12.4Hz,3H),8.01–7.91(m,2H),7.45(d,J＝1.8Hz,1H),7.33(d,J＝9.5Hz,1H),7.08(t,J＝13.6Hz,2H),5.22(m,1H),5.04(m,1H),4.57(m,1H),4.45(m,1H),4.07(m,2H),4.01–3.88(m,2H),3.84(m,1H),3.63(m,1H),3.55(m,2H),2.26–2.10(m,2H),1.80(m,2H),1.72(m,2H),1.58(m,6H),0.98–0.81(m,9H).
实施例A204
Figure PCTCN2021080167-appb-000369
LCMS([M+H] +):1048.3
1HNMR(400MHz,DMSO-d6)δ12.17(d,J＝70.6Hz,1H),8.99–8.80(m,1H),8.63(s,1H),8.30(d,J＝11.6Hz,2H),8.20(dd,J＝9.7,1.7Hz,1H),8.01(d,J＝28.8Hz,1H),7.55(d,J＝9.2Hz,1H),7.44(t,J＝4.8Hz,1H),7.37(d,J＝6.7Hz,2H),7.33(d,J＝9.6Hz,1H),5.21(m,1H),5.04(m,1H),4.57(m,1H),4.44(s,1H),4.17(m,2H),4.03–3.90(m,2H),3.84(m,1H),3.63(m,1H),3.56(m,2H),2.26–2.09(m,2H),1.83(m,2H),1.74(m,2H),1.60(m,6H),0.97–0.81(m,9H).
实施例A205
Figure PCTCN2021080167-appb-000370
LCMS([M+H] +):1062.1
1HNMR(400MHz,DMSO-d6)δ12.22(s,1H),8.77(d,J＝10.0Hz,1H),8.62(s,1H),8.29(s,2H),8.20(d,J＝9.8Hz,1H),7.56(d,J＝8.5Hz,1H),7.37(t,J＝10.7Hz,3H),7.22(s,1H),6.37(d,J＝7.9Hz,1H),5.38–5.29(m,1H),5.06(d,J＝7.3Hz,1H),4.57(d,J＝9.5Hz,1H),4.38(s,2H),4.20–4.08(m,3H),4.00–3.82(m,4H),3.75–3.64(m,2H),3.57(s,2H),3.43(s,2H),2.45(s,3H),1.99(dd,J＝14.4,7.0Hz,3H),1.75(s,2H),1.63(d,J＝18.2Hz,6H),1.45(s,1H),0.89(d,J＝35.1Hz,7H),0.59(s,2H).
实施例A206
Figure PCTCN2021080167-appb-000371
LCMS([M+H] +):976.1
1HNMR(400MHz,DMSO-d6)δ12.13(d,J＝72.7Hz,1H),8.77(d,J＝7.7Hz,1H),8.65(s,1H),8.29(q,J＝8.6Hz,2H),8.11(dd,J＝8.4,4.7Hz,3H),7.95(dd,J＝8.4,2.5Hz,1H),7.41–7.19(m,2H),7.06(dd,J＝15.5,8.9Hz,2H),6.32(dd,J＝40.6,6.2Hz,1H),5.67(d,J＝9.3Hz,0H),5.07(d,J＝7.6Hz,1H),4.76(d,J＝8.9Hz,0H),4.56(d,J＝9.4Hz,1H),4.38(s,1H),4.13–3.83(m,5H),3.69(dd,J＝22.9,8.1Hz,1H),3.56(s,1H),3.41(d,J＝8.3Hz,2H),2.46(d,J＝12.6Hz,3H),2.09–1.97(m,1H),1.76(dd,J＝39.5,6.4Hz,3H),1.66–1.52(m,7H),0.94(s,6H),0.59(s,3H).
实施例A207
Figure PCTCN2021080167-appb-000372
LCMS([M+H] +):973.3
1HNMR(400MHz,DMSO-d6)δ12.31–11.85(m,1H),8.65(d,J＝2.3Hz,1H),8.35–8.24(m,2H),8.11(t,J＝6.9Hz,3H),7.93(dd,J＝8.5,2.4Hz,1H),7.68(ddd,J＝30.2,8.7,5.5Hz,2H),7.48–7.18(m,2H),7.17–7.03(m,4H),5.37–5.19(m,1H),5.14–5.04(m,1H),4.57(m,1H),4.47(m,1H),4.08(m,2H),4.01–3.90(m,2H),3.86(m,1H),3.64(m,1H),3.56(m,2H),2.30–2.09(m,2H),1.89–1.77(m,2H),1.77–1.67(m,2H),1.58(s,6H),0.98–0.79(m,9H).
实施例A208
Figure PCTCN2021080167-appb-000373
LCMS([M+H] +):973.3
1HNMR(400MHz,DMSO-d6)δ12.32–11.83(m,1H),8.63(s,1H),8.34–8.25(m,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.67(m,2H),7.55(d,J＝9.1Hz,1H),7.48–7.08(m,6H),5.20(d,J＝3.7Hz,1H),5.06(t,J＝7.8Hz,1H),4.58(d,J＝9.6Hz,1H),4.47(m,1H),4.17(m,2H),3.96(m,2H),3.85(m,1H),3.69–3.52(m,3H),2.27–2.06(m,2H),1.92–1.80(m,2H),1.74(m,2H),1.60(s,6H),0.99–0.78(m,9H).
实施例A209
Figure PCTCN2021080167-appb-000374
LCMS([M+H] +):961.3
1HNMR(400MHz,DMSO-d6)δ12.40–11.86(m,1H),8.65(d,J＝2.4Hz,1H),8.32–8.26(m,2H),8.10(d,J＝8.7Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.41–7.28(m,2H),7.28–7.22(m,1H),7.20–7.11(m,1H),7.07(d,J＝8.9Hz,2H),7.03–6.95(m,1H),5.21(d,J＝3.7Hz,1H),5.13–4.98(m,1H),4.57(d,J＝9.6Hz,1H),4.46–4.44(m,1H),4.08(t,J＝6.2Hz,2H),4.01–3.89(m,2H),3.84(dd,J＝10.6,4.3Hz,1H),3.67–3.62(m,1H),3.60–3.54(m,2H),2.23–2.11(m,2H),1.83–1.78(m,2H),1.75–1.70(m,2H),1.58(s,6H),0.93–0.85(m,9H).
实施例A210
Figure PCTCN2021080167-appb-000375
LCMS([M+H] +):1047.3
1HNMR(400MHz,DMSO-d6)δ12.35–11.92(m,1H),8.63(s,1H),8.32–8.27(m,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.55(d,J＝9.2Hz,1H),7.39–7.30(m,4H),7.27–7.23(m,1H),7.16(d,J＝2.5Hz,1H),7.00–6.96(m,1H),5.20(d,J＝3.7Hz,1H),5.09–5.02(m,1H),4.57(d,J＝9.6Hz,1H),4.46–4.43(m,1H),4.17(t,J＝6.1Hz,2H),4.00–3.92(m,2H),3.84(dd,J＝10.6,4.3Hz,1H),3.64–3.55(m,3H),2.22–2.10(m,2H),1.86–1.82(m,2H),1.77–1.72(m,2H),1.60(s,6H),0.93–0.84(m,9H).
实施例A211
Figure PCTCN2021080167-appb-000376
LCMS([M+H] +):973.3
1HNMR(400MHz,DMSO-d6)δ12.04(s,1H),8.65(d,J＝2.4Hz,1H),8.34–8.25(m,2H),8.10(d,J＝8.8Hz,3H),7.93(dd,J＝8.5,2.5Hz,1H),7.65–7.44(m,3H),7.34(d,J＝9.5Hz,2H),7.06(d,J＝8.9Hz,2H),6.96(s,1H),5.24(s,1H),5.09(t,J＝7.8Hz,1H),4.58(d,J＝9.6Hz,1H),4.47(d,J＝9.5Hz,1H),4.07(t,J＝6.1Hz,2H),4.01–3.73(m,3H),3.64(dd,J＝14.4,7.8Hz,1H),3.55(t,J＝6.3Hz,2H),2.31–2.11(m,2H),1.81(dt,J＝13.7,6.3Hz,2H),1.71(dq,J＝15.4,8.3,7.0Hz,2H),1.58(s,6H),0.91(d,J＝23.4Hz,9H).
实施例A212
Figure PCTCN2021080167-appb-000377
LCMS([M+H] +):1059.3
1HNMR(400MHz,DMSO-d6)δ12.17(d,J＝148.3Hz,1H),8.63(s,1H),8.28(s,2H),8.19(dd,J＝9.7,1.6Hz,1H),7.61–7.42(m,4H),7.42–7.27(m,4H),6.93(td,J＝8.6,2.3Hz,1H),5.21(d,J＝3.6Hz,1H),5.07(t,J＝7.7Hz,1H),4.59(d,J＝9.5Hz,1H),4.46(d,J＝13.4Hz,1H),4.17(t,J＝5.9Hz,2H),3.96(s,2H),3.87(dd,J＝10.4,4.1Hz,1H),3.69–3.60(m,1H),3.56(t,J＝6.2Hz,2H),2.32–2.10(m,2H),1.92–1.79(m,2H),1.74(dt,J＝13.3,6.4Hz,2H),1.60(s,6H),0.96–0.80(m,9H).
实施例A213
Figure PCTCN2021080167-appb-000378
LCMS([M+H] +):1042.3
1HNMR(400MHz,DMSO-d6)δ12.51–12.00(m,1H),8.89(dd,J＝19.1,1.9Hz,1H),8.63(s,1H),8.41–8.32(m,1H),8.32–8.25(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),8.00(ddd,J＝13.9,7.9,6.0Hz,1H),7.61(dd,J＝12.5,2.0Hz,1H),7.55(d,J＝9.2Hz,1H),7.43–7.28(m,4H),5.25(t,J＝23.5Hz,1H),5.09(d,J＝7.9Hz,1H),4.57(t,J＝8.1Hz,1H),4.52–4.32(m,1H),4.17(t,J＝6.1Hz,2H),4.05–3.91(m,2H),3.87(dd,J＝10.5,4.1Hz,1H),3.60(dt,J＝12.4,8.3Hz,3H),2.29–2.11(m,2H),1.93–1.68(m,4H),1.60(s,6H),1.00–0.77(m,9H).
实施例A214
Figure PCTCN2021080167-appb-000379
LCMS([M+H] +):956.4
1HNMR(400MHz,DMSO-d6)δ12.17(s,1H),8.92(dd,J＝7.7,1.9Hz,1H),8.66(d,J＝2.4Hz,1H),8.36(dd,J＝4.7,1.4Hz,1H),8.34–8.24(m,2H),8.11(t,J＝7.4Hz,3H),8.03(dt,J＝7.9,1.8Hz,1H),7.94(dd,J＝8.5,2.5Hz,1H),7.62(s,1H),7.41–7.30(m,2H),7.07(d,J＝8.9Hz,2H),5.24(d,J＝3.0Hz,1H),5.10(t,J＝7.8Hz,1H),4.59(d,J＝9.6Hz,1H),4.54–4.41(m,1H),4.08(t,J＝6.2Hz,2H),4.02–3.83(m,3H),3.71(dd,J＝38.2,12.9Hz,1H),3.56(t,J＝6.2Hz,2H),2.36–2.10(m,2H),1.92–1.67(m,4H),1.59(s,6H),0.92(d,J＝22.6Hz,9H).
实施例A215
Figure PCTCN2021080167-appb-000380
LCMS([M+H] +):1041.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.6Hz,1H),8.60(dd,J＝11.6,5.6Hz,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.84(dd,J＝13.0,6.2Hz,3H),7.51(dd,J＝8.4,6.4Hz,1H),7.47–7.29(m,6H),5.16(m,1H),4.57(m,1H),4.50–4.33(m,3H),4.31–4.15(m,3H),4.13(d,J＝2.6Hz,3H),4.02–3.89(m,2H),3.71–3.52(m,4H),2.43(d,J＝7.3Hz,3H),2.07(m,1H),1.89(m,3H),1.80–1.69(m,2H),1.59(d,J＝3.2Hz,6H),0.93(d,J＝7.1Hz,9H).
实施例A216
Figure PCTCN2021080167-appb-000381
LCMS([M+H] +):953.3
1HNMR(400MHz,DMSO-d6)δ8.96–8.93(m,1H),8.70(t,J＝6.0Hz,1H),8.65(d,J＝2.4Hz,1H),8.32–8.26(m,2H),8.11(d,J＝8.9Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.78(d,J＝0.7Hz,1H),7.36(d,J＝9.6Hz,1H),7.08(d,J＝8.9Hz,2H),5.16(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.47(d,J＝6.0Hz,2H),4.39–4.33(m,2H),4.09(t,J＝6.2Hz,2H),3.99–3.90(m,2H),3.68–3.60(m,2H),3.55(t,J＝6.3Hz,2H),2.03–1.98(m,1H),1.86–1.81(m,3H),1.76–1.71(m,2H),1.58(s,6H),0.92(d,J＝14.3Hz,9H).
实施例A217
Figure PCTCN2021080167-appb-000382
LCMS([M+H] +):1038.3
1HNMR(400MHz,DMSO-d6)δ8.96–8.93(m,1H),8.70(t,J＝5.9Hz,1H),8.63(d,J＝0.9Hz,1H),8.31–8.27(m,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.79(d,J＝0.6Hz,1H),7.58–7.55(m,1H),7.39–7.35(m,3H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.47(d,J＝6.0Hz,2H),4.39–4.33(m,2H),4.18(t,J＝6.2Hz,2H),3.99–3.90(m,2H),3.68–3.55(m,4H),2.03–1.98(m,1H),1.86–1.80(m,3H),1.78–1.72(m,2H),1.61(s,6H),0.94–0.90(m,9H).
实施例A218
Figure PCTCN2021080167-appb-000383
LCMS([M+H] +):937.3
1HNMR(400MHz,DMSO-d6)δ8.65(d,J＝2.5Hz,1H),8.56(t,J＝5.7Hz,1H),8.34–8.21(m,3H),8.11(d,J＝8.9Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.36(d,J＝9.5Hz,1H),7.08(d,J＝8.9Hz,2H),7.03(d,J＝6.5Hz,1H),5.15(m,1H),4.55(m,1H),4.42–4.29(m,4H),4.09(m,2H),4.01–3.87(m,2H),3.61(m,4H),2.02(m,1H),1.91–1.79(m,3H),1.78–1.69(m,2H),1.58(s,6H),0.91(d,J＝10.5Hz,9H).
实施例A219
Figure PCTCN2021080167-appb-000384
LCMS([M+H] +):1023.3
1HNMR(400MHz,DMSO-d6)δ8.62(d,J＝0.9Hz,1H),8.56(t,J＝5.7Hz,1H),8.34–8.23(m,3H),8.19(dd,J＝9.7,1.9Hz,1H),7.59–7.53(m,1H),7.38(dd,J＝8.7,6.0Hz,3H),7.03(d,J＝6.7Hz,1H),5.15(m,1H),4.56(m,1H),4.43–4.24(m,4H),4.19(m,2H),4.02–3.86(m,2H),3.61(m,4H),2.02(m,1H),1.91–1.79(m,3H),1.79–1.70(m,2H),1.60(s,6H),0.91(d,J＝10.6Hz,9H).
实施例A220
Figure PCTCN2021080167-appb-000385
LCMS([M+H] +):990.3
1HNMR(400MHz,DMSO-d6)δ8.72(s,1H),8.65(d,J＝2.4Hz,1H),8.35–8.24(m,2H),8.11(t,J＝8.5Hz,3H),7.93(dd,J＝8.5,2.5Hz,1H),7.36–7.27(m,2H),7.06(d,J＝8.9Hz,2H),5.23(m,1H),5.07(m,1H),4.55(m,2H),4.08(m,2H),3.94(s,2H),3.86(m,1H),3.78–3.62(m,4H),3.55(m,2H),2.45(s,3H),2.21–2.13(m,1H),1.81(m,2H),1.72(m,2H),1.58(m,6H),0.92–0.75(m,9H).
实施例A221
Figure PCTCN2021080167-appb-000386
LCMS([M+H] +):1076.3
1HNMR(400MHz,DMSO-d6)δ8.72(d,J＝4.1Hz,1H),8.63(s,1H),8.33–8.25(m,2H),8.19(dd,J＝9.7,1.8Hz,1H),7.55(d,J＝8.5Hz,1H),7.41–7.25(m,4H),5.22(d,J＝3.8Hz,1H),5.06(t,J＝7.9Hz,1H),4.61–4.47(m,2H),4.17(m,2H),3.95(m,2H),3.86(m,1H),3.73(d,J＝11.7Hz,3H),3.66(m,1H),3.56(m,2H),2.44(s,3H),2.17(m,1H),1.83(m,2H),1.74(m,2H),1.61(s,6H),0.82(d,J＝19.6Hz,9H).
实施例A222
Figure PCTCN2021080167-appb-000387
LCMS([M+H] +):939.3
1HNMR(400MHz,DMSO-d6)δ11.59(s,1H),8.65(d,J＝2.4Hz,1H),8.55(d,J＝0.6Hz,1H),8.32–8.26(m,2H),8.11–8.08(m,3H),7.95–7.93(m,1H),7.64–7.59(m,1H),7.33(d,J＝9.5Hz,1H),7.09–7.05(m,2H),5.27(d,J＝3.5Hz,1H),4.58–4.52(m,2H),4.38(s,1H),4.07(t,J＝6.2Hz,2H),3.99–3.91(m,2H),3.73–3.64(m,2H),3.55(t,J＝6.2Hz,2H),2.16–2.11(m,1H),1.94–1.88(m,1H),1.80(dd,J＝14.0,6.2Hz,2H),1.72(dd,J＝13.8,6.1Hz,2H),1.58(s,6H),0.94–0.91(m,9H).
实施例A223
Figure PCTCN2021080167-appb-000388
LCMS([M+H] +):1025.3
1HNMR(400MHz,DMSO-d6)δ11.58(s,1H),8.62(d,J＝1.0Hz,1H),8.56–8.54(m,1H),8.31–8.26(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.58(d,J＝0.7Hz,1H),7.54–7.52(m,1H),7.38–7.33(m,3H),5.26(d,J＝3.5Hz,1H),4.58–4.51(m,2H),4.38(s,1H),4.16(t,J＝6.2Hz,2H),3.99–3.91(m,2H),3.73– 3.64(m,2H),3.56(t,J＝6.2Hz,2H),2.16–2.10(m,1H),1.94–1.80(m,3H),1.76–1.71(m,2H),1.61(s,6H),0.94–0.91(m,9H).
实施例A224
Figure PCTCN2021080167-appb-000389
LCMS([M+H] +):1046.2
1HNMR(400MHz,DMSO-d6)δ12.11(s,1H),8.30(d,J＝11.4Hz,2H),8.19(dd,J＝9.7,1.8Hz,1H),8.12(d,J＝6.3Hz,1H),7.55(d,J＝9.2Hz,1H),7.37(d,J＝6.6Hz,2H),7.32(d,J＝9.6Hz,1H),7.24(t,J＝6.8Hz,1H),5.20(d,J＝3.7Hz,1H),5.07(t,J＝7.7Hz,1H),4.56(d,J＝9.5Hz,1H),4.48(s,1H),4.17(t,J＝6.2Hz,2H),4.02–3.90(m,2H),3.84(dd,J＝10.6,4.3Hz,1H),3.63(d,J＝10.3Hz,1H),3.56(t,J＝6.2Hz,2H),2.31(d,J＝14.1Hz,3H),2.24–2.09(m,2H),1.90–1.79(m,2H),1.74(dd,J＝13.8,6.4Hz,2H),1.61(s,6H),0.88(d,J＝30.2Hz,9H).
实施例A225
Figure PCTCN2021080167-appb-000390
LCMS([M+H] +):960.0
1HNMR(400MHz,DMSO-d6)δ12.19(d,J＝61.7Hz,1H),8.65(d,J＝2.3Hz,1H),8.33–8.26(m,2H),8.10(d,J＝8.7Hz,4H),7.94(dd,J＝8.5,2.4Hz,1H),7.32(d,J＝9.5Hz,1H),7.25(t,J＝4.1Hz,1H),7.07(d,J＝8.9Hz,2H),5.21(d,J＝3.7Hz,1H),5.08(t,J＝7.6Hz,1H),4.56(d,J＝9.5Hz,1H),4.49(s,1H),4.08(t,J＝6.2Hz,2H),4.01–3.89(m,2H),3.84(dd,J＝10.5,4.3Hz,1H),3.63 (d,J＝10.3Hz,1H),3.60–3.49(m,2H),2.35(d,J＝43.7Hz,3H),2.26–2.09(m,2H),1.81(dd,J＝13.9,6.2Hz,2H),1.76–1.66(m,2H),1.58(s,6H),0.89(d,J＝30.6Hz,9H).
实施例A226
Figure PCTCN2021080167-appb-000391
LCMS([M+H] +):1078.3
1HNMR(400MHz,DMSO-d6)δ10.64(s,1H),8.96(s,1H),8.69(d,J＝2.3Hz,1H),8.63(t,J＝6.1Hz,1H),8.39–8.17(m,8H),8.00–7.96(m,2H),7.91–7.88(m,2H),7.79–7.75(m,1H),7.40(q,J＝8.4Hz,3H),5.32–5.26(m,2H),4.76(d,J＝9.1Hz,1H),4.49(d,J＝7.9Hz,1H),4.43–4.39(m,2H),4.27(d,J＝5.3Hz,1H),2.43(s,2H),2.11–2.08(m,1H),2.02–1.90(m,2H),1.59(s,6H),1.03–1.01(m,7H).
实施例A227
Figure PCTCN2021080167-appb-000392
LCMS([M+H] +):1043.0
1HNMR(400MHz,DMSO-d6)δ12.22(s,1H),9.10–8.93(m,3H),8.61(s,1H),8.31–8.24(m,2H),8.17(dd,J＝9.6,1.9Hz,1H),7.73(t,J＝5.0Hz,1H),7.54(dd,J＝11.0,6.2Hz,1H),7.42–7.28(m,3H),5.25(d,J＝3.6Hz,1H),5.07(t,J＝7.9Hz,1H),4.58(d,J＝9.6Hz,1H),4.46(s,1H),4.16(t,J＝6.1Hz,2H),3.95(s,2H),3.89–3.85(m,1H),2.18(dd,J＝7.5,4.0Hz,2H),2.04–1.91(m,1H), 1.88–1.78(m,2H),1.73(dd,J＝13.7,6.2Hz,2H),1.60(d,J＝3.6Hz,6H),0.98–0.79(m,9H).
实施例A228
Figure PCTCN2021080167-appb-000393
LCMS([M+H] +):957.1
1HNMR(400MHz,DMSO-d6)δ12.26(s,1H),9.05(s,1H),9.05–8.94(m,1H),8.64(d,J＝2.2Hz,1H),8.33–8.23(m,2H),8.09(t,J＝7.3Hz,3H),7.93(dd,J＝8.5,2.4Hz,1H),7.73(s,1H),7.32(d,J＝9.5Hz,1H),7.07(t,J＝7.2Hz,2H),5.33–5.21(m,1H),5.08(t,J＝7.9Hz,1H),4.57(d,J＝9.6Hz,1H),4.47(s,1H),4.07(t,J＝6.2Hz,2H),4.00–3.83(m,3H),3.67(s,1H),2.18(dd,J＝7.5,4.1Hz,1H),1.80(dd,J＝14.0,6.3Hz,2H),1.70(dd,J＝13.7,7.0Hz,2H),1.57(s,6H),0.97–0.79(m,9H).
