Bcl-2 protein apoptosis inducer and its application

Abstract

The present invention discloses a Bcl-2 protein apoptosis inducer, and also discloses the use of the compound and a pharmaceutical composition containing the compound in the preparation of drugs 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 inhibition activity on mutated cell lines. It can be used to treat infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation that benefit from the inhibition of anti-apoptotic protein BCL-2 alone or in combination with other drugs.

Description

Technical Field

[0001] The present invention relates to a class of compounds or pharmaceutically acceptable salts that can inhibit anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, and as drugs for treating hyperproliferative diseases such as cancer and inflammation, as well as immune and autoimmune diseases. Background Art

[0002] Apoptosis is regulated through two different pathways, namely the extrinsic pathway and the intrinsic pathway. The extrinsic pathway is mediated by cell surface death receptors, and the intrinsic pathway involves 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, and pro-apoptotic proteins such as Bid, Bim, Bad, Bak and Bax.

[0003] Anti-apoptotic Bcl-2 family members have been found to be upregulated in tumor cells and correlated with disease stage and prognosis. Therefore, Bcl-2 proteins are studied as potential drug treatment 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 is associated with disease extent and stage, and in hepatocellular carcinoma, Bcl-XL expression can be used as an independent indicator of prognosis.

[0004] Bcl-2 inhibitors have been reported in the literature, such as WO 2011149492A / CN110546151A / WO2020140005A2 / WO2019210828A1, etc., which disclose an apoptosis inducer, but many of them have problems such as short half-life or high toxicity.

[0005] Studies have reported that some patients develop resistance after receiving Bcl-2 inhibitor treatment. The BCL-2 gene has G101V mutation and D103Y mutation, which reduces the efficacy of BCL-2 inhibitors (Cancer Discov. 2019, 9, 342-353). There is an urgent need to find a treatment that is more suitable for patients with resistance to BCL-2 inhibitors.

[0006] Therefore, there is an urgent need to develop new Bcl-2 inhibitors with better efficacy, higher stability, better safety, and greater effectiveness against mutant cell lines. Summary of the invention

[0007] The present invention relates to a new class of compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof, as well as their use as medicines.

[0008] A compound having a structure shown by general formula (I):

[0009]

[0010] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof; wherein:

[0011] m is selected from 0, 1, 2, 3;

[0012] When forming a ring, Z is substituted by two substituents to form a ring; when not forming a ring, Z is substituted by one substituent;

[0013] Z is selected from (CH2) u , NH, O, S, C(O) (indicating C=O), S(O2) (indicating the presence of two S=O groups on S), OC(O), N(H)C(O) (indicating that Z substitution occurs on N and C respectively), S(O2)N(H), N(H)S(O2), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium, alkyl, spirocyclic, bridged, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl, halogen, nitro, oxo(=O), cyano, OR a , SR a , alkyl-R a 、NH(CH2)R a 、C(O)R a 、S(O)R a 、SO2R 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, cycloalkenyl, bridged ring, heterocyclic, aryl or heteroaryl group may be further replaced by one or more R d Substitution; when Z is a main chain containing two or more than two, taking "OC(O)" as an example, OC(O) has no limitation on the order of substitution, that is, in actual substitution, it may be that the O atom on the left is connected to the benzene ring, or it may indicate that the carbonyl carbon atom is connected to the benzene ring.

[0014] R a , R b , R c and R dmay be independently selected from hydrogen, deuterium, alkyl, spirocyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring group, heterocyclic group, spirocyclic group, aryl or heteroaryl, and the alkyl, cycloalkenyl, cycloalkyl, bridged ring group, spirocyclic group, heterocyclic group, aryl or heteroaryl may be further substituted by one or more R e replace;

[0015] Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, haloalkylhydroxy, haloalkylamino, cycloalkyl;

[0016] X is NR8, CR8R8', O, C(O), S, S(O), S(O)2;

[0017] in:

[0018] X and Z may form a ring B or not; when a B ring is formed, the dotted line connected to X represents a chemical bond; when B is an open ring, the dotted line connected to X represents non-existence; when a B ring is formed, R2 may be substituted on Z or on any atom between Z and X; when B is an open ring, R2 is substituted on X;

[0019] Y1, Y2, and Y3 are each independently selected from CR9 and N; and:

[0020] When at least one of Y1, Y2, and Y3 is N, n is 0, 1, 2, 3, or 4;

[0021] When Y1, Y2, and Y3 are CH at the same time, X and Z form a ring B, and n is 2, 3, or 4;

[0022] When two of Y1, Y2, and Y3 are CH, the other Y1 / Y2 / Y3 is N or CR9, and R9 is not H, and the other Y1 / Y2 / Y3 is CR9, n is 1, 2, 3, or 4;

[0023] o is selected from 0, 1, 2, 3, 4;

[0024] p is selected from 0, 1, 2;

[0025] q is selected from 0, 1, 2, 3;

[0026] r is selected from 0, 1, 2, 3, 4, 5;

[0027] s is selected from 0, 1, 2, 3, 4, 5;

[0028] t is selected from 0, 1, 2, 3, 4;

[0029] u is selected from 0, 1, 2, 3, 4;

[0030] Ring A0 is selected from cycloalkane, cycloalkenyl, bridged ring, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0031] R1, R2, R3, R4, R5, R6, R7, R8, R8', R9 are each independently selected from hydrogen, deuterium, alkyl, cyclyl, spirocyclyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR g , SR g , alkyl-R g 、NH(CH2)R g 、C(O)R g 、S(O)R g 、SO2R 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, bridged ring, spirocyclic, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl group may be further substituted by one or more R j Substitution; R7 can be substituted on the carbon or nitrogen atom of the azaindole fragment;

[0032] Two R2, R3, R5, R6 or R7 groups can form a ring to form a cycloalkyl group or a heterocycloalkyl group, and can further have one or more R k replace;

[0033] R f , R g , R h , R i , R j and R k may be independently selected from hydrogen, deuterium, alkyl, spirocyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring group, heterocyclic group, aryl or heteroaryl, and the alkyl, spirocyclic group, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, cycloalkyl, cycloalkenyl, bridged ring group, heterocyclic group, aryl or heteroaryl may be further substituted by one or more Rm replace;

[0034] R m Selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, and cycloalkyl.

[0035] A compound having a structure shown by general formula (II):

[0036]

[0037] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0038] in:

[0039] m is selected from 0, 1, 2, 3;

[0040] 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(O2), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium, alkyl, spirocyclic, bridged, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR a , SR a , alkyl-R a 、NH(CH2)R a 、C(O)R a 、S(O)R a 、SO2R 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, cycloalkenyl, bridged ring, heterocyclic, aryl or heteroaryl group may be further replaced by one or more R d replace;

[0041] R a , R b , R c and R dEach independently selected from hydrogen, deuterium, alkyl, spirocyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring group, heterocyclic group, spirocyclic group, aryl or heteroaryl, and the alkyl, cycloalkenyl, cycloalkyl, bridged ring group, spirocyclic group, heterocyclic group, aryl or heteroaryl may be further substituted by one or more R e replace;

[0042] Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, haloalkylhydroxy, haloalkylamino, cycloalkyl;

[0043] X is NR8 or CR8R8'; wherein:

[0044] X and Z may form a ring B or not; when a B ring is formed, the dotted line connected to X represents a chemical bond; when B is an open ring, the dotted line connected to X represents non-existence; when a B ring is formed, R2 may be substituted on Z or on any atom between Z and X; when B is an open ring, R2 is substituted on X;

[0045] Y1, Y2, and Y3 are each independently selected from CR9 and N; and:

[0046] When at least one of Y1, Y2, and Y3 is N, n is 0, 1, 2, 3, or 4;

[0047] When Y1, Y2, and Y3 are CH at the same time, X and Z form a ring B, and n is 2, 3, or 4;

[0048] When two of Y1, Y2, and Y3 are CH, the other Y1 / Y2 / Y3 is N or CR9, and R9 is not H, and the other Y1 / Y2 / Y3 is CR9, n is 1, 2, 3, or 4;

[0049] o is selected from 0, 1, 2, 3, 4;

[0050] p is selected from 0, 1, 2;

[0051] q is selected from 0, 1, 2, 3;

[0052] r is selected from 0, 1, 2, 3, 4, 5;

[0053] s is selected from 0, 1, 2, 3, 4, 5;

[0054] t is selected from 0, 1, 2, 3, 4;

[0055] u is selected from 0, 1, 2, 3, 4;

[0056] Ring A is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclic, aryl or heteroaryl;

[0057] R1, R2, R3, R4, R5, R6, R7, R8, R8', R9 are each independently selected from hydrogen, deuterium, alkyl, 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 、SO2R 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, bridged ring, spirocyclic, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl group may be further substituted by one or more R j Substitution; R7 can be substituted on the carbon or nitrogen atom of the azaindole fragment;

[0058] Two R2, R3, R5, R6 or R7 groups can form a ring to form a cycloalkyl group or a heterocycloalkyl group, and can further have one or more R k replace;

[0059] R f , R g , R h , R i , R j and R k Each independently selected from hydrogen, deuterium, alkyl, spirocyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring group, heterocyclic group, aryl or heteroaryl, and the alkyl, spirocyclic group, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, cycloalkyl, cycloalkenyl, bridged ring group, heterocyclic group, aryl or heteroaryl may be further replaced by one or more R m replace;

[0060] R mSelected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, and cycloalkyl.

[0061] Preferably, the C marked with * in formula (I) is in R configuration or S configuration.

[0062] Preferably, a compound has a structure shown in general formula (II-A) or (II-B):

[0063]

[0064] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.

[0065] Furthermore, the preferred compounds of the present invention have the structure of general formula (III-A) or (III-B):

[0066]

[0067] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0068] wherein: Y1, Y2, Y3, Z, R2, R5, R6, R7, n, r, q, s are as defined in the general formula (I).

[0069] Furthermore, preferred compounds of the present invention have the structure of general formula (IV-A) or (IV-B):

[0070]

[0071] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0072] Wherein: Y1, Y2, Y3, Z, R2, R5, R6, n, r, q are defined as in the general formula (III-A) and (III-B).

[0073] Furthermore, preferred compounds of the present invention have the structure of general formula (VA):

[0074]

[0075] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0076] wherein: Y1, Y2, Y3, R2, R5, R6, n, r, q are as defined in Formula IV-A.

[0077] The preferred compounds of the present invention have the structures of the general formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5):

[0078]

[0079] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0080] wherein: Y1, Y2, Y3, R2, R5, R6, r, q are as defined in the general formula (IV-B).

[0081] As further preferred, the compounds of the present invention have the structures of the general formula VI-A1 and VI-A2:

[0082]

[0083] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0084] Wherein, Y1, Y2, Y3, R5, R6, r, q are as defined in Formula VA;

[0085] T is selected from absent, NR n , O, S;

[0086] R k , R n independently selected from hydrogen, deuterium, alkane, spirocyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclic group, aryl or heteroaryl, and the alkyl, cycloalkyl, cycloalkenyl, bridged ring, heterocyclic group, spirocyclic group, aryl or heteroaryl may be further substituted by one or more R o replace;

[0087] R o is selected from the group consisting of hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, and cycloalkyl;

[0088] n1 is selected from 0, 1, 2, 3.

[0089] Preferably, when forming a B ring, Z is selected from O, NH, CH2, CO; when not forming a ring, Z is selected from H;

[0090] Y1, Y2, and Y3 are independently selected from CR9 and N;

[0091] R1 is H, nitro;

[0092] R3 is H; R4 is H; R5 is H;

[0093] R7 is H. Preferably, the compound of the present invention has the structure of general formula (VII):

[0094]

[0095]

[0096] or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt; wherein,

[0097] Y1, Y2, Y3, R2, R5, R6, R7, r, q, s are as defined in the general formula (I);

[0098] Preferably, the compounds of the present invention have the structures of the general formula (VIII-A1), (VIII-A2), (VIII-A3), (VIII-A4), (VIII-A5):

[0099]

[0100] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0101] Y1, Y2, Y3, R2, R5, R6, r, q are as defined in Formula VII;

[0102] Preferably, the compound of the present invention has a structure represented by the general formula (IX):

[0103]

[0104] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0105] X is selected from NR 11 , O;

[0106] L1 is selected from a chemical bond, an alkyl group, a cycloalkyl group, a heterocyclic group, a bridged ring group, and a spirocyclic group;

[0107] Ring C is selected from cycloalkyl, cycloalkenyl, bridged ring group, heterocyclic group, aryl, heteroaryl;

[0108] R 10 , R 11 Each is independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxy, alkoxycarbonyl, spirocyclyl, alkenyl, alkynyl, carboxyl, amide, cycloalkenyl, bridged ring, aryl or heteroaryl;

[0109] f is selected from 0, 1, 2, 3, 4;

[0110] Preferably, among the compounds described in general formula (I) to (IX):

[0111] R m Can be further replaced by one or more R r replace;

[0112] R r is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spirocyclyl, alkenyl, alkynyl, nitro, carboxyl, amide, cycloalkenyl, bridged ring, aryl or heteroaryl;

[0113] Preferably, in the compounds of general formulae I to IX, the C marked with * is preferably in S configuration;

[0114] As further preferred, when forming the B ring, R2 is methyl, methoxycarbonyl, 4-hydroxycyclohexyloxymethyl, a spirocyclic structure formed by sharing a C atom with the B ring (including cyclopropane, cyclobutane, cyclopentane, N-methyl substituted azocyclopentane, N-methyl substituted azocyclohexane), (4-methylpiperazin-1-yl)methyl, 2-(dimethylamino)ethyl, morpholinemethyl, (4-(oxetane-3-yl)piperazin-1-yl)methyl, (1,1-dioxythiomorpholine)methyl, (4-acetylpiperazin-1-yl)methyl, (4-hydroxycyclohexyl)methyl, (2-(4-methylpiperazin-1-yl)ethyl, (4 -(methylsulfonylamino)piperidin-1-yl)methyl, (4-methoxycarbonylaminopyridin-1-yl)methyl, (dimethylamino)methyl, (3-hydroxy-3-methylazetidin-1-yl)methyl, 2-(1,1-dioxythiomorpholino)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-acetylpiperidin-4-yl, 4-hydroxycyclohexyl, oxo, (4-hydroxy-4-methylcyclohexyl)methyl, (1,4-dioxan-2-yl)methyl.

