WO2022089463A1 - Bcl-2 protein apoptosis-inducing agent and application thereof - Google Patents

Bcl-2 protein apoptosis-inducing agent and application thereof Download PDF

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WO2022089463A1
WO2022089463A1 PCT/CN2021/126588 CN2021126588W WO2022089463A1 WO 2022089463 A1 WO2022089463 A1 WO 2022089463A1 CN 2021126588 W CN2021126588 W CN 2021126588W WO 2022089463 A1 WO2022089463 A1 WO 2022089463A1
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methyl
oxy
pyridin
amino
pyrrolo
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PCT/CN2021/126588
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French (fr)
Chinese (zh)
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刘兴国
苏明波
吴一哲
高安慧
周星露
钟利
胡苗
黄景来
景杭辉
金欣欣
朱建荣
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杭州和正医药有限公司
百极弘烨(南通)医药科技有限公司
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Publication of WO2022089463A1 publication Critical patent/WO2022089463A1/en

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to a class of compounds or pharmaceutically acceptable salts that inhibit anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, and as drugs for the treatment of hyperproliferative diseases such as cancer and inflammation, as well as immune and autologous immune disease.
  • Bcl-2 anti-apoptotic B-cell lymphoma-2
  • Bcl-2 family proteins include anti-apoptotic proteins such as BCL-2, BCL-XL and MCL-1, etc., and pro-apoptotic proteins such as Bid, Bim, Bad, Bak and Bax, etc.
  • Bcl-2 proteins have been investigated as potential drug therapy targets, including Bcl-2 and Bcl-XL.
  • Bcl-2 protein expression can be used as an independent indicator of poor prognosis in tumors such as chronic lymphocytic leukemia (CLL), prostate cancer and small cell lung cancer (SCLC).
  • CLL chronic lymphocytic leukemia
  • SCLC small cell lung cancer
  • Bcl-XL expression correlates with disease severity and stage, and in hepatocellular carcinoma, Bcl-XL expression can be an independent indicator of prognosis.
  • Bcl-2 inhibitors have been reported in the literature, such as WO 2011149492A/CN110546151A/WO2020140005A2/WO2019210828A1, etc., which disclose an apoptosis inducer, but many have problems such as short half-life or high toxicity.
  • the present invention relates to a new class of compounds, their pharmaceutically acceptable salts and their pharmaceutical compositions, and their use as medicines.
  • n 0, 1, 2, 3;
  • Z When forming a ring, Z is substituted by two substituents to form a ring; when not forming a ring, Z is replaced by one substituent;
  • R a , R b , R c and R d can each be independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl , amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, Heterocyclyl, spirocyclyl, aryl or heteroaryl, said alkyl, cycloalkenyl, cycloalkyl, bridged, spiro, heterocyclyl, aryl or heteroaryl may be further one or more R e substitutions;
  • Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino , haloalkoxy, haloalkamino, cycloalkyl;
  • X is NR 8 , CR 8 R 8 ′, O, C(O), S, S(O), S(O) 2 ;
  • X and Z may form a ring B or not form a ring; when the B ring is formed, the dashed line connected to X is represented as a chemical bond; when B is an open ring, the dashed line connected to X is represented as absent; when the B ring is formed, R 2 can be substituted on Z, and can also be substituted on any atom between Z and X; when B is an open ring, R 2 is substituted on X;
  • Y 1 , Y 2 , Y 3 are each independently selected from CR 9 , N; and:
  • n is 0, 1, 2, 3, or 4;
  • X and Z form a ring B, and n is 2, 3, or 4;
  • n 1, 2, 3, 4;
  • o is selected from 0, 1, 2, 3, 4;
  • p is selected from 0, 1, 2;
  • q is selected from 0, 1, 2, 3;
  • r is selected from 0, 1, 2, 3, 4, 5;
  • s is selected from 0, 1, 2, 3, 4, 5;
  • t is selected from 0, 1, 2, 3, 4;
  • u is selected from 0, 1, 2, 3, 4;
  • Ring A is selected from cycloalkane, cycloalkenyl, bridged ring, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ′, R 9 are each independently selected from hydrogen, deuterium, alkyl, bridged cyclyl, spirocyclyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR g , SR g , alkyl-R g , NH ( CH 2 )R g , C(O)R g , S(O)R g , SO 2 R g , C(O)OR g , OC(O)R g , NR h R i , C(O)N ( R h )R i , N(R h )C(O)R i , -P(O)R h R i
  • R 2 , R 3 , R 5 , R 6 or R 7 groups can form a ring to form cycloalkyl, heterocycloalkyl, and can be further substituted by one or more R k ;
  • R f , R g , R h , R i , R j and R k may each be independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl , bridged ring group, heterocyclic group, aryl group or heteroaryl group, said alkyl group, spirocyclic group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, aminoalkyl group, alkanecarbonyl group, alkoxycarbonyl group , alkylamino,
  • R m is selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, alkylamino, halo Substituted hydroxyalkyl, haloalkylamino, cycloalkyl.
  • n 0, 1, 2, 3;
  • Z is selected from ( CH2 ) u , NH, O, S, C(O), S( O2 ), OC(O), N(H)C(O), S( O2 )N(H), N(H)S(O 2 ), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium, alkyl, spirocyclyl, bridged ring, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR a , SR a , alkyl-R a , NH(CH 2 )R a , C(O)R a , S(O)R a , SO 2 R a , C(O)OR a , OC(O)R a , NR b R c , C(O)N(R
  • R a , R b , R c and R d are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, Amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, hetero Cyclic, spiro, aryl or heteroaryl, the alkyl, cycloalkenyl, cycloalkyl, bridged, spiro, heterocyclyl, aryl or heteroaryl may be further replaced by a or multiple R e substitutions;
  • Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino , haloalkoxy, haloalkamino, cycloalkyl;
  • X is NR 8 or CR 8 R 8 ′;
  • X and Z may form a ring B or not form a ring; when the B ring is formed, the dashed line connected to X is represented as a chemical bond; when B is an open ring, the dashed line connected to X is represented as absent; when the B ring is formed, R 2 can be substituted on Z, and can also be substituted on any atom between Z and X; when B is an open ring, R 2 is substituted on X;
  • Y 1 , Y 2 , Y 3 are each independently selected from CR 9 , N; and:
  • n is 0, 1, 2, 3, or 4;
  • X and Z form a ring B, and n is 2, 3, or 4;
  • o is selected from 0, 1, 2, 3, 4;
  • p is selected from 0, 1, 2;
  • q is selected from 0, 1, 2, 3;
  • r is selected from 0, 1, 2, 3, 4, 5;
  • s is selected from 0, 1, 2, 3, 4, 5;
  • t is selected from 0, 1, 2, 3, 4;
  • u is selected from 0, 1, 2, 3, 4;
  • Ring A is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ′, R 9 are each independently selected from hydrogen, deuterium, alkyl, bridged cyclyl, spirocyclyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR g , SR g , alkyl-R g , NH ( CH)R g , C(O)R g , S(O)R g , SO 2 R g , C(O)OR g , OC(O)R g , NR h R i , C(O)N(R h ) R i , N(R h )C(O)R i , -P(O)R h R i , the
  • R 2 , R 3 , R 5 , R 6 or R 7 groups can form a ring to form cycloalkyl, heterocycloalkyl, and can be further substituted by one or more R k ;
  • R f , R g , Rh , R i , R j and R k are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl , oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, Bridged cyclyl, heterocyclyl, aryl or heteroaryl, said alkyl, spirocyclyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, alkoxycarbonyl, Alkylamino, cycloalkyl, cycloalken
  • R m is selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, alkylamino, halo Substituted hydroxyalkyl, haloalkylamino, cycloalkyl.
  • C marked with * in formula (I) is R configuration or S configuration.
  • a compound has the structure shown in general formula (II-A) or (II-B):
  • the preferred compound of the present invention has the structure of general formula (III-A) or (III-B):
  • Y 1 , Y 2 , Y 3 , Z, R 2 , R 5 , R 6 , R 7 , n, r, q, s are defined as in the general formula (I).
  • preferred compounds of the present invention have the structure of general formula (IV-A) or (IV-B):
  • Y 1 , Y 2 , Y 3 , Z, R 2 , R 5 , R 6 , n, r, and q are defined as in general formulae (III-A) and (III-B).
  • preferred compounds of the present invention have the structure of general formula (V-A):
  • Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , n, r, q are as defined in general formula IV-A.
  • Preferred compounds of the present invention have the structures of general formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5):
  • Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , r, q are as defined in general formula (IV-B).
  • the compound of the present invention has the structure of general formula VI-A1, VI-A2:
  • Y 1 , Y 2 , Y 3 , R 5 , R 6 , r, and q are as defined in the general formula VA;
  • T is selected from absent, NRn , O, S;
  • R k , R n are independently selected from hydrogen, deuterium, alkane, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, alkoxy, haloalkyl , hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged, heterocyclyl, aryl or heteroaryl , the alkyl group, cycloalkyl group, cycloalkenyl group, bridged ring group, heterocyclic group, spirocyclic group, aryl group or heteroaryl group can be further substituted by 1 or more R o ;
  • R is selected from hydrogen, deuterium , alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkane Amino, halogenated hydroxyalkyl, halogenated alkylamino, cycloalkyl;
  • n 1 is selected from 0, 1, 2, 3.
  • Z is selected from O, NH, CH 2 , CO; when not forming a ring, Z is selected from H;
  • Y 1 , Y 2 , Y 3 are independently selected from CR 9 , N;
  • R 1 is H, nitro
  • R7 is H.
  • the compound of the present invention has the structure of general formula (VII):
  • Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , R 7 , r, q, s are as defined in general formula (I);
  • the compound of the present invention has the structure of general formula (VIII-A1), (VIII-A2), (VIII-A3), (VIII-A4), (VIII-A5):
  • Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , r, q are as defined in general formula VII;
  • the compound of the present invention has the structure shown by the general formula (IX):
  • X is selected from NR 11 , O;
  • L 1 is selected from a chemical bond, an alkyl group, a cycloalkyl group, a heterocyclic group, a bridged ring group, and a spirocyclic group;
  • Ring C is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl, heteroaryl;
  • R 10 and R 11 are each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyl, alkoxycarbonyl, spirocyclyl, alkenyl, alkynyl, Carboxyl, amide, cycloalkenyl, bridged ring, aryl or heteroaryl;
  • f is selected from 0, 1, 2, 3, 4;
  • R m may be further substituted by one or more R r ;
  • R r is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclyl, alkylamino, alkylcarbonyl, alkane Oxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spiro, alkenyl, alkynyl, nitro, carboxyl, amide, cycloalkenyl, bridged, aryl or heteroaryl;
  • the C marked with * is preferably the S configuration
  • R 2 is methyl, methoxycarbonyl, 4-hydroxycyclohexyloxymethyl, a spiro ring structure formed by sharing a C atom with ring B (including cyclopropanyl, cyclobutanyl , cyclopentyl, N-methyl substituted azacyclopentanyl, N-methyl substituted azacyclohexyl), (4-methylpiperazin-1-yl) methyl, 2-(two Methylamino)ethyl, morpholinemethyl, (4-(oxetan-3-yl)piperazin-1-yl)methyl, (1,1-dioxythiomorpholine)methyl base, (4-acetylpiperazin-1-yl)methyl, (4-hydroxycyclohexyl)methyl, (2-(4-methylpiperazin-1-yl)ethyl, (4-(methyl) Sulfonamido)piperidin-1-yl)methyl, (4-
  • two substituents that occur in X can form a ring structure with X, including monocyclic, polycyclic (spiro-ring structure), such as R2 and X can form 6-(oxygen Etetan-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl, 6-(oxetan-3-yl)-2,6-diazaspiro [3.4]Octan-2-yl, 7-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl).
  • Parts are preferably the following structural segments:
  • the Bcl-2 inhibitor is preferably the following specific compound:
  • the compound is the following compound:
  • Substituted means that a hydrogen atom is replaced by a substituent. It should be noted that the substituents on a particular atom are restricted by their valence. In the Definitions section, " Cij " refers to a range including a starting point and an ending point, where i and j are both integers and represent the number of carbon atoms. For example, C 1-4 , C 1-10 , C 3-10 and the like.
  • alkyl used in the present invention refers to a linear saturated monovalent hydrocarbon group having one to six carbon atoms or a branched saturated monovalent hydrocarbon group having three to six carbon atoms, preferably methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.
  • the alkyl group can be unsubstituted or mono-substituted or multi-substituted, and the substituents can be the same or different when multi-substituted; the substituents of the alkyl group are selected from D (deuterium), halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, Ethyl carboxylate, isopropyl ester, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, alkoxycarbonyl, alkylthio, alkyl Sulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3- to 10-membered heterocyclic group, or amino or mono- or poly-substituted amino, wherein the amino substituents may be the same or different, and are selected from hydrogen , C 1 -C 6 alkyl, C 1 -C 6
  • cycloalkyl refers to a non-aromatic monovalent monocyclic or polycyclic (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) having three to ten carbon atoms. Hydrocarbyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., wherein one or two carbon atoms may be replaced by an oxygen.
  • the cycloalkyl can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the same
  • alkenyl refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, containing at least one double bond and having 2 to 10 carbon atoms (ie, C 2 -C 10 alkenyl) , including but not limited to vinyl, allyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
  • Alkenyl may be substituted with one or more substituents independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halo Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
  • alkynyl refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, containing at least one triple bond and having 2 to 10 carbon atoms (ie C 2 -C 10 alkynyl) , including but not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl and the like.
  • the alkynyl group may be substituted with one or more substituents independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halo Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • alkoxy refers to an -O-alkyl group, wherein alkyl is as defined above.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
  • Alkoxy also includes substituted alkoxy, the substituents of which may be D, halogen, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy , C 1 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • alkylamino refers to alkyl-NH-, wherein alkyl is as defined above.
  • alkylamino used in the present invention include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like.
  • Alkylamino also includes substituted alkylamino groups, the substituents of which may be D, halogen, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 cycloalkyl group, 3- to 10-membered heterocyclic group, C 6 -C 12 aryl group, C 5 -C 14 heteroaryl group, the substituents thereof may be substituted on alkyl or N.
  • aryl refers to an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms (wherein one fused ring may be partially saturated).
  • aromatic rings are: benzene ring, naphthalene ring, anthracene ring, indene ring, dihydroindenyl (indanyl).
  • Aromatic rings can be unsubstituted or substituted.
  • the substituent of the aromatic ring is selected from D, halogen (preferably fluorine, chlorine, bromine, iodine), cyano, nitro, amino, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 - C6 alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), C1 -C 6 hydroxyalkyl (preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc.), C 1 -C 6 alkoxy (preferably methoxy, ethoxy, propoxy , isopropyloxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halogenated C 1 -C
  • heteroaryl refers to a monocyclic or fused polycyclic group of 5 to 14 ring atoms (one of which may be partially saturated), corresponding to one or more carbons in the above-mentioned "aryl” Replaced by heteroatoms such as oxygen, nitrogen, sulfur, and the like.
  • the heteroaromatic ring can be monocyclic or bicyclic, that is, formed by the fusion of two rings.
  • heteroaryl groups can be: pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, Indoline, benzimidazole, etc.
  • Heterocyclic aryl groups can be unsubstituted or substituted.
  • the substituent of the heterocyclic aryl group is selected from halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 - C6 alkyl, halogenated C1 - C6 hydroxyalkyl, halogenated C1 - C6 alkoxy, C3 - C6 cycloalkyl, halogenated C3- C6 cycloalkyl, 3 to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • heterocyclyl refers to a non-aromatic ring having three to ten ring atoms of a monocyclic or polycyclic ring (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) group, has one or more heteroatoms selected from N, O, S, and may have one or more chemical bonds that are double bonds or triple bonds.
  • the heterocyclic group can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, oxo, thio, C 1 - C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, halo C 1 -C 6 hydroxyalkyl, halo C 1 -C 6alkoxy , C3 - C6cycloalkyl , halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, Sulfonamide group, 3- to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group
  • spirocyclyl used in the present invention refers to a polycyclic structure in which at least two rings share one atom (usually a C atom), and in this polycyclic structure, One or more of the chemical bonds are double or triple bonds, and one or more heteroatoms may be present.
  • the spirocyclic group can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the
  • bridged ring group used in the present invention refers to a polycyclic structure in which at least two rings share two or more atoms, and in this polycyclic structure there may be One or more of the chemical bonds are double or triple bonds, and one or more heteroatoms may be present.
  • the bridged ring group can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the same or
  • cycloalkenyl refers to a non-aromatic hydrocarbon group having three to ten carbon atoms in a monocyclic or polycyclic ring (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) And it contains at least one double bond, preferably cyclobutenyl, cyclopentenyl, cyclohexenyl, etc., wherein one or two carbon atoms can be replaced by an oxygen atom.
  • the cycloalkenyl can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the
  • hydroxyalkyl refers to -alkyl-OH, wherein alkyl is as defined above.
  • alkyl is as defined above.
  • examples of "hydroxyalkyl” as used herein include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like.
  • Hydroalkyl also includes substituted hydroxyalkyl groups, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • aminoalkyl refers to -alkyl- NH2 , wherein alkyl is as defined above.
  • alkyl is as defined above.
  • aminoalkyl include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, and the like.
  • Aminoalkyl also includes substituted aminoalkyl, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl, and its substituents can be substituted on alkyl or N .
  • alkylcarbonyl refers to alkyl-C(O)-, wherein alkyl is as defined above.
  • Alkylcarbonyl also includes substituted alkylcarbonyl, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • alkoxycarbonyl refers to alkyl-OC(O)-, wherein alkyl is as defined above.
  • Alkoxycarbonyl also includes substituted alkoxycarbonyl, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 1 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • halohydroxyalkyl refers to a hydroxyalkyl group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein hydroxyalkyl is as defined above. "Halohydroxyalkyl” may be substituted one or more times with halogen.
  • haloalkylamino refers to an alkylamino group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein alkylamino is as defined above. "Haloalkylamino” may be substituted one or more times with halogen.
  • alkyl, cycloalkyl, heterocyclylalkyl, aryl and/or heteroaryl substitution it means that each of these groups is substituted individually, or that these Group mixed substitution.
  • “Pharmaceutically acceptable salts” refers to salts prepared with pharmaceutically acceptable non-toxic acid and base salts, including inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases can be selected from, for example, ammonium, calcium, magnesium, potassium, sodium, zinc salts. Further, salts of pharmaceutically acceptable inorganic bases may be selected from ammonium, calcium, magnesium, potassium and sodium salts. One or more crystal structures may exist in solid salts, and hydrated forms may also exist.
  • “Pharmaceutically acceptable base-added salts” are those that retain the biological potency and properties of the free acid of the compound and require the preparation of salts thereof with at least one pharmaceutically acceptable non-toxic base selected from inorganic and organic bases .
  • primary, secondary and tertiary amine salts, substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethyl Diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, heba amine, isopropylamine, lysine, morpholine, piperazine, piperidine, purine, theobromine, triethylamine, trimethylamine and tripropyl
  • “Pharmaceutically acceptable addition salts” refers to those that retain the biological potency and properties of the compound's free base and require the preparation of its salts with at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids .
  • administering or “administering” a compound or a pharmaceutically acceptable salt thereof refers to providing a compound of the present invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment.
  • an "effective amount” refers to a dose of a compound, or a pharmaceutically acceptable salt thereof, that elicits a biological or medical response in a tissue, system, animal or human observable by a researcher, veterinarian, clinician or other clinician.
  • the result can be a reduction and/or amelioration of signs, symptoms or causes, or any other desired change in the biological system.
  • “Pharmaceutical composition” includes: a product mixed with the compound of the present invention (active ingredient) and an inert ingredient as a carrier, and any two or more ingredients directly or indirectly made by combining, compounding or aggregating A product, or a product that results from the decomposition of one or more components, or a product that results from other types of reactions or interactions of one or more components.
  • “Pharmaceutically acceptable” means those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues and are not unacceptable to the subject of administration of poison.
  • “Individual” refers to an individual suffering from a disease, disorder, or the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian species: humans, non-human primates (such as chimpanzees, and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as Rabbits, dogs and cats; experimental animals include rodents such as rats, mice and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In one embodiment of the present invention, the mammal is a human.
  • Treatment means the treatment of an associated disease or condition in mammals, particularly humans, including prevention of other symptoms, amelioration or prevention of underlying metabolic factors of symptoms, inhibition of disease or symptoms, for example, arresting the progression of disease or symptoms, alleviation of disease or symptoms , to promote the remission of a disease or symptom, or to stop the symptoms of a disease or symptom, and by extension to include prevention; alleviation, alleviation or amelioration of a disease or symptom; inhibition of a disease or condition, i.e. controlling its progression.
  • Treatment also includes achieving a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the condition being treated.
  • therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, although the patient may still have the underlying disease, but improvement in the patient's disease may be observed.
  • Prophylactic benefit refers to the use of a composition by a patient to prevent a risk of a disease, or when a patient develops one or more physiological conditions of the disease, even though the disease has not been diagnosed.
  • Protecting group refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. These functional groups include amino, carboxyl, sulfhydryl and hydroxyl groups. For a general description and instructions for use of protecting groups, see reference: T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • NH protecting groups include, but are not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), p-nitro Benzylcarbonyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-pentyloxycarbonyl, tertiary Butoxycarbonyl (Boc), p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl , phthaloyl
  • C(O)OH protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, Naphthyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, Acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidylmethyl, cyclopropyl, methoxymethyl, methoxy Ethoxymethyl,
  • OH or SH protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl Oxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2, 2,2-Trichloroethoxycarbonyl, 2,2,2-Tribromoethoxycarbonyl, 2-(trimethylsilane)ethoxycarbonyl, 2-(benzenesulfonyl)ethoxycarbonyl, 2 -(Triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-
  • Geometric isomers may exist in the compounds of the present invention.
  • the compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in E or Z configuration, wherein "E” represents the preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond, and "Z” represents that the preferred substituent is on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, and the preferred substituent can be determined according to the Cahn-Ingold-Prelog precedence rule.
  • the compounds of the present invention may also exist as mixtures of "E” and "Z” isomers. Substituents around a cycloalkyl or heterocyclyl group can be designated in either the cis or trans configuration.
  • the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system.
  • the two substituents around a single ring in the adamantane ring system are assigned the Z or E relative configuration. See, for example, C.D. Jones, M. Kaselj, R.N. Salvatore, W.J.le Noble J.Org.Chem. 1998, 63, 2758-2760.
  • the compounds of the present invention may contain asymmetric centers, which may independently be in the R or S configuration.
  • R and S are defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45 , 13-10.
  • a compound containing an asymmetrically substituted carbon atom is a racemate if the amounts of R and S configurations are the same. If one of the configurations is present in greater quantity than the other, the configuration of the chiral carbon atom is represented by the configuration in which the quantity is greater, preferably about 85-90% enantiomeric excess, more preferably about 95-99% , further about 99% above. Accordingly, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
  • the compounds of the present invention may exist in isotopically labeled or enriched forms, containing one or more atoms that differ in atomic mass and mass number from those most commonly found in nature.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.
  • Isotopically-labeled compounds of the present invention can be used as standard compounds in binding assays to determine the efficacy of Bcl-2 inhibitors.
  • Compounds containing isotopes can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotopically labeled parent compounds, and to study the in vivo metabolic fate of compounds (Blake et al.J.Pharm.Sci.64,3,367-391( 1975)).
  • Such metabolic studies are very important for the design of safe and effective therapeutic drugs, which can determine whether the active compound administered to the patient or the metabolite of the parent compound is toxic or carcinogenic (Foster et al., Advances in Drug Research Vol.14, pp.
  • the second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any one of the above technical solutions.
  • the pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above technical solutions and other compounds, or one or more of the compounds described in any of the above-mentioned technical solutions composition.
  • the compounds or pharmaceutically acceptable salts of the present invention may be used alone or in combination with other therapeutic agents.
  • an adjuvant drug enhances the therapeutic effect of a compound of the invention (eg, the adjuvant drug alone has minimal therapeutic benefit, but when used in combination with another drug, enhances the individual's therapeutic benefit), or
  • the combination of a compound of the present invention with another therapeutic agent that is also therapeutic can enhance the therapeutic benefit of an individual.
  • an anti-nausea drug may be used in combination.
  • therapies that may be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy on the diseased area, rest, dietary modification, and the like. Regardless of the disease, disorder or condition being treated, the two therapies should have an additive or synergistic effect to benefit the individual's treatment.
  • the route of administration may be the same as that of other drugs, or the route of administration may be different due to different physical and chemical properties.
  • a compound described herein and another therapeutic agent can be administered simultaneously, sequentially or separately.
  • condition, disorder or focus includes, but is not limited to, infectious disease, immune disease, inflammatory disease or abnormal cell proliferation.
  • infectious diseases, immune diseases, and inflammatory diseases described therein include, but are not limited to, asthma, diseases caused by neutrophil chemotaxis (eg, myocardial infarction and stroke, reperfusion injury and inflammatory joints). inflammation), septic shock, T cell-mediated diseases, immunosuppression-related diseases (eg, prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis), pancreatitis, and angiogenesis or angiogenesis-related diseases (eg acute and chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma); chronic obstructive pulmonary disease (COPD) and other diseases .
  • COPD chronic obstructive pulmonary disease
  • abnormal cell proliferation diseases include cancerous proliferative diseases, non-cancerous proliferative diseases, including but not limited to lymphoma, osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, Thyroid, ovarian, pancreatic, glioma, epidermoid, hemangioma, lung or gastric cancer, restenosis and benign prostatic hypertrophy (BPH).
  • cancerous proliferative diseases including but not limited to lymphoma, osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, Thyroid, ovarian, pancreatic, glioma, epidermoid, hemangioma, lung or gastric cancer, restenosis and benign prostatic hypertrophy (BPH).
  • non-cancerous proliferative diseases including but not limited to lymphoma, osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, Thyroid, ovarian, pancre
  • the compounds of the present invention can be administered in the form of pharmaceutical compositions, which can be administered by any conventional route; the compounds of the present invention can be formed into pharmaceutical preparations in the form of solid, semi-solid, liquid or gas, such as tablets, capsules, and injections , suspensions, lotions, gels, ointments, creams, suppositories, inhalants and the like.
  • composition containing the compound of the present invention in the form of a free base or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent can be mixed, granulated, coated, dissolved or lyophilized in a conventional manner. process to manufacture.
  • a unit dosage form for oral administration contains, for example, from about 0.1 mg to about 500 mg of active substance.
  • the inventors of the present invention have confirmed through experiments that the compounds of the present invention have potent BCL2/BAK blocking activity and in vitro anti-tumor cell proliferation inhibitory activity. It can be used alone or in combination with other drugs to treat infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation that benefit from the inhibition of anti-apoptotic protein BCL-2.
  • Step 1 Dissolve (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylate tert-butyl ester (4.5g) and isopropylboronic acid (3.1g) in 15mL of 1,4-epoxyhexanol To a mixed solvent of ring and 3 mL of water, potassium carbonate (6 g) and Pd(dffp) 2 Cl 2 (0.9 g) were added under nitrogen protection, and heated to reflux for overnight reaction.
  • step 2 (S)-2-(2-isopropylphenyl)pyrrolidine-1-carboxylate tert-butyl ester (3g) was dissolved in 18mL of dichloromethane, trifluoroacetic acid (9mL) was added, and The reaction was stirred at room temperature overnight. TLC monitoring, after the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude product (S)-2-(2-isopropylphenyl)pyrrolidine (1.92g), which was used in the next reaction without further purification.
  • Step 3 (S)-2-(2-isopropylphenyl)pyrrolidine (1.85g) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (2.4g) was dissolved in 25mL of 1,2-dichloroethane, stirred at room temperature for 15 minutes, and then added sodium borohydride (4.2g), after about 4 hours of reaction, TLC monitoring the completion of the reaction, adding sodium bicarbonate aqueous solution to quench The reaction was extracted with dichloromethane.
  • Step 4 (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester ( 3g) was dissolved in 15 mL of dichloromethane, trifluoroacetic acid (7.5 mL) was added, and the reaction was stirred at room temperature overnight. TLC monitoring, after the reaction was completed, the solvent was concentrated under reduced pressure to dry, and dichloromethane was added to redissolve, washed with saturated aqueous sodium bicarbonate solution and water, respectively, and the organic phase was separated.
  • Step 5 Methyl 2,4-difluorobenzoate (3.5 g) and 1H-pyrrolo[2,3-b]pyridin-5-ol (4.1 g) were dissolved in 50 mL diethylene glycol dimethyl ether , adding potassium phosphate (6.4g), heating to reflux reaction for about 12 hours. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, water and ethyl acetate were added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 6 (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (1.56g) and 2-((1H -Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester (1.72g) was dissolved in 20mL DMF, sodium carbonate (3.2g) was added, and the reaction was heated to reflux overnight. TLC monitoring, after the reaction was basically completed, it was lowered to room temperature, water and a large amount of ethyl acetate were added for extraction, the separated organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 7 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl) Methyl pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzoate (1.5 g) was dissolved in a mixed solvent of 15 mL methanol and 15 mL tetrahydrofuran, and 3N aqueous sodium hydroxide solution (10 mL) was added. ), heated to 50°C for reaction for about 3 hours, TCL monitored the completion of the reaction, neutralized with 4N aqueous hydrochloric acid solution to about pH 5.
  • Step 8 dissolve 3-bromo-4-chloro-5-nitrobenzenesulfonamide (3.2g) and 1-aminocyclopropanemethanol (0.78g) in 40mL acetonitrile, add DIPEA (N,N-diisopropyl alcohol) ethylethylamine, 8.2 mL), heated to reflux and stirred the reaction overnight. TLC monitoring, after the reaction was completed, the temperature was lowered to room temperature, and the dry solvent was concentrated under reduced pressure.
  • DIPEA N,N-diisopropyl alcohol
  • Step 9 dissolve 3-bromo-4-((1-(hydroxymethyl)cyclopropyl)amino)-5-nitrobenzenesulfonamide (1.83g) in 30mL of toluene, add cesium carbonate (3.26g) , CuI (200 mg) and 3,4,7,8-tetramethyl-1,10-phenanthroline (118 mg), heated and refluxed for about 6 hours under nitrogen protection.
  • Step 10 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzoic acid (0.17g) was dissolved in 3mL of dichloromethane, triethylamine (0.2mL) was added, HATU (N,N ,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea, 0.15g), stirred at room temperature for about 1 hour, then added 5-nitro- 2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7-sulfonamide (0.11 g) and DMAP (4-dimethylaminopyridine, 6 mg), plus After completion, the reaction was continued at room temperature
  • the target compound (S)-2-(((1H-pyrrolo) can be synthesized [2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]- 7-yl)sulfonyl)benzamide (66 mg), LC-MS (ESI-MS): 850 [M+H] + .
  • the target compound (S)-2-(((1H) can be synthesized -pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-difluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-Azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1' -Cyclopropan]-7-yl)sulfonyl)benzamide (73 mg), LC-MS (ESI-MS): 868 [M+H] + .
  • Example 6 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-((S)-2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((((S)-3-(morpholinomethyl)-5-nitro -3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (006)
  • Example 7 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)pyridineamide (024)
  • 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (10.00g, 42.00mmol) was dissolved in 1,4-dioxane (52.00mL), and 4mol/ L HCl (52.00 mL) in 1,4-dioxane (52.00 mL) was heated to 60 °C for 4 h.
  • Step 9 Preparation of Compound 24: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy- 4-Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1- yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (024)
  • Example 8 N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)pyridineamide (025)
  • Example 11 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-cyclopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)-N-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino )-3-Nitrophenyl)sulfonyl)pyridineamide (028)
  • Example 12 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-(trifluoromethyl)phenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (029)
  • Example 13 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-methoxyphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]non-7-yl)pyridineamide (030)
  • Example 14 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-fluorophenyl)pyrrolidine -1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)pyridineamide (031)
  • Example 15 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-N-((4-(((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (032)
  • Example 16 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (033)
  • Example 17 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-difluoro-N-((4-((((((1r,4r) )-4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (034)
  • Example 18 (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)nicotinamide (035)
  • Example 19 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)benzamide (084)
  • Example 20 N-((4-(((((1,4-dioxane-2 -yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4 -(2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (085)
  • Example 21 N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)benzamide (086)
  • Methyl 4-bromo-2,6-difluorobenzoate (5.00 g, 19.92 mmol), 1H-pyrrolo[2,3-b]pyridin-5-ol (2.94 g, 21.91 mmol), potassium phosphate ( 5.07 g, 23.91 mmol) was dissolved in diethylene glycol dimethyl ether (70.00 mL), and the temperature was raised to 100 °C for 21 h. After the completion of the TLC monitoring reaction, H 2 O and 2M hydrochloric acid aqueous solution were added to adjust the pH to neutrality.
  • Example 22 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)benzamide (087)
  • Example 21 Referring to the synthesis method of Example 21, replacing (1,4-dioxan-2-yl)methanamine hydrochloride with (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride, it can be synthesized
  • Example 24 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoropiperidin-4-yl)methyl )amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)picolinamide (089)
  • Example 25 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((morpholin-2-ylmethyl)amino)-3-nitrophenyl)sulfonyl) Picolinamide (090)
  • Example 26 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2-morpholinoacetyl) yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)picolinamide (091)
  • Example 27 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-(2-(dimethylamino)acetyl) )-4-Fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (092)
  • Example 28 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[ b][1,4]oxazin-7-yl)sulfonyl)benzamide (093)
  • Example 29 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-(2-morpholinoacetyl)morpholin-2-yl)methyl)amino )-3-Nitrophenyl)sulfonyl)picolinamide (094)
  • Example 30 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-(2-(dimethylamino)acetyl) )morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)picolinamide (095)
  • Example 31 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (096)
  • Example 32 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((4-(oxetan-3-yl)morpholine- 2-yl)methyl)amino)phenyl)sulfonyl)picolinamide (097)
  • Example 33 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoropiperidin-4-yl)methoxy) )-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7 -yl)picolinamide (099)
  • Example 34 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)picolinamide (098)
  • Example 35 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinoacetyl) )piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7 -Azaspiro[3.5]nonan-7-yl)picolinamide (100)
  • Example 36 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)picolinamide (101)
  • Example 37 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-hydroxy-4-methylcyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (102)
  • Example 38 4-(((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-( 2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl) Amino)methyl)-4-fluoropiperidine-1-carboxylic acid ethyl ester (103)
  • Example 39 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((2-(dimethylamino)ethyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (104)
  • Example 40 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((3-isopropyloxypropyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (105)
  • Example 41 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (106)
  • Example 42 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((3-(dimethylamino)propyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (107)
  • Example 43 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino )phenyl)sulfonyl)nicotinamide (108)
  • Example 44 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl) yl)-4-fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (109)
  • the target compound 109 can be synthesized by replacing methyl 3,5-difluoropicolinate with methyl 2,6-dichloronicotinate.
  • LC-MS (ESI-MS): m/ z 965[M+H] + .
  • Example 45 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl)) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (110)
  • Example 36 methyl 3,5-difluoropicolinate was replaced with methyl 2,6-dichloronicotinate, and the target compound 110 could be synthesized.
  • LC-MS (ESI-MS): m/ z 966[M+H] + .
  • Example 46 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinoacetyl) )piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7 - Azaspiro[3.5]nonan-7-yl)nicotinamide (111)
  • Example 48 N-((4-((1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2 ,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (113)
  • the methyl 3,5-difluoropyridine-2-carboxylate was replaced by methyl 2,6-dichloronicotinate, and the 4-fluoro-4-(hydroxymethyl)piperidine-
  • Example 50 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((morpholin-2-ylmethyl)amino)-3-nitrophenyl)sulfonyl) Niacinamide (114)
  • the target compound 114 can be synthesized by replacing methyl 3,5-difluoropyridine-2-carboxylate with methyl 2,6-dichloronicotinate.
  • Example 51 N-((4-((1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2 ,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)picolinamide (116)
  • Example 52 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((4-(oxetan-3-yl)morpholine- 2-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (117)
  • Example 53 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (118)
  • the target compound 118 can be synthesized by replacing methyl 3,5-difluoropyridine-2-carboxylate with methyl 4,6-dichloronicotinate.
  • Example 54 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (119)
  • the target compound 121 can be synthesized by replacing methyl 2,3,4-trifluorobenzoate with methyl 2,4,5-trifluorobenzoate.
  • LC-MS (ESI-MS ): m/z 880 [M+H] + .
  • Example 56 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoropiperidin-4-yl)methyl )amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (135)
  • Example 57 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (125)
  • Example 58 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(6-(oxetan-3-yl)-2,6- Diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)benzamide (122)
  • Example 59 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(6-(oxetan-3-yl)-2,6- Diazaspiro[3.4]octan-2-yl)phenyl)sulfonyl)benzamide (123)
  • Example 60 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(7-(oxetan-3-yl)-2,7- Diazaspiro[3.5]nonan-2-yl)phenyl)sulfonyl)benzamide (124)
  • Example 61 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (126)
  • Example 62 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl) yl)-4-fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (127)
  • Example 64 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl) Methyl)amino)phenyl)sulfonyl)benzamide (120)
  • Example 65 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl) yl)-4-fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (130)
  • Example 66 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((4-fluoro-1-(oxa Cyclobutan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (128)
  • Example 68 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((S)-pyrrolidin-3-ylmethyl) Amino)phenyl)sulfonyl)benzamide (134)
  • Example 69 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((R)-1-(oxetane) -3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (131)
  • Example 70 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((R)-1-(oxetane) -3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (132)
  • Example 69 Referring to the synthesis method of Example 69, substituting (R)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-3-(aminomethyl)pyrrolidine-1-carboxylic acid
  • Example 71 2-((1H-pyrro[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((1r,4r)-4-hydroxy- 4-Methylcyclohexyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)benzamide (136)
  • Example 72 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-phenylpyrrolidin-1-yl)-7-azaspiro[ 3.5] Nonan-7-yl)benzamide (137)
  • Example 73 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-phenylpyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (138)
  • Example 74 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-fluorophenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)benzamide (139)
  • Example 75 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(tert-butyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino )-3-Nitrophenyl)sulfonyl)benzamide (140)
  • Example 76 4-(((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-( 2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl) Amino)methyl)-4-fluoropiperidine-1-carboxylic acid methyl ester (141)
  • Example 77 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)nicotinamide (142)
  • Example 78 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)nicotinamide (143)
  • Example 64 Referring to the synthetic method of Example 64, substituting 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylic acid for tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate
  • Example 80 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((piperidin-4-ylmethyl)amino)phenyl )sulfonyl)benzamide (148)
  • Example 81 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((piperidin-4-ylmethyl)amino)phenyl)sulfonyl) Niacinamide (147)
  • Example 82 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((1-(oxetan-3-yl)piperidine- 4-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (145)
  • Example 83 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((1-(oxetan-3-yl) )piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (146)
  • Example 84 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((5-oxopyrrolidin-2-yl)methan yl)amino)phenyl)sulfonyl)benzamide (149)
  • Example 85 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(2-oxoimidazolidine-1-yl) )ethyl)amino)phenyl)sulfonyl)benzamide (150)
  • Example 86 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((((4-fluoro- 1-(oxetan-3-yl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-iso) Propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (151)
  • Example 87 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-isopropyl ylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)benzamide (153)
  • Example 88 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-(2 ,2,2-Trifluoroethyl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylbenzene) yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (155)
  • Example 90 (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-isopropyl ylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)nicotinamide (154)
  • Example 91 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2,2,2 -Trifluoroethyl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (156)
  • Example 92 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-5-methylbenzamide (157)
  • Example 93 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-2,3-difluoro-N-((4-(((4-fluoro-1 -(oxetan-3-yl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (158)
  • the target compound 158 can be synthesized by replacing methyl 2,4,5-trifluorobenzoate with methyl 2,3,4,6-tetrafluorobenzoate.
  • LC-MS (ESI -MS): m/z 971 [M+H] + .
  • Example 94 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(1-(oxetane-3 -yl)piperidin-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide (159)
  • Example 63 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester was replaced with 4-carbamoylpiperidine-1-carboxylate tert-butyl ester, which can be synthesized
  • Example 96 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(piperidin-4-carboxamido)phenyl)sulfonyl)nicotinamide ( 161)
  • Example 56 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester was replaced with 4-carbamoylpiperidine-1-carboxylate tert-butyl ester, which can be synthesized
  • Example 97 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((1r,4r)-4-hydroxy -4-Methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1- yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (162)
  • Example 98 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-hydroxycyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)benzamide (163)
  • Example 99 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (164)
  • Example 100 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1s,3s)-3- Hydroxy-3-methylcyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (165)
  • Example 101 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,3s)-3-hydroxy-3- Methylcyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (166)
  • Example 102 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,3r)-3- Hydroxycyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)benzamide (167)
  • Example 103 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(((4-((((1r,3r)-3-hydroxycyclobutyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonan-7-yl)nicotinamide (168)
  • Example 104 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((azetidin-3-yl Methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)benzamide (169)
  • Example 105 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((1-(oxetane) -3-yl)azetidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (170)
  • Example 106 (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((1-(oxetan-3-yl) )azetidin-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (171)
  • Example 107 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((3-methylazetidin-3-yl )methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (172)
  • Example 108 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((((1-isopropyl) yl-3-methylazetidin-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (173)
  • Example 109 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2,3-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-(((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (174)
  • Example 110 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2,3-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (175)
  • Example 111 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2,6-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-(((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (176)
  • Example 112 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2,6-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (177)
  • Example 88 With reference to the synthetic method of Example 88, the following compounds can be synthesized by a similar synthetic route and method:
  • Example 91 With reference to the synthetic method of Example 91, the following compounds can be synthesized by a similar synthetic route and method:
  • the 500nM Tag1-BCL2 protein stock solution was diluted to 5nM with the dilution buffer in the kit (model: BCL2/BAK(BH3) BINDING ASSAY KIT, Cisbio), and the 20 ⁇ M Tag2-BAK protein stock solution was diluted to 120nM.
  • Tag1-BCL2 protein dilution Add 5 ⁇ L of Tag1-BCL2 protein dilution to the well, and then add compounds of different concentrations (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM), DMSO
  • 5 ⁇ L of Tag2-BAK protein dilution solution was added to each well, centrifuged to mix well, and incubated at room temperature for 15 minutes. Then add anti-Tag1-Eu3+ and anti-Tag2-XL665 in the kit, and react at room temperature for 2 hours.
  • the plate was read with a BIO-Tek NEO2 multifunctional microplate reader (excitation 620 nM, emission 665 nM), and IC 50 was calculated with GraphPad Prism 5.0. The results are shown in Table 1.
  • the total volume of the reaction was 10 ⁇ L. Specifically, 2 ⁇ L of the test compound (2% DMSO), 4 ⁇ L of His-tagged recombinant protein and 4 ⁇ L of Biotin-tagged BIM protein polypeptide were added. After 1 hour of reaction, anti-His and streptavidin-tagged XL665 antibodies diluted with detection buffer were added respectively. After 4 hours of incubation at room temperature, the Envision multi-function microplate microplate reader was used to read the value, so as to detect the effect of the test compound on the binding ability of BCL-XL and Bim protein polypeptide. Envision parameter settings are excitation light 320nm, emission light 615nm and 665nm.
  • binding ability of anti-apoptotic protein to Bim protein polypeptide is indirectly reflected by the ratio of 665nm and 615nm signals.
  • background wells without BCL2 and full binding activity wells of recombinant protein without compound and Bim protein polypeptide were set.
  • anti-apoptotic protein BCL2(G101V) The binding ability of anti-apoptotic protein BCL2(G101V) to apoptosis pro-apoptotic protein Bim was detected by time homogeneous phase-resolved fluorescence technique. Reactions for this method were in 384 white shallow well plates and the total reaction volume was 10 ⁇ L. Specifically, 2 ⁇ L of the test compound (2% DMSO), 4 ⁇ L of His-tagged recombinant protein and 4 ⁇ L of Biotin-tagged BIM protein polypeptide were added. After 1 hour of reaction, anti-His and streptavidin-tagged XL665 antibodies diluted with detection buffer were added respectively.
  • Envision multi-function microplate microplate reader After incubation at room temperature for 4 hours, use the Envision multi-function microplate microplate reader to read the value, so as to detect the effect of the test compound on the binding ability of BCL2 (G101V) and Bim protein polypeptide.
  • Envision parameter settings are excitation light 320nm, emission light 615nm and 665nm.
  • the binding ability of anti-apoptotic protein to Bim protein polypeptide is indirectly reflected by the ratio of 665nm and 615nm signals.
  • background wells without BCL2 and full binding activity wells of recombinant protein without compound and Bim protein polypeptide were set.
  • anti-apoptotic protein BCL2(D103Y) The binding ability of anti-apoptotic protein BCL2(D103Y) to apoptosis pro-apoptotic protein Bim was detected by time homogeneous phase-resolved fluorescence technique. Reactions for this method were in 384 white shallow well plates and the total reaction volume was 10 ⁇ L. Specifically, 2 ⁇ L of the test compound (2% DMSO), 4 ⁇ L of His-tagged recombinant protein and 4 ⁇ L of Biotin-tagged BIM protein polypeptide were added. After 1 hour of reaction, anti-His and streptavidin-tagged XL665 antibodies diluted with detection buffer were added respectively.
  • the Envision multi-function microplate microplate reader was used to read the value, so as to detect the effect of the test compound on the binding ability of BCL2 (D103Y) and Bim protein polypeptide.
  • Envision parameter settings are excitation light 320nm, emission light 615nm and 665nm.
  • the binding ability of anti-apoptotic protein to Bim protein polypeptide is indirectly reflected by the ratio of 665nm and 615nm signals.
  • background wells without BCL2 and full binding activity wells of recombinant protein without compound and Bim protein polypeptide were set.
  • RS4;11 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. The cells were digested, and the cells were seeded in a 96-well plate at a cell concentration of RS4; 11 30000/well and incubated overnight at 37°C with 5% CO 2 . Compounds at different concentrations (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) were added to the 96-well plate and incubated at 37°C with 5% CO2 , RS4 ; 11 Incubation for 72 hours.
  • Molt-4 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. The cells were digested, and Molt-4 cells were seeded at a cell concentration of 30,000/well in a 96-well plate and incubated overnight at 37°C with 5% CO 2 . Compounds at different concentrations (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) were added to the 96-well plate and incubated at 37°C with 5% CO2 , Molt -4 Incubation for 72 hours. Add 20 ⁇ L of MTS to each well.
  • mice There were 3 female mice, and the animals were reared for at least 3 days before the experiment to adapt to the environment. Animals were fasted overnight before administration and had free access to water.
  • the blood samples were centrifuged at 8000 rpm for 5 minutes at 4 degrees Celsius within 30 minutes after the blood samples were obtained to extract the plasma.

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Abstract

Disclosed is a BCL-2 protein apoptosis-inducing agent. Also disclosed are the compound and an application of a pharmaceutical composition comprising the compound in preparing a drug for treating diseases related to anti-apoptotic protein BCL-2 such as infectious diseases, immune diseases, inflammatory diseases, and abnormal cell proliferation diseases. The compound of the present invention has potent BCL2/BAK blocking activity, potent inhibitory activity on BCL-2(G101V) and BCL-2(D103Y), and potent proliferation inhibitory activity on mutant cell strains. The compound can be applied to individually treat or treat in combination with other drugs infectious diseases, immune diseases, inflammatory diseases, or abnormal cell proliferation diseases, etc. which benefit from the inhibition of the anti-apoptotic protein BCL-2.

Description

Bcl-2蛋白凋亡诱导剂及应用Bcl-2 protein apoptosis inducer and its application 技术领域technical field
本发明涉及一类可抑制抗凋亡B细胞淋巴瘤-2(Bcl-2)家族蛋白的化合物或药学可接受的盐，以及作为药物治疗过度增殖性疾病，如癌症和炎症，以及免疫和自身免疫疾病。The present invention relates to a class of compounds or pharmaceutically acceptable salts that inhibit anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, and as drugs for the treatment of hyperproliferative diseases such as cancer and inflammation, as well as immune and autologous immune disease.
背景技术Background technique
细胞凋亡通过两条不同的通路实现调控，即外部通路和内部通路。外部通路，由细胞表面死亡受体介导，内部通路涉及B细胞淋巴瘤-2(Bcl-2)家族蛋白。Bcl-2家族蛋白包括抗凋亡蛋白如BCL-2、BCL-XL和MCL-1等，和促进凋亡蛋白，如Bid、Bim、Bad、Bak和Bax等。Apoptosis is regulated through two distinct pathways, the external pathway and the internal pathway. The external pathway, mediated by cell surface death receptors, and the internal pathway involve B-cell lymphoma-2 (Bcl-2) family proteins. Bcl-2 family proteins include anti-apoptotic proteins such as BCL-2, BCL-XL and MCL-1, etc., and pro-apoptotic proteins such as Bid, Bim, Bad, Bak and Bax, etc.
抗凋亡Bcl-2家族成员被发现在肿瘤细胞中出现上调，并与疾病分期和预后相关。因此，Bcl-2蛋白被作为潜在药物治疗靶点进行研究，这些靶点包括Bcl-2和Bcl-XL。Bcl-2蛋白表达可作为肿瘤如慢性淋巴性白血病(CLL)、前列腺癌和小细胞肺癌(SCLC)不良预后的独立指标。在另一些肿瘤，如结肠癌中，Bcl-XL的表达与疾病程度和分期相关，在肝细胞癌中，Bcl-XL的表达可以作为预后的独立指标。Anti-apoptotic Bcl-2 family members were found to be upregulated in tumor cells and correlated with disease stage and prognosis. Therefore, Bcl-2 proteins have been investigated as potential drug therapy targets, including Bcl-2 and Bcl-XL. Bcl-2 protein expression can be used as an independent indicator of poor prognosis in tumors such as chronic lymphocytic leukemia (CLL), prostate cancer and small cell lung cancer (SCLC). In other tumors, such as colon cancer, Bcl-XL expression correlates with disease severity and stage, and in hepatocellular carcinoma, Bcl-XL expression can be an independent indicator of prognosis.
Bcl-2抑制剂在文献中已有报道，如WO 2011149492A/CN110546151A/WO2020140005A2/WO2019210828A1等，公开了一种细胞凋亡诱导剂，但是许多都存在半衰期较短或者毒性较大等问题。Bcl-2 inhibitors have been reported in the literature, such as WO 2011149492A/CN110546151A/WO2020140005A2/WO2019210828A1, etc., which disclose an apoptosis inducer, but many have problems such as short half-life or high toxicity.
研究报道，部分患者接受Bcl-2抑制剂治疗后出现耐药。BCL-2的基因出现G101V突变和D103Y突变，降低BCL-2抑制剂的疗效(Cancer Discov.2019,9,342-353)。亟需寻找更加适合BCL-2抑制剂耐药患者的治疗。Studies have reported that some patients develop drug resistance after receiving Bcl-2 inhibitors. G101V mutation and D103Y mutation in BCL-2 gene reduce the efficacy of BCL-2 inhibitors (Cancer Discov. 2019, 9, 342-353). There is an urgent need to find more suitable treatments for BCL-2 inhibitor-resistant patients.
因此，亟需开发疗效更好、稳定性更高、安全性更优异，且对突变细胞株更加有效的新型Bcl-2抑制剂。Therefore, there is an urgent need to develop novel Bcl-2 inhibitors with better efficacy, higher stability, better safety, and more effective against mutant cell lines.
发明内容SUMMARY OF THE INVENTION
本发明涉及一类新化合物、其药学可接受的盐及其药物组合物，以及作为药物的应用。The present invention relates to a new class of compounds, their pharmaceutically acceptable salts and their pharmaceutical compositions, and their use as medicines.
一种化合物，具有通式(I)所示的结构：A compound having the structure shown in general formula (I):
Figure PCTCN2021126588-appb-000001
Figure PCTCN2021126588-appb-000001
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；其中：or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof; wherein:
m选自0、1、2、3；m is selected from 0, 1, 2, 3;
成环时，Z被两个取代基取代成环；不成环时，Z被一个取代基取代；When forming a ring, Z is substituted by two substituents to form a ring; when not forming a ring, Z is replaced by one substituent;
Z选自(CH 2) u、NH、O、S、C(O)(表示C＝O)、S(O 2)(表示S上存在两个S＝O基团)、OC(O)、N(H)C(O)(表示Z取代分别发生在N和C上)、S(O 2)N(H)、N(H)S(O 2)、OC(O)N(H)、N(H)C(O)S，或氢、氘、烷基、螺环基、桥环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基、卤素、硝基、氧代(＝O)、氰基、OR a、SR a、烷基-R a、NH(CH 2)R a、C(O)R a、S(O)R a、SO 2R a、C(O)OR a、OC(O)R a、NR bR c、C(O)N(R b)R c、N(R b)C(O)R c、-P(O)R bR c，所述的烷基、环烯基、桥环基、杂环基、芳基或者杂芳基可进一步被一个或者多个R d取代；当Z为包含两个或两个以上主链以“OC(O)”为例，OC(O)对取代顺序没有限定，即实际取代时，可能是左侧O原子与苯环相连，也可以表示羰基碳原子与苯环相连。 Z is selected from (CH 2 ) u , NH, O, S, C(O) (representing C=O), S(O 2 ) (representing the presence of two S=O groups on S), OC(O), N(H)C(O) (indicating that Z substitutions occur on N and C, respectively), S(O 2 )N(H), N(H)S(O 2 ), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium, alkyl, spirocyclyl, bridged, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl , halogen, nitro, oxo(=O), cyano, OR a , SR a , alkyl-R a , NH(CH 2 )R a , C(O)R a , S(O)R a , SO 2 R a , C(O)OR a , OC(O)R a , NR b R c , C(O)N(R b )R c , N(R b )C(O)R c , -P (O) R b R c , the alkyl group, cycloalkenyl group, bridged ring group, heterocyclic group, aryl group or heteroaryl group may be further substituted by one or more R d ; Take "OC(O)" as an example for two or more main chains. OC(O) has no restriction on the substitution order, that is, when actually substituted, the O atom on the left may be connected to the benzene ring, or it may represent the carbonyl carbon atom and the benzene ring. connected.