实施例A229
Figure PCTCN2021080167-appb-000394
LCMS([M+H] +):1065.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.66(d,J＝2.2Hz,1H),8.61(t,J＝5.9Hz,1H),8.34–8.24(m,2H),8.13(dd,J＝8.5,4.7Hz,3H),8.07(dd,J＝8.8,5.6Hz,1H),7.95(dd,J＝8.5,2.2Hz,1H),7.72(t,J＝7.8Hz,1H),7.40(q,J＝7.9Hz,6H),7.18(d,J＝8.8Hz,2H),5.28(s,2H),5.18(d,J＝3.4Hz,1H),4.75(m,1H),4.53–4.35(m,3H),4.26(m,1H),3.73(m,2H),2.44(s,3H),2.07(m,1H),1.93(m,1H),1.58(s,6H),1.01(d,J＝9.1Hz,9H).
实施例A230
Figure PCTCN2021080167-appb-000395
LCMS([M+H] +):978.3
1HNMR(400MHz,DMSO-d6)δ9.23(d,J＝4.7Hz,1H),8.65(d,J＝2.4Hz,1H),8.34–8.24(m,2H),8.10(dd,J＝8.8,2.4Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.39(d,J＝9.5Hz,1H),7.06(d,J＝8.9Hz,2H),5.41–5.34(m,1H),5.26(m,1H),4.62(m,1H),4.46(m,1H),4.07(m,2H),4.01–3.84(m,3H),3.73(m,1H),3.54(m,2H),2.69(m,3H),2.33–2.18(m,2H),1.80(m,2H),1.72(m,2H),1.58(s,6H),0.93(d,J＝5.2Hz,9H).
实施例A231
Figure PCTCN2021080167-appb-000396
LCMS([M+H] +):1064.2
1HNMR(400MHz,DMSO-d6)δ9.24(s,1H),8.62(s,1H),8.29(d,J＝3.1Hz,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.54(d,J＝9.2Hz,1H),7.38(dd,J＝11.7,8.1Hz,3H),5.37(d,J＝3.9Hz,1H),5.25(t,J＝8.1Hz,1H),4.62(m,1H),4.45(m,1H),4.16(m,2H),3.98(m,2H),3.89(m,1H),3.72(m,1H),3.55(m,2H),2.69(d,J＝14.7Hz,3H),2.34–2.18(m,2H),1.82(m,2H),1.73(m,2H),1.61(s,6H),0.91(s,9H).
实施例A232
Figure PCTCN2021080167-appb-000397
LCMS([M+H] +):959.4
1HNMR(400MHz,DMSO-d6)δ9.09(s,1H),8.71(d,J＝2.3Hz,1H),8.36(d,J＝6.3Hz,2H),8.24–8.11(m,3H),8.01(dd,J＝8.5,2.4Hz,1H),7.72(d,J＝45.5Hz,2H),7.40(d,J＝9.5Hz,1H),7.13(d,J＝8.9Hz,2H),5.18(t,J＝7.9Hz,1H),4.64(d,J＝9.5Hz,1H),4.15(t,J＝6.2Hz,2H),4.02(dd,J＝10.5,8.9Hz,5H),3.91(s,1H),3.73(d,J＝10.6Hz,2H),3.62(t,J＝6.3Hz,3H),2.26(d,J＝7.2Hz,3H),1.93–1.73(m,4H),1.65(s,6H),0.95(d,J＝28.8Hz,9H).
实施例A233
Figure PCTCN2021080167-appb-000398
LCMS([M+H] +):1045.3
1HNMR(400MHz,DMSO-d6)δ8.81(s,1H),8.62(s,1H),8.34–8.23(m,2H),8.18(dd,J＝9.7,1.7Hz,1H),7.64–7.52(m,2H),7.49(d,J＝4.2Hz,1H),7.42–7.26(m,3H),5.29(d,J＝7.2Hz,1H),5.09(t,J＝7.8Hz,1H),4.57(d,J＝9.6Hz,1H),4.47(s,1H),4.16(t,J＝6.1Hz,2H),3.98–3.82(m,7H),2.25–2.13(m,3H),1.89–1.78(m,2H),1.74(dd,J＝14.0,6.3Hz,2H),1.60(d,J＝2.7Hz,6H),1.26(td,J＝7.3,3.9Hz,2H),0.87(d,J＝25.8Hz,9H).
实施例A234
Figure PCTCN2021080167-appb-000399
LCMS([M+H] +):1012.3
1HNMR(400MHz,DMSO-d6)δ11.98(s,1H),8.64(d,J＝2.4Hz,1H),8.36–8.24(m,4H),8.09(d,J＝8.8Hz,3H),7.95–7.90(m,1H),7.77(s,4H),7.57(s,1H),7.32(d,J＝9.4Hz,1H),7.06(d,J＝8.8Hz,2H),5.21(s,1H),5.08(t,J＝7.6Hz,1H),4.58(d,J＝9.4Hz,1H),4.49(s,1H),4.08(t,J＝6.2Hz,2H),4.00–3.91(m,2H),3.86(d,J＝6.2Hz,1H),3.64(d,J＝10.4Hz,1H),3.56(t,J＝6.3Hz,2H),2.77(d,J＝4.4Hz,3H),2.04–1.93(m,1H),1.87–1.67(m,4H),1.58(s,6H),1.51–1.41(m,1H),0.97–0.85(m,9H).
实施例A235
Figure PCTCN2021080167-appb-000400
LCMS([M+H] +):1098.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.63(s,1H),8.59(t,J＝6.0Hz,1H),8.29(s,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.87–7.79(m,2H),7.47(t,J＝6.9Hz,1H),7.40(d,J＝4.2Hz,5H),5.16(s,1H),4.59(d,J＝9.6Hz,1H),4.49–4.39(m,2H),4.38–4.33(m,3H),4.24(dd,J＝15.9,5.5Hz,1H),4.10(s,2H),3.96–3.88(m,2H),3.69(dd,J＝10.6,3.8Hz,1H),3.63(d,J＝10.9Hz,1H),2.43 (s,3H),2.10–2.02(m,1H),1.92(ddd,J＝12.9,8.8,4.5Hz,1H),1.62(s,6H),0.94(s,9H).
实施例A236
Figure PCTCN2021080167-appb-000401
LCMS([M+H] +):1078.3
1HNMR(400MHz,DMSO-d6)δ10.75(s,1H),8.98(s,1H),8.70(d,J＝2.5Hz,1H),8.60(t,J＝6.1Hz,1H),8.41(d,J＝9.0Hz,1H),8.33–8.26(m,2H),8.21–8.17(m,3H),7.91–7.86(m,1H),7.88(dd,J＝14.7,7.1Hz,4H),7.82–7.75(m,1H),7.44–7.39(m,4H),5.18(d,J＝3.6Hz,1H),4.81(d,J＝9.0Hz,1H),4.50–4.40(m,3H),4.25(dd,J＝15.9,5.6Hz,1H),3.74(s,2H),2.45(s,3H),2.09–2.05(m,1H),1.97–1.90(m,1H),1.60(s,6H),1.05–1.02(m,9H).
实施例A237
Figure PCTCN2021080167-appb-000402
LCMS([M+H] +):1063.3
1HNMR(400MHz,DMSO-d6)δ8.94(s,1H),8.62(s,1H),8.37(s,1H),8.29–8.28(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.54(d,J＝9.3Hz,1H),7.38–7.34(m,3H),5.32(d,J＝3.8Hz,1H),5.07(t,J＝8.2Hz,1H),4.61(d,J＝9.6Hz,1H),4.43(s,1H),4.16(t,J＝6.2Hz,2H),3.96(s,2H),3.86(dd,J＝10.6,4.1Hz,1H),3.70(d,J＝11.0Hz,1H),3.56(t,J＝6.3Hz,2H),2.48(s,3H),2.30–2.23(m,1H),2.10–2.06(m,1H),1.84–1.82(m,2H),1.75–1.71(m,2H),1.61(s,6H),0.94–0.91(m,9H).
实施例A238
Figure PCTCN2021080167-appb-000403
LCMS([M+H] +):1079.1
1HNMR(400MHz,DMSO-d6)δ8.92(d,J＝3.6Hz,1H),8.62(s,1H),8.33–8.25(m,2H),8.19(dd,J＝9.7,1.8Hz,1H),7.73(d,J＝5.5Hz,1H),7.55(d,J＝9.2Hz,1H),7.40(dd,J＝17.2,7.9Hz,3H),5.36(t,J＝7.4Hz,1H),5.29(s,1H),4.63(d,J＝9.5Hz,1H),4.44(s,1H),4.17(t,J＝6.2Hz,2H),4.04–3.90(m,2H),3.85(dd,J＝10.7,4.6Hz,1H),3.69(dd,J＝10.7,2.9Hz,1H),3.57(t,J＝6.2Hz,2H),2.58(s,3H),2.26(dd,J＝7.2,4.8Hz,2H),1.84(dd,J＝13.8,6.3Hz,2H),1.79–1.68(m,2H),1.60(s,6H),0.93(s,9H).
实施例A239
Figure PCTCN2021080167-appb-000404
LCMS([M+H] +):1065.3
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝23.2Hz,1H),8.65(dd,J＝6.7,2.4Hz,1H),8.58(t,J＝6.0Hz,1H),8.34–8.22(m,3H),8.18–8.07(m,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.81–7.64(m,3H),7.46–7.37(m,3H),7.13(dd,J＝51.5,8.9Hz,3H),5.17(d,J＝3.5Hz,1H),4.77(d,J＝9.1Hz,1H),4.45(dd,J＝16.8,8.9Hz,2H),4.39(d,J＝6.4Hz,1H),4.24(dd,J＝15.8,5.4Hz,1H),4.13–4.05(m,1H),3.73(s,2H),2.58(s,1H),2.44(s,3H),2.10–2.02(m,1H),1.96–1.89(m,1H),1.58(s,6H),1.09–0.89(m,9H).
实施例A240
Figure PCTCN2021080167-appb-000405
LCMS([M+H] +):1074.3
1HNMR(400MHz,DMSO-d6)δ10.40–10.38(m,1H),8.97(d,J＝10.0Hz,1H),8.69(d,J＝2.6Hz,1H),8.59(t,J＝6.0Hz,1H),8.33–8.28(m,2H),8.27–8.15(m,4H),8.02–7.89(m,5H),7.48–7.37(m,6H),5.14(d,J＝3.5Hz,1H),4.55(d,J＝9.4Hz,1H),4.47–4.41(m,2H),4.35(s,1H),4.22(dd,J＝15.8,5.4Hz,1H),3.77(d,J＝14.0Hz,1H),3.68–3.62(m,2H),3.57(d,J＝13.9Hz,1H),2.45–2.43(m,3H),2.08–1.99(m,1H),1.95–1.87(m,1H),1.59(s,6H),0.93–0.90(m,9H).
实施例A241
Figure PCTCN2021080167-appb-000406
LCMS([M+H] +):1110.3
1HNMR(400MHz,DMSO-d6)δ11.98(s,1H),8.62(s,1H),8.36–8.27(m,4H),8.19(d,J＝9.7Hz,1H),7.85–7.74(m,5H),7.59–7.53(m,2H),7.41–7.31(m,4H),5.32(t,J＝4.7Hz,2H),5.20(d,J＝3.7Hz,1H),5.08(t,J＝7.8Hz,2H),4.58(d,J＝9.4Hz,1H),4.48(s,1H),4.16(d,J＝6.5Hz,2H),3.96(s,2H),3.86(s,2H),3.66(s,1H),3.57(d,J＝6.2Hz,3H),2.77(d,J＝4.4Hz,3H),2.03–1.94(m,4H),1.84(s,2H),1.73(s,2H),1.60(s,6H),1.45(s,2H),0.95–0.85(m,8H).
实施例A242
Figure PCTCN2021080167-appb-000407
LCMS([M+H] +):993.1
1HNMR(400MHz,DMSO-d6)δ8.92(s,1H),8.65(d,J＝2.4Hz,1H),8.29(q,J＝8.4Hz,2H),8.10(d,J＝8.8Hz,3H),7.93(dd,J＝8.5,2.5Hz,1H),7.74(d,J＝11.5Hz,1H),7.41(d,J＝9.5Hz,1H),7.07(d,J＝8.9Hz,2H),5.36(t,J＝7.5Hz,1H),5.29(d,J＝4.1Hz,1H),4.63(d,J＝9.4Hz,1H),4.44(d,J＝3.8Hz,1H),4.08(t,J＝6.2Hz,2H),4.02–3.91(m,2H),3.85(dd,J＝10.6,4.6Hz,1H),3.69(dd,J＝10.9,2.9Hz,1H),3.56(t,J＝6.2Hz,2H),2.57(d,J＝4.9Hz,3H),2.26(dd,J＝7.4,4.6Hz,2H),1.81(dd,J＝14.0,6.5Hz,2H),1.77–1.68(m,2H),1.58(s,6H),0.92(d,J＝6.1Hz,9H).
实施例A243
Figure PCTCN2021080167-appb-000408
LCMS([M+H] +):1088.4
1HNMR(400MHz,DMSO-d6)δ10.41(s,1H),8.98(s,1H),8.66(d,J＝2.4Hz,1H),8.57(t,J＝6.0Hz,1H),8.34–8.24(m,2H),8.14–8.09(m,4H),7.96(dd,J＝8.5,2.4Hz,1H),7.76(d,J＝8.8Hz,2H),7.40(q,J＝8.3Hz,4H),7.24(q,J＝8.2Hz,4H),5.12(d,J＝3.5Hz,1H),4.51(d,J＝9.3Hz,1H),4.43(dd,J＝15.5,7.1Hz,2H),4.33(s,1H),4.21(dd,J＝15.9,5.3Hz,1H),3.65–3.61(m,4H),3.45 (s,2H),2.44–2.43(m,3H),2.06–1.97(m,1H),1.93–1.85(m,1H),1.58(s,6H),0.92–0.89(m,9H).
实施例A244
Figure PCTCN2021080167-appb-000409
LCMS([M+H] +):1074.3
1HNMR(400MHz,DMSO-d6)δ10.43(s,1H),8.97(d,J＝6.1Hz,1H),8.67(d,J＝2.2Hz,1H),8.58(t,J＝6.0Hz,1H),8.29(q,J＝8.6Hz,2H),8.13(dd,J＝8.6,3.1Hz,3H),7.99–7.91(m,2H),7.85(d,J＝8.2Hz,2H),7.76(d,J＝8.7Hz,2H),7.54–7.35(m,6H),5.16(m,1H),4.77(m,1H),4.50–4.35(m,3H),4.24(m,1H),3.74(m,4H),2.43(d,J＝5.9Hz,3H),2.06–1.89(m,2H),1.58(s,6H),1.01(d,J＝10.8Hz,9H).
实施例A245
Figure PCTCN2021080167-appb-000410
LCMS([M+H] +):997.1
1HNMR(400MHz,DMSO-d6)δ9.03(s,1H),8.65(d,J＝2.3Hz,1H),8.29(q,J＝8.6Hz,2H),8.16–8.05(m,3H),7.94(dd,J＝8.5,2.4Hz,1H),7.41(s,1H),7.36(d,J＝9.6Hz,1H),7.06(d,J＝8.8Hz,2H),5.32(d,J＝3.8Hz,1H),5.10(t,J＝8.0Hz,1H),4.61(d,J＝9.5Hz,1H),4.43(s,1H),4.07(t,J＝6.2Hz,2H),4.01–3.90(m,2H),3.86(dd,J＝10.6,4.2Hz,1H),3.70(d,J＝10.3Hz,1H),3.55 (t,J＝6.2Hz,2H),2.49–2.48(m,3H),2.28–2.20(m,1H),2.15–2.05(m,1H),1.86–1.76(m,2H),1.76–1.66(m,2H),1.58(s,6H),0.92(s,9H).
实施例A246
Figure PCTCN2021080167-appb-000411
LCMS([M+H] +):1063.1
1HNMR(400MHz,DMSO-d6)δ9.04(d,J＝4.8Hz,1H),8.62(s,1H),8.32–8.25(m,2H),8.19(dd,J＝9.7,1.8Hz,1H),7.54(d,J＝9.2Hz,1H),7.37(dd,J＝12.6,6.5Hz,4H),5.32(d,J＝3.9Hz,1H),5.09(t,J＝8.1Hz,1H),4.61(d,J＝9.5Hz,1H),4.43(s,1H),4.16(t,J＝6.1Hz,2H),3.96(s,2H),3.86(dd,J＝10.6,4.1Hz,1H),3.70(d,J＝10.8Hz,1H),3.56(t,J＝6.2Hz,2H),2.28–2.20(m,1H),2.15–2.08(m,1H),1.88–1.79(m,2H),1.74(dd,J＝13.9,6.2Hz,2H),1.61(s,6H),0.92(s,9H).
实施例A247
Figure PCTCN2021080167-appb-000412
LCMS([M+H] +):1039.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝3.8Hz,1H),8.60(t,J＝6.0Hz,1H),8.29–8.21(m,2H),8.19(d,J＝2.6Hz,1H),7.76(dd,J＝8.8,2.7Hz,1H),7.45–7.33(m,5H),6.96(d,J＝8.8Hz,1H),5.18(d,J＝3.5Hz,1H),4.55(m,1H),4.49–4.32(m,3H),4.30–4.20(m,3H),3.95–3.86(m,2H),3.64(m,2H), 3.53(m,2H),3.36(m,2H),2.43(d,J＝4.8Hz,3H),2.06(m,1H),1.90(m,1H),1.81–1.66(m,4H),1.53(m,8H),1.46–1.36(m,2H),0.92(d,J＝6.9Hz,9H).
实施例A248
Figure PCTCN2021080167-appb-000413
LCMS([M+H] +):1025.1
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝4.6Hz,1H),8.60(t,J＝6.0Hz,1H),8.29–8.22(m,2H),8.19(d,J＝2.5Hz,1H),7.77(dd,J＝8.8,2.7Hz,1H),7.46–7.32(m,5H),7.01–6.94(m,1H),5.18(d,J＝2.7Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.26(dt,J＝15.9,6.0Hz,3H),3.94–3.85(m,2H),3.70–3.46(m,8H),2.43(d,J＝4.6Hz,3H),2.06(t,J＝10.3Hz,1H),1.95–1.85(m,1H),1.83–1.69(m,4H),1.61(dt,J＝13.0,6.4Hz,2H),1.51(s,6H),0.92(d,J＝7.2Hz,9H).
实施例A252
Figure PCTCN2021080167-appb-000414
LCMS([M+H] +):1088.4
1HNMR(400MHz,DMSO-d6)δ10.36(s,1H),8.98(s,1H),8.69(d,J＝2.5Hz,1H),8.56(t,J＝6.0Hz,1H),8.34–8.25(m,2H),8.17(d,J＝8.8Hz,3H),7.99–7.95(m,4H),7.91(d,J＝8.2Hz,2H),7.40(q,J＝8.4Hz,6H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.4Hz,1H),4.46–4.41(m,2H),4.36(s,1H),4.22(dd,J＝15.8, 5.5Hz,1H),3.67–3.64(m,2H),2.96–2.87(m,2H),2.69–2.62(m,1H),2.44(s,3H),2.09–2.00(m,1H),1.96–1.86(m,1H),1.59(s,6H),0.91–0.89(m,9H).
实施例A254
Figure PCTCN2021080167-appb-000415
LCMS([M+H] +):1011.1
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝8.0Hz,1H),8.58(t,J＝6.0Hz,1H),8.30–8.22(m,2H),8.18(d,J＝2.5Hz,1H),7.76(dd,J＝8.8,2.7Hz,1H),7.49–7.34(m,5H),6.95(d,J＝8.8Hz,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.25(dt,J＝15.8,5.9Hz,3H),3.94(d,J＝16.8Hz,2H),3.68–3.49(m,8H),2.43(d,J＝6.8Hz,3H),2.04(dd,J＝18.4,10.1Hz,1H),1.95–1.85(m,1H),1.76(dd,J＝14.2,6.5Hz,2H),1.66(dd,J＝14.1,6.5Hz,2H),1.51(s,6H),0.92(d,J＝8.6Hz,9H).
实施例A255
Figure PCTCN2021080167-appb-000416
LCMS([M+H] +):983.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝8.5Hz,1H),8.63(dt,J＝40.5,5.8Hz,1H),8.31–8.23(m,2H),8.21–8.16(m,1H),7.77(dd,J＝8.8,2.1Hz,1H),7.48–7.35(m,5H),7.02(t,J＝9.6Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.33(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),3.97(d,J＝15.4Hz,2H),3.88–3.76(m,2H),3.71–3.58(m,6H),2.44(d,J＝6.2Hz,3H),2.12– 2.01(m,1H),1.96–1.85(m,1H),1.51(d,J＝3.5Hz,6H),0.92(d,J＝7.4Hz,9H).
实施例A256
Figure PCTCN2021080167-appb-000417
LCMS([M+H] +):1160.3
1HNMR(400MHz,DMSO-d6)δ10.68(s,1H),8.97(s,1H),8.65(s,1H),8.58(t,J＝5.7Hz,1H),8.41(s,1H),8.34–8.18(m,5H),7.94(d,J＝8.0Hz,2H),7.65(d,J＝8.4Hz,1H),7.47(d,J＝8.1Hz,2H),7.41(q,J＝8.2Hz,4H),5.16(d,J＝3.3Hz,1H),4.54(d,J＝9.3Hz,1H),4.48–4.40(m,2H),4.35(s,1H),4.22(dd,J＝15.9,5.4Hz,1H),3.78(d,J＝13.8Hz,1H),3.65(d,J＝5.2Hz,2H),3.59(s,1H),2.45(s,3H),2.03(d,J＝7.0Hz,1H),1.92(d,J＝12.9Hz,1H),1.68–1.55(m,6H),0.93(s,9H).
实施例A257
Figure PCTCN2021080167-appb-000418
LCMS([M+H] +):939.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.59(t,J＝5.9Hz,1H),8.32–8.24(m,2H),8.21(d,J＝2.6Hz,1H),7.74(d,J＝8.8Hz,1H),7.50(d,J＝9.5Hz,1H),7.46–7.35(m,4H),7.18–7.10(m,1H),5.16(d,J＝3.5Hz,1H),4.59(d,J＝9.6Hz,1H),4.54–4.42(m,3H),4.39–4.25(m,3H),4.06–4.01(m,2H),3.88(t,J＝4.3Hz,2H),3.72–3.57(m,2H),2.45–2.42(m,3H),2.11–2.02(m,1H),1.97–1.88(m,1H),1.57–1.42(m,6H),0.95(s,9H).
实施例A260
Figure PCTCN2021080167-appb-000419
LCMS([M+H] +):923.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.55(t,J＝6.0Hz,1H),8.31–8.23(m,2H),8.20(d,J＝2.6Hz,1H),7.96(d,J＝9.3Hz,1H),7.79(dd,J＝8.8,2.6Hz,1H),7.40(q,J＝8.3Hz,4H),6.99(d,J＝8.8Hz,1H),5.13(d,J＝3.5Hz,1H),4.56(d,J＝9.3Hz,1H),4.48–4.39(m,2H),4.35(s,1H),4.30(t,J＝6.5Hz,2H),4.22(dd,J＝15.8,5.4Hz,1H),3.74–3.61(m,2H),2.47–2.39(m,4H),2.36–2.29(m,1H),2.10–1.85(m,4H),1.52–1.50(m,6H),0.94–0.92(m,9H).
实施例A262
Figure PCTCN2021080167-appb-000420
LCMS([M+H] +):997.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.3Hz,1H),8.59(t,J＝6.0Hz,1H),8.30–8.23(m,2H),8.19(dd,J＝7.2,2.6Hz,1H),7.77(dd,J＝8.8,2.7Hz,1H),7.48–7.35(m,5H),6.97(dd,J＝17.2,8.9Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.31(m,5H),4.24(m,1H),3.95(m,2H),3.71–3.53(m,8H),2.44(M,J＝6.2Hz,3H),2.10–1.95(m,3H),1.90(m,1H),1.51(d,J＝1.8Hz,6H),0.92(d,J＝7.7Hz,9H).