[0115] When not ring-forming, (4-hydroxy-4-methylcyclohexyl)methyl, (4-fluoro-1-(trifluoromethyl)piperidin-4-yl)methyl, (1,4-dioxane-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-(dimethylamino)acetyl)-4-fluoropiperidin-4-yl)methyl, (4-(2-morpholinoacetyl)morpholin-2-yl)methyl, ((4-(2-( methyl, (4-fluoro-1-(ethoxy)piperidin-4-yl)methyl, 2-(dimethylamino)ethyl, 3-isopropyloxypropyl, 3-(dimethylamino)propyl, (4-fluoro-1-(2-morpholinacetyl)piperidin-4-yl)methyl, pyrrolidin-3-ylmethyl, (1-(oxetan-3-yl)pyrrolidin-3-yl)methyl, (4-fluoro-1-(methoxy)piperidin-4-yl)methyl 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-carbonyl, (4-hydroxy-4-methylcyclohexyl)methyl, (4-hydroxycyclohexyl)methyl, (3-hydroxy-3-methylcyclobutyl)methyl yl, (3-hydroxycyclobutyl)methyl, azetidin-3-ylmethyl, (1-(oxetane-3-yl)azetidin-3-yl)methyl, (3-methylazetidin-3-yl)methyl, (1-isopropyl-3-methylazetidin-3-yl)methyl, (1-cyclopropyl-4-fluoropiperidin-4-yl)methyl, (1-cyclobutyl-4-fluoropiperidin-4-yl)methyl, (1-cyclopentyl-4-fluoropiperidin-4-yl)methyl, ((4-fluoro-1-(1,1,1-trifluoropropane-2-yl))piperidin-4-yl)methyl, (4-fluoro-1-(1,1,1,3,3,3-hexafluoropropan-2-yl)piperidin-4-yl)methyl, (1-acetyl-4-fluoropiperidin-4-yl)methyl, (4-fluoro-1-(1-hydroxypropan-2-yl)piperidin-4-yl)methyl, ((tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl, (4-fluoro-1-(isopropyloxyacyl)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-(oxetane-3-yl)piperidin-4-yl)methyl, (4-amino-4-methylcyclohexyl)methyl, (4-aminocyclohexyl)methyl, 3-amino-3-methylcyclobutylmethyl, 3-aminocyclobutylmethyl. ,

[0116] In addition, when there is no ring formation, two substituents occurring on X (such as N) can form a ring structure with X, including a monocyclic ring or a polycyclic ring (spirocyclic structure), for example, R2 and X can form 6-(oxetane-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl, 6-(oxetane-3-yl)-2,6-diazaspiro[3.4]octane-2-yl, 7-(oxetane-3-yl)-2,7-diazaspiro[3.5]nonane-2-yl).

[0117] As a preferred embodiment, Part of the preferred structure is as follows:

[0118]

[0119] Preferably, the Bcl-2 inhibitor is preferably the following specific compound:

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132] Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt. Preferably, the compound is the following compound:

[0133] (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 (001)

[0134] (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 (002)

[0135] (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'-cyclopropane]-7-yl)sulfonyl)benzamide (003)

[0136] (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)

[0137] 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-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (005)

[0138] 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)

[0139] (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-2-oxo-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)benzamide (007)

[0140] (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)

[0141] (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'-cyclobutane]-7-yl)sulfonyl)benzamide (009)

[0142] (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'-cyclopentane]-7-yl)sulfonyl)benzamide (010)

[0143] 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)-N-((1'-methyl-5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-pyrrolidin]-7-yl)sulfonyl)benzamide (011)

[0144] (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-((1'-methyl-5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidin-7-yl)sulfonyl)benzamide (012)

[0145] 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)-N-((1'-methyl-5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-piperidin-7-yl)sulfonyl)benzamide (013)

[0146] (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)

[0147] 7-(N-(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)benzoyl)sulfamoyl)-2,2-dimethyl-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxylic acid methyl ester (015)

[0148] 2-((1H-pyrrolo[2,3-b]pyridin-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-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (016)

[0149] 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)-N-((3-(morpholinomethyl)-5-nitro-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)sulfonyl)benzamide (017)

[0150] 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)-N-((3-(methoxymethyl)-3-methyl-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (018)

[0151] 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)

[0152] 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)-N-((3-methyl-3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (020)

[0153] 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)-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)

[0154] 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-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (022)

[0155] 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)-N-((3-(morpholinomethyl)-5-nitro-2-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (023)

[0156] 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)picolinamide (024)

[0157] 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)picolinamide (025)

[0158] (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)methyl)amino)phenyl)sulfonyl)picolinamide (026)

[0159] (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-nitrophenyl)sulfonyl)picolinamide (027)

[0160] 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)picolinamide (028)

[0161] 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)picolinamide (029)

[0162] 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]nonan-7-yl)picolinamide (030)

[0163] 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)

[0164] 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)

[0165] 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)

[0166] 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)

[0167] (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)methyl)amino)phenyl)sulfonyl)nicotinamide (035)

[0168] 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-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (036)

[0169] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(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)nicotinamide (037)

[0170] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(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)nicotinamide (038)

[0171] 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)

[0172] 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)

[0173] 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)

[0174] 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)-5-nitro-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (042)

[0175] 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-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (043)

[0176] 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(((S)-3-((1,1-dioxythiomorpholino)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)picolinamide (044)

[0177] 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)picolinamide (045)

[0178] 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-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (046)

[0179] 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-(2-(4-methylpiperazin-1-yl)ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (047)

[0180] 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-(2-morpholinoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (048)

[0181] 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)picolinamide (049)

[0182] 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)picolinamide (050)

[0183] 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)

[0184] 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-(trifluoromethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (052)

[0185] 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)

[0186] 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)

[0187] 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)picolinamide (055)

[0188] 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2,3-difluorophenyl)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 (056)

[0189] 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-((4-(methylsulfonyl)piperidin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (057)

[0190] Methyl (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)

[0191] 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]nonan-7-yl)picolinamide (059)

[0192] 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(((S)-3-((3-hydroxy-3-methylazetidin-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)picolinamide (060)

[0193] 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(((S)-3-(2-(1,1-dioxythiomorpholino)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)picolinamide (061)

[0194] 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-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (062)

[0195] 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-((3-(1-methylpiperidin-4-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (063)

[0196] 4-(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)piperidine-1-carboxylic acid methyl ester (064)

[0197] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (065)

[0198] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (066)

[0199] 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)-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)

[0200] 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)-N-(((S)-3-methyl-3-(2-morpholinoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (068)

[0201] 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)

[0202] 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)-N-((3-methyl-3-(1-methylpiperidin-4-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (070)

[0203] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((S)-2,2-dimethyl-3-((4-methylpiperazin-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]nonan-7-yl)benzamide (071)

[0204] 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)-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)

[0205] 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)-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)

[0206] 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)-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)

[0207] 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)-N-((S)-2-((4-methylpiperazin-1-yl)methyl)-8-nitro-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)sulfonyl)benzamide (075)

[0208] 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)-N-((1-((1-methylpiperidin-4-yl)methyl)-7-nitro-3-oxo-1,3-dihydroisobenzofuran-5-yl)sulfonyl)benzamide (076)

[0209] 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)-N-((7-nitro-3-oxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3-dihydroisobenzofuran-5-yl)sulfonyl)benzamide (077)

[0210] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (078)

[0211] (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-((7-nitro-1-((tetrahydro-2H-pyran-4-yl)methyl)indol-5-yl)sulfonyl)benzamide (079)

[0212] (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)

[0213] 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)

[0214] (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-((7-nitro-2-oxy-1-((tetrahydro-2H-pyran-4-yl)methyl)indol-5-yl)sulfonyl)benzamide (082)

[0215] (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-((7-nitro-2-oxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)sulfonyl)benzamide (083)

[0216] 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)methyl)amino)phenyl)sulfonyl)benzamide (084)

[0217] 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]nonan-7-yl)benzamide (085)

[0218] 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)

[0219] 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)methyl)amino)phenyl)sulfonyl)benzamide (087)

[0220] 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)

[0221] 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)

[0222] 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)

[0223] 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2-morpholinoacetyl)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)

[0224] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (092)

[0225] 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)

[0226] 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)

[0227] 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)

[0228] 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)

[0229] 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)

[0230] 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)

[0231] 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)picolinamide (099)

[0232] 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)

[0233] 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)

[0234] 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)nicotinamide (102)

[0235] 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-carboxylate (103)

[0236] 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)nicotinamide (104)

[0237] 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)nicotinamide (105)

[0238] 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)

[0239] 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)nicotinamide (107)

[0240] 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)

[0241] 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)

[0242] 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)

[0243] 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)

[0244] 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)

[0245] 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)nicotinamide (113)

[0246] 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)

[0247] 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)nicotinamide (115)

[0248] 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)

[0249] 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)

[0250] 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)

[0251] 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)

[0252] 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)

[0253] 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)

[0254] 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-(oxetane-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)sulfonyl)benzamide (122)

[0255] 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-(oxetane-3-yl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)sulfonyl)benzamide (123)

[0256] 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-(oxetane-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)sulfonyl)benzamide (124)

[0257] 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)

[0258] 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)

[0259] 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)

[0260] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((4-fluoro-1-(oxetan-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)

[0261] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (129)

[0262] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (130)

[0263] 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-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (131)

[0264] 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-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (132)

[0265] 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)

[0266] 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)

[0267] 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)nicotinamide (135)

[0268] 2-((1H-pyrrolo[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)

[0269] 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)

[0270] 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)nicotinamide (138)

[0271] 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)

[0272] 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)

[0273] 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)

[0274] 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)

[0275] 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)

[0276] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-hydroxy-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)(144)

[0277] 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)

[0278] 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)

[0279] 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)

[0280] 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)

[0281] 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)methyl)amino)phenyl)sulfonyl)benzamide (149)

[0282] 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-oxoimidazolidin-1-yl)ethyl)amino)phenyl)sulfonyl)benzamide (150)

[0283] (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-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (151)

[0284] (S)-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 (152)

[0285] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (153)

[0286] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (154)

[0287] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (155)

[0288] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (156)

[0289] 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)

[0290] 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-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (158)

[0291] 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-(oxetan-3-yl)piperidin-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide (159)

[0292] 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)

[0293] 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)

[0294] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (162)

[0295] 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)

[0296] 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)nicotinamide (164)

[0297] 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)

[0298] 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)

[0299] 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)

[0300] 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)

[0301] (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)

[0302] (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-(oxetane-3-yl)azetidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (170)

[0303] (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-(oxetane-3-yl)azetidin-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (171)

[0304] (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)

[0305] (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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (173)

[0306] 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)

[0307] 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)

[0308] 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)

[0309] 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)

[0310] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-(trifluoromethyl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (178)

[0311] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-cyclopropyl-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 (179)

[0312] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-cyclobutyl-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 (180)

[0313] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-cyclopentyl-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 (181)

[0314] (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)

[0315] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-cyclopropyl-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 (183)

[0316] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-cyclobutyl-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 (184)

[0317] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-cyclopentyl-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 (185)

[0318] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(1,1,1-trifluoropropan-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)

[0319] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(1,1,1,3,3,3-hexafluoropropan-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)

[0320] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-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 (188)

[0321] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(1-hydroxypropyl-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 (189)

[0322] (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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (190)

[0323] (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-carboxylic acid methyl ester (191)

[0324] (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-carboxylic acid ethyl ester (192)

[0325] (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-carboxylic acid isopropyl ester (193)

[0326] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (194)

[0327] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((5-oxopyrrolidin-2-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (195)

[0328] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((2-oxopiperidin-4-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (196)

[0329] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((6-oxopiperidin-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (197)

[0330] (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-((4-(methyl((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (198)

[0331] 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-azaspiro[3.5]nonan-7-yl)nicotinamide (199)

[0332] 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]nonan-7-yl)nicotinamide (200)

[0333] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,3s)-3-amino-3-methylcyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (201)

[0334] 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)

[0335] 4-((1H-Pyrrolo[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]nonan-7-yl)nicotinamide (203) 4-((1H-Pyrrolo[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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (204)

[0336] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1r,3r)-3-(dimethylamino)cyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (205)

[0337] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1s,3s)-3-(dimethylamino)cyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (206)

[0338] 4-((1H-pyrrolo[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]nonan-7-yl)nicotinamide (207)

[0339] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((((((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (208)

[0340] 4-((1H-pyrrolo[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)

[0341] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((((((1R)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (210)

[0342] 4-((1H-pyrrolo[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)

[0343] 4-((1H-pyrrolo[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)

[0344] 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-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (213)

[0345] 4-((1H-pyrrolo[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-azaspiro[3.5]nonan-7-yl)nicotinamide (214)

[0346] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-isobutylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (215)

[0347] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-neopentylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (216)

[0348] Terminology

[0349] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by professionals in the field. Unless otherwise indicated, all patent documents, publicly disclosed materials, etc. referenced in the present invention are incorporated by reference in their entirety. If there are multiple definitions of the same term in the present invention, the definition in this section shall prevail.

[0350] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and are not limiting to any claims. In the present invention, unless otherwise stated, the singular includes the plural. It should be noted that in the specification and the appended claims, unless otherwise stated, singular forms such as "a", "an", "the" include plural references. It should also be noted that, unless otherwise stated, "or" means "and / or". In addition, "comprises", "includes" and similar terms are not limiting.

[0351] "Substitution" means that a hydrogen atom is replaced by a substituent. It should be noted that the substituents on a particular atom are limited by their valence state. In the definition section, "C i-j " refers to a range including a starting point and an end point, wherein i and j are integers representing the number of carbon atoms. For example, C 1-4 , C 1-10 , C 3-10 wait.

[0352] The term "alkyl" as used in the present invention refers to a straight chain saturated monovalent hydrocarbon group having one to six carbon atoms or a branched chain 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 may be unsubstituted, monosubstituted or polysubstituted, and the substituents may be the same or different when polysubstituted; the substituents of the alkyl group are selected from D (deuterium), halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, isopropyl, carbamoyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0353] The term "cycloalkyl" used in the present invention refers to a non-aromatic monovalent hydrocarbon group having a monocyclic or polycyclic ring (two monocyclic rings are connected by a chemical bond or bridged or spirocyclic or fused) with three to ten carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., in which one or two carbon atoms can be replaced by one oxygen. The cycloalkyl group may be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0354] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain group (i.e., C2-C 10 The alkenyl group may be substituted with one or more substituents, each of which is independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.

[0355] The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain group (i.e., C2-C 10 Alkynyl) includes but is not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl, etc. Alkynyl may be substituted with one or more substituents, and the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro.