R a、R b、R c和R d可各自独立的选自氢、氘、烷基、螺环基、烯基、炔基、卤素、氰基、氨基、硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环基、杂环基、螺环基、芳基或者杂芳基，所述的烷基、环烯基、环烷基、桥环基、螺环基、杂环基、芳基或者杂芳基可进一步被一个或者多个R e取代； R a , R b , R c and R d can each be independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl , amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, Heterocyclyl, spirocyclyl, aryl or heteroaryl, said alkyl, cycloalkenyl, cycloalkyl, bridged, spiro, heterocyclyl, aryl or heteroaryl may be further one or more R e substitutions;
Re选自氢、氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代烷羟基、卤代烷氨基、环烷基；Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino , haloalkoxy, haloalkamino, cycloalkyl;
X为NR 8、CR 8R 8’、O、C(O)、S、S(O)、S(O) 2； X is NR 8 , CR 8 R 8 ′, O, C(O), S, S(O), S(O) 2 ;
其中：in:
X和Z可能成环B或不成环；当形成B环时，与X相连的虚线表示为化学键；当B为开环时，与X相连的虚线表示为不存在；当形成B环时，R 2可取代在Z上，也可取代在Z跟X之间的任一原子上；当B为开环时，R 2取代在X上； X and Z may form a ring B or not form a ring; when the B ring is formed, the dashed line connected to X is represented as a chemical bond; when B is an open ring, the dashed line connected to X is represented as absent; when the B ring is formed, R 2 can be substituted on Z, and can also be substituted on any atom between Z and X; when B is an open ring, R 2 is substituted on X;
Y 1、Y 2、Y 3各自独立的选自CR 9、N；且： Y 1 , Y 2 , Y 3 are each independently selected from CR 9 , N; and:
当Y 1、Y 2、Y 3至少一个为N时，n为0、1、2、3、4； When at least one of Y 1 , Y 2 , and Y 3 is N, n is 0, 1, 2, 3, or 4;
当Y 1、Y 2、Y 3同时为CH时，X和Z成环B，且n为2、3、4； When Y 1 , Y 2 , and Y 3 are CH at the same time, X and Z form a ring B, and n is 2, 3, or 4;
当Y 1、Y 2、Y 3其中两个为CH时，另一个Y 1/Y 2/Y 3为N或CR 9，且R9不为H，另一个Y 1/Y 2/Y 3为CR 9时，n为1、2、3、4； When two of Y 1 , Y 2 , and Y 3 are CH, the other Y 1 /Y 2 /Y 3 is N or CR 9 , and R9 is not H, and the other Y 1 /Y 2 /Y 3 is CR At 9 , n is 1, 2, 3, 4;
o选自0、1、2、3、4；o is selected from 0, 1, 2, 3, 4;
p选自0、1、2；p is selected from 0, 1, 2;
q选自0、1、2、3；q is selected from 0, 1, 2, 3;
r选自0、1、2、3、4、5；r is selected from 0, 1, 2, 3, 4, 5;
s选自0、1、2、3、4、5；s is selected from 0, 1, 2, 3, 4, 5;
t选自0、1、2、3、4；t is selected from 0, 1, 2, 3, 4;
u选自0、1、2、3、4；u is selected from 0, 1, 2, 3, 4;
环A选自环烷烃、环烯烃基、桥环、杂环烷基、杂环烯烃基、芳基或者杂芳基；Ring A is selected from cycloalkane, cycloalkenyl, bridged ring, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 8’、R 9各自独立的选自氢、氘、烷基、桥环基、螺环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基、卤素、硝基、氧代、氰基、OR g、SR g、烷基-R g、NH(CH 2)R g、C(O)R g、S(O)R g、SO 2R g、C(O)OR g、OC(O)R g、NR hR i、C(O)N(R h)R i、N(R h)C(O)R i、-P(O)R hR i，所述的烷基、桥环基、螺环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基可进一步被1个或者多个R j取代；R 7可取代在氮杂吲哚片段的碳、氮原子上； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ′, R 9 are each independently selected from hydrogen, deuterium, alkyl, bridged cyclyl, spirocyclyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR g , SR g , alkyl-R g , NH ( CH 2 )R g , C(O)R g , S(O)R g , SO 2 R g , C(O)OR g , OC(O)R g , NR h R i , C(O)N ( R h )R i , N(R h )C(O)R i , -P(O)R h R i , the alkyl group, bridged ring group, spirocyclic group, alkenyl group, alkynyl group, cycloalkane group Radical, cycloalkenyl, heterocyclyl, aryl or heteroaryl can be further substituted by one or more R j ; R 7 can be substituted on the carbon and nitrogen atoms of the azaindole fragment;
两个R 2、R 3、R 5、R 6或者R 7基团可成环形成环烷基、杂环烷基，并可进一步1个或者多个R k取代； Two R 2 , R 3 , R 5 , R 6 or R 7 groups can form a ring to form cycloalkyl, heterocycloalkyl, and can be further substituted by one or more R k ;
R f、R g、R h、R i、R j和R k可各自独立的选自氢、氘、烷基、螺环基、烯基、炔基、卤素、氰基、氨基、硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基，所述的烷基、螺环基、烯基、炔基、烷氧基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基可进一步被1个或者多个R m取代； R f , R g , R h , R i , R j and R k may each be independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl , bridged ring group, heterocyclic group, aryl group or heteroaryl group, said alkyl group, spirocyclic group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, aminoalkyl group, alkanecarbonyl group, alkoxycarbonyl group , alkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl may be further substituted by one or more R m ;
R m选自氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基。 R m is selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, alkylamino, halo Substituted hydroxyalkyl, haloalkylamino, cycloalkyl.
一种化合物，具有通式(II)所示的结构：A compound having the structure shown in general formula (II):
Figure PCTCN2021126588-appb-000002
Figure PCTCN2021126588-appb-000002
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
其中：in:
m选自0、1、2、3；m is selected from 0, 1, 2, 3;
Z选自(CH 2) u、NH、O、S、C(O)、S(O 2)、OC(O)、N(H)C(O)、S(O 2)N(H)、N(H)S(O 2)、OC(O)N(H)、N(H)C(O)S，或氢、氘、烷基、螺环基、桥环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基、卤素、硝基、氧代、氰基、OR a、SR a、烷基-R a、NH(CH 2)R a、C(O)R a、S(O)R a、SO 2R a、C(O)OR a、OC(O)R a、NR bR c、C(O)N(R b)R c、N(R b)C(O)R c、-P(O)R bR c，所述的烷基、环烯基、桥环基、杂环基、芳基或者杂芳基可进一步被一个或者多个R d取代； Z is selected from ( CH2 ) u , NH, O, S, C(O), S( O2 ), OC(O), N(H)C(O), S( O2 )N(H), N(H)S(O 2 ), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium, alkyl, spirocyclyl, bridged ring, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR a , SR a , alkyl-R a , NH(CH 2 )R a , C(O)R a , S(O)R a , SO 2 R a , C(O)OR a , OC(O)R a , NR b R c , C(O)N(R b )R c , N(R b )C(O)R c , -P(O)R b R c , the alkyl group, cycloalkenyl group, bridged ring group, heterocyclic group, aryl group or heteroaryl group can be further represented by One or more R d substitutions;
R a、R b、R c和R d各自独立的选自氢、氘、烷基、螺环基、烯基、炔基、卤素、氰基、氨基、硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环基、杂环基、螺环基、芳基或者杂芳基，所述的烷基、环烯基、环烷基、桥环基、螺环基、杂环基、芳基或者杂芳基可进一步被一个或者多个R e取代； R a , R b , R c and R d are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, Amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, hetero Cyclic, spiro, aryl or heteroaryl, the alkyl, cycloalkenyl, cycloalkyl, bridged, spiro, heterocyclyl, aryl or heteroaryl may be further replaced by a or multiple R e substitutions;
Re选自氢、氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代烷羟基、卤代烷氨基、环烷基；Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino , haloalkoxy, haloalkamino, cycloalkyl;
X为NR 8或CR 8R 8’；其中： X is NR 8 or CR 8 R 8 ′; where:
X和Z可能成环B或不成环；当形成B环时，与X相连的虚线表示为化学键；当B为开环时，与X相连的虚线表示为不存在；当形成B环时，R 2可取代在Z上，也可取代在Z跟X之间的任一原子上；当B为开环时，R 2取代在X上； X and Z may form a ring B or not form a ring; when the B ring is formed, the dashed line connected to X is represented as a chemical bond; when B is an open ring, the dashed line connected to X is represented as absent; when the B ring is formed, R 2 can be substituted on Z, and can also be substituted on any atom between Z and X; when B is an open ring, R 2 is substituted on X;
Y 1、Y 2、Y 3各自独立的选自CR 9、N；且： Y 1 , Y 2 , Y 3 are each independently selected from CR 9 , N; and:
当Y 1、Y 2、Y 3至少一个为N时，n为0、1、2、3、4； When at least one of Y 1 , Y 2 , and Y 3 is N, n is 0, 1, 2, 3, or 4;
当Y 1、Y 2、Y 3同时为CH时，X和Z成环B，且n为2、3、4； When Y 1 , Y 2 , and Y 3 are CH at the same time, X and Z form a ring B, and n is 2, 3, or 4;
当Y 1、Y 2、Y 3其中两个为CH时，另一个Y 1/Y 2/Y 3为N或CR 9，且R 9不为H，另一个Y 1/Y 2/Y 3为CR 9时，n为1、2、3、4； When two of Y 1 , Y 2 , and Y 3 are CH, the other Y 1 /Y 2 /Y 3 is N or CR 9 , and R 9 is not H, and the other Y 1 /Y 2 /Y 3 is When CR 9 , n is 1, 2, 3, 4;
o选自0、1、2、3、4；o is selected from 0, 1, 2, 3, 4;
p选自0、1、2；p is selected from 0, 1, 2;
q选自0、1、2、3；q is selected from 0, 1, 2, 3;
r选自0、1、2、3、4、5；r is selected from 0, 1, 2, 3, 4, 5;
s选自0、1、2、3、4、5；s is selected from 0, 1, 2, 3, 4, 5;
t选自0、1、2、3、4；t is selected from 0, 1, 2, 3, 4;
u选自0、1、2、3、4；u is selected from 0, 1, 2, 3, 4;
环A选自环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基；Ring A is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl;
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 8’、R 9各自独立的选自氢、氘、烷基、桥环基、螺环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基、卤素、硝基、氧代、氰基、OR g、SR g、烷基-R g、NH(CH)R g、C(O)R g、S(O)R g、SO 2R g、C(O)OR g、OC(O)R g、NR hR i、C(O)N(R h)R i、N(R h)C(O)R i、-P(O)R hR i，所述的烷基、桥环基、螺环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基可进一步被1个或者多个R j取代；R 7可取代在氮杂吲哚片段的碳、氮原子上； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ′, R 9 are each independently selected from hydrogen, deuterium, alkyl, bridged cyclyl, spirocyclyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR g , SR g , alkyl-R g , NH ( CH)R g , C(O)R g , S(O)R g , SO 2 R g , C(O)OR g , OC(O)R g , NR h R i , C(O)N(R h ) R i , N(R h )C(O)R i , -P(O)R h R i , the alkyl group, bridged ring group, spirocyclic group, alkenyl group, alkynyl group, cycloalkyl group , cycloalkenyl, heterocyclyl, aryl or heteroaryl can be further substituted by one or more R j ; R 7 can be substituted on the carbon and nitrogen atoms of the azaindole fragment;
两个R 2、R 3、R 5、R 6或者R 7基团可成环形成环烷基、杂环烷基，并可进一步1个或者多个R k取代； Two R 2 , R 3 , R 5 , R 6 or R 7 groups can form a ring to form cycloalkyl, heterocycloalkyl, and can be further substituted by one or more R k ;
R f、R g、R h、R i、R j和R k各自独立的选自氢、氘、烷基、螺环基、烯基、炔基、卤素、氰基、氨基、硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基，所述的烷基、螺环基、烯基、炔基、烷氧基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基可进一步被1个或者多个R m取代； R f , R g , Rh , R i , R j and R k are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl , oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, Bridged cyclyl, heterocyclyl, aryl or heteroaryl, said alkyl, spirocyclyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, alkoxycarbonyl, Alkylamino, cycloalkyl, cycloalkenyl, bridged cyclyl , heterocyclyl, aryl or heteroaryl groups may be further substituted with one or more R;
R m选自氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基。 R m is selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, alkylamino, halo Substituted hydroxyalkyl, haloalkylamino, cycloalkyl.
作为优选，式(I)中*标注的C为R构型或者S构型。Preferably, C marked with * in formula (I) is R configuration or S configuration.
作为优选，一种化合物具有通式(II-A)或(II-B)所示的结构：Preferably, a compound has the structure shown in general formula (II-A) or (II-B):
Figure PCTCN2021126588-appb-000003
Figure PCTCN2021126588-appb-000003
或其立体异构体或其立体异构体混合物或其药学上可接受的盐。or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
进一步地，本发明优选的化合物，具有通式(III-A)或(III-B)的结构：Further, the preferred compound of the present invention has the structure of general formula (III-A) or (III-B):
Figure PCTCN2021126588-appb-000004
Figure PCTCN2021126588-appb-000004
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
其中：Y 1、Y 2、Y 3、Z、R 2、R 5、R 6、R 7、n、r、q、s的定义如通式(I)中所定义。 Wherein: Y 1 , Y 2 , Y 3 , Z, R 2 , R 5 , R 6 , R 7 , n, r, q, s are defined as in the general formula (I).
更进一步地，本发明优选的化合物具有通式(IV-A)或(IV-B)的结构：Further, preferred compounds of the present invention have the structure of general formula (IV-A) or (IV-B):
Figure PCTCN2021126588-appb-000005
Figure PCTCN2021126588-appb-000005
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
其中：Y 1、Y 2、Y 3、Z、R 2、R 5、R 6、n、r、q的定义如通式(III-A)、(III-B)中所定义。 Wherein: Y 1 , Y 2 , Y 3 , Z, R 2 , R 5 , R 6 , n, r, and q are defined as in general formulae (III-A) and (III-B).
更进一步地，本发明优选的化合物具有通式(V-A)的结构：Further, preferred compounds of the present invention have the structure of general formula (V-A):
Figure PCTCN2021126588-appb-000006
Figure PCTCN2021126588-appb-000006
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
其中：Y 1、Y 2、Y 3、R 2、R 5、R 6、n、r、q的定义如通式IV-A中所定义。 Wherein: Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , n, r, q are as defined in general formula IV-A.
本发明优选的化合物具有通式(V-B1)、(V-B2)、(V-B3)、(V-B4)、(V-B5)的结构：Preferred compounds of the present invention have the structures of general formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5):
Figure PCTCN2021126588-appb-000007
Figure PCTCN2021126588-appb-000007
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
其中：Y 1、Y 2、Y 3、R 2、R 5、R 6、r、q的定义如通式(IV-B)中所定义。 Wherein: Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , r, q are as defined in general formula (IV-B).
作为进一步优选，本发明的化合物具有通式VI-A1、VI-A2的结构：As further preferred, the compound of the present invention has the structure of general formula VI-A1, VI-A2:
Figure PCTCN2021126588-appb-000008
Figure PCTCN2021126588-appb-000008
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
其中，Y 1、Y 2、Y 3、R 5、R 6、r、q的定义如通式V-A中所定义； Wherein, the definitions of Y 1 , Y 2 , Y 3 , R 5 , R 6 , r, and q are as defined in the general formula VA;
T选自不存在、NR n、O、S； T is selected from absent, NRn , O, S;
R k、R n独立地选自氢、氘、烷烃、螺环基、烯基、炔基、卤素、氰基、氨基、硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环、杂环基、芳基或者杂芳基，所述的烷基、环烷基、环烯基、桥环基、杂环基、螺环基、芳基或者杂芳基可进一步被1或者多个R o取代； R k , R n are independently selected from hydrogen, deuterium, alkane, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, alkoxy, haloalkyl , hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged, heterocyclyl, aryl or heteroaryl , the alkyl group, cycloalkyl group, cycloalkenyl group, bridged ring group, heterocyclic group, spirocyclic group, aryl group or heteroaryl group can be further substituted by 1 or more R o ;
R o选自氢、氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基； R is selected from hydrogen, deuterium , alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkane Amino, halogenated hydroxyalkyl, halogenated alkylamino, cycloalkyl;
n 1选自0、1、2、3。 n 1 is selected from 0, 1, 2, 3.
作为优选，其中成B环时，Z选自O、NH、CH 2、CO；不成环时，Z选自H； Preferably, when forming a B ring, Z is selected from O, NH, CH 2 , CO; when not forming a ring, Z is selected from H;
Y 1、Y 2、Y 3独自选自CR 9、N； Y 1 , Y 2 , Y 3 are independently selected from CR 9 , N;
R 1为H、硝基； R 1 is H, nitro;
R 3为H；R 4为H；R 5为H； R 3 is H; R 4 is H; R 5 is H;
R 7为H。作为优选，本发明的化合物具有通式(VII)的结构： R7 is H. Preferably, the compound of the present invention has the structure of general formula (VII):
Figure PCTCN2021126588-appb-000009
Figure PCTCN2021126588-appb-000009
Figure PCTCN2021126588-appb-000010
Figure PCTCN2021126588-appb-000010
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；其中，or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof; wherein,
Y 1、Y 2、Y 3、R 2、R 5、R 6、R 7、r、q、s的定义如通式(I)中所定义； Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , R 7 , r, q, s are as defined in general formula (I);
作为优选，本发明的化合物具有通式(VIII-A1)、(VIII-A2)、(VIII-A3)、(VIII-A4)、(VIII-A5)的结构：Preferably, the compound of the present invention has the structure of general formula (VIII-A1), (VIII-A2), (VIII-A3), (VIII-A4), (VIII-A5):
Figure PCTCN2021126588-appb-000011
Figure PCTCN2021126588-appb-000011
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
Y 1、Y 2、Y 3、R 2、R 5、R 6、r、q的定义如通式VII中所定义； Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , r, q are as defined in general formula VII;
作为优选，本发明的化合物具有通式(IX)所示的结构：Preferably, the compound of the present invention has the structure shown by the general formula (IX):
Figure PCTCN2021126588-appb-000012
Figure PCTCN2021126588-appb-000012
或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
X选自NR 11、O； X is selected from NR 11 , O;
L 1选自化学键、烷基、环烷基、杂环基、桥环基、螺环基； L 1 is selected from a chemical bond, an alkyl group, a cycloalkyl group, a heterocyclic group, a bridged ring group, and a spirocyclic group;
环C选自环烷基、环烯基、桥环基、杂环基、芳基、杂芳基；Ring C is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl, heteroaryl;
R 10、R 11各自独立地选自氢、烷基、卤素、卤代烷基、环烷基、卤代环烷基、杂环基、羟基、烷氧羰基、螺环基、烯基、炔基、羧基、酰胺、环烯基、桥环、芳基或者杂芳基； R 10 and R 11 are each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyl, alkoxycarbonyl, spirocyclyl, alkenyl, alkynyl, Carboxyl, amide, cycloalkenyl, bridged ring, aryl or heteroaryl;
f选自0、1、2、3、4；f is selected from 0, 1, 2, 3, 4;
作为优选，通式(I)～(IX)所述的化合物中：As a preference, in the compounds described in general formulas (I) to (IX):
R m可进一步被1个或者多个R r取代； R m may be further substituted by one or more R r ;
R r选自氢、氘、烷基、卤素、氰基、氨基、羟基、氧代、烷氧基、羟烷基、氨基烷基、烷基羰、杂环基、烷氨基、烷羰基、烷氧羰基、卤代羟烷基、卤代烷氨基、卤代烷基、环烷基、螺环基、烯基、炔基、硝基、羧基、酰胺、环烯基、桥环、芳基或者杂芳基； R r is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclyl, alkylamino, alkylcarbonyl, alkane Oxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spiro, alkenyl, alkynyl, nitro, carboxyl, amide, cycloalkenyl, bridged, aryl or heteroaryl;
作为优选，通式I～IX所述的化合物，*标注的C优选S构型；As a preference, in the compounds described in the general formulae I to IX, the C marked with * is preferably the S configuration;
作为进一步优选，成B环时，R 2为甲基、甲氧羰基、4-羟基环己基氧甲基、与B环共用一个C原子形成的螺环结构(包括环丙烷基、环丁烷基、环戊烷基、N-甲基取代氮杂环戊烷基、N-甲基取代氮杂环己烷基)、(4-甲基哌嗪-1-基)甲基、2-(二甲胺基)乙基、吗啉甲基、(4-(氧杂环丁烷-3-基)哌嗪-1-基)甲基、(1,1-二氧基硫代吗啉)甲基、(4-乙酰哌嗪-1-基)甲基、(4-羟基环己基)甲基、(2-(4-甲基哌嗪-1-基)乙基、(4-(甲基磺胺基)哌啶-1-基)甲基、(4-甲氧羰基氨基吡啶-1-基)甲基、(二甲胺基)甲基、(3-羟基-3-甲基氮杂环丁烷-1-基)甲基、2-(1,1-二氧基硫代吗啉)乙基、四氢-2H-吡喃-4-基、((四氢-2H-吡喃-4-基)甲基)氨基、1-甲基哌啶-4-基、1-甲基哌啶-4-基)甲基氨基、1-甲氧羰基哌啶-4-基、1-乙酰哌啶-4-基、4-羟基环己基、氧代、(4-羟基-4-甲基环己基)甲基、(1,4-二恶烷-2-基)甲基。 As a further preference, when forming ring B, R 2 is methyl, methoxycarbonyl, 4-hydroxycyclohexyloxymethyl, a spiro ring structure formed by sharing a C atom with ring B (including cyclopropanyl, cyclobutanyl , cyclopentyl, N-methyl substituted azacyclopentanyl, N-methyl substituted azacyclohexyl), (4-methylpiperazin-1-yl) methyl, 2-(two Methylamino)ethyl, morpholinemethyl, (4-(oxetan-3-yl)piperazin-1-yl)methyl, (1,1-dioxythiomorpholine)methyl base, (4-acetylpiperazin-1-yl)methyl, (4-hydroxycyclohexyl)methyl, (2-(4-methylpiperazin-1-yl)ethyl, (4-(methyl) Sulfonamido)piperidin-1-yl)methyl, (4-methoxycarbonylaminopyridin-1-yl)methyl, (dimethylamino)methyl, (3-hydroxy-3-methylazacycle Butan-1-yl)methyl, 2-(1,1-dioxythiomorpholine)ethyl, tetrahydro-2H-pyran-4-yl, ((tetrahydro-2H-pyran- 4-yl)methyl)amino, 1-methylpiperidin-4-yl, 1-methylpiperidin-4-yl)methylamino, 1-methoxycarbonylpiperidin-4-yl, 1-acetyl Piperidin-4-yl, 4-hydroxycyclohexyl, oxo, (4-hydroxy-4-methylcyclohexyl)methyl, (1,4-dioxan-2-yl)methyl.
没有成环时，(4-羟基-4-甲基环己基)甲基、(4-氟-1-(三氟甲基)哌啶-4-基)甲基、(1,4-二恶烷-2-基)甲基、(四氢-2H-吡喃-4-基)甲基、(1-甲基哌啶-4-基)甲基、(4-氟哌啶-4-基)甲基、吗啉-2-基甲基、(4-氟-1-(2-吗啉乙酰基)哌啶-4-基)甲基、4-(((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲基、(4-(2-吗啉乙酰基)吗啉-2-基)甲基、((4-(2-(二甲氨基)乙酰基)吗啉-2-基)甲基、(4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基、(4-(氧杂环丁烷-3-基)吗啉-2-基)甲基、(4-氟-1-(乙氧酰基)哌啶-4-基)甲基、2-(二甲氨基)乙基、3-异丙基氧基丙基、3-(二甲氨基)丙基、(4-氟-1-(2-吗啉乙酰基)哌啶-4-基)甲基、吡咯烷-3-基甲基、(1-(氧杂环丁烷-3-基)吡咯烷-3-基)甲基、(4-氟-1-(甲氧酰基)哌啶-4-基)甲基、4-羟基-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基、哌啶-4-基甲基、5-氧代吡咯烷-2-基)甲基、2-(2-氧代咪唑烷-1-基)乙基、(((4-氟-1-(2,2,2-三氟乙基))哌啶-4-基)甲基、(4-氟-1-异丙基哌啶-4-基)甲基、(4-氟-1-(2,2,2-三氟乙基)哌啶-4-基)甲基、哌啶-4-甲酰基、(4-羟基-4-甲基环己基)甲基、(4-羟基环己基)甲基、(3-羟基-3-甲基环丁基)甲基、(3-羟基环丁基)甲基、氮杂环丁烷-3-基甲基、(1-(氧杂环丁烷-3-基)氮杂环丁烷-3-基)甲基、(3-甲基氮杂环丁烷-3-基)甲基、(1-异丙基-3-甲基氮杂环丁烷-3-基)甲基、(1-环丙基-4-氟哌啶-4-基)甲基、(1-环丁基-4-氟哌啶-4-基)甲基、(1-环戊基-4-氟哌啶-4-基)甲基、((4-氟-1-(1,1,1-三氟丙-2-基))哌啶-4-基)甲基、(4-氟-1-(1,1,1,3,3,3-六氟丙-2-基)哌啶-4-基)甲基、(1-乙酰基-4-氟哌啶-4-基)甲基、(4-氟-1-(1-羟基丙-2-基)哌啶-4-基)甲基、((四氢-2H-吡喃-4-基)哌啶-4-基)甲基、(4-氟-1-(异丙基氧酰基)哌啶-4-基)甲基、(1-甲基-5-氧代吡咯烷-2-基)甲基、(5-氧代吡咯烷-2-基)甲基、(2-氧代哌啶-4-基)甲基、(6-氧代哌啶-3-基)甲基、(1-(氧杂环丁烷-3-基)哌啶-4-基)甲基、(4-氨基-4-甲基环己基)甲基、(4-氨基环己基)甲基、3-氨基-3-甲基环丁基甲基、3-氨基环丁基甲基。When there is no ring formation, (4-hydroxy-4-methylcyclohexyl)methyl, (4-fluoro-1-(trifluoromethyl)piperidin-4-yl)methyl, (1,4-dioxane) Alk-2-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, (1-methylpiperidin-4-yl)methyl, (4-fluoropiperidin-4-yl) ) methyl, morpholin-2-ylmethyl, (4-fluoro-1-(2-morpholinoacetyl)piperidin-4-yl)methyl, 4-(((1-(2-(di Methylamino)acetyl)-4-fluoropiperidin-4-yl)methyl, (4-(2-morpholinoacetyl)morpholin-2-yl)methyl, ((4-(2-(bis) Methylamino)acetyl)morpholin-2-yl)methyl, (4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl, (4-(oxa) Cyclobutan-3-yl)morpholin-2-yl)methyl, (4-fluoro-1-(ethoxyyl)piperidin-4-yl)methyl, 2-(dimethylamino)ethyl, 3-Isopropyloxypropyl, 3-(dimethylamino)propyl, (4-fluoro-1-(2-morpholinoacetyl)piperidin-4-yl)methyl, pyrrolidine-3- ylmethyl, (1-(oxetan-3-yl)pyrrolidin-3-yl)methyl, (4-fluoro-1-(methoxyacyl)piperidin-4-yl)methyl, 4-Hydroxy-1-(oxetan-3-yl)piperidin-4-yl)methyl, piperidin-4-ylmethyl, 5-oxopyrrolidin-2-yl)methyl, 2-(2-Oxoimidazolidin-1-yl)ethyl, (((4-fluoro-1-(2,2,2-trifluoroethyl))piperidin-4-yl)methyl, ( 4-Fluoro-1-isopropylpiperidin-4-yl)methyl, (4-fluoro-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl, piperidine -4-Formyl, (4-hydroxy-4-methylcyclohexyl)methyl, (4-hydroxycyclohexyl)methyl, (3-hydroxy-3-methylcyclobutyl)methyl, (3-hydroxycyclohexyl)methyl Hydroxycyclobutyl)methyl, azetidine-3-ylmethyl, (1-(oxetan-3-yl)azetidine-3-yl)methyl, (3- Methylazetidine-3-yl)methyl, (1-isopropyl-3-methylazetidine-3-yl)methyl, (1-cyclopropyl-4-fluoropiperidine pyridin-4-yl)methyl, (1-cyclobutyl-4-fluoropiperidin-4-yl)methyl, (1-cyclopentyl-4-fluoropiperidin-4-yl)methyl, ( (4-Fluoro-1-(1,1,1-trifluoropropan-2-yl))piperidin-4-yl)methyl, (4-fluoro-1-(1,1,1,3,3) ,3-hexafluoroprop-2-yl)piperidin-4-yl)methyl, (1-acetyl-4-fluoropiperidin-4-yl)methyl, (4-fluoro-1-(1- Hydroxyprop-2-yl)piperidin-4-yl)methyl, ((tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl, (4-fluoro-1-(iso) Propyloxyacyl)piperidin-4-yl)methyl, (1-methyl-5-oxopyrrolidin-2-yl)methyl, (5-oxopyrrolidin-2-yl)methyl, (2-oxopiperidin-4-yl)methyl, (6 -Oxopiperidin-3-yl)methyl, (1-(oxetan-3-yl)piperidin-4-yl)methyl, (4-amino-4-methylcyclohexyl)methyl group, (4-aminocyclohexyl)methyl, 3-amino-3-methylcyclobutylmethyl, 3-aminocyclobutylmethyl.
另外，没有成环时，两个发生在X(比如N)的取代基，与X可以形成环结构，包括单环、多环(螺环结构)，比如与R2与X可以形成6-(氧杂环丁烷-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基、6-(氧杂环丁烷-3-基)-2,6-二氮杂螺[3.4]辛烷-2-基、7-(氧杂环丁烷-3-基)-2,7-二氮杂螺[3.5]壬烷-2-基)。In addition, when there is no ring formation, two substituents that occur in X (such as N) can form a ring structure with X, including monocyclic, polycyclic (spiro-ring structure), such as R2 and X can form 6-(oxygen Etetan-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl, 6-(oxetan-3-yl)-2,6-diazaspiro [3.4]Octan-2-yl, 7-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl).
作为优选，通式中
Figure PCTCN2021126588-appb-000013
部分优选为如下结构段： Preferably, in the general formula
Figure PCTCN2021126588-appb-000013
Parts are preferably the following structural segments:
Figure PCTCN2021126588-appb-000014
Figure PCTCN2021126588-appb-000014
Figure PCTCN2021126588-appb-000015
Figure PCTCN2021126588-appb-000015
作为优选，所述的Bcl-2抑制剂优选为以下具体化合物：Preferably, the Bcl-2 inhibitor is preferably the following specific compound:
Figure PCTCN2021126588-appb-000016
Figure PCTCN2021126588-appb-000016
Figure PCTCN2021126588-appb-000017
Figure PCTCN2021126588-appb-000017
Figure PCTCN2021126588-appb-000018
Figure PCTCN2021126588-appb-000018
Figure PCTCN2021126588-appb-000019
Figure PCTCN2021126588-appb-000019
Figure PCTCN2021126588-appb-000020
Figure PCTCN2021126588-appb-000020
Figure PCTCN2021126588-appb-000021
Figure PCTCN2021126588-appb-000021
Figure PCTCN2021126588-appb-000022
Figure PCTCN2021126588-appb-000022
Figure PCTCN2021126588-appb-000023
Figure PCTCN2021126588-appb-000023
Figure PCTCN2021126588-appb-000024
Figure PCTCN2021126588-appb-000024
Figure PCTCN2021126588-appb-000025
Figure PCTCN2021126588-appb-000025
Figure PCTCN2021126588-appb-000026
Figure PCTCN2021126588-appb-000026
Figure PCTCN2021126588-appb-000027
Figure PCTCN2021126588-appb-000027
或其立体异构体或其立体异构体混合物或其药学上可接受的盐。作为优选，所述化合物为如下化合物：or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. Preferably, the compound is the following compound:
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(001)(S)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3 ,1'-Cyclopropan]-7-yl)sulfonyl)benzamide (001)
(S)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)吡啶酰胺(002)(S)-3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3 ,1'-Cyclopropan]-7-yl)sulfonyl)pyridineamide (002)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(003)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4] Oxazine-3,1'-cyclopropan]-7-yl)sulfonyl)benzamide (003)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3,5-二氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(004)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-difluoro-4-(2-(2-(2-isopropyl) Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1, 4] Oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)benzamide (004)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡 咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((S)-3-(吗啉甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(005)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]non-7-yl)-N-(((S)-3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H- Benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (005)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((((S)-3-(吗啉甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(006)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-((S)-2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((((S)-3-(morpholinomethyl)-5-nitro-3,4 -Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (006)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2-氧代-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(007)(S)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2-oxo-2H,4H-spiro[benzo[b][1,4 ]oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)benzamide (007)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((3,3-二甲基-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(008)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3,3-dimethyl-5-nitro-3,4- Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)benzamide (008)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺[苯并[b][1,4]恶嗪-3,1'-环丁烷]-7-基)磺酰基)苯甲酰胺(009)(S)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3, 1'-Cyclobutane]-7-yl)sulfonyl)benzamide (009)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺[苯并[b][1,4]恶嗪-3,1'-环戊烷]-7-基)磺酰基)苯甲酰胺(010)(S)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3, 1'-Cyclopentane]-7-yl)sulfonyl)benzamide (010)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((1'-甲基-5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,3'-吡咯烷]-7-基)磺酰基)苯甲酰胺(011)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((1'-methyl-5-nitro-2H,4H-spiro[benzo[b][1, 4] Oxazine-3,3'-pyrrolidin]-7-yl)sulfonyl)benzamide (011)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-((1'-甲基-5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,4'-哌啶]-7-基)磺酰基)苯甲酰胺(012)(S)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((1'-methyl-5-nitro-2H,4H-spiro[benzo[b][1,4 ]oxazine-3,4'-piperidin]-7-yl)sulfonyl)benzamide (012)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((1'-甲基-5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,3'-哌啶]-7-基)磺酰基)苯甲酰胺(013)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((1'-methyl-5-nitro-2H,4H-spiro[benzo[b][1, 4] Oxazine-3,3'-piperidin]-7-yl)sulfonyl)benzamide (013)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((2,2-二甲基-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(014)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((2,2-dimethyl-5-nitro-3,4- Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)benzamide (014)
7-(N-(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰基)氨磺酰基)-2,2-二甲基-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-3-羧酸甲酯(015)7-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylbenzene) yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2,2-dimethyl-5-nitro-3,4 -Dihydro-2H-benzo[b][1,4]oxazine-3-carboxylate methyl ester (015)
2-((1H-吡咯并[2,3-b]吡啶基-5-基)氧基)-N-(((2,2-二甲基-3-(吗啉代甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(016)2-((1H-pyrrolo[2,3-b]pyridinyl-5-yl)oxy)-N-(((2,2-dimethyl-3-(morpholinomethyl)-5 -Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(2-((S)-2-(2-iso) Propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (016)
2-((1H-吡咯并[2,3-b]吡啶基-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-(吗啉甲基)-5-硝基-3,4-二氢螺[苯 并[b][1,4]恶嗪-2,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(017)2-((1H-Pyrrolo[2,3-b]pyridinyl-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-(morpholinomethyl)-5-nitro-3,4-dihydrospiro[benzo[ b][1,4]oxazine-2,1'-cyclopropane]-7-yl)sulfonyl)benzamide (017)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-(甲氧基甲基)-3-甲基-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(018)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-(methoxymethyl)-3-methyl-5-nitro-3,4-dihydro -2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (018)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-(3-((((1r，4r)-4-羟基环己基)氧基)甲基)-3-甲基-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(019)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(3-((((1r,4r)-4-hydroxycyclohexyl)oxy)methyl )-3-methyl-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(2-((S )-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (019)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-甲基-3-(吗啉甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(020)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-methyl-3-(morpholinomethyl)-5-nitro-3,4-dihydro- 2H-Benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (020)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-甲基-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(021)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-methyl-3-((4-methylpiperazin-1-yl)methyl)-5- Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (021)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((3-(2-(二甲胺基)乙基)-3-甲基-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(022)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-(2-(dimethylamino)ethyl)-3-methyl-5 -Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(2-((S)-2-(2-iso) Propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (022)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-(吗啉甲基)-5-硝基-2-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(023)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-(morpholinomethyl)-5-nitro-2-oxo-3,4-dihydro- 2H-Benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (023)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(024)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonan-7-yl)pyridineamide (024)
N-((4-((((S)-1,4-二恶烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(025)N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)pyridineamide (025)
(S)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)吡啶酰胺(026)(S)-3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino) Phenyl)sulfonyl)picolinamide (026)
(S)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(((1-甲基哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)吡啶酰胺(027)(S)-3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitro Phenyl)sulfonyl)picolinamide (027)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-环丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)吡啶酰胺(028)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]non-7-yl)-N-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3- Nitrophenyl)sulfonyl)picolinamide (028)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-((S)-2-(2-(三氟甲基)苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(029)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)pyridineamide (029)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-((S)-2-(2-甲氧基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)吡啶酰胺(030)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]non-7-yl)pyridineamide (030)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)吡啶酰胺(031)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-fluorophenyl)pyrrolidin-1-yl )-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)- 3-Nitrophenyl)sulfonyl)picolinamide (031)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(032)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-N-((4-(((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)benzamide (032)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(033)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)benzamide (033)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3,5-二氟-N-((4-(((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(034)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-difluoro-N-((4-((((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (034)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)烟酰胺(035)(S)-4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino) Phenyl)sulfonyl)nicotinamide (035)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(036)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]non-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro -3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (036)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)烟酰胺(037)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro yl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)nicotinamide (037)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)烟酰胺(038)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro yl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)nicotinamide (038)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(039)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-((S)-2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl) -5-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (039)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-氟-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(040)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-((S)-2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl) -5-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (040)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(041)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-((S)-2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl) -5-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (041)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡 咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-5-硝基-3-((4-(氧杂环丁烷-3-基)哌嗪-1-基)甲基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(042)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-5-nitro-3-((4-(oxetan-3-yl) Piperazin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)pyridineamide (042)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((S)-3-(吗啉甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(043)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]non-7-yl)-N-(((S)-3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H- Benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (043)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-(((S)-3-((1,1-二氧基硫代吗啉)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(044)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(((S)-3-((1,1-dioxythiomorpholine)methan yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-5-(2-((S)-2- (2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (044)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((S)-3-((4-乙酰哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(045)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((S)-3-((4-acetylpiperazin-1-yl)methyl)- 5-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-5-(2-((S)-2-(2- Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (045)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((S)-3-((4-羟基环己基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(046)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((S)-3-((4-hydroxycyclohexyl)methyl)-5-nitro -3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-5-(2-((S)-2-(2-isopropylbenzene) yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (046)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-(2-(4-甲基哌嗪-1-基)乙基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(047)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-(2-(4-methylpiperazin-1-yl)ethyl)-5 -Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (047)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((S)-3-(2-吗啉乙基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(048)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]non-7-yl)-N-(((S)-3-(2-morpholinoethyl)-5-nitro-3,4-dihydro- 2H-Benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (048)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(049)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)pyridineamide (049)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-乙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(050)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7 -Azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4 -Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)pyridineamide (050)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-环丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(051)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4 -Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (051)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-5-(2-(2-(2-(三氟甲基)苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)吡啶酰胺(052)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((S)-3-((4-methylpiperazin-1-yl)methyl) -5-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-5-(2-(2-(2-(trifluoro) Methyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)pyridineamide (052)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(二甲胺基)苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(053)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (053)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-氰基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4- 二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(054)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-cyanophenyl)pyrrolidin-1-yl)-7 -Azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4 - Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (054)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(055)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-fluorophenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4- Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)pyridineamide (055)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2,3-二氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(056)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2,3-difluorophenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]non-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (056)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-((4-(甲基磺胺基)哌啶-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(057)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-((4-(methylsulfonamido)piperidin-1-yl)methyl) -5-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)pyridineamide (057)
(1-(((S)-7-(N-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰)磺胺甲酰基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-3-基)甲基)哌啶-4-基)氨基甲酸甲酯(058)(1-(((S)-7-(N-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)- 2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)pyridinyl)sulfamoyl)-5-nitro-3,4 -Dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl)piperidin-4-yl)carbamate (058)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((S)-3-((二甲胺基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)吡啶酰胺(059)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((S)-3-((dimethylamino)methyl)-5-nitro- 3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)pyridineamide (059)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-(((S)-3-((3-羟基-3-甲基氮杂环丁烷-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)吡啶酰胺(060)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(((S)-3-((3-hydroxy-3-methylazetidine -1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-5-(2-( (S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)pyridineamide (060)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-(((S)-3-(2-(1,1-二氧基硫代吗啉)乙基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(061)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(((S)-3-(2-(1,1-dioxythiomorpholine) )ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-5-(2-((S)- 2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (061)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-3-(四氢-2H-吡喃-4-基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(062)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-di Hydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)pyridineamide (062)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-((3-(1-甲基哌啶-4-基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(063)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-(1-methylpiperidin-4-yl)-5-nitro-3,4-dihydro- 2H-Benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (063)
4-(7-(N-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)吡啶酰)氨磺酰基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-3-基)哌啶-1-羧酸甲酯(064)4-(7-(N-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-iso) Propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)pyridinoyl)sulfamoyl)-5-nitro-3,4-dihydro-2H-benzene Methyl [b][1,4]oxazin-3-yl)piperidine-1-carboxylate (064)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((3-(1-乙酰哌啶-4-基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)吡啶酰胺(065)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-(1-acetylpiperidin-4-yl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl)pyrrole Alk-1-yl)-7-azaspiro[3.5]non-7-yl)pyridineamide (065)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((3-(4-羟基环己基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)吡啶酰胺(066)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-(4-hydroxycyclohexyl)-5-nitro-3,4-dihydro -2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1- yl)-7-azaspiro[3.5]non-7-yl)pyridineamide (066)
2-(((1H-吡咯并[2,3-b]吡啶基-5-基)氧基]-4-(2-(((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-甲基-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(067)2-(((1H-pyrrolo[2,3-b]pyridinyl-5-yl)oxy]-4-(2-(((S)-2-(2-isopropylphenyl)pyrrole Alk-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-methyl-3-((4-methylpiperazin-1-yl) )methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (067)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-(((S)-3-甲基-3-(2-吗啉乙基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(068)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-methyl-3-(2-morpholinoethyl)-5-nitro-3 ,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (068)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((3-(4-羟基环己基)-3-甲基-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(069)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-(4-hydroxycyclohexyl)-3-methyl-5-nitro-3 ,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (069)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-((3-甲基-3-(1-甲基哌啶-4-基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(070)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]non-7-yl)-N-((3-methyl-3-(1-methylpiperidin-4-yl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (070)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((S)-2,2-二甲基-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)苯甲酰胺(071)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((S)-2,2-dimethyl-3-((4-methylpiperazine) -1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(2-( (S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzamide (071)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢螺[苯并[b][1,4]恶嗪-2,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(072)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro -3,4-Dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)sulfonyl)benzamide (072)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢螺[苯并[b][1,4]恶嗪-2,1'-环丁烷]-7-基)磺酰基)苯甲酰胺(073)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro -3,4-Dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclobutane]-7-yl)sulfonyl)benzamide (073)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((S)-3-((4-甲基哌嗪-1-基)甲基)-5-硝基-2-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(074)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]non-7-yl)-N-(((S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro -2-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (074)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((S)-2-((4-甲基哌嗪-1-基)甲基)-8-硝基-3-氧代-1,2,3,4-四氢喹啉-6-基)磺酰基)苯甲酰胺(075)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((S)-2-((4-methylpiperazin-1-yl)methyl)-8-nitro -3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)sulfonyl)benzamide (075)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((1-((1-甲基哌啶-4-基)甲基)-7-硝基-3-氧代-1,3-二氢异苯并呋喃-5-基)磺酰基)苯甲酰胺(076)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((1-((1-methylpiperidin-4-yl)methyl)-7-nitro-3- Oxo-1,3-dihydroisobenzofuran-5-yl)sulfonyl)benzamide (076)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((7-硝基-3-氧基-1-((四氢-2H-吡喃-4-基)甲基)-1,3-二氢异苯并呋喃-5-基)磺酰基)苯甲酰胺(077)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-nitro-3-oxy-1-((tetrahydro-2H-pyran-4-yl) Methyl)-1,3-dihydroisobenzofuran-5-yl)sulfonyl)benzamide (077)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((1-((4-羟基-4-甲基环己基)甲基)-7-硝基-3-氧代-1,3-二氢异苯并呋喃-5-基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(078)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((1-((4-hydroxy-4-methylcyclohexyl)methyl)-7- Nitro-3-oxo-1,3-dihydroisobenzofuran-5-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (078)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡 咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((7-硝基-1-((四氢-2H-吡喃-4-基)甲基)吲哚-5-基)磺酰基)苯甲酰胺(079)(S)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-nitro-1-((tetrahydro-2H-pyran-4-yl)methyl)indole -5-yl)sulfonyl)benzamide (079)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((1-((4-羟基-4-甲基环己基)甲基)-7-硝基吲哚-5-基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(080)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((1-((4-hydroxy-4-methylcyclohexyl)methyl )-7-nitroindol-5-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5] Nonan-7-yl)benzamide (080)
N-((1-((1,4-二恶烷-2-基)甲基)-7-硝基吲哚-5-基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(081)N-((1-((1,4-dioxan-2-yl)methyl)-7-nitroindol-5-yl)sulfonyl)-2-((1H-pyrrolo[2, 3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)benzamide (081)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((7-硝基-2-氧基-1-((四氢-2H-吡喃-4-基)甲基)吲哚-5-基)磺酰基)苯甲酰胺(082)(S)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-nitro-2-oxy-1-((tetrahydro-2H-pyran-4-yl) Methyl)indol-5-yl)sulfonyl)benzamide (082)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((7-硝基-2-氧基-1-((四氢-2H-吡喃-4-基)甲基)-2,3-二氢-1H-苯并[d]咪唑-5-基)磺酰基)苯甲酰胺(083)(S)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-nitro-2-oxy-1-((tetrahydro-2H-pyran-4-yl) Methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)sulfonyl)benzamide (083)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(084)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino) Phenyl)sulfonyl)benzamide (084)
N-((4-(((1,4-二恶烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(085)N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3 -b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane- 7-yl)benzamide (085)
N-((4-(((1,4-二恶烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(086)N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3 -b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5] Nonan-7-yl)benzamide (086)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(087)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino) Phenyl)sulfonyl)benzamide (087)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(((1-甲基哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(088)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitro Phenyl)sulfonyl)benzamide (088)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(089)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoropiperidin-4-yl)methyl)amino)- 3-Nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) picolinamide (089)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((吗啉-2-基甲基)氨基)-3-硝基苯基)磺酰基)吡啶甲酰胺(090)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((4-((morpholin-2-ylmethyl)amino)-3-nitrophenyl)sulfonyl)picolinamide ( 090)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(2-吗啉乙酰基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷 -1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(091)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2-morpholinoacetyl)piperidine -4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonan-7-yl)picolinamide (091)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(092)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl)-4- Fluoroperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)picolinamide (092)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-(吗啉甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(093)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-7-yl)sulfonyl)benzamide (093)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(((4-(2-吗啉乙酰基)吗啉-2-基)甲基)氨基)-3-硝基苯基)磺酰基)吡啶甲酰胺(094)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((4-(((4-(2-morpholinoacetyl)morpholin-2-yl)methyl)amino)-3- Nitrophenyl)sulfonyl)picolinamide (094)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-(2-(二甲氨基)乙酰基)吗啉-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(095)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((4-(2-(dimethylamino)acetyl)morpholine- 2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)picolinamide (095)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(096)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((4-fluoro-1-(oxetan-3-yl) )piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)picolinamide (096)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)吡啶甲酰胺(097)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((4-(oxetan-3-yl)morpholin-2-yl) Methyl)amino)phenyl)sulfonyl)picolinamide (097)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(098)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetan-3-yl) Piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)picolinamide (098)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(099)3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoropiperidin-4-yl)methoxy)-3- Nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)pyridine Formamide (099)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(2-吗啉乙酰基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(100)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinoacetyl)piperidine- 4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5]Nonan-7-yl)picolinamide (100)
3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(101)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl)-4-fluoro Piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)picolinamide (101)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(102)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-hydroxy-4-methylcyclohexyl)methyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (102)
乙基4-(((4-(N-(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)-4-氟哌啶-1-甲酸乙酯(103)Ethyl 4-(((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2- (2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino) Methyl)-4-fluoropiperidine-1-carboxylic acid ethyl ester (103)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((2-(二甲氨基)乙基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(104)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((2-(dimethylamino)ethyl)amino)-3-nitro Phenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide ( 104)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((3-异丙基氧基丙基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(105)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((3-isopropyloxypropyl)amino)-3-nitro Phenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide ( 105)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(106)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro -2H-Benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (106)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((3-(二甲氨基)丙基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(107)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitro Phenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide ( 107)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)烟酰胺(108)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl) sulfonyl)nicotinamide (108)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(109)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1-(2-(dimethylamino)acetyl)-4 -Fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)nicotinamide (109)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(110)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl)-4-fluoro Piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)nicotinamide (110)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(2-吗啉乙酰基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(111)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinoacetyl)piperidine- 4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5]Nonan-7-yl)nicotinamide (111)
N-((4-(((1,4-二恶烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(112)N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3 -b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7 -yl)nicotinamide (112)
N-((4-((1,4-二恶烷-2-基)甲氧基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(113)N-((4-((1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b ]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (113)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((吗啉-2-基甲基)氨基)-3-硝基苯基)磺酰基)烟酰胺(114)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((4-((morpholin-2-ylmethyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (114 )
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(115)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoropiperidin-4-yl)methoxy)-3- Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotine Amide (115)
N-((4-((1,4-二恶烷-2-基)甲氧基)-3-硝基苯基)磺酰基)-3-((1H-吡咯并 [2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(116)N-((4-((1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3-b ]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) picolinamide (116)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)烟酰胺(117)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((4-(oxetan-3-yl)morpholin-2-yl) Methyl)amino)phenyl)sulfonyl)nicotinamide (117)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(118)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl)-4-fluoro Piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)nicotinamide (118)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(119)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetan-3-yl) Piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)nicotinamide (119)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(120)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino )phenyl)sulfonyl)benzamide (120)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(121)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino )phenyl)sulfonyl)benzamide (121)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(6-(氧杂环丁烷-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)苯基)磺酰基)苯甲酰胺(122)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(6-(oxetan-3-yl)-2,6-diazaspiro [3.3]Heptan-2-yl)phenyl)sulfonyl)benzamide (122)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(6-(氧杂环丁烷-3-基)-2,6-二氮杂螺[3.4]辛烷-2-基)苯基)磺酰基)苯甲酰胺(123)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(6-(oxetan-3-yl)-2,6-diazaspiro [3.4] Octan-2-yl)phenyl)sulfonyl)benzamide (123)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(7-(氧杂环丁烷-3-基)-2,7-二氮杂螺[3.5]壬烷-2-基)苯基)磺酰基)苯甲酰胺(124)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(7-(oxetan-3-yl)-2,7-diazaspiro [3.5] Nonan-2-yl)phenyl)sulfonyl)benzamide (124)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(125)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((4-fluoro-1-(oxetan-3-yl) )piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)nicotinamide (125)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(126)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetan-3-yl) Piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)nicotinamide (126)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(127)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1-(2-(dimethylamino)acetyl)-4 -Fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)nicotinamide (127)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡 咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(128)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)benzamide (128)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(129)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl)-4-fluoro Piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)benzamide (129)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(130)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1-(2-(dimethylamino)acetyl)-4 -Fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (130)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((((R)-1-(氧杂环丁烷-3-基)吡咯烷-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(131)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((R)-1-(oxetan-3-yl) )pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (131)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((((R)-1-(氧杂环丁烷-3-基)吡咯烷-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(132)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((R)-1-(oxetan-3-yl) )pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (132)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(133)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoropiperidin-4-yl)methyl )amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)benzamide (133)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((S)-吡咯烷-3-基甲基)氨基)苯基)磺酰基)苯甲酰胺(134)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((S)-pyrrolidin-3-ylmethyl)amino)phenyl )sulfonyl)benzamide (134)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(135)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoropiperidin-4-yl)methyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (135)
2-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((1r，4r)-4-羟基-4-甲基环己基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(136)2-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((1r,4r)-4-hydroxy-4-methyl Cyclohexyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane- 7-yl)benzamide (136)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-苯基吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(137)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-phenylpyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)benzamide (137)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-苯基吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(138)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-phenylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (138)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(139)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-fluorophenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)- 3-Nitrophenyl)sulfonyl)benzamide (139)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(叔丁基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(140)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(tert-butyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)-5-fluoro-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3- Nitrophenyl)sulfonyl)benzamide (140)
4-(((4-(N-(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)-4-氟哌啶-1-甲酸甲酯(141)4-(((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2 -Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl )-4-fluoropiperidine-1-carboxylic acid methyl ester (141)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(142)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonan-7-yl)nicotinamide (142)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((R)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(143)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonan-7-yl)nicotinamide (143)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-羟基-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)(144)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-hydroxy-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl) (144)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)苯基)磺酰基)烟酰胺(145)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((1-(oxetan-3-yl)piperidin-4-yl) Methyl)amino)phenyl)sulfonyl)nicotinamide (145)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(146)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((1-(oxetan-3-yl)piperidine- 4-yl)methyl)amino)phenyl)sulfonyl)benzamide (146)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((哌啶-4-基甲基)氨基)苯基)磺酰基)烟酰胺(147)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((piperidin-4-ylmethyl)amino)phenyl)sulfonyl)nicotinamide (147 )
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((哌啶-4-基甲基)氨基)苯基)磺酰基)苯甲酰胺(148)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((piperidin-4-ylmethyl)amino)phenyl)sulfonyl) Benzamide (148)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((5-氧代吡咯烷-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(149)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((5-oxopyrrolidin-2-yl)methyl)amino) Phenyl)sulfonyl)benzamide (149)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((2-(2-氧代咪唑烷-1-基)乙基)氨基)苯基)磺酰基)苯甲酰胺(150)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(2-oximidazolidin-1-yl)ethyl) Amino)phenyl)sulfonyl)benzamide (150)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-氟-1-(氧杂环丁烷-3-基))哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(151)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-(oxy) Hetetan-3-yl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (151)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(152)(S)-4-(((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((4-fluoro-1-(oxetane) -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (152)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-氟-1-异丙基哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1- 基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(153)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-isopropylpiperidine- 4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)benzamide (153)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-异丙基哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(154)(S)-4-(((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-isopropylpiperidine- 4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)nicotinamide (154)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-氟-1-(2,2,2-三氟乙基))哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(155)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-(2,2,2 -Trifluoroethyl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (155)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(2,2,2-三氟乙基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(156)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2,2,2-trifluoroethyl) yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)nicotinamide (156)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-5-甲基苯甲酰胺(157)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((4-fluoro-1-(oxetan-3-yl) )piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-5-methylbenzamide (157)
6-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-2,3-二氟-N-((4-(((4-氟-1-(氧杂环丁烷-3-基))哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(158)6-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-2,3-difluoro-N-((4-(((4-fluoro-1-(oxa Cyclobutan-3-yl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (158)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((2-(1-(氧杂环丁烷-3-基)哌啶-4-基)乙基)氨基)苯基)磺酰基)苯甲酰胺(159)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(1-(oxetan-3-yl)piperidine) Perid-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide (159)
N-(4-(N-(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰基)氨磺酰基)-2-硝基苯基)哌啶-4-甲酰胺(160)N-(4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-iso Propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl)piperidine-4-methyl Amide (160)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(哌啶-4-甲酰胺基)苯基)磺酰基)烟酰胺(161)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(piperidine-4-carboxamido)phenyl)sulfonyl)nicotinamide (161)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((1r，4r)-4-羟基-4-甲基环己基)甲氧基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(162)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((1r,4r)-4-hydroxy-4-methyl cyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7 - Azaspiro[3.5]nonan-7-yl)benzamide (162)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-羟基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(163)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-hydroxycyclohexyl)methyl)amino)- 3-Nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) benzamide (163)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-羟基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(164)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitro Phenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide ( 164)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((((1s，3s)-3-羟基-3-甲基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(165)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((((1s,3s)-3-hydroxy-3- Methylcyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)benzamide (165)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1s，3s)-3-羟基-3-甲基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(166)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1s,3s)-3-hydroxy-3-methylcyclobutane) yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)nicotinamide (166)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((((1r，3r)-3-羟基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(167)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,3r)-3-hydroxycyclobutyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonan-7-yl)benzamide (167)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，3r)-3-羟基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(168)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,3r)-3-hydroxycyclobutyl)methyl) Amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)nicotinamide (168)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((氮杂环丁烷-3-基甲基)氨基)-3-硝基苯基)磺酰基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(169)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((azetidin-3-ylmethyl)amino )-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5] Nonan-7-yl)benzamide (169)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((1-(氧杂环丁烷-3-基)氮杂环丁烷-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(170)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((1-(oxetan-3-yl) )azetidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (170)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((1-(氧杂环丁烷-3-基)氮杂环丁烷-3-基)甲基)氨基)苯基)磺酰基)烟酰胺(171)(S)-4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((1-(oxetan-3-yl)azetidine) Butan-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (171)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(((3-甲基氮杂环丁烷-3-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(172)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((3-methylazetidin-3-yl)methyl) Amino)-3-nitrophenyl)sulfonyl)benzamide (172)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((((1-异丙基-3-甲基氮杂环丁烷-3-基)甲基))氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(173)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((((1-isopropyl-3 -Methylazetidin-3-yl)methyl))amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (173)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2,3-二氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(174)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2,3-difluorophenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl )methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (174)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2,3-二氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)烟酰胺(175)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2,3-difluorophenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl) Amino)-3-nitrophenyl)sulfonyl)nicotinamide (175)
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2,6-二氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(176)2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2,6-difluorophenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl )methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (176)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2,6-二氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)烟酰胺(177)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2,6-difluorophenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl) Amino)-3-nitrophenyl)sulfonyl)nicotinamide (177)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-氟-1-(三 氟甲基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(178)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-(tri Fluoromethyl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1- yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (178)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-环丙基-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(179)(S)-2-(((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-cyclopropyl-4-fluoropiperidine- 4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)benzamide (179)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1-环丁基-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(180)(S)-2-(((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((1-cyclobutyl-4-fluoropiperidine) -4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)benzamide (180)
(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-环戊基-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(181)(S)-2-(((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-cyclopentyl-4-fluoropiperidine- 4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)benzamide (181)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(三氟甲基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(182)(S)-4-(((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((4-fluoro-1-(trifluoromethyl)) Piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7 - Azaspiro[3.5]nonan-7-yl)nicotinamide (182)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-环丙基-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(183)(S)-4-(((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-cyclopropyl-4-fluoropiperidine- 4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)nicotinamide (183)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-环丁基-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(184)(S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-cyclobutyl-4-fluoropiperidine- 4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)nicotinamide (184)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-环戊基-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(185)(S)-4-(((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-cyclopentyl-4-fluoropiperidine- 4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)nicotinamide (185)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(1,1,1-三氟丙-2-基))哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(186)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(1,1,1-trifluoropropane) -2-yl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (186)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(1,1,1,3,3,3-六氟丙-2-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(187)(S)-4-(((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(1,1,1 ,3,3,3-Hexafluoroprop-2-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2- Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (187)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-乙酰基-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(188)(S)-4-(((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-acetyl-4-fluoropiperidine-4) -yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5]Nonan-7-yl)nicotinamide (188)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(1-羟基丙-2-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(189)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(1-hydroxypropan-2-yl) Piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1- yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (189)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(四氢-2H-吡喃-4-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯 基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(190)(S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(tetrahydro-2H- Pyran-4-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (190)
(S)-4-(((4-(N-(4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟碱酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)-4-氟哌啶-1-羧酸甲酯(191)(S)-4-(((4-(N-(4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2 -Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinyl)sulfamoyl)-2-nitrophenyl)amino)methyl )-4-fluoropiperidine-1-carboxylate methyl ester (191)
(S)-4-(((4-(N-(4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟碱酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)-4-氟哌啶-1-羧酸乙酯(192)(S)-4-(((4-(N-(4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2 -Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinyl)sulfamoyl)-2-nitrophenyl)amino)methyl )-4-fluoropiperidine-1-carboxylate ethyl ester (192)
(S)-4-(((4-(N-(4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟碱酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)-4-氟哌啶-1-羧酸异丙酯(193)(S)-4-(((4-(N-(4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2 -Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinyl)sulfamoyl)-2-nitrophenyl)amino)methyl )-4-Fluoropiperidine-1-carboxylate isopropyl ester (193)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(((1-甲基-5-氧代吡咯烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)烟酰胺(194)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino) -3-Nitrophenyl)sulfonyl)nicotinamide (194)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((5-氧代吡咯烷-2-基)甲基)氨基)苯基)磺酰基)烟酰胺(195)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((5-oxopyrrolidin-2-yl)methyl)amino) Phenyl)sulfonyl)nicotinamide (195)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((2-氧代哌啶-4-基)甲基)氨基)苯基)磺酰基)烟酰胺(196)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((2-oxopiperidin-4-yl)methyl)amino) Phenyl)sulfonyl)nicotinamide (196)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((6-氧代哌啶-3-基)甲基)氨基)苯基)磺酰基)烟酰胺(197)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((6-oxopiperidin-3-yl)methyl)amino) Phenyl)sulfonyl)nicotinamide (197)
(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(甲基((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)烟酰胺(198)(S)-4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(methyl((1-(oxetan-3-yl)piperidin-4-yl) )methyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (198)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-氨基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(199)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-amino-4-methylcyclohexyl )methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonan-7-yl)nicotinamide (199)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1r，4r)-(4-氨基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(200)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1r,4r)-(4-aminocyclohexyl)methyl)amino )-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7 - base) niacinamide (200)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1s，3s)-3-氨基-3-甲基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(201)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,3s)-3-amino-3-methylcyclobutane yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)nicotinamide (201)
4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，3r)-3-氨基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(202)4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,3r)-3-aminocyclobutyl)methyl) Amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)nicotinamide (202)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-(((1r，4r)-4-(二甲氨基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(203)4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-((((((1s，4s)-4-(二甲氨基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(204)4-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1r,4r)-4-(dimethylamino)cyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (203)4-((1H-pyrro[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((((1s,4s) -4-(Dimethylamino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (204)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-(((1r，3r)-3-(二甲氨基)环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(205)4-((1H-Pyrro[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1r,3r)-3-(dimethylamino)cyclobutyl)methane yl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5]Nonan-7-yl)nicotinamide (205)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-(((1s，3s)-3-(二甲氨基)环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(206)4-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1s,3s)-3-(dimethylamino)cyclobutyl)methan yl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5]Nonan-7-yl)nicotinamide (206)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-((1r，4r)-4-(羟甲基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(207)4-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-N-((4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl) Amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane- 7-yl)nicotinamide (207)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-(((((((1r，4r)-4-(2-羟基丙烷-2-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(208)4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((((1r,4r)-4-(2-hydroxypropane- 2-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)nicotinamide (208)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-((((((((1R)-3-羟基环戊基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(209)4-((1H-pyrro[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((((((1R)-3-hydroxycyclopentyl)methyl) )amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[ 3.5] Nonan-7-yl)nicotinamide (209)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-((((((((1R)-3-(羟甲基)环戊基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺环[3.5]壬-7-基)烟酰胺(210)4-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((((((1R)-3-(hydroxymethyl)cyclopentan) yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]non-7-yl)nicotinamide (210)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-((3-(羟甲基)环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺环[3.5]壬-7-基)烟酰胺(211)4-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-N-((4-((3-(hydroxymethyl)cyclobutyl)methyl)amino)-3 -Nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan- 7-yl)nicotinamide (211)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-((4-羟基-1-(氧烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(212)4-((1H-pyrro[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-hydroxy-1-(oxan-3-yl)piperidin-4 -yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5]Nonan-7-yl)nicotinamide (212)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-(((((((1s，3s)-3-羟基-3-甲基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(213)4-((1H-Pyrro[2,3-b]pyridin-5-yl)oxy)-N-((4-((((((((1s,3s)-3-hydroxy-3-methyl) Cyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)nicotinamide (213)
4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-((((((((1s，3s)-3-羟基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(214)4-((1H-Pyrro[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((((((1s,3s)-3-hydroxycyclobutyl) Methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)nicotinamide (214)
(S)-4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-异丁基哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(215)(S)-4-((1H-pyrro[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-isobutylpiperidine-4- yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan Alk-7-yl)nicotinamide (215)
(S)-4-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-新戊基哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(216)(S)-4-((1H-pyrro[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-neopentylpiperidine-4- yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[ 3.5] Nonan-7-yl)nicotinamide (216)
术语说明Glossary
除非另有定义，本发明使用的所有技术和科学术语与该领域专业人员通常理解的含义相同。除非另有说明，本发明参考的所有专利文献、公开披露的资料等全文纳入参考文献。如本发明中同一术语有多个定义，以本节中的定义为准。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise stated, all patent documents, publicly disclosed materials, etc. referred to herein are incorporated by reference in their entirety. If there are multiple definitions for the same term in the present invention, the definitions in this section shall prevail.