实施例A263
Figure PCTCN2021080167-appb-000421
LCMS([M+H] +):895.2
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝0.8Hz,1H),8.58(t,J＝6.0Hz,1H),8.31–8.22(m,2H),8.21–8.15(m,1H),7.85(ddd,J＝8.5,7.1,5.6Hz,2H),7.44–7.35(m,4H),7.13(d,J＝8.8Hz,1H),5.15(d,J＝3.4Hz,1H),4.91(q,J＝14.9Hz,2H),4.57(d,J＝9.5Hz,1H),4.49–4.33(m,3H),4.24(dd,J＝15.9,5.5Hz,1H),3.64(dt,J＝23.4,7.3Hz,2H),2.44(s,3H),2.09–2.01(m,1H),1.95–1.85(m,1H),1.49(dd,J＝18.1,7.2Hz,6H),0.89(d,J＝15.8Hz,9H).
实施例A264
Figure PCTCN2021080167-appb-000422
LCMS([M+H] +):913.2
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59(t,J＝6.0Hz,1H),8.28–8.22(m,2H),8.11(d,J＝9.4Hz,1H),8.03(ddd,J＝9.1,5.9,2.1Hz,2H),7.41(q,J＝8.4Hz,4H),5.08(d,J＝14.6Hz,2H),5.01–4.95(m,1H),4.58(d,J＝9.4Hz,1H),4.43(ddd,J＝32.4,19.0,11.7Hz,3H),4.24(dd,J＝15.8,5.5Hz,1H),3.70–3.58(m,2H),2.45(s,3H),2.11–2.02(m,1H),1.91(ddd,J＝12.9,8.7,4.5Hz,1H),1.56–1.45(m,6H),0.92(d,J＝14.2Hz,9H).
实施例A265
Figure PCTCN2021080167-appb-000423
LCMS([M+H] +):1001.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.6Hz,1H),8.58(t,J＝6.0Hz,1H),8.29–8.21(m,2H),8.05(t,J＝1.9Hz,1H),7.96(dd,J＝10.7,2.1Hz,1H),7.47–7.36(m,5H),4.56(dd,J＝10.9,6.1Hz,3H),4.41(ddd,J＝24.7,14.3,8.5Hz,3H),4.29–4.21(m,1H),3.95(d,J＝17.0Hz,2H),3.91–3.79(m,2H),3.73–3.56(m,4H),2.44(d,J＝6.2Hz,3H),2.08–2.01(m,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.54(s,6H),0.91(d,J＝8.3Hz,9H).
实施例A266
Figure PCTCN2021080167-appb-000424
LCMS([M+H] +):1051.3
1HNMR(400MHz,DMSO-d6)δ8.84(d,J＝6.8Hz,1H),8.47(t,J＝2.5Hz,1H),8.22(d,J＝2.5Hz,1H),8.19–8.10(m,2H),7.86(t,J＝5.9Hz,1H),7.43(ddd,J＝23.9,17.3,8.9Hz,5H),4.77–4.52(m,6H),4.46–4.32(m,2H),4.05–3.89(m,4H),3.89–3.70(m,6H),2.47(d,J＝3.3Hz,3H),2.20–2.13(m,2H),1.72(d,J＝4.2Hz,3H),1.67(d,J＝4.6Hz,3H),0.99(s,9H).
实施例A267
Figure PCTCN2021080167-appb-000425
LCMS([M+H] +):1015.3
1HNMR(400MHz,DMSO-d6)δ8.84(d,J＝7.8Hz,1H),8.19–8.10(m,2H),8.06(dd,J＝4.9,3.0Hz,1H),7.87(t,J＝5.8Hz,1H),7.78(dd,J＝10.5,2.2Hz,1H),7.51–7.32(m,5H),4.72–4.51(m,7H),4.47(d,J＝3.5Hz,1H),4.34(dd,J＝15.4,5.2Hz,1H),3.98(m,2H),3.88–3.83(m,1H),3.80–3.64(m,8H),2.47(d,J＝2.7Hz,3H),2.18–2.10(m,5H),1.66(d,J＝13.8Hz,6H),1.00(s,9H).
实施例A268
Figure PCTCN2021080167-appb-000426
LCMS([M+H] +):957.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.58(t,J＝6.0Hz,1H),8.31–8.21(m,2H),8.08(d,J＝2.0Hz,1H),7.95(dt,J＝10.7,1.9Hz,1H),7.51–7.33(m,5H),5.16(d,J＝3.5Hz,1H),4.67–4.52(m,3H),4.48–4.33(m,3H),4.25(dd,J＝15.8,5.7Hz,1H),4.07–4.03(m,2H),3.92(t,J＝4.6Hz,2H),3.69–3.60(m,2H),2.45–2.43(m,3H),2.08–2.01(m,1H),1.96–1.85(m,1H),1.54(s,6H),0.92–0.90(m,9H).
实施例A269
Figure PCTCN2021080167-appb-000427
LCMS([M+H] +):1007.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.64–8.49(m,2H),8.36–8.17(m,3H),7.43–7.39(m,5H),5.14(d,J＝3.1Hz,1H),4.72–4.52(m,3H),4.47–4.32(m,3H),4.25(dd,J＝15.4,5.5Hz,1H),4.07–4.03(m,2H),3.92(s,2H),3.64(dd,J＝25.7,8.9Hz,2H),2.43(s,3H),2.05–2.03(m,1H),1.90(s,1H),1.56(d,J＝4.3Hz,6H),0.92–0.90(m,9H).
实施例A270
Figure PCTCN2021080167-appb-000428
LCMS([M+H] +):1095.3
1HNMR(400MHz,DMSO-d6)δ8.96–8.95(m,1H),8.58(t,J＝6.0Hz,1H),8.50(d,J＝2.3Hz,1H),8.30–8.19(m,3H),7.46–7.34(m,5H),5.18(d,J＝3.5Hz,1H),4.58–4.54(m,3H),4.47–4.31(m,3H),4.24(dd,J＝15.8,5.6Hz,1H),3.95–3.91(m,2H),3.81–3.75(m,2H),3.65–3.54(m,12H),2.44–2.43(m,3H),2.06(t,J＝10.3Hz,1H),1.95–1.84(m,1H),1.55(d,J＝5.5Hz,6H),0.93–0.91(m,9H).
实施例A271
Figure PCTCN2021080167-appb-000429
LCMS([M+H] +):1065.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝11.1Hz,1H),8.57(t,J＝6.0Hz,1H),8.50(t,J＝3.7Hz,1H),8.32–8.19(m,3H),7.47–7.33(m,5H),5.14(d,J＝3.5Hz,1H),4.59–4.48(m,3H),4.48–4.32(m,3H),4.24(m,1H),3.94(m,2H),3.70–3.52(m,8H),2.44(d,J＝7.4Hz,3H),2.09–1.96(m,3H),1.90(m,1H),1.56(d,J＝4.8Hz,6H),0.91(d,J＝8.7Hz,9H).
实施例A272
Figure PCTCN2021080167-appb-000430
LCMS([M+H] +):1093.1
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.7Hz,1H),8.59(t,J＝6.1Hz,1H),8.51(d,J＝2.3Hz,1H),8.31–8.20(m,3H),7.46–7.33(m,5H),5.14(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.50–4.33(m,6H),4.25(dd,J＝15.8,5.7Hz,2H),3.91(s,2H),3.69–3.59(m,3H),3.53(t,J＝6.4Hz,2H),3.45(dd,J＝14.1,6.6Hz,5H),2.68(d,J＝7.8Hz,2H),2.43(s,3H),2.10–1.94(m,3H),1.90(s,2H),1.84–1.73(m,4H),1.69–1.60(m,2H),1.56(d,J＝4.9Hz,5H),0.92(d,J＝7.5Hz,9H).
实施例A274
Figure PCTCN2021080167-appb-000431
LCMS([M+H] +):997.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝11.0Hz,1H),8.58(t,J＝6.0Hz,1H),8.32–8.20(m,2H),8.00(s,1H),7.65(d,J＝1.9Hz,1H),7.48–7.31(m,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.52–4.31(m,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.97(d,J＝15.8Hz,2H),3.90–3.76(m,2H),3.74–3.58(m,6H),2.44(d,J＝7.2Hz,3H),2.19(d,J＝9.4Hz,3H),2.13–2.01(m,1H),1.91(ddd,J＝13.0,8.8,4.5Hz,1H),1.51(d,J＝5.4Hz,6H),0.92(d,J＝7.4Hz,9H).
实施例A275
Figure PCTCN2021080167-appb-000432
LCMS([M+H] +):1045.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.59(t,J＝6.0Hz,1H),8.26–8.23(m,2H),8.07(d,J＝2.1Hz,1H),7.97(dd,J＝10.7,2.1Hz,1H),7.48–7.35(m,5H),5.15(d,J＝3.5Hz,1H),4.60–4.49(m,3H),4.48–4.32(m,3H),4.24(dd,J＝15.8,5.5Hz,1H),3.96–3.92(m,2H),3.84–3.75(m,2H),3.70–3.55(m,10H),2.45–2.43(m,3H),2.08–2.03(m,1H),1.90(ddd,J＝12.7,8.6,4.4Hz,1H),1.54(d,J＝1.2Hz,6H),0.94–0.91(d,J＝8.6Hz,9H).
实施例A276
Figure PCTCN2021080167-appb-000433
LCMS([M+H] +):1079.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.58(t,J＝6.0Hz,1H),8.50(d,J＝2.3Hz,1H),8.30–8.19(m,3H),7.40(d,J＝6.6Hz,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.51–4.31(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),3.96(s,2H),3.68–3.48(m,8H),2.43(s,3H),2.10–2.02(m,1H),1.90(ddd,J＝12.9,8.9,4.5Hz,1H),1.86–1.75(m,2H),1.67(p,J＝6.5Hz,2H),1.56(d,J＝5.1Hz,6H),0.93(s,9H).
实施例A277
Figure PCTCN2021080167-appb-000434
LCMS([M+H] +):1041.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.60(t,J＝6.0Hz,1H),8.31–8.22(m,2H),8.02(d,J＝2.3Hz,1H),7.66(s,1H),7.47–7.34(m,5H),5.18–5.17(m,1H),4.56(d,J＝9.6Hz,1H),4.46–4.36(m,5H),4.24(dd,J＝15.8,5.7Hz,1H),3.96–3.92(m,2H),3.80–3.74(m,2H),3.66–3.58(m,10H), 2.44–2.43(m,3H),2.19–2.18(m,3H),2.11–1.97(m,2H),1.94–1.85(m,1H),1.51(d,J＝6.2Hz,6H),0.93–0.91(m,9H).
实施例A278
Figure PCTCN2021080167-appb-000435
LCMS([M+H] +):997.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.7Hz,1H),8.59(t,J＝5.9Hz,1H),8.31(dt,J＝40.9,6.0Hz,2H),7.74–7.55(m,1H),7.48–7.36(m,5H),6.85–6.73(m,1H),5.15(d,J＝3.4Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.31(m,5H),4.29–4.17(m,1H),3.96(d,J＝15.1Hz,2H),3.85–3.74(m,2H),3.70–3.57(m,6H),2.44(d,J＝7.0Hz,3H),2.33(dd,J＝19.2,7.7Hz,3H),2.06(dd,J＝14.3,6.0Hz,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.63–1.55(m,3H),1.50–1.41(m,3H),0.92(d,J＝7.8Hz,9H).
实施例A279
Figure PCTCN2021080167-appb-000436
LCMS([M+H] +):1029.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.58(t,J＝5.9Hz,1H),8.25(d,J＝3.6Hz,2H),8.06(dd,J＝6.2,2.1Hz,1H),7.95(dd,J＝10.7,2.1Hz,1H),7.39(s,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.41(dq,J＝14.3,7.7,7.3Hz,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.97(s,2H),3.71–3.53(m,6H),3.53–3.47(m,2H),2.43(s,3H),2.06(dd,J＝15.1,6.4Hz,1H),1.90(ddd,J＝13.0, 8.9,4.6Hz,1H),1.86–1.76(m,2H),1.72–1.63(m,2H),1.54(s,6H),0.93(d,J＝9.4Hz,9H).
实施例A280
Figure PCTCN2021080167-appb-000437
LCMS([M+H] +):1107.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.0Hz,1H),8.59(t,J＝6.0Hz,1H),8.51(d,J＝2.3Hz,1H),8.30–8.19(m,3H),7.47–7.31(m,5H),5.14(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.41(m,5H),4.25(m,1H),3.89(m,2H),3.64(m,2H),3.53(m,2H),3.44(m,2H),3.36(m,2H),2.44(d,J＝5.1Hz,3H),2.06(m,1H),1.90(m,1H),1.83–1.70(m,4H),1.62–1.50(m,8H),1.49–1.39(m,2H),0.92(d,J＝7.4Hz,9H).
实施例A281
Figure PCTCN2021080167-appb-000438
LCMS([M+H] +):997.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.58(t,J＝6.0Hz,1H),8.26(s,2H),8.03(s,1H),7.40(s,5H),6.94–6.84(m,1H),5.14(d,J＝3.5Hz,1H),4.56(d,J＝8.7Hz,1H),4.43(s,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.98(s,2H),3.89–3.75(m,2H),3.63(d,J＝9.7Hz,6H),2.43(s,3H),2.23(d,J＝17.3Hz,3H),2.06(dd,J＝14.0,6.3Hz,1H),1.96–1.85(m,1H),1.67–1.57(m,3H),1.51–1.37(m,3H),0.92(d,J＝8.2Hz,9H).
实施例A282
Figure PCTCN2021080167-appb-000439
LCMS([M+H] +):953.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.58(t,J＝6.0Hz,1H),8.29–8.23(m,2H),8.03(d,J＝2.4Hz,1H),7.68–7.65(m,1H),7.46–7.37(m,6H),5.16(d,J＝3.5Hz,1H),4.61–4.48(m,3H),4.48–4.36(m,3H),4.25(dd,J＝15.7,5.7Hz,1H),4.08–4.03(m,2H),3.90(t,J＝4.4Hz,2H),3.69–3.59(m,2H),2.45–2.43(m,3H),2.24–2.22(m,3H),2.08–2.02(m,1H),1.90(ddd,J＝12.8,8.7,4.4Hz,1H),1.51(d,J＝5.2Hz,6H),0.92–0.90(m,11H).
实施例A283
Figure PCTCN2021080167-appb-000440
LCMS([M+H] +):1041.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.27(m,1H),8.59(t,J＝5.9Hz,1H),8.39–8.23(m,2H),8.09(d,J＝31.1Hz,1H),7.48–7.36(m,5H),6.90–6.87(m,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.33(m,5H),4.24(dd,J＝15.8,5.5Hz,1H),3.96–3.92(m,2H),3.73(s,2H),3.61–3.57(m,10H),2.44(d,J＝4.6Hz,3H),2.24(d,J＝17.2Hz,3H),2.07–1.99(m,2H),1.95–1.86(m,1H),1.63(d,J＝12.4Hz,3H),1.43(d,J＝9.7Hz,3H),0.94–0.92(m,9H).
实施例A284
Figure PCTCN2021080167-appb-000441
LCMS([M+H] +):1025.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.58(t,J＝6.0Hz,1H),8.26(d,J＝4.2Hz,2H),8.01(d,J＝2.4Hz,1H),7.64(d,J＝1.8Hz,1H),7.40(d,J＝9.6Hz,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.20(m,6H),3.97(s,2H),3.71–3.46(m,8H),2.43(s,3H),2.17(s,3H),2.10–2.02(m,1H),1.90(ddd,J＝12.9,8.8,4.5Hz,1H),1.84–1.74(m,2H),1.68(dt,J＝13.2,6.4Hz,2H),1.51(d,J＝6.0Hz,6H),0.94(s,9H).
实施例A285
Figure PCTCN2021080167-appb-000442
LCMS([M+H] +):1043.1
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.3Hz,1H),8.60(t,J＝6.0Hz,1H),8.30–8.20(m,2H),8.07(d,J＝2.1Hz,1H),7.95(dd,J＝10.7,2.1Hz,1H),7.47–7.32(m,5H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.50–4.32(m,5H),4.25(dd,J＝15.7,5.6Hz,1H),3.98–3.83(m,2H),3.71–3.50(m,4H),3.44(dt,J＝14.6,6.3Hz,4H),2.44(d,J＝4.7Hz,3H),2.06(dd,J＝13.3,6.7Hz,1H),1.95–1.85(m,1H),1.85–1.73(m,4H),1.64(dd,J＝14.5,6.4Hz,2H),1.54(d,J＝1.7Hz,6H),0.93(d,J＝7.6Hz,9H).
实施例A286
Figure PCTCN2021080167-appb-000443
LCMS([M+H] +):1039.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.9Hz,1H),8.60(t,J＝5.9Hz,1H),8.31–8.22(m,2H),8.02(d,J＝2.2Hz,1H),7.64(d,J＝1.7Hz,1H),7.47–7.32(m,5H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.49–4.20(m,6H),3.90(d,J＝18.8Hz,2H),3.71–3.50(m,4H),3.50–3.39(m,4H),2.44(d,J＝4.9Hz,3H),2.18(s,3H),2.11–2.02(m,1H),1.96–1.84(m,1H),1.84–1.72(m,4H),1.65(dd,J＝14.5,6.4Hz,2H),1.51(d,J＝6.1Hz,6H),0.92(d,J＝7.5Hz,9H).
实施例A287
Figure PCTCN2021080167-appb-000444
LCMS([M+H] +):1053.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.7Hz,1H),8.60(t,J＝6.0Hz,1H),8.30–8.22(m,2H),8.02(d,J＝2.3Hz,1H),7.64(d,J＝1.8Hz,1H),7.48–7.31(m,5H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.49–4.19(m,6H),3.96–3.83(m,2H),3.71–3.50(m,4H),3.44(m,2H),3.37(m,2H),2.44(d,J＝5.1Hz,3H),2.18(m,3H),2.06(m,1H),1.90(m,1H),1.83–1.68(m,4H),1.60–1.38(m,10H),0.92(d,J＝7.4Hz,9H).
实施例A288
Figure PCTCN2021080167-appb-000445
LCMS([M+H] +):1041.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.59(t,J＝5.8Hz,1H),8.40–8.21(m,2H),7.66(dd,J＝42.8,8.7Hz,1H),7.48–7.33(m,5H),6.80(dd,J＝13.4,8.6Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.32(m,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.96–3.92(m,2H),3.77–3.71(m,2H),3.67–3.55(m,10H),2.44(d,J＝4.4Hz,3H),2.34(d,J＝19.4Hz,3H),2.10–2.02(m,1H),1.94–1.85(m,1H),1.60(d,J＝12.4Hz,3H),1.46(d,J＝11.1Hz,3H),0.94–0.92(m,9H).
实施例A289
Figure PCTCN2021080167-appb-000446
LCMS([M+H] +):1061.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.59(t,J＝5.9Hz,1H),8.29–8.21(m,2H),8.20(d,J＝2.3Hz,1H),8.15(d,J＝2.3Hz,1H),7.47–7.35(m,5H),5.15(d,J＝3.5Hz,1H),4.60–4.48(m,3H),4.47–4.33(m,3H),4.24(dd,J＝15.8,5.5Hz,1H),3.96–3.92(m,2H),3.82–3.75(m,2H),3.70–3.55(m,10H),2.45–2.44(m,3H),2.08–2.03(m,1H),1.90(ddd,J＝12.8,8.7,4.4Hz,1H),1.54(s,6H),0.94–0.92(m,9H).
实施例A290
Figure PCTCN2021080167-appb-000447
LCMS([M+H] +):1057.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.61(t,J＝5.7Hz,1H),8.25(s,2H),8.07(d,J＝1.6Hz,1H),7.95(d,J＝10.7Hz,1H),7.48–7.31(m,5H),5.16(d,J＝3.2Hz,1H),4.62–4.19(m,7H),3.90(m,2H),3.71–3.58(m,2H),3.54(m,2H),3.45(m,2H),3.38(m,2H),2.44(s,3H),2.07(m,1H),1.97–1.86(m,1H),1.77(m,4H),1.54(m,8H),1.49–1.38(m,2H),0.94(s,9H).
实施例A291
Figure PCTCN2021080167-appb-000448
LCMS([M+H] +):1017.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.58(s,1H),8.26(d,J＝8.8Hz,2H),7.46–7.38(m,4H),7.31–7.19(m,3H),5.37–5.27(m,1H),5.14(s,1H),4.56(d,J＝8.7Hz,1H),4.51–4.40(m,3H),4.36(d,J＝8.9Hz,2H),4.26(d,J＝5.5Hz,2H),3.98(s,2H),3.81(d,J＝4.7Hz,3H),3.68–3.58(m,6H),2.46–2.29(m,1H),1.68–1.61(m,4H),1.52–1.46(m,3H),1.02–0.84(m,9H).
实施例A292
Figure PCTCN2021080167-appb-000449
LCMS([M+H] +):1013.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝7.8Hz,1H),8.58(t,J＝6.0Hz,1H),8.33–8.19(m,2H),8.08–7.90(m,1H),7.49–7.35(m,5H),6.67(d,J＝11.7Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝8.7Hz,1H),4.41(ddd,J＝22.3,12.2,7.0Hz,5H),4.25(dd,J＝15.7,5.6Hz,1H),3.97(d,J＝15.6Hz,2H),3.86–3.74(m,5H),3.72–3.58(m,6H),2.44(d,J＝5.5Hz,3H),2.10–2.00(m,1H),1.90(ddd,J＝12.9,8.8,4.5Hz,1H),1.55(dd,J＝7.8,2.8Hz,3H),1.39(d,J＝14.8Hz,3H),0.92(d,J＝8.7Hz,9H).
实施例A293
Figure PCTCN2021080167-appb-000450
LCMS([M+H] +):1039.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.8Hz,1H),8.60(t,J＝6.0Hz,1H),8.32(dt,J＝40.6,6.0Hz,2H),7.65(dd,J＝42.9,8.6Hz,1H),7.46–7.32(m,5H),6.77(dd,J＝13.7,8.7Hz,1H),5.15(d,J＝3.2Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.32(m,3H),4.31–4.20(m,3H),3.95–3.86(m,2H),3.64(dt,J＝23.6,7.4Hz,2H),3.54(t,J＝6.5Hz,2H),3.44(dt,J＝18.1,6.3Hz,4H),2.44(d,J＝4.6Hz,3H),2.33(d,J＝19.3Hz,3H),2.06(dd,J＝14.1,6.4Hz,1H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.83–1.69(m,4H),1.66–1.55(m,5H),1.46(d,J＝11.5Hz,3H),0.93(d,J＝7.6Hz,9H).
实施例A294
Figure PCTCN2021080167-appb-000451
LCMS([M+H] +):1039.1
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.5Hz,1H),8.60(t,J＝6.1Hz,1H),8.40–8.23(m,2H),8.09(d,J＝31.1Hz,1H),7.47–7.33(m,5H),6.86(d,J＝9.8Hz,1H),5.15(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.32(m,3H),4.31–4.20(m,3H),3.96–3.86(m,2H),3.64(dt,J＝23.6,7.4Hz,2H),3.54(t,J＝6.4Hz,2H),3.43(dt,J＝18.8,6.3Hz,5H),2.44(d,J＝4.5Hz,3H),2.24(d,J＝17.2Hz,3H),2.10–2.02(m,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.83–1.69(m,4H),1.62(t,J＝11.2Hz,5H),1.43(d,J＝9.9Hz,3H),0.93(d,J＝7.6Hz,9H).
实施例A295
Figure PCTCN2021080167-appb-000452
LCMS([M+H] +):953.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.61–8.59(m,1H),8.40–8.24(m,2H),7.70–7.54(m,1H),7.51–7.36(m,5H),6.97–6.86(m,1H),5.16(d,J＝3.4Hz,1H),4.58(d,J＝9.5Hz,1H),4.52–4.22(m,7H),4.06(s,2H),3.88–3.87(m,2H),3.64(dd,J＝26.7,8.8Hz,2H),2.45–2.42(m,3H),2.36–2.31(m,3H),2.09–2.04(m,1H),1.96–1.87(m,1H),1.63–1.51(m,3H),1.50–1.42(m,3H),0.94(s,9H).