[0356] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0357] 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 tert-butoxy. "Alkoxy" also includes substituted alkoxy groups, whose substituents may be D, halogen, amino, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, 3 to 10 membered heterocyclyl, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0358] The term "alkylamino" as used in the present invention 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, etc. "Alkylamino" also includes substituted alkylamino, whose substituents may be D, halogen, amino, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, 3 to 10 membered heterocyclyl, C6-C 12 Aryl, C5-C 14 The substituent of the heteroaryl group may be substituted on the alkyl group or on the nitrogen group.

[0359] The term "aryl" as used herein refers to an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms (one of the fused rings may be partially saturated). Non-limiting examples of aromatic rings include: benzene ring, naphthalene ring, anthracene ring, indene ring, dihydroindenyl (indanyl). The aromatic ring may be unsubstituted or substituted. The substituents of the aromatic ring are selected from D, halogen (preferably fluorine, chlorine, bromine, iodine), cyano, nitro, amino, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C1-C6 alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), C1-C6 hydroxyalkyl (preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc.), C1-C6 alkoxy (preferably methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halogenated C1-C6 alkyl (preferably halogenated methyl, halogenated ethyl, halogenated propyl, halogenated isopropyl, halogenated butyl, halogenated isobutyl, halogenated sec-butyl, halogenated tert-butyl, etc.), halogenated C1-C6 hydroxyalkyl (preferably halogenated hydroxymethyl, halogenated hydroxyethyl, halogenated hydroxypropyl, halogenated hydroxyisopropyl, etc.), halogenated C1-C6 alkoxy (preferably halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropyloxy, halogenated butoxy, halogenated isobutyloxy, halogenated sec-butyloxy, halogenated tert-butyloxy, etc.), C3-C6 cycloalkyl (preferably cyclopropyl, cyclopentyl, cyclohexyl, etc.), halogenated C3-C6 cycloalkyl (preferably halogenated cyclopropyl, halogenated cyclopentyl, halogenated cyclohexyl, etc.), 3- to 10-membered heterocyclic group (preferably tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.), C6-C 12 Aryl, C5-C 14 Heteroaryl: The substitution of the aromatic ring may be monosubstituted (such as ortho-, meta-, para-substituted), disubstituted, trisubstituted, etc.

[0360] The term "heteroaryl" used in the present invention refers to a monocyclic or fused polycyclic group of 5 to 14 ring atoms (one of the fused rings may be partially saturated), which is equivalent to one or more carbons in the above-mentioned "aryl" being replaced by heteroatoms such as oxygen, nitrogen, sulfur, etc. The heteroaromatic ring can be a monocyclic ring or a bicyclic ring, that is, formed by the fusion of two rings. Specific heteroaryl (heterocyclic aryl) can be: pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, dihydroindole, benzimidazole, etc. The heterocyclic aryl can be unsubstituted or substituted. The substituents of the heterocyclic aromatic group are selected from halogen, cyano, nitro, amino, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3 to 10 membered heterocyclic group, C6-C 12 Aryl, C5-C 14Heteroaryl.

[0361] The term "heterocyclic group" as used in the present invention refers to a monocyclic or polycyclic (two monocyclic rings are connected by a chemical bond or bridged or spirocyclic or fused) non-aromatic ring group having three to ten ring atoms, having one or more heteroatoms selected from N, O, and S, and one or more chemical bonds may be double bonds or triple bonds. The heterocyclic group may be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, oxo, thio, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0362] The term "spirocyclyl" as used in the present invention refers to a polycyclic structure in which at least two rings share an atom (generally a C atom), one or more chemical bonds in the polycyclic structure may be double bonds or triple bonds, and one or more heteroatoms may be present. The spirocyclic group may be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl, haloalkyl.

[0363] 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, one or more chemical bonds in the polycyclic structure may be double bonds or triple bonds, and one or more heteroatoms may be present. The bridged ring group may be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl. Haloalkyl.

[0364] The term "cycloalkenyl" used in the present invention refers to a non-aromatic hydrocarbon group having a monocyclic or polycyclic ring (two monocyclic rings are connected by a chemical bond or bridged or spirocyclic or fused) with three to ten carbon atoms and at least one double bond, preferably a cyclobutenyl, cyclopentenyl, cyclohexenyl, etc., in which one or two carbon atoms can be replaced by an oxygen atom. The cycloalkenyl group may be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or monosubstituted or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl. Haloalkyl:

[0365] The term "hydroxyalkyl" as used in the present invention refers to -alkyl-OH, wherein alkyl is as defined above. Examples of "hydroxyalkyl" as used in the present invention include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc. "Hydroxyalkyl" also includes substituted hydroxyalkyl, whose substituents may be D, halogen, amino, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3 to 10 membered heterocyclyl, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0366] The term "aminoalkyl" as used in the present invention refers to -alkyl-NH2, wherein alkyl is as defined above. Examples of "aminoalkyl" used in the present invention include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, etc. "Aminoalkyl" also includes substituted aminoalkyl, whose substituents may be D, halogen, amino, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3 to 10 membered heterocyclyl, C6-C 12 Aryl, C5-C 14 The substituent of the heteroaryl group may be substituted on the alkyl group or on the nitrogen group.

[0367] The term "alkylcarbonyl" as used herein refers to alkyl-C(O)-, wherein alkyl is as defined above. "Alkylcarbonyl" also includes substituted alkylcarbonyl, whose substituents may be D, halogen, amino, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3 to 10 membered heterocyclyl, C6-C 12 Aryl, C5-C 14 Heteroaryl, wherein "C(O)" represents C=O.

[0368] The term "alkoxycarbonyl" as used in the present invention refers to alkyl-OC(O)-, wherein the alkyl group is as defined above. "Alkoxycarbonyl" also includes substituted alkoxycarbonyl groups, whose substituents may be D, halogen, amino, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, 3 to 10 membered heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0369] The term "halohydroxyalkyl" as used herein refers to a hydroxyalkyl group substituted by halogen (preferably fluorine, chlorine, bromine, iodine), wherein hydroxyalkyl is as defined above. "Halohydroxyalkyl" may be substituted by halogen one or more times.

[0370] The term "haloalkylamino" as used herein refers to an alkylamino group substituted by halogen (preferably fluorine, chlorine, bromine, iodine), wherein alkylamino is as defined above. "Haloalkylamino" may be substituted by halogen one or more times.

[0371] For the avoidance of doubt, for example, when referring to alkyl, cycloalkyl, heterocyclylalkyl, aryl and / or heteroaryl groups as substituted, this means that each of these groups is substituted individually or that these groups are substituted in combination.

[0372] "Pharmaceutically acceptable salts" refer to salts with pharmaceutically acceptable non-toxic acid salts and bases, including salts made from inorganic or organic bases and inorganic or organic acids. Salts with inorganic bases can be selected from, for example, ammonium, calcium, magnesium, potassium, sodium, and zinc salts. Further, pharmaceutically acceptable salts with inorganic bases can be selected from ammonium, calcium, magnesium, potassium, and sodium salts. There may be one or more crystal structures in the solid salt, and there may also be hydrates.

[0373] "Pharmaceutically acceptable base-added salts" refer to those salts which retain the biological effectiveness and properties of the free acid of the compound and which require preparation with at least one pharmaceutically acceptable non-toxic base selected from inorganic and organic bases. For example: salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hybamine, isopropylamine, lysine, morpholine, piperazine, piperidine, purine, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.

[0374] "Pharmaceutically acceptable salt addition" refers to those that retain the biological effectiveness and characteristics of the free base of the compound and require the preparation of its salt with at least one pharmaceutically acceptable non-toxic acid, which is 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, maleic 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 preferably, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid and tartaric acid.

[0375] "Administration" or "administration" of a compound or a pharmaceutically acceptable salt thereof means providing a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0376] "Effective amount" refers to a dose of a compound or a pharmaceutically acceptable salt thereof that can cause a biological or medical response in a tissue, system, animal or human that can be observed by researchers, veterinarians, clinicians or other clinical personnel. The result can be the reduction and / or alleviation of signs, symptoms or causes of disease, or any other desired changes in a biological system.

[0377] "Pharmaceutical composition" includes: a product in which the compound of the present invention (active ingredient) is mixed with an inert ingredient as a carrier, as well as a product made by combining, compounding or aggregating any two or more ingredients directly or indirectly, or a product produced by the decomposition of one or more ingredients, or a product produced by other types of reactions or interactions of one or more ingredients.

[0378] "Pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues and are not unacceptably toxic to the subjects.

[0379] "Individual" refers to an individual suffering from a disease, condition, or the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of the class mammals: humans, non-human primates (such as chimpanzees, and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, pigs; livestock such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs, etc. Non-mammals include, but are not limited to, birds, fish, etc. In one embodiment of the present invention, the mammal is a human.

[0380] "Treatment" refers to the treatment of a relevant disease or condition in mammals, especially humans, including the prevention of other symptoms, the improvement or prevention of the underlying metabolic factors of the symptoms, the inhibition of the disease or symptoms, for example, preventing the development of the disease or symptom, alleviating the disease or symptoms, promoting the remission of the disease or symptoms, or stopping the symptoms of the disease or symptoms, and extends to include prevention; alleviating, alleviating or improving the disease or symptoms; inhibiting the disease or condition, that is, controlling its development. "Treatment" also includes achieving therapeutic benefits and / or preventive benefits. Therapeutic benefit refers to the eradication or improvement of the condition being treated. In addition, therapeutic benefits are achieved by eradicating or improving one or more physiological symptoms associated with the underlying disease, and although the patient may still suffer from the underlying disease, the improvement of the patient's disease can be observed. Preventive benefit refers to the use of the composition by the patient to prevent the risk of a certain disease, or when the patient has one or more physiological symptoms of the disease, although the disease has not yet been diagnosed.

[0381] "Protective group" (Pg) refers to a class of substituents used to block or protect specific functional groups by reacting with other functional groups on a compound. These functional groups include amino, carboxyl, sulfhydryl and hydroxyl. For a general description and instructions for use of protecting groups, see the reference: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0382] The "NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), p-nitrobenzylformyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-pentyloxycarbonyl, tert-butyloxycarbonyl (Boc), p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropyloxycarbonyl, isopropyloxycarbonyl, , phthaloyl (Pht), succinyl, alanyl, leucyl, benzyl, diphenylmethyl, triphenylmethyl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N,N-dimethylaminomethylene, benzylmethyl, 2-hydroxybenzylidene 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylcyclohexylene, 2-ethoxycarbonylcyclopentylene, 2-acetylcyclohexylene, 3,3-dimethyl-5-oxycyclohexylene, diphenylphosphoryl, dibenzylphosphoryl, trimethylsilyl, triethylsilyl and triphenylsilyl.

[0383] The protecting group for "C(O)OH" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, phenacyl, p-nitrophenacyl, p-bromophenacyl, p-methylsulfonylphenacyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthal ... carboximidomethyl, succinimidylmethyl, cyclopropyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

[0384] The "OH or SH" protecting group includes, but is not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl. , 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, Phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl(phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

[0385] 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 with E or Z configurations, wherein "E" represents a preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond, and "Z" represents a preferred substituent 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 priority rule. The compounds of the present invention may also exist in the form of a mixture of "E" and "Z" isomers. The substituents around the cycloalkyl or heterocyclic group can be defined as 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. Two substituents around a single ring in the adamantane ring system are defined as Z or E relative configurations. For example, see CD Jones, M. Kaselj, RN Salvatore, WJle Noble J. Org. Chem. 1998, 63, 2758-2760.

[0386] The compounds of the present invention may contain asymmetric centers, which may be independently in R or S configuration. The definitions of "R" and "S" are given in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds containing asymmetrically substituted carbon atoms are racemates if the amounts of R and S configurations are the same. If one configuration is greater than the amount of the other configuration, the configuration of the chiral carbon atom is represented by the configuration with the greater amount, preferably with an enantiomeric excess of about 85-90%, more preferably about 95-99%, and further about 99% or more. Therefore, the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

[0387] Isotopically enriched or labeled compounds

[0388] The compounds of the invention may exist in isotopically labeled or enriched form, containing one or more atoms having a different mass and mass number from the most common atomic mass in nature. Isotopes may 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.

[0389] The isotope-labeled compounds of the present invention can be used as standard compounds for binding tests to determine the effects of Bcl-2 inhibitors. Compounds containing isotopes can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotope-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 designing safe and effective therapeutic drugs, and can determine whether the in vivo active compound or the metabolite of the parent compound administered to the patient 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)).

[0390] 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 technical solutions above. The pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any one of the technical solutions above and other compounds, or one or more of the compounds described in any one of the technical solutions above.

[0391] Use of any of the above compounds in the preparation of a medicament for treating a disease, disorder or condition that benefits from the inhibition of BCL-2 activity, alone or in combination with other drugs.

[0392] The compounds or pharmaceutically acceptable salts of the present invention can be used alone or in combination with other therapeutic agents.

[0393] For example, the use of adjuvant drugs can enhance the therapeutic effect of the compounds of the present invention (for example, the therapeutic benefit of the adjuvant drug alone is minimal, but when used in combination with another drug, the therapeutic benefit of the individual can be enhanced), or, for example, the combination of the compounds of the present invention with another therapeutic agent that also has therapeutic effects can enhance the therapeutic benefit of the individual. Or, for example, if the adverse reaction of using the compounds of the present invention is nausea, then an anti-nausea drug can be used in combination. Alternatively, the combined therapy includes, but is not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of the diseased area, rest, dietary improvement, etc. Regardless of the disease, disorder or condition being treated, the two therapies should have an additive effect or a synergistic effect to benefit the individual's treatment.

[0394] In the case of the compounds described herein being used in combination with other therapeutic agents, the route of administration may be the same as that of the other drugs, or due to differences in physical and chemical properties, the route of administration may be different. Thus, the compounds described herein and the other therapeutic agent may be administered simultaneously, sequentially or separately.

[0395] The compounds represented by formula (I), (II), (III-A) or formula (III-B) (IV-A), (IV-B), (VA), (V-B1) to (V-B5), (VI-A1), (VI-A2), (VII), (VIII-A1) to (VIII-A5), IX are expected to be effective when used 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 (e.g., 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 homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone acetylase (HDAC) inhibitors, hormone therapy, immunotherapies, inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian rapamycin inhibitors, 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-based 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 analogs.

[0396] Specifically, the conditions, disorders or lesions include but are not limited to infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation diseases.

[0397] Specifically, the infectious diseases, immune diseases, inflammatory diseases include but are not limited to asthma, diseases caused by neutrophil chemotaxis (e.g., reperfusion injury of myocardial infarction and stroke and inflammatory arthritis), septic shock, T cell-mediated diseases, immunosuppression-related diseases (e.g., prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis and rheumatoid arthritis), pancreatitis, diseases related to angiogenesis or angiogenesis (e.g., 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.