需要理解的是，前文的一般描述和后文的详细描述仅仅是示范性的和解释性的，对任何权利要求都无限制性。在本发明中，除非另有说明，使用的单数包含复数。需要注意的是，说明书和所附权利要求书中，除非文中另有说明，单数形式指代如“一”、“一个”、“这个”，包含复数指代。还需注意的是，除非另有说明，“或”代表“和/或”。此外，“包含”、“包括”等类似术语不是限制性的。It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claims. In the present invention, unless otherwise stated, the singular number used includes the plural number. It should be noted that, in the specification and the appended claims, unless the context dictates otherwise, singular references such as "a," "an," and "the" include plural references. It is also noted that "or" means "and/or" unless stated otherwise. Furthermore, terms such as "comprising", "including" and the like are not limiting.
“取代”是指氢原子被取代基取代。需要注意的是，特定原子上的取代基是被其价态限制的。在定义部分，“C i-j”是指包括起点和终点的范围，其中i和j都是整数，表示碳原子的数目。例如，C 1-4，C 1-10，C 3-10等。 "Substituted" means that a hydrogen atom is replaced by a substituent. It should be noted that the substituents on a particular atom are restricted by their valence. In the Definitions section, " Cij " refers to a range including a starting point and an ending point, where i and j are both integers and represent the number of carbon atoms. For example, C 1-4 , C 1-10 , C 3-10 and the like.
本发明所用术语“烷基”是指一个具有一至六个碳原子的直链饱和单价烃基或一个具有三至六个碳原子的支链饱和的单价烃基，优选为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基等。烷基可以是无取代或单取代或多取代，多取代时取代基可以相同也可以不同；烷基的取代基选自D(氘)、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、异丙酯、胺甲酰基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基，或者氨基或单取代或多取代氨基，其中氨基的取代基可以相同也可以不同，选自氢、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。 The term "alkyl" used in the present invention refers to a linear saturated monovalent hydrocarbon group having one to six carbon atoms or a branched saturated monovalent hydrocarbon group having three to six carbon atoms, preferably methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc. The alkyl group can be unsubstituted or mono-substituted or multi-substituted, and the substituents can be the same or different when multi-substituted; the substituents of the alkyl group are selected from D (deuterium), halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, Ethyl carboxylate, isopropyl ester, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, alkoxycarbonyl, alkylthio, alkyl Sulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3- to 10-membered heterocyclic group, or amino or mono- or poly-substituted amino, wherein the amino substituents may be the same or different, and are selected from hydrogen , C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6 -C 12 aryl base, C 5 -C 14 heteroaryl.
本发明所用术语“环烷基”是指具有三个至十个碳原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性单价烃基，优选为环丙基、环丁基、环戊基、环己基等，其中一个或两个碳原子可以由一个氧替代。该环烷基可以是无取代或取代的，其取代基选自D、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲 酰胺、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6羟烷基、卤代C 1-C 6烷氧基、C 3-C 6环烷基、卤代C 3-C 6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基，或者氨基或单取代或多取代氨基，其中氨基的取代基可以相同也可以不同，选自氢、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。 The term "cycloalkyl" as used in the present invention refers to a non-aromatic monovalent monocyclic or polycyclic (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) having three to ten carbon atoms. Hydrocarbyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., wherein one or two carbon atoms may be replaced by an oxygen. The cycloalkyl can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the same or different, and are selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
本发明所用术语“烯基”指由碳和氢原子组成，含至少一个双键且具有2至10个碳原子的直链或支链的烃链基团(即C 2-C 10烯基)，包括但不限于乙烯基、烯丙基、丁-1-烯基、戊-1-烯基、戊-1，4-二-烯基等。烯基可被一个或者多个取代基取代，所述取代基独立为D、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、环烷基、卤代环烷基、杂环烷基、芳基、杂芳基、羟基、卤素、氰基、硝基。 The term "alkenyl" as used in the present invention refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, containing at least one double bond and having 2 to 10 carbon atoms (ie, C 2 -C 10 alkenyl) , including but not limited to vinyl, allyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl and the like. Alkenyl may be substituted with one or more substituents independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halo Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
本发明所用术语“炔基”指由碳和氢原子组成，含至少一个叁键且具有2至10个碳原子的直链或支链的烃链基团(即C 2-C 10炔基)，包括但不限于乙炔基、丙炔基、丁炔基、戊炔基和己炔基等。炔基可被一个或者多个取代基取代，所述取代基独立为D、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、环烷基、卤代环烷基、杂环烷基、芳基、杂芳基、羟基、卤素、氰基、硝基。 The term "alkynyl" as used in the present invention refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, containing at least one triple bond and having 2 to 10 carbon atoms (ie C 2 -C 10 alkynyl) , including but not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl and the like. The alkynyl group may be substituted with one or more substituents independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halo Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
“卤素”是指氟、氯、溴和碘。"Halogen" refers to fluorine, chlorine, bromine and iodine.
本发明所用术语“烷氧基”是指-O-烷基基团，其中烷基如上所定义。本发明所用“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。“烷氧基”还包括取代烷氧基，其取代基可为D、卤素、氨基、羟基、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 1-C 6环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。 The term "alkoxy" as used herein refers to an -O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy. "Alkoxy" also includes substituted alkoxy, the substituents of which may be D, halogen, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy , C 1 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
本发明所用术语“烷氨基”是指烷基-NH-，其中烷基如上所定义。本发明所用“烷氨基”的实例包括但不限于甲氨基、乙氨基、丙氨基、异丙氨基等。“烷氨基”还包括取代烷氨基，其取代基可为D、卤素、氨基、羟基、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 1-C 6环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基，其取代基可以取代在烷基上也可以取代在N上。 The term "alkylamino" as used herein refers to alkyl-NH-, wherein alkyl is as defined above. Examples of "alkylamino" used in the present invention include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like. "Alkylamino" also includes substituted alkylamino groups, the substituents of which may be D, halogen, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 cycloalkyl group, 3- to 10-membered heterocyclic group, C 6 -C 12 aryl group, C 5 -C 14 heteroaryl group, the substituents thereof may be substituted on alkyl or N.
本发明所用术语“芳基”是指6到12个碳原子的全碳单环或稠合多环基团(其中一个稠合环可以部分饱和)。芳环的非限制性实例有：苯环、萘环、蒽环、茚环、二氢茚基(茚满基)。芳环可以是无取代或取代的。芳环的取代基选自D、卤素(优选为氟、氯、溴、碘)、氰基、硝基、氨基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲酰胺、C 1-C 6烷基(优选为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基等)、C 1-C 6羟烷基(优选为羟甲基、羟乙基、羟丙基、羟异丙基等)、C 1-C 6烷氧基(优选为甲氧基、乙氧基、丙氧基、异丙基氧基、丁氧基、异丁基氧基、仲丁基氧基、叔丁基氧基等)、卤代C 1-C 6烷基(优选为卤代甲基、卤代乙基、卤代丙基、卤代异丙基、卤代丁基、卤代异丁基、卤代仲丁基、卤代叔丁基等)、卤代C 1-C 6羟烷基(优选为卤代羟甲基、卤代羟乙基、卤代羟丙基、卤代羟异丙基等)、卤代C 1-C 6烷氧(优选为卤代甲氧基、卤代乙氧基、卤代丙氧基、卤代异丙基氧基、 卤代丁氧基、卤代异丁基氧基、卤代仲丁基氧基、卤代叔丁基氧基等)基、C 3-C 6环烷基(优选为环丙基、环戊基、环己基等)、卤代C 3-C 6环烷基(优选为卤代环丙基、卤代环戊基、卤代环己基等)、3至10元杂环基(优选为四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基等)、C 6-C 12芳基、C 5-C 14杂芳基；芳环的取代，可以是单取代(比如邻位、间位、对位取代)，也可以是双取代或者三取代等。 The term "aryl" as used herein refers to an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms (wherein one fused ring may be partially saturated). Non-limiting examples of aromatic rings are: benzene ring, naphthalene ring, anthracene ring, indene ring, dihydroindenyl (indanyl). Aromatic rings can be unsubstituted or substituted. The substituent of the aromatic ring is selected from D, halogen (preferably fluorine, chlorine, bromine, iodine), cyano, nitro, amino, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 - C6 alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), C1 -C 6 hydroxyalkyl (preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc.), C 1 -C 6 alkoxy (preferably methoxy, ethoxy, propoxy , isopropyloxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halogenated C 1 -C 6 alkyl (preferably halogenated methyl, halogenated ethyl, halopropyl, haloisopropyl, halobutyl, haloisobutyl, halosec-butyl, halotert-butyl, etc.), haloC 1 -C 6 hydroxyalkyl ( Preferably halogenated hydroxymethyl, halogenated hydroxyethyl, halogenated hydroxypropyl, halogenated hydroxyisopropyl, etc.), halogenated C 1 -C 6 alkoxy (preferably halogenated methoxy, halogenated ethyl oxy, halopropoxy, haloisopropyloxy, halobutoxy, haloisobutyloxy, halosec-butyloxy, halotert-butyloxy, etc.), C 3 -C 6 cycloalkyl (preferably cyclopropyl, cyclopentyl, cyclohexyl, etc.), halogenated C 3 -C 6 cycloalkyl (preferably halogenated cyclopropyl, halogenated cyclopentyl, halogenated substituted cyclohexyl, etc.), 3- to 10-membered heterocyclic groups (preferably tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.), C 6 -C 12 aryl, C 5 -C 14 Heteroaryl; the substitution of the aromatic ring can be mono-substitution (such as ortho-position, meta-position, para-position substitution), di-substitution or tri-substitution, etc.
本发明所用术语“杂芳基”指5到14个环原子的单环或稠合多环基团(其中一个稠合环可以部分饱和)，相当于上述“芳基”中一个或多个碳被杂原子例如氧、氮、硫等置换。杂芳环可以是单环，也可以是双环，即通过两个环稠合而成。具体的杂芳基(杂环芳基)可以是：吡啶基、嘧啶基、吡嗪基、异恶唑基、异噻唑基、吡唑基、噻唑基、恶唑基、咪唑基、吲哚、二氢吲哚、苯并咪唑等。杂环芳基可以是无取代或取代的。杂环芳基的取代基选自卤素、氰基、硝基、氨基、羟基、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6羟烷基、卤代C 1-C 6烷氧基、C 3-C 6环烷基、卤代C 3-C 6环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。 The term "heteroaryl" as used in the present invention refers to a monocyclic or fused polycyclic group of 5 to 14 ring atoms (one of which may be partially saturated), corresponding to one or more carbons in the above-mentioned "aryl" Replaced by heteroatoms such as oxygen, nitrogen, sulfur, and the like. The heteroaromatic ring can be monocyclic or bicyclic, that is, formed by the fusion of two rings. Specific heteroaryl groups (heterocyclic aryl groups) can be: pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, Indoline, benzimidazole, etc. Heterocyclic aryl groups can be unsubstituted or substituted. The substituent of the heterocyclic aryl group is selected from halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 - C6 alkyl, halogenated C1 - C6 hydroxyalkyl, halogenated C1 - C6 alkoxy, C3 - C6 cycloalkyl, halogenated C3- C6 cycloalkyl, 3 to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
本发明所用术语“杂环基”是指具有三个至十个环原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性环基，具有一个及以上的选自N、O、S的杂原子，且可有1个或多个化学键为双键或三键。该杂环基可以是无取代或取代的，其取代基选自D、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲酰胺、氧代、硫代、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6羟烷基、卤代C 1-C 6烷氧基、C 3-C 6环烷基、卤代C 3-C 6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基，或者氨基或单取代或多取代氨基，其中氨基的取代基可以相同也可以不同，选自氢、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。 The term "heterocyclyl" as used in the present invention refers to a non-aromatic ring having three to ten ring atoms of a monocyclic or polycyclic ring (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) group, has one or more heteroatoms selected from N, O, S, and may have one or more chemical bonds that are double bonds or triple bonds. The heterocyclic group can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, oxo, thio, C 1 - C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, halo C 1 -C 6 hydroxyalkyl, halo C 1 -C 6alkoxy , C3 - C6cycloalkyl , halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, Sulfonamide group, 3- to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group may be the same or different, and are selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
本发明所用术语“螺环基”是指一种多环结构，在这种多环结构中至少有2个环存在共用一个原子(一般为C原子)的情况，在这种多环结构中可以有一个或多个化学键是双键或者三键，且可以有一个或多个杂原子存在。该螺环基可以是无取代或取代的，其取代基选自D、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲酰胺、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6羟烷基、卤代C 1-C 6烷氧基、C 3-C 6环烷基、卤代C 3-C 6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基，或者氨基或单取代或多取代氨基，其中氨基的取代基可以相同也可以不同，选自氢、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基、卤代烷基。 The term "spirocyclyl" used in the present invention refers to a polycyclic structure in which at least two rings share one atom (usually a C atom), and in this polycyclic structure, One or more of the chemical bonds are double or triple bonds, and one or more heteroatoms may be present. The spirocyclic group can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the same or different, and are selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl, haloalkyl.
本发明所用术语“桥环基”是指一种多环结构，在这种多环结构中至少有2个环存在共用2个或2个以上原子的情况，在这种多环结构中可以有一个或多个化学键是双键或者三键，且可以有一个或多个杂原子存在。该桥环基可以是无取代或取代的，其取代基选自D、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲酰胺、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6羟烷基、卤代C 1-C 6烷氧基、 C 3-C 6环烷基、卤代C 3-C 6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基，或者氨基或单取代或多取代氨基，其中氨基的取代基可以相同也可以不同，选自氢、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。卤代烷基。 The term "bridged ring group" used in the present invention refers to a polycyclic structure in which at least two rings share two or more atoms, and in this polycyclic structure there may be One or more of the chemical bonds are double or triple bonds, and one or more heteroatoms may be present. The bridged ring group can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the same or different, and are selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl. haloalkyl.
本发明所用术语“环烯基”是指具有三个至十个碳原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性烃基且至少含有一个双键，优选为环丁烯基、环戊烯基、环己烯基等，其中一个或两个碳原子可以由一个氧原子替代。该环烯基可以是无取代或取代的，其取代基选自D、卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、甲酰胺、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6羟烷基、卤代C 1-C 6烷氧基、C 3-C 6环烷基、卤代C 3-C 6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基，或者氨基或单取代或多取代氨基，其中氨基的取代基可以相同也可以不同，选自氢、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。卤代烷基： The term "cycloalkenyl" as used in the present invention refers to a non-aromatic hydrocarbon group having three to ten carbon atoms in a monocyclic or polycyclic ring (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) And it contains at least one double bond, preferably cyclobutenyl, cyclopentenyl, cyclohexenyl, etc., wherein one or two carbon atoms can be replaced by an oxygen atom. The cycloalkenyl can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the same or different, and are selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl. Haloalkyl:
本发明所用术语“羟烷基”是指-烷基-OH，其中烷基如上所定义。本发明所用“羟烷基”的实例包括但不限于羟甲基、羟乙基、羟丙基、羟异丙基等。“羟烷基”还包括取代羟烷基，其取代基可为D、卤素、氨基、羟基、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。 The term "hydroxyalkyl" as used herein refers to -alkyl-OH, wherein alkyl is as defined above. Examples of "hydroxyalkyl" as used herein include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like. "Hydroxyalkyl" also includes substituted hydroxyalkyl groups, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
本发明所用术语“氨基烷基”是指-烷基-NH 2，其中烷基如上所定义。本发明所用“氨基烷基”的实例包括但不限于氨基甲基、氨基乙基、氨基丙基、氨基异丙基等。“氨基烷基”还包括取代氨基烷基，其取代基可为D、卤素、氨基、羟基、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基，其取代基可以取代在烷基上也可以取代在N上。 The term "aminoalkyl" as used herein refers to -alkyl- NH2 , wherein alkyl is as defined above. Examples of "aminoalkyl" as used herein include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, and the like. "Aminoalkyl" also includes substituted aminoalkyl, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl, and its substituents can be substituted on alkyl or N .
本发明所用术语“烷基羰基”是指烷基-C(O)-，其中烷基如上所定义。“烷基羰基”还包括取代烷基羰基，其取代基可为D、卤素、氨基、羟基、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 3-C 6环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。其中“C(O)”代表C＝O。 The term "alkylcarbonyl" as used herein refers to alkyl-C(O)-, wherein alkyl is as defined above. "Alkylcarbonyl" also includes substituted alkylcarbonyl, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl. Wherein "C(O)" represents C=O.
本发明所用术语“烷氧羰基”：是指烷基-O-C(O)-，其中烷基如上所定义。“烷氧羰基”还包括取代烷氧羰基，其取代基可为D、卤素、氨基、羟基、C 1-C 6烷基、C 1-C 6羟烷基、C 1-C 6烷氧基、C 1-C 6环烷基、3至10元杂环基、C 6-C 12芳基、C 5-C 14杂芳基。 The term "alkoxycarbonyl" as used herein: refers to alkyl-OC(O)-, wherein alkyl is as defined above. "Alkoxycarbonyl" also includes substituted alkoxycarbonyl, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 1 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
本发明所用术语“卤代羟烷基”是指被卤素(优选为氟、氯、溴、碘)取代的羟烷基基团，其中羟烷基如上所定义。“卤代羟烷基”可被卤素取代一次或多次。The term "halohydroxyalkyl" as used herein refers to a hydroxyalkyl group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein hydroxyalkyl is as defined above. "Halohydroxyalkyl" may be substituted one or more times with halogen.
本发明所用术语“卤代烷氨基”是指被卤素(优选为氟、氯、溴、碘)取代的烷氨基基团，其中烷氨基如上所定义。“卤代烷氨基”可被卤素取代一次或多次。The term "haloalkylamino" as used herein refers to an alkylamino group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein alkylamino is as defined above. "Haloalkylamino" may be substituted one or more times with halogen.
为避免歧义，例如：当提到烷基、环烷基、杂环基烷基、芳基和/或杂芳基取代时，其意是指每个这些基团单独地取代，或是指这些基团混合取代。For the avoidance of doubt, for example: when referring to alkyl, cycloalkyl, heterocyclylalkyl, aryl and/or heteroaryl substitution, it means that each of these groups is substituted individually, or that these Group mixed substitution.
“药学上可接受的盐”是指与药学上可接受的无毒酸盐和碱盐，包括无机或有机碱 和无机或有机酸制成的盐。无机碱的盐可以选自，例如：铵、钙、镁、钾、钠、锌盐。进一步，药学上可接受的无机碱的盐可选自铵、钙、镁、钾和钠盐。在固体盐中可能存在一个或多个晶体结构，也有可能存在水合物的形式。"Pharmaceutically acceptable salts" refers to salts prepared with pharmaceutically acceptable non-toxic acid and base salts, including inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases can be selected from, for example, ammonium, calcium, magnesium, potassium, sodium, zinc salts. Further, salts of pharmaceutically acceptable inorganic bases may be selected from ammonium, calcium, magnesium, potassium and sodium salts. One or more crystal structures may exist in solid salts, and hydrated forms may also exist.
“药学上可接受的加碱盐”是指那些保留了化合物的游离酸的生物效力和特性，需要与至少一种药学上可接受的无毒碱制备其盐，这些碱选自无机和有机碱。例如：伯胺、仲胺和叔胺盐，取代胺包括自然存在的取代胺、环胺和碱性离子交换树脂如精氨酸、甜菜碱、咖啡碱、胆碱、N,N-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、氨基葡萄糖、组氨酸，海巴明胺、异丙胺、赖氨酸、吗啉、哌嗪、哌啶、嘌呤、可可碱、三乙胺、三甲胺和三丙胺、氨丁三醇。"Pharmaceutically acceptable base-added salts" are those that retain the biological potency and properties of the free acid of the compound and require the preparation of salts thereof with at least one pharmaceutically acceptable non-toxic base selected from inorganic and organic bases . For example: primary, secondary and tertiary amine salts, substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethyl Diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, heba amine, isopropylamine, lysine, morpholine, piperazine, piperidine, purine, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.
“药学上可接受的加酸盐”是指那些保留了化合物的游离碱的生物效力和特性，需要与至少一种药学上可接受的无毒酸制备其盐，这些酸选自无机和有机酸。例如，选自醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙烷磺酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、粘酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸和对甲苯磺酸。更为优选为柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸、富马酸和酒石酸。"Pharmaceutically acceptable addition salts" refers to those that retain the biological potency and properties of the compound's free base and require the preparation of its salts with at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids . For example, selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, horse Lactic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. More preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid and tartaric acid.
化合物或其药学上可接受的盐的“给予”或“给药”是指为需要治疗的个体提供本发明中的化合物或其药学可接受的盐。"Administering" or "administering" a compound or a pharmaceutically acceptable salt thereof refers to providing a compound of the present invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment.
“有效量”是指化合物或其药学上可接受的盐能够引起组织、系统、动物或人类出现可被研究人员、兽医、临床医生或其他临床人员观察到的生物学或医学反应的剂量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其他所需的变化。An "effective amount" refers to a dose of a compound, or a pharmaceutically acceptable salt thereof, that elicits a biological or medical response in a tissue, system, animal or human observable by a researcher, veterinarian, clinician or other clinician. The result can be a reduction and/or amelioration of signs, symptoms or causes, or any other desired change in the biological system.
“药物组合物”包括：混合有本发明的化合物(有效成分)和作为载体的惰性成分的产品，以及任何两个或两个以上的成分直接或间接，通过组合、复合或聚集而制成的产品，或通过一个或更多的成分分解产生的产品，或通过一个或更多的成分发生其他类型反应或相互作用产生的产品。"Pharmaceutical composition" includes: a product mixed with the compound of the present invention (active ingredient) and an inert ingredient as a carrier, and any two or more ingredients directly or indirectly made by combining, compounding or aggregating A product, or a product that results from the decomposition of one or more components, or a product that results from other types of reactions or interactions of one or more components.
“药学可接受”是指针对那些化合物、材料、组合物和/或剂型而言，在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，并且对施用对象无不可接受的毒害。"Pharmaceutically acceptable" means those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues and are not unacceptable to the subject of administration of poison.
“个体”是指患有疾病、病症之类的个体，包括哺乳动物和非哺乳动物。哺乳动物包括，但不仅限于，哺乳类的任何成员：人类，非人类的灵长类动物(如黑猩猩，和其他猿类和猴子)；农场动物如牛、马、绵羊、山羊、猪；家畜如兔、狗和猫；实验动物包括啮齿类如大鼠、小鼠和豚鼠等。非哺乳类动物包括，但不仅限于，鸟类、鱼类等。本发明的一个实施例中，哺乳动物为人类。"Individual" refers to an individual suffering from a disease, disorder, or the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian species: humans, non-human primates (such as chimpanzees, and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as Rabbits, dogs and cats; experimental animals include rodents such as rats, mice and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In one embodiment of the present invention, the mammal is a human.
“治疗”是指对哺乳动物特别是人类的相关疾病或病症的治疗，包括预防其他症状，改善或预防症状的潜在代谢因素，抑制疾病或症状，例如，阻止疾病或症状发展，减轻疾病或症状，促进疾病或症状缓解，或使疾病或症状的病征停止，和延伸至包括预防；缓解、减轻或改善疾病或症状；抑制疾病或病症，即控制其发展。“治疗”还包括 实现治疗性获益和/或预防性获益。治疗性获益是指根除或改善所治疗的病症。此外，治疗性获益通过根除或改善一个或多个与潜在疾病相关的生理病征达到，尽管患者可能仍患有潜在疾病，但可观察到患者疾病的改善。预防性获益是指，患者为预防某种疾病风险而使用组合物，或患者出现一个或多个疾病生理病症时使用，尽管尚未诊断此疾病。"Treatment" means the treatment of an associated disease or condition in mammals, particularly humans, including prevention of other symptoms, amelioration or prevention of underlying metabolic factors of symptoms, inhibition of disease or symptoms, for example, arresting the progression of disease or symptoms, alleviation of disease or symptoms , to promote the remission of a disease or symptom, or to stop the symptoms of a disease or symptom, and by extension to include prevention; alleviation, alleviation or amelioration of a disease or symptom; inhibition of a disease or condition, i.e. controlling its progression. "Treatment" also includes achieving a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the condition being treated. Furthermore, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, although the patient may still have the underlying disease, but improvement in the patient's disease may be observed. Prophylactic benefit refers to the use of a composition by a patient to prevent a risk of a disease, or when a patient develops one or more physiological conditions of the disease, even though the disease has not been diagnosed.
“保护基”(Pg)是指一类用于与化合物上其它官能团反应而阻隔或保护特定官能团的取代基。这些官能团包括氨基、羧基、巯基和羟基。对于保护基的一般描述和使用说明，见参考文献：T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。"Protecting group" (Pg) refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. These functional groups include amino, carboxyl, sulfhydryl and hydroxyl groups. For a general description and instructions for use of protecting groups, see reference: T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
“NH保护基”包含，但不仅限于，三氯乙氧羰基、三溴乙氧羰基、苄氧羰基(Cbz)、芴基甲氧基羰基(Fmoc)、烯丙氧羰基(Alloc)、对硝基苄甲酰基、邻溴苄氧羰基、氯乙酰基、二氯乙酰基、三氯乙酰基、三氟乙酰基、苯乙酰基、甲酰基、乙酰基、苯甲酰基、叔戊氧羰基、叔丁氧羰基(Boc)、对甲氧基苄氧羰基、3,4-二甲氧基苄氧羰基、二苯基甲氧羰基、1,1-二甲基丙氧基羰基、异丙氧羰基、邻苯二甲酰(Pht)、琥珀酰、丙氨酰、亮氨酰、苄基、二苯甲基、三苯甲基、2-硝基苯基硫基、甲磺酰基、对甲苯磺酰基、N,N-二甲基氨基亚甲基、苯亚甲基、2-羟基苯亚甲基3-羟基-4-吡啶基亚甲基、亚环己基、2-乙氧基羰基亚环己基、2-乙氧基羰基亚环戊基、2-乙酰基亚环己基、3,3-二甲基-5-氧亚环己基、二苯基磷酰基、二苄基磷酰基、三甲基硅烷基、三乙基硅烷基和三苯基硅烷基。"NH protecting groups" include, but are not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), p-nitro Benzylcarbonyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-pentyloxycarbonyl, tertiary Butoxycarbonyl (Boc), p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl , phthaloyl (Pht), succinyl, alanyl, leucyl, benzyl, benzyl, trityl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl Acyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylidene Hexyl, 2-ethoxycarbonylcyclopentylene, 2-acetylcyclohexylene, 3,3-dimethyl-5-oxycyclohexylene, diphenylphosphoryl, dibenzylphosphoryl, trimethyl silyl, triethylsilyl and triphenylsilyl.
“C(O)OH”保护基包含，但不仅限于，甲基、乙基、正丙基、异丙基、1,1-二甲基丙基、正丁基、叔丁基、苯基、萘基、苄基、二苯甲基、三苯甲基、对硝基苄基、对甲氧基苄基、双(对甲氧苯基)甲基、乙酰甲基、苯甲酰甲基、对硝基苯甲酰甲基、对溴苯甲酰甲基、对甲磺酰苯甲酰甲基、2,2,2-三氯乙基、2-(三甲基硅烷基)乙基、乙酰氧基甲基、丙酰氧基甲基、新戊酰氧基甲基、邻苯二甲酰亚胺甲基、琥珀酰亚胺甲基、环丙基、甲氧基甲基、甲氧基乙氧基甲基、2-(三甲基硅烷基)乙氧基甲基、苄基氧基甲基、甲基硫基甲基、2-甲基硫基乙基、苯基硫基甲基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、三甲基硅烷基、三乙基硅烷基、三异丙基硅烷基、二乙基异丙基硅烷基、叔丁基二甲基硅烷基、叔丁基二苯基硅烷基、二苯基甲基硅烷基和叔丁基甲氧基苯基硅烷基。"C(O)OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, Naphthyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, Acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidylmethyl, cyclopropyl, methoxymethyl, methoxy Ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl group, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diisopropylsilyl Ethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.
“OH或SH”保护基包含，但不仅限于，苄氧羰基、4-硝基苄氧羰基、4-溴苄氧羰基、4-甲氧基苄氧羰基、3,4-二甲氧基苄氧羰基、甲氧基羰基、乙氧基羰基、叔丁氧羰基、1,1-二甲基丙氧基羰基、异丙氧羰基、异丁氧羰基、二苯基甲氧基羰基、2,2,2-三氯乙氧基羰基、2,2,2-三溴乙氧基羰基、2-(三甲基硅烷)乙氧基羰基、2-(苯磺酰基)乙氧基羰基、2-(三苯基磷鎓基)乙氧基羰基、2-糠基氧基羰基、1-金刚烷氧基羰基、乙烯基氧基羰基、烯丙基氧基羰基、4-乙氧基-1-萘基氧基羰基、8-喹啉基氧基羰基、乙酰基、甲酰基、氯乙酰基、二氯乙酰基、三氯乙酰基、三氟乙酰基、甲氧基乙酰基、苯氧基乙酰基、特戊酰基、苯甲酰基、甲基、叔丁基、2,2,2-三氯乙基、2-三甲基硅 烷基乙基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、苄基(苯基甲基)、对甲氧基苄基、3,4-二甲氧基苄基、二苯基甲基、三苯基甲基、四氢呋喃基、四氢吡喃基、四氢噻喃基、甲氧基甲基、甲基硫基甲基、苄基氧基甲基、2-甲氧基乙氧基甲基、2,2,2-三氯-乙氧基甲基、2-(三甲基硅烷基)乙氧基甲基、1-乙氧基乙基、甲磺酰基、对甲苯磺酰基、三甲基硅烷基、三乙基硅烷基、三异丙基硅烷基、二乙基异丙基硅烷基、叔丁基二甲基硅烷基、叔丁基二苯基硅烷基、二苯基甲基硅烷基和叔丁基甲氧基苯基硅烷基。"OH or SH" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl Oxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2, 2,2-Trichloroethoxycarbonyl, 2,2,2-Tribromoethoxycarbonyl, 2-(trimethylsilane)ethoxycarbonyl, 2-(benzenesulfonyl)ethoxycarbonyl, 2 -(Triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1 - Naphthyloxycarbonyl, 8-quinolinyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxy Acetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propene base, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, Triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl group, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsulfonyl Methylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethyl Silyl and tert-butylmethoxyphenylsilyl.
本发明化合物中可能存在几何异构体。本发明化合物可能存在E或Z构型的碳-碳双键或碳-氮双键，其中“E”代表较优的取代基在碳-碳双键或碳-氮双键的异侧，而“Z”代表较优的取代基在碳-碳双键或碳-氮双键的同侧，较优的取代基可以按Cahn-Ingold-Prelog优先规则确定。本发明化合物也可能以“E”和“Z”异构体的混合物形式存在。环烷基或杂环基周围的取代基可以定为顺式或反式构型。此外，本发明包括由金刚烷环系周围取代基排列不同形成的不同异构体及其混合物。金刚烷环系中的一个单环周围的两个取代基被定为Z或E相对构型。例如，见C.D.Jones,M.Kaselj,R.N.Salvatore,W.J.le Noble J.Org.Chem.1998,63,2758-2760。Geometric isomers may exist in the compounds of the present invention. The compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in E or Z configuration, wherein "E" represents the preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond, and "Z" represents that the preferred substituent is on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, and the preferred substituent can be determined according to the Cahn-Ingold-Prelog precedence rule. The compounds of the present invention may also exist as mixtures of "E" and "Z" isomers. Substituents around a cycloalkyl or heterocyclyl group can be designated in either the cis or trans configuration. In addition, the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. The two substituents around a single ring in the adamantane ring system are assigned the Z or E relative configuration. See, for example, C.D. Jones, M. Kaselj, R.N. Salvatore, W.J.le Noble J.Org.Chem. 1998, 63, 2758-2760.
本发明化合物可能含有不对称中心，这些不对称中心可以独立的为R或S构型“R”和“S”的定义见IUPAC 1974Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.Chem.(1976)45,13-10。含有不对称取代碳原子的化合物，若R和S构型的量相同，则为外消旋体。若其中一种构型比另一构型的量更多，则手性碳原子的构型以量多的构型表示，优选对映体过量约85-90％，更优选约95-99％，进一步约99％以上。因此，本发明包含外消旋混合物、相对和绝对立体异构体、和相对和绝对立体异构体的混合物。The compounds of the present invention may contain asymmetric centers, which may independently be in the R or S configuration. "R" and "S" are defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45 , 13-10. A compound containing an asymmetrically substituted carbon atom is a racemate if the amounts of R and S configurations are the same. If one of the configurations is present in greater quantity than the other, the configuration of the chiral carbon atom is represented by the configuration in which the quantity is greater, preferably about 85-90% enantiomeric excess, more preferably about 95-99% , further about 99% above. Accordingly, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
同位素富集或标记化合物Isotopically enriched or labeled compounds
本发明化合物可以同位素标记或富集的形式存在，包含一个或多个与自然界最普遍原子质量和质量数不同的原子。同位素可以为放射性或非放射性同位素。原子如氢、碳、氮、磷、硫、氟、氯和碘的同位素包括，但不仅限于， 2H、 3H、 13C、 14C、 15N、 18O、 31P、 32P、 35S、 18F、 36Cl、 123I和 125I。 The compounds of the present invention may exist in isotopically labeled or enriched forms, containing one or more atoms that differ in atomic mass and mass number from those most commonly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.
本发明同位素标记化合物可作为测定Bcl-2抑制剂效果的结合试验的标准化合物。含同位素的化合物可用于药学研究，评价非同位素标记母体化合物的作用机制和代谢途径，研究化合物的体内代谢(in vivo metabolic fate)(Blake et al.J.Pharm.Sci.64,3,367-391(1975))。这类代谢研究对于设计安全有效的治疗药物十分重要，可判断是给予患者的体内活性化合物或是母体化合物的代谢产物具有毒性或致癌性(Foster et al.,Advances in Drug Research Vol.14,pp.2-36,Academic press,London,1985；Katoetal,J.Labelled Comp.Radiopharmaceut.,36(10):927-932(1995)；Kushner et al.,Can.J.Physiol.Pharmacol,77,79-88(1999))。Isotopically-labeled compounds of the present invention can be used as standard compounds in binding assays to determine the efficacy of Bcl-2 inhibitors. Compounds containing isotopes can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotopically labeled parent compounds, and to study the in vivo metabolic fate of compounds (Blake et al.J.Pharm.Sci.64,3,367-391( 1975)). Such metabolic studies are very important for the design of safe and effective therapeutic drugs, which can determine whether the active compound administered to the patient or the metabolite of the parent compound is toxic or carcinogenic (Foster et al., Advances in Drug Research Vol.14, pp. 2-36, Academic press, London, 1985; Kato et al, J. Labelled Comp. Radiopharmaceut., 36(10): 927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol, 77, 79 -88 (1999)).
本发明的第二个目的是提供一种药物组合物，包括上述任意一项技术方案所述的化合物中的一种或多种。本发明所述的药物组合物可以是上述任意一项技术方案所述 的化合物中的一种或多种与其他化合物组成，或者上述任意一项技术方案所述的化合物中的一种或多种组成。The second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any one of the above technical solutions. The pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above technical solutions and other compounds, or one or more of the compounds described in any of the above-mentioned technical solutions composition.
一种如上述任一项所述化合物在制备单独或与其他药物联合应用治疗从BCL-2活性的抑制中获益的疾病、障碍或病症的药物中的应用。Use of a compound as described in any of the above in the manufacture of a medicament for use alone or in combination with other medicaments for the treatment of diseases, disorders or conditions that benefit from inhibition of BCL-2 activity.
本发明所述化合物或药学可接受的盐可单独使用，或与其他治疗剂联合使用。The compounds or pharmaceutically acceptable salts of the present invention may be used alone or in combination with other therapeutic agents.
例如，使用辅佐药物可增强本发明中的化合物的治疗效果(例如，单独使用辅佐药物的治疗性获益极小，但与另一种药物合用时，可增强个体的治疗性获益)，或者，例如，本发明的化合物与另一个同样具有疗效的治疗剂合用可增强个体的治疗获益。或者，例如，如果使用本发明化合物的不良反应是恶心，那么可合用抗恶心的药物。或者，可以联合的疗法包括，但不仅限于物理疗法、心理疗法、放射疗法、疾病区域的压迫疗法、休息、膳食改善等。无论治疗何种疾病、病症或病况，两种疗法使个体的治疗受益应具有加成效应或协同效应。For example, the use of an adjuvant drug enhances the therapeutic effect of a compound of the invention (eg, the adjuvant drug alone has minimal therapeutic benefit, but when used in combination with another drug, enhances the individual's therapeutic benefit), or For example, the combination of a compound of the present invention with another therapeutic agent that is also therapeutic can enhance the therapeutic benefit of an individual. Alternatively, for example, if nausea is an adverse reaction to the use of the compounds of the present invention, an anti-nausea drug may be used in combination. Alternatively, therapies that may be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy on the diseased area, rest, dietary modification, and the like. Regardless of the disease, disorder or condition being treated, the two therapies should have an additive or synergistic effect to benefit the individual's treatment.
在本发明所述化合物与其他治疗剂合用情况下，给药途径可与其他药物相同，或由于物理和化学性质不同，给药途径可以不相同。因此本文描述的化合物与另一治疗剂可同时、先后或分别给药。When the compound of the present invention is used in combination with other therapeutic agents, the route of administration may be the same as that of other drugs, or the route of administration may be different due to different physical and chemical properties. Thus a compound described herein and another therapeutic agent can be administered simultaneously, sequentially or separately.
式(I)、(II)、(III-A)或式(III-B)(IV-A)、(IV-B)、(V-A)、(V-B1)～(V-B5)、(VI-A1)、(VI-A2)、(VII)、(VIII-A1)～(VIII-A5)、IX所示的化合物与如下一种或多种药物合用预期有效：烷化剂、血管生成抑制剂、抗体、抗代谢物、抗有丝分裂、抗增殖、抗病毒剂、aurora激酶抑制剂、其他细胞凋亡的启动子(例如，Bcl-xL、Bcl-w和Bfl-1)抑制剂、死亡受体途径活化剂、Bcr-Abl激酶抑制剂、BiTE(双特异性T细胞衔接器)的抗体、抗体药物偶联物、生物反应调节剂、细胞周期蛋白依赖性激酶抑制剂、细胞周期抑制剂、环氧合酶-2抑制剂、DVDs、白血病病毒癌基因同源基因(ErbB2)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白乙酰化酶(HDAC)抑制剂、激素疗法、免疫制剂、细胞凋亡蛋白抑制剂的抑制剂(IAPs)、嵌入抗生素、激酶抑制剂、驱动蛋白抑制剂、Jak2抑制剂、针对哺乳动物的雷帕霉素抑制剂、微RNA、丝裂原活化的细胞外信号调节的激酶抑制剂、多价结合蛋白、非类固醇类抗炎药(NSAIDs)、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制剂、铂类化疗药物、polo样激酶(Plk)抑制剂、磷酸肌醇3激酶(PI3K)抑制剂、BTK抑制剂、蛋白酶体抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、类视黄醇/deltoid植物生物碱、小干扰RNA(siRNAs)、拓扑异构酶抑制剂、泛素连接酶抑制剂和类似物。Formula (I), (II), (III-A) or formula (III-B) (IV-A), (IV-B), (V-A), (V-B1)～(V-B5), ( The compounds represented by VI-A1), (VI-A2), (VII), (VIII-A1) to (VIII-A5), and IX are expected to be effective in combination with one or more of the following drugs: alkylating agents, angiogenesis Inhibitors, antibodies, antimetabolites, antimitotic, antiproliferative, antiviral agents, aurora kinase inhibitors, other apoptosis promoters (eg, Bcl-xL, Bcl-w, and Bfl-1) inhibitors, death Receptor pathway activators, Bcr-Abl kinase inhibitors, BiTE (bispecific T cell engager) antibodies, antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors , cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogene homologous gene (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone acetylase (HDAC) ) inhibitors, hormone therapy, immunologic agents, inhibitors of apoptosis proteins (IAPs), intercalated antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, rapamycin inhibitors for mammals, MicroRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, nonsteroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, Platinum chemotherapy drugs, polo-like kinase (Plk) inhibitors, phosphoinositide 3 kinase (PI3K) inhibitors, BTK inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors , retinoid/deltoid plant alkaloids, small interfering RNAs (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors and the like.
特定的，其中所述病症、障碍或病灶包括但不仅限于感染性疾病、免疫性疾病、炎性疾病或细胞增殖异常疾病。In particular, wherein the condition, disorder or focus includes, but is not limited to, infectious disease, immune disease, inflammatory disease or abnormal cell proliferation.
特定的，其中所述的感染性疾病、免疫性疾病、炎性疾病包括但不限于哮喘、由中性粒细胞趋化性导致的疾病(例如，心肌梗死和中风的再灌注损伤和炎症性关节炎)、感染性休克、T细胞介导的疾病、免疫抑制相关疾病(如预防器官移植排斥、移植物抗宿主病、红斑狼疮、多发性硬化和类风湿关节炎)、胰腺炎、与血管发生或血管生成相关疾病(例如急性和慢性炎症性疾病如类风湿性关节炎、炎性肠病、皮肤病如银屑病、 湿疹和硬皮病)；肺慢性阻塞性疾病(COPD)和其他疾病。In particular, infectious diseases, immune diseases, and inflammatory diseases described therein include, but are not limited to, asthma, diseases caused by neutrophil chemotaxis (eg, myocardial infarction and stroke, reperfusion injury and inflammatory joints). inflammation), septic shock, T cell-mediated diseases, immunosuppression-related diseases (eg, prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis), pancreatitis, and angiogenesis or angiogenesis-related diseases (eg acute and chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma); chronic obstructive pulmonary disease (COPD) and other diseases .
特定的，其中所述细胞增殖异常疾病包括癌性增殖性疾病、非癌性增殖性疾病，包括但不限于淋巴瘤、骨肉瘤、皮肤癌、乳腺癌、肾癌、前列腺癌、结肠直肠癌、甲状腺癌、卵巢癌、胰腺癌、神经胶质瘤、表皮样癌、血管瘤、肺癌或胃癌，再狭窄和良性前列腺肥大(BPH)。In particular, wherein the abnormal cell proliferation diseases include cancerous proliferative diseases, non-cancerous proliferative diseases, including but not limited to lymphoma, osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, Thyroid, ovarian, pancreatic, glioma, epidermoid, hemangioma, lung or gastric cancer, restenosis and benign prostatic hypertrophy (BPH).
本发明所述化合物可以以药物组合物形式给药，可以通过任何常规途径给药；本发明所述的化合物可以形成固体、半固体、液体或气体形态的药物制剂，比如片剂、胶囊、注射剂、混悬液、洗剂、凝胶剂、软膏剂、乳膏剂、栓剂、吸入剂等形式。The compounds of the present invention can be administered in the form of pharmaceutical compositions, which can be administered by any conventional route; the compounds of the present invention can be formed into pharmaceutical preparations in the form of solid, semi-solid, liquid or gas, such as tablets, capsules, and injections , suspensions, lotions, gels, ointments, creams, suppositories, inhalants and the like.
含有本发明所述的以游离碱或药学可接受盐型的化合物与至少一种药学可接受的载体或稀释剂的药物组合物，可以常规方式通过混合、制粒、包衣、溶解或冷冻干燥流程来制造。用于口服的单位剂量形式包含，例如，从约0.1mg至约500mg活性物质。The pharmaceutical composition containing the compound of the present invention in the form of a free base or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent can be mixed, granulated, coated, dissolved or lyophilized in a conventional manner. process to manufacture. A unit dosage form for oral administration contains, for example, from about 0.1 mg to about 500 mg of active substance.