实施例A296
Figure PCTCN2021080167-appb-000453
LCMS([M+H] +):953.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.61–8.60(m,1H),8.41–8.23(m,2H),8.14–8.06(m,1H),7.56–7.36(m,5H),7.03(dd,J＝17.2,8.2Hz, 1H),5.17(d,J＝3.4Hz,1H),4.60(dd,J＝9.6,4.8Hz,1H),4.52–4.26(m,6H),4.12–4.00(m,2H),3.87–3.82(m,2H),3.72–3.60(m,2H),2.45–2.42(m,3H),2.20(dd,J＝18.4,5.6Hz,3H),2.09–2.04(m,1H),1.95–1.86(m,1H),1.63(dd,J＝11.9,3.5Hz,3H),1.45–1.38(m,3H),0.95–0.93(m,9H).
实施例A297
Figure PCTCN2021080167-appb-000454
LCMS([M+H] +):1059.5
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝4.1Hz,1H),8.60(t,J＝6.0Hz,1H),8.31(dt,J＝22.9,12.5Hz,3H),7.48–7.34(m,5H),7.25(dd,J＝7.5,1.5Hz,1H),5.15(d,J＝3.3Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.29(m,7H),4.24(dd,J＝15.8,5.8Hz,1H),3.90(d,J＝16.2Hz,2H),3.69–3.58(m,2H),3.54(t,J＝6.5Hz,2H),3.46(t,J＝6.4Hz,5H),3.41(t,J＝6.3Hz,2H),2.44(d,J＝4.5Hz,3H),2.06(dd,J＝14.0,6.2Hz,2H),1.94–1.86(m,1H),1.78(dt,J＝16.9,8.4Hz,4H),1.63(dd,J＝17.3,8.5Hz,5H),1.55–1.46(m,3H),0.93(d,J＝7.7Hz,9H).
实施例A298
Figure PCTCN2021080167-appb-000455
LCMS([M+H] +):1059.5
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.4Hz,1H),8.60(t,J＝5.9Hz,1H),8.23(dt,J＝7.8,5.4Hz,3H),8.14(d,J＝2.3Hz,1H),7.47–7.32(m,5H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.47–4.32(m,5H),4.25(dd,J＝15.8,5.5Hz,1H),3.90(d,J＝16.7Hz,2H),3.69–3.57(m,2H),3.54(t,J＝6.4Hz,2H),3.45(dt,J＝12.6,6.4Hz,4H),2.44(d,J＝4.6Hz,3H),2.10–2.02(m, 1H),1.90(ddd,J＝12.9,8.8,4.3Hz,1H),1.79(dd,J＝11.9,5.9Hz,4H),1.66(dd,J＝14.4,6.4Hz,2H),1.54(s,6H),0.93(d,J＝7.6Hz,9H).
实施例A299
Figure PCTCN2021080167-appb-000456
LCMS([M+H] +):969.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.57(s,1H),8.26(s,2H),7.98(s,1H),7.55(d,J＝9.6Hz,1H),7.40(d,J＝2.8Hz,4H),6.95(dd,J＝21.2,14.5Hz,1H),5.11(dd,J＝60.7,3.0Hz,1H),4.73–4.58(m,1H),4.47(s,6H),4.07(d,J＝2.9Hz,2H),3.85(d,J＝22.2Hz,5H),3.73–3.61(m,2H),2.51(s,3H),2.22–1.84(m,2H),1.56(d,J＝7.9Hz,3H),1.44–1.30(m,3H),0.97(d,J＝9.5Hz,9H).
实施例A300
Figure PCTCN2021080167-appb-000457
LCMS([M+H] +):969.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.8Hz,1H),8.60(dd,J＝12.2,7.6Hz,1H),8.37–8.19(m,2H),7.74–7.56(m,1H),7.53–7.35(m,5H),6.70–6.57(m,1H),5.16(d,J＝3.3Hz,1H),4.63–4.55(m,1H),4.55–4.32(m,5H),4.27(dd,J＝15.5,5.5Hz,1H),4.04(d,J＝19.4Hz,2H),3.88(d,J＝4.2Hz,5H),3.66(dt,J＝24.3,7.3Hz,2H),2.44(d,J＝9.9Hz,3H),2.06(dd,J＝12.6,7.9Hz,1H),1.98–1.85(m,1H),1.58–1.35(m,6H),0.94(d,J＝6.6Hz,9H).
实施例A301
Figure PCTCN2021080167-appb-000458
LCMS([M+H] +):1053.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.60(t,J＝6.0Hz,1H),8.40–8.23(m,2H),8.09(d,J＝31.0Hz,1H),7.47–7.31(m,5H),6.86(t,J＝7.0Hz,1H),5.15(d,J＝3.4Hz,1H),4.55(m,1H),4.49–4.32(m,3H),4.30–4.21(m,3H),3.96–3.86(m,2H),3.64(m,2H),3.53(m,2H),3.44(m,2H),3.36(m,2H),2.44(d,J＝4.7Hz,3H),2.24(d,J＝17.5Hz,3H),2.06(m,1H),1.90(m,1H),1.75(m,4H),1.63(d,J＝12.4Hz,3H),1.58–1.48(m,2H),1.47–1.35(m,5H),0.93(d,J＝7.1Hz,9H).
实施例A302
Figure PCTCN2021080167-appb-000459
LCMS([M+H] +):1025.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝7.8Hz,1H),8.59(t,J＝6.0Hz,1H),8.40–8.23(m,2H),8.08(d,J＝31.1Hz,1H),7.40(d,J＝10.0Hz,5H),6.84(d,J＝9.5Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.46–4.33(m,3H),4.24(d,J＝12.7Hz,3H),3.97(s,2H),3.70–3.57(m,5H),3.55(d,J＝4.7Hz,2H),3.49(s,2H),2.44(d,J＝6.7Hz,3H),2.23(d,J＝17.1Hz,3H),2.10–2.02(m,1H),1.95–1.86(m,1H),1.75(d,J＝6.8Hz,2H),1.64(t,J＝12.0Hz,5H),1.43(d,J＝9.8Hz,3H),0.93(d,J＝8.8Hz,9H).
实施例A303
Figure PCTCN2021080167-appb-000460
LCMS([M+H] +):1053.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.0Hz,1H),8.60(t,J＝6.0Hz,1H),8.31(dt,J＝40.0,5.8Hz,2H),7.64(dd,J＝40.8,8.7Hz,1H),7.47–7.32(m,5H),6.77(dd,J＝13.7,8.7Hz,1H),5.16(d,J＝2.8Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.30–4.19(m,3H),3.92(m,2H),3.64(m,2H),3.53(m,2H),3.44(m,2H),2.44(d,J＝4.7Hz,3H),2.33(m,3H),2.06(m,1H),1.94–1.86(m,1H),1.82–1.66(m,4H),1.59(d,J＝12.5Hz,3H),1.52(m,2H),1.49–1.37(m,5H),0.92(d,J＝7.3Hz,9H).
实施例A304
Figure PCTCN2021080167-appb-000461
LCMS([M+H] +):1025.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.59(t,J＝5.9Hz,1H),8.41–8.22(m,2H),7.64(dd,J＝42.3,8.7Hz,1H),7.39(s,5H),6.75(dd,J＝13.2,8.7Hz,1H),5.15(d,J＝3.1Hz,1H),4.57(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.24(dd,J＝16.0,5.3Hz,3H),3.97(s,2H),3.71–3.58(m,4H),3.58–3.43(m,4H),2.43(s,3H),2.33(dd,J＝19.3,5.0Hz,3H),2.06(dd,J＝14.2,6.9Hz,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.76(p,J＝6.7Hz,2H),1.67(q,J＝6.3Hz,2H),1.59(d,J＝12.6Hz,3H),1.45(d,J＝11.3Hz,3H),0.94(s,9H).
实施例A305
Figure PCTCN2021080167-appb-000462
LCMS([M+H] +):1073.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.3Hz,1H),8.60(t,J＝6.0Hz,1H),8.28–8.21(m,2H),8.20(d,J＝2.3Hz,1H),8.13(d,J＝2.3Hz,1H),7.49–7.30(m,5H),5.16(d,J＝3.5Hz,1H),4.55(m,1H),4.48–4.33(m,5H),4.24(m,1H),3.95–3.86(m,2H),3.64(m,2H),3.53(m,2H),3.45(m,2H),3.38(m,2H),2.44(d,J＝4.8Hz,3H),2.06(m,1H),1.90(m,1H),1.82–1.72(m,4H),1.60–1.50(m,8H),1.50–1.39(m,2H),0.92(d,J＝7.4Hz,9H).
实施例A306
Figure PCTCN2021080167-appb-000463
LCMS([M+H] +):1057.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.7Hz,1H),8.59(t,J＝5.9Hz,1H),8.35–8.20(m,2H),8.07–7.92(m,1H),7.48–7.36(m,5H),6.66(d,J＝9.7Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.33(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),3.95(d,J＝16.2Hz,2H),3.83(d,J＝3.6Hz,3H),3.76–3.70(m,2H),3.69–3.53(m,10H),2.44(d,J＝4.3Hz,3H),2.10–2.01(m,1H),1.94–1.85(m,1H),1.55(d,J＝10.3Hz,3H),1.39(d,J＝14.7Hz,3H),0.93(d,J＝8.9Hz,9H).
实施例A307
Figure PCTCN2021080167-appb-000464
LCMS([M+H] +):1041.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.59(t,J＝6.0Hz,1H),8.36–8.21(m,2H),8.06–7.92(m,1H),7.47–7.35(m,5H),6.58(s,1H),5.15(d,J＝3.1Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.31–4.20(m,3H),3.97(s,2H),3.82(d,J＝3.7Hz,3H),3.71–3.46(m,9H),2.43(s,3H),2.11–2.01(m,1H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.75(q,J＝6.7Hz,2H),1.67(q,J＝6.4Hz,2H),1.54(d,J＝10.3Hz,3H),1.39(d,J＝14.8Hz,3H),0.94(s,9H).
实施例A308
Figure PCTCN2021080167-appb-000465
LCMS([M+H] +):1045.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.59(t,J＝6.0Hz,1H),8.29–8.16(m,3H),8.13(d,J＝2.3Hz,1H),7.40(d,J＝10.0Hz,5H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.42(dt,J＝21.3,7.5Hz,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.97(s,2H),3.64(dtd,J＝16.7,11.7,11.2,4.5Hz,4H),3.58–3.48(m,4H),2.43(s,3H),2.10–2.01(m,1H),1.91(ddd,J＝13.0,8.8,4.5Hz,1H),1.81(dt,J＝14.5,6.3Hz,2H),1.69(q,J＝6.4Hz,2H),1.54(s,6H),0.94(s,9H).
实施例A309
Figure PCTCN2021080167-appb-000466
LCMS([M+H] +):1057.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.3Hz,1H),8.59(t,J＝6.0Hz,1H),8.36–8.20(m,2H),7.78–7.60(m,1H),7.46–7.35(m,5H),6.57–6.49(m,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.32(m,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.94(d,J＝16.1Hz,2H),3.87(t,J＝4.1Hz,3H),3.79–3.72(m,2H),3.70–3.53(m,10H),2.44(d,J＝4.7Hz,3H),2.09–2.01(m,1H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.53(d,J＝11.0Hz,3H),1.43(d,J＝16.0Hz,3H),0.93(d,J＝8.8Hz,9H).
实施例A310
Figure PCTCN2021080167-appb-000467
LCMS([M+H] +):1055.1
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.60(t,J＝5.7Hz,1H),8.36–8.18(m,2H),8.00(d,J＝35.8Hz,1H),7.49–7.31(m,5H),6.60(s,1H),5.15(d,J＝3.1Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.19(m,6H),3.90(d,J＝16.7Hz,2H),3.83(d,J＝3.3Hz,3H),3.70–3.51(m,4H),3.44(dt,J＝18.7,6.0Hz,4H),2.44(s,3H),2.06(dd,J＝12.4,7.4Hz,1H),1.91(dd,J＝14.9,6.2Hz,1H),1.84–1.69(m,4H),1.68–1.59(m,2H),1.55(d,J＝10.5Hz,3H),1.39(d,J＝14.9Hz,3H),0.94(s,9H).
实施例A311
Figure PCTCN2021080167-appb-000468
LCMS([M+H] +):973.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.58(s,1H),8.36–8.23(m,3H),7.50(dd,J＝9.5,4.5Hz,1H),7.46–7.36(m,5H),5.16(d,J＝3.5Hz,1H),4.60(dd,J＝9.6,3.0Hz,1H),4.55–4.44(m,4H),4.38–4.26(m,4H),4.06(s,2H),3.88(m,2H),3.68(dd,J＝10.6,3.5Hz,2H),3.61(d,J＝10.6Hz,2H),2.42(s,3H),2.09–2.04(m,1H),1.93–1.88(m,1H),1.64(d,J＝9.1Hz,3H),1.48(dd,J＝13.3,4.5Hz,3H),0.94(s,9H).
实施例A312
Figure PCTCN2021080167-appb-000469
LCMS([M+H] +):1073.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.3Hz,1H),8.60(t,J＝6.0Hz,1H),8.28–8.21(m,2H),8.20(d,J＝2.3Hz,1H),8.13(d,J＝2.3Hz,1H),7.49–7.30(m,5H),5.16(d,J＝3.5Hz,1H),4.55(m,1H),4.48–4.33(m,5H),4.24(m,1H),3.95–3.86(m,2H),3.64(m,2H),3.53(m,2H),3.45(m,2H),3.38(m,2H),2.44(d,J＝4.8Hz,3H),2.06(m,1H),1.90(m,1H),1.82–1.72(m,4H),1.60–1.50(m,8H),1.50–1.39(m,2H),0.92(d,J＝7.4Hz,9H).
实施例A313
Figure PCTCN2021080167-appb-000470
LCMS([M+H] +):1069.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝3.2Hz,1H),8.60(t,J＝6.0Hz,1H),8.35–8.20(m,2H),8.00(d,J＝35.8Hz,1H),7.48–7.32(m,5H),6.61(d,J＝4.5Hz,1H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.31–4.20(m,3H),3.95–3.87(m,2H),3.83(d,J＝3.7Hz,3H),3.64(m,2H),3.54(m,2H),3.45(m,2H),3.37(m,2H),2.44(d,J＝4.5Hz,3H),2.06(m,1H),1.90(m,1H),1.82–1.75(m,2H),1.70(m,2H),1.59–1.48(m,5H),1.42(m,5H),0.93(d,J＝7.6Hz,9H).
实施例A314
Figure PCTCN2021080167-appb-000471
LCMS([M+H] +):1061.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.59(t,J＝6.0Hz,1H),8.41–8.30(m,1H),8.27–8.25(m,2H),7.45–7.37(m,5H),7.30(dd,J＝7.1,1.8Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.33(m,5H),4.24(dd,J＝15.7,5.5Hz,1H),3.97–3.92(m,2H),3.77–3.72(m,2H),3.67–3.56(m,10H),2.45–2.44(m,3H),2.08–2.03(m,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.65(d,J＝9.9Hz,3H),1.49(d,J＝12.6Hz,3H),0.93(d,J＝8.7Hz,9H).
实施例A315
Figure PCTCN2021080167-appb-000472
LCMS([M+H] +):1045.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.59(t,J＝6.0Hz,1H),8.41–8.23(m,3H),7.40(d,J＝10.0Hz,5H),7.29–7.19(m,1H),5.15(d,J＝3.3Hz,1H),4.57(d,J＝9.6Hz,1H),4.48–4.20(m,6H),3.97(s,2H),3.71–3.46(m,8H),2.43(s,3H),2.06(dd,J＝13.6,6.8Hz,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.78(p,J＝6.7Hz,2H),1.66(q,J＝9.8,8.0Hz,5H),1.49(d,J＝12.6Hz,3H),0.94(s,9H).
实施例A316
Figure PCTCN2021080167-appb-000473
LCMS([M+H] +):982.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.58(t,J＝6.0Hz,1H),8.38(d,J＝2.7Hz,1H),8.29–8.27(m,3H),7.83(d,J＝11.8Hz,2H),7.58(d,J＝9.4Hz,1H),7.40(s,4H),5.19(d,J＝3.5Hz,1H),4.64(m,2H),4.56(d,J＝9.4Hz,1H),4.45(d,J＝8.0Hz,1H),4.38–4.36(m,2H),4.25(d,J＝10.1Hz,1H),4.09(s,2H),3.96–3.92(m,2H),3.67(m,2H),2.44(d,J＝3.0Hz,3H),2.06–2.04(m,1H),1.93–1.88(m,1H),1.54(d,J＝5.4Hz,6H),0.93–0.91(m,9H).
实施例A317
Figure PCTCN2021080167-appb-000474
LCMS([M+H] +):1041.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.59(t,J＝5.9Hz,1H),8.36–8.20(m,2H),7.78–7.57(m,1H),7.40(d,J＝9.3Hz,5H),6.55–6.44(m,1H),5.15(d,J＝3.3Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.33(m,3H),4.27(dt,J＝17.6,8.5Hz,3H),3.97(s,2H),3.86(d,J＝4.1Hz,3H),3.72–3.46(m,8H),2.43(s,3H),2.06(q,J＝7.6Hz,1H),1.91(ddd,J＝12.9,8.9,4.4Hz,1H),1.78(q,J＝6.6Hz,2H),1.73–1.61(m,2H),1.53(d,J＝10.6Hz,3H),1.42(d,J＝15.9Hz,3H),0.93(d,J＝8.7Hz,9H).
实施例A318
Figure PCTCN2021080167-appb-000475
LCMS([M+H] +):1055.1
1HNMR(400MHz,DMSO-d6)δ9.01–8.92(m,1H),8.60(t,J＝5.9Hz,1H),8.36–8.19(m,2H),7.68(dd,J＝48.8,8.3Hz,1H),7.49–7.32(m,5H),6.55–6.44(m,1H),5.15(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.49–4.32(m,3H),4.26(dt,J＝15.8,6.1Hz,3H),3.89(dd,J＝14.3,7.8Hz,5H),3.64(dt,J＝23.3,7.2Hz,2H),3.54(t,J＝6.4Hz,2H),3.44(dt,J＝16.2,6.3Hz,4H),2.44(d,J＝4.9Hz,3H),2.06(dd,J＝13.3,7.1Hz,1H),1.94–1.86(m,1H),1.83–1.72(m,4H),1.62(dt,J＝13.1,6.4Hz,2H),1.53(d,J＝11.1Hz,3H),1.43(d,J＝16.2Hz,3H),0.93(d,J＝7.5Hz,9H).
实施例A319
Figure PCTCN2021080167-appb-000476
LCMS([M+H] +):1011.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.6Hz,1H),8.59(t,J＝6.0Hz,1H),8.32(dt,J＝40.7,5.9Hz,2H),7.74–7.55(m,1H),7.48–7.34(m,5H),6.80–6.62(m,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.33(dddd,J＝25.1,21.4,15.9,6.8Hz,5H),4.00–3.91(m,2H),3.71–3.54(m,8H),2.48–2.39(m,4H),2.33(dd,J＝19.6,5.7Hz,3H),2.11–1.86(m,4H),1.60(d,J＝11.8Hz,3H),1.52–1.37(m,3H),0.93(d,J＝7.9Hz,9H).
实施例A320
Figure PCTCN2021080167-appb-000477
LCMS([M+H] +):1011.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.59(t,J＝5.9Hz,1H),8.41–8.23(m,2H),8.17–8.02(m,1H),7.41(d,J＝12.4Hz,5H),6.84(t,J＝10.5Hz,1H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.29(m,5H),4.24(dd,J＝15.9,5.5Hz,1H),3.97(s,2H),3.71–3.53(m,8H),2.43(s,3H),2.24(dd,J＝17.6,4.8Hz,3H),2.11–1.86(m,4H),1.63(d,J＝12.2Hz,3H),1.48–1.38(m,3H),0.93(d,J＝7.5Hz,9H).
实施例A321
Figure PCTCN2021080167-appb-000478
LCMS([M+H] +):1027.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.8Hz,1H),8.59(t,J＝5.9Hz,1H),8.34–8.20(m,2H),8.06–7.92(m,1H),7.46–7.34(m,5H),6.61(d,J＝16.7Hz,1H),5.15(m,1H),4.57(m,1H),4.48–4.30(m,5H),4.29–4.21(m,1H),3.95(m,2H),3.85–3.79(m,3H),3.71–3.53(m,8H),2.44(d,J＝5.9Hz,3H),1.97(m,4H),1.55(d,J＝10.2Hz,3H),1.39(d,J＝14.7Hz,3H),0.93(d,J＝8.2Hz,9H).
实施例A322
Figure PCTCN2021080167-appb-000479
LCMS([M+H] +):1011.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝11.8Hz,1H),8.59(t,J＝6.0Hz,1H),8.32–8.20(m,2H),8.02(dd,J＝7.0,2.4Hz,1H),7.64(d,J＝1.9Hz,1H),7.47–7.31(m,5H),5.08(dd,J＝62.4,3.2Hz,1H),4.56(d,J＝9.6Hz,1H),4.50–4.30(m,5H),4.24(dd,J＝15.9,5.6Hz,1H),3.95(d,J＝16.8Hz,2H),3.71–3.51(m,8H),2.44(d,J＝7.3Hz,3H),2.18(d,J＝12.2Hz,3H),2.10–1.86(m,4H),1.51(d,J＝5.9Hz,6H),0.92(d,J＝8.0Hz,9H).
实施例A323
Figure PCTCN2021080167-appb-000480
LCMS([M+H] +):1097.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.6Hz,1H),8.60(t,J＝6.1Hz,1H),8.43(d,J＝2.6Hz,1H),8.24(dd,J＝12.9,3.3Hz,3H),7.46–7.33(m,5H),5.16(s,1H),4.55(d,J＝9.6Hz,1H),4.47–4.34(m,5H),4.24(m,1H),3.91(m, 2H),3.85(d,J＝18.4Hz,3H),3.64(m,2H),3.53(m,2H),3.44(m,4H),2.44(d,J＝4.9Hz,3H),2.11–1.94(m,3H),1.94–1.87(m,1H),1.77(m,4H),1.50(m,10H),0.92(d,J＝7.6Hz,9H).
实施例A324
Figure PCTCN2021080167-appb-000481
LCMS([M+H] +):1031.5
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.3Hz,1H),8.59(t,J＝5.8Hz,1H),8.40–8.23(m,3H),7.41(d,J＝10.3Hz,5H),7.22(d,J＝7.2Hz,1H),5.15(s,1H),4.56(d,J＝9.6Hz,1H),4.41(dt,J＝12.2,7.3Hz,5H),4.24(dd,J＝15.7,5.4Hz,1H),3.95(d,J＝16.9Hz,2H),3.70–3.56(m,8H),2.44(d,J＝6.0Hz,3H),2.07–1.96(m,3H),1.94–1.86(m,1H),1.64(d,J＝9.7Hz,3H),1.49(d,J＝11.8Hz,3H),0.92(d,J＝8.4Hz,9H).
实施例A325
Figure PCTCN2021080167-appb-000482
LCMS([M+H] +):1031.5
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝10.8Hz,1H),8.58(t,J＝6.1Hz,1H),8.30–8.11(m,4H),7.41(d,J＝9.4Hz,5H),5.15(d,J＝3.2Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.33(m,5H),4.24(dd,J＝15.7,5.4Hz,1H),3.95(d,J＝17.1Hz,2H),3.68–3.56(m,8H),2.44(d,J＝6.4Hz,3H),2.04(dd,J＝14.3,8.1Hz,3H),1.94–1.86(m,1H),1.54(s,6H),0.92(d,J＝7.9Hz,9H).