[0398] Specifically, the abnormal cell proliferation disease includes 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 cancer, ovarian cancer, pancreatic cancer, glioma, epidermoid carcinoma, hemangioma, lung cancer or gastric cancer, restenosis and benign prostatic hypertrophy (BPH).

[0399] The compounds described in the present invention can be administered in the form of pharmaceutical compositions and can be administered by any conventional route; the compounds described in the present invention can be formed into pharmaceutical preparations in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, injections, suspensions, lotions, gels, ointments, creams, suppositories, inhalants and the like.

[0400] The pharmaceutical composition containing the compound of the present invention in the form of free alkali or pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating, coating, dissolving or freeze drying processes. The unit dosage form for oral administration comprises, for example, from about 0.1 mg to about 500 mg of active substance.

[0401] The inventors of the present invention have experimentally confirmed that the compounds of the present invention have potent BCL2 / BAK blocking activity and in vitro anti-tumor cell proliferation inhibitory activity. They 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 the anti-apoptotic protein BCL-2. DETAILED DESCRIPTION

[0402] The feasibility of the present invention is illustrated below by using embodiments. Those skilled in the art should understand that according to the teachings of the prior art, modifications or replacements of corresponding technical features still fall within the scope of protection claimed by the present invention.

[0403] 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'-cyclopropane]-7-yl)sulfonyl)benzamide (001)

[0404]

[0405] Step 1, dissolve (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.5g) and isopropylboric acid (3.1g) in a mixed solvent of 15mL 1,4-epoxyhexacyclopentane and 3mL water, add potassium carbonate (6g) and Pd(dffp)2Cl2 (0.9g) under nitrogen protection, and heat to reflux for overnight reaction. TLC monitoring, after the reaction is completed, cool to room temperature, add ethyl acetate, wash with water and saturated brine respectively, separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography to obtain the product (S)-2-(2-isopropylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.4g), with a yield of 85%.

[0406] Step 2, dissolve (S)-2-(2-isopropylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3 g) in 18 mL of dichloromethane, add trifluoroacetic acid (9 mL), and stir the reaction at room temperature overnight. After the reaction is completed, monitor by TLC, and concentrate the solvent under reduced pressure to obtain a crude product (S)-2-(2-isopropylphenyl)pyrrolidine (1.92 g), which is directly used in the next step without further purification.

[0407] Step 3, (S)-2-(2-isopropylphenyl)pyrrolidine (1.85g) and 2-oxo-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (2.4g) were dissolved in 25mL1,2-dichloroethane, stirred at room temperature for 15 minutes, and then sodium acetate borohydride (4.2g) was added. After about 4 hours of reaction, TLC monitoring was completed, and sodium bicarbonate aqueous solution was added to quench the reaction, and extracted with dichloromethane. After separation of the organic phase, the mixture was 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-carboxylic acid tert-butyl ester (3.6g), with a yield of 90%. LC-MS (ESI-MS): 413 [M+H] + .

[0408] Step 4, (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3g) was dissolved in 15mL of dichloromethane, trifluoroacetic acid (7.5mL) was added, and the reaction was stirred at room temperature overnight. TLC monitoring, after the reaction was completed, the dry solvent was concentrated under reduced pressure, dichloromethane was added to dissolve again, and the organic phase was separated and concentrated under reduced pressure. The 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 (1.92g), with a yield of 83%.

[0409] Step 5, dissolve methyl 2,4-difluorobenzoate (3.5g) and 1H-pyrrolo[2,3-b]pyridine-5-ol (4.1g) in 50mL diethylene glycol dimethyl ether, add potassium phosphate (6.4g), and heat to reflux for about 12 hours. TLC monitoring, after the reaction is completed, cool to room temperature, add water and ethyl acetate to extract, separate the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography to obtain a solid product 2-((1H-pyrrolo[2,3-b]pyridine-5-yl)oxy)-4-fluorobenzoic acid methyl ester (3.04g), with a yield of 53%. LC-MS (ESI-MS): 287[M+H] + .

[0410] Step 6, (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (1.56 g) and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.72 g) were dissolved in 20 mL of DMF, sodium carbonate (3.2 g) was added, and the mixture was heated to reflux for reaction overnight. After TLC monitoring, the reaction was almost complete and the temperature was lowered to room temperature. Water and a large amount of ethyl acetate were added for extraction. The organic phase was separated and dried over 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)-7-azaspiro[3.5]non-7-yl)benzoic acid methyl ester (1.79 g), with a yield of 62%. LC-MS (ESI-MS): 579 [M+H] + .

[0411] Step 7, dissolve (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)benzoic acid methyl ester (1.5 g) in a mixed solvent of 15 mL of methanol and 15 mL of tetrahydrofuran, add 3N aqueous sodium hydroxide solution (10 mL), heat to 50° C. and react for about 3 hours. The reaction is completed after monitoring by TCL, and neutralized with 4N aqueous hydrochloric acid to a pH of about 5. The mixture was extracted with dichloromethane, the organic phase was separated, and the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a 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 (1.25 g), with a yield of 85%. LC-MS (ESI-MS): 565 [M+H] + .

[0412] Step 8, 3-bromo-4-chloro-5-nitrobenzenesulfonamide (3.2 g) and 1-aminocyclopropylmethanol (0.78 g) were dissolved in 40 mL of acetonitrile, DIPEA (N, N-diisopropylethylamine, 8.2 mL) was added, and the mixture was heated to reflux and stirred to react overnight. TLC monitoring, after the reaction was completed, the mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure. The resulting 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), with a yield of 65%. LC-MS (ESI-MS): 366 [M+H] + .

[0413] Step 9, 3-bromo-4-((1-(hydroxymethyl)cyclopropyl)amino)-5-nitrobenzenesulfonamide (1.83 g) was dissolved in 30 mL of toluene, cesium carbonate (3.26 g), CuI (200 mg) and 3,4,7,8-tetramethyl-1,10-phenanthroline (118 mg) were added, and the mixture was heated under reflux under nitrogen protection for about 6 hours. TLC monitoring, after the reaction was completed, the temperature was cooled to room temperature, water and ethyl acetate were added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure. 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), with a yield of 53%. LC-MS (ESI-MS): 286 [M+H] + .

[0414] 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 (0.17 g) was dissolved in 3 mL of dichloromethane, triethylamine (0.2 mL) and HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, 0.15 g) were added, and the mixture was stirred at room temperature for about 1 hour. Then, 5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1′-cyclopropane]-7-sulfonamide (0.11 g) and DMAP (4-dimethylaminopyridine, 6 mg) were added. After the addition was complete, the reaction was continued at room temperature overnight. After the reaction was completed as monitored by TLC, water was added to quench the reaction, and the mixture was extracted with dichloromethane, washed with water and saturated brine. The organic phase was separated and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a 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]nonane-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)benzamide (112 mg), with a yield of 45%. LC-MS (ESI-MS): 832 [M+H] + .

[0415] 1 H NMR(400MHz,Chloroform-d)δ9.91(s,1H),8.66–8.54(m,1H),8.27–8.20(m,1H),8.1 7–8.10(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),3.34–2.8 9(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).

[0416] 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'-cyclopropane]-7-yl)sulfonyl)picolinamide (002)

[0417]

[0418] Parameters The synthesis method of Example 1, except that methyl 2,4-difluorobenzoate is replaced by methyl 3,5-difluoropyridine-2-carboxylate, can synthesize 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]nonane-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] + .

[0419] Example 3: (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'-cyclopropane]-7-yl)sulfonyl)benzamide (003)

[0420]

[0421] Parameters The synthesis method of Example 1, except that 2,4-difluorobenzoic acid methyl ester is replaced by 2,3,4-trifluorobenzoic acid methyl ester, can synthesize the target compound (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]nonane-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] + .

[0422] 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)

[0423]

[0424] Parameters The synthesis method of Example 1, except that methyl 2,4-difluorobenzoate is replaced by methyl 2,3,4,5-tetrafluorobenzoate, can synthesize the target compound (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]nonane-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)benzamide (73 mg), LC-MS (ESI-MS): 868 [M+H] + .

[0425] 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]nonan-7-yl)-N-(((S)-3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (005)

[0426]

[0427] Referring to the synthesis method of Example 1, methyl 2,4-difluorobenzoate was replaced with methyl 3,5-difluoropyridine-2-carboxylate, and 1-aminocyclopropylmethanol was replaced with (S)-2-amino-3-morpholinopropane-1-ol to synthesize 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-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)picolinamide (59 mg), LC-MS (ESI-MS): 906 [M+H] + .

[0428] Example 6: 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)

[0429]

[0430] Referring to the synthesis method of Example 1, methyl 2,4-difluorobenzoate was replaced with methyl 2,3,4-trifluorobenzoate, and 1-aminocyclopropylmethanol was replaced with (S)-2-amino-3-morpholinopropane-1-ol to synthesize 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]nonane-7-yl)-N-((((S)-3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (38 mg), LC-MS (ESI-MS): 923 [M+H] + .

[0431] 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)picolinamide (024)

[0432]

[0433]

[0434] Step 1 Preparation of intermediate 24-1: 7-azaspiro[3.5]nonan-2-one hydrochloride (24-1)

[0435] 2-Oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (10.00 g, 42.00 mmol) was dissolved in 1,4-dioxane (52.00 mL), and then 4 mol / L HCl (52.00 mL) in 1,4-dioxane (52.00 mL) was added, and the mixture was heated to 60°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated to near dryness, methyl tert-butyl ether (100.00 mL) was added, and the mixture was slurried at room temperature for 1 h and then filtered. The filter cake was rinsed with methyl tert-butyl ether and dried under reduced pressure for 16 h to obtain intermediate 24-1 (7.30 g) with a yield of 99%, LC-MS (ESI-MS): m / z=140 [M+H] + .

[0436] Step 2 Preparation of intermediate 24-2: 3-fluoro-5-(2-oxo-7-azaspiro[3.5]nonane-7-yl)pyridine-2-carboxylic acid methyl ester (24-2):

[0437] Methyl 3,5-difluoropyridine-2-carboxylate (2.38 g, 13.75 mmol, 1.00 eq) and intermediate 24-1 (2.42 g, 13.75 mmol) were dissolved in DMF, sodium carbonate (7.30 g, 68.74 mmol) was added, and the temperature was raised to 100°C for reaction for 12 h. TLC monitoring was performed, and EA and water were added for extraction after the reaction was completed. The organic phase was separated, dried and filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate 24-2 (2.20 g) with a yield of 54%. LC-MS (ESI-MS): m / z=293 [M+H] + .

[0438] Step 3 Preparation of intermediate 24-3: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-oxo-7-azaspiro[3.5]nonane-7-yl)pyridine-2-carboxylic acid methyl ester (24-3)

[0439] Intermediate 24-2 (1.54 g, 5.27 mmol) and 1H-pyrrolo[2,3-b]pyridine-5-ol (778.00 mg, 5.80 mmol) were dissolved in diethylene glycol dimethyl ether (30.00 mL), potassium phosphate (1.34 g, 6.32 mmol) was added, and the mixture was stirred and heated in an oil bath at 110°C for 9 h. TLC monitoring, after the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure until diethylene glycol dimethyl ether was nearly dry, methyltetrahydrofuran and water were added for extraction, the organic phase was separated, dried and filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate 24-3 (817.00 mg) with a yield of 38%, LC-MS (ESI-MS): m / z=407 [M+H] + .

[0440] Step 4 Preparation of intermediate 24-4: (S)-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)pyridine-2-carboxylic acid methyl ester (24-4)

[0441] 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 added, and the mixture was reacted at room temperature for 10 h. After the reaction was completed by TLC monitoring, water and DCM were added for extraction, the DCM phase was separated, dried and filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate 24-4 (1.10 g) with a yield of 83%. LC-MS (ESI-MS): m / z=580 [M+H]+ .

[0442] Step 5 Preparation of intermediate 24-5: (S)-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)pyridine-2-carboxylic acid (24-5)

[0443] The intermediate 24-4 (1.10 g, 1.90 mmol) was dissolved in THF (20.00 mL), 3M NaOH aqueous 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 reaction was completed by TLC monitoring, THF was concentrated, and the pH was adjusted to about 5 with 2N HCl aqueous solution, and then the pH was adjusted to about 10 with saturated sodium bicarbonate. Methyltetrahydrofuran was added to the reaction solution to extract the product, and the organic phase was separated and concentrated. Methyl tert-butyl ether (30.00 mL) was added, and the mixture was slurried at room temperature for 1 h and then filtered. After drying at 50°C under normal pressure for 16 h, the intermediate 24-5 (996.00 mg) was obtained, with a yield of 92%, LC-MS (ESI-MS): m / z=566[M+H] + .

[0444] Step 6 Preparation of intermediate 24-6: 4-(aminomethyl)-1-methylcyclohexanol (24-6)

[0445] 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, fill with nitrogen for protection, place at -40 ° C for low temperature cooling, control the internal temperature to be maintained at -30 ° C to -40 ° C, add methylmagnesium bromide THF solution (35.20 mL, 35.20 mmol) dropwise, place at 0 ° C for 2 h after the addition is complete, and then add water (5.00 ml) to quench the reaction. Monitor by TLC, add EA and water for extraction, separate the liquids, and extract the aqueous phase with EA again. Combine the two EA (ethyl acetate) phases, add DCM (20.00 mL) after concentration, and then add TFA (trifluoroacetic acid, 6.00 g, 52.80 mmol) at room temperature, and react for 15 h overnight. The reaction was completed by TLC monitoring, and the reaction solution was concentrated to near dryness to obtain intermediate 24-6 (566.00 mg), with a yield of 26%, LC-MS (ESI-MS): m / z=144 [M+H] + .

[0446] Step 7 Preparation of intermediate 24-7: 4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (24-7)

[0447] The 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, and TEA (2.20 g, 22.00 mmol) was added, and the reaction was carried out at room temperature for 8 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated, and DCM and water were added for extraction, and the organic phase was separated and purified by silica gel column chromatography to obtain the crude intermediate 24-7 (623.00 mg), with a yield of 77%, LC-MS (ESI-MS): m / z=344 [M+H] + .

[0448] Step 8 Preparation of intermediate 24-8: 4-((((1r, 4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (24-8)

[0449] Intermediate 24-7 (623.00 mg, 1.81 mmol, 1.00 eq) was separated and purified by preparative HPLC to obtain intermediate 24-8, LC-MS (ESI-MS): m / z=344 [M+H] + .