本发明发明人通过实验证实，本发明化合物具有强效的BCL2/BAK阻断活性和体外抗肿瘤细胞增殖抑制活性。可应用于在单独或与其他药物联合应用治疗从抗凋亡蛋白BCL-2抑制中获益的感染性疾病、免疫性疾病、炎性疾病或细胞增殖异常等。The inventors of the present invention have confirmed through experiments that the compounds of the present invention have potent BCL2/BAK blocking activity and in vitro anti-tumor cell proliferation inhibitory activity. It can be used alone or in combination with other drugs to treat infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation that benefit from the inhibition of anti-apoptotic protein BCL-2.
具体实施方式Detailed ways
下面通过实施例来说明本发明的可实施性，本领域的技术人员应当理解，根据现有技术的教导，对相应的技术特征进行修改或替换，仍然属于本发明要求保护的范围。The practicability of the present invention will be described below through examples. Those skilled in the art should understand that, according to the teachings of the prior art, modification or replacement of corresponding technical features still belongs to the scope of protection of the present invention.
实施例1：(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(001)Example 1: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4] Oxazine-3,1'-cyclopropan]-7-yl)sulfonyl)benzamide (001)
Figure PCTCN2021126588-appb-000028
Figure PCTCN2021126588-appb-000028
步骤1，将(S)-2-(2-溴苯基)吡咯烷-1-羧酸叔丁基酯(4.5g)和异丙基硼酸(3.1g)溶解于15mL1,4-环氧六环和3mL水的混合溶剂中，在氮气保护下加入碳酸钾(6g)和Pd(dffp) 2Cl 2(0.9g)，加热至回流反应过夜。TLC监测，反应完毕之后降至室温，加入乙酸乙酯，分别用水和饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化得到产物(S)-2-(2-异丙基苯基)吡咯烷-1-羧酸叔丁基酯(3.4g)，收率85％。 Step 1, Dissolve (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylate tert-butyl ester (4.5g) and isopropylboronic acid (3.1g) in 15mL of 1,4-epoxyhexanol To a mixed solvent of ring and 3 mL of water, potassium carbonate (6 g) and Pd(dffp) 2 Cl 2 (0.9 g) were added under nitrogen protection, and heated to reflux for overnight reaction. TLC monitoring, after the reaction was completed, it was lowered to room temperature, ethyl acetate was added, washed with water and saturated brine respectively, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the product (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (3.4 g), 85% yield.
步骤2，将(S)-2-(2-异丙基苯基)吡咯烷-1-羧酸叔丁基酯(3g)溶解于18mL二氯甲烷中，加入三氟乙酸(9mL)，在室温下搅拌反应过夜。TLC监测，反应完毕之后，减压浓缩干溶剂，得到粗品(S)-2-(2-异丙基苯基)吡咯烷(1.92g)，产物无需进一步纯化直接用于下一步反应。In step 2, (S)-2-(2-isopropylphenyl)pyrrolidine-1-carboxylate tert-butyl ester (3g) was dissolved in 18mL of dichloromethane, trifluoroacetic acid (9mL) was added, and The reaction was stirred at room temperature overnight. TLC monitoring, after the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude product (S)-2-(2-isopropylphenyl)pyrrolidine (1.92g), which was used in the next reaction without further purification.
步骤3，将(S)-2-(2-异丙基苯基)吡咯烷(1.85g)和2-氧代-7-氮杂螺[3.5]壬 烷-7-羧酸叔丁基酯(2.4g)溶解于25mL1,2-二氯乙烷中，室温下搅拌15分钟后加入醋酸硼氢化钠(4.2g)，反应约4小时之后，TLC监测反应完毕，加入碳酸氢钠水溶液淬灭反应，用二氯甲烷萃取。有机相分离之后减压浓缩，所得粗品经硅胶柱层析纯化得到固体产物(S)-2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-羧酸叔丁基酯(3.6g)，收率90％。LC-MS(ESI-MS):413[M+H] +。 Step 3, (S)-2-(2-isopropylphenyl)pyrrolidine (1.85g) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (2.4g) was dissolved in 25mL of 1,2-dichloroethane, stirred at room temperature for 15 minutes, and then added sodium borohydride (4.2g), after about 4 hours of reaction, TLC monitoring the completion of the reaction, adding sodium bicarbonate aqueous solution to quench The reaction was extracted with dichloromethane. The organic phase was separated and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain a solid product (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5] Nonane-7-carboxylate tert-butyl ester (3.6 g), yield 90%. LC-MS (ESI-MS): 413 [M+H] + .
步骤4，将(S)-2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-羧酸叔丁基酯(3g)溶解于15mL二氯甲烷中，加入三氟乙酸(7.5mL)，在室温下搅拌反应过夜。TLC监测，反应完毕之后，减压浓缩干溶剂，加入二氯甲烷重新溶解，分别用饱和碳酸氢钠水溶液和清水洗涤，分离有机相，减压浓缩后所得粗品经硅胶柱层析纯化得到固体产物(S)-2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷(1.92g)，收率83％。Step 4, (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester ( 3g) was dissolved in 15 mL of dichloromethane, trifluoroacetic acid (7.5 mL) was added, and the reaction was stirred at room temperature overnight. TLC monitoring, after the reaction was completed, the solvent was concentrated under reduced pressure to dry, and dichloromethane was added to redissolve, washed with saturated aqueous sodium bicarbonate solution and water, respectively, and the organic phase was separated. After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain a solid product (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (1.92 g), 83% yield.
步骤5，将2,4-二氟苯甲酸甲酯(3.5g)和1H-吡咯并[2,3-b]吡啶-5-醇(4.1g)溶解于50mL二乙二醇二甲醚中，加入磷酸钾(6.4g)，加热至回流反应约12小时。TLC监测，反应完成后降温至室温，加入水和乙酸乙酯萃取，分离有机相，用无水硫酸钠干燥后，减压浓缩。所得粗品经硅胶柱层析纯化得到固体产物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-氟苯甲酸甲酯(3.04g)，收率53％。LC-MS(ESI-MS):287[M+H] +。 Step 5, Methyl 2,4-difluorobenzoate (3.5 g) and 1H-pyrrolo[2,3-b]pyridin-5-ol (4.1 g) were dissolved in 50 mL diethylene glycol dimethyl ether , adding potassium phosphate (6.4g), heating to reflux reaction for about 12 hours. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, water and ethyl acetate were added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain a solid product, methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (3.04g), yield 53%. LC-MS (ESI-MS): 287 [M+H] + .
步骤6，将(S)-2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷(1.56g)和2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-氟苯甲酸甲酯(1.72g)溶解于20mLDMF中，加入碳酸钠(3.2g)，加热至回流反应过夜。TLC监测，反应基本完全后降至室温，加入水和大量乙酸乙酯萃取，分离有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化得到固体产物(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)苯甲酸甲酯(1.79g)，收率62％。LC-MS(ESI-MS):579[M+H] +。 Step 6, (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (1.56g) and 2-((1H -Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester (1.72g) was dissolved in 20mL DMF, sodium carbonate (3.2g) was added, and the reaction was heated to reflux overnight. TLC monitoring, after the reaction was basically completed, it was lowered to room temperature, water and a large amount of ethyl acetate were added for extraction, the separated organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain a solid product (S )-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-methyl 7-azaspiro[3.5]non-7-yl)benzoate (1.79 g), 62% yield. LC-MS (ESI-MS): 579 [M+H] + .
步骤7，将(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)苯甲酸甲酯(1.5g)溶解于15mL甲醇和15mL四氢呋喃的混合溶剂中，加入3N氢氧化钠水溶液(10mL)，加热至50℃反应约3小时，TCL监测反应完毕，用4N盐酸水溶液中和至pH约为5左右。用二氯甲烷萃取，分离有机相，减压浓缩，所得粗品经硅胶柱层析纯化得到固体产物(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)苯甲酸(1.25g)，收率85％。LC-MS(ESI-MS):565[M+H] +。 Step 7, (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl) Methyl pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzoate (1.5 g) was dissolved in a mixed solvent of 15 mL methanol and 15 mL tetrahydrofuran, and 3N aqueous sodium hydroxide solution (10 mL) was added. ), heated to 50°C for reaction for about 3 hours, TCL monitored the completion of the reaction, neutralized with 4N aqueous hydrochloric acid solution to about pH 5. Extracted with dichloromethane, separated the organic phase, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain solid product (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl) oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzoic acid (1.25g), Yield 85%. LC-MS (ESI-MS): 565 [M+H] + .
步骤8，将3-溴-4-氯-5-硝基苯磺酰胺(3.2g)和1-氨基环丙甲醇(0.78g)溶解于40mL乙腈中，加入DIPEA(N,N-二异丙基乙胺，8.2mL)，加热至回流搅拌反应过夜。TLC监测，反应完成后降至室温，减压浓缩干溶剂，所得残留物经硅胶柱层析纯化得到固体产物3-溴-4-((1-(羟甲基)环丙基)氨基)-5-硝基苯磺酰胺(2.2g)，收率65％。LC-MS(ESI-MS):366[M+H] +。 Step 8, dissolve 3-bromo-4-chloro-5-nitrobenzenesulfonamide (3.2g) and 1-aminocyclopropanemethanol (0.78g) in 40mL acetonitrile, add DIPEA (N,N-diisopropyl alcohol) ethylethylamine, 8.2 mL), heated to reflux and stirred the reaction overnight. TLC monitoring, after the reaction was completed, the temperature was lowered to room temperature, and the dry solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a solid product 3-bromo-4-((1-(hydroxymethyl)cyclopropyl)amino)- 5-Nitrobenzenesulfonamide (2.2 g), 65% yield. LC-MS (ESI-MS): 366 [M+H] + .
步骤9，将3-溴-4-((1-(羟甲基)环丙基)氨基)-5-硝基苯磺酰胺(1.83g)溶解于30mL甲苯中，加入碳酸铯(3.26g)、CuI(200mg)和3,4,7,8-四甲基-1,10-菲咯 啉(118mg)，在氮气保护下加热回流反应约6小时。TLC监测，反应完毕后降至室温，加入水和乙酸乙酯萃取，分离有机相无水硫酸钠干燥，过滤，所得滤液减压浓缩，粗品经硅胶柱层析纯化得到产物5-硝基-2H,4H-螺[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-磺酰胺(0.76g)，收率53％。LC-MS(ESI-MS):286[M+H] +。 Step 9, dissolve 3-bromo-4-((1-(hydroxymethyl)cyclopropyl)amino)-5-nitrobenzenesulfonamide (1.83g) in 30mL of toluene, add cesium carbonate (3.26g) , CuI (200 mg) and 3,4,7,8-tetramethyl-1,10-phenanthroline (118 mg), heated and refluxed for about 6 hours under nitrogen protection. TLC monitoring, after the reaction was completed, the temperature was lowered to room temperature, water and ethyl acetate were added for extraction, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, the obtained filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the product 5-nitro-2H ,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7-sulfonamide (0.76 g), yield 53%. LC-MS (ESI-MS): 286 [M+H] + .
步骤10，将(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)苯甲酸(0.17g)溶解于3mL二氯甲烷中，加入三乙胺(0.2mL)，HATU(N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲，0.15g)，在室温搅拌约1小时，然后加入5-硝基-2H,4H-螺[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-磺酰胺(0.11g)和DMAP(4-二甲氨基吡啶，6mg)，加完之后继续在室温反应过夜。TLC监测反应完成后，加水淬灭，用二氯甲烷萃取，水洗和饱和食盐水洗涤，分离有机相减压浓缩，所得粗品经硅胶柱层析纯化得到固体产物(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(112mg)，收率45％。LC-MS(ESI-MS):832[M+H] +。 Step 10, (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzoic acid (0.17g) was dissolved in 3mL of dichloromethane, triethylamine (0.2mL) was added, HATU (N,N ,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea, 0.15g), stirred at room temperature for about 1 hour, then added 5-nitro- 2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7-sulfonamide (0.11 g) and DMAP (4-dimethylaminopyridine, 6 mg), plus After completion, the reaction was continued at room temperature overnight. After monitoring the reaction by TLC, quenched by adding water, extracted with dichloromethane, washed with water and saturated brine, separated the organic phase and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain solid product (S)-2-((1H -pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5]Nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7 -yl)sulfonyl)benzamide (112 mg), 45% yield. LC-MS (ESI-MS): 832 [M+H] + .
1H NMR(400MHz,Chloroform-d)δ9.91(s,1H),8.66–8.54(m,1H),8.27–8.20(m,1H),8.17–8.10(m,1H),7.98(d,1H),7.79–7.71(m,2H),7.56–7.48(m,1H),7.30–7.10(m,3H),6.67–6.50(m,2H),6.06–5.97(m,1H),5.41–5.30(m,1H),4.13–4.02(m,2H),3.34–2.89(m,8H),2.37–2.21(m,2H),2.14–1.74(m,8H),1.60–1.42(m,8H),1.15–0.86(m,5H). 1 H NMR (400MHz, Chloroform-d)δ9.91(s,1H), 8.66-8.54(m,1H), 8.27-8.20(m,1H), 8.17-8.10(m,1H), 7.98(d, 1H), 7.79–7.71 (m, 2H), 7.56–7.48 (m, 1H), 7.30–7.10 (m, 3H), 6.67–6.50 (m, 2H), 6.06–5.97 (m, 1H), 5.41– 5.30 (m, 1H), 4.13–4.02 (m, 2H), 3.34–2.89 (m, 8H), 2.37–2.21 (m, 2H), 2.14–1.74 (m, 8H), 1.60–1.42 (m, 8H) ),1.15–0.86(m,5H).
实施例2：(S)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)吡啶酰胺(002)Example 2: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4] Oxazine-3,1'-cyclopropan]-7-yl)sulfonyl)pyridineamide (002)
Figure PCTCN2021126588-appb-000029
Figure PCTCN2021126588-appb-000029
参数实施例1的合成方法，把2,4-二氟苯甲酸甲酯替换为3,5-二氟吡啶-2-甲酸甲酯，可合成得到目标化合物(S)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)吡啶酰胺(90mg)，LC-MS(ESI-MS):833[M+H] +。 The synthetic method of parameter example 1, 2,4-difluorobenzoic acid methyl ester is replaced with 3,5-difluoropyridine-2-methyl carboxylate, the target compound (S)-3-((1H- Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[ 3.5] Nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7- yl)sulfonyl)picolinamide (90 mg), LC-MS (ESI-MS): 833 [M+H] + .
实施例3：(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(003)Example 3: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][ 1,4]oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)benzamide (003)
Figure PCTCN2021126588-appb-000030
Figure PCTCN2021126588-appb-000030
参数实施例1的合成方法，把2,4-二氟苯甲酸甲酯替换为2,3,4三氟苯甲酸甲酯，可合成得到目标化合物(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺环[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(66mg)，LC-MS(ESI-MS):850[M+H] +。 The synthetic method of parameter example 1, the 2,4-difluorobenzoic acid methyl ester is replaced with 2,3,4 trifluorobenzoic acid methyl ester, the target compound (S)-2-(((1H-pyrrolo) can be synthesized [2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]- 7-yl)sulfonyl)benzamide (66 mg), LC-MS (ESI-MS): 850 [M+H] + .
实施例4：(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3,5-二氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(004)Example 4: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-difluoro-4-(2-(2-(2 -Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b] ][1,4]oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)benzamide (004)
Figure PCTCN2021126588-appb-000031
Figure PCTCN2021126588-appb-000031
参数实施例1的合成方法，把2,4-二氟苯甲酸甲酯替换为2,3,4,5-四氟苯甲酸甲酯，可合成得到目标化合物(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3,5-二氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((5-硝基-2H,4H-螺[苯并[b][1,4]恶嗪-3,1'-环丙烷]-7-基)磺酰基)苯甲酰胺(73mg)，LC-MS(ESI-MS):868[M+H] +。 The synthetic method of parameter example 1, the 2,4-difluorobenzoic acid methyl ester is replaced with 2,3,4,5-tetrafluorobenzoic acid methyl ester, the target compound (S)-2-(((1H) can be synthesized -pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-difluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-Azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1' -Cyclopropan]-7-yl)sulfonyl)benzamide (73 mg), LC-MS (ESI-MS): 868 [M+H] + .
实施例5：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((S)-3-(吗啉甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(005)Example 5: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)-N-(((S)-3-(morpholinomethyl)-5-nitro-3,4-di Hydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)pyridineamide (005)
Figure PCTCN2021126588-appb-000032
Figure PCTCN2021126588-appb-000032
参考实施例1的合成方法，把2,4-二氟苯甲酸甲酯替换为3,5-二氟吡啶-2-甲酸甲酯，把1-氨基环丙甲醇替换为(S)-2-氨基-3-吗啉丙烷-1-醇，可合成得到目标化合物3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((S)-3-(吗啉甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)吡啶酰胺(59mg)，LC-MS(ESI-MS):906[M+H] +。 Referring to the synthetic method of Example 1, replace methyl 2,4-difluorobenzoate with methyl 3,5-difluoropyridine-2-carboxylate, and replace 1-aminocyclopropylcarbinol with (S)-2- Amino-3-morpholinopropan-1-ol can be synthesized to obtain the target compound 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S )-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((S)-3-(morpholina) yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)pyridineamide (59 mg), LC-MS (ESI-MS ):906[M+H] + .
实施例6：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((((S)-3-(吗啉甲基) -5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(006)Example 6: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-((S)-2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((((S)-3-(morpholinomethyl)-5-nitro -3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (006)
Figure PCTCN2021126588-appb-000033
Figure PCTCN2021126588-appb-000033
参考实施例1的合成方法，把2,4-二氟苯甲酸甲酯替换为2,3,4三氟苯甲酸甲酯，把1-氨基环丙甲醇替换为(S)-2-氨基-3-吗啉丙烷-1-醇，可合成得到目标化合物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((((S)-3-(吗啉甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(38mg)，LC-MS(ESI-MS):923[M+H] +。 With reference to the synthetic method of Example 1, methyl 2,4-difluorobenzoate was replaced with methyl 2,3,4 trifluorobenzoate, and 1-aminocyclopropylcarbinol was replaced with (S)-2-amino- 3-morpholinopropan-1-ol can be synthesized to obtain the target compound 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-( (S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((((S)-3- (Morpholinemethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (38 mg), LC- MS (ESI-MS): 923 [M+H] + .
实施例7：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(024)Example 7: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)pyridineamide (024)
Figure PCTCN2021126588-appb-000034
Figure PCTCN2021126588-appb-000034
Figure PCTCN2021126588-appb-000035
Figure PCTCN2021126588-appb-000035
步骤1制备中间体24-1：7-氮杂螺[3.5]壬烷-2-酮盐酸盐(24-1)Step 1 Preparation of Intermediate 24-1: 7-Azaspiro[3.5]nonan-2-one hydrochloride (24-1)
将2-氧代-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(10.00g，42.00mmol)溶解于1，4-二氧六环(52.00mL)，再加入4mol/L HCl(52.00mL)的1，4-二氧六环(52.00mL)，加热至60℃反应4h。TLC监测反应完成后直接浓缩反应液近干，加入甲基叔丁基醚(100.00mL)，室温打浆1h后过滤，滤饼用甲基叔丁基醚漂洗后减压干燥16h，得到中间体24-1(7.30g)，收率99％，LC-MS(ESI-MS)：m/z＝140[M+H] +。 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (10.00g, 42.00mmol) was dissolved in 1,4-dioxane (52.00mL), and 4mol/ L HCl (52.00 mL) in 1,4-dioxane (52.00 mL) was heated to 60 °C for 4 h. After the completion of the reaction monitored by TLC, the reaction solution was directly concentrated to near dryness, methyl tert-butyl ether (100.00 mL) was added, slurried at room temperature for 1 h, filtered, and the filter cake was rinsed with methyl tertiary butyl ether and dried under reduced pressure for 16 h to obtain intermediate 24 -1 (7.30 g), 99% yield, LC-MS (ESI-MS): m/z=140 [M+H] + .
步骤2制备中间体24-2：3-氟-5-(2-氧代-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-甲酸甲酯(24-2)：Step 2 Preparation of Intermediate 24-2: Methyl 3-fluoro-5-(2-oxo-7-azaspiro[3.5]nonan-7-yl)pyridine-2-carboxylate (24-2):
将3,5-二氟吡啶-2-甲酸甲酯(2.38g，13.75mmol，1.00eq)和中间体24-1(2.42g，13.75mmol)溶解于DMF中，加入碳酸钠(7.30g，68.74mmol)，升温至100℃反应12h。TLC监测，反应完成后加入EA和水萃取，分离有机相，干燥过滤，减压浓缩，所得粗品经硅胶柱层析纯化得到中间体24-2(2.20g)，收率54％，LC-MS(ESI-MS)：m/z＝293[M+H] +。 Methyl 3,5-difluoropyridine-2-carboxylate (2.38g, 13.75mmol, 1.00eq) and intermediate 24-1 (2.42g, 13.75mmol) were dissolved in DMF and sodium carbonate (7.30g, 68.74g) was added mmol), the temperature was raised to 100 °C and reacted for 12 h. TLC monitoring, after the reaction was completed, EA and water were added for extraction, the organic phase was separated, dried and filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain Intermediate 24-2 (2.20 g), yield 54%, LC-MS (ESI-MS): m/z=293 [M+H] + .
步骤3制备中间体24-3：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-氧代-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-甲酸甲酯(24-3)Step 3 Preparation of Intermediate 24-3: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-oxo-7-azaspiro[3.5] Nonan-7-yl)pyridine-2-carboxylic acid methyl ester (24-3)
将中间体24-2(1.54g，5.27mmol)和1H-吡咯并[2,3-b]吡啶-5-醇(778.00mg，5.80mmol)溶解于二乙二醇二甲醚(30.00mL)中，加入磷酸钾(1.34g，6.32mmol)，在110℃油浴中加热搅拌反应9h。TLC监测，反应完成后冷却至室温，减压浓缩至二乙二醇二甲醚近干，加入甲基四氢呋喃和水萃取，分离有机相，干燥过滤，减压浓缩，所得粗品经硅胶柱层析纯化得到中间体24-3(817.00mg)，收率38％，LC-MS(ESI-MS)：m/z＝407[M+H] +。 Intermediate 24-2 (1.54 g, 5.27 mmol) and 1H-pyrrolo[2,3-b]pyridin-5-ol (778.00 mg, 5.80 mmol) were dissolved in diethylene glycol dimethyl ether (30.00 mL) In the solution, potassium phosphate (1.34 g, 6.32 mmol) was added, and the reaction was heated and stirred in an oil bath at 110° C. for 9 h. TLC monitoring, after the reaction was completed, cooled to room temperature, concentrated under reduced pressure to diethylene glycol dimethyl ether to near dryness, added methyltetrahydrofuran and water for extraction, separated the organic phase, dried and filtered, concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography Purification gave intermediate 24-3 (817.00 mg) in 38% yield, LC-MS (ESI-MS): m/z=407 [M+H] + .
步骤4制备中间体24-4：(S)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-甲酸甲酯(24-4)Step 4 Preparation of Intermediate 24-4: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-iso) Propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)pyridine-2-carboxylic acid methyl ester (24-4)
将中间体24-3(924.00mg，2.27mmol)和(S)-2-(2-异丙基苯基)吡咯烷(559.00mg，2.96mmol)溶解于DCM(80.00mL)中，加入STAB(三乙酰氧基硼氢化钠，1.45g，6.82mmol)，在室温下反应10h。TLC监测反应完成后，加入水和DCM萃取，分离DCM相，干燥过滤，减压浓缩，所得粗品经硅胶柱层析纯化得到中间体24-4(1.10g)，收率83％，LC-MS(ESI-MS)：m/z＝580[M+H] +。 Intermediate 24-3 (924.00 mg, 2.27 mmol) and (S)-2-(2-isopropylphenyl)pyrrolidine (559.00 mg, 2.96 mmol) were dissolved in DCM (80.00 mL) and STAB ( Sodium triacetoxyborohydride, 1.45 g, 6.82 mmol) was reacted at room temperature for 10 h. After the completion of the reaction monitored by TLC, water and DCM were added for extraction, the DCM phase was separated, dried and filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain Intermediate 24-4 (1.10 g), yield 83%, LC-MS (ESI-MS): m/z=580 [M+H] + .
步骤5制备中间体24-5：(S)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-甲酸(24-5)Step 5 Preparation of Intermediate 24-5: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-iso) Propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)pyridine-2-carboxylic acid (24-5)
将中间体24-4(1.10g，1.90mmol)溶解于THF(20.00mL)中，加入3M NaOH水溶液(19.00mL，18.97mmol)，再加入水(20.00mL)，60℃加热6h。TLC监测反应完成后，浓缩THF，用2N HCl盐酸水溶液调节PH约为5，再用饱和碳酸氢钠调节PH约为10左右。向反应液中加入甲基四氢呋喃萃取产物，分离浓缩有机相，加入甲基叔丁基醚(30.00mL)室温打浆1h后抽滤，50℃常压鼓风干燥16h后，得到中间体24-5(996.00mg)，收率92％，LC-MS(ESI-MS)：m/z＝566[M+H] +。 Intermediate 24-4 (1.10 g, 1.90 mmol) was dissolved in THF (20.00 mL), 3M aqueous NaOH solution (19.00 mL, 18.97 mmol) was added, and then water (20.00 mL) was added, and heated at 60 °C for 6 h. After the completion of the reaction monitored by TLC, the THF was concentrated, and the pH was adjusted to about 5 with 2N aqueous HCl hydrochloric acid, and then adjusted to about 10 with saturated sodium bicarbonate. Methyltetrahydrofuran was added to the reaction solution to extract the product, the organic phase was separated and concentrated, methyl tert-butyl ether (30.00 mL) was added to make a slurry at room temperature for 1 h, suction filtered, and air-dried at 50°C under normal pressure for 16 h to obtain intermediate 24-5 (996.00 mg), yield 92%, LC-MS (ESI-MS): m/z=566 [M+H] + .
步骤6制备中间体24-6：4-(氨基甲基)-1-甲基环己醇(24-6)Step 6 Preparation of intermediate 24-6: 4-(aminomethyl)-1-methylcyclohexanol (24-6)
将((4-氧代环己基)甲基)氨基甲酸叔丁酯(2.00g，8.80mmol)溶解于THF(40.00mL)中，内置温度计测内温，充氮气保护，置于-40℃低温冷却，控制内温保持在-30℃至-40℃，滴加甲基溴化镁的THF溶液(35.20mL，35.20mmol)，滴加完毕后置于0℃保温2h后加水(5.00ml)淬灭反应。TLC监测，加入EA和水萃取，分液，水相再用EA反萃一次，合并2次EA(乙酸乙酯)相，浓缩后加入DCM(20.00mL)，室温下再加入TFA(三氟乙酸，6.00g，52.80mmol)，反应15h过夜。TLC监测反应完毕，浓缩反应液近干，得到中间体24-6(566.00mg)，收率26％，LC-MS(ESI-MS)：m/z＝144[M+H] +。 Dissolve tert-butyl ((4-oxocyclohexyl)methyl)carbamate (2.00 g, 8.80 mmol) in THF (40.00 mL), measure the internal temperature with a built-in thermometer, protect with nitrogen, and place it at a low temperature of -40°C Cool, keep the internal temperature at -30°C to -40°C, add dropwise a solution of methylmagnesium bromide in THF (35.20mL, 35.20mmol), place it at 0°C for 2h and then add water (5.00ml) to quench it. kill the reaction. TLC monitoring, adding EA and water for extraction, separation, the aqueous phase was back-extracted once with EA, the EA (ethyl acetate) phases were combined twice, concentrated and then added DCM (20.00 mL), and then TFA (trifluoroacetic acid) was added at room temperature , 6.00g, 52.80mmol), reacted for 15h overnight. The completion of the reaction was monitored by TLC, and the reaction solution was concentrated to near dryness to obtain intermediate 24-6 (566.00 mg), yield 26%, LC-MS (ESI-MS): m/z=144 [M+H] + .
步骤7制备中间体24-7：4-(((4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯磺酰胺(24-7)Step 7 Preparation of Intermediate 24-7: 4-(((4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (24-7)
将中间体24-6(566.00mg，2.35mmol)溶解于THF(10.00mL)中，加入4-氟-3-硝基苯磺酰胺(484.00mg，2.35mmol)，再加入TEA(2.20g，22.00mmol)，室温反应8h。TLC监测反应完毕后，直接浓缩反应液，加入DCM和水萃取，分离有机相，经硅胶柱层析分离纯化得到粗品中间体24-7(623.00mg)，收率77％，LC-MS(ESI-MS)：m/z＝344[M+H] +。 Intermediate 24-6 (566.00 mg, 2.35 mmol) was dissolved in THF (10.00 mL), 4-fluoro-3-nitrobenzenesulfonamide (484.00 mg, 2.35 mmol) was added, followed by TEA (2.20 g, 22.00 mmol), and reacted at room temperature for 8 h. After the completion of the reaction monitored by TLC, the reaction solution was directly concentrated, extracted with DCM and water, the organic phase was separated and purified by silica gel column chromatography to obtain the crude intermediate 24-7 (623.00 mg), the yield was 77%, LC-MS (ESI -MS): m/z=344 [M+H] + .
步骤8制备中间体24-8：4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯磺酰胺(24-8)Step 8 Preparation of Intermediate 24-8: 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (24-8)
将中间体24-7(623.00mg，1.81mmol，1.00eq)经制备HPLC分离纯化，得到中间体24-8，LC-MS(ESI-MS)：m/z＝344[M+H] +。 Intermediate 24-7 (623.00 mg, 1.81 mmol, 1.00 eq) was isolated and purified by preparative HPLC to give intermediate 24-8, LC-MS (ESI-MS): m/z=344 [M+H] + .
步骤9制备化合物24：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-((S)-2-(2- 异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(024)Step 9 Preparation of Compound 24: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy- 4-Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1- yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (024)
将中间体24-5(679.00mg，1.20mmol)溶解于二氯甲烷中，加入三乙胺、HATU，在室温下搅拌约1h，再加入中间体24-8(275.00mg，0.80mmol)和DMAP，继续在室温反应过夜。TLC监测反应完成后，加水淬灭，用二氯甲烷萃取，水洗和饱和食盐水洗涤，分离有机相，减压浓缩，所得粗品经硅胶柱层析纯化得到固体化合物024，LC-MS(ESI-MS)：m/z＝891[M+H] +。 Intermediate 24-5 (679.00 mg, 1.20 mmol) was dissolved in dichloromethane, triethylamine and HATU were added, stirred at room temperature for about 1 h, and then intermediate 24-8 (275.00 mg, 0.80 mmol) and DMAP were added. , and continue to react overnight at room temperature. After the completion of the reaction monitored by TLC, water was added to quench, extracted with dichloromethane, washed with water and saturated brine, the organic phase was separated, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain solid compound 024, LC-MS (ESI- MS): m/z=891 [M+H] + .
实施例8：N-((4-((((S)-1,4-二恶烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(025)Example 8: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)pyridineamide (025)
Figure PCTCN2021126588-appb-000036
Figure PCTCN2021126588-appb-000036
参考实施例7的合成方法，把中间体24-6替换为(1,4-二恶烷-2-基)甲胺盐酸盐，可合成得到目标化合物025，LC-MS(ESI-MS)：m/z＝865[M+H] +。 Referring to the synthetic method of Example 7, the intermediate 24-6 was replaced with (1,4-dioxan-2-yl)methanamine hydrochloride, and the target compound 025 could be synthesized by LC-MS (ESI-MS) : m/z=865 [M+H] + .
1H NMR(400MHz,Chloroform-d)δ9.74(s,1H),8.91(d,J＝2.3Hz,1H),8.61(t,J＝5.2Hz,1H),8.25(d,J＝9.3Hz,1H),8.13–8.08(m,1H),7.89–7.83(m,1H),7.59–7.56(m,1H),7.41–7.38(m,1H),7.22(d,J＝15.2Hz,4H),6.92(d,J＝9.1Hz,1H),6.50–6.46(m,1H),6.37–6.24(m,1H),4.03–3.73(m,8H),3.73–3.65(m,2H),3.56–3.26(m,6H),3.16–2.92(m,7H),2.51–2.13(m,4H),1.90–1.77(m,4H),1.56–1.50(m,5H). 1 H NMR (400MHz, Chloroform-d)δ9.74(s,1H),8.91(d,J=2.3Hz,1H),8.61(t,J=5.2Hz,1H),8.25(d,J=9.3 Hz, 1H), 8.13–8.08 (m, 1H), 7.89–7.83 (m, 1H), 7.59–7.56 (m, 1H), 7.41–7.38 (m, 1H), 7.22 (d, J=15.2Hz, 4H), 6.92 (d, J=9.1Hz, 1H), 6.50–6.46 (m, 1H), 6.37–6.24 (m, 1H), 4.03–3.73 (m, 8H), 3.73–3.65 (m, 2H) ,3.56–3.26(m,6H),3.16–2.92(m,7H),2.51–2.13(m,4H),1.90–1.77(m,4H),1.56–1.50(m,5H).
实施例9：(S)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)吡啶酰胺(026)Example 9: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)picolinamide (026)
Figure PCTCN2021126588-appb-000037
Figure PCTCN2021126588-appb-000037
参考实施例7的合成方法，把中间体24-6替换为(四氢-2H-吡喃-4-基)甲胺盐酸盐(并省略手型拆分步骤)，可合成得到目标化合物026，LC-MS(ESI-MS)：m/z＝863[M+H] +。 1H NMR(400MHz,Chloroform-d)δ9.63(s,1H),8.95(d,J＝2.3Hz,1H),8.56(t,J＝5.5Hz,1H),8.28(dd,J＝9.1,2.3Hz,1H),8.14(d,J＝2.5Hz,1H),7.88(d,J＝2.3Hz,1H),7.64–7.58(m,2H),7.43(t,J＝3.0Hz,1H),7.26–7.17(m,3H),6.95(d,J＝9.3Hz,1H),6.57–6.46(m,1H),6.31(d,J＝2.3Hz,1H),4.10–4.04(m,2H),3.69–3.63(m,1H),3.49–3.42(m,2H),3.40–3.25(m,4H),3.24–3.18(m,1H),3.17–2.96(m,6H),2.39–2.30(m,1H),2.25–2.17(m,1H),2.08–1.89(m,3H),1.85–1.74(m,6H),1.71–1.65(m,1H),1.58–1.40(m,10H). With reference to the synthetic method of Example 7, the intermediate 24-6 was replaced with (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (and the chiral resolution step was omitted), and the target compound 026 could be synthesized. , LC-MS (ESI-MS): m/z=863 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ 9.63 (s, 1H), 8.95 (d, J=2.3Hz, 1H), 8.56 (t, J=5.5Hz, 1H), 8.28 (dd, J=9.1 ,2.3Hz,1H),8.14(d,J＝2.5Hz,1H),7.88(d,J＝2.3Hz,1H),7.64–7.58(m,2H),7.43(t,J＝3.0Hz,1H) ), 7.26–7.17 (m, 3H), 6.95 (d, J=9.3Hz, 1H), 6.57–6.46 (m, 1H), 6.31 (d, J=2.3Hz, 1H), 4.10–4.04 (m, 2H), 3.69–3.63 (m, 1H), 3.49–3.42 (m, 2H), 3.40–3.25 (m, 4H), 3.24–3.18 (m, 1H), 3.17–2.96 (m, 6H), 2.39– 2.30 (m, 1H), 2.25–2.17 (m, 1H), 2.08–1.89 (m, 3H), 1.85–1.74 (m, 6H), 1.71–1.65 (m, 1H), 1.58–1.40 (m, 10H) ).
实施例10：(S)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异 丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(((1-甲基哌啶-4-基)甲基)氨基)-3-硝基苯)磺酰基)吡啶酰胺(027)Example 10: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)- 3-Nitrobenzene)sulfonyl)picolinamide (027)
Figure PCTCN2021126588-appb-000038
Figure PCTCN2021126588-appb-000038
参考实施例7的合成方法，把中间体24-6替换为(1-甲基哌啶-4-基)甲胺，可合成得到目标化合物027，LC-MS(ESI-MS)：m/z＝876[M+H] +。 Referring to the synthetic method of Example 7, the intermediate 24-6 was replaced with (1-methylpiperidin-4-yl)methanamine, and the target compound 027 could be synthesized, LC-MS (ESI-MS): m/z =876[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.61(s,1H),8.46–8.38(m,2H),8.04–7.93(m,2H),7.74(d,J＝8.7Hz,1H),7.53(d,J＝7.2Hz,1H),7.47(d,J＝3.0Hz,1H),7.43(d,J＝2.6Hz,1H),7.22(d,J＝7.4Hz,1H),7.16–7.11(m,2H),6.93(d,J＝9.2Hz,1H),6.72–6.65(m,1H),6.35(d,J＝3.1Hz,1H),3.17–3.09(m,7H),3.04–2.99(m,3H),2.97–2.92(m,3H),2.35–2.15(m,2H),1.85–1.68(m,11H),1.54–1.44(m,6H),1.42–1.32(m,8H),0.92–0.82(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ11.61(s, 1H), 8.46-8.38(m, 2H), 8.04-7.93(m, 2H), 7.74(d, J=8.7Hz, 1H), 7.53(d,J＝7.2Hz,1H),7.47(d,J＝3.0Hz,1H),7.43(d,J＝2.6Hz,1H),7.22(d,J＝7.4Hz,1H),7.16– 7.11 (m, 2H), 6.93 (d, J=9.2Hz, 1H), 6.72–6.65 (m, 1H), 6.35 (d, J=3.1Hz, 1H), 3.17–3.09 (m, 7H), 3.04 –2.99(m,3H),2.97–2.92(m,3H),2.35–2.15(m,2H),1.85–1.68(m,11H),1.54–1.44(m,6H),1.42–1.32(m, 8H),0.92–0.82(m,1H).
实施例11：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-环丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)-N-(((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)吡啶酰胺(028)Example 11: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-cyclopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)-N-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino )-3-Nitrophenyl)sulfonyl)pyridineamide (028)
Figure PCTCN2021126588-appb-000039
Figure PCTCN2021126588-appb-000039
参考实施例7的合成方法，把(S)-2-(2-异丙基苯基)吡咯烷替换为(S)-2-(2-环丙基苯基)吡咯烷，可合成得到目标化合物028，LC-MS(ESI-MS)：m/z＝889[M+H] +。 Referring to the synthetic method of Example 7, replace (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine, the target can be synthesized Compound 028, LC-MS (ESI-MS): m/z=889 [M+H] + .
实施例12：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-((S)-2-(2-(三氟甲基)苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶酰胺(029)Example 12: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-(trifluoromethyl)phenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (029)
Figure PCTCN2021126588-appb-000040
Figure PCTCN2021126588-appb-000040
参考实施例11的合成方法，把(S)-2-(2-环丙基苯基)吡咯烷替换为(S)-2-(2-(三氟甲基)苯基)吡咯烷，可合成得到目标化合物029，LC-MS(ESI-MS)：m/z＝917[M+H] +。 Referring to the synthetic method of Example 11, replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-2-(2-(trifluoromethyl)phenyl)pyrrolidine, the The target compound 029 was synthesized, LC-MS (ESI-MS): m/z=917 [M+H] + .
实施例13：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-((S)-2-(2-甲氧基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬-7-基)吡啶酰胺(030)Example 13: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-methoxyphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]non-7-yl)pyridineamide (030)
Figure PCTCN2021126588-appb-000041
Figure PCTCN2021126588-appb-000041
参考实施例11的合成方法，把(S)-2-(2-环丙基苯基)吡咯烷替换为(S)-2-(2-甲氧基苯基)吡咯烷，可合成得到目标化合物030，LC-MS(ESI-MS)：m/z＝879[M+H] +。 Referring to the synthetic method of Example 11, replace (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-2-(2-methoxyphenyl)pyrrolidine, the target can be synthesized Compound 030, LC-MS (ESI-MS): m/z=879 [M+H] + .
实施例14：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-((S)-2-(2-氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)吡啶酰胺(031)Example 14: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-fluorophenyl)pyrrolidine -1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)pyridineamide (031)
Figure PCTCN2021126588-appb-000042
Figure PCTCN2021126588-appb-000042
参考实施例11的合成方法，把(S)-2-(2-环丙基苯基)吡咯烷替换为(S)-2-(2-氟苯基)吡咯烷，可合成得到目标化合物031，LC-MS(ESI-MS)：m/z＝867[M+H] +。 Referring to the synthetic method of Example 11, replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-2-(2-fluorophenyl)pyrrolidine, the target compound 031 can be synthesized , LC-MS (ESI-MS): m/z=867 [M+H] + .
实施例15：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(032)Example 15: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-N-((4-(((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (032)
Figure PCTCN2021126588-appb-000043
Figure PCTCN2021126588-appb-000043
参考实施例7合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为2,3,4-三氟苯甲酸甲酯，可合成得到目标化合物032，LC-MS(ESI-MS)：m/z＝908[M+H] +。 Referring to the synthetic method of Example 7, replace methyl 3,5-difluoropyridine-2-carboxylate with methyl 2,3,4-trifluorobenzoate, the target compound 032 can be synthesized and obtained by LC-MS (ESI-MS ): m/z=908 [M+H] + .
实施例16：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(033)Example 16: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (033)
Figure PCTCN2021126588-appb-000044
Figure PCTCN2021126588-appb-000044
参考实施例7的合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为2,4,5-三氟苯甲酸甲酯，可合成得到目标化合物033，LC-MS(ESI-MS)：m/z＝908[M+H] +。 Referring to the synthetic method of Example 7, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,4,5-trifluorobenzoic acid methyl ester, and the target compound 033 could be synthesized, LC-MS (ESI- MS): m/z=908 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.53(s,1H),8.42–8.30(m,2H),7.89(d,J＝2.7Hz,1H),7.60(t,J＝9.5Hz,1H),7.54–7.46(m,2H),7.39(t,J＝3.0Hz,1H),7.27(d,J＝11.4Hz,4H),6.81(d,J＝9.2Hz,1H),6.33(d,J＝7.6Hz,1H),6.26(dd,J＝3.4,1.9Hz,1H),4.21(s,1H),3.19(q,J＝6.8,6.3Hz,3H),2.76(t,J＝5.7Hz,3H),2.66(t,J＝5.4Hz,2H),1.64(dd,J＝13.2,3.8Hz,3H),1.48(tt,J＝16.2,4.2Hz,8H),1.31–1.24(m,4H),1.21–1.15(m,9H),1.07(d,J＝13.8Hz,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.53 (s, 1H), 8.42-8.30 (m, 2H), 7.89 (d, J=2.7Hz, 1H), 7.60 (t, J=9.5Hz, 1H), 7.54–7.46(m, 2H), 7.39(t, J=3.0Hz, 1H), 7.27(d, J=11.4Hz, 4H), 6.81(d, J=9.2Hz, 1H), 6.33( d, J＝7.6Hz, 1H), 6.26(dd, J＝3.4, 1.9Hz, 1H), 4.21(s, 1H), 3.19(q, J＝6.8, 6.3Hz, 3H), 2.76(t, J =5.7Hz,3H),2.66(t,J=5.4Hz,2H),1.64(dd,J=13.2,3.8Hz,3H),1.48(tt,J=16.2,4.2Hz,8H),1.31–1.24 (m, 4H), 1.21–1.15 (m, 9H), 1.07 (d, J=13.8Hz, 9H).
实施例17：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3,5-二氟-N-((4-(((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(034)Example 17: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-difluoro-N-((4-((((((1r,4r) )-4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (034)
Figure PCTCN2021126588-appb-000045
Figure PCTCN2021126588-appb-000045
参考实施例7的合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为2,3,4,5-四氟苯甲酸甲酯，可合成得到目标化合物034，LC-MS(ESI-MS)：m/z＝926[M+H] +。 With reference to the synthetic method of Example 7, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,3,4,5-tetrafluorobenzoic acid methyl ester, and the target compound 034 could be synthesized, and LC-MS ( ESI-MS): m/z=926 [M+H] + .
实施例18：(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)烟酰胺(035)Example 18: (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)nicotinamide (035)
Figure PCTCN2021126588-appb-000046
Figure PCTCN2021126588-appb-000046
制备中间体35-1：2,2,2-三氟乙酸与7-氮杂螺[3.5]壬烷-2-酮(1:1)(35-1)Preparation of Intermediate 35-1: 2,2,2-Trifluoroacetic acid with 7-azaspiro[3.5]nonan-2-one (1:1)(35-1)
将2-氧代-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(5.0g，20.9mmol)溶解于DCM(100.00mL)中，缓慢加入TFA(15.50mL)，加热至40℃回流反应2h，TLC监测反应完毕后直接浓缩反应液近干，得到中间体35-1(4.80g)，收率97％，LC-MS(ESI-MS)：m/z＝140[M+H] +。 2-Oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (5.0 g, 20.9 mmol) was dissolved in DCM (100.00 mL), TFA (15.50 mL) was added slowly and heated to The reaction was refluxed at 40°C for 2 h. After the reaction was monitored by TLC, the reaction solution was directly concentrated to near dryness to obtain intermediate 35-1 (4.80 g), yield 97%, LC-MS (ESI-MS): m/z=140 [M +H] + .
制备中间体35-2：4-氯-6-(2-氧代-7-氮杂螺[3.5]壬烷-7-基)烟酸甲酯(35-2)Preparation of Intermediate 35-2: Methyl 4-chloro-6-(2-oxo-7-azaspiro[3.5]nonan-7-yl)nicotinate (35-2)
将4,6-二氯烟酸甲酯(13.94g，67.66mmol)、中间体35-1(16.00g，67.66mmol)、碳酸钠(35.86g，338.3mmol)溶解于DMF中，升温至80℃，反应2h。TLC监测反应完毕后加入EA和水萃取，分离有机相，减压浓缩，所得粗品经硅胶柱层析分离纯化得到中间体35-2(3.97g)，收率19％，LC-MS(ESI-MS)：m/z＝309[M+H] +。 Methyl 4,6-dichloronicotinate (13.94 g, 67.66 mmol), intermediate 35-1 (16.00 g, 67.66 mmol), and sodium carbonate (35.86 g, 338.3 mmol) were dissolved in DMF, and the temperature was raised to 80 °C , the reaction 2h. After the reaction was monitored by TLC, EA and water were added for extraction, the organic phase was separated, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to obtain Intermediate 35-2 (3.97 g), yield 19%, LC-MS (ESI- MS): m/z=309 [M+H] + .
制备中间体35-3：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-氧代-7-氮杂螺[3.5]壬烷-7-基)烟酸甲酯(35-3)Preparation of Intermediate 35-3: 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-oxo-7-azaspiro[3.5]nonane -7-yl) Methyl nicotinate (35-3)
将中间体35-2(3.00g，9.72mmol)、1H-吡咯并[2,3-b]吡啶-5-醇(1.40g，10.70mmol)、C S2CO 3(9.50g，29.16mmol)溶解于DMF(60.00mL)中，在100℃油浴 中加热搅拌反应2h，反应完成后冷却至室温，加入EA和水萃取，分离有机相，减压浓缩，所得粗品经硅胶柱层析纯化得到中间体35-3(3.20g)，收率81％，LC-MS(ESI-MS)：m/z＝407[M+H] +。 Intermediate 35-2 (3.00 g, 9.72 mmol), 1H-pyrrolo[2,3-b]pyridin-5-ol (1.40 g, 10.70 mmol), C S2 CO 3 (9.50 g, 29.16 mmol) were dissolved In DMF (60.00 mL), the reaction was heated and stirred in an oil bath at 100 °C for 2 h. After the reaction was completed, it was cooled to room temperature, EA and water were added for extraction, the organic phase was separated, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the intermediate Body 35-3 (3.20 g), 81% yield, LC-MS (ESI-MS): m/z=407 [M+H] + .
制备化合物35：(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)烟酰胺(035)Preparation of Compound 35: (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)nicotinamide (035)
参考实施例9的合成方法，把中间体24-3替换为中间体35-3，可合成得到目标化合物035，LC-MS(ESI-MS)：m/z＝863[M+H] +。 Referring to the synthesis method of Example 9, the intermediate 24-3 was replaced by the intermediate 35-3, and the target compound 035 could be synthesized, LC-MS (ESI-MS): m/z=863 [M+H] + .
1H NMR(400MHz,)δ11.71(d,J＝2.9Hz,1H),8.56–8.47(m,2H),8.27(s,1H),8.00(d,J＝2.6Hz,1H),7.80(dd,J＝9.3,2.3Hz,1H),7.64(s,1H),7.54(d,J＝7.5Hz,1H),7.49(t,J＝3.0Hz,1H),7.31–7.12(m,3H),7.09(d,J＝9.2Hz,1H),6.39(dd,J＝3.4,1.8Hz,1H),5.72(s,1H),3.80(ddd,J＝11.4,4.5,1.8Hz,2H),3.25–3.21(m,4H),3.19(d,J＝2.0Hz,2H),3.13(q,J＝4.6,4.0Hz,2H),2.30–2.19(m,1H),1.86(tdt,J＝12.8,9.1,5.0Hz,4H),1.60–1.55(m,2H),1.43(d,J＝7.8Hz,1H),1.29(dd,J＝6.7,3.6Hz,4H),1.24–1.21(m,2H),1.20(d,J＝3.7Hz,3H),1.16(d,J＝6.7Hz,4H),1.08(d,J＝6.7Hz,4H). 1 H NMR(400MHz,)δ11.71(d,J=2.9Hz,1H),8.56-8.47(m,2H),8.27(s,1H),8.00(d,J=2.6Hz,1H),7.80 (dd, J=9.3, 2.3Hz, 1H), 7.64 (s, 1H), 7.54 (d, J=7.5Hz, 1H), 7.49 (t, J=3.0Hz, 1H), 7.31–7.12 (m, 3H), 7.09(d, J=9.2Hz, 1H), 6.39(dd, J=3.4, 1.8Hz, 1H), 5.72(s, 1H), 3.80(ddd, J=11.4, 4.5, 1.8Hz, 2H ), 3.25–3.21 (m, 4H), 3.19 (d, J=2.0Hz, 2H), 3.13 (q, J=4.6, 4.0Hz, 2H), 2.30–2.19 (m, 1H), 1.86 (tdt, J=12.8, 9.1, 5.0Hz, 4H), 1.60–1.55 (m, 2H), 1.43 (d, J=7.8Hz, 1H), 1.29 (dd, J=6.7, 3.6Hz, 4H), 1.24–1.21 (m, 2H), 1.20 (d, J=3.7Hz, 3H), 1.16 (d, J=6.7Hz, 4H), 1.08 (d, J=6.7Hz, 4H).
实施例19：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(084)Example 19: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)benzamide (084)
Figure PCTCN2021126588-appb-000047
Figure PCTCN2021126588-appb-000047
参考实施例9的合成方法，把(S)-2-(2-异丙基苯基)吡咯烷替换为2-(2-异丙基苯基)吡咯烷，3,5-二氟吡啶-2-甲酸甲酯替换为2,3,4-三氟苯甲酸甲酯，可合成得到目标化合物084，LC-MS(ESI-MS)：m/z＝880[M+H] +。 Referring to the synthetic method of Example 9, replacing (S)-2-(2-isopropylphenyl)pyrrolidine with 2-(2-isopropylphenyl)pyrrolidine, 3,5-difluoropyridine- The target compound 084 can be synthesized by replacing methyl 2-carboxylate with methyl 2,3,4-trifluorobenzoate, LC-MS (ESI-MS): m/z=880 [M+H] + .
1H NMR(400MHz,Chloroform-d)δ9.33(s,1H),8.73(d,J＝2.2Hz,1H),8.52–8.47(m,1H),8.20(d,J＝2.8Hz,1H),7.90(d,J＝9.0Hz,1H),7.79(d,J＝9.0Hz,1H),7.43–7.38(m,3H),6.78(d,J＝11.9Hz,2H),6.43–6.41(m,1H),4.11–4.03(m,3H),3.52–3.38(m,4H),3.27–3.20(m,4H),3.14–2.93(m,7H),2.10–1.92(m,7H),1.78–1.71(m,5H),1.64–1.54(m,8H),1.48–1.32(m,3H).实施例20：N-((4-(((1,4-二恶烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(085) 1 H NMR (400MHz, Chloroform-d) δ9.33(s, 1H), 8.73(d, J=2.2Hz, 1H), 8.52-8.47(m, 1H), 8.20(d, J=2.8Hz, 1H) ),7.90(d,J=9.0Hz,1H),7.79(d,J=9.0Hz,1H),7.43-7.38(m,3H),6.78(d,J=11.9Hz,2H),6.43-6.41 (m, 1H), 4.11–4.03 (m, 3H), 3.52–3.38 (m, 4H), 3.27–3.20 (m, 4H), 3.14–2.93 (m, 7H), 2.10–1.92 (m, 7H) , 1.78–1.71 (m, 5H), 1.64–1.54 (m, 8H), 1.48–1.32 (m, 3H). Example 20: N-((4-((((1,4-dioxane-2 -yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4 -(2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (085)
Figure PCTCN2021126588-appb-000048
Figure PCTCN2021126588-appb-000048
参考实施例19的合成方法，把(四氢-2H-吡喃-4-基)甲胺盐酸盐替换为(1,4-二恶烷-2-基)甲胺盐酸盐，可合成得到目标化合物085，LC-MS(ESI-MS)：m/z＝882[M+H] +。 Referring to the synthesis method of Example 19, replacing (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride with (1,4-dioxan-2-yl)methanamine hydrochloride, it can be synthesized The title compound 085 was obtained, LC-MS (ESI-MS): m/z=882 [M+H] + .