实施例A326
Figure PCTCN2021080167-appb-000483
LCMS([M+H] +):1085.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.9Hz,1H),8.59(t,J＝6.0Hz,1H),8.43(d,J＝2.6Hz,1H),8.30–8.21(m,3H),7.47–7.35(m,5H),5.15(d,J＝3.5Hz,1H),4.60–4.49(m,3H),4.48–4.33(m,3H),4.25(dd,J＝15.7,5.6Hz,1H),3.94(d,J＝16.4Hz,2H),3.86–3.75(m,5H),3.71–3.54(m,10H),2.44(d,J＝5.1Hz,3H),2.10–2.02(m,1H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.55(d,J＝4.5Hz,6H),0.93(d,J＝8.8Hz,9H).
实施例A327
Figure PCTCN2021080167-appb-000484
LCMS([M+H] +):997.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.58(t,J＝6.0Hz,1H),8.44(d,J＝2.6Hz,1H),8.31–8.22(m,3H),7.47–7.36(m,5H),5.16(d,J＝3.5Hz,1H),4.64–4.54(m,3H),4.48–4.32(m,3H),4.25(dd,J＝15.7,5.6Hz,1H),4.17–4.08(m,2H),3.96–3.90(m,2H),3.84(s,3H),3.68–3.59(m,2H),2.45–2.44(m,3H),2.08–2.03(m,1H),1.95–1.85(m,1H),1.54(d,J＝4.6Hz,6H),0.97–0.86(m,9H).
实施例A328
Figure PCTCN2021080167-appb-000485
LCMS([M+H] +):1070.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.60(t,J＝6.0Hz,1H),8.38(d,J＝2.6Hz,1H),8.32–8.24(m,3H),7.93(s,1H),7.75(s,1H),7.47–7.37(m,5H),5.17(d,J＝3.5Hz,1H),4.61–4.54(m,3H),4.47–4.37(m,2H),4.27–4.22(m,1H),3.97(s,2H),3.84–3.79(m,2H),3.66–3.56(m,10H),2.44–2.43(m,3H),2.09–1.95(m,2H),1.94–1.86(m,1H),1.54(d,J＝5.2Hz,6H),0.93–0.91(m,9H).
实施例A329
Figure PCTCN2021080167-appb-000486
LCMS([M+H] +):1026.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.59(t,J＝5.9Hz,1H),8.40–8.23(m,4H),7.95(s,1H),7.77(s,1H),7.50–7.36(m,5H),5.15(d,J＝3.5Hz,1H),4.66–4.53(m,3H),4.48–4.33(m,3H),4.28–4.22(m,1H),3.97(s,2H),3.90–3.87(m,2H),3.72–3.59(m,6H),2.44–2.43(m,3H),2.08–2.03(m,1H),1.91(ddd,J＝13.0,8.9,4.5Hz,1H),1.53(d,J＝4.7Hz,6H),0.91–0.89(m,9H).
实施例A330
Figure PCTCN2021080167-appb-000487
LCMS([M+H] +):1017.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.9Hz,1H),8.59(t,J＝6.0Hz,1H),8.30–8.19(m,2H),8.19–8.11(m,2H),7.49–7.35(m,5H),5.15(d,J＝3.5 Hz,1H),4.55(dd,J＝9.4,5.1Hz,3H),4.49–4.32(m,3H),4.24(dd,J＝15.8,5.6Hz,1H),3.98(s,2H),3.92–3.78(m,2H),3.75–3.57(m,6H),2.44(d,J＝6.2Hz,3H),2.11–2.01(m,1H),1.91(td,J＝8.7,4.5Hz,1H),1.54(s,6H),0.92(d,J＝7.9Hz,9H).
实施例A331
Figure PCTCN2021080167-appb-000488
LCMS([M+H] +):1013.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.58(t,J＝5.9Hz,1H),8.37–8.20(m,2H),7.79–7.58(m,1H),7.52–7.33(m,5H),6.53(dd,J＝5.9,2.2Hz,1H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.42(dd,J＝26.1,15.3Hz,5H),4.26(d,J＝5.5Hz,1H),3.99(s,2H),3.84(dd,J＝13.9,4.8Hz,5H),3.64(d,J＝12.3Hz,6H),2.44(d,J＝7.4Hz,3H),2.11–2.00(m,1H),1.95–1.85(m,1H),1.58–1.47(m,3H),1.47–1.37(m,3H),0.92(d,J＝9.7Hz,9H).
实施例A332
Figure PCTCN2021080167-appb-000489
LCMS([M+H] +):982.3
1HNMR(400MHz,DMSO-d6)δ8.97(t,J＝5.0Hz,1H),8.60(d,J＝5.7Hz,1H),8.24(d,J＝7.5Hz,2H),7.98(d,J＝18.4Hz,1H),7.90–7.70(m,1H),7.61(d,J＝9.8Hz,1H),7.51(d,J＝9.6Hz,1H),7.41(d,J＝7.6Hz,4H),7.29(dd,J＝14.3,8.9Hz,1H),5.17(d,J＝3.4Hz,1H),4.61(d,J＝9.3Hz,3H),4.41(d,J＝37.2Hz,3H),4.29(d,J＝5.0Hz,1H),4.08(s,2H),3.89(s,2H),3.74–3.56(m, 2H),2.43(s,3H),2.07(dd,J＝12.5,8.3Hz,1H),1.93(dd,J＝8.7,4.4Hz,1H),1.62(dd,J＝13.1,4.1Hz,3H),1.43(dd,J＝13.7,7.5Hz,3H),0.95(s,9H).
实施例A333
Figure PCTCN2021080167-appb-000490
LCMS([M+H] +):1041.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝10.3Hz,1H),8.60(t,J＝5.9Hz,1H),8.46–8.39(m,1H),8.30–8.22(m,3H),7.49–7.36(m,5H),5.16(d,J＝3.5Hz,1H),4.55(dd,J＝9.4,5.0Hz,3H),4.47–4.32(m,3H),4.24(dd,J＝15.8,5.6Hz,1H),3.96(d,J＝17.0Hz,2H),3.91–3.79(m,5H),3.75–3.58(m,6H),2.44(d,J＝6.5Hz,3H),2.06(dd,J＝15.2,5.9Hz,1H),1.90(ddd,J＝12.9,8.9,4.4Hz,1H),1.54(d,J＝4.2Hz,6H),0.91(d,J＝8.5Hz,9H).
实施例A334
Figure PCTCN2021080167-appb-000491
LCMS([M+H] +):1082.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.61(t,J＝5.9Hz,1H),8.37(d,J＝2.6Hz,1H),8.29–8.22(m,3H),7.91(s,1H),7.68(s,1H),7.46–7.33(m,5H),5.17(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.47–4.33(m,5H),4.27–4.22(m,1H),3.92–3.88(m,2H),3.68–3.59(m,2H),3.53(t,J＝6.3Hz,2H),3.45(d,J＝6.3Hz,2H),2.45–2.43(m,3H),2.10–2.02(m,1H),1.94–1.86 (m,1H),1.82–1.76(m,4H),1.54(d,J＝5.2Hz,8H),1.43(dd,J＝14.5,7.8Hz,2H),0.93–0.91(m,9H).
实施例A335
Figure PCTCN2021080167-appb-000492
LCMS([M+H] +):1054.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.60(t,J＝5.9Hz,1H),8.35(d,J＝2.5Hz,1H),8.29–8.21(m,3H),7.90(s,1H),7.69(s,1H),7.46–7.36(m,5H),5.16(d,J＝3.4Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.33(m,5H),4.25(dd,J＝15.6,5.4Hz,1H),3.97(s,2H),3.69–3.60(m,4H),3.55(m,2H),3.51–3.48(m,2H),2.45–2.43(m,3H),2.08–2.03(m,1H),1.94–1.80(m,3H),1.68(dd,J＝14.5,6.6Hz,2H),1.53(d,J＝4.8Hz,6H),0.93–0.91(m,9H).
实施例A336
Figure PCTCN2021080167-appb-000493
LCMS([M+H] +):1040.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.60(t,J＝5.9Hz,1H),8.35(d,J＝2.2Hz,1H),8.26–8.25(m,3H),7.90(s,1H),7.80(s,1H),7.49–7.35(m,5H),5.16(d,J＝3.4Hz,1H),4.60–4.48(m,3H),4.47–4.31(m,3H),4.27–4.22(m,1H),3.98–3.93(m,2H),3.70–3.54(m,8H),2.44–2.43(m,3H),2.08–2.05(m,3H),1.94–1.85(m,1H),1.53(d,J＝5.1Hz,6H),0.92–0.90(m,9H).
实施例A337
Figure PCTCN2021080167-appb-000494
LCMS([M+H] +):1069.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.60(t,J＝6.0Hz,1H),8.43(dd,J＝6.0,2.5Hz,1H),8.29–8.21(m,3H),7.40(d,J＝5.5Hz,5H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.33(m,5H),4.24(dd,J＝15.7,5.5Hz,1H),3.97(s,2H),3.83(d,J＝5.6Hz,3H),3.69–3.58(m,4H),3.58–3.49(m,4H),2.43(s,3H),2.08–2.02(m,1H),1.90(ddd,J＝12.9,8.9,4.4Hz,1H),1.82–1.75(m,2H),1.71(q,J＝6.3Hz,2H),1.54(d,J＝4.2Hz,6H),0.93(s,9H).
实施例A338
Figure PCTCN2021080167-appb-000495
LCMS([M+H] +):1119.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59(t,J＝6.0Hz,1H),8.28–8.22(m,2H),8.07(d,J＝2.0Hz,1H),7.96(dd,J＝10.7,1.8Hz,1H),7.86(d,J＝8.8Hz,2H),7.79(d,J＝9.0Hz,1H),7.44–7.37(m,4H),6.97(m,2H),5.16(m,1H),4.75(m,1H),4.42(m,5H),4.24(m,1H),4.08(m,2H),3.72(m,2H),3.52(m,2H),3.41(m,2H),2.46–2.42(m,3H),2.09–1.87(m,5H),1.83–1.74(m,2H),1.62–1.51(m,8H),1.46(m,2H),1.00(d,J＝11.6Hz,9H).
实施例A339
Figure PCTCN2021080167-appb-000496
LCMS([M+H] +):1101.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59(t,J＝5.9Hz,1H),8.30–8.23(m,2H),8.20(d,J＝2.5Hz,1H),7.86(d,J＝8.7Hz,2H),7.78(dd,J＝13.5,5.3Hz,2H),7.44–7.37(m,4H),6.97(d,J＝8.8Hz,3H),5.16(d,J＝3.5Hz,1H),4.75(d,J＝9.1Hz,1H),4.42(dt,J＝13.9,7.8Hz,3H),4.32–4.22(m,3H),4.08(m,2H),3.72(m,2H),3.52(m,2H),3.41(m,2H),2.43(d,J＝7.0Hz,3H),2.09–1.88(m,5H),1.78–1.70(m,2H),1.61–1.40(m,10H),1.00(d,J＝11.4Hz,9H).
实施例A340
Figure PCTCN2021080167-appb-000497
LCMS([M+H] +):1083.1
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.6Hz,1H),8.60(t,J＝6.0Hz,1H),8.43(d,J＝2.6Hz,1H),8.30–8.21(m,3H),7.48–7.33(m,5H),5.15(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.33(m,5H),4.25(dd,J＝15.7,5.5Hz,1H),3.92(s,2H),3.83(s,3H),3.64(dt,J＝23.1,7.2Hz,2H),3.54(t,J＝6.4Hz,2H),3.45(dt,J＝12.9,6.3Hz,4H),2.44(d,J＝4.7Hz,3H),2.06(dd,J＝13.5,6.8Hz,1H),1.94–1.86(m,1H),1.78(dq,J＝11.9,6.1Hz,4H),1.67(dd,J＝13.9,6.5Hz,2H),1.54(d,J＝4.3Hz,6H),0.92(d,J＝7.7Hz,9H).
实施例A341
Figure PCTCN2021080167-appb-000498
LCMS([M+H] +):1068.1
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝5.0Hz,1H),8.61(t,J＝5.9Hz,1H),8.36(d,J＝2.5Hz,1H),8.31–8.22(m,3H),7.91(s,1H),7.69(s,1H),7.46–7.34(m,5H),5.17(d,J＝3.4Hz,1H),4.55(d,J＝9.5Hz,1H),4.50–4.33(m,5H),4.25(dd,J＝15.9,5.5Hz,1H),3.90(d,J＝16.1Hz,2H),3.64(dt,J＝22.6,7.3Hz,2H),3.53(t,J＝6.4Hz,2H),3.49–3.40(m,5H),2.44(d,J＝4.3Hz,3H),2.06(dd,J＝13.5,6.6Hz,1H),1.80(ddt,J＝18.7,12.5,6.4Hz,4H),1.64(dd,J＝14.5,6.5Hz,2H),1.54(d,J＝5.2Hz,6H),0.92(d,J＝8.1Hz,9H).
实施例A347
Figure PCTCN2021080167-appb-000499
LCMS([M+H] +):1072.3
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝7.8Hz,1H),8.65–8.53(m,2H),8.28(d,J＝3.8Hz,2H),8.22(d,J＝2.6Hz,1H),8.00(dd,J＝8.7,2.6Hz,1H),7.93(d,J＝8.7Hz,2H),7.49(d,J＝9.6Hz,1H),7.40(s,4H),7.30(dd,J＝8.6,4.1Hz,3H),5.18(d,J＝3.4Hz,1H),4.58(d,J＝9.6Hz,1H),4.48–4.22(m,4H),3.97(s,2H),3.69–3.59(m,2H),3.56(t,J＝6.3Hz,2H),2.44(s,3H),2.10–1.86(m,2H),1.86–1.78(m,2H),1.55(s,6H),1.24(s,2H),0.94(s,9H).
实施例A348
Figure PCTCN2021080167-appb-000500
LCMS([M+H] +):1153.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.60(m,1H),8.52(d,J＝2.0Hz,1H),8.31–8.21(m,3H),7.84(dd,J＝24.7,8.9Hz,3H),7.41(t,J＝4.2Hz,4H),6.98(d,J＝8.8Hz,2H),5.17(m,1H),4.76(m,1H),4.46(m,5H),4.25(m,1H),4.09(m,2H),3.73(m,2H),3.52(m,2H),3.40(m,2H),2.45(m,3H),2.08(m,1H),1.96(t,J＝6.2Hz,3H),1.77(m,2H),1.57(m,8H),1.48(m,2H),1.01(d,J＝11.7Hz,9H).
实施例A349
Figure PCTCN2021080167-appb-000501
LCMS([M+H] +):1127.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.63(s,1H),8.46(d,J＝5.2Hz,2H),8.25(d,J＝6.5Hz,2H),7.50–7.35(m,5H),7.15(d,J＝9.0Hz,2H),6.99(d,J＝9.0Hz,2H),5.18(d,J＝3.4Hz,1H),4.58(d,J＝9.6Hz,1H),4.41(dd,J＝31.2,7.2Hz,3H),4.29(d,J＝5.6Hz,1H),4.02(t,J＝6.2Hz,2H),3.97(d,J＝1.2Hz,2H),3.77–3.60(m,2H),3.56(t,J＝6.2Hz,2H),2.45(d,J＝6.9Hz,3H),2.08(s,2H),1.78(dt,J＝14.0,6.6Hz,5H),1.57(d,J＝4.0Hz,6H),0.94(d,J＝6.7Hz,9H).
实施例A350
Figure PCTCN2021080167-appb-000502
LCMS([M+H] +):1077.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.64(s,1H),8.27(s,2H),8.15(dd,J＝10.5,1.6Hz,1H),8.01(d,J＝1.6Hz,1H),7.42(d,J＝10.9Hz,5H),7.17(d,J＝8.9Hz,2H),6.99(d,J＝8.9Hz,2H),5.19(d,J＝3.2Hz,1H),4.58(d,J＝9.6Hz,1H),4.50–4.19(m,4H),4.01(dd,J＝16.3,10.5Hz,4H),3.75–3.51(m,4H),2.45(d,J＝6.9Hz,3H),2.08(s,1H),1.97–1.66(m,5H),1.55(s,6H),0.95(s,9H).
实施例A351
Figure PCTCN2021080167-appb-000503
LCMS([M+H] +):1058.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.63(s,1H),8.28(d,J＝4.9Hz,2H),8.19(d,J＝2.4Hz,1H),7.93(dd,J＝8.7,2.5Hz,1H),7.42(d,J＝11.1Hz,5H),7.14(dd,J＝17.8,8.8Hz,3H),6.98(d,J＝8.9Hz,2H),5.18(d,J＝3.4Hz,1H),4.58(d,J＝9.6Hz,1H),4.41(dd,J＝30.8,7.2Hz,3H),4.28(d,J＝5.6Hz,1H),4.00(dd,J＝15.5,9.3Hz,4H),3.61(dt,J＝12.3,4.6Hz,4H),2.45(d,J＝7.2Hz,3H),2.08(s,1H),1.78(dt,J＝13.9,6.6Hz,5H),1.53(d,J＝1.8Hz,6H),0.94(d,J＝6.6Hz,9H).
实施例A352
Figure PCTCN2021080167-appb-000504
LCMS([M+H] +):1073.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.59(t,J＝6.0Hz,1H),8.27(d,J＝4.2Hz,2H),8.21(d,J＝2.4Hz,1H),7.86(d,J＝8.6Hz,2H),7.84–7.76(m,2H),7.45–7.36(m,4H),7.00(d,J＝8.7Hz,3H),5.32(t,J＝4.9Hz,1H),5.16(s,1H),4.76(d,J＝9.0Hz,1H),4.45(t,J＝7.7Hz,2H),4.42–4.35(m,2H),4.32(t,J＝6.5Hz,2H),4.24(dd,J＝15.7,5.6Hz,1H),4.16(t,J＝4.6Hz,2H),3.74(d,J＝7.9Hz,3H),3.53(q,J＝5.4,4.4Hz,3H),3.17(d,J＝3.9Hz,2H),2.45(s,4H),1.98(ddd,J＝29.2,14.0,7.9Hz,5H),1.80(t,J＝7.4Hz,2H),1.68(t,J＝7.4Hz,2H),1.52(d,J＝2.3Hz,6H),1.02(s,9H).
实施例A353
Figure PCTCN2021080167-appb-000505
LCMS([M+H] +):1057.4
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.60(t,J＝6.0Hz,1H),8.31–8.23(m,2H),8.21(d,J＝2.5Hz,1H),7.86(d,J＝8.7Hz,2H),7.83–7.75(m,2H),7.45–7.37(m,4H),6.98(t,J＝8.6Hz,3H),5.16(d,J＝3.5Hz,1H),4.76(d,J＝9.1Hz,1H),4.47–4.37(m,3H),4.31(t,J＝6.5Hz,2H),4.24(dd,J＝15.8,5.5Hz,1H),4.04(t,J＝6.3Hz,2H),3.73(s,2H),2.45–2.43(m,3H),2.04(d,J＝8.2Hz,1H),1.91(ddd,J＝12.7,8.5,4.5Hz,1H),1.77(d,J＝5.8Hz,4H),1.56–1.46(m,10H),1.02–0.99(m,9H).
实施例A354
Figure PCTCN2021080167-appb-000506
LCMS([M+H] +):1127.3
1HNMR(400MHz,DMSO-d6)δ8.99(m,1H),8.60(t,J＝6.0Hz,1H),8.53(m,1H),8.26(m,3H),7.84(dd,J＝21.0,8.9Hz,3H),7.41(m,4H),6.99(d,J＝8.7Hz,2H),5.17(m,1H),4.76(m,1H),4.55(m,2H),4.43(m,3H),4.25(m,1H),4.20–4.11(m,2H),3.79–3.69(m,4H),3.65(m,2H),2.45(m,3H),2.05(m,3H),1.92(m,1H),1.57(d,J＝4.9Hz,6H),1.02(s,9H).
实施例A355
Figure PCTCN2021080167-appb-000507
LCMS([M+H] +)::1056.1
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.61(t,J＝6.0Hz,1H),8.42(d,J＝1.9Hz,1H),8.25(dd,J＝9.4,3.1Hz,3H),7.48–7.34(m,5H),5.17(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.45(d,J＝5.2Hz,6H),3.98(s,2H),3.83(s,3H),3.72–3.53(m,8H),2.43(s,3H),2.01(s,4H),1.55(d,J＝4.4Hz,6H),0.92(d,J＝9.6Hz,9H).
实施例A356
Figure PCTCN2021080167-appb-000508
LCMS([M+H] +):1043.1
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.70(t,J＝5.9Hz,1H),8.66(s,1H),8.29(s,2H),8.14–8.07(m,3H),7.95(dd,J＝8.5,2.1Hz,1H),7.41(d,J＝9.0Hz,5H),7.06(d,J＝8.7Hz,2H),5.47(d,J＝7.2Hz,1H),4.53(d,J＝9.2Hz,1H),4.41(dt,J＝14.7,7.4Hz,2H),4.33–4.20(m,2H),4.09(s,2H),3.95(d,J＝3.7Hz,2H),3.89(dd,J＝10.0,5.7Hz,1H),3.56(s,2H),3.47(dd,J＝9.9,5.4Hz,1H),2.43(s,3H),2.40–2.31(m,1H),1.87–1.80(m,2H),1.77–1.70(m,3H),1.59(s,6H),0.96(s,9H).
实施例A357
Figure PCTCN2021080167-appb-000509
LCMS([M+H] +):1040.1
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝8.3Hz,1H),8.66–8.56(m,2H),8.52(s,1H),8.49(s,1H),8.30–8.19(m,2H),7.95(d,J＝8.6Hz,2H),7.48(d,J＝9.4Hz,1H),7.40(s,4H),7.35(d,J＝8.6Hz,2H),5.18(d,J＝3.4Hz,1H),4.58(d,J＝9.5Hz,1H),4.49–4.22(m,4H),3.95(d,J＝12.1Hz,2H),3.64(dd,J＝22.9,8.9Hz,2H),3.56(t,J＝6.2Hz,2H),2.44(s,3H),2.11–1.88(m,2H),1.84(dd,J＝15.5,9.0Hz,2H),1.58(d,J＝4.2Hz,6H),1.24(s,2H),0.94(s,9H).
实施例A358
Figure PCTCN2021080167-appb-000510
LCMS([M+H] +):1090.2
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.60(d,J＝17.4Hz,2H),8.32–8.19(m,3H),8.06(s,1H),7.94(d,J＝8.6Hz,2H),7.49(d,J＝9.8Hz,1H),7.40(s,6H),5.18(s,1H),4.58(d,J＝9.5Hz,1H),4.49–4.20(m,4H),3.97(s,2H),3.56(s,4H),2.44(s,3H),2.00(d,J＝52.2Hz,2H),1.82(s,2H),1.57(s,6H),1.24(s,2H),0.94(s,9H).
实施例A359
Figure PCTCN2021080167-appb-000511
LCMS([M+H] +):1077.3
1HNMR(400MHz,DMSO-d6)δ8.99(m,1H),8.60(t,J＝6.0Hz,1H),8.53(s,1H),8.26(s,3H),7.84(dd,J＝21.0,8.9Hz,3H),7.41(s,4H),6.99(d,J＝8.7Hz,2H),5.17(m,1H),4.76(m,1H),4.55(m,2H),4.43(m,3H),4.25(m,1H),4.20–4.11(m,2H),3.79–3.69(m,4H),3.65(m,2H),2.45(m,3H),2.05(dd,J＝13.6,7.6Hz,3H),1.92(m,1H),1.57(d,J＝4.9Hz,6H),1.02(s,9H).
实施例A360
Figure PCTCN2021080167-appb-000512
LCMS([M+H] +):1029.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.60(t,J＝5.9Hz,1H),8.25(dd,J＝22.4,3.1Hz,3H),7.91–7.73(m,4H),7.48–7.35(m,4H),7.00(dd,J＝8.7,3.5Hz,3H),5.17(m,1H),4.76(m,1H),4.51–4.33(m,5H),4.30–4.21(m,1H),4.21–4.13(m,2H),3.76(m,4H),3.65(m,2H),2.45(d,J＝5.9Hz,3H),2.11–1.97(m,3H),1.92(m,1H),1.53(s,6H),1.01(d,J＝11.9Hz,9H).