[0450] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (024)

[0451] Intermediate 24-5 (679.00 mg, 1.20 mmol) was dissolved in dichloromethane, triethylamine and HATU were added, and the mixture was stirred at room temperature for about 1 h, and then intermediate 24-8 (275.00 mg, 0.80 mmol) and DMAP were added, and the reaction was continued at room temperature overnight. After the reaction was completed by TLC monitoring, water was added to quench the mixture, and the mixture was extracted with dichloromethane, washed with water and saturated brine, and the organic phase was separated and 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] + .

[0452] Example 8: N-((4-((((S)-1,4-dioxane-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)picolinamide (025)

[0453]

[0454] Referring to the synthesis method of Example 7, the intermediate 24-6 was replaced with (1,4-dioxane-2-yl)methylamine hydrochloride to synthesize the target compound 025. LC-MS (ESI-MS): m / z=865[M+H] + .

[0455] 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. 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=15.2 Hz,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).

[0456] 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)methyl)amino)phenyl)sulfonyl)picolinamide (026)

[0457]

[0458] Referring to the synthesis method of Example 7, the intermediate 24-6 was replaced with (tetrahydro-2H-pyran-4-yl)methylamine hydrochloride (and the chiral resolution step was omitted) to synthesize the target compound 026, LC-MS (ESI-MS): m / z=863[M+H] + . 1HNMR(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).

[0459] 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)

[0460]

[0461] Referring to the synthesis method of Example 7, the intermediate 24-6 was replaced with (1-methylpiperidin-4-yl)methylamine to synthesize the target compound 027. LC-MS (ESI-MS): m / z=876 [M+H] + .

[0462] 1H NMR (400MHz, DMSO-d6) 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).

[0463] 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]nonan-7-yl)-N-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)picolinamide (028)

[0464]

[0465] Referring to the synthesis method of Example 7, (S)-2-(2-isopropylphenyl)pyrrolidine was replaced with (S)-2-(2-cyclopropylphenyl)pyrrolidine to synthesize the target compound 028. LC-MS (ESI-MS): m / z=889[M+H] + .

[0466] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (029)

[0467]

[0468] Referring to the synthesis method of Example 11, (S)-2-(2-cyclopropylphenyl)pyrrolidine was replaced with (S)-2-(2-(trifluoromethyl)phenyl)pyrrolidine to synthesize the target compound 029. LC-MS (ESI-MS): m / z=917 [M+H] + .

[0469] 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)picolinamide (030)

[0470]

[0471] Referring to the synthesis method of Example 11, (S)-2-(2-cyclopropylphenyl)pyrrolidine was replaced with (S)-2-(2-methoxyphenyl)pyrrolidine to synthesize the target compound 030. LC-MS (ESI-MS): m / z=879[M+H] + .

[0472] Example 14: 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)

[0473]

[0474] Referring to the synthesis method of Example 11, (S)-2-(2-cyclopropylphenyl)pyrrolidine was replaced with (S)-2-(2-fluorophenyl)pyrrolidine to synthesize the target compound 031. LC-MS (ESI-MS): m / z=867[M+H] + .

[0475] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (032)

[0476]

[0477] Referring to the synthesis method of Example 7, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,3,4-trifluorobenzoic acid methyl ester to synthesize the target compound 032. LC-MS (ESI-MS): m / z=908 [M+H] + .

[0478] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (033)

[0479]

[0480] Referring to the synthesis method of Example 7, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,4,5-trifluorobenzoic acid methyl ester to synthesize the target compound 033. LC-MS (ESI-MS): m / z=908[M+H] + .

[0481] 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),8.42–8.30(m,2H),7.89(d,J=2.7Hz,1H),7.60(t,J=9.5Hz,1H),7.54–7.4 6(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).

[0482] 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)

[0483]

[0484] Referring to the synthesis method of Example 7, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,3,4,5-tetrafluorobenzoic acid methyl ester to synthesize the target compound 034. LC-MS (ESI-MS): m / z=926[M+H] + .

[0485] 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)methyl)amino)phenyl)sulfonyl)nicotinamide (035)

[0486]

[0487] Preparation of intermediate 35-1: 2,2,2-trifluoroacetic acid and 7-azaspiro[3.5]nonan-2-one (1:1) (35-1)

[0488] 2-Oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (5.0 g, 20.9 mmol) was dissolved in DCM (100.00 mL), TFA (15.50 mL) was slowly added, and the mixture was heated to 40°C and refluxed for 2 h. After the reaction was completed, the reaction solution was directly concentrated to near dryness to obtain intermediate 35-1 (4.80 g) with a yield of 97%. LC-MS (ESI-MS): m / z=140 [M+H] + .

[0489] Preparation of intermediate 35-2: 4-chloro-6-(2-oxo-7-azaspiro[3.5]nonan-7-yl)nicotinate methyl ester (35-2)

[0490] 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, heated to 80°C, and reacted for 2 h. After the reaction was completed, EA and water were added for extraction, the organic phase was separated, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 35-2 (3.97 g), with a yield of 19%, LC-MS (ESI-MS): m / z=309 [M+H] + .

[0491] Preparation of intermediate 35-3: 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-oxo-7-azaspiro[3.5]nonan-7-yl)nicotinate (35-3)

[0492] 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 CO3 (9.50 g, 29.16 mmol) was dissolved in DMF (60.00 mL), heated and stirred in an oil bath at 100°C for 2 h, cooled to room temperature after the reaction was completed, extracted with EA and water, separated the organic phase, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate 35-3 (3.20 g) with a yield of 81%. LC-MS (ESI-MS): m / z=407 [M+H] + .

[0493] 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)methyl)amino)phenyl)sulfonyl)nicotinamide (035)

[0494] Referring to the synthesis method of Example 9, intermediate 24-3 was replaced by intermediate 35-3 to synthesize the target compound 035. LC-MS (ESI-MS): m / z=863[M+H] + .

[0495] 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).

[0496] 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)methyl)amino)phenyl)sulfonyl)benzamide (084)

[0497]

[0498] Referring to the synthesis method of Example 9, (S)-2-(2-isopropylphenyl)pyrrolidine was replaced by 2-(2-isopropylphenyl)pyrrolidine, and 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced by 2,3,4-trifluorobenzoic acid methyl ester to synthesize the target compound 084. LC-MS (ESI-MS): m / z=880[M+H] + .

[0499] 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). Example 20: 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]nonan-7-yl)benzamide (085)

[0500]

[0501] Referring to the synthesis method of Example 19, (tetrahydro-2H-pyran-4-yl)methylamine hydrochloride was replaced with (1,4-dioxane-2-yl)methylamine hydrochloride to synthesize the target compound 085, LC-MS (ESI-MS): m / z=882 [M+H] + .

[0502] 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).

[0503] Example 21: N-((4-(((1,4-dioxane-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)

[0504]

[0505] Preparation of Intermediate 86-1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-6-fluorobenzoic acid methyl ester (86-1)

[0506] 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), and potassium phosphate (5.07 g, 23.91 mmol) were dissolved in diethylene glycol dimethyl ether (70.00 mL), and the temperature was raised to 100°C for reaction for 21 h. After the reaction was completed, H2O and 2M aqueous hydrochloric acid solution were added to adjust the pH to neutral. The diethylene glycol dimethyl ether was concentrated under reduced pressure by a vacuum oil pump, and EA and water were added for extraction. The organic phase was separated and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain solid intermediate 86-1 (3.30 g) with a yield of 45%. LC-MS (ESI-MS): m / z=365[M+H] + .

[0507] Preparation of Intermediate 86-2: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-6-fluorobenzoic acid (86-2)

[0508] Intermediate 86-1 (3.30 g, 9.04 mmol) was dissolved in THF (66.00 mL), 3M NaOH aqueous solution (31.00 mL, 90.40 mmol) was added, and heated at 60°C for 14 h. After the reaction was completed by TLC monitoring, THF was directly concentrated, the pH was adjusted to about 2-3, filtered, the filter cake was rinsed with water and PE, and dried at 50°C under normal pressure to obtain solid intermediate 86-2 (2.90 g), with a yield of 91%, LC-MS (ESI-MS): m / z=351 [M+H] + .

[0509] Preparation of Intermediate 86-3: 2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (86-3)

[0510] 2-(2-isopropylphenyl)pyrrolidine (7.00 g, 37.00 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (13.30 g, 55.5 mmol) were dissolved in DCM (150.00 mL), stirred at room temperature for 10 min, and then STAB (sodium triacetoxyborohydride, 31.40 g, 148.00 mmol) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 mixture was reacted at room temperature for 16 h. After the reaction was completed by LC-MS tracking, the reaction solution was directly concentrated to near dryness, dissolved in water, and the pH was adjusted to about 8-10 with saturated sodium bicarbonate. DCM was added to extract the liquid, the DCM phase was separated, and the mixture was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain intermediate 86-3 (6.60 g) with a yield of 57%. LC-MS (ESI-MS): m / z=313[M+H] + .

[0511] Preparation of Intermediate 86-4: 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)benzoic acid (86-4)

[0512] 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-butylphosphine, [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 a mixed solution of THF (16.00 mL) and toluene (16.00 mL), stirred at room temperature for 5 min, 1 mol / L THF solution of LiHMDS (18.00 ml, 18.24 mmol) was added, and then the temperature was raised to 50 °C for 4 h. After the reaction was completed by LC-MS tracking, the reaction system was cooled to 0°C, 2 mol / L HCl aqueous solution was added to adjust the pH to about 5-6, and then saturated sodium bicarbonate was used to adjust the pH to 8, EA and water were added for extraction, the organic phase was separated, concentrated under reduced pressure, and purified by silica gel column chromatography. The obtained product was further slurried and filtered with methyl tert-butyl ether to obtain solid intermediate 86-4 (690.00 mg), with a yield of 52%, LC-MS (ESI-MS): m / z=583[M+H] + .

[0513] 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-azaspiro[3.5]nonan-7-yl)benzamide (086)

[0514] Referring to the synthesis method of steps 6 to 9 of Example 7, intermediate 24-5 was replaced by intermediate 86-4, and intermediate 24-6 was replaced by (1,4-dioxane-2-yl)methylamine hydrochloride, to synthesize the target compound 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,1 H),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).

[0515] 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)methyl)amino)phenyl)sulfonyl)benzamide (087)

[0516]

[0517] Referring to the synthesis method of Example 21, (1,4-dioxane-2-yl)methylamine hydrochloride was replaced with (tetrahydro-2H-pyran-4-yl)methylamine hydrochloride to synthesize the target compound 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).

[0518] 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)

[0519]

[0520] Referring to the synthesis method of Example 19, the intermediate (tetrahydro-2H-pyran-4-yl)methylamine hydrochloride was replaced with the intermediate (1-methylpiperidin-4-yl)methylamine to synthesize the target compound 088. LC-MS (ESI-MS): m / z=893 [M+H] + .

[0521] 1H NMR (400MHz, DMSO-d6) 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=7.1H z,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).

[0522] 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]nonan-7-yl)picolinamide (089)

[0523]

[0524] Preparation of Intermediate 89-1: 4-(((4-fluoropiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide (89-1)

[0525] 4-Fluoro-3-nitrobenzenesulfonamide (1.9 g, 8.61 mmol) was dissolved in THF (60.00 mL), and tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate (2 g, 8.61 mmol) and TEA (2 g, 8.61 mmol) were added in sequence, and the mixture was stirred at 30°C for 12 h. After the reaction was completed, EA and water were added for extraction, the organic phase was separated, and the mixture was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain solid intermediate 89-1 (2.88 g), with a yield of 77.4%, LC-MS (ESI-MS): m / z=433 [M+H] + .

[0526] 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]nonan-7-yl)picolinamide (089)

[0527] Referring to the synthesis method of Example 19, methyl 2,3,4-trifluorobenzoate is replaced with methyl 3,5-difluoropyridine-2-carboxylate, and the intermediate 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide is replaced with intermediate 89-1 to synthesize 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]nonane-7-yl)picolinyl)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, and the reaction was stirred at room temperature for 14 h, filtered and dried, and concentrated under reduced pressure to synthesize the target compound 089. LC-MS (ESI-MS): m / z=880[M+H] + .

[0528] 1 H NMR (400MHz, DMSO-d6) 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).

[0529] Example 25: 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)

[0530]

[0531] Referring to the synthesis method of Example 24, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 2-aminomethyl-4-BOC-morpholine to synthesize the target compound 090. LC-MS (ESI-MS): m / z=864 [M+H] + .

[0532] Example 26: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2-morpholinacetyl)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)

[0533]

[0534] Compound 089 (1.32 g, 1.50 mmol), 2-morpholineacetic acid (0.30 g, 2.07 mmol), and 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, and the reaction was stirred for 12 h. After the reaction was completed, EA and water were added for extraction, and the organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 091 (1.18 g), with a yield of 78%, LC-MS (ESI-MS): m / z=1007 [M+H] + .

[0535] 1H NMR (400MHz, DMSO-d6) 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=2.3H z,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=5.6Hz,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).

[0536] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (092)

[0537]

[0538] Referring to the synthesis method of Example 26, 2-morpholineacetic acid was replaced with 2-(dimethylamino)acetic acid to synthesize the target compound 092. LC-MS (ESI-MS): m / z=965[M+H] + .

[0539] 1H NMR (400MHz, DMSO-d6) 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).

[0540] Example 28: 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)

[0541]

[0542] Referring to the synthesis method of Example 1, (S)-2-(2-isopropylphenyl)pyrrolidine was replaced by the intermediate 2-(2-isopropylphenyl)pyrrolidine, and (1-aminocyclopropyl)methanol was replaced by 2-amino-3-morpholinopropane-1-ol to synthesize compound 093. LC-MS (ESI-MS): m / z=905[M+H] + . 1H NMR (400MHz, DMSO-d6) 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).

[0543] Example 29: 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)

[0544]

[0545] Referring to the synthesis method of Example 26, compound 089 was replaced by compound 090 to synthesize the target compound 094. LC-MS (ESI-MS): m / z=991[M+H] + . 1H NMR (400MHz, DMSO-d6) 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).

[0546] 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)

[0547]

[0548] Referring to the synthesis method of Example 29, 2-morpholineacetic acid was replaced with 2-(dimethylamino)acetic acid to synthesize the target compound 095. LC-MS (ESI-MS): m / z=949 [M+H] + .

[0549] 1H NMR (400MHz, DMSO-d6) δ11.61(s,1H),8.50–8.44(m,2H),8.02(s,1H),7.96(d,J=2.6H z,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).