1H NMR(400MHz,Chloroform-d)δ9.92(s,1H),8.71(d,J＝2.3Hz,1H),8.58(t,J＝5.2Hz,1H),8.10(d,J＝2.7Hz,1H),7.82(dd,J＝9.2,2.3Hz,1H),7.77–7.73(m,1H),7.42–7.32(m,6H),6.75(t,J＝8.3Hz,1H),6.69(d,J＝9.3Hz,1H),6.38(dd,J＝3.5,1.9Hz,1H),3.95–3.76(m,6H),3.73–3.66(m,1H),3.58–3.45(m,2H),3.44–3.24(m,3H),3.19–3.10(m,1H),3.06–2.89(m,5H),2.53–2.37(m,3H),2.17–2.04(m,2H),1.93–1.83(m,1H),1.79–1.61(m,3H),1.59–1.50(m,2H),1.47–1.37(m,2H),1.35–1.28(m,5H). 1 H NMR (400MHz, Chloroform-d) δ 9.92 (s, 1H), 8.71 (d, J=2.3Hz, 1H), 8.58 (t, J=5.2Hz, 1H), 8.10 (d, J=2.7 Hz,1H),7.82(dd,J=9.2,2.3Hz,1H),7.77-7.73(m,1H),7.42-7.32(m,6H),6.75(t,J=8.3Hz,1H),6.69 (d, J=9.3Hz, 1H), 6.38 (dd, J=3.5, 1.9Hz, 1H), 3.95–3.76 (m, 6H), 3.73–3.66 (m, 1H), 3.58–3.45 (m, 2H) ), 3.44–3.24 (m, 3H), 3.19–3.10 (m, 1H), 3.06–2.89 (m, 5H), 2.53–2.37 (m, 3H), 2.17–2.04 (m, 2H), 1.93–1.83 (m, 1H), 1.79–1.61 (m, 3H), 1.59–1.50 (m, 2H), 1.47–1.37 (m, 2H), 1.35–1.28 (m, 5H).
实施例21：N-((4-(((1,4-二恶烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(086)Example 21: N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)benzamide (086)
Figure PCTCN2021126588-appb-000049
Figure PCTCN2021126588-appb-000049
制备中间体86-1：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-溴-6-氟苯甲酸甲酯(86-1)Preparation of Intermediate 86-1: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-6-fluorobenzoate (86-1)
将4-溴-2,6-二氟苯甲酸甲酯(5.00g，19.92mmol)、1H-吡咯并[2,3-b]吡啶-5-醇(2.94g，21.91mmol)、磷酸钾(5.07g，23.91mmol)溶解于二乙二醇二甲醚(70.00mL)中，升温至100℃反应21h。TLC监测反应完毕后加入H 2O和2M的盐酸水溶液，调节PH至中性，真空油泵减压浓缩二乙二醇二甲醚，加入EA和水萃取，分离有机相，减压浓缩，所得粗品经硅胶柱层析纯化得到固体中间体86-1(3.30g)，收率45％，LC-MS(ESI-MS)：m/z＝365[M+H] +。 Methyl 4-bromo-2,6-difluorobenzoate (5.00 g, 19.92 mmol), 1H-pyrrolo[2,3-b]pyridin-5-ol (2.94 g, 21.91 mmol), potassium phosphate ( 5.07 g, 23.91 mmol) was dissolved in diethylene glycol dimethyl ether (70.00 mL), and the temperature was raised to 100 °C for 21 h. After the completion of the TLC monitoring reaction, H 2 O and 2M hydrochloric acid aqueous solution were added to adjust the pH to neutrality. Diethylene glycol dimethyl ether was concentrated under reduced pressure by a vacuum oil pump, EA and water were added for extraction, the organic phase was separated, and the resulting crude product was concentrated under reduced pressure. Purification by silica gel column chromatography gave solid intermediate 86-1 (3.30 g), yield 45%, LC-MS (ESI-MS): m/z=365 [M+H] + .
制备中间体86-2：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-溴-6-氟苯甲酸(86-2)Preparation of Intermediate 86-2: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-6-fluorobenzoic acid (86-2)
将中间体86-1(3.30g，9.04mmol)溶解于THF(66.00mL)中，加入3M NaOH水溶液(31.00mL，90.40mmol)，60℃加热14h。TLC监测反应完毕后，直接浓缩THF，调节PH大约至2～3，过滤，滤饼用水漂洗，PE漂洗，常压50℃烘干可得固体中间体86-2(2.90g)，收率91％，LC-MS(ESI-MS)：m/z＝351[M+H] +。 Intermediate 86-1 (3.30 g, 9.04 mmol) was dissolved in THF (66.00 mL), 3M aqueous NaOH solution (31.00 mL, 90.40 mmol) was added, and heated at 60° C. for 14 h. After the completion of the TLC monitoring reaction, the THF was directly concentrated, the pH was adjusted to about 2-3, filtered, the filter cake was rinsed with water, rinsed with PE, and dried at normal pressure at 50°C to obtain solid intermediate 86-2 (2.90g), yield 91 %, LC-MS (ESI-MS): m/z=351 [M+H] + .
制备中间体86-3：2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷(86-3)Preparation of Intermediate 86-3: 2-(2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (86-3)
将2-(2-异丙基苯基)吡咯烷(7.00g，37.00mmol)、2-氧代-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(13.30g，55.5mmol)溶解于DCM(150.00mL)，室温搅拌10min后加入STAB(三乙酰氧基硼氢化钠，31.40g，148.00mmol)，室温反应1h。TLC监测反应完毕后，加入DCM和水萃取，分离有机相，浓缩近干，再次加入DCM(150.00mL)溶解产物，加入TFA(50.00mL)，室温反应16h。LC-MS跟踪反应完毕后，直接浓缩反应液近干，加水溶解，用饱和碳酸氢钠调解PH大约至8～10，加入DCM萃 取分液，分离DCM相，减压浓缩，粗品经硅胶柱层析可得中间体86-3(6.60g)，收率57％，LC-MS(ESI-MS)：m/z＝313[M+H] +。 2-(2-Isopropylphenyl)pyrrolidine (7.00 g, 37.00 mmol), tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (13.30 g, 55.5 mmol) was dissolved in DCM (150.00 mL), stirred at room temperature for 10 min, added STAB (sodium triacetoxyborohydride, 31.40 g, 148.00 mmol), and reacted at room temperature for 1 h. After the reaction was monitored by TLC, DCM and water were added for extraction, the organic phase was separated, concentrated to near dryness, DCM (150.00 mL) was added again to dissolve the product, TFA (50.00 mL) was added, and the reaction was carried out at room temperature for 16 h. After the LC-MS tracking reaction was completed, the reaction solution was directly concentrated to near dryness, dissolved in water, adjusted to pH 8-10 with saturated sodium bicarbonate, DCM was added for extraction and separation, the DCM phase was separated, concentrated under reduced pressure, and the crude product was passed through a silica gel column layer. The intermediate 86-3 (6.60 g) was obtained by analysis, yield 57%, LC-MS (ESI-MS): m/z=313 [M+H] + .
制备中间体86-4：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酸(86-4)Preparation of Intermediate 86-4: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropyl) Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (86-4)
将中间体86-2(800.00mg，2.28.00mmol)、中间体86-3(1.43g，4.56mmol)、Aphos((4-(N,N-二甲氨基)苯基)二-叔丁基膦,[4-(二甲氨基)苯基]双(叔丁基)苯基，182.00mg，0.68mmol)和Pd 3(dba) 2(418.00mg，1.92mmol)溶解于THF(16.00mL)和甲苯(16.00mL)的混合溶液中，室温搅拌5min，加入1mol/L的THF的LiHMDS(18.00ml，18.24mmol)溶液，然后升温至50℃反应4h。LC-MS跟踪反应完毕后，将反应体系降温至0℃，加入2mol/L的HCl水溶液调节PH大约至5～6，再用饱和碳酸氢钠调节PH至8，加入EA和水萃取，分离有机相，减压浓缩，经硅胶柱层析纯化，所得产物继续用甲基叔丁基醚打浆过滤，可得固体中间体86-4(690.00mg)，收率52％，LC-MS(ESI-MS)：m/z＝583[M+H] +。 Intermediate 86-2 (800.00 mg, 2.28.00 mmol), Intermediate 86-3 (1.43 g, 4.56 mmol), Aphos ((4-(N,N-dimethylamino)phenyl)di-tert-butyl Phosphine, [4-(dimethylamino)phenyl]bis(tert-butyl)phenyl, 182.00 mg, 0.68 mmol) and Pd3 (dba) 2 (418.00 mg, 1.92 mmol) were dissolved in THF (16.00 mL) and To the mixed solution of toluene (16.00 mL), stir at room temperature for 5 min, add 1 mol/L THF in LiHMDS (18.00 mL, 18.24 mmol) solution, and then warm to 50 °C for 4 h. After the LC-MS tracking reaction was completed, the reaction system was cooled to 0°C, 2 mol/L HCl aqueous solution was added to adjust the pH to about 5 to 6, then the pH was adjusted to 8 with saturated sodium bicarbonate, EA and water were added for extraction, and the organic matter was separated. phase, concentrated under reduced pressure, purified by silica gel column chromatography, and the obtained product was further filtered with methyl tert-butyl ether to obtain solid intermediate 86-4 (690.00 mg), yield 52%, LC-MS (ESI- MS): m/z=583 [M+H] + .
制备化合物86：N-((4-(((1,4-二恶烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(086)Preparation of Compound 86: N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)benzamide (086)
参考实施例7步骤6～9的合成方法，把中间体24-5替换为中间体86-4，将中间体24-6替换为(1,4-二恶烷-2-基)甲胺盐酸盐，，可合成得到目标化合物086，LC-MS(ESI-MS)：m/z＝882[M+H] +。 1H NMR(400MHz,Chloroform-d)δ9.40(s,1H),8.77(d,J＝2.2Hz,1H),8.59–8.56(m,1H),8.10(dd,J＝9.2,2.3Hz,1H),8.06(d,J＝2.5Hz,1H),7.51(d,J＝2.6Hz,1H),7.40(d,J＝2.8Hz,1H),7.22(dt,J＝25.2,7.5Hz,4H),6.80(d,J＝9.2Hz,1H),6.48–6.45(m,1H),6.28(dd,J＝14.9,2.3Hz,1H),5.99–5.89(m,1H),4.02–3.93(m,2H),3.92–3.88(m,2H),3.88–3.86(m,1H),3.85–3.79(m,2H),3.78–3.65(m,3H),3.56–3.51(m,1H),3.45–3.20(m,6H),3.17–2.90(m,8H),2.30–2.18(m,2H),2.08–1.96(m,2H),1.89–1.79(m,4H),0.96–0.83(m,3H). Referring to the synthetic methods of steps 6 to 9 of Example 7, replace intermediate 24-5 with intermediate 86-4, and replace intermediate 24-6 with (1,4-dioxan-2-yl)methanamine salt acid salt, the target compound 086 can be synthesized, LC-MS (ESI-MS): m/z=882 [M+H] + . 1 H NMR (400MHz, Chloroform-d)δ9.40(s,1H),8.77(d,J=2.2Hz,1H),8.59-8.56(m,1H),8.10(dd,J=9.2,2.3Hz ,1H),8.06(d,J＝2.5Hz,1H),7.51(d,J＝2.6Hz,1H),7.40(d,J＝2.8Hz,1H),7.22(dt,J＝25.2,7.5Hz ,4H),6.80(d,J＝9.2Hz,1H),6.48-6.45(m,1H),6.28(dd,J＝14.9,2.3Hz,1H),5.99-5.89(m,1H),4.02- 3.93 (m, 2H), 3.92–3.88 (m, 2H), 3.88–3.86 (m, 1H), 3.85–3.79 (m, 2H), 3.78–3.65 (m, 3H), 3.56–3.51 (m, 1H) ), 3.45–3.20 (m, 6H), 3.17–2.90 (m, 8H), 2.30–2.18 (m, 2H), 2.08–1.96 (m, 2H), 1.89–1.79 (m, 4H), 0.96–0.83 (m,3H).
实施例22：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(087)Example 22: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)benzamide (087)
Figure PCTCN2021126588-appb-000050
Figure PCTCN2021126588-appb-000050
参考实施例21的合成方法，把(1,4-二恶烷-2-基)甲胺盐酸盐替换为(四氢-2H-吡喃-4-基)甲胺盐酸盐，可合成得到目标化合物087，LC-MS(ESI-MS)：m/z＝880[M+H] +。 1H NMR(400MHz,Chloroform-d)δ9.22(s,1H),8.82(d,J＝2.3Hz,1H),8.51(t,J＝5.5Hz,1H),8.19–8.06(m,2H),7.59(d,J＝2.5Hz,2H),7.44(t,J＝2.9Hz,1H),7.29–7.17(m,3H),6.86(d,J＝9.2Hz,1H),6.52(d,J＝2.9Hz,1H),6.26(d,J＝14.8Hz,1H), 5.93–5.81(m,1H),4.11–4.05(m,2H),3.56–3.37(m,3H),3.33–3.23(m,4H),3.05–2.81(m,5H),2.31–2.22(m,2H),2.10–1.93(m,5H),1.86–1.72(m,6H),1.53–1.41(m,9H),0.94–0.85(m,2H). Referring to the synthesis method of Example 21, replacing (1,4-dioxan-2-yl)methanamine hydrochloride with (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride, it can be synthesized The target compound 087 was obtained, LC-MS (ESI-MS): m/z=880 [M+H] + . 1 H NMR (400MHz, Chloroform-d)δ9.22(s,1H),8.82(d,J=2.3Hz,1H),8.51(t,J=5.5Hz,1H),8.19-8.06(m,2H) ), 7.59(d, J＝2.5Hz, 2H), 7.44(t, J＝2.9Hz, 1H), 7.29–7.17(m, 3H), 6.86(d, J＝9.2Hz, 1H), 6.52(d , J=2.9Hz, 1H), 6.26 (d, J=14.8Hz, 1H), 5.93–5.81 (m, 1H), 4.11–4.05 (m, 2H), 3.56–3.37 (m, 3H), 3.33– 3.23 (m, 4H), 3.05–2.81 (m, 5H), 2.31–2.22 (m, 2H), 2.10–1.93 (m, 5H), 1.86–1.72 (m, 6H), 1.53–1.41 (m, 9H) ),0.94–0.85(m,2H).
实施例23：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-3-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(((1-甲基哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(088)Example 23: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)- 3-Nitrophenyl)sulfonyl)benzamide (088)
Figure PCTCN2021126588-appb-000051
Figure PCTCN2021126588-appb-000051
参考实施例19的合成方法，把中间体(四氢-2H-吡喃-4-基)甲胺盐酸盐替换为中间体(1-甲基哌啶-4-基)甲胺，可合成得到目标化合物088，LC-MS(ESI-MS)：m/z＝893[M+H] +。 Referring to the synthetic method of Example 19, the intermediate (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride was replaced by the intermediate (1-methylpiperidin-4-yl)methanamine, which could be synthesized The target compound 088 was obtained, LC-MS (ESI-MS): m/z=893 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.48(s,1H),8.40–8.33(m,2H),7.93(d,J＝2.7Hz,1H),7.56(dt,J＝9.2,2.2Hz,3H),7.41(dd,J＝6.2,2.7Hz,3H),7.28–7.21(m,1H),7.17(d,J＝7.1Hz,2H),6.81–6.74(m,1H),6.27(dd,J＝3.4,1.8Hz,1H),2.92–2.77(m,6H),2.04–1.98(m,1H),1.89–1.74(m,13H),1.57–1.47(m,14H),1.43–1.38(m,5H),0.93–0.84(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.48 (s, 1H), 8.40-8.33 (m, 2H), 7.93 (d, J=2.7Hz, 1H), 7.56 (dt, J=9.2, 2.2 Hz, 3H), 7.41 (dd, J=6.2, 2.7Hz, 3H), 7.28–7.21 (m, 1H), 7.17 (d, J=7.1Hz, 2H), 6.81–6.74 (m, 1H), 6.27 (dd, J=3.4, 1.8Hz, 1H), 2.92–2.77 (m, 6H), 2.04–1.98 (m, 1H), 1.89–1.74 (m, 13H), 1.57–1.47 (m, 14H), 1.43 –1.38(m,5H),0.93–0.84(m,2H).
实施例24：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(089)Example 24: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoropiperidin-4-yl)methyl )amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)picolinamide (089)
Figure PCTCN2021126588-appb-000052
Figure PCTCN2021126588-appb-000052
制备中间体89-1：4-(((4-氟哌啶-4-基)甲基)氨基)-3-硝基苯磺酰胺(89-1)Preparation of Intermediate 89-1: 4-(((4-Fluoropiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide (89-1)
将4-氟-3-硝基苯磺酰胺(1.9g，8.61mmol)溶解于THF(60.00mL)中，依次加入4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯(2g，8.61mmol)、TEA(2g，8.61mmol)，30℃搅拌反应12h。LC-MS跟踪反应完成后，加入EA和水萃取，分离有机相，减压浓缩，所得粗品经硅胶柱层析纯化得到固体中间体89-1(2.88g)，收率：77.4％，LC-MS(ESI-MS)：m/z＝433[M+H] +。 4-Fluoro-3-nitrobenzenesulfonamide (1.9 g, 8.61 mmol) was dissolved in THF (60.00 mL), followed by the addition of 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl Ester (2 g, 8.61 mmol), TEA (2 g, 8.61 mmol), and the reaction was stirred at 30 °C for 12 h. After the completion of the LC-MS tracking reaction, EA and water were added for extraction, the organic phase was separated, and concentrated under reduced pressure. MS (ESI-MS): m/z=433 [M+H] + .
制备化合物89：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(089)Preparation of Compound 89: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoropiperidin-4-yl)methyl )amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)picolinamide (089)
参考实施例19的合成方法，把2,3,4-三氟苯甲酸甲酯替换为3,5-二氟吡啶-2-甲酸甲酯，中间体3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺替换为中间体89-1，可合成得到产物4-(((4-(N-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基) -5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)-4-氟哌啶-1-羧酸叔丁酯。将所得产物溶解于二氯甲烷(20.00mL)中，缓慢滴加三氟乙酸(8.00mL)，在室温下搅拌反应14h，过滤干燥，减压浓缩，可合成得到目标化合物089，LC-MS(ESI-MS)：m/z＝880[M+H] +。 Referring to the synthetic method of Example 19, replace methyl 2,3,4-trifluorobenzoate with methyl 3,5-difluoropyridine-2-carboxylate, intermediate 3-nitro-4-(((tetra Hydrogen-2H-pyran-4-yl)methyl)amino)benzenesulfonamide was replaced by intermediate 89-1, and the product 4-((((4-(N-(3-((1H-pyrrolo) [2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5] Nonan-7-yl)picolinoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester. The obtained product was dissolved in dichloromethane (20.00 mL), trifluoroacetic acid (8.00 mL) was slowly added dropwise, the reaction was stirred at room temperature for 14 h, filtered, dried, and concentrated under reduced pressure to obtain the target compound 089. LC-MS ( ESI-MS): m/z=880 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.70(d,J＝2.7Hz,1H),8.69(s,1H),8.58(d,J＝2.3Hz,1H),8.08(d,J＝2.4Hz,2H),7.96(d,J＝2.7Hz,2H),7.87(d,J＝9.3Hz,1H),7.51(s,2H),7.47(s,2H),7.41(s,5H),7.28(s,2H),6.64(d,J＝2.4Hz,1H),6.37(dd,J＝3.4,1.8Hz,1H),4.68(s,1H),3.84(d,J＝6.5Hz,2H),3.79(d,J＝6.3Hz,4H),3.06(s,4H),3.02–2.95(m,5H),2.37(s,1H),2.07(d,J＝9.8Hz,12H),2.01(s,4H),1.52(s,2H),1.25(s,6H),1.15(d,J＝6.7Hz,8H). 1 H NMR (400MHz, DMSO-d 6 )δ11.70(d,J=2.7Hz,1H),8.69(s,1H),8.58(d,J=2.3Hz,1H),8.08(d,J= 2.4Hz, 2H), 7.96(d, J=2.7Hz, 2H), 7.87(d, J=9.3Hz, 1H), 7.51(s, 2H), 7.47(s, 2H), 7.41(s, 5H) ,7.28(s,2H),6.64(d,J＝2.4Hz,1H),6.37(dd,J＝3.4,1.8Hz,1H),4.68(s,1H),3.84(d,J＝6.5Hz, 2H), 3.79(d, J=6.3Hz, 4H), 3.06(s, 4H), 3.02–2.95(m, 5H), 2.37(s, 1H), 2.07(d, J=9.8Hz, 12H), 2.01(s, 4H), 1.52(s, 2H), 1.25(s, 6H), 1.15(d, J=6.7Hz, 8H).
实施例25：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((吗啉-2-基甲基)氨基)-3-硝基苯基)磺酰基)吡啶甲酰胺(090)Example 25: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((morpholin-2-ylmethyl)amino)-3-nitrophenyl)sulfonyl) Picolinamide (090)
Figure PCTCN2021126588-appb-000053
Figure PCTCN2021126588-appb-000053
参考实施例24的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为2-氨基甲基-4-BOC-吗啉，可合成得到目标化合物090，LC-MS(ESI-MS)：m/z＝864[M+H] +。 Referring to the synthetic method of Example 24, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester is replaced with 2-aminomethyl-4-BOC-morpholine, and the target compound can be synthesized 090, LC-MS (ESI-MS): m/z=864 [M+H] + .
实施例26：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(2-吗啉乙酰基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(091)Example 26: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2-morpholinoacetyl) yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)picolinamide (091)
Figure PCTCN2021126588-appb-000054
Figure PCTCN2021126588-appb-000054
将化合物089(1.32g，1.50mmol)、2-吗啉乙酸(0.30g，2.07mmol)、HOBT(0.27g，2.00mmol)溶解于乙腈(5.00mL)中，加入EDAC.HCl(0.38g，2.00mmol)，反应搅拌12h。TCL监测反应完毕后加入EA和水萃取，分离有机相，无水硫酸镁干燥，减压浓缩，所得粗品经硅胶柱层析纯化得到化合物091(1.18g)，收率：78％，LC-MS(ESI-MS)：m/z＝1007[M+H] +。 Compound 089 (1.32 g, 1.50 mmol), 2-morpholinoacetic acid (0.30 g, 2.07 mmol), HOBT (0.27 g, 2.00 mmol) were dissolved in acetonitrile (5.00 mL), and EDAC.HCl (0.38 g, 2.00 mmol) was added. mmol), the reaction was stirred for 12 h. After the reaction was monitored by TCL, EA and water were added for extraction, the organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain compound 091 (1.18 g), yield: 78%, LC-MS (ESI-MS): m/z=1007 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.66(d,J＝2.4Hz,1H),8.61(t,J＝6.5Hz,1H),8.57(d,J＝2.2Hz,1H),8.05(d,J＝2.4Hz,1H),7.97(d,J＝2.6Hz,1H),7.87(dd,J＝9.2,2.3Hz,1H),7.58(d,J＝7.1Hz,1H),7.53–7.44(m,3H),7.28(d,J＝8.1Hz,3H),6.62(d,J＝2.3Hz,1H),6.40–6.34(m,1H),4.21(d,J＝13.2Hz,1H),3.95(d,J＝13.5Hz,2H),3.58-3.21(m,4H),2.85(t,J＝11.8Hz,1H),1.88(t,J＝13.2Hz,10H),1.46(d,J＝5.6 Hz,3H),1.42–1.35(m,6H),1.30–1.25(m,8H),1.21(d,J＝6.7Hz,6H),1.16(d,J＝6.8Hz,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.66 (d, J=2.4Hz, 1H), 8.61 (t, J=6.5Hz, 1H), 8.57 (d, J=2.2Hz, 1H), 8.05 (d, J=2.4Hz, 1H), 7.97 (d, J=2.6Hz, 1H), 7.87 (dd, J=9.2, 2.3Hz, 1H), 7.58 (d, J=7.1Hz, 1H), 7.53 –7.44(m,3H),7.28(d,J=8.1Hz,3H),6.62(d,J=2.3Hz,1H),6.40–6.34(m,1H),4.21(d,J=13.2Hz, 1H), 3.95(d, J＝13.5Hz, 2H), 3.58-3.21(m, 4H), 2.85(t, J＝11.8Hz, 1H), 1.88(t, J＝13.2Hz, 10H), 1.46( d, J=5.6 Hz, 3H), 1.42–1.35 (m, 6H), 1.30–1.25 (m, 8H), 1.21 (d, J=6.7 Hz, 6H), 1.16 (d, J=6.8 Hz, 6H) ).
实施例27：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(092)Example 27: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-(2-(dimethylamino)acetyl) )-4-Fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (092)
Figure PCTCN2021126588-appb-000055
Figure PCTCN2021126588-appb-000055
参考实施例26的合成方法，把2-吗啉乙酸替换为2-(二甲氨基)乙酸，可合成得到目标化合物092，LC-MS(ESI-MS)：m/z＝965[M+H] +。 Referring to the synthesis method of Example 26, the target compound 092 can be synthesized by replacing 2-morpholinoacetic acid with 2-(dimethylamino)acetic acid, LC-MS (ESI-MS): m/z=965 [M+H ] + .
1H NMR(400MHz,DMSO-d 6)δ11.61(s,1H),8.47(dd,J＝8.0,4.2Hz,2H),8.01(d,J＝2.3Hz,1H),7.96(d,J＝2.6Hz,1H),7.76(dd,J＝9.1,2.1Hz,1H),7.53(d,J＝7.4Hz,1H),7.47(t,J＝3.0Hz,1H),7.42(d,J＝2.6Hz,1H),7.23(d,J＝7.4Hz,1H),7.16–7.07(m,3H),6.68(d,J＝2.3Hz,1H),6.34(t,J＝2.6Hz,1H),4.23(d,J＝13.1Hz,1H),3.82(d,J＝13.9Hz,2H),3.70(dd,J＝20.8,6.7Hz,6H),3.19–3.10(m,3H),3.07–2.98(m,3H),2.92–2.82(m,1H),2.21(dq,J＝12.5,6.9,5.4Hz,1H),1.94–1.67(m,9H),1.57–1.34(m,9H),1.31–1.12(m,11H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.61 (s, 1H), 8.47 (dd, J=8.0, 4.2 Hz, 2H), 8.01 (d, J=2.3 Hz, 1H), 7.96 (d, J=2.6Hz, 1H), 7.76(dd, J=9.1, 2.1Hz, 1H), 7.53(d, J=7.4Hz, 1H), 7.47(t, J=3.0Hz, 1H), 7.42(d, J=2.6Hz, 1H), 7.23 (d, J=7.4Hz, 1H), 7.16–7.07 (m, 3H), 6.68 (d, J=2.3Hz, 1H), 6.34 (t, J=2.6Hz, 1H), 4.23(d, J＝13.1Hz, 1H), 3.82(d, J＝13.9Hz, 2H), 3.70(dd, J＝20.8, 6.7Hz, 6H), 3.19–3.10(m, 3H), 3.07–2.98 (m, 3H), 2.92–2.82 (m, 1H), 2.21 (dq, J=12.5, 6.9, 5.4Hz, 1H), 1.94–1.67 (m, 9H), 1.57–1.34 (m, 9H) ),1.31–1.12(m,11H).
实施例28：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-(吗啉甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(093)Example 28: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[ b][1,4]oxazin-7-yl)sulfonyl)benzamide (093)
Figure PCTCN2021126588-appb-000056
Figure PCTCN2021126588-appb-000056
参考实施例1的合成方法，把(S)-2-(2-异丙基苯基)吡咯烷替换为中间体2-(2-异丙基苯基)吡咯烷，(1-氨基环丙基)甲醇替换为2-氨基-3-吗啉丙烷-1-醇，可合成得到化合物093，LC-MS(ESI-MS)：m/z＝905[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),8.84(s,1H),8.16(d,J＝2.1Hz,1H),8.00(d,J＝2.6Hz,1H),7.54(t,J＝7.7Hz,3H),7.35(d,J＝2.1Hz,1H),7.29–7.17(m,4H),6.67(dd,J＝9.0,2.4Hz,1H),6.40–6.32(m,1H),6.19(d,J＝2.3Hz,1H),4.24(dd,J＝10.5,3.0Hz,1H),3.98–3.86(m,3H),3.63(t,J＝4.7Hz,7H),2.94(t,J＝5.5Hz,3H),2.29–2.22(m,1H),1.95–1.81(m,4H),1.76(s,1H),1.38(ddd,J＝23.7,12.9,7.4Hz,8H),1.27–1.14(m,12H)。 Referring to the synthetic method of Example 1, replace (S)-2-(2-isopropylphenyl)pyrrolidine with the intermediate 2-(2-isopropylphenyl)pyrrolidine, (1-aminocyclopropane) base) methanol was replaced with 2-amino-3-morpholinopropan-1-ol, and compound 093 could be synthesized, LC-MS (ESI-MS): m/z=905 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.63 (s, 1H), 8.84 (s, 1H), 8.16 (d, J=2.1 Hz, 1H), 8.00 (d, J=2.6 Hz, 1H) ,7.54(t,J=7.7Hz,3H),7.35(d,J=2.1Hz,1H),7.29–7.17(m,4H),6.67(dd,J=9.0,2.4Hz,1H),6.40– 6.32 (m, 1H), 6.19 (d, J=2.3Hz, 1H), 4.24 (dd, J=10.5, 3.0Hz, 1H), 3.98–3.86 (m, 3H), 3.63 (t, J=4.7Hz) ,7H),2.94(t,J＝5.5Hz,3H),2.29-2.22(m,1H),1.95-1.81(m,4H),1.76(s,1H),1.38(ddd,J＝23.7,12.9 , 7.4Hz, 8H), 1.27–1.14 (m, 12H).
实施例29：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(((4-(2-吗啉乙酰基)吗啉-2-基)甲基)氨基)-3-硝基苯基)磺酰基)吡啶甲酰胺(094)Example 29: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-(2-morpholinoacetyl)morpholin-2-yl)methyl)amino )-3-Nitrophenyl)sulfonyl)picolinamide (094)
Figure PCTCN2021126588-appb-000057
Figure PCTCN2021126588-appb-000057
参考实施例26的合成方法，把化合物089替换为化合物090，可合成得到目标化合物094，LC-MS(ESI-MS)：m/z＝991[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.62(s,1H),8.52(d,J＝6.5Hz,2H),8.05(s,1H),7.96(d,J＝2.6Hz,1H),7.81(dd,J＝21.0,9.1Hz,1H),7.54(d,J＝7.4Hz,1H),7.48(t,J＝3.0Hz,1H),7.44(d,J＝3.4Hz,1H),7.24(d,J＝7.5Hz,1H),7.19–7.13(m,2H),7.06(dd,J＝12.6,9.2Hz,1H),6.66(s,1H),6.37–6.32(m,1H),4.13(t,J＝11.3Hz,1H),4.00–3.72(m,3H),3.09(ddd,J＝41.8,21.5,8.4Hz,12H),2.39(dt,J＝20.7,4.6Hz,6H),2.23(s,1H),1.84–1.71(m,4H),1.60–1.34(m,9H),1.18(dd,J＝9.6,6.8Hz,10H)。 Referring to the synthesis method of Example 26, compound 089 was replaced by compound 090, and the target compound 094 could be synthesized, LC-MS (ESI-MS): m/z=991 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.62(s, 1H), 8.52(d, J=6.5Hz, 2H), 8.05(s, 1H), 7.96(d, J=2.6Hz, 1H) ,7.81(dd,J＝21.0,9.1Hz,1H),7.54(d,J＝7.4Hz,1H),7.48(t,J＝3.0Hz,1H),7.44(d,J＝3.4Hz,1H) ,7.24(d,J＝7.5Hz,1H),7.19-7.13(m,2H),7.06(dd,J＝12.6,9.2Hz,1H),6.66(s,1H),6.37-6.32(m,1H) ),4.13(t,J＝11.3Hz,1H),4.00–3.72(m,3H),3.09(ddd,J＝41.8,21.5,8.4Hz,12H),2.39(dt,J＝20.7,4.6Hz, 6H), 2.23 (s, 1H), 1.84–1.71 (m, 4H), 1.60–1.34 (m, 9H), 1.18 (dd, J=9.6, 6.8Hz, 10H).
实施例30：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-(2-(二甲氨基)乙酰基)吗啉-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(095)Example 30: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-(2-(dimethylamino)acetyl) )morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)picolinamide (095)
Figure PCTCN2021126588-appb-000058
Figure PCTCN2021126588-appb-000058
参考实施例29的合成方法，把2-吗啉乙酸替换为2-(二甲氨基)乙酸，可合成得到目标化合物095，LC-MS(ESI-MS)：m/z＝949[M+H] +。 Referring to the synthesis method of Example 29, the target compound 095 can be synthesized by replacing 2-morpholinoacetic acid with 2-(dimethylamino)acetic acid, LC-MS (ESI-MS): m/z=949 [M+H ] + .
1H NMR(400MHz,DMSO-d 6)δ11.61(s,1H),8.50–8.44(m,2H),8.02(s,1H),7.96(d,J＝2.6Hz,1H),7.55–7.38(m,4H),7.24–7.11(m,4H),6.98(t,J＝8.2Hz,1H),6.37–6.29(m,1H),3.92(d,J＝12.4Hz,2H),3.19–2.95(m,12H),2.26–2.12(m,2H),1.87–1.64(m,6H),1.45(dddd,J＝41.8,19.3,11.7,7.3Hz,11H),1.25(d,J＝4.8Hz,2H),1.17(t,J＝6.3Hz,10H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.61 (s, 1H), 8.50–8.44 (m, 2H), 8.02 (s, 1H), 7.96 (d, J=2.6Hz, 1H), 7.55– 7.38 (m, 4H), 7.24–7.11 (m, 4H), 6.98 (t, J=8.2Hz, 1H), 6.37–6.29 (m, 1H), 3.92 (d, J=12.4Hz, 2H), 3.19 –2.95(m,12H),2.26–2.12(m,2H),1.87–1.64(m,6H),1.45(dddd,J=41.8,19.3,11.7,7.3Hz,11H),1.25(d,J= 4.8Hz, 2H), 1.17(t, J=6.3Hz, 10H).
实施例31：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(096)Example 31: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (096)
Figure PCTCN2021126588-appb-000059
Figure PCTCN2021126588-appb-000059
将化合物089(1.20g，1.36mmol)溶解于DMF(20.00mL)中，加入氧杂环丁烷-3-酮(0.30g，4.08mmol)，室温搅拌2h，加入氰基硼氢化钠(0.17g，2.72mmol)， 冰醋酸调解pH大约至5.5后，室温搅拌12h。TCL监测反应完毕后，加水淬灭反应，用饱和碳酸氢钠溶液(500.00mL)洗涤，用DCM和水萃取，无水硫酸钠干燥，减压浓缩，所得粗品经硅胶柱层析纯化得到固体产物096(920.00mg)，收率：72.3％，LC-MS(ESI-MS)：m/z＝936[M+H] +。 Compound 089 (1.20 g, 1.36 mmol) was dissolved in DMF (20.00 mL), oxetan-3-one (0.30 g, 4.08 mmol) was added, stirred at room temperature for 2 h, and sodium cyanoborohydride (0.17 g) was added. , 2.72 mmol), after adjusting the pH to about 5.5 with glacial acetic acid, stirring at room temperature for 12 h. After the completion of the reaction monitored by TCL, water was added to quench the reaction, washed with saturated sodium bicarbonate solution (500.00 mL), extracted with DCM and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain a solid product 096 (920.00 mg), yield: 72.3%, LC-MS (ESI-MS): m/z=936 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),8.51(s,2H),8.04(s,1H),7.95(d,J＝2.6Hz,1H),7.78(d,J＝9.1Hz,1H),7.53(d,J＝7.4Hz,1H),7.47(d,J＝3.1Hz,1H),7.43(d,J＝2.7Hz,1H),7.23–7.12(m,4H),6.65(s,1H),6.34(d,J＝3.2Hz,1H),4.53(d,J＝6.5Hz,2H),4.43(d,J＝6.1Hz,2H),3.87–3.79(m,1H),3.73–3.65(m,3H),3.18(t,J＝8.2Hz,3H),3.10–3.04(m,3H),3.00(d,J＝5.5Hz,2H),2.28–2.17(m,1H),2.07–1.89(m,3H),1.82(dd,J＝15.6,7.7Hz,7H),1.71(dd,J＝12.6,7.2Hz,3H),1.57–1.44(m,4H),1.25(d,J＝5.1Hz,2H),1.17(d,J＝3.0Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.63(s, 1H), 8.51(s, 2H), 8.04(s, 1H), 7.95(d, J=2.6Hz, 1H), 7.78(d, J＝9.1Hz,1H),7.53(d,J＝7.4Hz,1H),7.47(d,J＝3.1Hz,1H),7.43(d,J＝2.7Hz,1H),7.23–7.12(m, 4H), 6.65(s, 1H), 6.34(d, J=3.2Hz, 1H), 4.53(d, J=6.5Hz, 2H), 4.43(d, J=6.1Hz, 2H), 3.87–3.79( m, 1H), 3.73–3.65 (m, 3H), 3.18 (t, J=8.2Hz, 3H), 3.10–3.04 (m, 3H), 3.00 (d, J=5.5Hz, 2H), 2.28–2.17 (m, 1H), 2.07–1.89 (m, 3H), 1.82 (dd, J=15.6, 7.7Hz, 7H), 1.71 (dd, J=12.6, 7.2Hz, 3H), 1.57–1.44 (m, 4H) ), 1.25 (d, J=5.1 Hz, 2H), 1.17 (d, J=3.0 Hz, 6H).
实施例32：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)吡啶甲酰胺(097)Example 32: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((4-(oxetan-3-yl)morpholine- 2-yl)methyl)amino)phenyl)sulfonyl)picolinamide (097)
Figure PCTCN2021126588-appb-000060
Figure PCTCN2021126588-appb-000060
参考实施例31的合成方法，把化合物089替换为化合物090，可合成得到化合物097，LC-MS(ESI-MS)：m/z＝920[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced by compound 090, and compound 097 could be synthesized, LC-MS (ESI-MS): m/z=920 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),8.51(s,2H),8.04(s,1H),7.95(s,1H),7.79(d,J＝9.1Hz,1H),7.54(d,J＝7.4Hz,1H),7.48(d,J＝3.4Hz,2H),7.24(d,J＝7.5Hz,1H),7.17(d,J＝8.7Hz,2H),7.00(d,J＝9.3Hz,1H),6.66(s,1H),6.35(s,1H),4.56(d,J＝6.5Hz,2H),4.47(q,J＝5.4Hz,3H),3.88(d,J＝11.2Hz,2H),3.79–3.75(m,2H),3.19(s,3H),3.08(d,J＝6.7Hz,3H),3.01(t,J＝5.5Hz,2H),2.76(d,J＝11.0Hz,1H),2.60(s,1H),2.22(q,J＝8.3,6.6Hz,1H),1.99(dd,J＝11.4,3.3Hz,1H),1.81(s,4H),1.55(d,J＝11.3Hz,2H),1.46(d,J＝5.6Hz,2H),1.40(d,J＝4.4Hz,2H),1.27–1.25(m,1H),1.19(d,J＝8.6Hz,9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.63(s, 1H), 8.51(s, 2H), 8.04(s, 1H), 7.95(s, 1H), 7.79(d, J=9.1Hz, 1H), 7.54(d, J＝7.4Hz, 1H), 7.48(d, J＝3.4Hz, 2H), 7.24(d, J＝7.5Hz, 1H), 7.17(d, J＝8.7Hz, 2H) ,7.00(d,J＝9.3Hz,1H),6.66(s,1H),6.35(s,1H),4.56(d,J＝6.5Hz,2H),4.47(q,J＝5.4Hz,3H) ,3.88(d,J＝11.2Hz,2H),3.79–3.75(m,2H),3.19(s,3H),3.08(d,J＝6.7Hz,3H),3.01(t,J＝5.5Hz, 2H), 2.76(d, J=11.0Hz, 1H), 2.60(s, 1H), 2.22(q, J=8.3, 6.6Hz, 1H), 1.99(dd, J=11.4, 3.3Hz, 1H), 1.81(s, 4H), 1.55(d, J＝11.3Hz, 2H), 1.46(d, J＝5.6Hz, 2H), 1.40(d, J＝4.4Hz, 2H), 1.27–1.25(m, 1H ), 1.19 (d, J=8.6 Hz, 9H).
实施例33：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(099)Example 33: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoropiperidin-4-yl)methoxy) )-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7 -yl)picolinamide (099)
Figure PCTCN2021126588-appb-000061
Figure PCTCN2021126588-appb-000061
制备中间体99-1：4-氟-4-((2-硝基-4-氨磺酰基苯氧基)甲基)哌啶-1-羧酸叔丁 酯(099-1)Preparation of Intermediate 99-1: tert-butyl 4-fluoro-4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate (099-1)
将4-氟-3-硝基苯磺酰胺(1.00g，4.54mmol)溶解于THF(20.00mL)中，加入4-氟-4-(羟甲基)哌啶-1-羧酸叔丁酯(1.06g，4.54mmol)，冰浴降温至0℃，分批加入NaH(727mg，18.17mmol)，在0℃搅拌反应5h，LC-MS跟踪反应完毕后加入DCM和水萃取，分离有机相，过滤干燥，减压浓缩，所得粗品经硅胶柱层析纯化得到中间体99-1(1.76g)，收率：89.3％，LC-MS(ESI-MS)：m/z＝434[M+H] +。 4-Fluoro-3-nitrobenzenesulfonamide (1.00 g, 4.54 mmol) was dissolved in THF (20.00 mL) and tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate was added (1.06 g, 4.54 mmol), cooled to 0 °C in an ice bath, NaH (727 mg, 18.17 mmol) was added in batches, and the reaction was stirred at 0 °C for 5 h. After the reaction was followed by LC-MS, DCM and water were added for extraction, and the organic phase was separated. It was dried by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain Intermediate 99-1 (1.76 g), yield: 89.3%, LC-MS (ESI-MS): m/z=434 [M+H ] + .
制备化合物099：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(099)Preparation of Compound 099: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoropiperidin-4-yl)methoxy) )-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7 -yl)picolinamide (099)
参考实施例24的合成方法，把中间体89-1替换为99-1，可合成得到目标化合物099，LC-MS(ESI-MS)：m/z＝881[M+H] +。 Referring to the synthesis method of Example 24, substituting the intermediate 89-1 with 99-1, the target compound 099 can be synthesized, LC-MS (ESI-MS): m/z=881[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),8.27(s,1H),7.97(s,3H),7.66–7.62(m,1H),7.46(d,J＝17.1Hz,3H),7.28(s,2H),7.19(d,J＝8.5Hz,2H),6.67(s,1H),6.36(s,1H),4.38(d,J＝20.5Hz,3H),3.11(d,J＝4.6Hz,1H),3.09(s,2H),3.02(s,2H),2.94(d,J＝5.6Hz,2H),2.27(d,J＝11.3Hz,1H),2.14(s,1H),2.12(s,1H),2.04(s,1H),1.86(s,2H),1.47(s,2H),1.42–1.40(m,2H),1.36(s,1H),1.32(s,1H),1.25(d,J＝3.6Hz,5H),1.21(d,J＝6.7Hz,5H),1.16(d,J＝6.7Hz,5H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.63(s, 1H), 8.27(s, 1H), 7.97(s, 3H), 7.66-7.62(m, 1H), 7.46(d, J=17.1 Hz, 3H), 7.28(s, 2H), 7.19(d, J=8.5Hz, 2H), 6.67(s, 1H), 6.36(s, 1H), 4.38(d, J=20.5Hz, 3H), 3.11(d,J＝4.6Hz,1H),3.09(s,2H),3.02(s,2H),2.94(d,J＝5.6Hz,2H),2.27(d,J＝11.3Hz,1H), 2.14(s, 1H), 2.12(s, 1H), 2.04(s, 1H), 1.86(s, 2H), 1.47(s, 2H), 1.42–1.40(m, 2H), 1.36(s, 1H) , 1.32 (s, 1H), 1.25 (d, J=3.6Hz, 5H), 1.21 (d, J=6.7Hz, 5H), 1.16 (d, J=6.7Hz, 5H).
实施例34：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(098)Example 34: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)picolinamide (098)
Figure PCTCN2021126588-appb-000062
Figure PCTCN2021126588-appb-000062
参考实施例31的合成方法，把化合物089替换为化合物099，可合成得到目标化合物098，LC-MS(ESI-MS)：m/z＝937[M+H] +。 Referring to the synthesis method of Example 31, compound 089 is replaced by compound 099, and the target compound 098 can be synthesized. LC-MS (ESI-MS): m/z=937 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.62(s,1H),8.25(d,J＝2.3Hz,1H),8.01–7.93(m,3H),7.54(d,J＝7.5Hz,1H),7.48(t,J＝3.0Hz,1H),7.43(d,J＝2.7Hz,1H),7.29–7.25(m,2H),7.20(dd,J＝17.9,7.6Hz,2H),6.66(d,J＝2.4Hz,1H),6.37–6.34(m,1H),4.55(d,J＝6.5Hz,2H),4.45(t,J＝6.1Hz,2H),4.29(d,J＝20.3Hz,2H),3.10(d,J＝7.3Hz,1H),3.04(d,J＝6.8Hz,2H),2.96(t,J＝5.6Hz,2H),2.60–2.57(m,2H),2.23(d,J＝4.2Hz,1H),2.08(d,J＝2.8Hz,1H),1.94(d,J＝12.4Hz,2H),1.88(s,2H),1.79–1.74(m,2H),1.47(t,J＝5.6Hz,2H),1.40(d,J＝4.9Hz,2H),1.35(s,1H),1.31(s,1H),1.25(d,J＝3.4Hz,5H),1.22–1.18(m,5H),1.15(d,J＝6.9Hz,5H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.62 (s, 1H), 8.25 (d, J=2.3Hz, 1H), 8.01-7.93 (m, 3H), 7.54 (d, J=7.5Hz, 1H), 7.48 (t, J=3.0Hz, 1H), 7.43 (d, J=2.7Hz, 1H), 7.29–7.25 (m, 2H), 7.20 (dd, J=17.9, 7.6Hz, 2H), 6.66(d,J=2.4Hz,1H),6.37–6.34(m,1H),4.55(d,J=6.5Hz,2H),4.45(t,J=6.1Hz,2H),4.29(d,J ＝20.3Hz, 2H), 3.10(d, J＝7.3Hz, 1H), 3.04(d, J＝6.8Hz, 2H), 2.96(t, J＝5.6Hz, 2H), 2.60–2.57(m, 2H) ), 2.23(d, J＝4.2Hz, 1H), 2.08(d, J＝2.8Hz, 1H), 1.94(d, J＝12.4Hz, 2H), 1.88(s, 2H), 1.79–1.74(m ,2H),1.47(t,J＝5.6Hz,2H),1.40(d,J＝4.9Hz,2H),1.35(s,1H),1.31(s,1H),1.25(d,J＝3.4Hz , 5H), 1.22–1.18 (m, 5H), 1.15 (d, J=6.9Hz, 5H).
实施例35：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(2-吗啉乙酰基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(100)Example 35: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinoacetyl) )piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7 -Azaspiro[3.5]nonan-7-yl)picolinamide (100)
Figure PCTCN2021126588-appb-000063
Figure PCTCN2021126588-appb-000063
参考实施例24和实施例26的合成方法，把实施例26中的中间体89-1替换为中间体99-1，可合成得到目标化合物100，LC-MS(ESI-MS)：m/z＝1008[M+H] +。 Referring to the synthesis methods of Example 24 and Example 26, the intermediate 89-1 in Example 26 was replaced by the intermediate 99-1, and the target compound 100 could be synthesized, LC-MS (ESI-MS): m/z =1008[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.62(s,1H),8.27(d,J＝2.2Hz,1H),8.03–7.99(m,1H),7.97–7.92(m,2H),7.55(d,J＝7.5Hz,1H),7.48(t,J＝3.0Hz,1H),7.43(d,J＝2.6Hz,1H),7.31–7.26(m,2H),7.25–7.17(m,2H),6.67(d,J＝2.4Hz,1H),6.38–6.34(m,1H),4.33(d,J＝19.6Hz,2H),4.23(d,J＝13.0Hz,1H),3.99(d,J＝13.5Hz,1H),3.59(t,J＝4.6Hz,6H),3.32(s,2H),3.31–3.29(m,2H),3.27(d,J＝3.6Hz,1H),3.11(d,J＝13.4Hz,1H),3.05(s,2H),2.97(t,J＝5.3Hz,2H),2.44(t,J＝4.6Hz,4H),2.00(d,J＝12.6Hz,1H),1.88(d,J＝13.7Hz,3H),1.77(d,J＝4.9Hz,1H),1.65(q,J＝8.3Hz,1H),1.52(d,J＝8.7Hz,1H),1.48(t,J＝5.7Hz,2H),1.42–1.39(m,2H),1.37(d,J＝4.1Hz,1H),1.25(d,J＝3.6Hz,3H),1.21(d,J＝6.8Hz,4H),1.16(d,J＝6.8Hz,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.62(s, 1H), 8.27(d, J=2.2Hz, 1H), 8.03-7.99(m, 1H), 7.97-7.92(m, 2H), 7.55(d,J＝7.5Hz,1H),7.48(t,J＝3.0Hz,1H),7.43(d,J＝2.6Hz,1H),7.31-7.26(m,2H),7.25-7.17(m ,2H),6.67(d,J＝2.4Hz,1H),6.38–6.34(m,1H),4.33(d,J＝19.6Hz,2H),4.23(d,J＝13.0Hz,1H),3.99 (d, J=13.5Hz, 1H), 3.59 (t, J=4.6Hz, 6H), 3.32 (s, 2H), 3.31–3.29 (m, 2H), 3.27 (d, J=3.6Hz, 1H) ,3.11(d,J＝13.4Hz,1H),3.05(s,2H),2.97(t,J＝5.3Hz,2H),2.44(t,J＝4.6Hz,4H),2.00(d,J＝ 12.6Hz, 1H), 1.88 (d, J=13.7Hz, 3H), 1.77 (d, J=4.9Hz, 1H), 1.65 (q, J=8.3Hz, 1H), 1.52 (d, J=8.7Hz) ,1H),1.48(t,J＝5.7Hz,2H),1.42–1.39(m,2H),1.37(d,J＝4.1Hz,1H),1.25(d,J＝3.6Hz,3H),1.21 (d, J=6.8 Hz, 4H), 1.16 (d, J=6.8 Hz, 4H).
实施例36：3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(101)Example 36: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)picolinamide (101)
Figure PCTCN2021126588-appb-000064
Figure PCTCN2021126588-appb-000064
参考实施例35的合成方法，把2-吗啉乙酸-酮替换为2-(二甲氨基)乙酸，可合成得到目标化合物101，LC-MS(ESI-MS)：m/z＝966[M+H] +。 Referring to the synthesis method of Example 35, substituting 2-morpholinoacetic acid-ketone with 2-(dimethylamino)acetic acid, the target compound 101 can be synthesized, LC-MS (ESI-MS): m/z=966 [M +H] + .
1H NMR(400MHz,DMSO-d 6)δ11.61(s,1H),8.24(s,1H),7.99(d,J＝16.9Hz,2H),7.89(d,J＝8.8Hz,1H),7.53(d,J＝7.4Hz,1H),7.47(s,1H),7.41(s,1H),7.23(d,J＝6.5Hz,2H),7.14(d,J＝8.2Hz,2H),6.70(s,1H),6.35(s,1H),4.34–4.31(m,1H),4.27(t,J＝7.1Hz,2H),3.81(d,J＝14.7Hz,2H),3.68(s,2H),3.33–3.29(m,3H),3.15(d,J＝8.5Hz,3H),3.02(t,J＝6.4Hz,2H),2.98–2.93(m,3H),2.53(s,4H),2.21(dd,J＝11.6,6.8Hz,1H),1.99(s,1H),1.81–1.74(m,4H),1.52(s,2H),1.45(d,J＝5.8Hz,2H),1.40(s,2H),1.36(s,1H),1.25(s,3H),1.17(t,J＝7.0Hz,7H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.61 (s, 1H), 8.24 (s, 1H), 7.99 (d, J=16.9 Hz, 2H), 7.89 (d, J=8.8 Hz, 1H) ,7.53(d,J＝7.4Hz,1H),7.47(s,1H),7.41(s,1H),7.23(d,J＝6.5Hz,2H),7.14(d,J＝8.2Hz,2H) ,6.70(s,1H),6.35(s,1H),4.34–4.31(m,1H),4.27(t,J=7.1Hz,2H),3.81(d,J=14.7Hz,2H),3.68( s, 2H), 3.33–3.29 (m, 3H), 3.15 (d, J=8.5Hz, 3H), 3.02 (t, J=6.4Hz, 2H), 2.98–2.93 (m, 3H), 2.53 (s ,4H),2.21(dd,J=11.6,6.8Hz,1H),1.99(s,1H),1.81–1.74(m,4H),1.52(s,2H),1.45(d,J=5.8Hz, 2H), 1.40(s, 2H), 1.36(s, 1H), 1.25(s, 3H), 1.17(t, J=7.0Hz, 7H).
实施例37：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(102)Example 37: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-hydroxy-4-methylcyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (102)
Figure PCTCN2021126588-appb-000065
Figure PCTCN2021126588-appb-000065
参考实施例7的合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为2,6-二氯烟酸甲酯(得与中间体24-5对应的中间体102-5)，(S)-2-(2-异丙基苯基)吡咯烷替换为2-(2-异丙基苯基)吡咯烷，其中中间体24-7不经过手型拆分，直接进行实施例7中第9步(与中间体102-5)的反应，可合成得到目标化合物102，LC-MS(ESI-MS)：m/z＝891[M+H] +。 With reference to the synthetic method of Example 7, methyl 3,5-difluoropyridine-2-carboxylate was replaced with methyl 2,6-dichloronicotinate (to obtain intermediate 102-5 corresponding to intermediate 24-5) , (S)-2-(2-isopropylphenyl)pyrrolidine was replaced by 2-(2-isopropylphenyl)pyrrolidine, and the intermediate 24-7 was directly implemented without chiral resolution The target compound 102 can be synthesized by the reaction of step 9 (with intermediate 102-5) in Example 7, LC-MS (ESI-MS): m/z=891 [M+H] + .
实施例38：4-(((4-(N-(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)-4-氟哌啶-1-甲酸乙酯(103)Example 38: 4-(((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-( 2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl) Amino)methyl)-4-fluoropiperidine-1-carboxylic acid ethyl ester (103)
Figure PCTCN2021126588-appb-000066
Figure PCTCN2021126588-appb-000066
参考实施例24和实施例26的合成方法，把实施例26中的3,5-二氟吡啶甲酸甲酯替换为2,4,5-三氟苯甲酸甲酯，2-吗啉乙酸替换为碳酸氢乙酯，可合成得到目标化合物103，LC-MS(ESI-MS)：m/z＝969[M+H] +。 Referring to the synthetic methods of Example 24 and Example 26, the methyl 3,5-difluoropicolinate in Example 26 was replaced by methyl 2,4,5-trifluorobenzoate, and the 2-morpholine acetic acid was replaced by Ethyl bicarbonate can be synthesized to obtain the target compound 103, LC-MS (ESI-MS): m/z=969 [M+H] + .