实施例A361
Figure PCTCN2021080167-appb-000513
LCMS([M+H] +):1075.4
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.60(t,J＝6.0Hz,1H),8.26–8.23(m,2H),8.08(d,J＝1.9Hz,1H),7.97(dd,J＝10.7,1.9Hz,1H),7.86(d,J＝8.7Hz,2H),7.79(d,J＝9.0Hz,1H),7.46–7.37(m,4H),6.97(d,J＝8.7Hz,2H),5.17(d,J＝3.5Hz,1H),4.75(d,J＝9.1Hz,1H),4.47–4.37(m,5H),4.24(dd,J＝15.8,5.5Hz,1H),4.04(t,J＝6.3Hz,2H),3.72(s,2H),2.45–2.43(m,3H),2.03(d,J＝8.0Hz,1H),1.96–1.87(m,1H),1.81–1.76(m,4H),1.58–1.46(m,10H),1.02–0.99(m,9H).
实施例A362
Figure PCTCN2021080167-appb-000514
LCMS([M+H] +):1125.4
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.60(t,J＝6.0Hz,1H),8.52(d,J＝2.0Hz,1H),8.32–8.20(m,3H),7.87–7.78(m,3H),7.46–7.36(m,4H),6.96(d,J＝8.8Hz,2H),5.16(d,J＝3.5Hz,1H),4.75(d,J＝9.1Hz,1H),4.50–4.37(m,5H),4.24(dd,J＝15.7,5.5Hz,1H),4.03(t,J＝6.3Hz,2H),3.72(s,2H),2.44–2.43(m,3H),2.03(d,J＝8.0Hz,1H),1.91(ddd,J＝12.7,8.6,4.5Hz,1H),1.80–1.75(m,4H),1.56(d,J＝4.7Hz,6H),1.50(m,4H),1.02–0.99(m,9H).
二、 生物学活性测定：
活性测定实施例1：化合物对LNCaP细胞AR表达的影响
1.细胞株与细胞培养
人前列腺癌细胞LNCaP(上海中科院细胞库)。LNCaP培养于含10％胎牛血清的1640培养液中。细胞贴壁成簇生长，与底物贴附力弱，增殖慢，倍增时间为72h，细胞间粘连紧密，需用含0.025％EDTA的0.05％胰酶消化。每3天传代1次。细胞培养于37℃恒温，体积分数为0.05的CO 2，饱和湿度的培养箱中。
2.细胞铺板：取对数生长期的细胞Lncap，倒掉上清，PBS洗一遍，加入适当0.05％胰酶消化液充分消化成单细胞悬液，离心重悬计数使细胞量约为每孔15000个，接种于96孔板，放置于37℃，5％CO 2过夜培养24h。
3.化合物溶液的制备与加入
各称取化合物约2mg，用DMSO溶解，使其母液浓度为10mmol/L。稀释过程(终浓度稀释为：2，0.667，0.222，0.074，0.0245，0.008，0.003，0.001，0.0003，0.0001μmol/L)：取10个1.5mL离心管，编号分别为1、2、3、4、5、6、7、8、9、10，在1号管中加入80μLDMSO，在2到10号管中加入60μLDMSO，从母液中吸取20μL到1号管中，混匀；从1号管中吸取30μL到2号管中，混匀。从2号管中吸取30μL到3号管中，混匀，以此类推，获得4-10号样品，分别得到各不同浓度的化合物的工作液。分别从上述1-10号管中吸取2μL到各对应的无菌深孔板，加198μL培养液，混匀。每孔加入11ul至过夜培养的96孔细胞板中，即获得相对应的所需浓度(2，0.667，0.222，0.074，0.0245，0.008，0.003，0.001，0.0003，0.0001μmol/L)。
4.ELISA法测药物对细胞表达AR的影响
药物作用24h后，吸掉上清，加200μLPBS洗涤，再吸掉上清，加100μL细胞裂解液冰上裂解20min,4℃、4000转/min离心20min，取上清待用。上清检测步骤按ELISA试剂盒说明书：
4.1从已平衡至室温的密封袋中取出试验所需板条，未用的板条和干燥剂请放回铝箔袋内压实自封条，密封口袋，放回4℃。
4.2空白孔加标准品和标本稀释液，其余相应孔中加不同浓度标准品(10ul/孔)以及样品稀释液(90ul/孔)用封板胶纸封住反应孔，4℃冷藏过夜。
4.3每孔加一抗稀释液(100ul/孔)。用封板胶纸封住反应孔，37℃孵箱孵育60min。
4.4每孔加二抗稀释液(100ul/孔)。用封板胶纸封住反应孔，37℃孵箱孵育30min。
4.5加入显色底物(TMB)100ul/孔，室温孵育30min。
4.6加入终止液100ul/孔,混匀后酶标仪测量OD450值。
5.结果分析
试验结果所得到的数据OD Tsample，不加细胞的培养基组为空白组OD Blank，只加DMSO不加药的细胞组为对照组OD Control。抑制率inhi％＝(1-(OD Tsample-OD Blank)/(OD Control-OD Blank))*100％，通过XLFit软件计算出化合物的DC 50值，具体结果见表1
表1：化合物对LNCaP细胞的DC 50值
Figure PCTCN2021080167-appb-000515
Figure PCTCN2021080167-appb-000516
Figure PCTCN2021080167-appb-000517
以上结果表明，本发明提供的化合物对LNCaP细胞具有很好的增殖抑制作用，说明本发明化合物具备成为抗肿瘤药物，特别是前列腺癌的治疗药物。
活性测定实施例2：Western blot试验
1.细胞处理
Lncap细胞在指数生长期时，消化细胞后将细胞铺板至6孔板中，每孔1×10 6个细胞，细胞贴壁生长一天后，加药物培养，药物处理24h后提取蛋白质。
2.细胞蛋白质提取
6孔板中细胞去除培养基，用PBS洗一遍后用胰酶将细胞消化后分别离心收集于1.5mL离心管中，每管中加入100μLRIPA裂解液(含100μMPMSF)，充分混合后冰上静置30min，之后用离心机4℃12000rpm离心20min，取上清用于WB实验，样品可放于-80℃保存。
3蛋白质浓度测定
使用BCA蛋白浓度测定试剂盒，按照下表配制BSA标准测定溶液和待测样品(待测样品可稀释后检测)，使用96孔板加样，各孔用PBS补足至20μl后，分别加入200μlBCA工作液(按试剂盒配制)，混匀后于60℃放置10min后于562nm处检测吸光度，记录读数后以标准品浓度梯度作标准曲线，代入样品吸光度计算样品蛋白质浓度。
4Westernbloting实验标准流程
4.1蛋白质变性：取蛋白裂解液，加入5×LoadingBuffer，100℃变性5min。
4.2上样及电泳：使用10％预制胶及专用电泳液，每孔上样同质量蛋白样品及蛋白marker后，200V电泳30min。
4.3封闭：将胶取下后切下多余部分，通过湿转法转移到PVDF膜上(PVDF膜需要先用甲醇活化1min后使用)，300mA，2h，转膜过程中大量产热，需要用冰盒降温。
4.4封闭：将转膜结束的PVDF膜放于5％脱脂牛奶中室温摇晃封闭1h。
4.5孵育一抗：将PVDF膜按照marker上指示分子量大小分别剪开，分别置于AR和GAPDH一抗中，抗体按照1:1000比例用TBST稀释，4℃摇床封闭过夜。
4.6孵育二抗：孵育一抗后的PVDF膜在摇床上用TBST清洗3次，每次10min，清洗后将膜分别置于对应种属二抗中，摇床振荡室温孵育2h。
4.7洗膜及曝光：孵育二抗结束后将膜放于TBST中摇床振荡清洗3次，每次10min，洗膜后使用ECL法激发膜上荧光。
所得实验结果见图1，其表明本发明提供的化合物对LNCaP细胞AR蛋白具有很好的降解作用，说明本发明化合物具备成为抗肿瘤药物，特别是前列腺癌的治疗药物。
活性测定实施例3：化合物在小鼠中的药代动力学研究
1.实验设计
本次试验选用3只雄性小鼠，分成1组，3只/组。给药前所有动物禁食过夜。
2.实验方法
2.1给药剂量
灌胃给药剂量为10mg/kg，给药体积为10mL/kg。
2.2药液配制
根据动物体重结合给药剂量先算得所需给药溶液的量，称取适量的供试品，先加最终体积的5％的乙醇溶解，再加最终体积5％的SolutolHS15，最后加PBS到目标体积，涡旋混匀充分溶解得到灌胃给药溶液(1mg/mL)，所有溶液现配现用。
2.3给药方法
给药前，将药液放置在动物实验室的磁力搅拌器上搅拌，至少10min。给药过程中，继续保持涡旋状态，确保药液均匀。灌胃给药理论给药体积为10mL/kg，使用配有灌胃针头的注射器给药。
给药前动物称量并记录参与实验的动物体重，根据体重计算每只动物的给药体积。给药结束后，迅速将动物转移回实验笼具内收集样品。
2.4动物状态观察
给药后立即观察动物有无异常反应，若无异常反应，则实验期间每天观察动物两次，若发现有异常反应，应及时记录并增加观察次数直至动物恢复正常或实验结束。
2.5样品采集和保存
所有实验动物给药前禁食过夜，给药后于相应时间点采血至含有肝素钠抗凝剂的采血管中，采集全血后，立即轻轻晃动采血管并置于冰上，然后离心(4℃、4000rpm，10min)，收集上清血浆样品，分析前置于约-80℃冰箱保存。
2.6血浆样品处理和分析
采集得到的血浆样品交由药代部进行样品提取处理，采用含有内标的有机试剂进行蛋白沉淀法提取血浆中的受试物(乙腈：血浆＝4:1,v/v)，提取处理后的样品交由LC-MS/MS进行定量浓度分析。根据分析得到的每只动物的血药浓度，采用Kinetica软件(version5.0)按照非房室模型计算主要的药动学参数eAUC 30-120用以评估暴露量；试验结果见表2：
表2：本发明化合物在小鼠中的药代动力学参数
Figure PCTCN2021080167-appb-000518
Figure PCTCN2021080167-appb-000519
活性测定实施例4：化合物对LNCaP小鼠移植瘤的PK/PD实验研究
1.实验材料
1.1受试样品
称取以上化合物于2.5mL离心管中，加入终体积5％EtOH,5％solutolHSinPBS配。配制终浓度为5mg/mL。
1.2肿瘤细胞
LNCaP细胞购自中国科学院上海生命科学研究院，培养在含10％胎牛血清的RPMI-1640培养液中。细胞生长至80～90％融合，约2-3天传代，细胞生长至足够数量后接种SCID小鼠。
1.3实验动物
SCID小鼠，雄性，6-7w，21只，购自北京维通利华股份公司。小鼠饲养于苏州康迈博诊断科技有限公司SPF级动物房，温度20～25℃，湿度40％～70％，每日光照/黑暗各12小时。动物分笼饲养，每笼5只，可自由摄食饮水， 饲料辐照灭菌，水为高压灭菌。
2.研究方法
2.1肿瘤模型构建
体外培养LNCaP细胞至足够量，胰酶消化离心，预冷的PBS重悬后再离心。加入适量预冷的PBS和基质胶调整细胞浓度至7.5×10 7个/mL。预冷的1mL注射器吸取细胞悬液，注射至裸鼠右侧背部皮下，成规则的小丘形，每只0.2mL，即1.5×10 7个/只。
2.2分组与给药方案
接种肿瘤细胞后，观察肿瘤大小。待肿瘤增长至200mm 3左右，选取形状良好，肿瘤大小合适的老鼠按照肿瘤体积进行系统随机分组。从裸鼠肿瘤模型中选取若干小鼠，每组3只，通过口服给予化合物，给药3天结束后取肿瘤检测AR的表达情况。
2.3血浆化合物浓度检测
血液采集：给药前、给药后3天后采集2小时血样检测药物浓度。收集血样于小鼠眼眶后静脉丛取血30μL(血浆)至肝素化离心管中，然后在4℃、4000rpm条件下离心10min后转移上层血浆，-80℃保存。
所得实验结果见图2。
活性测定实施例5：激素依赖性的前列腺癌症长期药效试验
1.肿瘤模型构建
1.5*10^7LNCaP(人前列腺癌)购自中国科学院细胞库，培养在含10％胎牛血清的RPMI-1640培养液中。细胞生长至80～90％融合，约4-5天传代，细胞生长至足够数量后接种裸鼠。
2.实验动物
SCID裸小鼠，6～7周龄，18-20g，购自北京维通利华有限责任公司。小鼠饲养于SPF级动物房，温度20～25℃，湿度40％～70％，每日光照/黑暗各12小时。动物分笼饲养，每笼5只，可自由摄食饮水，饲料辐照灭菌，水为高压灭菌。饲养至10～11周龄时分组实验。将LNCaP肿瘤细胞直接接种于裸鼠右侧后背。
3.分组与给药方案设计
在平均肿瘤体积达到200-300mm 3时，选取形状良好的肿瘤按照肿瘤体积进行随机数字分组，并标记入选动物,分成5个组，每组5只。给药溶媒：5％EtOH,5％solutolHS15inPBS。灌胃相应剂量的化合物。
4.统计分析
数据均以均值±标准差(Mean±SD)表示。统计采用单因素多水平方差分析，各用药组与模型组的比较采用Stundent’st或秩和检验，计算p值，p<0.05为两组间有显著性差异,化合物A88的肿瘤生长抑制率(TGI)结果如表3。
表3：化合物A88的肿瘤生长抑制率
给药剂量 3天 7天 10天 14天
10mpk 19.81％ 38.44％ 31.33％ 13.15％
25mpk 14.98％ 36.36％ 37.51％ 24.68％
50mpk 22.30％ 51.85％ 42.62％ 24.47％
活性测定实施例6：利用ELISA方法检测化合物对前列腺癌细胞株Lncap中AR蛋白活性的降解作用。
1、试验材料
LNCaP：1.5*10^7LNCaP(人前列腺癌)购自中国科学院细胞库，培养在含10％胎牛血清的RPMI-1640培养液中。在条件为37℃，5％饱和湿度的CO 2培养箱中常规培养Lncap细胞。待培养至覆盖率达80％左右时，按照1:3比例传代。
ELISA试剂盒：TotalAndrogenReceptorSandwichELISAKit(品牌CST，货号#12850)。
2、试验方法
2.1细胞铺板
细胞离心后用新鲜培养基稀释至1.5×10 4个/100ul,铺到96孔板中，每孔100ul。
2.2细胞加药
受试化合物配制:称取化合物，用DMSO稀释化合物浓度为10mM储液备用。根据实验需求，将药物由2uM起三倍稀释10个浓度梯度，最终向每孔加入2μl药物，空白对照组加入2μlDMSO。
2.3 24小时后，除去培养基，并用冰冷的1XPBS冲洗细胞一次。除去PBS， 向每个孔板中加入0.5ml冰冷的1XCellLysisBuffer加上1mMPMSF，并在冰上孵育20分钟。4000RPM4℃离心10min后备用。
2.4 ELISAkit中试剂及抗体准备
微孔板：使用前将其全部置于室温下。
检测抗体：冻干，呈绿色蛋糕或粉末状。加入1.0ml的检测抗体稀释剂(绿色溶液)以产生浓缩的原液。在室温下孵育5min，偶尔轻轻混匀以完全溶解。要制成最终的工作溶液，请在干净的试管中将全部1.0ml体积的重构检测抗体添加到10.0ml检测抗体稀释剂中，然后轻轻混合。
HRP抗体：冻干，呈红色蛋糕或粉末状。加入1.0mlHRP稀释剂(红色溶液)以产生浓缩的储备溶液。在室温下孵育5min，偶尔轻轻混匀以完全溶解。要制成最终的工作溶液，请在干净的试管中将完整的1.0ml体积的重组HRP-LinkedAntibody加入10.0mlHRPDiluent中。
检测抗体稀释剂：绿色稀释剂，用于重组和稀释检测抗体
HRP稀释剂：红色稀释剂，用于重组和稀释HRP连接的抗体
样品稀释液：蓝色稀释液，用于稀释细胞裂解液。
1X洗涤缓冲液：通过在纯净水中稀释20X洗涤缓冲液
3.5 ELISA
3.5.1将准备好的细胞裂解液20μl加到适当的孔中，并加入70ul抗体稀释剂，用胶带密封并用力压在微孔的顶部。在37℃下孵育平板2h。
3.5.2轻轻撕下胶带并清洗孔：将板内容物丢弃到容器中。用1X洗涤缓冲液洗涤4次，每孔每次200μl。每次清洗时，请用足够强度的新鲜毛巾敲打板，以除去每个孔中的残留溶液，但不要让孔在任何时候完全干燥。用不起毛的纸巾清洁所有孔的底部。
3.5.3向每个孔中添加100μl重构的检测抗体(绿色)。用胶带密封并在37℃下孵育平板1h。
3.5.4重复洗涤程序
3.5.5向每个孔中添加100μl重构的HRP-Linked二抗(红色)用胶带密封并在37℃下将板孵育30min。
3.5.6重复洗涤程序
3.5.7向每个孔中添加100μlTMB底物。用胶带密封，然后将板在37℃ 下孵育10min或在25℃下孵育30min。
3.5.8向每个孔中添加100μlSTOP溶液。轻轻摇动几秒钟。酶标仪读取450nm的吸光度。
4.试验结果
采用化合物A46作为受试化合物，其对Lncap细胞株中的AR蛋白的抑制率随浓度变化的结果，表明该化合物对AR活性有良好抑制作用，并且经该组数据统计可得A46化合物的IC50(抑制率为50％时的药物浓度)为49nM。
活性测试实施例7：化合物对雌性金黄地鼠痤疮的体内药效
1、试验目的：金黄地鼠侧腹皮脂腺斑是雄性激素依赖器官，丙酸睾酮(雄性激素)促使皮脂腺增大。本实验主要为了研究CB-03-01(阳性药物)，Flutamide(阳性药物)，化合物在雌性金黄地鼠痤疮模型(雄性激素依赖)中对皮脂腺增大的抑制作用，来进一步观察化合物的体内药效，为针对由雄激素引起的痤疮症状临床试验提供依据。
2、试验材料：
2.1供试品
雄激素(丙酸睾酮-TP)；CB-03-01(Clascoterone，CAS号19608-29-8)；Flutamide(氟他胺，CAS号13311-84-7)；本发明化合物A46。
2.2试验动物，详见表4
表4试验动物信息
品系种属： 金黄地鼠
动物等级： 清洁级
性别和数量 a： 雌性，72只
鼠龄(体重) b： 7-8周，90-110g
动物来源： 北京维通利华实验动物技术有限公司
动物识别： 苦味酸标记
2.3给药溶媒：丙酮。
3.试验设计
本次实验从72只雌性金黄地鼠中，按照皮脂腺大小和体重，将金黄地鼠平均分配到各组，6只/每组，共7组，连续给药21天。具体动物分组，给药方案等信息详见下表5：
表5试验分组及其给药方案
Figure PCTCN2021080167-appb-000520
注：TP代表丙酸睾酮。
按照表格中方案，每次给药25μL，均匀涂抹皮脂腺，每天给药一次。
动物分组与状态观察：分组前，称体重，并将两侧皮脂腺处进行剃毛，观察皮脂腺大小。给药后及给药期间内每天上下午观察动物两次。给药后第21天，观察记录皮脂腺大小及动物体重。
皮脂腺的大小即是其面积，游标卡尺记录其长边(a)和短边(b)，根据长方形面积计算公式得皮脂腺的面积(S)，造模组及给药组的Δ S＝S-S(vehicle)。生长抑制率(％)＝(ΔS(丙酮睾酮组)-ΔS(给药组))/ΔS(丙酮睾酮组)*100％。
4.试验结果
4.1对雌性金黄地鼠皮脂腺斑生长的抑制作用
试验结果如图3所示，由图3实验结果可以看出，丙酸睾酮(TP)涂抹21天后，雌性金黄地鼠的皮脂腺斑明显变大，面积达到了40-50mm 2。各组给药后，与建模组比较，阳性药物CB-03-01(400μg，1.6％)，Flutamide(400μg，1.6％)组的皮脂腺斑生长抑制率分别为69.53％(p<0.001)，40.74％(P<0.01)。A46药物100μg(0.4％)剂量组的皮脂腺斑生长抑制率为19.24％(P>0.05)，未表现出明显的抑制作用。A46的200μg(0.8％),400μg(1.6％)和800μg(3.2％)剂量组皮脂腺斑生长抑制率分别为35.20％(P<0.01)，49.54％(p<0.001)，51.61％(P<0.001),与建模组相比较，具有统计性差异。在A46设定为0.4％，0.8％，1.6％，3.2％剂量中，与建模组相比较痤疮药效时，0.8％剂量开始起效有统计性差异。与阳性药物比较，A46药物400μg(1.6％)和800μg(3.2％)剂量在抑制皮脂腺斑面积作用上均优于药物Flutamide(400μg，1.6％)。
A46化合物给药21天后对雄性激素引起的金黄地鼠皮脂腺斑面积增大的抑制作用，如下表6所示：
表6化合物对金黄地鼠皮脂腺斑生长抑制率
Figure PCTCN2021080167-appb-000521
Figure PCTCN2021080167-appb-000522
4.2对雌性金黄地鼠体重的影响作用
实验开始前，各组金黄地鼠的体重没有显著性差异。实验开始后，各组体重呈缓慢增长趋势，在实验21天，各组地鼠体重均无显著性差异。说明全部受试物在所设定的浓度下经皮给药不会对小鼠的体重产生明显影响(如图4所示)。
活性测定实施例8：化合物对C57小鼠雄激素脱发模型的毛发再生作用
1、试验目的
本研究的目的是通过经皮肤涂抹给药途径，在C57BL/6J小鼠体内对比本发明制备的化合物作为AR蛋白降解剂对雄激素脱发模型的毛发再生作用，为后续临床实验提供数据支持。
2.试验原理
用脱毛膏将小鼠进行脱毛后，皮下注射一定剂量的二氢睾酮(DHT)溶液，可以导致小鼠的毛发再生延迟，用来模拟AR介导的雄激素脱发模型。本发明化合物做为一种AR蛋白的降解剂，对AR介导的雄激素脱发模型的毛发生长促进作用可以一定程度的反映其疗效优劣。
3、受试化合物
受试化合物I名称：二羟睾酮DHT；受试化合物II名称：本发明化合物 A46；受试化合物III名称：米诺地尔。
4、试验动物：品系：C57BL/6N小鼠；年龄：6-7周；性别：雄性；动物数量：70只(10只备用)；饲养环境：无特定病原体(SpecificpathogenFree,SPF)。
5.实验设计
5.1模型建立
将70只小鼠深度麻醉，先用动物剃毛器将小鼠背部毛发剔除，然后将脱毛膏(Veethttps://item.jd.com/6291245.html)在小鼠皮肤表面涂抹均匀，静置7-10分钟后用脱毛刮逆毛方向轻轻将毛刮干净，最后用清水充分洗净皮肤表面残留的脱毛膏，避免其灼伤小鼠皮肤。
5.2分组
本次实验共分6组，DHT给药开始时间为脱毛当天，A46给药时间为脱毛后第2天，计为第1天(脱毛当天计为第0天)。随机选取36只状态良好的小鼠分组如下表7：
表7小鼠分组及其给药方案
Figure PCTCN2021080167-appb-000523
Figure PCTCN2021080167-appb-000524
5.3受试化合物配置方法
药物配制方法及保存条件如下表8所示；
表8受试药物配置方法
Figure PCTCN2021080167-appb-000525
5.4观察检测指标
1)体重/g：从第一天给药开始，每周称量并记录两次体重。
2)发再生(anagen)评分(0分：所有区域未见肤色转黑；1分：灰色肤色区域转黑；2分：可见短毛；3分：毛发稀疏；4分：毛发浓密；5分：毛发完全生长)。
在剃毛后第1天对所有小鼠进行拍照，然后从第4天开始每天对小鼠进行拍照和评分，直至实验终点。
3)实验结束时按需进行取皮取血操作。
5.5停药及实验终止标准
在发生以下情况时，单只动物或者整组动物的在体实验部分将被终止。动物将在死亡或者昏迷前被安乐死。
当动物健康状况持续恶化，动物连续遭受痛苦，无法饮食或饮水；或当动物消瘦，体重下降超过20％时。
5.6统计分析
数据均以均值±标准误(AVE±SEM)表示。统计采用单因素多水平方差分析，各用药组与模型组的比较采用Stundent’st或秩和检验，计算p值，p<0.05为两组间有显著性差异,p<0.01为两组间有极显著性差异。
6.实验结果
本实验共设6个组，分别是Vehicle、DHT(30mg/kg)浓度组、DHT(30mg/kg)+米诺地尔5％浓度组、DHT(30mg/kg)+A46 0.5％浓度组、DHT(30mg/kg)+A46 1％浓度组和DHT(30mg/kg)+A463％浓度组。对C57小鼠雄激素脱发模型的毛发再生作用结果见下表9所示：
表9对C57小鼠雄激素脱发模型的毛发再生作用(AVER，n＝6)
Figure PCTCN2021080167-appb-000526
Figure PCTCN2021080167-appb-000527
从结果中可以看出，DHT(30mg/kg)浓度组在给药17天后毛发发育的评分为0.5，几乎没有毛发的发育，显著地低于Vehicle组，显示造模成功。DHT(30mg/kg)+米诺地尔5％浓度组的评分均值为2.33，显著地高于DHT(30mg/kg)模型组，展现了良好的生发效果。DHT(30mg/kg)+A460.5％浓度组与造模组DHT(二氢睾酮)组相比评分略高，但并无统计性差异。A461％浓度剂量与3％浓度剂量组在Day17时的评分与5％米诺地尔组大致相当，且分值与DHT(二氢睾酮)组，具有显著差异(p<0.05；p<0.01)。
(2)体重变化
小鼠体重的变化在整个给药期间结果如图5所示，由图可以看出，在整个给药期间，所有受试物组及溶剂对照组的体重均保持平稳且略有上升，说明全部受试物在所设定的浓度下经皮给药不会对小鼠的体重产生影响。
活性测试测试实施例8：化合物与阳性对照化合物在LNCaP细胞AR蛋白降解作用的比对
1、实验材料
LNCaP：LNCaP(人前列腺癌)购自中国科学院细胞库，培养在含10％胎牛血清的RPMI-1640培养液中。在条件为37℃，5％饱和湿度的CO2培养箱中常规培养Lncap细胞。待培养至覆盖率达80％左右时，按照1:3比例传代。
2、实验试剂
Figure PCTCN2021080167-appb-000528
Figure PCTCN2021080167-appb-000529
注：ARD-69制备参考J.Med.Chem.2019,62,2,941–964中教导完成。
3.使用仪器
使用仪器 型号
酶标仪 BioTek Synergy H1 Hybird reader
化学发光凝胶成像仪 AllianceQ9 Advance
4.Western blot步骤
4.1细胞培养：
取液氮罐冻存的Lncap，细胞复苏培养至生长对数期，将其铺6至孔板中 (每孔约10^6个细胞)，加药物处理。
4.2药物处理
称取适量的化合物溶于DMSO溶剂中，涡旋混匀，配置成10mM的储存溶液，分别加药作用Lncap细胞，control组为只加DMSO处理，药物处理组分别加入对应的化合物处理，其作用的终浓度分别为50nM和200nM,阳性对照组ARD-69的作用浓度为100nM。24h后收集细胞。
4.3收集细胞
取出经化合物作用后的细胞六孔板及其他未加药细胞系，弃去培养基，PBS洗涤，胰酶消化，终止，吹打，离心，PBS再次洗涤，完全弃去PBS。
4.4裂解细胞收集蛋白
收集的细胞加入适量的裂解液(裂解液中加入蛋白酶体抑制剂PMSF)，冰上裂解30min，12000rpm离心20min，取上清。
4.5 BCA法测定蛋白总量
①配制梯度浓度的标准蛋白，取20μL于96孔板中，每个标准品做一个复孔；
②取2μL蛋白裂解液溶于18μL的PBS中，每个样品做一个复孔；
③每个孔加200μL的BCA工作液，37℃孵育30min；
④测定562nm吸光度；
⑤计算每个样品的蛋白浓度，计算50μg所需的蛋白裂解液体积。
4.6 Western blot检测蛋白表达水平
变性：取蛋白裂解液，加入适量的5×蛋白上样缓冲液，100℃变性5min。
电泳：使用10％预制胶电泳200V 30min；
转膜：切去浓缩胶，将分离胶上的蛋白通过湿转法转移到PVDF膜上,270mA，2h。
封闭：将PVDF膜置于5％的脱脂牛奶中室温封闭1h。
一抗：将PVDF膜按Mark的分子量大小剪开，分别置于AR和β-Actin抗体中，4℃摇床孵育过夜。
洗膜：将PVDF膜置于PBST中，摇床振荡清洗4次，每次6min。
二抗：将PVDF膜置于AR和β-Actin抗体对应的二抗(山羊抗兔和山羊抗鼠)溶液中，摇床振荡室温孵育1～2h。
洗膜：将PVDF膜置于PBST中，摇床振荡清洗4次，每次6min。
曝光：显影液激发PVDF上的荧光。
所得实验结果见图6-17，其表明本发明提供的化合物对LNCaP细胞AR蛋白具有很好的降解作用(基本达到或优于ARD-69的降解作用效果)，说明本发明化合物具备成为抗肿瘤药物，特别是前列腺癌的治疗药物。
本发明内容仅仅举例说明了要求保护的一些具体实施方案，其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合，这些经组合而得到的技术方案也在本申请保护范围内，就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。

Claims (64)

  1. 式(I)所示的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药：
    ABM-L-ULM(I)，
    其中ABM具有式(IV)结构，其中
    Figure PCTCN2021080167-appb-100001
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100002
    Z 1选自：氢、卤素、氰基、任选地被一个或更多个卤素所取代的C 1-4烷基和任选地被一个或更多个卤素所取代的C 1-4烷氧基；
    X选自：卤素、羟基、氰基和任选地被一个或更多个卤素所取代的C 1-4烷氧基；
    Y 1、Y 2各自独立地选自：O、S；
    R 1、R 2各自独立地选自：H、卤素、任选被卤素、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，或R 1、R 2连同它们所连接的原子一起形成含有0到2个杂原子的3到8元环；
    W 1选自：化学键，C 6-10芳基，5-10元杂芳基、联C 6-10芳基或联5-10元杂芳基，各自任选地被1-10个R W1取代；
    每个R W1独立地选自：H、卤基、氰基、羟基、胺基、-COOR W11、-CONR W11R W12、任选被卤素、羟基、氰基、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，C 3-6环烷基、C 4-6环杂烷基、C 6-10芳基或5-10元杂芳基；R W11和R W12各自独立地选自：氢、任选被卤素取代的C 1-6烷基或C 3-6环烷基；
    L是连接ABM和ULM的化学连接部分；
    ULM是羟脑苷脂E3泛素连接酶结合部分(CLM)或VHLE3连接酶结合部分(VLM)。
  2. 式(I)所示的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药：
    ABM-L-ULM(I)，
    其中ABM具有式(IV)结构，其中
    Figure PCTCN2021080167-appb-100003
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100004
    Z 1选自：氢、卤素、氰基、任选地被一个或更多个卤素所取代的C 1-4烷基和任选地被一个或更多个卤素所取代的C 1-4烷氧基；
    X选自：卤素、羟基、氰基和任选地被一个或更多个卤素所取代的C 1-4烷氧基；
    Y 1、Y 2各自独立地选自：O、S；
    R 1、R 2各自独立地选自：H、卤素、任选被卤素、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，或R 1、R 2连同它们所连接的原子一起形成含有0到2个杂原子的3到8元环；
    W 1选自：化学键，C 6-10芳基，5-10元杂芳基、联C 6-10芳基或联5-10元杂芳基，各自任选地被1-10个R W1取代；
    每个R W1独立地选自：H、卤基、氰基、羟基、胺基、任选被卤素、羟基、氰基、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，C 3-6环烷基、C 4-6环杂烷基、C 6-10芳基或5-10元杂芳基；
    L是连接ABM和ULM的化学连接部分；
    ULM是羟脑苷脂E3泛素连接酶结合部分(CLM)或VHLE3连接酶结合部分(VLM)。