[0550] Example 31: 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)

[0551]

[0552] Compound 089 (1.20 g, 1.36 mmol) was dissolved in DMF (20.00 mL), oxetane-3-one (0.30 g, 4.08 mmol) was added, and the mixture was stirred at room temperature for 2 h. Sodium cyanoborohydride (0.17 g, 2.72 mmol) was added, and the pH was adjusted to about 5.5 by glacial acetic acid, and the mixture was stirred at room temperature for 12 h. After the reaction was completed by TCL monitoring, water was added to quench the reaction, and the mixture was 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 solid product 096 (920.00 mg), with a yield of 72.3%, LC-MS (ESI-MS): m / z=936 [M+H] + .

[0553] 1H NMR (400MHz, DMSO-d6) 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=6.1H z,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).

[0554] Example 32: 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)

[0555]

[0556] Referring to the synthesis method of Example 31, Compound 089 was replaced by Compound 090 to obtain Compound 097. LC-MS (ESI-MS): m / z=920 [M+H] + .

[0557] 1H NMR(400MHz,DMSO-d6)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=11.2H z,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).

[0558] 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]nonan-7-yl)picolinamide (099)

[0559]

[0560] Preparation of Intermediate 99-1: tert-butyl 4-fluoro-4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate (099-1)

[0561] 4-Fluoro-3-nitrobenzenesulfonamide (1.00 g, 4.54 mmol) was dissolved in THF (20.00 mL), tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.06 g, 4.54 mmol) was added, and the mixture was cooled to 0°C in an ice bath. NaH (727 mg, 18.17 mmol) was added in batches, and the mixture was stirred at 0°C for 5 h. After the reaction was completed, DCM and water were added for extraction using LC-MS tracking. The organic phase was separated, filtered, dried, and concentrated under reduced pressure. The 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] + .

[0562] 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]nonan-7-yl)picolinamide (099)

[0563] Referring to the synthesis method of Example 24, intermediate 89-1 was replaced by 99-1 to synthesize the target compound 099. LC-MS (ESI-MS): m / z=881[M+H] + .

[0564] 1 H NMR (400MHz, DMSO-d6) 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,2 H),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,2 H), 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).

[0565] Example 34: 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)

[0566]

[0567] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 099 to synthesize the target compound 098. LC-MS (ESI-MS): m / z=937[M+H] + .

[0568] 1 H NMR(400MHz,DMSO-d6)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),7.29–7.2 5(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,2 H),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).

[0569] Example 35: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinacetyl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (100)

[0570]

[0571] 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 to synthesize the target compound 100. LC-MS (ESI-MS): m / z=1008[M+H] + .

[0572] 1 H NMR(400MHz, DMSO-d6)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).

[0573] 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)

[0574]

[0575] Referring to the synthesis method of Example 35, 2-morpholineacetic acid-ketone was replaced with 2-(dimethylamino)acetic acid to synthesize the target compound 101, LC-MS (ESI-MS): m / z=966[M+H] + .

[0576] 1 H NMR (400MHz, DMSO-d6) 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=14.7H z,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=11.6,6.8 Hz,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).

[0577] 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]nonan-7-yl)nicotinamide (102)

[0578]

[0579] Referring to the synthesis method of Example 7, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced by 2,6-dichloronicotinate methyl ester (to obtain intermediate 102-5 corresponding to intermediate 24-5), (S)-2-(2-isopropylphenyl)pyrrolidine was replaced by 2-(2-isopropylphenyl)pyrrolidine, wherein intermediate 24-7 was not subjected to chiral resolution, and the reaction in step 9 (with intermediate 102-5) in Example 7 was directly carried out to synthesize the target compound 102, LC-MS (ESI-MS): m / z=891[M+H] + .

[0580] 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)

[0581]

[0582] Referring to the synthesis methods of Examples 24 and 26, the target compound 103 was synthesized by replacing 3,5-difluoropicolinic acid methyl ester in Example 26 with 2,4,5-trifluorobenzoic acid methyl ester and 2-morpholineacetic acid with ethyl bicarbonate. LC-MS (ESI-MS): m / z=969 [M+H] + .

[0583] 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)nicotinamide (104)

[0584]

[0585] Referring to the synthesis method of Example 18, (S)-2-(2-isopropylphenyl)pyrrolidine was replaced by 2-(2-isopropylphenyl)pyrrolidine, and (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride was replaced by N,N-dimethylethylenediamine to synthesize the target compound 104. LC-MS (ESI-MS): m / z=836[M+H] + .

[0586] 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)nicotinamide (105)

[0587]

[0588] Referring to the synthesis method of Example 39, N,N-dimethylethylenediamine was replaced with 3-isopropoxypropan-1-amine to synthesize the target compound 105. LC-MS (ESI-MS): m / z=865[M+H] + .

[0589] 1 H NMR (400MHz, DMSO-d6) 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).

[0590] Example 41: 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)

[0591]

[0592] Referring to the synthesis method of Example 28, 2-amino-3-morpholinopropane-1-ol was replaced with 2-amino-3-(4-methylpiperazin-1-yl)propan-1-ol to synthesize the target compound 106. LC-MS (ESI-MS): m / z=918 [M+H] + .

[0593] 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)nicotinamide (107)

[0594]

[0595] Referring to the synthesis method of Example 39, N,N-dimethylethylenediamine was replaced by N 1 ,N 1 -Dimethylpropane-1,3-diamine, can be used to synthesize the target compound 107, LC-MS (ESI-MS): m / z=850[M+H] + .

[0596] Example 43: 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)

[0597]

[0598] Referring to the synthesis method of Example 19, 2,3,4-trifluorobenzoic acid methyl ester was replaced with 2,6-dichloronicotinate methyl ester to synthesize the target compound 108. LC-MS (ESI-MS): m / z=863[M+H] + .

[0599] 1 H NMR (400MHz, DMSO-d6) 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).

[0600] Example 44: 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)

[0601]

[0602] Referring to the synthesis method of Example 27, 3,5-difluoropicolinic acid methyl ester was replaced with 2,6-dichloronicotinate methyl ester to synthesize the target compound 109. LC-MS (ESI-MS): m / z=965 [M+H] + .

[0603] 1H NMR (400MHz, DMSO-d6) 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).

[0604] 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)

[0605]

[0606] Referring to the synthesis method of Example 36, 3,5-difluoropicolinic acid methyl ester was replaced with 2,6-dichloronicotinate methyl ester to synthesize the target compound 110. LC-MS (ESI-MS): m / z=966 [M+H] + .

[0607] 1H NMR (400MHz, DMSO-d6) δ11.55(d,J=2.3Hz,1H),8.29(d,J=2.2Hz,1H),8.07(d d,J=8.9,2.3Hz,1H),7.95–7.88(m,2H),7.66(d,J=8.2Hz,1H),7.57(d,J=2.5H z,1H),7.42(dd,J=5.6,2.7Hz,2H),7.23(dt,J=9.3,4.6Hz,2H),7.16(d,J=7.4 Hz,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).

[0608] Example 46: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinacetyl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (111)

[0609]

[0610] Referring to the synthesis method of Example 45, 2-(dimethylamino)acetic acid was replaced with 2-morpholineacetic acid to synthesize the target compound 111. LC-MS (ESI-MS): m / z=1008 [M+H] + .

[0611] 1H NMR (400MHz, DMSO-d6) 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=13.2 Hz,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).

[0612] 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)

[0613]

[0614] Referring to the synthesis method of Example 20, 2,3,4-trifluorobenzoic acid methyl ester was replaced with 2,6-dichloronicotinate methyl ester to synthesize the target compound 112. LC-MS (ESI-MS): m / z=865[M+H] + .

[0615] 1H NMR (400MHz, DMSO-d6) δ11.64–11.58(m,1H),8.59(d,J=2.2Hz,1H),8.52(t,J=5.7H z,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=7.9,4.0H z,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).

[0616] Example 48: N-((4-((1,4-dioxane-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)nicotinamide (113)

[0617]

[0618] Referring to the synthesis method of Example 33, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,6-dichloronicotinate methyl ester, and 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester was replaced with (1,4-dioxane-2-yl)methanol to synthesize the target compound 113. LC-MS (ESI-MS): m / z=866 [M+H] + .

[0619] 1H NMR (400MHz, DMSO-d6) 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=2 4.9,13.3,5.7Hz,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).

[0620] 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]nonan-7-yl)nicotinamide (115)

[0621]

[0622] Referring to the synthesis method of Example 48, (1,4-dioxane-2-yl)methanol was replaced with 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 115. LC-MS (ESI-MS): m / z=881[M+H] + .

[0623] Example 50: 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)

[0624]

[0625] Referring to the synthesis method of Example 25, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,6-dichloronicotinate methyl ester to synthesize the target compound 114. LC-MS (ESI-MS): m / z=864 [M+H] + .

[0626] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),8.46(d,J=2.0Hz,1H),8.40(t,J=5.9Hz,1H),7.93–7.84(m,3 H),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,1 H),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=3.4,1.9H z,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),2.3 1(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).

[0627] 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]nonan-7-yl)picolinamide (116)

[0628]

[0629] Referring to the synthesis method of Example 48, 2,6-dichloronicotinic acid methyl ester was replaced with 3,5-difluoropyridine-2-carboxylic acid methyl ester to synthesize the target compound 116. LC-MS (ESI-MS): m / z=866[M+H] + .

[0630] 1 H NMR (400MHz, DMSO-d6) 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).

[0631] Example 52: 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)

[0632]

[0633] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 114 to synthesize the target compound 117. LC-MS (ESI-MS): m / z=920 [M+H] + .

[0634] 1 H NMR (400MHz, DMSO-d6) 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=29.6H z,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).

[0635] 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)

[0636]

[0637] Referring to the synthesis method of Example 36, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 4,6-dichloronicotinate methyl ester to synthesize the target compound 118. LC-MS (ESI-MS): m / z=966 [M+H] + . 1H NMR (400MHz, DMSO-d6) 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,1 H),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=12.8,8.1H z, 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).

[0638] Example 54: 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)

[0639]

[0640] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 115 to synthesize the target compound 119. LC-MS (ESI-MS): m / z=937 [M+H] + .

[0641] 1H NMR (400MHz, DMSO-d6) δ11.57(s,1H),8.35–8.29(m,1H),8.12–8.06(m,1H),7.94(d,J=2.5H z,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).

[0642] 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)

[0643]

[0644] Referring to the synthesis method of Example 19, 2,3,4-trifluorobenzoic acid methyl ester was replaced with 2,4,5-trifluorobenzoic acid methyl ester to synthesize the target compound 121. LC-MS (ESI-MS): m / z=880 [M+H] + .

[0645] 1H NMR (400MHz, DMSO-d6) 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=3.4,1.9H z,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).

[0646] 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]nonan-7-yl)nicotinamide (135)

[0647]

[0648] Referring to the synthesis method of Example 24, intermediate 24-3 was replaced by intermediate 35-3 to synthesize the target compound 135. LC-MS (ESI-MS): m / z=880[M+H] + .

[0649] 1H NMR (400MHz, DMSO-d6) 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,3 H),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).

[0650] Example 57: 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)

[0651]

[0652] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 135 to synthesize the target compound 125. LC-MS (ESI-MS): m / z=936[M+H] + .

[0653] 1 H NMR (400MHz, DMSO-d6) 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).

[0654] Example 58: 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-(oxetane-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)sulfonyl)benzamide (122)

[0655]

[0656] Referring to the synthesis methods of Examples 24 and 57, the target compound 122 was synthesized by replacing tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate in Example 57 with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate. LC-MS (ESI-MS): m / z=902[M+H] + .

[0657] Example 59: 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-(oxetane-3-yl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)sulfonyl)benzamide (123)

[0658]

[0659] Referring to the synthesis method of Example 58, 2,6-diazaspiro[3.3]heptane was replaced with 2,6-diazaspiro[3.4]octane-6-carboxylic acid tert-butyl ester to synthesize the target compound 123. LC-MS (ESI-MS): m / z=916[M+H] + .

[0660] Example 60: 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-(oxetane-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)sulfonyl)benzamide (124)

[0661]

[0662] Referring to the synthesis method of Example 58, 2,6-diazaspiro[3.3]heptane was replaced with 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester to synthesize the target compound 124. LC-MS (ESI-MS): m / z=930[M+H] + .

[0663] Example 61: 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)

[0664]

[0665] Referring to the synthesis methods of Example 24 and Example 57, the intermediate 89-1 in Example 57 was replaced by the intermediate 99-1 to synthesize the target compound 126. LC-MS (ESI-MS): m / z=937 [M+H] + .

[0666] Example 62: 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)

[0667]

[0668] Referring to the synthesis methods of Examples 24 and 27, the intermediate 24-3 in Example 27 was replaced by the intermediate 35-3 to synthesize the target compound 127. LC-MS (ESI-MS): m / z=965[M+H] + .

[0669] 1H NMR (400MHz, DMSO-d6) 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=13.3,7.0H z,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).

[0670] 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)

[0671]

[0672] 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 to synthesize the target compound 133. LC-MS (ESI-MS): m / z=897 [M+H] + .

[0673] 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),2.8 2–2.57(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).

[0674] 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)

[0675]

[0676] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 133 to synthesize the target compound 120. LC-MS (ESI-MS): m / z=953[M+H] + .

[0677] 1H NMR (400MHz, DMSO-d6) 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,2 H),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=10.8H z,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).

[0678] Example 65: 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (130)

[0679]

[0680] Referring to the synthesis method of Example 27, compound 089 was replaced by compound 133 to synthesize the target compound 130. LC-MS (ESI-MS): m / z=982[M+H] + .

[0681] 1H NMR (400MHz, DMSO-d6) 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=7.3,2.0H z,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).

[0682] Example 66: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((4-fluoro-1-(oxetan-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)

[0683]

[0684] Referring to the synthesis method of Example 34, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2,4,5-trifluorobenzoic acid methyl ester to synthesize the target compound 128. LC-MS (ESI-MS): m / z=954 [M+H] + .

[0685] 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),7.88(s,1H),7.53(s,1H),7.41(d,J=3.1Hz,1 H),7.35–7.28(m,6H),7.16(s,2H),6.34(d,J=7.5Hz,1H),6.28(d,J=3.3Hz,1H),4.5 2(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).

[0686] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (129)

[0687]

[0688] 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 to synthesize the target compound 129. LC-MS (ESI-MS): m / z=983 [M+H] + .

[0689] 1H NMR (400MHz, DMSO-d6) 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).