实施例39：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((2-(二甲氨基)乙基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(104)Example 39: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((2-(dimethylamino)ethyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (104)
Figure PCTCN2021126588-appb-000067
Figure PCTCN2021126588-appb-000067
参考实施例18的合成方法，把(S)-2-(2-异丙基苯基)吡咯烷替换为2-(2-异丙基苯基)吡咯烷，把(四氢-2H-吡喃-4-基)甲胺盐酸盐替换为替换为N,N-二甲基乙二胺，可合成得到目标化合物104，LC-MS(ESI-MS)：m/z＝836[M+H] +。 Referring to the synthesis method of Example 18, (S)-2-(2-isopropylphenyl)pyrrolidine was replaced by 2-(2-isopropylphenyl)pyrrolidine, and (tetrahydro-2H-pyrrolidine) was replaced by 2-(2-isopropylphenyl)pyrrolidine. Ran-4-yl)methylamine hydrochloride is replaced with N,N-dimethylethylenediamine, the target compound 104 can be synthesized, LC-MS (ESI-MS): m/z=836[M+ H] + .
实施例40：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((3-异丙基氧基丙基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(105)Example 40: 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((3-isopropyloxypropyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (105)
Figure PCTCN2021126588-appb-000068
Figure PCTCN2021126588-appb-000068
参考化实施例39的合成方法，把N,N-二甲基乙二胺替换为3-异丙氧基丙-1-胺，可合成得到目标化合物105，LC-MS(ESI-MS)：m/z＝865[M+H] +。 Referring to the synthetic method of Example 39, N,N-dimethylethylenediamine was replaced by 3-isopropoxypropan-1-amine, and the target compound 105 could be synthesized, LC-MS (ESI-MS): m/z=865 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.59(t,J＝2.3Hz,1H),8.58(t,J＝5.4Hz,1H),8.48(d,J＝2.3Hz,1H),7.96(d,J＝2.6Hz,1H),7.70(dd,J＝9.2,2.3Hz,1H),7.50(dd,J＝7.6,1.7Hz,1H),7.46(d,J＝8.9Hz,1H),7.44–7.39(m,2H),7.21–7.08(m,3H),6.91(d,J＝9.3Hz,1H),6.60(dd,J＝9.0,2.3Hz,1H),6.31(dd,J＝3.4,1.9Hz,1H),6.13(d,J＝2.3Hz,1H),3.49–3.46(m,2H),3.43(t,J＝5.6Hz,4H),3.25–3.20(m,3H),2.95(d,J＝7.0Hz,2H),2.87(d,J＝5.7Hz,2H),2.46(q,J＝1.8Hz,2H),2.19(d,J＝7.3Hz,1H),1.78(q,J＝6.1Hz,4H),1.70(d,J＝2.8Hz,1H),1.60(s,1H),1.48–1.41(m,1H),1.36–1.24(m,5H),1.13(d,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,3H),1.04(d,J＝6.1Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.59 (t, J=2.3Hz, 1H), 8.58 (t, J=5.4Hz, 1H), 8.48 (d, J=2.3Hz, 1H), 7.96 (d, J=2.6Hz, 1H), 7.70 (dd, J=9.2, 2.3Hz, 1H), 7.50 (dd, J=7.6, 1.7Hz, 1H), 7.46 (d, J=8.9Hz, 1H) ,7.44–7.39(m,2H),7.21–7.08(m,3H),6.91(d,J=9.3Hz,1H),6.60(dd,J=9.0,2.3Hz,1H),6.31(dd,J =3.4,1.9Hz,1H),6.13(d,J=2.3Hz,1H),3.49-3.46(m,2H),3.43(t,J=5.6Hz,4H),3.25-3.20(m,3H) ,2.95(d,J＝7.0Hz,2H),2.87(d,J＝5.7Hz,2H),2.46(q,J＝1.8Hz,2H),2.19(d,J＝7.3Hz,1H),1.78 (q, J=6.1Hz, 4H), 1.70 (d, J=2.8Hz, 1H), 1.60 (s, 1H), 1.48–1.41 (m, 1H), 1.36–1.24 (m, 5H), 1.13 ( d, J=6.8 Hz, 3H), 1.08 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.1 Hz, 6H).
实施例41：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-((4-甲基哌嗪-1-基)甲基)-5-硝基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)磺酰基)苯甲酰胺(106)Example 41: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (106)
Figure PCTCN2021126588-appb-000069
Figure PCTCN2021126588-appb-000069
参考化实施例28的合成方法，把2-氨基-3-吗啉丙烷-1-醇替换为2-氨基-3-(4-甲基哌嗪-1-基)丙-1-醇，可合成得到目标化合物106，LC-MS(ESI-MS)：m/z＝918[M+H] +。 Referring to the synthetic method of Example 28, replacing 2-amino-3-morpholinopropan-1-ol with 2-amino-3-(4-methylpiperazin-1-yl)propan-1-ol, the The target compound 106 was synthesized, LC-MS (ESI-MS): m/z=918 [M+H] + .
实施例42：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((3-(二甲氨基)丙基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(107)Example 42: 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((3-(dimethylamino)propyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (107)
Figure PCTCN2021126588-appb-000070
Figure PCTCN2021126588-appb-000070
参考实施例39的合成方法，把N,N-二甲基乙二胺替换为N 1,N 1-二甲基丙烷-1,3-二胺，可合成得到目标化合物107，LC-MS(ESI-MS)：m/z＝850[M+H] +。 Referring to the synthetic method of Example 39, N,N - dimethylethylenediamine was replaced with N1,N1 - dimethylpropane-1,3-diamine, the target compound 107 could be synthesized, and LC-MS ( ESI-MS): m/z=850 [M+H] + .
实施例43：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)烟酰胺(108)Example 43: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino )phenyl)sulfonyl)nicotinamide (108)
Figure PCTCN2021126588-appb-000071
Figure PCTCN2021126588-appb-000071
参考实施例19的合成方法，把2,3,4-三氟苯甲酸甲酯替换为2,6-二氯烟酸甲酯，可合成得到目标化合物108，LC-MS(ESI-MS)：m/z＝863[M+H] +。 Referring to the synthetic method of Example 19, methyl 2,3,4-trifluorobenzoate was replaced with methyl 2,6-dichloronicotinate to obtain the target compound 108, LC-MS (ESI-MS): m/z=863 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.58(s,1H),8.59–8.55(m,1H),8.53(s,1H),7.98(s,1H),7.90(d,J＝9.0Hz,1H),7.80(d,J＝8.6Hz,1H),7.66(s,1H),7.48–7.43(m,2H),7.20(d,J＝7.2Hz,1H),7.17(d,J＝10.0Hz,2H),7.11(d,J＝7.6Hz,1H),6.39–6.36(m,2H),3.79(dd,J＝11.4,4.2Hz,3H),3.21(d,J＝6.6Hz,4H),3.05(d,J＝7.3Hz,4H),2.18(dd,J＝13.7,7.4Hz,1H),1.87–1.74(m,4H),1.67(d,J＝8.9Hz,1H),1.60–1.54(m,3H),1.44(d,J＝11.2Hz,1H),1.28(d,J＝9.5Hz,1H),1.23–1.18(m,4H),1.14(d,J＝6.5Hz,6H),1.11(s,2H),1.08(d,J＝6.8Hz,4H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.58(s, 1H), 8.59-8.55(m, 1H), 8.53(s, 1H), 7.98(s, 1H), 7.90(d, J=9.0 Hz, 1H), 7.80(d, J=8.6Hz, 1H), 7.66(s, 1H), 7.48–7.43(m, 2H), 7.20(d, J=7.2Hz, 1H), 7.17(d, J =10.0Hz,2H),7.11(d,J=7.6Hz,1H),6.39–6.36(m,2H),3.79(dd,J=11.4,4.2Hz,3H),3.21(d,J=6.6Hz ,4H),3.05(d,J＝7.3Hz,4H),2.18(dd,J＝13.7,7.4Hz,1H),1.87–1.74(m,4H),1.67(d,J＝8.9Hz,1H) ,1.60–1.54(m,3H),1.44(d,J=11.2Hz,1H),1.28(d,J=9.5Hz,1H),1.23–1.18(m,4H),1.14(d,J=6.5 Hz, 6H), 1.11 (s, 2H), 1.08 (d, J=6.8 Hz, 4H).
实施例44：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(109)Example 44: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl) yl)-4-fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (109)
Figure PCTCN2021126588-appb-000072
Figure PCTCN2021126588-appb-000072
参考实施例27的合成方法，把3,5-二氟吡啶甲酸甲酯替换为2,6-二氯烟酸甲酯，可合成得到目标化合物109，LC-MS(ESI-MS)：m/z＝965[M+H] +。 Referring to the synthesis method of Example 27, the target compound 109 can be synthesized by replacing methyl 3,5-difluoropicolinate with methyl 2,6-dichloronicotinate. LC-MS (ESI-MS): m/ z=965[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.58(d,J＝2.3Hz,1H),8.60–8.45(m,2H),7.95(d,J＝2.5Hz,1H),7.90(dd,J＝9.2,2.4Hz,1H),7.84(d,J＝8.6Hz,1H),7.62(d,J＝2.5Hz,1H),7.61–7.51(m,1H),7.44(q,J＝3.0Hz,1H),7.27(d,J＝9.3Hz,1H),7.20(d,J＝7.7Hz,1H),7.13(dd,J＝20.6,7.3Hz,2H),6.41–6.33(m,2H),4.25–4.14(m,1H),3.89–3.60(m,6H),2.89–2.82(m,1H),2.53(s,5H),2.18(q,J＝8.0,5.2Hz,1H),1.94–1.66(m,8H),1.26–1.07(m,23H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.58 (d, J=2.3 Hz, 1H), 8.60-8.45 (m, 2H), 7.95 (d, J=2.5 Hz, 1H), 7.90 (dd, J=9.2, 2.4Hz, 1H), 7.84 (d, J=8.6Hz, 1H), 7.62 (d, J=2.5Hz, 1H), 7.61–7.51 (m, 1H), 7.44 (q, J=3.0 Hz, 1H), 7.27 (d, J=9.3Hz, 1H), 7.20 (d, J=7.7Hz, 1H), 7.13 (dd, J=20.6, 7.3Hz, 2H), 6.41–6.33 (m, 2H) ), 4.25–4.14 (m, 1H), 3.89–3.60 (m, 6H), 2.89–2.82 (m, 1H), 2.53 (s, 5H), 2.18 (q, J=8.0, 5.2Hz, 1H), 1.94–1.66 (m, 8H), 1.26–1.07 (m, 23H).
实施例45：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(110)Example 45: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl)) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (110)
Figure PCTCN2021126588-appb-000073
Figure PCTCN2021126588-appb-000073
参考实施例36的合成方法，把3,5-二氟吡啶甲酸甲酯替换为2,6-二氯烟酸甲酯， 可合成得到目标化合物110，LC-MS(ESI-MS)：m/z＝966[M+H] +。 Referring to the synthesis method of Example 36, methyl 3,5-difluoropicolinate was replaced with methyl 2,6-dichloronicotinate, and the target compound 110 could be synthesized. LC-MS (ESI-MS): m/ z=966[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.55(d,J＝2.3Hz,1H),8.29(d,J＝2.2Hz,1H),8.07(dd,J＝8.9,2.3Hz,1H),7.95–7.88(m,2H),7.66(d,J＝8.2Hz,1H),7.57(d,J＝2.5Hz,1H),7.42(dd,J＝5.6,2.7Hz,2H),7.23(dt,J＝9.3,4.6Hz,2H),7.16(d,J＝7.4Hz,1H),6.35(dd,J＝3.5,1.9Hz,1H),6.33(d,J＝8.7Hz,1H),4.40–4.30(m,2H),4.19(q,J＝3.1,2.5Hz,1H),4.14–3.97(m,2H),3.62–3.55(m,2H),3.23(s,4H),3.08(q,J＝7.3Hz,3H),2.99(dd,J＝13.0,3.4Hz,3H),2.67(s,5H),2.31–2.20(m,1H),1.99–1.88(m,4H),1.76–1.60(m,2H),1.30(t,J＝3.5Hz,1H),1.23(d,J＝7.4Hz,5H),1.20(d,J＝4.1Hz,3H),1.16(d,J＝6.8Hz,4H),1.08(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.55 (d, J=2.3Hz, 1H), 8.29 (d, J=2.2Hz, 1H), 8.07 (dd, J=8.9, 2.3Hz, 1H) ,7.95–7.88(m,2H),7.66(d,J＝8.2Hz,1H),7.57(d,J＝2.5Hz,1H),7.42(dd,J＝5.6,2.7Hz,2H),7.23( dt,J＝9.3,4.6Hz,2H),7.16(d,J＝7.4Hz,1H),6.35(dd,J＝3.5,1.9Hz,1H),6.33(d,J＝8.7Hz,1H), 4.40–4.30 (m, 2H), 4.19 (q, J=3.1, 2.5Hz, 1H), 4.14–3.97 (m, 2H), 3.62–3.55 (m, 2H), 3.23 (s, 4H), 3.08 ( q, J=7.3Hz, 3H), 2.99 (dd, J=13.0, 3.4Hz, 3H), 2.67 (s, 5H), 2.31–2.20 (m, 1H), 1.99–1.88 (m, 4H), 1.76 –1.60(m, 2H), 1.30(t, J=3.5Hz, 1H), 1.23(d, J=7.4Hz, 5H), 1.20(d, J=4.1Hz, 3H), 1.16(d, J= 6.8Hz, 4H), 1.08 (d, J=6.8Hz, 3H).
实施例46：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(2-吗啉乙酰基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(111)Example 46: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinoacetyl) )piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7 - Azaspiro[3.5]nonan-7-yl)nicotinamide (111)
Figure PCTCN2021126588-appb-000074
Figure PCTCN2021126588-appb-000074
参考实施例45的合成方法，把2-(二甲氨基)乙酸替换为2-吗啉乙酸，可合成得到目标化合物111，LC-MS(ESI-MS)：m/z＝1008[M+H] +。 Referring to the synthesis method of Example 45, substituting 2-(dimethylamino)acetic acid with 2-morpholinoacetic acid, the target compound 111 can be synthesized, LC-MS (ESI-MS): m/z=1008 [M+H ] + .
1H NMR(400MHz,DMSO-d 6)δ11.55(d,J＝2.4Hz,1H),8.32(d,J＝2.3Hz,1H),8.09(d,J＝4.1Hz,1H),7.94(d,J＝2.5Hz,1H),7.86(d,J＝8.6Hz,1H),7.60(d,J＝2.5Hz,1H),7.52–7.44(m,2H),7.42(d,J＝3.1Hz,1H),7.20(d,J＝27.7Hz,3H),6.37–6.34(m,2H),4.38–4.32(m,2H),4.16(d,J＝13.2Hz,1H),3.90(d,J＝13.4Hz,1H),3.54(t,J＝4.6Hz,5H),3.21(d,J＝7.0Hz,4H),3.12–2.99(m,6H),2.91–2.85(m,1H),2.41(s,5H),2.30–2.21(m,1H),1.88(q,J＝13.1,11.3Hz,5H),1.72(dd,J＝15.2,10.0Hz,2H),1.45(s,2H),1.20(s,2H),1.16(d,J＝6.7Hz,6H),1.08(d,J＝6.7Hz,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.55 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.09 (d, J=4.1 Hz, 1H), 7.94 (d, J=2.5Hz, 1H), 7.86 (d, J=8.6Hz, 1H), 7.60 (d, J=2.5Hz, 1H), 7.52–7.44 (m, 2H), 7.42 (d, J= 3.1Hz, 1H), 7.20 (d, J=27.7Hz, 3H), 6.37–6.34 (m, 2H), 4.38–4.32 (m, 2H), 4.16 (d, J=13.2Hz, 1H), 3.90 ( d, J=13.4Hz, 1H), 3.54 (t, J=4.6Hz, 5H), 3.21 (d, J=7.0Hz, 4H), 3.12–2.99 (m, 6H), 2.91–2.85 (m, 1H) ), 2.41(s, 5H), 2.30–2.21(m, 1H), 1.88(q, J=13.1, 11.3Hz, 5H), 1.72(dd, J=15.2, 10.0Hz, 2H), 1.45(s, 2H), 1.20 (s, 2H), 1.16 (d, J=6.7Hz, 6H), 1.08 (d, J=6.7Hz, 4H).
实施例47：N-((4-(((1,4-二恶烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(112)Example 47: N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5] Nonan-7-yl)nicotinamide (112)
Figure PCTCN2021126588-appb-000075
Figure PCTCN2021126588-appb-000075
参考实施例20的合成方法，把2,3,4-三氟苯甲酸甲酯替换为2,6-二氯烟酸甲酯，可合成得到目标化合物112，LC-MS(ESI-MS)：m/z＝865[M+H] +。 Referring to the synthetic method of Example 20, methyl 2,3,4-trifluorobenzoate was replaced with methyl 2,6-dichloronicotinate, and the target compound 112 could be synthesized by LC-MS (ESI-MS): m/z=865 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.64–11.58(m,1H),8.59(d,J＝2.2Hz,1H),8.52(t,J＝5.7Hz,1H),8.00(d,J＝2.5Hz,1H),7.94(dd,J＝9.2,2.3Hz,1H),7.80(d,J＝8.7Hz,1H),7.68(d,J＝2.5Hz,1H),7.51(d,J＝7.7Hz,1H),7.45(t,J＝3.0Hz,1H),7.16(dt, J＝17.3,10.0Hz,4H),6.41–6.36(m,2H),3.74(ddt,J＝9.3,6.6,3.3Hz,3H),3.64–3.55(m,2H),3.54–3.48(m,1H),3.47(d,J＝2.9Hz,1H),3.44–3.39(m,2H),3.38–3.33(m,2H),3.31(s,1H),3.28(d,J＝1.7Hz,1H),3.25(s,1H),3.24–3.20(m,2H),3.14–3.09(m,2H),3.04(d,J＝5.2Hz,2H),2.22–2.15(m,1H),1.83–1.76(m,2H),1.44(td,J＝7.9,4.0Hz,1H),1.34–1.24(m,2H),1.18(s,1H),1.13(d,J＝6.8Hz,5H),1.09(d,J＝6.7Hz,4H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.64-11.58 (m, 1H), 8.59 (d, J=2.2Hz, 1H), 8.52 (t, J=5.7Hz, 1H), 8.00 (d, J=2.5Hz, 1H), 7.94(dd, J=9.2, 2.3Hz, 1H), 7.80(d, J=8.7Hz, 1H), 7.68(d, J=2.5Hz, 1H), 7.51(d, J=7.7Hz, 1H), 7.45 (t, J=3.0Hz, 1H), 7.16 (dt, J=17.3, 10.0Hz, 4H), 6.41–6.36 (m, 2H), 3.74 (ddt, J=9.3 ,6.6,3.3Hz,3H),3.64–3.55(m,2H),3.54–3.48(m,1H),3.47(d,J=2.9Hz,1H),3.44–3.39(m,2H),3.38– 3.33(m, 2H), 3.31(s, 1H), 3.28(d, J=1.7Hz, 1H), 3.25(s, 1H), 3.24-3.20(m, 2H), 3.14-3.09(m, 2H) , 3.04(d, J=5.2Hz, 2H), 2.22–2.15 (m, 1H), 1.83–1.76 (m, 2H), 1.44 (td, J=7.9, 4.0Hz, 1H), 1.34–1.24 (m , 2H), 1.18 (s, 1H), 1.13 (d, J=6.8Hz, 5H), 1.09 (d, J=6.7Hz, 4H).
实施例48：N-((4-((1,4-二恶烷-2-基)甲氧基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(113)Example 48: N-((4-((1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2 ,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (113)
Figure PCTCN2021126588-appb-000076
Figure PCTCN2021126588-appb-000076
参考实施例33的合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为2,6-二氯烟酸甲酯，把4-氟-4-(羟甲基)哌啶-1-羧酸叔丁酯替换为(1,4-二恶烷-2-基)甲醇可合成得到目标化合物113，LC-MS(ESI-MS)：m/z＝866[M+H] +。 Referring to the synthetic method of Example 33, the methyl 3,5-difluoropyridine-2-carboxylate was replaced by methyl 2,6-dichloronicotinate, and the 4-fluoro-4-(hydroxymethyl)piperidine- The target compound 113 can be synthesized by replacing tert-butyl 1-carboxylate with (1,4-dioxan-2-yl)methanol, LC-MS (ESI-MS): m/z=866[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.57(s,1H),8.32(d,J＝2.3Hz,1H),8.09(dd,J＝8.7,2.3Hz,1H),7.95(d,J＝2.5Hz,1H),7.86(d,J＝8.7Hz,1H),7.61(d,J＝2.5Hz,1H),7.55–7.50(m,1H),7.46–7.42(m,2H),7.24(d,J＝6.6Hz,2H),7.16(d,J＝7.5Hz,1H),6.39–6.32(m,2H),4.21(q,J＝4.9,4.0Hz,2H),3.83(ddt,J＝9.5,4.9,2.4Hz,1H),3.78(dd,J＝11.3,2.7Hz,1H),3.74–3.69(m,1H),3.63–3.59(m,1H),3.56(dd,J＝11.6,2.6Hz,1H),3.42(d,J＝2.6Hz,1H),3.40–3.39(m,1H),3.37(s,1H),3.34–3.29(m,2H),3.23(q,J＝6.7Hz,2H),3.07(ddd,J＝24.9,13.3,5.7Hz,4H),2.32–2.18(m,1H),1.95–1.72(m,4H),1.42(d,J＝9.4Hz,1H),1.25(dd,J＝13.7,4.7Hz,2H),1.20–1.18(m,1H),1.16(d,J＝6.6Hz,5H),1.07(d,J＝6.7Hz,4H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 8.32 (d, J=2.3Hz, 1H), 8.09 (dd, J=8.7, 2.3Hz, 1H), 7.95 (d, J=2.5Hz, 1H), 7.86 (d, J=8.7Hz, 1H), 7.61 (d, J=2.5Hz, 1H), 7.55–7.50 (m, 1H), 7.46–7.42 (m, 2H), 7.24 (d, J=6.6Hz, 2H), 7.16 (d, J=7.5Hz, 1H), 6.39–6.32 (m, 2H), 4.21 (q, J=4.9, 4.0Hz, 2H), 3.83 (ddt , J=9.5, 4.9, 2.4Hz, 1H), 3.78 (dd, J=11.3, 2.7Hz, 1H), 3.74–3.69 (m, 1H), 3.63–3.59 (m, 1H), 3.56 (dd, J =11.6,2.6Hz,1H),3.42(d,J=2.6Hz,1H),3.40–3.39(m,1H),3.37(s,1H),3.34–3.29(m,2H),3.23(q, J=6.7Hz, 2H), 3.07 (ddd, J=24.9, 13.3, 5.7Hz, 4H), 2.32–2.18 (m, 1H), 1.95–1.72 (m, 4H), 1.42 (d, J=9.4Hz) ,1H),1.25(dd,J＝13.7,4.7Hz,2H),1.20–1.18(m,1H),1.16(d,J＝6.6Hz,5H),1.07(d,J＝6.7Hz,4H) .
实施例49：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(115)Example 49: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoropiperidin-4-yl)methoxy) )-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7 -yl)nicotinamide (115)
Figure PCTCN2021126588-appb-000077
Figure PCTCN2021126588-appb-000077
参考实施例48的合成方法，把(1,4-二恶烷-2-基)甲醇替换为4-氟-4-(羟甲基)哌啶-1-羧酸叔丁酯，可合成得到目标化合物115，LC-MS(ESI-MS)：m/z＝881[M+H] +。 Referring to the synthetic method of Example 48, replace (1,4-dioxan-2-yl)methanol with tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate, which can be synthesized to obtain Target compound 115, LC-MS (ESI-MS): m/z=881 [M+H] + .
实施例50：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((吗啉-2-基甲基)氨基)-3-硝基苯基)磺酰基)烟酰胺(114)Example 50: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((morpholin-2-ylmethyl)amino)-3-nitrophenyl)sulfonyl) Niacinamide (114)
Figure PCTCN2021126588-appb-000078
Figure PCTCN2021126588-appb-000078
参考实施例25的合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为2,6-二氯烟酸甲酯，可合成得到目标化合物114，LC-MS(ESI-MS)：m/z＝864[M+H] +。 Referring to the synthesis method of Example 25, the target compound 114 can be synthesized by replacing methyl 3,5-difluoropyridine-2-carboxylate with methyl 2,6-dichloronicotinate. LC-MS (ESI-MS) : m/z=864 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.54(s,1H),8.46(d,J＝2.0Hz,1H),8.40(t,J＝5.9Hz,1H),7.93–7.84(m,3H),7.54(d,J＝2.3Hz,1H),7.45(dd,J＝7.5,1.5Hz,1H),7.42–7.38(m,1H),7.16(dd,J＝7.6,1.5Hz,1H),7.10(dd,J＝7.1,1.5Hz,1H),7.07(d,J＝2.4Hz,1H),7.04(d,J＝5.4Hz,1H),6.34(dd,J＝3.4,1.9Hz,1H),6.30(d,J＝8.7Hz,1H),3.91(d,J＝9.5Hz,1H),3.82(d,J＝4.8Hz,1H),3.62(d,J＝10.7Hz,2H),3.51(d,J＝5.2Hz,1H),3.43(d,J＝6.9Hz,1H),3.40(d,J＝7.0Hz,1H),3.23(dd,J＝13.7,6.9Hz,2H),3.18(d,J＝11.5Hz,1H),3.05(s,2H),3.01–2.97(m,3H),2.91–2.85(m,1H),2.75(t,J＝11.7Hz,1H),2.31(d,J＝8.2Hz,1H),2.19–2.05(m,1H),1.72–1.65(m,2H),1.61–1.53(m,1H),1.42(d,J＝7.3Hz,2H),1.30–1.25(m,1H),1.20(d,J＝5.6Hz,2H),1.14(s,2H),1.11(d,J＝1.9Hz,3H),1.09(d,J＝2.0Hz,4H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.46 (d, J=2.0Hz, 1H), 8.40 (t, J=5.9Hz, 1H), 7.93-7.84 (m, 3H), 7.54 (d, J=2.3Hz, 1H), 7.45 (dd, J=7.5, 1.5Hz, 1H), 7.42–7.38 (m, 1H), 7.16 (dd, J=7.6, 1.5Hz, 1H) ),7.10(dd,J=7.1,1.5Hz,1H),7.07(d,J=2.4Hz,1H),7.04(d,J=5.4Hz,1H),6.34(dd,J=3.4,1.9Hz ,1H),6.30(d,J＝8.7Hz,1H),3.91(d,J＝9.5Hz,1H),3.82(d,J＝4.8Hz,1H),3.62(d,J＝10.7Hz,2H ),3.51(d,J＝5.2Hz,1H),3.43(d,J＝6.9Hz,1H),3.40(d,J＝7.0Hz,1H),3.23(dd,J＝13.7,6.9Hz,2H ), 3.18(d, J=11.5Hz, 1H), 3.05(s, 2H), 3.01–2.97(m, 3H), 2.91–2.85(m, 1H), 2.75(t, J=11.7Hz, 1H) ,2.31(d,J=8.2Hz,1H),2.19-2.05(m,1H),1.72-1.65(m,2H),1.61-1.53(m,1H),1.42(d,J=7.3Hz,2H ),1.30–1.25(m,1H),1.20(d,J＝5.6Hz,2H),1.14(s,2H),1.11(d,J＝1.9Hz,3H),1.09(d,J＝2.0Hz , 4H).
实施例51：N-((4-((1,4-二恶烷-2-基)甲氧基)-3-硝基苯基)磺酰基)-3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)吡啶甲酰胺(116)Example 51: N-((4-((1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2 ,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)picolinamide (116)
Figure PCTCN2021126588-appb-000079
Figure PCTCN2021126588-appb-000079
参考实施例48的合成方法，把2,6-二氯烟酸甲酯替换为3,5-二氟吡啶-2-甲酸甲酯，可合成得到目标化合物116，LC-MS(ESI-MS)：m/z＝866[M+H] +。 Referring to the synthetic method of Example 48, replacing methyl 2,6-dichloronicotinate with methyl 3,5-difluoropyridine-2-carboxylate, the target compound 116 can be synthesized by LC-MS (ESI-MS) : m/z=866 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.57(t,J＝2.3Hz,1H),8.18(d,J＝2.2Hz,1H),7.99(d,J＝2.4Hz,1H),7.92–7.77(m,2H),7.49(dd,J＝7.5,1.8Hz,1H),7.42(t,J＝3.0Hz,1H),7.34(d,J＝2.7Hz,1H),7.21–7.09(m,4H),6.64(d,J＝2.5Hz,1H),6.29(dd,J＝3.4,1.9Hz,1H),4.17–4.07(m,2H),3.82–3.68(m,3H),3.62–3.53(m,2H),3.42(ddd,J＝15.3,9.0,2.8Hz,4H),3.01(q,J＝5.2Hz,2H),2.92(d,J＝5.7Hz,2H),2.19(dq,J＝15.3,8.1Hz,1H),1.76(dd,J＝33.5,10.0Hz,4H),1.49–1.27(m,7H),1.22–1.04(m,9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.57 (t, J=2.3Hz, 1H), 8.18 (d, J=2.2Hz, 1H), 7.99 (d, J=2.4Hz, 1H), 7.92 –7.77(m,2H),7.49(dd,J=7.5,1.8Hz,1H),7.42(t,J=3.0Hz,1H),7.34(d,J=2.7Hz,1H),7.21–7.09( m, 4H), 6.64 (d, J=2.5Hz, 1H), 6.29 (dd, J=3.4, 1.9Hz, 1H), 4.17–4.07 (m, 2H), 3.82–3.68 (m, 3H), 3.62 –3.53(m,2H),3.42(ddd,J=15.3,9.0,2.8Hz,4H),3.01(q,J=5.2Hz,2H),2.92(d,J=5.7Hz,2H),2.19( dq, J=15.3, 8.1 Hz, 1H), 1.76 (dd, J=33.5, 10.0 Hz, 4H), 1.49–1.27 (m, 7H), 1.22–1.04 (m, 9H).
实施例52：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)烟酰胺(117)Example 52: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((4-(oxetan-3-yl)morpholine- 2-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (117)
Figure PCTCN2021126588-appb-000080
Figure PCTCN2021126588-appb-000080
参考实施例31的合成方法，把化合物089替换为化合物114，可合成得到目标化合物117，LC-MS(ESI-MS)：m/z＝920[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced with compound 114, and the target compound 117 could be synthesized. LC-MS (ESI-MS): m/z=920 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.60(s,1H),8.61–8.51(m,2H),8.00(d,J＝2.5Hz,1H),7.92(dd,J＝9.3,2.3Hz,1H),7.79(d,J＝8.7Hz,1H),7.68(s,1H),7.49–7.42(m,2H),7.18(s,4H),6.43–6.35(m,2H),4.50(d,J＝6.5Hz,2H),4.40(dt,J＝6.1,3.0Hz,2H),3.82(ddd,J＝11.2,3.2,1.9Hz,1H),3.75–3.69(m,1H),3.57–3.47(m,3H),3.40–3.36(m,2H),3.21(d,J＝6.9Hz,1H),3.09(d,J＝29.6Hz,4H),2.74–2.67(m,1H),2.00–1.85(m,3H),1.79–1.68(m,3H),1.42(d,J＝16.9Hz,2H),1.30–1.09(m,19H),0.84–0.77(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.60 (s, 1H), 8.61-8.51 (m, 2H), 8.00 (d, J=2.5Hz, 1H), 7.92 (dd, J=9.3, 2.3 Hz,1H),7.79(d,J=8.7Hz,1H),7.68(s,1H),7.49–7.42(m,2H),7.18(s,4H),6.43–6.35(m,2H),4.50 (d, J=6.5Hz, 2H), 4.40 (dt, J=6.1, 3.0Hz, 2H), 3.82 (ddd, J=11.2, 3.2, 1.9Hz, 1H), 3.75–3.69 (m, 1H), 3.57–3.47 (m, 3H), 3.40–3.36 (m, 2H), 3.21 (d, J=6.9Hz, 1H), 3.09 (d, J=29.6Hz, 4H), 2.74–2.67 (m, 1H) ,2.00–1.85(m,3H),1.79–1.68(m,3H),1.42(d,J=16.9Hz,2H),1.30–1.09(m,19H),0.84–0.77(m,1H).
实施例53：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(118)Example 53: 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (118)
Figure PCTCN2021126588-appb-000081
Figure PCTCN2021126588-appb-000081
参考实施例36的合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为4,6-二氯烟酸甲酯，可合成得到目标化合物118，LC-MS(ESI-MS)：m/z＝966[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.63(d,J＝2.4Hz,1H),8.38(s,1H),8.16(d,J＝2.2Hz,1H),7.90–7.85(m,2H),7.50–7.42(m,3H),7.22(d,J＝8.9Hz,1H),7.17(dd,J＝7.5,1.8Hz,1H),7.08(pd,J＝7.2,1.7Hz,2H),6.34(dd,J＝3.5,1.9Hz,1H),5.74(s,1H),4.27(dd,J＝20.2,4.9Hz,2H),4.16(d,J＝13.2Hz,1H),3.82–3.75(m,1H),3.50(dd,J＝19.0,6.7Hz,5H),3.07(d,J＝17.8Hz,6H),2.90(td,J＝12.8,3.2Hz,1H),2.12(dt,J＝12.8,8.1Hz,1H),1.71(d,J＝8.8Hz,4H),1.46(dd,J＝9.9,6.6Hz,2H),1.31(ddd,J＝11.5,7.4,4.4Hz,4H),1.19(d,J＝6.4Hz,12H),1.11(t,J＝6.4Hz,6H)。 Referring to the synthetic method of Example 36, the target compound 118 can be synthesized by replacing methyl 3,5-difluoropyridine-2-carboxylate with methyl 4,6-dichloronicotinate. LC-MS (ESI-MS) : m/z=966 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.63 (d, J=2.4Hz, 1H), 8.38 (s, 1H), 8.16 (d, J=2.2Hz, 1H), 7.90-7.85 (m, 2H), 7.50–7.42 (m, 3H), 7.22 (d, J=8.9Hz, 1H), 7.17 (dd, J=7.5, 1.8Hz, 1H), 7.08 (pd, J=7.2, 1.7Hz, 2H) ), 6.34(dd, J＝3.5, 1.9Hz, 1H), 5.74(s, 1H), 4.27(dd, J＝20.2, 4.9Hz, 2H), 4.16(d, J＝13.2Hz, 1H), 3.82 –3.75(m, 1H), 3.50(dd, J=19.0, 6.7Hz, 5H), 3.07(d, J=17.8Hz, 6H), 2.90(td, J=12.8, 3.2Hz, 1H), 2.12( dt, J＝12.8, 8.1Hz, 1H), 1.71 (d, J＝8.8Hz, 4H), 1.46 (dd, J＝9.9, 6.6Hz, 2H), 1.31 (ddd, J＝11.5, 7.4, 4.4Hz) , 4H), 1.19 (d, J=6.4Hz, 12H), 1.11 (t, J=6.4Hz, 6H).
实施例54：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(119)Example 54: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (119)
Figure PCTCN2021126588-appb-000082
Figure PCTCN2021126588-appb-000082
参考实施例31的合成方法，把化合物089替换为化合物115，可合成得到目标化合物119，LC-MS(ESI-MS)：m/z＝937[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced by compound 115, and the target compound 119 could be synthesized, LC-MS (ESI-MS): m/z=937 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.57(s,1H),8.35–8.29(m,1H),8.12–8.06(m,1H),7.94(d,J＝2.5Hz,1H),7.86(d,J＝8.6Hz,1H),7.61(d,J＝2.5Hz,1H),7.50(d,J＝7.7Hz,1H),7.43(t,J＝3.0Hz,2H),7.21(d,J＝26.7Hz,3H),6.40–6.32(m,2H),4.50(t,J＝6.5Hz,2H),4.42–4.27(m,5H),3.06(dq,J＝28.7,8.0,7.6Hz,5H),2.08–1.98(m,3H),1.92–1.71(m,8H),1.29–1.05(m,19H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.57(s, 1H), 8.35-8.29(m, 1H), 8.12-8.06(m, 1H), 7.94(d, J=2.5Hz, 1H), 7.86(d,J＝8.6Hz,1H),7.61(d,J＝2.5Hz,1H),7.50(d,J＝7.7Hz,1H),7.43(t,J＝3.0Hz,2H),7.21( d, J=26.7Hz, 3H), 6.40–6.32 (m, 2H), 4.50 (t, J=6.5Hz, 2H), 4.42–4.27 (m, 5H), 3.06 (dq, J=28.7, 8.0, 7.6Hz, 5H), 2.08–1.98 (m, 3H), 1.92–1.71 (m, 8H), 1.29–1.05 (m, 19H).
实施例55：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(121)Example 55: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl) Methyl)amino)phenyl)sulfonyl)benzamide (121)
Figure PCTCN2021126588-appb-000083
Figure PCTCN2021126588-appb-000083
参考实施例19的合成方法，把2,3,4-三氟苯甲酸甲酯替换为2,4,5-三氟苯甲酸甲酯，可合成得到目标化合物121，LC-MS(ESI-MS)：m/z＝880[M+H] +。 Referring to the synthesis method of Example 19, the target compound 121 can be synthesized by replacing methyl 2,3,4-trifluorobenzoate with methyl 2,4,5-trifluorobenzoate. LC-MS (ESI-MS ): m/z=880 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.52(t,J＝2.3Hz,1H),8.37(d,J＝2.2Hz,2H),7.89(d,J＝2.6Hz,1H),7.63–7.57(m,1H),7.51(d,J＝7.6Hz,1H),7.39(t,J＝3.0Hz,1H),7.34–7.19(m,5H),6.83(d,J＝9.2Hz,1H),6.33(d,J＝7.7Hz,1H),6.26(dd,J＝3.4,1.9Hz,1H),3.80(ddd,J＝11.3,4.5,1.8Hz,2H),3.26–3.17(m,8H),2.74(d,J＝6.5Hz,2H),2.66(t,J＝5.4Hz,2H),1.80(dh,J＝10.8,3.5Hz,3H),1.56(ddd,J＝12.7,4.0,1.8Hz,2H),1.42(dq,J＝21.9,4.7Hz,6H),1.23–1.14(m,9H),1.08(d,J＝6.7Hz,4H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.52 (t, J=2.3Hz, 1H), 8.37 (d, J=2.2Hz, 2H), 7.89 (d, J=2.6Hz, 1H), 7.63 –7.57(m,1H),7.51(d,J=7.6Hz,1H),7.39(t,J=3.0Hz,1H),7.34–7.19(m,5H),6.83(d,J=9.2Hz, 1H), 6.33 (d, J=7.7Hz, 1H), 6.26 (dd, J=3.4, 1.9Hz, 1H), 3.80 (ddd, J=11.3, 4.5, 1.8Hz, 2H), 3.26–3.17 (m ,8H),2.74(d,J＝6.5Hz,2H),2.66(t,J＝5.4Hz,2H),1.80(dh,J＝10.8,3.5Hz,3H),1.56(ddd,J＝12.7, 4.0, 1.8Hz, 2H), 1.42 (dq, J=21.9, 4.7Hz, 6H), 1.23–1.14 (m, 9H), 1.08 (d, J=6.7Hz, 4H).
实施例56：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(135)Example 56: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoropiperidin-4-yl)methyl )amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (135)
Figure PCTCN2021126588-appb-000084
Figure PCTCN2021126588-appb-000084
参考实施例24的合成方法，把中间体24-3替换为中间体35-3，可合成得到目标化合物135，LC-MS(ESI-MS)：m/z＝880[M+H] +。 Referring to the synthesis method of Example 24, the intermediate 24-3 was replaced by the intermediate 35-3, and the target compound 135 could be synthesized, LC-MS (ESI-MS): m/z=880 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.65(s,1H),8.51–8.25(m,4H),7.91(s,1H),7.74(d,J＝9.1Hz,1H),7.52–7.44(m,3H),7.18–7.03(m,5H),6.40–6.28(m,1H),3.71(dd, J＝20.4,6.6Hz,3H),2.93(t,J＝12.4Hz,4H),2.07–1.87(m,5H),1.75(q,J＝24.7,20.4Hz,7H),1.29(d,J＝8.2Hz,3H),1.26–1.22(m,3H),1.19(s,2H),1.11(t,J＝8.2Hz,9H),0.80(d,J＝7.2Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.65(s, 1H), 8.51-8.25(m, 4H), 7.91(s, 1H), 7.74(d, J=9.1Hz, 1H), 7.52- 7.44 (m, 3H), 7.18–7.03 (m, 5H), 6.40–6.28 (m, 1H), 3.71 (dd, J=20.4, 6.6Hz, 3H), 2.93 (t, J=12.4Hz, 4H) ,2.07–1.87(m,5H),1.75(q,J=24.7,20.4Hz,7H),1.29(d,J=8.2Hz,3H),1.26–1.22(m,3H),1.19(s,2H ), 1.11 (t, J=8.2Hz, 9H), 0.80 (d, J=7.2Hz, 1H).
实施例57：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(125)Example 57: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (125)
Figure PCTCN2021126588-appb-000085
Figure PCTCN2021126588-appb-000085
参考实施例31的合成方法，把化合物089替换为化合物135，可合成得到目标化合物125，LC-MS(ESI-MS)：m/z＝936[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced with compound 135, and the target compound 125 could be synthesized. LC-MS (ESI-MS): m/z=936 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.71(s,1H),8.55–8.46(m,2H),8.28(s,1H),7.99(d,J＝2.6Hz,1H),7.79(dd,J＝9.2,2.3Hz,1H),7.62(d,J＝2.5Hz,1H),7.54–7.45(m,2H),7.19(dd,J＝20.9,11.2Hz,4H),6.38(t,J＝2.6Hz,1H),4.48(t,J＝6.5Hz,2H),4.37(t,J＝6.1Hz,2H),3.66(dd,J＝20.7,6.3Hz,2H),2.52(dt,J＝11.4,3.7Hz,2H),2.24(s,1H),2.00–1.61(m,13H),1.43(d,J＝9.1Hz,1H),1.37–1.05(m,19H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.71(s, 1H), 8.55-8.46(m, 2H), 8.28(s, 1H), 7.99(d, J=2.6Hz, 1H), 7.79( dd, J=9.2, 2.3Hz, 1H), 7.62 (d, J=2.5Hz, 1H), 7.54–7.45 (m, 2H), 7.19 (dd, J=20.9, 11.2Hz, 4H), 6.38 (t ,J=2.6Hz,1H),4.48(t,J=6.5Hz,2H),4.37(t,J=6.1Hz,2H),3.66(dd,J=20.7,6.3Hz,2H),2.52(dt , J=11.4, 3.7Hz, 2H), 2.24 (s, 1H), 2.00–1.61 (m, 13H), 1.43 (d, J=9.1Hz, 1H), 1.37–1.05 (m, 19H).
实施例58：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(6-(氧杂环丁烷-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)苯基)磺酰基)苯甲酰胺(122)Example 58: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(6-(oxetan-3-yl)-2,6- Diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)benzamide (122)
Figure PCTCN2021126588-appb-000086
Figure PCTCN2021126588-appb-000086
参考实施例24和实施例57的合成方法，把实施例57中的4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯，可合成得到目标化合物122，LC-MS(ESI-MS)：m/z＝902[M+H] +。 Referring to the synthetic methods of Example 24 and Example 57, the tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate in Example 57 was replaced with 2,6-diazaspiro[ 3.3] Heptane-2-carboxylate tert-butyl ester can be synthesized to obtain the target compound 122, LC-MS (ESI-MS): m/z=902 [M+H] + .
实施例59：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(6-(氧杂环丁烷-3-基)-2,6-二氮杂螺[3.4]辛烷-2-基)苯基)磺酰基)苯甲酰胺(123)Example 59: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(6-(oxetan-3-yl)-2,6- Diazaspiro[3.4]octan-2-yl)phenyl)sulfonyl)benzamide (123)
Figure PCTCN2021126588-appb-000087
Figure PCTCN2021126588-appb-000087
参考实施例58的合成方法，把2,6-二氮杂螺[3.3]庚烷替换为2,6-二氮杂螺[3.4]辛烷-6-羧酸叔丁酯，可合成得到目标化合物123，LC-MS(ESI-MS)：m/z＝916[M+H] +。 Referring to the synthesis method of Example 58, 2,6-diazaspiro[3.3]heptane was replaced by 2,6-diazaspiro[3.4]octane-6-carboxylic acid tert-butyl ester, and the target can be synthesized Compound 123, LC-MS (ESI-MS): m/z=916 [M+H] + .
实施例60：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(7-(氧杂环丁烷-3-基)-2,7-二氮杂螺[3.5]壬烷-2-基)苯基)磺酰基)苯甲酰胺(124)Example 60: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(7-(oxetan-3-yl)-2,7- Diazaspiro[3.5]nonan-2-yl)phenyl)sulfonyl)benzamide (124)
Figure PCTCN2021126588-appb-000088
Figure PCTCN2021126588-appb-000088
参考实施例58的合成方法，把2,6-二氮杂螺[3.3]庚烷替换为2,7-二氮杂螺[3.5]壬烷-7-羧酸叔丁酯，可合成得到目标化合物124，LC-MS(ESI-MS)：m/z＝930[M+H] +。 Referring to the synthesis method of Example 58, substituting 2,6-diazaspiro[3.3]heptane with 2,7-diazaspiro[3.5]nonane-7-carboxylate tert-butyl ester can be synthesized to obtain the target Compound 124, LC-MS (ESI-MS): m/z=930 [M+H] + .
实施例61：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(126)Example 61: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (126)
Figure PCTCN2021126588-appb-000089
Figure PCTCN2021126588-appb-000089
参考实施例24和实施例57的合成方法，把实施例57中的中间体89-1替换为中间体99-1，可合成得到目标化合物126，LC-MS(ESI-MS)：m/z＝937[M+H] +。 Referring to the synthetic methods of Example 24 and Example 57, the intermediate 89-1 in Example 57 was replaced by the intermediate 99-1, and the target compound 126 could be synthesized, LC-MS (ESI-MS): m/z =937[M+H] + .
实施例62：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(127)Example 62: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl) yl)-4-fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (127)
Figure PCTCN2021126588-appb-000090
Figure PCTCN2021126588-appb-000090
参考实施例24和实施例27的合成方法，把实施例27中的中间体24-3替换为中间体35-3，可合成得到目标化合物127，LC-MS(ESI-MS)：m/z＝965[M+H] +。 Referring to the synthesis methods of Example 24 and Example 27, the intermediate 24-3 in Example 27 was replaced by the intermediate 35-3, and the target compound 127 could be synthesized, LC-MS (ESI-MS): m/z =965[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.80(s,1H),8.66(d,J＝6.4Hz,2H),8.57(s,1H),8.23(s,1H),8.05(d,J＝2.6Hz,1H),7.87(d,J＝9.2Hz,1H),7.72(d,J＝2.6Hz,1H),7.64(d,J＝7.7Hz,1H),7.52(d,J＝3.1Hz,1H),7.31(t,J＝7.7Hz,3H),7.22(dd,J＝8.1,4.2Hz,1H),6.44–6.38(m,1H),4.38–4.14(m,4H),3.85–3.70(m,4H),3.58(dq,J＝13.3,7.0Hz,13H),2.91(q,J＝12.6Hz,2H),2.46(s,5H),2.11–1.80(m,10H),1.06(d,J＝6.6Hz,6H),0.80(t,J＝6.7Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.80(s, 1H), 8.66(d, J=6.4Hz, 2H), 8.57(s, 1H), 8.23(s, 1H), 8.05(d, J=2.6Hz,1H),7.87(d,J=9.2Hz,1H),7.72(d,J=2.6Hz,1H),7.64(d,J=7.7Hz,1H),7.52(d,J= 3.1Hz, 1H), 7.31 (t, J=7.7Hz, 3H), 7.22 (dd, J=8.1, 4.2Hz, 1H), 6.44–6.38 (m, 1H), 4.38–4.14 (m, 4H), 3.85–3.70 (m, 4H), 3.58 (dq, J=13.3, 7.0Hz, 13H), 2.91 (q, J=12.6Hz, 2H), 2.46 (s, 5H), 2.11–1.80 (m, 10H) , 1.06 (d, J=6.6Hz, 6H), 0.80 (t, J=6.7Hz, 1H).
实施例63：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1- 基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(133)Example 63: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoropiperidin-4- (yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[ 3.5] Nonan-7-yl)benzamide (133)
Figure PCTCN2021126588-appb-000091
Figure PCTCN2021126588-appb-000091
参考实施例24的合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为2,4,5-三氟苯甲酸甲酯，可合成得到目标化合物133，LC-MS(ESI-MS)：m/z＝897[M+H] +。 Referring to the synthesis method of Example 24, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,4,5-trifluorobenzoic acid methyl ester, and the target compound 133 could be synthesized, LC-MS (ESI- MS): m/z=897 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),8.51(s,1H),8.40(d,J＝2.2Hz,1H),7.90(d,J＝2.6Hz,1H),7.64(d,J＝8.7Hz,1H),7.42(t,J＝3.0Hz,1H),7.34–7.15(m,7H),7.03(d,J＝9.4Hz,1H),6.37–6.25(m,2H),3.70(dd,J＝20.8,6.5Hz,3H),3.21(dd,J＝10.2,6.7Hz,5H),3.02(d,J＝7.3Hz,1H),2.92(d,J＝3.5Hz,3H),2.82–2.57(m,5H),1.99(d,J＝11.4Hz,7H),1.22–1.16(m,8H),1.07(d,J＝6.7Hz,4H),0.80(d,J＝7.0Hz,1H)。1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),8.51(s,1H),8.40(d,J=2.2Hz,1H),7.90(d,J=2.6Hz,1H),7.64 (d, J=8.7Hz, 1H), 7.42 (t, J=3.0Hz, 1H), 7.34–7.15 (m, 7H), 7.03 (d, J=9.4Hz, 1H), 6.37–6.25 (m, 2H), 3.70(dd, J＝20.8, 6.5Hz, 3H), 3.21(dd, J＝10.2, 6.7Hz, 5H), 3.02(d, J＝7.3Hz, 1H), 2.92(d, J＝3.5 Hz, 3H), 2.82–2.57 (m, 5H), 1.99 (d, J=11.4Hz, 7H), 1.22–1.16 (m, 8H), 1.07 (d, J=6.7Hz, 4H), 0.80 (d , J=7.0Hz, 1H).
实施例64：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(120)Example 64: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl) Methyl)amino)phenyl)sulfonyl)benzamide (120)
Figure PCTCN2021126588-appb-000092
Figure PCTCN2021126588-appb-000092
参考实施例31的合成方法，把化合物089替换为化合物133，可合成得到目标化合物120，LC-MS(ESI-MS)：m/z＝953[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced with compound 133, and the target compound 120 could be synthesized. LC-MS (ESI-MS): m/z=953 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.56(s,1H),8.41(d,J＝2.2Hz,2H),7.91(d,J＝2.7Hz,1H),7.66(dd,J＝9.1,2.2Hz,1H),7.54(d,J＝7.8Hz,1H),7.42(t,J＝3.0Hz,1H),7.35–7.21(m,5H),7.04(d,J＝9.3Hz,1H),6.36–6.24(m,2H),4.50(t,J＝6.5Hz,2H),4.39(t,J＝6.1Hz,2H),3.62(dd,J＝20.6,6.3Hz,3H),2.77(t,J＝5.7Hz,2H),2.67(t,J＝5.3Hz,2H),2.55(d,J＝10.8Hz,2H),2.12–1.93(m,6H),1.83–1.76(m,3H),1.49–1.35(m,6H),1.24–1.13(m,9H),1.07(d,J＝6.7Hz,4H),0.81(s,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.56 (s, 1H), 8.41 (d, J=2.2Hz, 2H), 7.91 (d, J=2.7Hz, 1H), 7.66 (dd, J= 9.1, 2.2Hz, 1H), 7.54 (d, J=7.8Hz, 1H), 7.42 (t, J=3.0Hz, 1H), 7.35–7.21 (m, 5H), 7.04 (d, J=9.3Hz, 1H), 6.36–6.24 (m, 2H), 4.50 (t, J=6.5Hz, 2H), 4.39 (t, J=6.1Hz, 2H), 3.62 (dd, J=20.6, 6.3Hz, 3H), 2.77(t,J＝5.7Hz,2H),2.67(t,J＝5.3Hz,2H),2.55(d,J＝10.8Hz,2H),2.12-1.93(m,6H),1.83-1.76(m , 3H), 1.49–1.35 (m, 6H), 1.24–1.13 (m, 9H), 1.07 (d, J=6.7Hz, 4H), 0.81 (s, 1H).