  3. 根据权利要求1或2所述的双官能化合物，其中Z 1选自卤素、氰基、甲基、CH 2F、CHF 2、CF 3、甲氧基和CF 3O；
    X选自：卤素、羟基、氰基、C 1-3烷氧基和CF 3O；
    Y 1、Y 2各自独立地选自：O、S；
    R 1、R 2各自独立地选自：任选被卤素、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，或R 1、R 2连同它们所连接的原子一起形成C 3-6环烷基；
    W 1选自：化学键，C 6-10芳基，5-10元杂芳基、联C 6-10芳基或联5-10元杂芳基，各自任选地被1、2或3个R W1取代；并且
    每个R W1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C 1-6烷基或C 1-6烷氧基。
  4. 根据前述权利要求任一项所述的双官能化合物，其中W 1选自：化学键、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基，各自任选地被1、2或3个R W1取代；并且
    每个R W1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C 1-6烷基或C 1-6烷氧基、-COOR W11、-CONR W11R W12；R W11和R W12各自独立地选自：氢、任选被卤素取代的C 1-6烷基。
  5. 根据权利要求1或2所述的双官能化合物，其中Z 1选自卤素、氰基、甲基、CH 2F、CHF 2、CF 3、甲氧基和CF 3O；
    X选自：卤素、羟基、氰基、C 1-3烷氧基和CF 3O；
    Y 1、Y 2各自独立地选自：O、S；
    R 1、R 2各自独立地选自：任选被卤素、C 1-6烷氧基取代的C 1-6烷基或C 1-6烷氧基，或R 1、R 2连同它们所连接的原子一起形成C 3-6环烷基；
    W 1选自：化学键，C 6-10芳基，5-10元杂芳基、联C 6-10芳基或联5-10元杂芳基，各自任选地被1、2或3个R W1取代；并且
    每个R W1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C 1-6烷基或C 1-6烷氧基、-COOR W11、-CONR W11R W12；R W11和R W12各自独立地选自：氢、任选被卤素取代的C 1-6烷基。
  6. 根据权利要求1或2所述的双官能化合物，其中Z 1选自：卤素、氰基、甲基、CH 2F、CHF 2、CF 3、甲氧基和CF 3O；
    X选自：卤素；
    Y 1、Y 2各自独立地选自：O、S；
    R 1、R 2各自独立地选自：甲基，或R 1、R 2连同它们所连接的原子一起形成C 3-6环烷基；
    W 1选自：化学键，
    Figure PCTCN2021080167-appb-100005
    Figure PCTCN2021080167-appb-100006
    其各自任选地被1、2或3个R W1取代；并且
    每个R W1独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基。
  7. 根据权利要求1或2所述的双官能化合物，其中Z 1选自：卤素、氰基、甲基、CH 2F、CHF 2、CF 3、甲氧基和CF 3O；
    X选自：卤素；
    Y 1、Y 2各自独立地选自：O、S；
    R 1、R 2各自独立地选自：甲基，或R 1、R 2连同它们所连接的原子一起形成C 3-6环烷基；
    W 1选自：化学键，
    Figure PCTCN2021080167-appb-100007
    Figure PCTCN2021080167-appb-100008
    其各自任选地被1、2或3个R W1取代；并且
    每个R W1独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基、-COOR W11、-CONR W11R W12；R W11和R W12各自独立地选自：氢、任选被卤素取代的C 1-6烷基。
  8. 根据权利要求1或2所述的双官能化合物，其中Z 1选自：CF 3；
    X选自：F；
    Y 1、Y 2各自独立地选自：O、S；
    R 1、R 2各自独立地选自：甲基，或R 1、R 2连同它们所连接的原子一起形成C 3-4环烷基；
    W 1选自：化学键，
    Figure PCTCN2021080167-appb-100009
    其各自任选地被1、2或3个R W1取代；并且
    每个R W1独立地选自：氢、卤基、氰基、任选被F取代的C 1-3烷基或C 1-3烷氧基。
  9. 根据权利要求1或2所述的双官能化合物，其中Z 1选自：CF 3；
    X选自：F；
    Y 1、Y 2各自独立地选自：O、S；
    R 1、R 2各自独立地选自：甲基，或R 1、R 2连同它们所连接的原子一起形成C 3-4环烷基；
    W 1选自：化学键，
    Figure PCTCN2021080167-appb-100010
    其各自任选地被1、2或3个R W1取代；并且
    每个R W1独立地选自：氢、卤基、氰基、任选被F取代的C 1-3烷基或C 1-3烷氧基、-CONH 2、-COOC 1-3烷基。
  10. 根据权利要求1或2所述的双官能化合物，其中ABM选自如下结构，其中
    Figure PCTCN2021080167-appb-100011
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100012
  11. 根据权利要求1或2所述的双官能化合物，其中ABM选自如下结构，其中
    Figure PCTCN2021080167-appb-100013
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100014
  12. 根据权利要求1或2所述的双官能化合物，其为式(II)结构的双官能化合物：
    ABM-L-CLM(II)，
    其中，ABM如权利要求1中定义；
    CLM为式(V)所示结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100015
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100016
    W选自：CH 2、CHR 11、C＝O、NH或-N-C 1-6烷基；
    每个T独立地选自：O或S；
    G选自：H、C 1-6烷基或羟基；
    Q 1、Q 2、Q 3和Q 4独立地选自：CR′或N；
    A选自：H、C 1-6烷基、C 3-6环烷基、或卤素；
    R 11选自：卤素、氰基、任选被卤素取代的C 1-6烷基或C 1-6烷氧基、C 3-6环烷基、-CONR′R″、-OR′、或-NR′R″；
    R′和R″各自独立地选自：氢、卤素、胺基、氰基、任选被卤素取代的C 1-6烷基或C 1-6烷氧基、C 3-6环烷基；
    连接基团(L)选自如下通式结构表示的基团：
    -(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
    -(CH 2) m-CO-N(R 31)-；
    -O-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -Cy-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -C≡C-Cy-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -O-(CH 2) n-N(R 31)-；
    -C≡C-(Cy) p-CO-(CH 2) o-O-；
    -O-(Cy) p-CO-(CH 2) o-O-；
    -O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
    -(CH 2) m-CO-Cy-CO-(CH 2) o-O-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-；
    -(Cy) q-O-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(Cy) q-Cy-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(Cy) q-C≡C-Cy-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(Cy) q-O-(CH 2) n-N(R 31)-；
    -(Cy) q-(Cy) q-C≡C-(Cy) p-CO-(CH 2) o-O-；
    -(Cy) q-O-(Cy) p-CO-(CH 2) o-O-；
    -(Cy) q-O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
    -(Cy) q-(CH 2) m-CO-Cy-CO-(CH 2) o-O-；
    -(CH 2) m-O-(CH 2) n-CO-N(R 31)-(CH 2) o-N(R 31)-CO-(CH 2) t-O-；
    -CO-N(R 31)-(CH 2) m-N(R 31)-(CH 2) n-CO-N(R 31)-；
    -(Cy) q-O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) t-O-；
    其中m、n、o、p、q和t各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R 31独立地选自基团H、甲基或乙基，Cy选自C 6-10芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选
    Figure PCTCN2021080167-appb-100017
    其各自任选地被1、2或3个R Cy取代；并且
    每个R Cy独立地选自：H、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基。
  13. 根据权利要求1或2所述的双官能化合物，其为式(II)结构的双官能化合物：
    ABM-L-CLM(II)，
    其中，ABM如权利要求1中定义；
    CLM为式(V)所示结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100018
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100019
    W选自：CH 2、CHR 11、C＝O、NH或-N-C 1-6烷基；
    每个T独立地选自：O或S；
    G选自：H、C 1-6烷基或羟基；
    Q 1、Q 2、Q 3和Q 4独立地选自：CR′或N；
    A选自：H、C 1-6烷基、C 3-6环烷基、或卤素；
    R 11选自：卤素、氰基、任选被卤素取代的C 1-6烷基或C 1-6烷氧基、C 3-6环烷基、-CONR′R″、-OR′、或-NR′R″；
    R′和R″各自独立地选自：氢、卤素、胺基、氰基、任选被卤素取代的C 1-6烷基或C 1-6烷氧基、C 3-6环烷基；
    连接基团(L)选自如下通式结构表示的基团：
    -(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
    -(CH 2) m-CO-N(R 31)-；
    -O-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -Cy-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -C≡C-Cy-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -O-(CH 2) n-N(R 31)-；
    -C≡C-(Cy) p-CO-(CH 2) o-O-；
    -O-(Cy) p-CO-(CH 2) o-O-；
    -O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
    -(CH 2) m-CO-Cy-CO-(CH 2) o-O-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-；
    -(Cy) q-O-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(Cy) q-Cy-CO-N(R 31)-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(Cy) q-C≡C-Cy-(CH 2) n-N(R 31)-CO-(CH 2) o-O-；
    -(Cy) q-O-(CH 2) n-N(R 31)-；
    -(Cy) q-(Cy) q-C≡C-(Cy) p-CO-(CH 2) o-O-；
    -(Cy) q-O-(Cy) p-CO-(CH 2) o-O-；
    -(Cy) q-O-(CH 2) m-CO-N(R 31)-(CH 2) n-N(R 31)-；
    -(Cy) q-(CH 2) m-CO-Cy-CO-(CH 2) o-O-；
    其中m、n、o、p和q各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R 31独立地选自基团H、甲基或乙基，Cy选自C 3-6芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选
    Figure PCTCN2021080167-appb-100020
    其各自任选地被1、 2或3个R Cy取代；并且
    每个R Cy独立地选自：H、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基。
  14. 根据权利要求12或13所述的双官能化合物，其中W选自：CH 2、CHR 11或C＝O；
    每个T独立地选自：O或S；
    G选自：氢、或C 1-6烷基；
    Q 1、Q 2、Q 3和Q 4独立地选自：CH；
    A选自：氢、C 1-6烷基或卤素；
    R 11选自：卤素、氰基、-CF 3、OCF 3、甲基、-CONR′R″、-OR′、或-NR′R″；
    R′和R″各自独立地选自：氢、卤素、氰基、胺基、-CF 3、OCF 3或甲基。
  15. 根据权利要求12或13所述的双官能化合物，其中CLM为式(V)-1所示结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100021
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100022
    其中：
    W选自：CH 2或C＝O；
    A选自：氢或C 1-6烷基。
  16. 根据权利要求12或13所述的双官能化合物，其中CLM为式(V)-2或(V)-3所示结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100023
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100024
  17. 根据权利要求12或13所述的双官能化合物，其中连接基团(L)选自如下基团：
    Figure PCTCN2021080167-appb-100025
    Figure PCTCN2021080167-appb-100026
  18. 根据权利要求12或13所述的双官能化合物，其中连接基团(L)选自如下基团：
    Figure PCTCN2021080167-appb-100027
    Figure PCTCN2021080167-appb-100028
  19. 根据权利要求1或2所述的双官能化合物，其为式(III)结构的双官能化合物：
    ABM-L-VLM(III)，
    其中，ABM如权利要求1中定义；
    VLM为式(VI)所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100029
    Y 3是NR Y3R Y4、OR Y3、SR Y3、
    Figure PCTCN2021080167-appb-100030
    R 21和R 22独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基；
    R Y3和R Y4独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、任选地被卤素、羟基、氰基取代的C 1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y3、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
    X Y3是O或S；
    R 23、R 24各自独立地选自：H、任选地被卤素、羟基、氰基取代的C 1-6烷基；
    W 2是C 6-10芳基或5-10元杂芳基；
    R 25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，6-10元杂芳基，噻吩基，或
    Figure PCTCN2021080167-appb-100031
    其中R 25a、R 25b各自独立地选自：H、任选地被卤素、羟基、氰基取代的C 1-6烷基；R 27是H、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基，且Xa是S、O或NR 28；R 28是氢、任选地被卤素取代的C 1-6烷基；所述C6-10芳基、6-10元杂芳基、噻吩基任选被一个或更多个选自氢、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、-CONHC 1-6烷基、-COOC 1-6烷基的基团取代；
    R 26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基；
    Figure PCTCN2021080167-appb-100032
    是连接基团L与上述结构式中任意一个H原子去掉后的基团相连；
    或VLM为式(VI)-4或式(VI)-5所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100033
    其中，R 21，R 22，Xa如上定义；R 27a，R 27b各自独立地选自：H、C 1-6烷基、5-10元杂芳基；
    或VLM为式(VI)-6、式(VI)-7或式(VI)-8所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100034
    其中，R 21，R 22，R 25，R 26如上定义；X V是S、O或NR 29；R 29是氢、任选地被卤素取代的C 1-6烷基；W是CH或N；
    连接基团(L)选自如下通式结构表示的基团：
    -(CH 2) m-CO-N(R 31)-(CH 2) n-CO-；
    -O-(CH 2) m-O-(CH 2) n-CO-；
    -O-(CH 2) m-CO-；
    -C≡C-(Cy) p-(CH 2) m-CO-；
    -CO-N(R 31)-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -CO-(Cy) p-(CH 2) n-CO-；
    -O-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -N(R 31)-CO-(CH 2) m-O-(CH 2) n-CO-；
    -N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
    -(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
    -(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
    -C≡C-(CH 2) m-CO-；
    -(CH 2) m-CO-N(R 31)-(CH 2) n-(Cy) p-CO-；
    -C≡C-(Cy) p-(CH 2) m-N(R 31)-CO-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-CO-；
    -(Cy) q-C≡C-(Cy) p-(CH 2) m-CO-；
    -(Cy) q-CO-N(R 31)-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -(Cy) q-CO-(Cy) p-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -(Cy) q-N(R 31)-CO-(CH 2) m-O-(CH 2) n-CO-；
    -(Cy) q-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
    -(Cy) q-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
    -(Cy) q-(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
    -(Cy) q-C≡C-(CH 2) m-CO-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-(Cy) p-CO-；
    -(Cy) q-C≡C-(Cy) p-(CH 2) m-N(R 31)-CO-；
    -O-(CH 2) m-O-(CH 2) n-；
    -CH＝CH-CO-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-N(R 31)-CO-；
    -(Cy) q-O-(Cy) p-(CH 2) m-N(R 31)-CO-；
    -(Cy) q-N(R 31)-CO-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-(Cy) p-CO-；
    -O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-O-(CH 2) t-CO-；
    -O-(Cy) q-CO-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
    -O-(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
    -O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-(Cy) q-CO-；
    -O-(CH 2) m-O-(CH 2) n-(Cy) q-CO-；
    其中m、n、o、p、q和t各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个-CH 2-中的一个或两个氢原子可以被氟原子替代，各个R 31独立地选自基团氢、甲基、乙基、或苄基，Cy选自C 6-10芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选
    Figure PCTCN2021080167-appb-100035
    Figure PCTCN2021080167-appb-100036
    Figure PCTCN2021080167-appb-100037
    其各自任选地被1、2或3个R Cy取代；并且
    每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或 C 1-3烷氧基。
  20. 根据权利要求1或2所述的双官能化合物，其为式(III)结构的双官能化合物：
    ABM-L-VLM(III)，
    其中，ABM如权利要求1中定义；
    VLM为式(VI)所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100038
    Y 3是NR Y3R Y4、OR Y3、SR Y3；
    R 21和R 22独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基；
    R Y3和R Y4独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、任选地被卤素、羟基、氰基取代的C 1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y3、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
    R 23、R 24各自独立地选自：H、任选地被卤素、羟基、氰基取代的C 1-6烷基；
    W 2是C 6-10芳基或5-10元杂芳基；
    R 25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的 C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，或
    Figure PCTCN2021080167-appb-100039
    其中R 25a、R 25b各自独立地选自：H、任选地被卤素、羟基、氰基取代的C 1-6烷基；R 27是H、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基，且Xa是S或O；
    R 26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基；
    Figure PCTCN2021080167-appb-100040
    是连接基团L与上述结构式中任意一个H原子去掉后的基团相连；
    或VLM为式(VI)-4或式(VI)-5所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100041
    其中，R 21，R 22，Xa如上定义；R 27a，R 27b各自独立地选自：H、C 1-6烷基；
    连接基团(L)选自如下通式结构表示的基团：
    -(CH 2) m-CO-N(R 31)-(CH 2) n-CO-；
    -O-(CH 2) m-O-(CH 2) n-CO-；
    -O-(CH 2) m-CO-；
    -C≡C-(Cy) p-(CH 2) m-CO-；
    -CO-N(R 31)-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -CO-(Cy) p-(CH 2) n-CO-；
    -O-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -N(R 31)-CO-(CH 2) m-O-(CH 2) n-CO-；
    -N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
    -(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
    -(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
    -C≡C-(CH 2) m-CO-；
    -(CH 2) m-CO-N(R 31)-(CH 2) n-(Cy) p-CO-；
    -C≡C-(Cy) p-(CH 2) m-N(R 31)-CO-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-CO-；
    -(Cy) q-C≡C-(Cy) p-(CH 2) m-CO-；
    -(Cy) q-CO-N(R 31)-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -(Cy) q-CO-(Cy) p-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -(Cy) q-N(R 31)-CO-(CH 2) m-O-(CH 2) n-CO-；
    -(Cy) q-N(R 31)-(CH 2) m-O-(CH 2) n-CO-；
    -(Cy) q-(CH 2) m-(Cy) p-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
    -(Cy) q-(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
    -(Cy) q-C≡C-(CH 2) m-CO-；
    -(Cy) q-(CH 2) m-CO-N(R 31)-(CH 2) n-(Cy) p-CO-；
    -(Cy) q-C≡C-(Cy) p-(CH 2) m-N(R 31)-CO-；
    其中m、n、o、p和q各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R 31独立地选自基团氢、甲基、乙基、或苄基，Cy选自C 3-6环烷基,C 3-6杂环烷基，优选
    Figure PCTCN2021080167-appb-100042
    Figure PCTCN2021080167-appb-100043
    Figure PCTCN2021080167-appb-100044
    其各自任选地被1、2或3个R Cy取代；并且
    每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基或C 1-3烷氧基。
  21. 根据权利要求19或20所述的双官能化合物，其中Y 3是NR Y3R Y4、OR Y3；
    R 21和R 22独立地选自：氢、C 1-6烷基；
    R Y3和R Y4独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y3、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
    R 23、R 24各自独立地选自：氢、C 1-6烷基；
    W 2是苯基；
    R 25是氢，卤素，C 1-6烷基，CONR 25aR 25b，或
    Figure PCTCN2021080167-appb-100045
    其中R 25a、R 25b各 自独立地选自：H、C 1-6烷基；R 27是H、C 1-6烷基，且Xa是S；