[0690] 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)

[0691]

[0692] Referring to the synthesis method of Example 63, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with (R)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 134. LC-MS (ESI-MS): m / z=865 [M+H] + .

[0693] 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-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (131)

[0694]

[0695] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 134 to synthesize the target compound 131. LC-MS (ESI-MS): m / z=921[M+H] + .

[0696] 1 H NMR (400MHz, DMSO-d6) 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).

[0697] 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-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (132)

[0698]

[0699] Referring to the synthesis method of Example 69, (R)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (S)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 132. LC-MS (ESI-MS): m / z=921 [M+H] + .

[0700] 1H NMR (400MHz, DMSO-d6) 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, 6.6 Hz, 9H), 1.29 (d, J = 3.2 Hz, 1H), 1.08 (d, J = 6.8 Hz, 4H), 0.91–0.76 (m, 4H).

[0701] Example 71: 2-((1H-pyrrolo[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)

[0702]

[0703] Referring to the synthesis method of Example 7, 3,5-difluoropyridine-2-carboxylic acid methyl ester was replaced by 2,4,5-trifluorobenzoic acid methyl ester, and (S)-2-(2-isopropylphenyl)pyrrolidine was replaced by 2-(2-isopropylphenyl)pyrrolidine to synthesize the target compound 136. LC-MS (ESI-MS): m / z=908 [M+H] + .

[0704] 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)

[0705]

[0706] Referring to the synthesis method of Example 16, (S)-2-(2-isopropylphenyl)pyrrolidine was replaced with 2-phenylpyrrolidine to synthesize the target compound 137. LC-MS (ESI-MS): m / z=866[M+H] + .

[0707] 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]nonan-7-yl)nicotinamide (138)

[0708]

[0709] Referring to the synthesis method of Example 72, methyl 2,4,5-trifluorobenzoate was replaced with methyl 4,6-dichloronicotinate to synthesize the target compound 138. LC-MS (ESI-MS): m / z=849 [M+H] + .

[0710] Example 74: 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)

[0711]

[0712] Referring to the synthesis method of Example 72, 2-phenylpyrrolidine was replaced with 2-(2-fluorophenyl)pyrrolidine to synthesize the target compound 139. LC-MS (ESI-MS): m / z=884 [M+H] + .

[0713] 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)

[0714]

[0715] Referring to the synthesis method of Example 72, 2-phenylpyrrolidine was replaced with 2-(tert-butyl)pyrrolidine to synthesize the target compound 140. LC-MS (ESI-MS): m / z=846 [M+H] + .

[0716] 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)

[0717]

[0718] Referring to the synthesis method of Example 38, ethyl bicarbonate was replaced with methyl bicarbonate to synthesize the target compound 141, LC-MS (ESI-MS): m / z=955 [M+H] + .

[0719] 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)

[0720]

[0721] Referring to the synthesis method of Example 7, intermediate 24-3 was replaced by intermediate 35-3 to synthesize the target compound 142. LC-MS (ESI-MS): m / z=890[M+H] + .

[0722] 1H NMR (400MHz, DMSO-d6) 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).

[0723] 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)

[0724]

[0725] Referring to the synthesis method of Example 77, (S)-2-(2-isopropylphenyl)pyrrolidine was replaced with (R)-2-(2-isopropylphenyl)pyrrolidine to synthesize the target compound 143. LC-MS (ESI-MS): m / z=891[M+H] + .

[0726] Example 79: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-hydroxy-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl) (144)

[0727]

[0728] Referring to the synthesis method of Example 64, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 144. LC-MS (ESI-MS): m / z=951 [M+H] + .

[0729] 1 H NMR (400MHz, DMSO-d6) 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,1 H),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),6.2 4(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).

[0730] 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)

[0731]

[0732] Referring to the synthesis method of Example 63, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 148. LC-MS (ESI-MS): m / z=879 [M+H] + .

[0733] 1H NMR (400MHz, DMSO-d6) 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),1.7 9(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).

[0734] Example 81: 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)

[0735]

[0736] Referring to the synthesis method of Example 56, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 147. LC-MS (ESI-MS): m / z=862[M+H] + .

[0737] 1 H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.48–8.31(m,4H),7.93(d,J=2.6Hz,1H),7.7 5(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).

[0738] Example 82: 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-(oxetane-3-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (145)

[0739]

[0740] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 147 to synthesize the target compound 145. LC-MS (ESI-MS): m / z=918 [M+H] + .

[0741] 1 H NMR (400MHz, DMSO-d6) 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).

[0742] 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)

[0743]

[0744] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 148 to synthesize the target compound 146. LC-MS (ESI-MS): m / z=935[M+H] + .

[0745] 1 H NMR (400MHz, DMSO-d6) 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),7.3 8(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).

[0746] 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)methyl)amino)phenyl)sulfonyl)benzamide (149)

[0747]

[0748] Referring to the synthesis method of Example 63, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 2-(aminomethyl)-5-oxopyrrolidine to synthesize the target compound 149. LC-MS (ESI-MS): m / z=879 [M+H] + .

[0749] 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-oxoimidazolidin-1-yl)ethyl)amino)phenyl)sulfonyl)benzamide (150)

[0750]

[0751] Referring to the synthesis method of Example 63, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 3-(2-aminoethyl)-2-oxoimidazolidine to synthesize the target compound 150. LC-MS (ESI-MS): m / z=894 [M+H] + .

[0752] 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-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (151)

[0753]

[0754] Referring to the synthesis method of Example 64, 2-(2-isopropylphenyl)pyrrolidine was replaced with (S)-2-(2-isopropylphenyl)pyrrolidine to synthesize the target compound 151. LC-MS (ESI-MS): m / z=953 [M+H] + .

[0755] 1H NMR (400MHz, DMSO-d6) 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).

[0756] Example 87: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (153)

[0757]

[0758] Referring to the synthesis method of Example 64, the target compound 153 was synthesized by replacing oxetane-3-one with propan-2-one. LC-MS (ESI-MS): m / z=939 [M+H] + .

[0759] 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-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (155)

[0760]

[0761] Referring to the synthesis method of Example 64, the target compound 155 was synthesized by replacing oxetane-3-one with 2,2,2-trifluoroacetaldehyde. LC-MS (ESI-MS): m / z=979 [M+H] + .

[0762] Example 89: (S)-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 (152)

[0763]

[0764] Referring to the synthesis method of Example 57, 2-(2-isopropylphenyl)pyrrolidine was replaced with (S)-2-(2-isopropylphenyl)pyrrolidine to synthesize the target compound 152. LC-MS (ESI-MS): m / z=936 [M+H] + .

[0765] 1 H NMR (400MHz, DMSO-d6) 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).

[0766] Example 90: (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (154)

[0767]

[0768] Referring to the synthesis method of Example 89, the target compound 154 was synthesized by replacing oxetane-3-one with propan-2-one. LC-MS (ESI-MS): m / z=922 [M+H] + .

[0769] 1 H NMR (400MHz, DMSO-d6) 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).

[0770] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (156)

[0771]

[0772] Referring to the synthesis method of Example 57, the target compound 156 was synthesized by replacing oxetane-3-one with 2,2,2-trifluoroacetaldehyde. LC-MS (ESI-MS): m / z=962 [M+H] + .

[0773] Example 92: 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)

[0774]

[0775] Referring to the synthesis method of Example 64, 2,4,5-trifluorobenzoic acid methyl ester was replaced with 2,4-difluoro-5-methylbenzoic acid methyl ester to synthesize the target compound 157. LC-MS (ESI-MS): m / z=949 [M+H] + .

[0776] 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-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (158)

[0777]

[0778] Referring to the synthesis method of Example 64, 2,4,5-trifluorobenzoic acid methyl ester was replaced with 2,3,4,6-tetrafluorobenzoic acid methyl ester to synthesize the target compound 158. LC-MS (ESI-MS): m / z=971 [M+H] + .

[0779] 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-(oxetan-3-yl)piperidin-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide (159)

[0780]

[0781] Referring to the synthesis method of Example 64, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 4-(2-aminoethyl)piperidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 158. LC-MS (ESI-MS): m / z=949 [M+H] + .

[0782] 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)

[0783]

[0784] Referring to the synthesis method of Example 63, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 4-carbamoylpiperidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 160. LC-MS (ESI-MS): m / z=893 [M+H] + .

[0785] Example 96: 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)

[0786]

[0787] Referring to the synthesis method of Example 56, 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 4-carbamoylpiperidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 161. LC-MS (ESI-MS): m / z=876 [M+H] + .

[0788] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (162)

[0789]

[0790] Referring to Example 33, the synthetic method for preparing intermediate 99-1 is used, and (4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester is replaced with (1r, 4r)-4-(hydroxymethyl)-1-methylcyclohexane-1-ol to obtain the product (1r, 4r)-4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrobenzenesulfonamide.

[0791] Referring to the synthesis method of Example 7, 3,5-difluoropicolinic acid methyl ester was replaced by 2,4,5-trifluorobenzoic acid methyl ester, and intermediate 24-7 was replaced by 4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrobenzenesulfonamide to synthesize the target compound 162. LC-MS (ESI-MS): m / z=909 [M+H] + .

[0792] 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]nonan-7-yl)benzamide (163)

[0793]

[0794] Referring to the synthesis method of Example 55, (tetrahydro-2H-pyran-4-yl)methylamine hydrochloride was replaced with 4-(aminomethyl)cyclohexan-1-ol to synthesize the target compound 163. LC-MS (ESI-MS): m / z=894 [M+H] + .

[0795] 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)nicotinamide (164)

[0796]

[0797] Referring to the synthesis method of Example 24, intermediate 24-3 was replaced by intermediate 35-3, and intermediate 24-6 was replaced by 4-(aminomethyl)cyclohexan-1-ol to synthesize the target compound 164. LC-MS (ESI-MS): m / z=877 [M+H] + .

[0798] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (165)

[0799]

[0800] Referring to the synthesis method of Example 16, the target compound 165 was synthesized by replacing tert-butyl ((4-oxocyclohexyl)methyl)carbamate with tert-butyl ((1s,3s)-(3-oxocyclobutyl)methyl)carbamate. LC-MS (ESI-MS): m / z=880 [M+H] + .

[0801] 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)

[0802]

[0803] Referring to the synthesis method of Example 7, intermediate 24-3 was replaced by intermediate 35-3, and ((4-oxocyclohexyl)methyl)carbamic acid tert-butyl ester was replaced by ((3-oxocyclobutyl)methyl)carbamic acid tert-butyl ester to synthesize the target compound 166. LC-MS (ESI-MS): m / z=863[M+H] + .

[0804] 1 H NMR (400MHz, DMSO-d6) 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),6.4 2–6.36(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).

[0805] 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)

[0806]

[0807] Referring to the synthesis method of Example 16, the intermediate 24-6 was replaced with 3-(aminomethyl)cyclobutane-1-ol to synthesize the target compound 167. LC-MS (ESI-MS): m / z=866[M+H] + .

[0808] 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-azaspiro[3.5]nonan-7-yl)nicotinamide (168)

[0809]

[0810] Referring to the synthesis method of Example 7, intermediate 24-3 was replaced by intermediate 35-3, and intermediate 24-6 was replaced by 3-(aminomethyl)cyclobutane-1-ol to synthesize the target compound 168. LC-MS (ESI-MS): m / z=849 [M+H] + .

[0811] Example 104: (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)

[0812]

[0813] Referring to the synthesis method of Example 63, 2-(2-isopropylphenyl)pyrrolidine was replaced with (S)-2-(2-isopropylphenyl)pyrrolidine, and 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with 3-(aminomethyl)azetidine-1-carboxylic acid tert-butyl ester to synthesize the target compound 169. LC-MS (ESI-MS): m / z=851 [M+H]+ .

[0814] Example 105: (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-(oxetane-3-yl)azetidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (170)

[0815]

[0816] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 169 to synthesize the target compound 170. LC-MS (ESI-MS): m / z=907 [M+H] + .

[0817] 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-(oxetane-3-yl)azetidin-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (171)

[0818]

[0819] Referring to the synthesis method of Example 105, methyl 2,4,5-trifluorobenzoate was replaced with methyl 4,6-dichloronicotinate to synthesize the target compound 171. LC-MS (ESI-MS): m / z=890 [M+H] + .

[0820] 1H NMR (400MHz, DMSO-d6) 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(d d,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=6.5H z,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).

[0821] Example 107: (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)

[0822]

[0823] Referring to the synthesis method of Example 104, tert-butyl 3-(aminomethyl)azetidine-1-carboxylate was replaced with tert-butyl 3-(aminomethyl)-3-methylazetidine-1-carboxylate to synthesize the target compound 172. LC-MS (ESI-MS): m / z=865 [M+H] + .

[0824] Example 108: (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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (173)

[0825]

[0826] Referring to the synthesis method of Example 31, compound 089 was replaced by compound 172 to synthesize the target compound 173. LC-MS (ESI-MS): m / z=907 [M+H] + .

[0827] 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)

[0828]

[0829] Referring to the synthesis method of Example 16, (S)-2-(2-isopropylphenyl)pyrrolidine was replaced with (S)-2-(2,3-difluorophenyl)pyrrolidine to synthesize the target compound 174. LC-MS (ESI-MS): m / z=902 [M+H] + .

[0830] 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)

[0831]

[0832] Referring to the synthesis method of Example 7, intermediate 24-3 was replaced by intermediate 35-3, and (S)-2-(2-isopropylphenyl)pyrrolidine was replaced by (S)-2-(2,3-difluorophenyl)pyrrolidine to synthesize the target compound 175. LC-MS (ESI-MS): m / z=885[M+H] + .

[0833] 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)

[0834]

[0835] Referring to the synthesis method of Example 109, (S)-2-(2,3-difluorophenyl)pyrrolidine was replaced with (S)-2-(2,6-difluorophenyl)pyrrolidine to synthesize the target compound 176. LC-MS (ESI-MS): m / z=902 [M+H] + .

[0836] 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)

[0837]

[0838] Referring to the synthesis method of Example 110, (S)-2-(2,3-difluorophenyl)pyrrolidine was replaced with (S)-2-(2,6-difluorophenyl)pyrrolidine to synthesize the target compound 177. LC-MS (ESI-MS): m / z=885 [M+H] + .