实施例65：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(130)Example 65: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl) yl)-4-fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (130)
Figure PCTCN2021126588-appb-000093
Figure PCTCN2021126588-appb-000093
参考实施例27的合成方法，把化合物089替换为化合物133，可合成得到目标化 合物130，LC-MS(ESI-MS)：m/z＝982[M+H] +。 Referring to the synthesis method of Example 27, compound 089 was replaced by compound 133, and the target compound 130 could be synthesized. LC-MS (ESI-MS): m/z=982 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.46(s,1H),8.35–8.29(m,2H),7.85(d,J＝2.7Hz,1H),7.58(dd,J＝9.0,2.1Hz,1H),7.46(dd,J＝7.3,2.0Hz,1H),7.36(t,J＝3.0Hz,1H),7.30(d,J＝13.7Hz,1H),7.18–7.14(m,2H),7.07(td,J＝7.1,1.8Hz,2H),6.90(d,J＝9.2Hz,1H),6.33(d,J＝7.7Hz,1H),6.23(dd,J＝3.4,1.9Hz,1H),4.21–4.11(m,1H),3.85(d,J＝13.7Hz,1H),3.61(dd,J＝21.4,6.5Hz,5H),2.96–2.87(m,11H),2.64(d,J＝7.2Hz,2H),1.75–1.67(m,4H),1.44(q,J＝5.0Hz,5H),1.20(d,J＝4.3Hz,5H),1.12(d,J＝2.5Hz,4H),1.08(s,7H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.46 (s, 1H), 8.35-8.29 (m, 2H), 7.85 (d, J=2.7Hz, 1H), 7.58 (dd, J=9.0, 2.1 Hz, 1H), 7.46(dd, J＝7.3, 2.0Hz, 1H), 7.36(t, J＝3.0Hz, 1H), 7.30(d, J＝13.7Hz, 1H), 7.18–7.14(m, 2H) ),7.07(td,J=7.1,1.8Hz,2H),6.90(d,J=9.2Hz,1H),6.33(d,J=7.7Hz,1H),6.23(dd,J=3.4,1.9Hz ,1H),4.21–4.11(m,1H),3.85(d,J=13.7Hz,1H),3.61(dd,J=21.4,6.5Hz,5H),2.96–2.87(m,11H),2.64( d, J=7.2Hz, 2H), 1.75–1.67 (m, 4H), 1.44 (q, J=5.0Hz, 5H), 1.20 (d, J=4.3Hz, 5H), 1.12 (d, J=2.5 Hz, 4H), 1.08 (s, 7H).
实施例66：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(128)Example 66: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((4-fluoro-1-(oxa Cyclobutan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (128)
Figure PCTCN2021126588-appb-000094
Figure PCTCN2021126588-appb-000094
参考实施例34的合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为2,4,5-三氟苯甲酸甲酯，可合成得到目标化合物128，LC-MS(ESI-MS)：m/z＝954[M+H] +。 Referring to the synthetic method of Example 34, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,4,5-trifluorobenzoic acid methyl ester to obtain the target compound 128, LC-MS (ESI- MS): m/z=954 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.53(s,1H),7.88(s,1H),7.53(s,1H),7.41(d,J＝3.1Hz,1H),7.35–7.28(m,6H),7.16(s,2H),6.34(d,J＝7.5Hz,1H),6.28(d,J＝3.3Hz,1H),4.52(t,J＝6.6Hz,3H),4.43(s,3H),4.26(s,1H),4.21(s,1H),3.45(s,1H),2.78(s,3H),2.00–1.83(m,14H),1.30(d,J＝6.2Hz,3H),1.07(d,J＝6.7Hz,7H),0.84–0.77(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.53(s,1H),7.88(s,1H),7.53(s,1H),7.41(d,J=3.1Hz,1H),7.35-7.28( m, 6H), 7.16(s, 2H), 6.34(d, J=7.5Hz, 1H), 6.28(d, J=3.3Hz, 1H), 4.52(t, J=6.6Hz, 3H), 4.43( s, 3H), 4.26(s, 1H), 4.21(s, 1H), 3.45(s, 1H), 2.78(s, 3H), 2.00–1.83(m, 14H), 1.30(d, J=6.2Hz , 3H), 1.07 (d, J=6.7Hz, 7H), 0.84–0.77 (m, 6H).
实施例67：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((1-(2-(二甲氨基)乙酰基)-4-氟哌啶-4-基)甲氧基)-3-硝基苯基)磺酰基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(129)Example 67: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl)) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (129)
Figure PCTCN2021126588-appb-000095
Figure PCTCN2021126588-appb-000095
参考实施例36的合成方法，把3,5-二氟吡啶-2-甲酸甲酯替换为2,4,5-三氟苯甲酸甲酯，可合成得到目标化合物129，LC-MS(ESI-MS)：m/z＝983[M+H] +。 Referring to the synthesis method of Example 36, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,4,5-trifluorobenzoic acid methyl ester, and the target compound 129 could be synthesized, LC-MS (ESI- MS): m/z=983 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.48(t,J＝2.3Hz,1H),8.10(d,J＝2.2Hz,1H),7.86(d,J＝2.6Hz,1H),7.75(dd,J＝8.8,2.2Hz,1H),7.50–7.46(m,1H),7.40–7.30(m,2H),7.18(dd,J＝11.7,2.3Hz,2H),7.10(dd,J＝8.7,5.9Hz,3H),6.34(d,J＝7.6Hz,1H),6.25(dd,J＝3.4,1.9Hz,1H),4.24(dd,J＝20.3,5.2Hz,3H),3.72(t,J＝7.0Hz,3H),3.09(dd,J＝18.0,10.4Hz,3H),2.96–2.88(m,1H),2.77–2.63(m,4H),2.19–2.10(m,1H),1.92(qd,J＝14.9,13.6,5.8Hz,3H),1.72(dt,J＝12.5,6.6Hz,4H),1.52–1.42(m,4H), 1.38(d,J＝10.0Hz,3H),1.22–1.16(m,9H),1.11(dd,J＝10.2,6.8Hz,7H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.48 (t, J=2.3Hz, 1H), 8.10 (d, J=2.2Hz, 1H), 7.86 (d, J=2.6Hz, 1H), 7.75 (dd, J=8.8, 2.2Hz, 1H), 7.50–7.46 (m, 1H), 7.40–7.30 (m, 2H), 7.18 (dd, J=11.7, 2.3Hz, 2H), 7.10 (dd, J ＝8.7,5.9Hz,3H),6.34(d,J＝7.6Hz,1H),6.25(dd,J＝3.4,1.9Hz,1H),4.24(dd,J＝20.3,5.2Hz,3H),3.72 (t, J=7.0Hz, 3H), 3.09 (dd, J=18.0, 10.4Hz, 3H), 2.96–2.88 (m, 1H), 2.77–2.63 (m, 4H), 2.19–2.10 (m, 1H) ),1.92(qd,J＝14.9,13.6,5.8Hz,3H),1.72(dt,J＝12.5,6.6Hz,4H),1.52–1.42(m,4H), 1.38(d,J＝10.0Hz, 3H), 1.22–1.16 (m, 9H), 1.11 (dd, J=10.2, 6.8Hz, 7H).
实施例68：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((S)-吡咯烷-3-基甲基)氨基)苯基)磺酰基)苯甲酰胺(134)Example 68: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((S)-pyrrolidin-3-ylmethyl) Amino)phenyl)sulfonyl)benzamide (134)
Figure PCTCN2021126588-appb-000096
Figure PCTCN2021126588-appb-000096
参考实施例63的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为(R)-3-(氨基甲基)吡咯烷-1-羧酸叔丁酯，可合成得到目标化合物134，LC-MS(ESI-MS)：m/z＝865[M+H] +。 Referring to the synthetic method of Example 63, substituting (R)-3-(aminomethyl)pyrrolidine-1-carboxylic acid for tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate The tert-butyl ester can be synthesized to obtain the target compound 134, LC-MS (ESI-MS): m/z=865 [M+H] + .
实施例69：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((((R)-1-(氧杂环丁烷-3-基)吡咯烷-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(131)Example 69: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((R)-1-(oxetane) -3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (131)
Figure PCTCN2021126588-appb-000097
Figure PCTCN2021126588-appb-000097
参考实施例31的合成方法，把化合物089替换为化合物134，可合成得到目标化合物131，LC-MS(ESI-MS)：m/z＝921[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced with compound 134, and the target compound 131 could be synthesized. LC-MS (ESI-MS): m/z=921 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.53(s,1H),8.57(s,1H),8.37(d,J＝2.2Hz,1H),7.88(d,J＝2.6Hz,1H),7.62–7.57(m,1H),7.52(s,1H),7.40(t,J＝3.0Hz,1H),7.33–7.11(m,5H),6.79(d,J＝9.1Hz,1H),6.36–6.24(m,2H),4.56–4.42(m,4H),3.66(s,1H),3.49–3.35(m,1H),2.81–2.62(m,6H),2.50(ddd,J＝7.4,4.4,1.9Hz,1H),1.99–1.91(m,3H),1.87(s,1H),1.42(d,J＝21.8Hz,6H),1.30(d,J＝4.1Hz,1H),1.27–1.14(m,10H),1.08(d,J＝6.7Hz,4H),0.91–0.66(m,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.53(s, 1H), 8.57(s, 1H), 8.37(d, J=2.2Hz, 1H), 7.88(d, J=2.6Hz, 1H) ,7.62–7.57(m,1H),7.52(s,1H),7.40(t,J=3.0Hz,1H),7.33–7.11(m,5H),6.79(d,J=9.1Hz,1H), 6.36–6.24 (m, 2H), 4.56–4.42 (m, 4H), 3.66 (s, 1H), 3.49–3.35 (m, 1H), 2.81–2.62 (m, 6H), 2.50 (ddd, J=7.4 ,4.4,1.9Hz,1H),1.99–1.91(m,3H),1.87(s,1H),1.42(d,J=21.8Hz,6H),1.30(d,J=4.1Hz,1H),1.27 -1.14 (m, 10H), 1.08 (d, J = 6.7Hz, 4H), 0.91 - 0.66 (m, 3H).
实施例70：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((((R)-1-(氧杂环丁烷-3-基)吡咯烷-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(132)Example 70: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((R)-1-(oxetane) -3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (132)
Figure PCTCN2021126588-appb-000098
Figure PCTCN2021126588-appb-000098
参考实施例69的合成方法，把(R)-3-(氨基甲基)吡咯烷-1-羧酸叔丁酯替换为(S)-3-(氨基甲基)吡咯烷-1-羧酸叔丁酯，可合成得到目标化合物132，LC-MS(ESI-MS)：m/z＝921[M+H] +。 Referring to the synthesis method of Example 69, substituting (R)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-3-(aminomethyl)pyrrolidine-1-carboxylic acid The tert-butyl ester can be synthesized to obtain the target compound 132, LC-MS (ESI-MS): m/z=921 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.53(d,J＝2.3Hz,1H),8.57(s,1H),8.38(d,J＝ 2.2Hz,1H),7.89(d,J＝2.7Hz,1H),7.72–7.49(m,3H),7.41(t,J＝3.0Hz,1H),7.32–7.24(m,4H),6.80(d,J＝9.1Hz,1H),6.33(d,J＝7.5Hz,1H),6.27(dd,J＝3.4,1.9Hz,1H),4.60–4.42(m,5H),4.18(t,J＝6.6Hz,1H),3.70(s,2H),3.05(q,J＝7.3Hz,1H),2.76(t,J＝5.9Hz,4H),2.70–2.59(m,4H),2.31–2.21(m,1H),2.03–1.91(m,5H),1.41(ddt,J＝15.9,12.3,6.6Hz,9H),1.29(d,J＝3.2Hz,1H),1.08(d,J＝6.8Hz,4H),0.91–0.76(m,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.53 (d, J=2.3 Hz, 1H), 8.57 (s, 1H), 8.38 (d, J= 2.2 Hz, 1H), 7.89 (d, J= 2.7Hz, 1H), 7.72–7.49 (m, 3H), 7.41 (t, J=3.0Hz, 1H), 7.32–7.24 (m, 4H), 6.80 (d, J=9.1Hz, 1H), 6.33 ( d, J=7.5Hz, 1H), 6.27 (dd, J=3.4, 1.9Hz, 1H), 4.60–4.42 (m, 5H), 4.18 (t, J=6.6Hz, 1H), 3.70 (s, 2H) ), 3.05 (q, J=7.3Hz, 1H), 2.76 (t, J=5.9Hz, 4H), 2.70–2.59 (m, 4H), 2.31–2.21 (m, 1H), 2.03–1.91 (m, 5H), 1.41 (ddt, J=15.9, 12.3, 6.6Hz, 9H), 1.29 (d, J=3.2Hz, 1H), 1.08 (d, J=6.8Hz, 4H), 0.91–0.76 (m, 4H) ).
实施例71：2-((1H-吡咯[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((1r，4r)-4-羟基-4-甲基环己基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(136)Example 71: 2-((1H-pyrro[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((1r,4r)-4-hydroxy- 4-Methylcyclohexyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)benzamide (136)
Figure PCTCN2021126588-appb-000099
Figure PCTCN2021126588-appb-000099
参考实施例7的合成方法3,5-二氟吡啶-2-甲酸甲酯替换为2,4,5-三氟苯甲酸甲酯，把(S)-2-(2-异丙基苯基)吡咯烷替换为2-(2-异丙基苯基)吡咯烷，可合成得到目标化合物136，LC-MS(ESI-MS)：m/z＝908[M+H] +。 The synthetic method of reference example 7 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,4,5-trifluorobenzoic acid methyl ester, (S)-2-(2-isopropylphenyl ) pyrrolidine was replaced by 2-(2-isopropylphenyl)pyrrolidine, the target compound 136 could be synthesized, LC-MS (ESI-MS): m/z=908 [M+H] + .
实施例72：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-苯基吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(137)Example 72: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-phenylpyrrolidin-1-yl)-7-azaspiro[ 3.5] Nonan-7-yl)benzamide (137)
Figure PCTCN2021126588-appb-000100
Figure PCTCN2021126588-appb-000100
参考实施例16的合成方法，把(S)-2-(2-异丙基苯基)吡咯烷替换为2-苯基吡咯烷，可合成得到目标化合物137，LC-MS(ESI-MS)：m/z＝866[M+H] +。 Referring to the synthesis method of Example 16, substituting (S)-2-(2-isopropylphenyl)pyrrolidine with 2-phenylpyrrolidine, the target compound 137 can be synthesized by LC-MS (ESI-MS) : m/z=866 [M+H] + .
实施例73：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-苯基吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(138)Example 73: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-phenylpyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (138)
Figure PCTCN2021126588-appb-000101
Figure PCTCN2021126588-appb-000101
参考实施例72的合成方法，把2,4,5-三氟苯甲酸甲酯替换为4,6-二氯烟酸甲酯，可合成得到目标化合物138，LC-MS(ESI-MS)：m/z＝849[M+H] +。 Referring to the synthetic method of Example 72, methyl 2,4,5-trifluorobenzoate was replaced with methyl 4,6-dichloronicotinate to obtain the target compound 138, LC-MS (ESI-MS): m/z=849 [M+H] + .
实施例74：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-氟苯 基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(139)Example 74: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-fluorophenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)benzamide (139)
Figure PCTCN2021126588-appb-000102
Figure PCTCN2021126588-appb-000102
参考实施例72的合成方法，把2-苯基吡咯烷替换为2-(2-氟苯基)吡咯烷，可合成得到目标化合物139，LC-MS(ESI-MS)：m/z＝884[M+H] +。 Referring to the synthesis method of Example 72, substituting 2-phenylpyrrolidine with 2-(2-fluorophenyl)pyrrolidine, the target compound 139 can be synthesized, LC-MS (ESI-MS): m/z=884 [M+H] + .
实施例75：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(叔丁基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(140)Example 75: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(tert-butyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino )-3-Nitrophenyl)sulfonyl)benzamide (140)
Figure PCTCN2021126588-appb-000103
Figure PCTCN2021126588-appb-000103
参考实施例72的合成方法，把2-苯基吡咯烷替换为2-(叔丁基)吡咯烷，可合成得到目标化合物140，LC-MS(ESI-MS)：m/z＝846[M+H] +。 Referring to the synthesis method of Example 72, substituting 2-phenylpyrrolidine with 2-(tert-butyl)pyrrolidine, the target compound 140 can be synthesized to obtain the target compound 140, LC-MS (ESI-MS): m/z=846 [M +H] + .
实施例76：4-(((4-(N-(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)-4-氟哌啶-1-甲酸甲酯(141)Example 76: 4-(((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-( 2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl) Amino)methyl)-4-fluoropiperidine-1-carboxylic acid methyl ester (141)
Figure PCTCN2021126588-appb-000104
Figure PCTCN2021126588-appb-000104
参考实施例38的合成方法，把碳酸氢乙酯替换为碳酸氢甲酯，可合成得到目标化合物141，LC-MS(ESI-MS)：m/z＝955[M+H] +。 Referring to the synthesis method of Example 38, the target compound 141 can be synthesized by replacing ethyl bicarbonate with methyl bicarbonate, LC-MS (ESI-MS): m/z=955 [M+H] + .
实施例77：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(142)Example 77: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)nicotinamide (142)
Figure PCTCN2021126588-appb-000105
Figure PCTCN2021126588-appb-000105
参考实施例7的合成方法，把中间体24-3替换为中间体35-3，可合成得到目标化合物142，LC-MS(ESI-MS)：m/z＝890[M+H] +。 Referring to the synthesis method of Example 7, the intermediate 24-3 was replaced by the intermediate 35-3, and the target compound 142 could be synthesized, LC-MS (ESI-MS): m/z=890 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.70(d,J＝2.3Hz,1H),8.53–8.40(m,2H),8.28(s,1H),7.99(d,J＝2.6Hz,1H),7.78(dd,J＝9.1,2.3Hz,1H),7.62(d,J＝2.7Hz,1H),7.48(q,J＝4.7,3.2Hz,2H),7.17(dt,J＝20.3,7.7Hz,3H),7.03(d,J＝9.3Hz,1H),6.38(dd,J＝3.4,1.9Hz,1H),5.71(s,1H),4.21(s,1H),3.24(t,J＝6.3Hz,6H),3.11(d,J＝12.7Hz,3H),2.21(s,1H),1.96–1.77(m,3H),1.69–1.57(m,4H),1.54–1.43(m,3H),1.30–1.23(m,5H),1.18(s,3H),1.14(d,J＝6.8Hz,4H),1.10–1.01(m,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.70 (d, J=2.3Hz, 1H), 8.53-8.40 (m, 2H), 8.28 (s, 1H), 7.99 (d, J=2.6Hz, 1H), 7.78(dd, J=9.1, 2.3Hz, 1H), 7.62(d, J=2.7Hz, 1H), 7.48(q, J=4.7, 3.2Hz, 2H), 7.17(dt, J=20.3 ,7.7Hz,3H),7.03(d,J=9.3Hz,1H),6.38(dd,J=3.4,1.9Hz,1H),5.71(s,1H),4.21(s,1H),3.24(t , J=6.3Hz, 6H), 3.11 (d, J=12.7Hz, 3H), 2.21 (s, 1H), 1.96–1.77 (m, 3H), 1.69–1.57 (m, 4H), 1.54–1.43 ( m, 3H), 1.30–1.23 (m, 5H), 1.18 (s, 3H), 1.14 (d, J=6.8Hz, 4H), 1.10–1.01 (m, 9H).
实施例78：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((R)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(143)Example 78: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)nicotinamide (143)
Figure PCTCN2021126588-appb-000106
Figure PCTCN2021126588-appb-000106
参考实施例77的合成方法，把(S)-2-(2-异丙基苯基)吡咯烷替换为(R)-2-(2-异丙基苯基)吡咯烷，可合成得到目标化合物143，LC-MS(ESI-MS)：m/z＝891[M+H] +。 Referring to the synthesis method of Example 77, (S)-2-(2-isopropylphenyl)pyrrolidine is replaced by (R)-2-(2-isopropylphenyl)pyrrolidine, the target can be synthesized Compound 143, LC-MS (ESI-MS): m/z=891 [M+H] + .
实施例79：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-羟基-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)(144)Example 79: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-hydroxy-1-(oxy Hetetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl) (144)
Figure PCTCN2021126588-appb-000107
Figure PCTCN2021126588-appb-000107
参考实施例64的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为4-(氨甲基)-4-羟基哌啶-1-羧酸叔丁酯，可合成得到目标化合物144，LC-MS(ESI-MS)：m/z＝951[M+H] +。 Referring to the synthetic method of Example 64, substituting 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylic acid for tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate The tert-butyl ester can be synthesized to obtain the target compound 144, LC-MS (ESI-MS): m/z=951 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.47(d,J＝2.4Hz,1H),8.39(s,1H),8.32(t,J＝2.1Hz,1H),7.86(d,J＝2.6Hz,1H),7.55(dd,J＝9.1,2.2Hz,1H),7.48(d,J＝6.1Hz,1H),7.37(t,J＝3.0Hz,1H),7.30(d,J＝13.7Hz,1H),7.23–7.06(m,4H),6.80(s,1H),6.33(d,J＝7.6Hz,1H),6.24(dd,J＝3.4,1.9Hz,1H),4.74(s,1H),4.48(t,J＝6.5Hz,2H),4.37(t,J＝6.1Hz,2H),3.54(d,J＝6.8Hz,4H),3.23(d,J＝2.8Hz,4H),3.13–3.00(m,3H),2.77–2.61(m,5H),2.00–1.91(m,2H),1.54(dd,J＝7.0,4.2Hz,5H),1.49–1.36(m,8H),1.11(dd,J＝11.0,6.7Hz,8H). 1 H NMR (400MHz, DMSO-d 6 )δ11.47(d,J=2.4Hz,1H),8.39(s,1H),8.32(t,J=2.1Hz,1H),7.86(d,J= 2.6Hz, 1H), 7.55 (dd, J=9.1, 2.2Hz, 1H), 7.48 (d, J=6.1Hz, 1H), 7.37 (t, J=3.0Hz, 1H), 7.30 (d, J= 13.7Hz, 1H), 7.23–7.06(m, 4H), 6.80(s, 1H), 6.33(d, J=7.6Hz, 1H), 6.24(dd, J=3.4, 1.9Hz, 1H), 4.74( s,1H),4.48(t,J＝6.5Hz,2H),4.37(t,J＝6.1Hz,2H),3.54(d,J＝6.8Hz,4H),3.23(d,J＝2.8Hz, 4H), 3.13–3.00 (m, 3H), 2.77–2.61 (m, 5H), 2.00–1.91 (m, 2H), 1.54 (dd, J=7.0, 4.2Hz, 5H), 1.49–1.36 (m, 8H),1.11(dd,J=11.0,6.7Hz,8H).
实施例80：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((哌啶-4-基甲基) 氨基)苯基)磺酰基)苯甲酰胺(148)Example 80: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((piperidin-4-ylmethyl)amino)phenyl )sulfonyl)benzamide (148)
Figure PCTCN2021126588-appb-000108
Figure PCTCN2021126588-appb-000108
参考实施例63的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为4-(氨基甲基)哌啶-1-羧酸叔丁酯，可合成得到目标化合物148，LC-MS(ESI-MS)：m/z＝879[M+H] +。 Referring to the synthetic method of Example 63, substituting tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, The target compound 148 can be synthesized, LC-MS (ESI-MS): m/z=879 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.55(s,1H),8.41(d,J＝29.6Hz,2H),7.89(d,J＝2.6Hz,1H),7.65–7.56(m,1H),7.45–7.28(m,8H),6.85(s,1H),6.33(d,J＝7.6Hz,1H),6.27(dd,J＝3.5,1.9Hz,1H),3.24(q,J＝5.2,3.7Hz,8H),2.81–2.71(m,6H),2.65(d,J＝7.1Hz,3H),2.01–1.91(m,4H),1.79(d,J＝14.3Hz,4H),1.60(s,1H),1.37–1.30(m,5H),1.07(d,J＝6.7Hz,5H),0.90–0.77(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 8.41 (d, J=29.6Hz, 2H), 7.89 (d, J=2.6Hz, 1H), 7.65-7.56 (m, 1H), 7.45–7.28(m, 8H), 6.85(s, 1H), 6.33(d, J=7.6Hz, 1H), 6.27(dd, J=3.5, 1.9Hz, 1H), 3.24(q, J =5.2,3.7Hz,8H),2.81-2.71(m,6H),2.65(d,J=7.1Hz,3H),2.01-1.91(m,4H),1.79(d,J=14.3Hz,4H) ,1.60(s,1H),1.37–1.30(m,5H),1.07(d,J=6.7Hz,5H),0.90–0.77(m,2H).
实施例81：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((哌啶-4-基甲基)氨基)苯基)磺酰基)烟酰胺(147)Example 81: 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((piperidin-4-ylmethyl)amino)phenyl)sulfonyl) Niacinamide (147)
Figure PCTCN2021126588-appb-000109
Figure PCTCN2021126588-appb-000109
参考实施例56的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为4-(氨基甲基)哌啶-1-羧酸叔丁酯，可合成得到目标化合物147，LC-MS(ESI-MS)：m/z＝862[M+H] +。 Referring to the synthetic method of Example 56, substituting tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, The target compound 147 can be synthesized, LC-MS (ESI-MS): m/z=862 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.67(s,1H),8.48–8.31(m,4H),7.93(d,J＝2.6Hz,1H),7.75(dd,J＝9.1,2.2Hz,1H),7.61–7.43(m,3H),7.15(dt,J＝26.4,7.8Hz,3H),6.98(d,J＝9.2Hz,1H),6.39–6.32(m,1H),5.73(s,1H),3.21(dt,J＝12.9,3.5Hz,6H),2.78(td,J＝12.8,3.0Hz,3H),2.16(d,J＝16.2Hz,1H),1.91–1.67(m,8H),1.35–1.07(m,20H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.67 (s, 1H), 8.48-8.31 (m, 4H), 7.93 (d, J=2.6Hz, 1H), 7.75 (dd, J=9.1, 2.2 Hz, 1H), 7.61–7.43 (m, 3H), 7.15 (dt, J=26.4, 7.8Hz, 3H), 6.98 (d, J=9.2Hz, 1H), 6.39–6.32 (m, 1H), 5.73 (s, 1H), 3.21 (dt, J=12.9, 3.5Hz, 6H), 2.78 (td, J=12.8, 3.0Hz, 3H), 2.16 (d, J=16.2Hz, 1H), 1.91–1.67( m,8H),1.35–1.07(m,20H).
实施例82：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)苯基)磺酰基)烟酰胺(145)Example 82: 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((1-(oxetan-3-yl)piperidine- 4-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (145)
Figure PCTCN2021126588-appb-000110
Figure PCTCN2021126588-appb-000110
参考实施例31的合成方法，把化合物089替换为化合物147，可合成得到目标化合物145，LC-MS(ESI-MS)：m/z＝918[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced by compound 147, and the target compound 145 could be synthesized. LC-MS (ESI-MS): m/z=918 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.69(d,J＝2.5Hz,1H),8.52–8.44(m,2H),8.30(s,1H),7.97(d,J＝2.6Hz,1H),7.77(dd,J＝9.1,2.3Hz,1H),7.60(d,J＝2.6Hz,1H),7.52–7.46(m,2H),7.16(dt,J＝27.1,7.4Hz,4H),7.02(s,1H),6.41–6.35(m,1H),4.48(t,J＝6.6Hz,2H),4.38(t,J＝6.2Hz,2H),3.11(q,J＝6.7Hz,3H),2.70(d,J＝10.9Hz,2H),2.28–2.11(m,1H),2.01–1.90(m,1H),1.87(s,6H),1.69–1.58(m,4H),1.27–1.18(m,12H),1.11(dd,J＝21.6,6.7Hz,9H),0.81(s,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.69 (d, J=2.5Hz, 1H), 8.52-8.44 (m, 2H), 8.30 (s, 1H), 7.97 (d, J=2.6Hz, 1H), 7.77 (dd, J=9.1, 2.3Hz, 1H), 7.60 (d, J=2.6Hz, 1H), 7.52–7.46 (m, 2H), 7.16 (dt, J=27.1, 7.4Hz, 4H) ), 7.02(s, 1H), 6.41–6.35(m, 1H), 4.48(t, J=6.6Hz, 2H), 4.38(t, J=6.2Hz, 2H), 3.11(q, J=6.7Hz) ,3H),2.70(d,J＝10.9Hz,2H),2.28-2.11(m,1H),2.01-1.90(m,1H),1.87(s,6H),1.69-1.58(m,4H), 1.27–1.18(m, 12H), 1.11(dd, J=21.6, 6.7Hz, 9H), 0.81(s, 1H).
实施例83：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(146)Example 83: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((1-(oxetan-3-yl) )piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (146)
Figure PCTCN2021126588-appb-000111
Figure PCTCN2021126588-appb-000111
参考实施例31的合成方法，把化合物089替换为化合物148，可合成得到目标化合物146，LC-MS(ESI-MS)：m/z＝935[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced with compound 148, and the target compound 146 could be synthesized. LC-MS (ESI-MS): m/z=935 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.51(t,J＝2.3Hz,1H),8.36(dd,J＝8.9,4.0Hz,2H),7.87(d,J＝2.6Hz,1H),7.57(dd,J＝9.1,2.2Hz,1H),7.38(t,J＝3.0Hz,1H),7.25(dt,J＝22.3,16.6Hz,6H),6.80(d,J＝9.2Hz,1H),6.33(d,J＝7.6Hz,1H),6.25(dd,J＝3.4,1.9Hz,1H),4.49(t,J＝6.6Hz,2H),4.43(t,J＝6.2Hz,2H),3.56(p,J＝6.6Hz,3H),3.21(t,J＝6.1Hz,6H),3.08(d,J＝7.4Hz,3H),2.75(q,J＝7.8,6.3Hz,4H),2.64(d,J＝5.8Hz,2H),1.68(d,J＝13.0Hz,3H),1.41(td,J＝11.4,5.8Hz,6H),1.18(dd,J＝12.0,5.5Hz,8H),1.08(d,J＝6.7Hz,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.51 (t, J=2.3 Hz, 1H), 8.36 (dd, J=8.9, 4.0 Hz, 2H), 7.87 (d, J=2.6 Hz, 1H) ,7.57(dd,J＝9.1,2.2Hz,1H),7.38(t,J＝3.0Hz,1H),7.25(dt,J＝22.3,16.6Hz,6H),6.80(d,J＝9.2Hz, 1H), 6.33(d, J＝7.6Hz, 1H), 6.25(dd, J＝3.4, 1.9Hz, 1H), 4.49(t, J＝6.6Hz, 2H), 4.43(t, J＝6.2Hz, 2H), 3.56(p, J＝6.6Hz, 3H), 3.21(t, J＝6.1Hz, 6H), 3.08(d, J＝7.4Hz, 3H), 2.75(q, J＝7.8, 6.3Hz, 4H), 2.64(d, J＝5.8Hz, 2H), 1.68(d, J＝13.0Hz, 3H), 1.41(td, J＝11.4, 5.8Hz, 6H), 1.18(dd, J＝12.0, 5.5 Hz,8H),1.08(d,J＝6.7Hz,4H).
实施例84：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((5-氧代吡咯烷-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(149)Example 84: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((5-oxopyrrolidin-2-yl)methan yl)amino)phenyl)sulfonyl)benzamide (149)
Figure PCTCN2021126588-appb-000112
Figure PCTCN2021126588-appb-000112
参考实施例63的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为2-(氨基甲基)-5-氧代吡咯烷，可合成得到目标化合物149，LC-MS(ESI-MS)：m/z＝879[M+H] +。 Referring to the synthesis method of Example 63, tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate was replaced with 2-(aminomethyl)-5-oxopyrrolidine, which could be synthesized to obtain Target compound 149, LC-MS (ESI-MS): m/z=879 [M+H] + .
实施例85：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基 苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((2-(2-氧代咪唑烷-1-基)乙基)氨基)苯基)磺酰基)苯甲酰胺(150)Example 85: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(2-oxoimidazolidine-1-yl) )ethyl)amino)phenyl)sulfonyl)benzamide (150)
Figure PCTCN2021126588-appb-000113
Figure PCTCN2021126588-appb-000113
参考实施例63的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为3-(2-氨基乙基)-2-氧代咪唑烷，可合成得到目标化合物150，LC-MS(ESI-MS)：m/z＝894[M+H] +。 Referring to the synthetic method of Example 63, substituting tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate with 3-(2-aminoethyl)-2-oxoimidazolidine, the The target compound 150 was synthesized, LC-MS (ESI-MS): m/z=894 [M+H] + .
实施例86：(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-氟-1-(氧杂环丁烷-3-基))哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(151)Example 86: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((((4-fluoro- 1-(oxetan-3-yl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-iso) Propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (151)
Figure PCTCN2021126588-appb-000114
Figure PCTCN2021126588-appb-000114
参考实施例64的合成方法，把2-(2-异丙基苯基)吡咯烷替换为(S)-2-(2-异丙基苯基)吡咯烷，可合成得到目标化合物151，LC-MS(ESI-MS)：m/z＝953[M+H] +。 Referring to the synthesis method of Example 64, substituting 2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-isopropylphenyl)pyrrolidine, the target compound 151 can be synthesized, LC -MS (ESI-MS): m/z=953 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.52(t,J＝2.3Hz,1H),8.44–8.36(m,2H),7.88(d,J＝2.6Hz,1H),7.62(dd,J＝9.1,2.2Hz,1H),7.52(d,J＝7.6Hz,1H),7.39(t,J＝3.0Hz,1H),7.35–7.10(m,6H),6.97(d,J＝9.2Hz,1H),6.32(d,J＝7.6Hz,1H),6.25(dd,J＝3.4,1.9Hz,1H),4.48(t,J＝6.5Hz,2H),4.37(t,J＝6.1Hz,2H),3.62(d,J＝6.2Hz,1H),3.57(d,J＝6.3Hz,1H),2.70(dt,J＝37.1,5.7Hz,5H),2.56–2.49(m,2H),2.02–1.88(m,5H),1.85–1.60(m,7H),1.51–1.34(m,6H),1.31–1.12(m,7H),1.07(d,J＝6.7Hz,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.52 (t, J=2.3Hz, 1H), 8.44-8.36 (m, 2H), 7.88 (d, J=2.6Hz, 1H), 7.62 (dd, J=9.1, 2.2Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 7.39 (t, J=3.0Hz, 1H), 7.35–7.10 (m, 6H), 6.97 (d, J=9.2 Hz, 1H), 6.32(d, J＝7.6Hz, 1H), 6.25(dd, J＝3.4, 1.9Hz, 1H), 4.48(t, J＝6.5Hz, 2H), 4.37(t, J＝6.1 Hz, 2H), 3.62 (d, J=6.2Hz, 1H), 3.57 (d, J=6.3Hz, 1H), 2.70 (dt, J=37.1, 5.7Hz, 5H), 2.56–2.49 (m, 2H) ), 2.02–1.88 (m, 5H), 1.85–1.60 (m, 7H), 1.51–1.34 (m, 6H), 1.31–1.12 (m, 7H), 1.07 (d, J=6.7Hz, 4H).
实施例87：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-氟-1-异丙基哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(153)Example 87: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-isopropyl ylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)benzamide (153)
Figure PCTCN2021126588-appb-000115
Figure PCTCN2021126588-appb-000115
参考实施例64的合成方法，把氧杂环丁烷-3-酮替换为丙-2-酮，可合成得到目标化合物153，LC-MS(ESI-MS)：m/z＝939[M+H] +。 Referring to the synthesis method of Example 64, substituting oxetan-3-one with propan-2-one, the target compound 153 can be synthesized, LC-MS (ESI-MS): m/z=939 [M+ H] + .
实施例88：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-氟 -1-(2,2,2-三氟乙基))哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(155)Example 88: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-(2 ,2,2-Trifluoroethyl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylbenzene) yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (155)
Figure PCTCN2021126588-appb-000116
Figure PCTCN2021126588-appb-000116
参考实施例64的合成方法，把氧杂环丁烷-3-酮替换为2,2,2-三氟乙醛，可合成得到目标化合物155，LC-MS(ESI-MS)：m/z＝979[M+H] +。 Referring to the synthesis method of Example 64, substituting oxetan-3-one with 2,2,2-trifluoroacetaldehyde, the target compound 155 can be synthesized, LC-MS (ESI-MS): m/z =979[M+H] + .
实施例89：(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(152)Example 89: (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxy Hetetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (152)
Figure PCTCN2021126588-appb-000117
Figure PCTCN2021126588-appb-000117
参考实施例57的合成方法，把2-(2-异丙基苯基)吡咯烷替换为(S)-2-(2-异丙基苯基)吡咯烷，可合成得到目标化合物152，LC-MS(ESI-MS)：m/z＝936[M+H] +。 Referring to the synthetic method of Example 57, substituting 2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-isopropylphenyl)pyrrolidine, the target compound 152 can be synthesized, LC -MS (ESI-MS): m/z=936 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.70(s,1H),8.55–8.44(m,2H),8.29(s,1H),7.98(d,J＝2.6Hz,1H),7.79(dd,J＝9.1,2.2Hz,1H),7.62(s,1H),7.55–7.46(m,2H),7.28–7.08(m,4H),6.43–6.34(m,1H),4.48(t,J＝6.5Hz,2H),4.37(t,J＝6.1Hz,2H),3.66(dd,J＝20.7,6.3Hz,2H),3.12(s,4H),2.56–2.48(m,2H),2.26(d,J＝24.4Hz,1H),1.96(dt,J＝12.5,6.4Hz,4H),1.89–1.58(m,10H),1.45(s,1H),1.40–1.05(m,16H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.70(s, 1H), 8.55-8.44(m, 2H), 8.29(s, 1H), 7.98(d, J=2.6Hz, 1H), 7.79( dd, J=9.1, 2.2Hz, 1H), 7.62 (s, 1H), 7.55–7.46 (m, 2H), 7.28–7.08 (m, 4H), 6.43–6.34 (m, 1H), 4.48 (t, J=6.5Hz, 2H), 4.37(t, J=6.1Hz, 2H), 3.66(dd, J=20.7, 6.3Hz, 2H), 3.12(s, 4H), 2.56–2.48(m, 2H), 2.26(d,J＝24.4Hz,1H),1.96(dt,J＝12.5,6.4Hz,4H),1.89-1.58(m,10H),1.45(s,1H),1.40-1.05(m,16H) .
实施例90：(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-异丙基哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(154)Example 90: (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-isopropyl ylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)nicotinamide (154)
Figure PCTCN2021126588-appb-000118
Figure PCTCN2021126588-appb-000118
参考实施例89的合成方法，把氧杂环丁烷-3-酮替换为丙-2-酮，可合成得到目标化合物154，LC-MS(ESI-MS)：m/z＝922[M+H] +。 Referring to the synthetic method of Example 89, substituting oxetan-3-one with propan-2-one, the target compound 154 can be synthesized to obtain the target compound 154, LC-MS (ESI-MS): m/z=922 [M+ H] + .
1H NMR(400MHz,DMSO-d 6)δ11.66(d,J＝2.4Hz,1H),8.51–8.41(m,2H),8.34(s,1H),7.93(d,J＝2.6Hz,1H),7.76(dd,J＝9.1,2.2Hz,1H),7.54(d,J＝2.6Hz,1H),7.52–7.45(m,2H),7.15(dt,J＝25.5,7.4Hz,5H),6.36(dd,J＝3.4,1.9Hz,1H),3.71(dd,J＝19.8,6.5Hz,2H),2.81(s,3H),2.21–2.10(m,1H),2.07–1.91(m,4H),1.83(d,J＝ 34.7Hz,7H),1.44(s,2H),1.30(dt,J＝6.4,3.2Hz,3H),1.27–1.23(m,3H),1.16–1.06(m,17H),0.84–0.75(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.66 (d, J=2.4Hz, 1H), 8.51-8.41 (m, 2H), 8.34 (s, 1H), 7.93 (d, J=2.6Hz, 1H), 7.76 (dd, J=9.1, 2.2Hz, 1H), 7.54 (d, J=2.6Hz, 1H), 7.52–7.45 (m, 2H), 7.15 (dt, J=25.5, 7.4Hz, 5H) ),6.36(dd,J=3.4,1.9Hz,1H),3.71(dd,J=19.8,6.5Hz,2H),2.81(s,3H),2.21–2.10(m,1H),2.07–1.91( m, 4H), 1.83 (d, J=34.7Hz, 7H), 1.44 (s, 2H), 1.30 (dt, J=6.4, 3.2Hz, 3H), 1.27–1.23 (m, 3H), 1.16–1.06 (m,17H),0.84–0.75(m,2H).
实施例91：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(2,2,2-三氟乙基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(156)Example 91: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2,2,2 -Trifluoroethyl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (156)
Figure PCTCN2021126588-appb-000119
Figure PCTCN2021126588-appb-000119
参考实施例57的合成方法，把氧杂环丁烷-3-酮替换为2,2,2-三氟乙醛，可合成得到目标化合物156，LC-MS(ESI-MS)：m/z＝962[M+H] +。 Referring to the synthesis method of Example 57, substituting oxetan-3-one with 2,2,2-trifluoroacetaldehyde, the target compound 156 can be synthesized, LC-MS (ESI-MS): m/z =962[M+H] + .
实施例92：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟-1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-5-甲基苯甲酰胺(157)Example 92: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-5-methylbenzamide (157)
Figure PCTCN2021126588-appb-000120
Figure PCTCN2021126588-appb-000120
参考实施例64的合成方法，把2,4,5-三氟苯甲酸甲酯替换为2,4-二氟-5-甲基苯甲酸甲酯，可合成得到目标化合物157，LC-MS(ESI-MS)：m/z＝949[M+H] +。 With reference to the synthetic method of Example 64, methyl 2,4,5-trifluorobenzoate was replaced with methyl 2,4-difluoro-5-methylbenzoate, and the target compound 157 could be synthesized by LC-MS ( ESI-MS): m/z=949 [M+H] + .
实施例93：6-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-2,3-二氟-N-((4-(((4-氟-1-(氧杂环丁烷-3-基))哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(158)Example 93: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-2,3-difluoro-N-((4-(((4-fluoro-1 -(oxetan-3-yl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (158)
Figure PCTCN2021126588-appb-000121
Figure PCTCN2021126588-appb-000121
参考实施例64的合成方法，把2,4,5-三氟苯甲酸甲酯替换为2,3,4,6-四氟苯甲酸甲酯，可合成得到目标化合物158，LC-MS(ESI-MS)：m/z＝971[M+H] +。 Referring to the synthesis method of Example 64, the target compound 158 can be synthesized by replacing methyl 2,4,5-trifluorobenzoate with methyl 2,3,4,6-tetrafluorobenzoate. LC-MS (ESI -MS): m/z=971 [M+H] + .
实施例94：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-((2-(1-(氧杂环丁烷-3-基)哌啶-4-基)乙基)氨基)苯基)磺酰基)苯甲酰胺(159)Example 94: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(1-(oxetane-3 -yl)piperidin-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide (159)
Figure PCTCN2021126588-appb-000122
Figure PCTCN2021126588-appb-000122
参考实施例64的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为4-(2-氨基乙基)哌啶-1-羧酸叔丁酯，可合成得到目标化合物158，LC-MS(ESI-MS)：m/z＝949[M+H] +。 Referring to the synthetic method of Example 64, substituting tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate with tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate ester, the target compound 158 can be synthesized, LC-MS (ESI-MS): m/z=949 [M+H] + .
实施例95：N-(4-(N-(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰基)氨磺酰基)-2-硝基苯基)哌啶-4-甲酰胺(160)Example 95: N-(4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2- (2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl)piperidine -4-Carboxamide (160)
Figure PCTCN2021126588-appb-000123
Figure PCTCN2021126588-appb-000123
参考实施例63的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为4-氨基甲酰基哌啶-1-羧酸叔丁酯，可合成得到目标化合物160，LC-MS(ESI-MS)：m/z＝893[M+H] +。 Referring to the synthetic method of Example 63, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester was replaced with 4-carbamoylpiperidine-1-carboxylate tert-butyl ester, which can be synthesized The title compound 160 was obtained, LC-MS (ESI-MS): m/z=893 [M+H] + .
实施例96：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(哌啶-4-甲酰胺基)苯基)磺酰基)烟酰胺(161)Example 96: 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(piperidin-4-carboxamido)phenyl)sulfonyl)nicotinamide ( 161)
Figure PCTCN2021126588-appb-000124
Figure PCTCN2021126588-appb-000124
参考实施例56的合成方法，把4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为4-氨基甲酰基哌啶-1-羧酸叔丁酯，可合成得到目标化合物161，LC-MS(ESI-MS)：m/z＝876[M+H] +。 Referring to the synthesis method of Example 56, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester was replaced with 4-carbamoylpiperidine-1-carboxylate tert-butyl ester, which can be synthesized The title compound 161 was obtained, LC-MS (ESI-MS): m/z=876 [M+H] + .
实施例97：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((1r，4r)-4-羟基-4-甲基环己基)甲氧基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(162)Example 97: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((1r,4r)-4-hydroxy -4-Methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1- yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (162)
Figure PCTCN2021126588-appb-000125
Figure PCTCN2021126588-appb-000125
参考实施例33制备中间体99-1的合成方法，把(4-氟-4-(羟甲基)哌啶-1-羧酸叔丁酯替换为(1r，4r)-4-(羟甲基)-1-甲基环己烷-1-醇，可得到产物(1r，4r)-4-((4-羟基-4-甲基环己基)甲氧基)-3-硝基苯磺酰胺。Referring to the synthetic method for the preparation of intermediate 99-1 in Example 33, (4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate tert-butyl ester was replaced by (1r,4r)-4-(hydroxymethyl) (1r,4r)-4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrobenzenesulfonic acid amide.
参考实施例7的合成方法，把3,5-二氟吡啶甲酸甲酯替换为2,4,5-三氟苯甲酸甲酯，中间体24-7替换为4-((4-羟基-4-甲基环己基)甲氧基)-3-硝基苯磺酰胺，可合成得到目标化合物162，LC-MS(ESI-MS)：m/z＝909[M+H] +。 Referring to the synthetic method of Example 7, methyl 3,5-difluoropicolinate was replaced by methyl 2,4,5-trifluorobenzoate, and intermediate 24-7 was replaced by 4-((4-hydroxy-4 -Methylcyclohexyl)methoxy)-3-nitrobenzenesulfonamide can be synthesized to obtain the target compound 162, LC-MS (ESI-MS): m/z=909 [M+H] + .
实施例98：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((4-羟基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(163)Example 98: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-hydroxycyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)benzamide (163)
Figure PCTCN2021126588-appb-000126
Figure PCTCN2021126588-appb-000126
参考实施例55的合成方法，把(四氢-2H-吡喃-4-基)甲胺盐酸盐替换为4-(氨基甲基)环己-1-醇，可合成得到目标化合物163，LC-MS(ESI-MS)：m/z＝894[M+H] +。 Referring to the synthetic method of Example 55, (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride was replaced with 4-(aminomethyl)cyclohexan-1-ol, the target compound 163 could be synthesized, LC-MS (ESI-MS): m/z=894 [M+H] + .
实施例99：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-羟基环己基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(164)Example 99: 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (164)
Figure PCTCN2021126588-appb-000127
Figure PCTCN2021126588-appb-000127
参考实施例24的合成方法，把中间体24-3替换为中间体35-3，中间体24-6替换为4-(氨基甲基)环己-1-醇，可合成得到目标化合物164，LC-MS(ESI-MS)：m/z＝877[M+H] +。 With reference to the synthetic method of Example 24, intermediate 24-3 is replaced by intermediate 35-3, and intermediate 24-6 is replaced by 4-(aminomethyl)cyclohexan-1-ol, the target compound 164 can be synthesized, LC-MS (ESI-MS): m/z=877 [M+H] + .
实施例100：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((((1s，3s)-3-羟基-3-甲基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(165)Example 100: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1s,3s)-3- Hydroxy-3-methylcyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (165)
Figure PCTCN2021126588-appb-000128
Figure PCTCN2021126588-appb-000128
参考实施例16的合成方法，把((4-氧代环己基)甲基)氨基甲酸叔丁酯替换为((1s,3s)-(3-氧代环丁基)甲基)氨基甲酸叔丁酯，可合成得到目标化合物165，LC-MS (ESI-MS)：m/z＝880[M+H] +。 Referring to the synthesis method of Example 16, replace ((4-oxocyclohexyl)methyl)carbamic acid tert-butyl ester with ((1s,3s)-(3-oxocyclobutyl)methyl)carbamic acid tertiary Butyl ester can be synthesized to obtain the target compound 165, LC-MS (ESI-MS): m/z=880 [M+H] + .
实施例101：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1s，3s)-3-羟基-3-甲基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(166)Example 101 : 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,3s)-3-hydroxy-3- Methylcyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (166)
Figure PCTCN2021126588-appb-000129
Figure PCTCN2021126588-appb-000129
参考实施例7的合成方法，把中间体24-3替换为中间体35-3，((4-氧代环己基)甲基)氨基甲酸叔丁酯替换为((3-氧代环丁基)甲基)氨基甲酸叔丁酯，可合成得到目标化合物166，LC-MS(ESI-MS)：m/z＝863[M+H] +。 Referring to the synthetic method of Example 7, intermediate 24-3 was replaced by intermediate 35-3, ((4-oxocyclohexyl)methyl) tert-butyl carbamate was replaced by ((3-oxocyclobutyl) ) methyl) tert-butyl carbamate can be synthesized to obtain the target compound 166, LC-MS (ESI-MS): m/z=863 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.70(d,J＝2.3Hz,1H),8.48(d,J＝2.2Hz,1H),8.32(d,J＝28.4Hz,2H),7.99(d,J＝2.7Hz,1H),7.78(dd,J＝9.2,2.3Hz,1H),7.61(d,J＝2.6Hz,1H),7.54–7.46(m,2H),7.17(dt,J＝27.1,7.5Hz,3H),6.99(d,J＝9.3Hz,1H),6.42–6.36(m,1H),4.88(s,1H),2.46(p,J＝1.8Hz,6H),2.22(s,1H),2.14–2.05(m,1H),2.03–1.95(m,2H),1.87(s,4H),1.73(td,J＝8.8,2.5Hz,4H),1.45(s,1H),1.33–1.23(m,5H),1.16(q,J＝6.3Hz,9H),1.08(d,J＝6.7Hz,4H),1.00(d,J＝6.1Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.70 (d, J=2.3 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H), 8.32 (d, J=28.4 Hz, 2H), 7.99 (d, J=2.7Hz, 1H), 7.78 (dd, J=9.2, 2.3Hz, 1H), 7.61 (d, J=2.6Hz, 1H), 7.54–7.46 (m, 2H), 7.17 (dt, J=27.1, 7.5Hz, 3H), 6.99 (d, J=9.3Hz, 1H), 6.42–6.36 (m, 1H), 4.88 (s, 1H), 2.46 (p, J=1.8Hz, 6H), 2.22(s, 1H), 2.14-2.05(m, 1H), 2.03-1.95(m, 2H), 1.87(s, 4H), 1.73(td, J=8.8, 2.5Hz, 4H), 1.45(s, 1H), 1.33–1.23 (m, 5H), 1.16 (q, J=6.3Hz, 9H), 1.08 (d, J=6.7Hz, 4H), 1.00 (d, J=6.1Hz, 1H).
实施例102：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-((((1r，3r)-3-羟基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(167)Example 102: 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,3r)-3- Hydroxycyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)benzamide (167)
Figure PCTCN2021126588-appb-000130
Figure PCTCN2021126588-appb-000130
参考实施例16的合成方法，把中间体24-6替换为3-(氨基甲基)环丁烷-1-醇，可合成得到目标化合物167，LC-MS(ESI-MS)：m/z＝866[M+H] +。 Referring to the synthesis method of Example 16, the intermediate 24-6 was replaced with 3-(aminomethyl)cyclobutan-1-ol, the target compound 167 could be synthesized, LC-MS (ESI-MS): m/z =866[M+H] + .
实施例103：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r，3r)-3-羟基环丁基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(2-((S)-2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)烟酰胺(168)Example 103: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(((4-((((1r,3r)-3-hydroxycyclobutyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonan-7-yl)nicotinamide (168)
Figure PCTCN2021126588-appb-000131
Figure PCTCN2021126588-appb-000131
参考实施例7的合成方法，把中间体24-3替换为中间体35-3，中间体24-6替换为3-(氨基甲基)环丁烷-1-醇，可合成得到目标化合物168，LC-MS(ESI-MS)：m/z＝ 849[M+H] +。 With reference to the synthetic method of Example 7, intermediate 24-3 is replaced with intermediate 35-3, and intermediate 24-6 is replaced with 3-(aminomethyl)cyclobutan-1-ol, the target compound 168 can be synthesized , LC-MS (ESI-MS): m/z = 849 [M+H] + .
实施例104：(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((氮杂环丁烷-3-基甲基)氨基)-3-硝基苯基)磺酰基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(169)Example 104: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((azetidin-3-yl Methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)benzamide (169)
Figure PCTCN2021126588-appb-000132
Figure PCTCN2021126588-appb-000132
参考实施例63的合成方法，把2-(2-异丙基苯基)吡咯烷替换为(S)-2-(2-异丙基苯基)吡咯烷，4-(氨甲基)-4-氟哌啶-1-羧酸叔丁酯替换为3-(氨基甲基)氮杂环丁烷-1-羧酸叔丁酯，可合成得到目标化合物169，LC-MS(ESI-MS)：m/z＝851[M+H] +。 Referring to the synthetic method of Example 63, replacing 2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-isopropylphenyl)pyrrolidine, 4-(aminomethyl)- 4-Fluoropiperidine-1-carboxylate tert-butyl ester was replaced with 3-(aminomethyl)azetidine-1-carboxylate tert-butyl ester, and the target compound 169 could be synthesized by LC-MS (ESI-MS ): m/z=851 [M+H] + .
实施例105：(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((1-(氧杂环丁烷-3-基)氮杂环丁烷-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺(170)Example 105: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((1-(oxetane) -3-yl)azetidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (170)
Figure PCTCN2021126588-appb-000133
Figure PCTCN2021126588-appb-000133
参考实施例31的合成方法，把化合物089替换为化合物169，可合成得到目标化合物170，LC-MS(ESI-MS)：m/z＝907[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced with compound 169, and the target compound 170 could be synthesized. LC-MS (ESI-MS): m/z=907 [M+H] + .