    R 26是H，C 1-6烷基。
  22. 根据权利要求19或20所述的双官能化合物，其中Y 3是NR Y3R Y4、OR Y3；
    R 21和R 22独立地选自：氢、C 1-6烷基；
    R Y3和R Y4独立地选自：氢、C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y3、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
    R 23、R 24各自独立地选自：氢、C 1-6烷基；
    W 2是苯基；
    R 25是CONR 25aR 25b，或
    Figure PCTCN2021080167-appb-100046
    其中R 25a、R 25b各自独立地选自：H、C 1-6烷基；R 27是C 1-6烷基，且Xa是S；
    R 26是氢。
  23. 根据权利要求19或20所述的双官能化合物，其中Y 3是
    Figure PCTCN2021080167-appb-100047
    R Y3选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基；
    X Y3是O或S。
  24. 根据权利要求19或20所述的双官能化合物，其中Y 3是
    Figure PCTCN2021080167-appb-100048
  25. 根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100049
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100050
  26. 根据权利要求19或20所述的双官能化合物，其中VLM为式(VI)-1所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100051
    其中，Y 3，R 21，R 23，R 25如权利要求19或20中定义。
  27. 根据权利要求19或20所述的双官能化合物，其中VLM为式(VI)-2所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100052
    Y 5是NR Y5、O；
    R 21和R 22独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、 任选地被卤素、羟基、氰基取代的C 3-6环烷基；
    R Y5是氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、任选地被卤素、羟基、氰基取代的C 1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y5、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
    R 23、R 24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；
    W 2是C 6-10芳基或5-10元杂芳基；
    R 25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基，NR 25aR 25b，CONR 25aR 25b，C 6-10芳基，或
    Figure PCTCN2021080167-appb-100053
    其中R 25a、R 25b各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；R 27是H、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基，且Xa是S或O；
    R 26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基。
  28. 根据权利要求19或20所述的双官能化合物，其中VLM为式(VI)-2所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100054
    Y 5是NR Y5、O；
    R 21和R 22独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基；
    R Y5是氢、任选地被卤素、羟基、氰基取代的C 1-6烷基、任选地被卤素、羟基、氰基取代的C 3-6环烷基、任选地被卤素、羟基、氰基取代的C 1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C 3-6环烷基-CO-；或R Y5、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
    R 23、R 24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；
    W 2是5-6元杂芳基；
    R 25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基，NR 25aR 25b，CONR 25aR 25b，C 6-10芳基，6-10元杂芳基，噻吩基，或
    Figure PCTCN2021080167-appb-100055
    其中R 25a、R 25b各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C 1-6烷基；R 27是H、卤素、任选地被卤素、羟基、氰基取代的C 1-6烷基，且Xa是S、O或NR 28；R 28是氢、任选地被卤素取代的C 1-6烷基；所述C6-10芳基、6-10元杂芳基、 噻吩基任选被一个或更多个选自氢、卤素、任选地被卤素取代的C 1-6烷基、任选地被卤素取代的C 3-6环烷基、-CONHC 1-6烷基、-COOC 1-6烷基的基团取代；
    R 26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C 1-6烷基，任选地被卤素、羟基、氰基取代的C 1-6烷氧基。
  29. 根据权利要求27所述的双官能化合物，其中Y 5是NR Y5、O；
    R 21和R 22独立地选自：氢、C 1-6烷基；
    R Y5是氢、C 1-6烷基；或R Y5、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
    R 23、R 24各自独立地选自：氢、C 1-6烷基；
    W 2是苯基；
    R 25是CONR 25aR 25b，或
    Figure PCTCN2021080167-appb-100056
    其中R 25a、R 25b各自独立地选自：H、C 1-6烷基；R 27是C 1-6烷基，且Xa是S；
    R 26是氢。
  30. 根据权利要求19-29任一项所述的双官能化合物，其中R 21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基。
  31. 根据权利要求27所述的双官能化合物，其中Y 5是NR Y5、O；
    R 21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基；
    R 22选自：氢；
    R Y5是氢、C 1-6烷基；
    R 23、R 24各自独立地选自：氢、C 1-6烷基；
    W 2是
    Figure PCTCN2021080167-appb-100057
    R 25是
    Figure PCTCN2021080167-appb-100058
    其中R 27是C 1-3烷基，且Xa是S；
    R 26是氢。
  32. 根据权利要求28所述的双官能化合物，其中Y 5是NR Y5、O；
    R 21和R 22独立地选自：氢、C 1-6烷基；
    R Y5是氢、C 1-6烷基；或R Y5、R 21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
    R 23、R 24各自独立地选自：氢、C 1-6烷基；
    W 2是噁唑基或噻唑基；
    R 25是氢；
    R 26是氢。
  33. 根据权利要求32所述的双官能化合物，其中Y 5是NR Y5、O；
    R 21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基；
    R 22选自：氢；
    R Y5是氢、C 1-6烷基；
    R 23、R 24各自独立地选自：氢、C 1-6烷基；
    W 2是噁唑基或噻唑基；
    R 25是氢；
    R 26是氢。
  34. 根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100059
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100060
  35. 根据权利要求27所述的双官能化合物，其中VLM为式(VI)-3所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100061
    其中，Y 5，R 21，R 23，R 25如权利要求27中定义。
  36. 根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100062
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100063
    Figure PCTCN2021080167-appb-100064
  37. 根据权利要求19或20所述的双官能化合物，其中所述VLM为式(VI)-5所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100065
    R 21和R 22独立地选自：氢、C 1-6烷基；
    R 27a，R 27b各自独立地选自：H、5-6元杂芳基，优选H、噻唑基。
  38. 根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100066
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100067
  39. 根据权利要求19或20所述的双官能化合物，其中所述VLM为式(VI)-61所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100068
    R 21和R 22独立地选自：氢、C 1-6烷基；
    R 29是任选地被卤素取代的C1-6烷基。
  40. 根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100069
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100070
  41. 根据权利要求19或20所述的双官能化合物，其中所述VLM为式(VI)-71或式(VI)-81所示结构片段或其立体异构体：
    Figure PCTCN2021080167-appb-100071
    R 21和R 22独立地选自：氢、C 1-6烷基；
    R 25是苯基，吡啶基，嘧啶基，噻吩基，或
    Figure PCTCN2021080167-appb-100072
    R 27是C 1-6烷基，且Xa是S、O或NR 28；R 28是C 1-6烷基；所述苯基、吡啶基、嘧啶基、噻吩基任选被一个或更多个选自卤素、C 1-6烷基、-CONHC 1-6烷基的基团取代；
    X V是S、O或NR 29；R 29是氢、C 1-6烷基；W是CH。
  42. 根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
    Figure PCTCN2021080167-appb-100073
    表示连接部分的连接点：
    Figure PCTCN2021080167-appb-100074
    Figure PCTCN2021080167-appb-100075
  43. 根据权利要求19-42任一项所述的双官能化合物，其中Cy选自C 6-10芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选苯基、吡啶基、三唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、氧代哌嗪基、四氢吡啶基、氧代二氢吡啶基、进一步优选
    Figure PCTCN2021080167-appb-100076
    Figure PCTCN2021080167-appb-100077
    Figure PCTCN2021080167-appb-100078
    其各自任选地被1、2或3个R Cy取代；并且
    每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基。
  44. 根据权利要求19或20所述的双官能化合物，其中连接基团(L)选自如下基团：
    -O-(CH 2) m-O-(CH 2) n-CO-；
    -O-(CH 2) m-CO-；
    -O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
    -(Cy) p-(CH 2) n-O-(CH 2) o-CO-；
    -(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
    -(Cy) q-O-(CH 2) m-CO-；
    -(Cy) q-O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-CO-；
    -O-(Cy) q-O-(CH 2) m-O-(CH 2) n-CO-；
    -O-(CH 2) m-O-(CH 2) n-O-(CH 2) o-(Cy) q-CO-；
    -O-(CH 2) m-O-(CH 2) n-(Cy) q-CO-；
    其中m、n和o各自独立地选自：1、2、3、4、5、6，q选自：1，Cy选自C 6-10芳基,C 3-6杂芳基，C 3-6环烷基,C 3-6杂环烷基，优选苯基、吡啶基、三唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、氧代哌嗪基、四氢吡啶基、氧代二氢吡啶基，进一步优选
    Figure PCTCN2021080167-appb-100079
    Figure PCTCN2021080167-appb-100080
    Figure PCTCN2021080167-appb-100081
    其各自任选地被1、2或3个R Cy取代；并且
    每个R Cy独立地选自：氢、卤基、氰基、任选被卤素取代的C 1-3烷基。
  45. 根据权利要求19或20所述的双官能化合物，其中连接基团(L)选自如下基团：
    Figure PCTCN2021080167-appb-100082
    Figure PCTCN2021080167-appb-100083
    Figure PCTCN2021080167-appb-100084
  46. 根据权利要求19或20所述的双官能化合物，其中连接基团(L)选自如下基团：
    Figure PCTCN2021080167-appb-100085
    Figure PCTCN2021080167-appb-100086
    Figure PCTCN2021080167-appb-100087
    Figure PCTCN2021080167-appb-100088
  47. 根据权利要求1或2所述的双官能化合物，其中所述化合物选自：
    Figure PCTCN2021080167-appb-100089
    Figure PCTCN2021080167-appb-100090
    Figure PCTCN2021080167-appb-100091
    Figure PCTCN2021080167-appb-100092
    Figure PCTCN2021080167-appb-100093
    Figure PCTCN2021080167-appb-100094
    Figure PCTCN2021080167-appb-100095
    Figure PCTCN2021080167-appb-100096
    Figure PCTCN2021080167-appb-100097
    Figure PCTCN2021080167-appb-100098
    Figure PCTCN2021080167-appb-100099
    Figure PCTCN2021080167-appb-100100
    Figure PCTCN2021080167-appb-100101
    Figure PCTCN2021080167-appb-100102
    Figure PCTCN2021080167-appb-100103
    Figure PCTCN2021080167-appb-100104
    Figure PCTCN2021080167-appb-100105
    Figure PCTCN2021080167-appb-100106
    Figure PCTCN2021080167-appb-100107
    Figure PCTCN2021080167-appb-100108
    Figure PCTCN2021080167-appb-100109
    Figure PCTCN2021080167-appb-100110
    Figure PCTCN2021080167-appb-100111
    Figure PCTCN2021080167-appb-100112
    Figure PCTCN2021080167-appb-100113
    Figure PCTCN2021080167-appb-100114
    Figure PCTCN2021080167-appb-100115
    Figure PCTCN2021080167-appb-100116
    Figure PCTCN2021080167-appb-100117
    Figure PCTCN2021080167-appb-100118
    Figure PCTCN2021080167-appb-100119
    Figure PCTCN2021080167-appb-100120
    Figure PCTCN2021080167-appb-100121
    Figure PCTCN2021080167-appb-100122
    Figure PCTCN2021080167-appb-100123
    Figure PCTCN2021080167-appb-100124
    Figure PCTCN2021080167-appb-100125
    Figure PCTCN2021080167-appb-100126
    Figure PCTCN2021080167-appb-100127
    Figure PCTCN2021080167-appb-100128
    Figure PCTCN2021080167-appb-100129
    Figure PCTCN2021080167-appb-100130
    Figure PCTCN2021080167-appb-100131
    Figure PCTCN2021080167-appb-100132
    Figure PCTCN2021080167-appb-100133
    Figure PCTCN2021080167-appb-100134
    Figure PCTCN2021080167-appb-100135
    Figure PCTCN2021080167-appb-100136
    Figure PCTCN2021080167-appb-100137
    Figure PCTCN2021080167-appb-100138
    Figure PCTCN2021080167-appb-100139
    Figure PCTCN2021080167-appb-100140
    Figure PCTCN2021080167-appb-100141
    Figure PCTCN2021080167-appb-100142
    Figure PCTCN2021080167-appb-100143
    Figure PCTCN2021080167-appb-100144
    Figure PCTCN2021080167-appb-100145
    Figure PCTCN2021080167-appb-100146
    Figure PCTCN2021080167-appb-100147
    Figure PCTCN2021080167-appb-100148
    Figure PCTCN2021080167-appb-100149
    Figure PCTCN2021080167-appb-100150
    Figure PCTCN2021080167-appb-100151
    Figure PCTCN2021080167-appb-100152
    Figure PCTCN2021080167-appb-100153
    Figure PCTCN2021080167-appb-100154
    Figure PCTCN2021080167-appb-100155
    Figure PCTCN2021080167-appb-100156
    Figure PCTCN2021080167-appb-100157
    Figure PCTCN2021080167-appb-100158
    Figure PCTCN2021080167-appb-100159
    Figure PCTCN2021080167-appb-100160
    Figure PCTCN2021080167-appb-100161
  48. 一种药物组合物，其包含有效量的权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药，以及药学上可接受的载体。
  49. 根据权利要求48所述药物组合物，其进一步包含至少一种其它生物活性剂。
  50. 根据权利要求49所述药物组合物，其中其他生物活性剂是抗癌剂。
  51. 权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药在制备将内源蛋白质募集到E3泛素连接酶进行降 解的药物中的用途。
  52. 权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药在制备将雄激素受体降解或抑制的药物中的用途。
  53. 根据权利要求51或52所述的用途，其中与内源蛋白质募集到E3泛素连接酶或雄激素受体相关疾病选自：痤疮、多毛症、皮脂腺增大、脱发、哮喘、多发性硬化症、癌症、肯尼亚病(Kenney′sdisease)、纤毛病、腭裂、糖尿病、心脏病、高血压、发炎性肠病、智力迟钝、情绪障碍、肥胖症、屈光不正、不育症、安格尔曼综合症(Angelmansyndrome)、卡纳万疾病(Canavandisease)、腹腔病、夏-马-图三氏病(Charcot-Marie-Toothdisease)、囊肿性纤维化、杜氏肌营养不良(Duchennemusculardystrophy)、血色病、血友病、克氏综合症(Klinefelter′ssyndrome)、神经纤维瘤、苯丙酮尿症、多囊性肾病(PKDl)或4(PKD2)、普拉德-威利综合症(Prader-Willisyndrome)、镰状细胞病、泰伊-萨克斯二氏病(Tay-Sachsdisease)、特纳综合症(Turnersyndrome)；
    所述癌症是鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌瘤；膀胱、肠道、乳房、子宫颈、结肠、食道、头、肾脏、肝脏、肺、颈、卵巢、胰腺、前列腺和胃的癌症；白血病；良性和恶性淋巴瘤，尤其伯基特氏淋巴瘤(Burkitt′slymphoma)和非霍奇金淋巴瘤(Non-Hodgkin′slymphoma)；良性和恶性黑色素瘤；骨髓增生性疾病；肉瘤，包括尤文氏肉瘤(Ewing′ssarcoma)、血管内皮瘤、卡波西肉瘤(Kaposi′ssarcoma)、脂肪肉瘤、肌肉瘤、末梢神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、寡突神经胶质细胞瘤、室管膜瘤、神经胶母细胞瘤、神经母细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和许旺细胞瘤(Schwannomas)；肠道 癌、乳癌、前列腺癌、子宫颈癌、子宫癌、肺癌、卵巢癌、睾丸癌、甲状腺癌、星形细胞瘤、食道癌、胰脏癌、胃癌、肝癌、结肠癌、黑色素瘤；癌肉瘤、霍奇金氏疾病、维尔姆斯瘤或畸胎癌。
  54. 根据权利要求53所述的用途，其中所述疾病是癌症、痤疮、皮脂腺增大、脱发或肯尼迪病。
  55. 根据权利要求54所述的用途，其中所述疾病是前列腺癌、痤疮或脱发。
  56. 一种在需要其的受试者中将内源蛋白质募集到E3泛素连接酶进行降解的方法，所述方法包括给予权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药。
  57. 一种在需要其的受试者中将雄激素受体降解或抑制的方法，所述方法包括给予权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药。
  58. 根据权利要求56或57所述的方法，其中与内源蛋白质募集到E3泛素连接酶或雄激素受体相关疾病选自：痤疮、多毛症、皮脂腺增大、脱发、哮喘、多发性硬化症、癌症、肯尼亚病(Kenney′sdisease)、纤毛病、腭裂、糖尿病、心脏病、高血压、发炎性肠病、智力迟钝、情绪障碍、肥胖症、屈光不正、不育症、安格尔曼综合症(Angelmansyndrome)、卡纳万疾病(Canavandisease)、腹腔病、夏-马-图三氏病(Charcot-Marie-Toothdisease)、囊肿性纤维化、杜氏肌营养不良(Duchennemusculardystrophy)、血色病、血友病、克氏综合症(Klinefelter′ssyndrome)、神经纤维瘤、苯丙酮尿症、多囊性肾病(PKDl)或4(PKD2)、普拉德-威利综合症(Prader-Willisyndrome)、镰状细胞病、泰伊-萨克斯二氏病(Tay-Sachsdisease)、特纳综合症(Turnersyndrome)；
    所述癌症是鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌瘤；膀胱、肠道、乳房、子宫颈、结肠、食道、头、肾脏、肝脏、肺、颈、卵巢、胰腺、前列腺和胃的癌症；白血病；良性和恶性淋巴瘤，尤其伯基特氏淋巴瘤(Burkitt′slymphoma)和非霍奇金淋巴瘤(Non-Hodgkin′slymphoma)；良性和恶性黑色素瘤；骨髓增生性疾病；肉瘤，包括尤文氏肉瘤(Ewing′ssarcoma)、血管内皮瘤、卡波西肉瘤(Kaposi′ssarcoma)、脂肪肉瘤、肌肉瘤、末梢神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、寡突神经胶质细胞瘤、室管膜瘤、神经胶母细胞瘤、神经母细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和许旺细胞瘤(Schwannomas)；肠道癌、乳癌、前列腺癌、子宫颈癌、子宫癌、肺癌、卵巢癌、睾丸癌、甲状腺癌、星形细胞瘤、食道癌、胰脏癌、胃癌、肝癌、结肠癌、黑色素瘤；癌肉瘤、霍奇金氏疾病、维尔姆斯瘤或畸胎癌。
  59. 根据权利要求58所述的方法，其中所述疾病是癌症、痤疮、皮脂腺增大、脱发或肯尼迪病。
  60. 根据权利要求59所述的方法，其中所述疾病是前列腺癌、痤疮或脱发。
  61. 一种治疗受试者的疾病或病症的方法，其包含以下步骤：向有需要的受试者施用组合物，所述组合物包含药学上可接受的载体和有效量的权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药。
  62. 根据权利要求61所述的方法，其中所述疾病或病症选自：痤疮、多毛症、皮脂腺增大、脱发、哮喘、多发性硬化症、癌症、肯尼亚病(Kenney′sdisease)、纤毛病、腭裂、糖尿病、心脏病、高血压、发炎性肠病、智力迟钝、情绪障碍、 肥胖症、屈光不正、不育症、安格尔曼综合症(Angelmansyndrome)、卡纳万疾病(Canavandisease)、腹腔病、夏-马-图三氏病(Charcot-Marie-Toothdisease)、囊肿性纤维化、杜氏肌营养不良(Duchennemusculardystrophy)、血色病、血友病、克氏综合症(Klinefelter′ssyndrome)、神经纤维瘤、苯丙酮尿症、多囊性肾病(PKDl)或4(PKD2)、普拉德-威利综合症(Prader-Willisyndrome)、镰状细胞病、泰伊-萨克斯二氏病(Tay-Sachsdisease)、特纳综合症(Turnersyndrome)；
    所述癌症是鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌瘤；膀胱、肠道、乳房、子宫颈、结肠、食道、头、肾脏、肝脏、肺、颈、卵巢、胰腺、前列腺和胃的癌症；白血病；良性和恶性淋巴瘤，尤其伯基特氏淋巴瘤(Burkitt′slymphoma)和非霍奇金淋巴瘤(Non-Hodgkin′slymphoma)；良性和恶性黑色素瘤；骨髓增生性疾病；肉瘤，包括尤文氏肉瘤(Ewing′ssarcoma)、血管内皮瘤、卡波西肉瘤(Kaposi′ssarcoma)、脂肪肉瘤、肌肉瘤、末梢神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、寡突神经胶质细胞瘤、室管膜瘤、神经胶母细胞瘤、神经母细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和许旺细胞瘤(Schwannomas)；肠道癌、乳癌、前列腺癌、子宫颈癌、子宫癌、肺癌、卵巢癌、睾丸癌、甲状腺癌、星形细胞瘤、食道癌、胰脏癌、胃癌、肝癌、结肠癌、黑色素瘤；癌肉瘤、霍奇金氏疾病、维尔姆斯瘤或畸胎癌。
  63. 根据权利要求62所述的用途，其中所述疾病是癌症、痤疮、皮脂腺增大、脱发或肯尼迪病。
  64. 根据权利要求63所述的用途，其中所述疾病是前列腺癌、痤疮或脱发。
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