实施例106：(S)-4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((1-(氧杂环丁烷-3-基)氮杂环丁烷-3-基)甲基)氨基)苯基)磺酰基)烟酰胺(171)Example 106: (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((1-(oxetan-3-yl) )azetidin-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (171)
Figure PCTCN2021126588-appb-000134
Figure PCTCN2021126588-appb-000134
参考实施例105的合成方法，把2,4,5-三氟苯甲酸甲酯替换为4,6-二氯烟酸甲酯，可合成得到目标化合物171，LC-MS(ESI-MS)：m/z＝890[M+H] +。 Referring to the synthetic method of Example 105, methyl 2,4,5-trifluorobenzoate was replaced with methyl 4,6-dichloronicotinate to obtain the target compound 171, LC-MS (ESI-MS): m/z=890 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ11.70(d,J＝2.4Hz,1H),8.71(d,J＝5.5Hz,1H),8.48(d,J＝2.3Hz,1H),8.30(s,1H),7.97(d,J＝2.6Hz,1H),7.84–7.67(m,1H),7.59(d,J＝2.7Hz,1H),7.55–7.45(m,2H),7.17(dt,J＝19.6,7.9Hz,3H),7.01(d,J＝9.2Hz,1H),6.38(dd,J＝3.4,1.9Hz,1H),4.52(t,J＝6.7Hz,2H),4.39–4.27(m,2H),3.78(t,J＝6.0Hz,1H),3.56(t,J＝6.0Hz,2H),3.15(t,J＝6.5Hz,3H),2.82–2.71(m,1H),2.20(s,1H),2.01–1.58(m,6H),1.43(d,J＝11.5Hz,1H),1.37–0.95(m,20H),0.81(t,J＝6.6 Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.70 (d, J=2.4Hz, 1H), 8.71 (d, J=5.5Hz, 1H), 8.48 (d, J=2.3Hz, 1H), 8.30 (s, 1H), 7.97 (d, J=2.6Hz, 1H), 7.84–7.67 (m, 1H), 7.59 (d, J=2.7Hz, 1H), 7.55–7.45 (m, 2H), 7.17 ( dt,J＝19.6,7.9Hz,3H),7.01(d,J＝9.2Hz,1H),6.38(dd,J＝3.4,1.9Hz,1H),4.52(t,J＝6.7Hz,2H), 4.39–4.27 (m, 2H), 3.78 (t, J=6.0Hz, 1H), 3.56 (t, J=6.0Hz, 2H), 3.15 (t, J=6.5Hz, 3H), 2.82–2.71 (m ,1H),2.20(s,1H),2.01-1.58(m,6H),1.43(d,J=11.5Hz,1H),1.37-0.95(m,20H),0.81(t,J=6.6Hz, 1H).
实施例107：(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-(((3-甲基氮杂环丁烷-3-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(172)Example 107: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((3-methylazetidin-3-yl )methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (172)
Figure PCTCN2021126588-appb-000135
Figure PCTCN2021126588-appb-000135
参考实施例104的合成方法，把3-(氨基甲基)氮杂环丁烷-1-羧酸叔丁酯替换为3-(氨基甲基)-3-甲基氮杂环丁烷-1-羧酸叔丁酯，可合成得到目标化合物172，LC-MS(ESI-MS)：m/z＝865[M+H] +。 Referring to the synthesis method of Example 104, tert-butyl 3-(aminomethyl)azetidine-1-carboxylate was replaced with 3-(aminomethyl)-3-methylazetidine-1 - tert-butyl carboxylate, the target compound 172 can be synthesized, LC-MS (ESI-MS): m/z=865 [M+H] + .
实施例108：(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-5-氟-N-((4-(((1-异丙基-3-甲基氮杂环丁烷-3-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(2-(2-(2-异丙基苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)苯甲酰胺(173)Example 108: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((((1-isopropyl) yl-3-methylazetidin-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (173)
Figure PCTCN2021126588-appb-000136
Figure PCTCN2021126588-appb-000136
参考实施例31的合成方法，把化合物089替换为化合物172，可合成得到目标化合物173，LC-MS(ESI-MS)：m/z＝907[M+H] +。 Referring to the synthesis method of Example 31, compound 089 was replaced with compound 172, and the target compound 173 could be synthesized. LC-MS (ESI-MS): m/z=907 [M+H] + .
实施例109：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2,3-二氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(174)Example 109: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2,3-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-(((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (174)
Figure PCTCN2021126588-appb-000137
Figure PCTCN2021126588-appb-000137
参考实施例16的合成方法，把(S)-2-(2-异丙基苯基)吡咯烷替换为(S)-2-(2,3-二氟苯基)吡咯烷，可合成得到目标化合物174，LC-MS(ESI-MS)：m/z＝902[M+H] +。 Referring to the synthetic method of Example 16, replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2,3-difluorophenyl)pyrrolidine, it can be synthesized to obtain Target compound 174, LC-MS (ESI-MS): m/z=902 [M+H] + .
实施例110：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2,3-二氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)烟酰胺(175)Example 110: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2,3-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (175)
Figure PCTCN2021126588-appb-000138
Figure PCTCN2021126588-appb-000138
参考实施例7的合成方法，把中间体24-3替换为中间体35-3，(S)-2-(2-异丙基苯基)吡咯烷替换为(S)-2-(2,3-二氟苯基)吡咯烷，可合成得到目标化合物175，LC-MS(ESI-MS)：m/z＝885[M+H] +。 Referring to the synthetic method of Example 7, intermediate 24-3 was replaced by intermediate 35-3, (S)-2-(2-isopropylphenyl)pyrrolidine was replaced by (S)-2-(2, 3-difluorophenyl)pyrrolidine can be synthesized to obtain the target compound 175, LC-MS (ESI-MS): m/z=885 [M+H] + .
实施例111：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2,6-二氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-5-氟-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(176)Example 111 : 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2,6-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-(((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (176)
Figure PCTCN2021126588-appb-000139
Figure PCTCN2021126588-appb-000139
参考实施例109的合成方法，把(S)-2-(2,3-二氟苯基)吡咯烷替换为(S)-2-(2,6-二氟苯基)吡咯烷，可合成得到目标化合物176，LC-MS(ESI-MS)：m/z＝902[M+H] +。 Referring to the synthesis method of Example 109, replacing (S)-2-(2,3-difluorophenyl)pyrrolidine with (S)-2-(2,6-difluorophenyl)pyrrolidine, it can be synthesized The title compound 176 was obtained, LC-MS (ESI-MS): m/z=902 [M+H] + .
实施例112：4-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-6-(2-((S)-2-(2,6-二氟苯基)吡咯烷-1-基)-7-氮杂螺[3.5]壬烷-7-基)-N-((4-((((1r，4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)烟酰胺(177)Example 112: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2,6-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (177)
Figure PCTCN2021126588-appb-000140
Figure PCTCN2021126588-appb-000140
参考实施例110的合成方法，把(S)-2-(2,3-二氟苯基)吡咯烷替换为(S)-2-(2,6-二氟苯基)吡咯烷，可合成得到目标化合物177，LC-MS(ESI-MS)：m/z＝885[M+H] +。 Referring to the synthesis method of Example 110, replacing (S)-2-(2,3-difluorophenyl)pyrrolidine with (S)-2-(2,6-difluorophenyl)pyrrolidine, it can be synthesized The title compound 177 was obtained, LC-MS (ESI-MS): m/z=885 [M+H] + .
参考实施例1的合成方法，可以用相似的合成路线和方法合成得到如下化合物：With reference to the synthetic method of Example 1, the following compounds can be synthesized by a similar synthetic route and method:
Figure PCTCN2021126588-appb-000141
Figure PCTCN2021126588-appb-000141
Figure PCTCN2021126588-appb-000142
Figure PCTCN2021126588-appb-000142
Figure PCTCN2021126588-appb-000143
Figure PCTCN2021126588-appb-000143
Figure PCTCN2021126588-appb-000144
Figure PCTCN2021126588-appb-000144
Figure PCTCN2021126588-appb-000145
Figure PCTCN2021126588-appb-000145
Figure PCTCN2021126588-appb-000146
Figure PCTCN2021126588-appb-000146
Figure PCTCN2021126588-appb-000147
Figure PCTCN2021126588-appb-000147
Figure PCTCN2021126588-appb-000148
Figure PCTCN2021126588-appb-000148
Figure PCTCN2021126588-appb-000149
Figure PCTCN2021126588-appb-000149
Figure PCTCN2021126588-appb-000150
Figure PCTCN2021126588-appb-000150
Figure PCTCN2021126588-appb-000151
Figure PCTCN2021126588-appb-000151
Figure PCTCN2021126588-appb-000152
Figure PCTCN2021126588-appb-000152
Figure PCTCN2021126588-appb-000153
Figure PCTCN2021126588-appb-000153
Figure PCTCN2021126588-appb-000154
Figure PCTCN2021126588-appb-000154
Figure PCTCN2021126588-appb-000155
Figure PCTCN2021126588-appb-000155
参考实施例88的合成方法，可以用相似的合成路线和方法合成得到如下化合物：With reference to the synthetic method of Example 88, the following compounds can be synthesized by a similar synthetic route and method:
Figure PCTCN2021126588-appb-000156
Figure PCTCN2021126588-appb-000156
参考实施例91的合成方法，可以用相似的合成路线和方法合成得到如下化合物：With reference to the synthetic method of Example 91, the following compounds can be synthesized by a similar synthetic route and method:
Figure PCTCN2021126588-appb-000157
Figure PCTCN2021126588-appb-000157
Figure PCTCN2021126588-appb-000158
Figure PCTCN2021126588-appb-000158
Figure PCTCN2021126588-appb-000159
Figure PCTCN2021126588-appb-000159
Figure PCTCN2021126588-appb-000160
Figure PCTCN2021126588-appb-000160
Figure PCTCN2021126588-appb-000161
Figure PCTCN2021126588-appb-000161
Figure PCTCN2021126588-appb-000162
Figure PCTCN2021126588-appb-000162
Figure PCTCN2021126588-appb-000163
Figure PCTCN2021126588-appb-000163
Figure PCTCN2021126588-appb-000164
Figure PCTCN2021126588-appb-000164
参考实施例31的合成方法，可以用相似的合成路线和方法合成得到如下化合物：With reference to the synthetic method of Example 31, the following compounds can be synthesized by a similar synthetic route and method:
Figure PCTCN2021126588-appb-000165
Figure PCTCN2021126588-appb-000165
Figure PCTCN2021126588-appb-000166
Figure PCTCN2021126588-appb-000166
实施例217：BCL2/BAK蛋白相互作用阻断活性测试Example 217: BCL2/BAK protein interaction blocking activity test
用试剂盒(型号：BCL2/BAK(BH3)BINDING ASSAY KIT，Cisbio)中的稀释缓冲液将500nM的Tag1-BCL2蛋白母液稀释成5nM，同时将20μM的Tag2-BAK蛋白母液稀释成120nM，先每孔加入5μL的Tag1-BCL2蛋白稀释液，然后加入不同浓度的化合物(10000nM，4倍稀释，8个点，分别为：10000、2500、625、156.25、39.06、 9.76、2.44、0.61nM)，DMSO作为空白对照，最后每个孔加入5μL的Tag2-BAK蛋白稀释液，离心混匀，室温孵育15分钟。然后加入试剂盒中的anti-Tag1-Eu3+和anti-Tag2-XL665，室温反应2小时。BIO-Tek NEO2多功能酶标仪进行读板(激发620nM，发射665nM),用GraphPad Prism 5.0计算IC 50。结果见表1。 The 500nM Tag1-BCL2 protein stock solution was diluted to 5nM with the dilution buffer in the kit (model: BCL2/BAK(BH3) BINDING ASSAY KIT, Cisbio), and the 20μM Tag2-BAK protein stock solution was diluted to 120nM. Add 5 μL of Tag1-BCL2 protein dilution to the well, and then add compounds of different concentrations (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM), DMSO As a blank control, 5 μL of Tag2-BAK protein dilution solution was added to each well, centrifuged to mix well, and incubated at room temperature for 15 minutes. Then add anti-Tag1-Eu3+ and anti-Tag2-XL665 in the kit, and react at room temperature for 2 hours. The plate was read with a BIO-Tek NEO2 multifunctional microplate reader (excitation 620 nM, emission 665 nM), and IC 50 was calculated with GraphPad Prism 5.0. The results are shown in Table 1.
表1蛋白阻断抑制活性结果Table 1 Results of protein blocking inhibitory activity
Figure PCTCN2021126588-appb-000167
Figure PCTCN2021126588-appb-000167
Figure PCTCN2021126588-appb-000168
Figure PCTCN2021126588-appb-000168
Figure PCTCN2021126588-appb-000169
Figure PCTCN2021126588-appb-000169
+:IC 50<10nM；++:10nM<IC 50<100nM；+++:100nM<IC 50<1000nM；++++:1000nM<IC 50 +: IC50 <10nM;++:10nM< IC50 <100nM;+++:100nM< IC50 <1000nM;++++:1000nM< IC50
表1结果表明，本发明化合物具有强效的BCL2/BAK阻断活性。The results in Table 1 show that the compounds of the present invention have potent BCL2/BAK blocking activity.
Figure PCTCN2021126588-appb-000170
Figure PCTCN2021126588-appb-000170
实施例218 BCL-XL酶分子水平活性试验Example 218 BCL-XL enzyme molecular level activity test
在384白色浅孔板中，反应总体积是10μL。具体包括2μL待测化合物(2％DMSO)、4μL His-tagged重组蛋白和4μL Biotin-tagged BIM蛋白多肽，反应1小时后，分别加入用检测缓冲液稀释的Anti-His和streptavidin-tagged XL665抗体稀释液各5μL，室温孵育4小时后利用Envision多功能微孔板酶标仪进行读值，从而检测待测化合物对BCL-XL与Bim蛋白多肽的结合能力的影响。Envision参数设置是激发光320nm，发射光615nm和665nm。通过665nm和615nm的信号比值间接反映抗凋亡蛋白与Bim蛋白多肽的结合能力。反应中设置不加BCL2的背景孔和不含化合物的重组蛋白与Bim蛋白多肽全结合活性孔。In a 384 white shallow well plate, the total volume of the reaction was 10 μL. Specifically, 2 μL of the test compound (2% DMSO), 4 μL of His-tagged recombinant protein and 4 μL of Biotin-tagged BIM protein polypeptide were added. After 1 hour of reaction, anti-His and streptavidin-tagged XL665 antibodies diluted with detection buffer were added respectively. After 4 hours of incubation at room temperature, the Envision multi-function microplate microplate reader was used to read the value, so as to detect the effect of the test compound on the binding ability of BCL-XL and Bim protein polypeptide. Envision parameter settings are excitation light 320nm, emission light 615nm and 665nm. The binding ability of anti-apoptotic protein to Bim protein polypeptide is indirectly reflected by the ratio of 665nm and 615nm signals. In the reaction, background wells without BCL2 and full binding activity wells of recombinant protein without compound and Bim protein polypeptide were set.
化合物抑制抗凋亡蛋白与Bim蛋白多肽的结合能力的IC 50值利用Graphpad Prism 7.00软件，通过公式：Y＝100/(1+10^((LogIC50-X)*HillSlope))计算获得。 The IC 50 value of the compound inhibiting the binding ability of anti-apoptotic protein to Bim protein polypeptide was calculated by using Graphpad Prism 7.00 software by formula: Y=100/(1+10^((LogIC50-X)*HillSlope)).
表2 BCL-XL酶分子水平活性试验Table 2 BCL-XL enzyme molecular level activity test
Figure PCTCN2021126588-appb-000171
Figure PCTCN2021126588-appb-000171
Figure PCTCN2021126588-appb-000172
Figure PCTCN2021126588-appb-000172
表2结果表明，本发明化合物对BCL-XL的抑制活性弱。The results in Table 2 show that the compounds of the present invention have weak inhibitory activity on BCL-XL.
实施例219抗凋亡蛋白BCL2(G101V)的分子水平活性测试Example 219 Molecular-level activity test of anti-apoptotic protein BCL2 (G101V)
抗凋亡蛋白BCL2(G101V)与凋亡促凋亡蛋白Bim结合能力的检测是通过时间均相分辨荧光技术进行。该方法的反应是在384白色浅孔板中，反应总体积是10μL。具体包括2μL待测化合物(2％DMSO)、4μL His-tagged重组蛋白和4μL Biotin-tagged BIM蛋白多肽，反应1小时后，分别加入用检测缓冲液稀释的Anti-His和streptavidin-tagged XL665抗体稀释液各5μL，室温孵育4小时后利用Envision多功能微孔板酶标仪进行读值，从而检测待测化合物对BCL2(G101V)与Bim蛋白多肽的结合能力的影响。Envision参数设置是激发光320nm，发射光615nm和665nm。通过665nm和615nm的信号比值间接反映抗凋亡蛋白与Bim蛋白多肽的结合能力。反应中设置不加BCL2的背景孔和不含化合物的重组蛋白与Bim蛋白多肽全结合活性孔。The binding ability of anti-apoptotic protein BCL2(G101V) to apoptosis pro-apoptotic protein Bim was detected by time homogeneous phase-resolved fluorescence technique. Reactions for this method were in 384 white shallow well plates and the total reaction volume was 10 μL. Specifically, 2 μL of the test compound (2% DMSO), 4 μL of His-tagged recombinant protein and 4 μL of Biotin-tagged BIM protein polypeptide were added. After 1 hour of reaction, anti-His and streptavidin-tagged XL665 antibodies diluted with detection buffer were added respectively. After incubation at room temperature for 4 hours, use the Envision multi-function microplate microplate reader to read the value, so as to detect the effect of the test compound on the binding ability of BCL2 (G101V) and Bim protein polypeptide. Envision parameter settings are excitation light 320nm, emission light 615nm and 665nm. The binding ability of anti-apoptotic protein to Bim protein polypeptide is indirectly reflected by the ratio of 665nm and 615nm signals. In the reaction, background wells without BCL2 and full binding activity wells of recombinant protein without compound and Bim protein polypeptide were set.
化合物抑制抗凋亡蛋白与Bim蛋白多肽的结合能力的IC 50值利用Graphpad Prism 7.00软件，通过公式：Y＝100/(1+10^((LogIC50-X)*HillSlope))计算获得。 The IC 50 value of the compound inhibiting the binding ability of anti-apoptotic protein to Bim protein polypeptide was calculated by using Graphpad Prism 7.00 software by formula: Y=100/(1+10^((LogIC50-X)*HillSlope)).
表3本发明化合物对BCL2(G101V)的抑制活性Table 3 Inhibitory activity of the compounds of the present invention on BCL2 (G101V)
Figure PCTCN2021126588-appb-000173
Figure PCTCN2021126588-appb-000173
Figure PCTCN2021126588-appb-000174
Figure PCTCN2021126588-appb-000174
表3结果表明，本发明化合物具有强效的BCL2(G101V)抑制活性。The results in Table 3 show that the compounds of the present invention have potent BCL2(G101V) inhibitory activity.
实施例220 BCL2(D103Y)分子水平活性试验Embodiment 220 BCL2 (D103Y) molecular level activity test
抗凋亡蛋白BCL2(D103Y)与凋亡促凋亡蛋白Bim结合能力的检测是通过时间均相分辨荧光技术进行。该方法的反应是在384白色浅孔板中，反应总体积是10μL。具体包括2μL待测化合物(2％DMSO)、4μL His-tagged重组蛋白和4μL Biotin-tagged BIM蛋白多肽，反应1小时后，分别加入用检测缓冲液稀释的Anti-His和streptavidin-tagged XL665抗体稀释液各5μL，室温孵育4小时后利用Envision多功能微孔板酶标仪进行读值，从而检测待测化合物对BCL2(D103Y)与Bim蛋白多肽的结合能力的影响。Envision参数设置是激发光320nm，发射光615nm和665nm。通过665nm和615nm的信号比值间接反映抗凋亡蛋白与Bim蛋白多肽的结合能力。反应中设置不加BCL2的背景孔和不含化合物的重组蛋白与Bim蛋白多肽全结合活性孔。The binding ability of anti-apoptotic protein BCL2(D103Y) to apoptosis pro-apoptotic protein Bim was detected by time homogeneous phase-resolved fluorescence technique. Reactions for this method were in 384 white shallow well plates and the total reaction volume was 10 μL. Specifically, 2 μL of the test compound (2% DMSO), 4 μL of His-tagged recombinant protein and 4 μL of Biotin-tagged BIM protein polypeptide were added. After 1 hour of reaction, anti-His and streptavidin-tagged XL665 antibodies diluted with detection buffer were added respectively. After 4 hours of incubation at room temperature, the Envision multi-function microplate microplate reader was used to read the value, so as to detect the effect of the test compound on the binding ability of BCL2 (D103Y) and Bim protein polypeptide. Envision parameter settings are excitation light 320nm, emission light 615nm and 665nm. The binding ability of anti-apoptotic protein to Bim protein polypeptide is indirectly reflected by the ratio of 665nm and 615nm signals. In the reaction, background wells without BCL2 and full binding activity wells of recombinant protein without compound and Bim protein polypeptide were set.
化合物抑制抗凋亡蛋白与Bim蛋白多肽的结合能力的IC 50值利用Graphpad Prism 7.00软件，通过公式：Y＝100/(1+10^((LogIC50-X)*HillSlope))计算获得。 The IC 50 value of the compound inhibiting the binding ability of anti-apoptotic protein to Bim protein polypeptide was calculated by using Graphpad Prism 7.00 software by formula: Y=100/(1+10^((LogIC50-X)*HillSlope)).
表4化合物对BCL2(D103Y)的抑制活性Table 4 Inhibitory activity of compounds on BCL2(D103Y)
化合物编号Compound number BCL‐2(D103Y)(nM)BCL‐2(D103Y)(nM) 化合物编号Compound number BCL‐2(D103Y)(nM)BCL‐2(D103Y)(nM)
025025 80.6380.63 121121 6.296.29
033033 31.4731.47 125125 1.811.81
049049 55.7855.78 127127 1.071.07
089089 32.3132.31 128128 24.4424.44
090090 30.8130.81 129129 7.527.52
091091 28.3628.36 130130 8.718.71
092092 14.1614.16 135135 9.449.44
093093 43.8743.87 142142 14.5814.58
095095 38.8538.85 151151 3.293.29
096096 52.3652.36 152152 1.971.97
097097 97.4397.43 154154 5.965.96
098098 23.4923.49 166166 23.3123.31
099099 2.062.06 171171 4.44.4
100100 20.3620.36 188188 10.8810.88
101101 2.782.78 189189 11.9911.99
104104 41.7841.78 190190 12.9812.98
109109 11.8611.86 194194 34.9534.95
110110 26.3826.38 195195 27.9027.90
111111 34.734.7 196196 24.1424.14
112112 46.5546.55 200200 14.3214.32
114114 11.2411.24 212212 12.4212.42
115115 87.3887.38 213213 44.6144.61
118118 1.571.57 化合物acompound a 122.61122.61
119119 36.6336.63 ABT‐199ABT‐199 409.8409.8
120120 2.842.84      
表4结果表明，本发明化合物具有强效的BCL2(D103Y)抑制活性。The results in Table 4 show that the compounds of the present invention have potent BCL2(D103Y) inhibitory activity.
实施例221肿瘤增殖抑制活性测试Example 221 Tumor proliferation inhibitory activity test
通过测定化合物对RS4；11细胞增殖的抑制作用。RS4；11细胞分别培养于含10％胎牛血清的RPMI-1640培养基中。消化细胞，将细胞按RS4；11 30000/孔的细胞浓度接种于96孔板37℃ 5％CO 2孵育过夜。96孔板中加入不同浓度(10000nM，4倍稀释，8个点，分别为：10000、2500、625、156.25、39.06、9.76、2.44、0.61nM)的化合物于37℃ 5％CO 2孵育，RS4；11孵育72小时。每孔加入20μL MTS。孵育2h后，每孔加入25μL 10％SDS终止反应。用酶标仪测量490nm和650nm处的吸收。用GraphPad Prism 5.0计算IC 50。结果见表5。 By measuring the inhibitory effect of compounds on the proliferation of RS4;11 cells. RS4;11 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. The cells were digested, and the cells were seeded in a 96-well plate at a cell concentration of RS4; 11 30000/well and incubated overnight at 37°C with 5% CO 2 . Compounds at different concentrations (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) were added to the 96-well plate and incubated at 37°C with 5% CO2 , RS4 ; 11 Incubation for 72 hours. Add 20 μL of MTS to each well. After 2 h of incubation, 25 μL of 10% SDS was added to each well to stop the reaction. Absorbance at 490 nm and 650 nm was measured with a microplate reader. IC50 was calculated with GraphPad Prism 5.0. The results are shown in Table 5.
表5化合物对RS4；11细胞的增殖抑制作用Table 5 Compounds inhibit the proliferation of RS4; 11 cells
化合物编号Compound number RS4；11(bcl-2)(nM)RS4;11(bcl-2)(nM) 化合物编号Compound number RS4；11(bcl-2)(nM)RS4;11(bcl-2)(nM)
033033 1.051.05 151151 0.840.84
035035 3.033.03 152152 1.251.25
119119 9.549.54 154154 0.940.94
120120 2.202.20 166166 1.881.88
121121 6.296.29 188188 2.812.81
125125 2.012.01 189189 2.182.18
128128 3.633.63 190190 0.50.5
142142 0.710.71 212212 1.051.05
144144 0.630.63 213213 2.992.99
145145 0.710.71 化合物acompound a 15.515.5
146146 2.492.49 ABT-199ABT-199 9.329.32
表5结果表明，本发明化合物对RS4；11细胞具有强效增殖抑制活性。The results in Table 5 show that the compounds of the present invention have potent proliferation inhibitory activity on RS4;11 cells.
实施例222肿瘤增殖抑制活性测试Example 222 Tumor proliferation inhibitory activity test
通过测定化合物对Molt-4细胞增殖的抑制作用。Molt-4细胞分别培养于含10％胎牛血清的RPMI-1640培养基中。消化细胞，将Molt-4细胞按30000/孔的细胞浓度接种于96孔板37℃ 5％CO 2孵育过夜。96孔板中加入不同浓度(10000nM，4倍稀释，8个点，分别为：10000、2500、625、156.25、39.06、9.76、2.44、0.61nM)的化合物于37℃ 5％CO 2孵育，Molt-4孵育72小时。每孔加入20μL MTS。孵育2h后，每孔加入25μL 10％SDS终止反应。用酶标仪测量490nm和650nm处的吸收。用GraphPad Prism 5.0计算IC 50。结果见表6。 The inhibitory effect of compounds on Molt-4 cell proliferation was determined. Molt-4 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. The cells were digested, and Molt-4 cells were seeded at a cell concentration of 30,000/well in a 96-well plate and incubated overnight at 37°C with 5% CO 2 . Compounds at different concentrations (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) were added to the 96-well plate and incubated at 37°C with 5% CO2 , Molt -4 Incubation for 72 hours. Add 20 μL of MTS to each well. After 2 h of incubation, 25 μL of 10% SDS was added to each well to stop the reaction. Absorbance at 490 nm and 650 nm was measured with a microplate reader. IC50 was calculated with GraphPad Prism 5.0. The results are shown in Table 6.
表6化合物对Molt-4细胞的增殖抑制作用Table 6 Inhibitory effect of compounds on the proliferation of Molt-4 cells
Figure PCTCN2021126588-appb-000175
Figure PCTCN2021126588-appb-000175
Figure PCTCN2021126588-appb-000176
Figure PCTCN2021126588-appb-000176
表6结果表明，本发明化合物对Molt-4细胞无明显增殖抑制活性。The results in Table 6 show that the compounds of the present invention have no significant proliferation inhibitory activity on Molt-4 cells.
实施例220小鼠吸收试验Example 220 Mice absorption test
雌性小鼠3只，试验前动物至少饲养3天以适应环境。给药前动物禁食过夜，自由饮水。There were 3 female mice, and the animals were reared for at least 3 days before the experiment to adapt to the environment. Animals were fasted overnight before administration and had free access to water.
实验步骤：Experimental steps:
1.化合物用5％DMSO+10％Solutol+85％生理盐水分别配置成1mg/mL的溶液。1. Compounds were formulated into 1 mg/mL solutions with 5% DMSO+10% Solutol+85% physiological saline, respectively.
2.将上述配好的溶液以口服灌胃的方式(10mg/kg)给到3只小鼠。2. The above prepared solution was administered to 3 mice by oral gavage (10 mg/kg).
3.在5、15、30分钟，1、2、4、8、24小时小鼠尾静脉取血100微升，置于EDTA抗凝管中，并置于冰上。3. At 5, 15, 30 minutes, 1, 2, 4, 8, and 24 hours, 100 microliters of blood was drawn from the tail vein of mice, placed in an EDTA anticoagulant tube, and placed on ice.
4.血样取得后30分钟内于4摄氏度8000rpm离心5分钟，提取血浆。4. The blood samples were centrifuged at 8000 rpm for 5 minutes at 4 degrees Celsius within 30 minutes after the blood samples were obtained to extract the plasma.
5.取小鼠血浆20微升，加入60微升ACN溶液，涡旋混合后低温离心(4℃)10分钟(13000rpm)，取50微升上清以及150微升去离子水加入96孔板中，摇床混匀10分钟后取2微升进LC-MS/MS分析。5. Take 20 microliters of mouse plasma, add 60 microliters of ACN solution, vortex and mix, and then centrifuge (4°C) for 10 minutes (13000 rpm) at low temperature. Take 50 microliters of supernatant and 150 microliters of deionized water and add them to a 96-well plate After 10 minutes of mixing on a shaker, 2 μl was taken for LC-MS/MS analysis.

Claims (19)

  1. 一种化合物，其特征在于，具有通式(I)所示的结构：A compound is characterized in that, has the structure shown in general formula (I):
    Figure PCTCN2021126588-appb-100001
    Figure PCTCN2021126588-appb-100001
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
    其中：in:
    m选自0、1、2、3；m is selected from 0, 1, 2, 3;
    Z选自(CH 2) u、NH、O、S、C(O)、S(O 2)、OC(O)、N(H)C(O)、S(O 2)N(H)、N(H)S(O 2)、OC(O)N(H)、N(H)C(O)S，或氢、氘、烷基、螺环基、桥环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基、卤素、硝基、氧代、氰基、OR a、SR a、烷基-R a、NH(CH 2)R a、C(O)R a、S(O)R a、SO 2R a、C(O)OR a、OC(O)R a、NR bR c、C(O)N(R b)R c、N(R b)C(O)R c、-P(O)R bR c，所述的烷基、环烯基、桥环基、杂环基、芳基或者杂芳基可进一步被一个或者多个R d取代； Z is selected from ( CH2 ) u , NH, O, S, C(O), S( O2 ), OC(O), N(H)C(O), S( O2 )N(H), N(H)S(O 2 ), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium, alkyl, spirocyclyl, bridged ring, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR a , SR a , alkyl-R a , NH(CH 2 )R a , C(O)R a , S(O)R a , SO 2 R a , C(O)OR a , OC(O)R a , NR b R c , C(O)N(R b )R c , N(R b )C(O)R c , -P(O)R b R c , the alkyl group, cycloalkenyl group, bridged ring group, heterocyclic group, aryl group or heteroaryl group can be further represented by One or more R d substitutions;
    R a、R b、R c和R d各自独立的选自氢、氘、烷基、螺环基、烯基、炔基、卤素、氰基、氨基、硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环基、杂环基、螺环基、芳基或者杂芳基，所述的烷基、环烯基、环烷基、桥环基、螺环基、杂环基、芳基或者杂芳基可进一步被一个或者多个R e取代； R a , R b , R c and R d are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, Amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, hetero Cyclic, spiro, aryl or heteroaryl, the alkyl, cycloalkenyl, cycloalkyl, bridged, spiro, heterocyclyl, aryl or heteroaryl may be further replaced by a or multiple R e substitutions;
    Re选自氢、氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代烷羟基、卤代烷氨基、环烷基；Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino , haloalkoxy, haloalkamino, cycloalkyl;
    X选自NR 8、CR 8R 8’、O、C(O)、S、S(O)、S(O) 2；其中： X is selected from NR8 , CR8R8 ', O, C(O), S, S(O), S(O) 2 ; wherein:
    X和Z可能成环B或不成环；当形成B环时，与X相连的虚线表示为化学键；当B为开环时，与X相连的虚线表示为不存在；当形成B环时，R 2可取代在Z上，也可取代在Z跟X之间的任一原子上；当B为开环时，R 2取代在X上； X and Z may form a ring B or not form a ring; when the B ring is formed, the dashed line connected to X is represented as a chemical bond; when B is an open ring, the dashed line connected to X is represented as absent; when the B ring is formed, R 2 can be substituted on Z, and can also be substituted on any atom between Z and X; when B is an open ring, R 2 is substituted on X;
    Y 1、Y 2、Y 3各自独立的选自CR 9、N；且： Y 1 , Y 2 , Y 3 are each independently selected from CR 9 , N; and:
    当Y 1、Y 2、Y 3至少一个为N时，n为0、1、2、3、4； When at least one of Y 1 , Y 2 , and Y 3 is N, n is 0, 1, 2, 3, or 4;
    当Y 1、Y 2、Y 3同时为CH时，X和Z成环B，且n为2、3、4； When Y 1 , Y 2 , and Y 3 are CH at the same time, X and Z form a ring B, and n is 2, 3, or 4;
    当Y 1、Y 2、Y 3其中两个为CH时，另一个Y 1/Y 2/Y 3为N或CR 9，且R 9不为H，另一个Y 1/Y 2/Y 3为CR 9时，n为1、2、3、4； When two of Y 1 , Y 2 , and Y 3 are CH, the other Y 1 /Y 2 /Y 3 is N or CR 9 , and R 9 is not H, and the other Y 1 /Y 2 /Y 3 is When CR 9 , n is 1, 2, 3, 4;
    o选自0、1、2、3、4；o is selected from 0, 1, 2, 3, 4;
    p选自0、1、2；p is selected from 0, 1, 2;
    q选自0、1、2、3；q is selected from 0, 1, 2, 3;
    r选自0、1、2、3、4、5；r is selected from 0, 1, 2, 3, 4, 5;
    s选自0、1、2、3、4、5；s is selected from 0, 1, 2, 3, 4, 5;
    t选自0、1、2、3、4；t is selected from 0, 1, 2, 3, 4;
    u选自0、1、2、3、4；u is selected from 0, 1, 2, 3, 4;
    环A选自烷基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基；Ring A is selected from alkyl, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl;
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 8’、R 9各自独立的选自氢、氘、烷基、桥环基、螺环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基、卤素、硝基、氧代、氰基、OR g、SR g、烷基-R g、NH(CH 2)R g、C(O)R g、S(O)R g、SO 2R g、C(O)OR g、OC(O)R g、NR hR i、C(O)N(R h)R i、N(R h)C(O)R i、-P(O)R hR i，所述的烷基、桥环基、螺环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基可进一步被1个或者多个R j取代；R 7可取代在氮杂吲哚片段的碳、氮原子上； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ′, R 9 are each independently selected from hydrogen, deuterium, alkyl, bridged cyclyl, spirocyclyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR g , SR g , alkyl-R g , NH ( CH 2 )R g , C(O)R g , S(O)R g , SO 2 R g , C(O)OR g , OC(O)R g , NR h R i , C(O)N ( R h )R i , N(R h )C(O)R i , -P(O)R h R i , the alkyl group, bridged ring group, spirocyclic group, alkenyl group, alkynyl group, cycloalkane group Radical, cycloalkenyl, heterocyclyl, aryl or heteroaryl can be further substituted by one or more R j ; R 7 can be substituted on the carbon and nitrogen atoms of the azaindole fragment;
    两个R 2、R 3、R 5、R 6或者R 7基团可成环形成环烷基、杂环烷基，并可进一步1个或者多个R k取代； Two R 2 , R 3 , R 5 , R 6 or R 7 groups can form a ring to form cycloalkyl, heterocycloalkyl, and can be further substituted by one or more R k ;
    R f、R g、R h、R i、R j和R k各自独立的选自氢、氘、烷基、螺环基、烯基、炔基、卤素、氰基、氨基、硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基，所述的烷基、螺环基、烯基、炔基、烷氧基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基可进一步被1个或者多个R m取代； R f , R g , Rh , R i , R j and R k are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl , oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, Bridged cyclyl, heterocyclyl, aryl or heteroaryl, said alkyl, spirocyclyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, alkoxycarbonyl, Alkylamino, cycloalkyl, cycloalkenyl, bridged cyclyl , heterocyclyl, aryl or heteroaryl groups may be further substituted with one or more R;
    R m选自氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、杂环烷基。 R m is selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, alkylamino, halo Substituted hydroxyalkyl, haloalkylamino, cycloalkyl, heterocycloalkyl.
  2. 一种化合物，其特征在，具有通式(II)所示的结构：A compound is characterized in that, has the structure shown in general formula (II):
    Figure PCTCN2021126588-appb-100002
    Figure PCTCN2021126588-appb-100002
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
    其中：in:
    m选自0、1、2、3；m is selected from 0, 1, 2, 3;
    Z选自(CH 2) u、NH、O、S、C(O)、S(O 2)、OC(O)、N(H)C(O)、S(O 2)N(H)、N(H)S(O 2)、OC(O)N(H)、N(H)C(O)S，或氢、氘、烷基、螺环基、桥环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基、卤素、硝基、氧代、氰基、OR a、SR a、烷基-R a、NH(CH 2)R a、C(O)R a、S(O)R a、SO 2R a、C(O)OR a、OC(O)R a、NR bR c、C(O)N(R b)R c、N(R b)C(O)R c、-P(O)R bR c，所述的烷基、环烯基、桥环基、杂环基、芳基或者杂芳基可进一步被一个或者多个R d取代； Z is selected from ( CH2 ) u , NH, O, S, C(O), S( O2 ), OC(O), N(H)C(O), S( O2 )N(H), N(H)S(O 2 ), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium, alkyl, spirocyclyl, bridged ring, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR a , SR a , alkyl-R a , NH(CH 2 )R a , C(O)R a , S(O)R a , SO 2 R a , C(O)OR a , OC(O)R a , NR b R c , C(O)N(R b )R c , N(R b )C(O)R c , -P(O)R b R c , the alkyl group, cycloalkenyl group, bridged ring group, heterocyclic group, aryl group or heteroaryl group can be further represented by One or more R d substitutions;
    R a、R b、R c和R d各自独立的选自氢、氘、烷基、螺环基、烯基、炔基、卤素、氰基、氨基、硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环基、杂环基、螺环基、芳基或者杂芳基，所述的烷基、环烯基、环烷基、桥环基、螺环基、杂环基、芳基或者杂芳基可进一步被一个或者多个R e取代； R a , R b , R c and R d are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, Amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, hetero Cyclic, spiro, aryl or heteroaryl, the alkyl, cycloalkenyl, cycloalkyl, bridged, spiro, heterocyclyl, aryl or heteroaryl may be further replaced by a or multiple R e substitutions;
    Re选自氢、氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代烷羟基、卤代烷氨基、环烷基；Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino , haloalkoxy, haloalkamino, cycloalkyl;
    X为NR 8或CR 8R 8’；其中： X is NR 8 or CR 8 R 8 ′; where:
    X和Z可能成环B或不成环；当形成B环时，与X相连的虚线表示为化学键；当B为开环时，与X相连的虚线表示为不存在；当形成B环时，R 2可取代在Z上，也可取代在Z跟X之间的任一原子上；当B为开环时，R 2取代在X上； X and Z may form a ring B or not form a ring; when the B ring is formed, the dashed line connected to X is represented as a chemical bond; when B is an open ring, the dashed line connected to X is represented as absent; when the B ring is formed, R 2 can be substituted on Z, and can also be substituted on any atom between Z and X; when B is an open ring, R 2 is substituted on X;
    Y 1、Y 2、Y 3各自独立的选自CR 9、N；且：当Y 1、Y 2、Y 3至少一个为N时，n为0、1、2、3、4； Y 1 , Y 2 , Y 3 are each independently selected from CR 9 , N; and: when at least one of Y 1 , Y 2 , and Y 3 is N, n is 0, 1, 2, 3, or 4;
    当Y 1、Y 2、Y 3同时为CH时，X和Z成环B，且n为2、3、4； When Y 1 , Y 2 , and Y 3 are CH at the same time, X and Z form a ring B, and n is 2, 3, or 4;
    当Y 1、Y 2、Y 3其中两个为CH时，另一个Y 1/Y 2/Y 3为N或CR 9，且R 9不为H，另一个Y 1/Y 2/Y 3为CR 9时，n为1、2、3、4； When two of Y 1 , Y 2 , and Y 3 are CH, the other Y 1 /Y 2 /Y 3 is N or CR 9 , and R 9 is not H, and the other Y 1 /Y 2 /Y 3 is When CR 9 , n is 1, 2, 3, 4;
    o选自0、1、2、3、4；o is selected from 0, 1, 2, 3, 4;
    p选自0、1、2；p is selected from 0, 1, 2;
    q选自0、1、2、3；q is selected from 0, 1, 2, 3;
    r选自0、1、2、3、4、5；r is selected from 0, 1, 2, 3, 4, 5;
    s选自0、1、2、3、4、5；s is selected from 0, 1, 2, 3, 4, 5;
    t选自0、1、2、3、4；t is selected from 0, 1, 2, 3, 4;
    u选自0、1、2、3、4；u is selected from 0, 1, 2, 3, 4;
    环A选自环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基；Ring A is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl;
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 8’、R 9各自独立的选自氢、氘、烷基、桥环基、螺环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基、卤素、硝基、氧代、氰基、OR g、SR g、烷基-R g、NH(CH)R g、C(O)R g、S(O)R g、SO 2R g、C(O)OR g、OC(O)R g、NR hR i、C(O)N(R h)R i、N(R h)C(O)R i、-P(O)R hR i，所述的烷基、桥环基、螺环基、烯基、炔基、环烷基、环烯基、杂环基、芳基或者杂芳基可进一步被1个或者多个R j取代；R 7可取代在氮杂吲哚片段的碳、氮原子上； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ′, R 9 are each independently selected from hydrogen, deuterium, alkyl, bridged cyclyl, spirocyclyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR g , SR g , alkyl-R g , NH ( CH)R g , C(O)R g , S(O)R g , SO 2 R g , C(O)OR g , OC(O)R g , NR h R i , C(O)N(R h ) R i , N(R h )C(O)R i , -P(O)R h R i , the alkyl group, bridged ring group, spirocyclic group, alkenyl group, alkynyl group, cycloalkyl group , cycloalkenyl, heterocyclyl, aryl or heteroaryl can be further substituted by one or more R j ; R 7 can be substituted on the carbon and nitrogen atoms of the azaindole fragment;
    两个R 2、R 3、R 5、R 6或者R 7基团可成环形成环烷基、杂环烷基，并可进一步1个或者多个R k取代； Two R 2 , R 3 , R 5 , R 6 or R 7 groups can form a ring to form cycloalkyl, heterocycloalkyl, and can be further substituted by one or more R k ;
    R f、R g、R h、R i、R j和R k各自独立的选自氢、氘、烷基、螺环基、烯基、炔基、卤素、氰基、氨基、硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基，所述的烷基、螺环基、烯基、炔基、烷氧基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基可进一步被1个或者多个R m取代； R f , R g , Rh , R i , R j and R k are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl , oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, Bridged cyclyl, heterocyclyl, aryl or heteroaryl, said alkyl, spirocyclyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, alkoxycarbonyl, Alkylamino, cycloalkyl, cycloalkenyl, bridged cyclyl , heterocyclyl, aryl or heteroaryl groups may be further substituted with one or more R;
    R m选自氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基。 R m is selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, alkylamino, halo Substituted hydroxyalkyl, haloalkylamino, cycloalkyl.
  3. 根据权利要求2所述的化合物，其特征在于，具有通式(III-A)或(III-B)所示的结构：The compound according to claim 2, is characterized in that, has the structure shown in general formula (III-A) or (III-B):
    Figure PCTCN2021126588-appb-100003
    Figure PCTCN2021126588-appb-100003
    Figure PCTCN2021126588-appb-100004
    Figure PCTCN2021126588-appb-100004
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐。or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
  4. 根据权利要求3所述的化合物，其特征在于，具有通式(IV-A)或(IV-B)所示的结构：The compound according to claim 3, is characterized in that, has the structure shown in general formula (IV-A) or (IV-B):
    Figure PCTCN2021126588-appb-100005
    Figure PCTCN2021126588-appb-100005
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐。or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
  5. 根据权利要求4所述的化合物，其特征在于具有通式(V-A)所示的结构：compound according to claim 4, is characterized in that having the structure shown in general formula (V-A):
    Figure PCTCN2021126588-appb-100006
    Figure PCTCN2021126588-appb-100006
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐。or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
  6. 根据权利要求4所述的化合物，其特征在于具有通式(V-B1)、(V-B2)、(V-B3)、(V-B4)、(V-B5)的结构：The compound according to claim 4 is characterized in that it has the structure of general formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5):
    Figure PCTCN2021126588-appb-100007
    Figure PCTCN2021126588-appb-100007
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐。or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
  7. 根据权利要求5所述的化合物，其特征在于，具有通式(VI-A1)、(VI-A2)的结构：The compound according to claim 5, is characterized in that, has the structure of general formula (VI-A1), (VI-A2):
    Figure PCTCN2021126588-appb-100008
    Figure PCTCN2021126588-appb-100008
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
    其中，T选自不存在、NR n、O、S； wherein T is selected from absent, NR n , O, S;
    Rk、R n各自独立选自氢、氘、烷烃、螺环基、烯基、炔基、卤素、氰基、氨基、 硝基、羟基、氧代、羧基、酰胺、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基、环烯基、桥环基、杂环基、芳基或者杂芳基，所述的烷基、环烷基、环烯基、桥环基、杂环基、螺环基、芳基或者杂芳基可进一步被1或者多个R o取代； Rk and Rn are each independently selected from hydrogen, deuterium, alkane, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, alkoxy, haloalkyl, Hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl , the alkyl group, cycloalkyl group, cycloalkenyl group, bridged ring group, heterocyclic group, spirocyclic group, aryl group or heteroaryl group can be further substituted by 1 or more R o ;
    R o选自氢、氘、烷基、卤素、氰基、氨基、硝基、羟基、氧代、烷氧基、卤代烷基、羟烷基、氨基烷基、烷基羰基、烷氧羰基、烷氨基、卤代羟烷基、卤代烷氨基、环烷基； R is selected from hydrogen, deuterium , alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkane Amino, halogenated hydroxyalkyl, halogenated alkylamino, cycloalkyl;
    n1选自0、1、2、3。n1 is selected from 0, 1, 2, and 3.
  8. 根据权利要求2所述的化合物，其特征在于，式(I)中*标注的C为R构型或者S构型。The compound according to claim 2, wherein the C marked with * in formula (I) is an R configuration or an S configuration.
  9. 根据权利要求2任一项所述的化合物，其特征在于：compound according to any one of claim 2, is characterized in that:
    成B环时，Z选自O、NH、CH 2、CO；不成环时，Z选自H； When forming B ring, Z is selected from O, NH, CH 2 , CO; when no ring is formed, Z is selected from H;
    Y 1、Y 2、Y 3各自独立的选自CR 9、N； Y 1 , Y 2 , Y 3 are each independently selected from CR 9 , N;
    R 1为H、硝基； R 1 is H, nitro;
    R 3为H；R 4为H；R 5为H； R 3 is H; R 4 is H; R 5 is H;
    R 7为H。 R7 is H.
  10. 根据权利要求1所述的化合物，其特征在于，具有通式(VII)的结构：compound according to claim 1, is characterized in that, has the structure of general formula (VII):
    Figure PCTCN2021126588-appb-100009
    Figure PCTCN2021126588-appb-100009
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
  11. 根据权利要求10所述的化合物，其特征在于，具有通式(VIII-A1)、(VIII-A2)、(VIII-A3)、(VIII-A4)、(VIII-A5)的结构：The compound according to claim 10, characterized in that, it has the structure of general formula (VIII-A1), (VIII-A2), (VIII-A3), (VIII-A4), (VIII-A5):
    Figure PCTCN2021126588-appb-100010
    Figure PCTCN2021126588-appb-100010
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐。or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
  12. 根据权利要求1所述的化合物，其特征在于，具有通式(IX)所示的结构：compound according to claim 1, is characterized in that, has the structure shown in general formula (IX):
    Figure PCTCN2021126588-appb-100011
    Figure PCTCN2021126588-appb-100011
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐；or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof;
    X选自NR 11、O； X is selected from NR 11 , O;
    L 1选自化学键、烷基、环烷基、杂环基、桥环基、螺环基； L 1 is selected from a chemical bond, an alkyl group, a cycloalkyl group, a heterocyclic group, a bridged ring group, and a spirocyclic group;
    环C选自环烷基、环烯基、桥环基、杂环基、芳基、杂芳基；Ring C is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl, heteroaryl;
    R 10、R 11各自独立地选自氢、烷基、卤素、卤代烷基、环烷基、卤代环烷基、杂环基、羟基、烷氧羰基、螺环基、烯基、炔基、羧基、酰胺、环烯基、桥环、芳基或者杂芳基； R 10 and R 11 are each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyl, alkoxycarbonyl, spirocyclyl, alkenyl, alkynyl, Carboxyl, amide, cycloalkenyl, bridged ring, aryl or heteroaryl;
    f选自0、1、2、3、4；f is selected from 0, 1, 2, 3, 4;
  13. 根据权利要求1-12任一项所述的化合物，其特征在于：The compound according to any one of claims 1-12, characterized in that:
    R m可进一步被1个或者多个R r取代； R m may be further substituted by one or more R r ;
    R r选自氢、氘、烷基、卤素、氰基、氨基、羟基、氧代、烷氧基、羟烷基、氨基烷基、烷基羰、杂环基、烷氨基、烷羰基、烷氧羰基、卤代羟烷基、卤代烷氨基、卤代烷基、环烷基、螺环基、烯基、炔基、硝基、羧基、酰胺、环烯基、桥环、芳基或者杂芳基 R r is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclyl, alkylamino, alkylcarbonyl, alkane Oxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spiro, alkenyl, alkynyl, nitro, carboxyl, amide, cycloalkenyl, bridged, aryl or heteroaryl
  14. 根据权利要求1-13任一项所述的化合物，其特征在于，*标注的C优选S构型；The compound according to any one of claims 1-13, wherein the C marked with * is preferably an S configuration;
  15. 根据权利要求1所述的化合物，其特征在于，具有如下结构之一：The compound according to claim 1, is characterized in that, has one of the following structures:
    Figure PCTCN2021126588-appb-100012
    Figure PCTCN2021126588-appb-100012
    Figure PCTCN2021126588-appb-100013
    Figure PCTCN2021126588-appb-100013
    Figure PCTCN2021126588-appb-100014
    Figure PCTCN2021126588-appb-100014
    Figure PCTCN2021126588-appb-100015
    Figure PCTCN2021126588-appb-100015
    Figure PCTCN2021126588-appb-100016
    Figure PCTCN2021126588-appb-100016
    Figure PCTCN2021126588-appb-100017
    Figure PCTCN2021126588-appb-100017
    Figure PCTCN2021126588-appb-100018
    Figure PCTCN2021126588-appb-100018
    Figure PCTCN2021126588-appb-100019
    Figure PCTCN2021126588-appb-100019
    Figure PCTCN2021126588-appb-100020
    Figure PCTCN2021126588-appb-100020
    Figure PCTCN2021126588-appb-100021
    Figure PCTCN2021126588-appb-100021
    Figure PCTCN2021126588-appb-100022
    Figure PCTCN2021126588-appb-100022
    Figure PCTCN2021126588-appb-100023
    Figure PCTCN2021126588-appb-100023
    或其立体异构体或其立体异构体混合物或其药学上可接受的盐。or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
  16. 一种药物组合物，其特征在于，包括权利要求1～15任一项所述的化合物中的一种或多种。A pharmaceutical composition, characterized by comprising one or more of the compounds according to any one of claims 1 to 15.
  17. 一种如权利要求1～15任一项所述化合物在制备单独或与其他药物联合应用治疗从BCL-2活性的抑制中获益的疾病、障碍或病症的药物中的应用。A use of a compound according to any one of claims 1 to 15 in the preparation of a medicament for use alone or in combination with other medicaments for the treatment of diseases, disorders or conditions that benefit from the inhibition of BCL-2 activity.
  18. 一种如权利要求17所述的应用，其特征在于，所述药物选自烷化剂、血管生成抑制剂、抗体、抗代谢物、抗有丝分裂、抗增殖、抗病毒剂、aurora激酶抑制剂、 其他细胞凋亡的启动子抑制剂、死亡受体途径活化剂、Bcr-Abl激酶抑制剂、双特异性T细胞衔接器的抗体、抗体药物偶联物、生物反应调节剂、细胞周期蛋白依赖性激酶抑制剂、细胞周期抑制剂、环氧合酶-2抑制剂、DVDs、白血病病毒癌基因同源基因同源物2受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白乙酰化酶(HDAC)抑制剂、激素疗法、免疫制剂、细胞凋亡蛋白抑制剂的抑制剂、嵌入抗生素、激酶抑制剂、驱动蛋白抑制剂、Jak2抑制剂、针对哺乳动物的雷帕霉素抑制剂、微RNA、丝裂原活化的细胞外信号调节的激酶抑制剂、多价结合蛋白、非类固醇类抗炎药、聚ADP(二磷酸腺苷)-核糖聚合酶抑制剂、铂类化疗药物、polo样激酶(Plk)抑制剂、磷酸肌醇3激酶抑制剂、BTK抑制剂、免疫检查点抑制剂、蛋白酶体抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、类视黄醇/deltoid植物生物碱、小干扰RNA、拓扑异构酶抑制剂、泛素连接酶抑制剂和类似物。17. The use of claim 17, wherein the drug is selected from the group consisting of alkylating agents, angiogenesis inhibitors, antibodies, anti-metabolites, anti-mitotic, anti-proliferative, anti-viral agents, aurora kinase inhibitors, Other promoter inhibitors of apoptosis, death receptor pathway activators, Bcr-Abl kinase inhibitors, antibodies to bispecific T cell adapters, antibody drug conjugates, biological response modifiers, cyclin-dependent Kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogene homolog 2 receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibition Agents, Histone Acetylase (HDAC) Inhibitors, Hormone Therapy, Immunologics, Inhibitors of Apoptotic Protein Inhibitors, Intercalated Antibiotics, Kinase Inhibitors, Kinesin Inhibitors, Jak2 Inhibitors, Ramen Against Mammals Pamycin inhibitors, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs, poly ADP (adenosine diphosphate)-ribose polymerase inhibitors, Platinum chemotherapy drugs, polo-like kinase (Plk) inhibitors, phosphoinositide 3-kinase inhibitors, BTK inhibitors, immune checkpoint inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine Kinase inhibitors, retinoid/deltoid plant alkaloids, small interfering RNAs, topoisomerase inhibitors, ubiquitin ligase inhibitors and the like.
  19. 一种如权利要求17所述的应用，其特征在于，所述疾病、障碍或病灶选自感染性疾病、免疫性疾病、炎性疾病和细胞增殖异常疾病。17. The use according to claim 17, wherein the diseases, disorders or lesions are selected from infectious diseases, immune diseases, inflammatory diseases and abnormal cell proliferation diseases.
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