[0839] Referring to the synthesis method of Example 1, the following compounds can be synthesized using similar synthesis routes and methods:

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854] Referring to the synthesis method of Example 88, the following compound can be synthesized using a similar synthesis route and method:

[0855]

[0856] Referring to the synthesis method of Example 91, the following compound can be synthesized using a similar synthesis route and method:

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865] Referring to the synthesis method of Example 31, the following compound can be synthesized using a similar synthesis route and method:

[0866]

[0867]

[0868] Example 217: BCL2 / BAK protein interaction blocking activity test

[0869] The 500nM Tag1-BCL2 protein stock solution was diluted to 5nM using 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. First, 5μL of Tag1-BCL2 protein dilution was added to each well, and then different concentrations of compounds (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) were added, and DMSO was used as a blank control. Finally, 5μL of Tag2-BAK protein dilution was added to each well, centrifuged and mixed, and incubated at room temperature for 15 minutes. Then anti-Tag1-Eu3+ and anti-Tag2-XL665 in the kit were added and reacted at room temperature for 2 hours. The plate was read using a BIO-Tek NEO2 multifunctional microplate reader (excitation 620 nM, emission 665 nM), and the IC was calculated using GraphPad Prism 5.0 50 The results are shown in Table 1.

[0870] Table 1 Protein blocking inhibitory activity results

[0871]

[0872]

[0873]

[0874] +:IC 50 <10nM;++:10nM <IC 50 <100nM;+++:100nM <IC 50 <1000nM;++++:1000nM <IC 50

[0875] The results in Table 1 show that the compounds of the present invention have potent BCL2 / BAK blocking activity.

[0876]

[0877] Example 218 BCL-XL enzyme molecular level activity test

[0878] In a 384 white shallow well plate, the total reaction volume is 10 μL. Specifically, it includes 2 μL of the test compound (2% DMSO), 4 μL of His-tagged recombinant protein and 4 μL of Biotin-tagged BIM protein peptide. After 1 hour of reaction, 5 μL of Anti-His and streptavidin-tagged XL665 antibody diluent diluted with detection buffer are added respectively. After incubation at room temperature for 4 hours, the Envision multi-function microplate reader is used to read the value to detect the effect of the test compound on the binding ability of BCL-XL and Bim protein peptide. The Envision parameter setting is 320nm excitation light, 615nm and 665nm emission light. The signal ratio of 665nm and 615nm indirectly reflects the binding ability of anti-apoptotic protein and Bim protein peptide. Background wells without BCL2 and full binding activity wells of recombinant protein and Bim protein peptide without compounds are set in the reaction.

[0879] IC of the compound's ability to inhibit the binding of anti-apoptotic proteins to Bim protein peptides 50 The values ​​were calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0880] Table 2 BCL-XL enzyme molecular level activity test

[0881]

[0882]

[0883] The results in Table 2 show that the inhibitory activity of the compounds of the present invention on BCL-XL is weak.

[0884] Example 219 Molecular Activity Test of Anti-apoptotic Protein BCL2 (G101V)

[0885] The binding ability of the anti-apoptotic protein BCL2 (G101V) and the pro-apoptotic protein Bim was detected by time-resolved fluorescence technology. The reaction of this method was carried out in a 384 white shallow well plate, and the total reaction volume was 10μL. Specifically, it included 2μL of the test compound (2% DMSO), 4μL of His-tagged recombinant protein and 4μL of Biotin-tagged BIM protein peptide. After 1 hour of reaction, 5μL of Anti-His and streptavidin-tagged XL665 antibody diluent diluted with detection buffer were added respectively. After incubation at room temperature for 4 hours, the Envision multi-function microplate microplate reader was used to read the value, thereby detecting the effect of the test compound on the binding ability of BCL2 (G101V) and Bim protein peptide. The Envision parameter setting is excitation light 320nm, emission light 615nm and 665nm. The signal ratio of 665nm and 615nm indirectly reflects the binding ability of anti-apoptotic protein and Bim protein peptide. In the reaction, background wells without BCL2 and active wells containing full binding of recombinant protein and Bim protein polypeptide without compounds were set.

[0886] IC of the compound's ability to inhibit the binding of anti-apoptotic proteins to Bim protein peptides 50 The values ​​were calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0887] Table 3 Inhibitory activity of the compounds of the present invention on BCL2 (G101V)

[0888]

[0889]

[0890] The results in Table 3 show that the compounds of the present invention have potent BCL2(G101V) inhibitory activity.

[0891] Example 220 BCL2 (D103Y) molecular activity test

[0892] The binding ability of the anti-apoptotic protein BCL2 (D103Y) and the pro-apoptotic protein Bim was detected by time-resolved fluorescence technology. The reaction of this method was carried out in a 384 white shallow well plate, and the total reaction volume was 10μL. Specifically, it included 2μL of the test compound (2% DMSO), 4μL of His-tagged recombinant protein and 4μL of Biotin-tagged BIM protein peptide. After 1 hour of reaction, 5μL of Anti-His and streptavidin-tagged XL665 antibody diluent diluted with detection buffer were added respectively. After incubation at room temperature for 4 hours, the Envision multi-function microplate microplate reader was used to read the value, thereby detecting the effect of the test compound on the binding ability of BCL2 (D103Y) and Bim protein peptide. The Envision parameter setting is excitation light 320nm, emission light 615nm and 665nm. The signal ratio of 665nm and 615nm indirectly reflects the binding ability of anti-apoptotic protein and Bim protein peptide. In the reaction, background wells without BCL2 and active wells containing full binding of recombinant protein and Bim protein polypeptide without compounds were set.

[0893] IC of the compound's ability to inhibit the binding of anti-apoptotic proteins to Bim protein peptides 50 The values ​​were calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0894] Table 4 Inhibitory activity of compounds against BCL2 (D103Y)

[0895]

[0896]

[0897] The results in Table 4 show that the compounds of the present invention have potent BCL2(D103Y) inhibitory activity.

[0898] Example 221 Tumor Proliferation Inhibition Activity Test

[0899] The inhibitory effect of the compounds on RS4;11 cell proliferation was determined. RS4;11 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. The cells were digested and seeded into 96-well plates at a concentration of 30,000 cells / well for RS4;11 and incubated overnight at 37°C 5% CO2. Compounds of different concentrations (10,000 nM, 4-fold dilution, 8 points, respectively: 10,000, 2,500, 625, 156.25, 39.06, 9.76, 2.44, 0.61 nM) were added to the 96-well plate and incubated at 37°C 5% CO2 for 72 hours for RS4;11. 20 μL of MTS was added to each well. After incubation for 2 hours, 25 μL of 10% SDS was added to each well to terminate the reaction. The absorption at 490 nm and 650 nm was measured using an enzyme reader. IC was calculated using GraphPad Prism 5.0 50 The results are shown in Table 5.

[0900] Table 5 Inhibitory effect of compounds on RS4;11 cell proliferation

[0901] Compound No. RS4;11(bcl-2)(nM) Compound No. RS4;11(bcl-2)(nM) 033 1.05 151 0.84 035 3.03 152 1.25 119 9.54 154 0.94 120 2.20 166 1.88 121 6.29 188 2.81 125 2.01 189 2.18 128 3.63 190 0.5 142 0.71 212 1.05 144 0.63 213 2.99 145 0.71 Compound a 15.5 146 2.49 ABT-199 9.32

[0902] The results in Table 5 show that the compounds of the present invention have a strong proliferation inhibitory activity on RS4;11 cells.

[0903] Example 222 Tumor Proliferation Inhibition Activity Test

[0904] The inhibitory effect of the compounds on the proliferation of Molt-4 cells was determined. Molt-4 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. The cells were digested and Molt-4 cells were seeded in a 96-well plate at a cell concentration of 30,000 / well and incubated overnight at 37°C 5% CO2. Compounds of different concentrations (10,000 nM, 4-fold dilution, 8 points, respectively: 10,000, 2,500, 625, 156.25, 39.06, 9.76, 2.44, 0.61 nM) were added to the 96-well plate and incubated at 37°C 5% CO2. Molt-4 was incubated for 72 hours. 20 μL of MTS was added to each well. After incubation for 2 hours, 25 μL of 10% SDS was added to each well to terminate the reaction. The absorption at 490 nm and 650 nm was measured using an enzyme reader. IC was calculated using GraphPad Prism 5.0 50 The results are shown in Table 6.

[0905] Table 6 Inhibitory effect of compounds on the proliferation of Molt-4 cells

[0906]

[0907]

[0908] The results in Table 6 show that the compounds of the present invention have no significant proliferation inhibitory activity on Molt-4 cells.

[0909] Example 220 Mouse absorption test

[0910] Three female mice were fed for at least 3 days before the experiment to adapt to the environment. Before administration, the animals were fasted overnight and had free access to water.

[0911] Experimental steps:

[0912] 1. The compounds were prepared into 1 mg / mL solutions using 5% DMSO + 10% Solutol + 85% saline.

[0913] 2. The prepared solution was given to three mice by oral gavage (10 mg / kg).

[0914] 3. At 5, 15, 30 minutes, 1, 2, 4, 8, and 24 hours, 100 μL of blood was collected from the tail vein of the mouse, placed in EDTA anticoagulant tubes, and kept on ice.

[0915] 4. Within 30 minutes after blood sample collection, centrifuge at 8000 rpm at 4 degrees Celsius for 5 minutes to extract plasma.

[0916] 5. Take 20 μl of mouse plasma, add 60 μl of ACN solution, vortex mix and centrifuge at low temperature (4°C) for 10 minutes (13000 rpm), take 50 μl of supernatant and 150 μl of deionized water and add them to a 96-well plate, shake and mix for 10 minutes, and then take 2 μl for LC-MS / MS analysis.

Claims

1. A compound, characterized in that It has the structure shown in general formula (I): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; in: m is selected from 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(O2), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium; X is selected from NR8, CR8R8', O, C(O), S, S(O), S(O)2; wherein: X and Z form a ring B or no ring; when forming a B ring, the dotted line connected to X represents a chemical bond; when B is an open ring, the dotted line connected to X represents non-existence; when forming a B ring, R2 can be substituted on Z or on any atom between Z and X; when B is an open ring, R2 is substituted on X; When two of Y1, Y2, and Y3 are CH, the other Y1 / Y2 / Y3 is N or CR9, and R9 is not H, and the other Y1 / Y2 / Y3 is CR9, n is 1, 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 tert-butyl and phenyl; When forming ring B, R2 is methyl, methoxycarbonyl, 4-hydroxycyclohexyloxymethyl, a spirocyclic structure formed by sharing a C atom with ring B, (4-methylpiperazin-1-yl)methyl, 2-(dimethylamino)ethyl, morpholinemethyl, (4-(oxetane-3-yl)piperazin-1-yl)methyl, (1,1-dioxythiomorpholine)methyl, (4-acetylpiperazin-1-yl)methyl, (4-hydroxycyclohexyl)methyl, (2-(4-methylpiperazin-1-yl)ethyl, (4-(methylsulfonylamino)piperidin-1-yl)methyl, (4-methoxycarbonylaminopyridin-1-yl)methyl, (dimethylamino)methyl, (3-hydroxy-3-methylazetidin-1-yl) Methyl, 2-(1,1-dioxythiomorpholinyl)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-acetylpiperidin-4-yl, 4-hydroxycyclohexyl, oxo, (4-hydroxy-4-methylcyclohexyl)methyl, (1,4-dioxane-2-yl)methyl; the spirocyclic structure formed by sharing a C atom with the B ring is a cyclopropane, cyclobutane, cyclopentane, N-methyl substituted azacyclopentane, N-methyl substituted azacyclohexane and the spirocyclic structure formed by sharing a C atom with the B ring; When there is no ring B, R2 is selected from deuterium, methyl, ethyl, propyl, ethyl-Rg, NH(CH2)R g 、C(O)R g 、S(O)R g 、SO2R g 、C(O)OR g 、OC(O)R g The methyl, ethyl and propyl groups may be further replaced by one or more R j replace; When there is no ring B, two R2 and X can form 6-(oxetane-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl, 6-(oxetane-3-yl)-2,6-diazaspiro[3.4]octan-2-yl, 7-(oxetane-3-yl)-2,7-diazaspiro[3.5]nonane-2-yl); R1 is selected from nitro; R3 is selected from hydrogen; R4 is selected from hydrogen; R5 is selected from hydrogen; R6 is selected from hydrogen, methyl, ethyl, isopropyl, halogen, cyclopropyl, NR h R i , cyano, methoxy, trifluoromethyl; R h , R i Each independently selected from methyl; R7 is selected from hydrogen; R8, R8' are each independently selected from hydrogen; R9 is selected from halogen, methyl; R g , R j Each independently selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, isopropoxy, aminomethyl, cyclobutyl, cyclohexyl, 4-6 membered heterocyclic group, wherein the isopropoxy, aminomethyl, cyclobutyl, cyclohexyl, heterocyclic group may be further replaced by one or more R m replace; R m Selected from deuterium, methyl, isopropyl, isobutyl, isopentyl, halogen, cyano, amino, nitro, hydroxy, oxo, halomethyl, haloethyl, haloisopropyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, methylcarbonyl, methyloxycarbonyl, ethyloxycarbonyl, isopropyloxycarbonyl, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, 4-membered heterocycloalkyl; * The marked C is R configuration or S configuration.

2. A compound characterized in that: It has the structure shown in general formula (II): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; in: m is selected from 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(O2), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium; X is NR8 or CR8R8'; wherein: X and Z form a ring B or no ring; when forming a B ring, the dotted line connected to X represents a chemical bond; when B is an open ring, the dotted line connected to X represents non-existence; when forming a B ring, R2 can be substituted on Z or on any atom between Z and X; when B is an open ring, R2 is substituted on X; When two of Y1, Y2, and Y3 are CH, the other Y1 / Y2 / Y3 is N or CR9, and R9 is not H, and the other Y1 / Y2 / Y3 is CR9, n is 1, 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 phenyl; When forming ring B, R2 is methyl, methoxycarbonyl, 4-hydroxycyclohexyloxymethyl, a spirocyclic structure formed by sharing a C atom with ring B, (4-methylpiperazin-1-yl)methyl, 2-(dimethylamino)ethyl, morpholinemethyl, (4-(oxetane-3-yl)piperazin-1-yl)methyl, (1,1-dioxythiomorpholine)methyl, (4-acetylpiperazin-1-yl)methyl, (4-hydroxycyclohexyl)methyl, (2-(4-methylpiperazin-1-yl)ethyl, (4-(methylsulfonylamino)piperidin-1-yl)methyl, (4-methoxycarbonylaminopyridin-1-yl)methyl, (dimethylamino)methyl, (3-hydroxy-3-methylazetidin-1-yl) Methyl, 2-(1,1-dioxythiomorpholinyl)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-acetylpiperidin-4-yl, 4-hydroxycyclohexyl, oxo, (4-hydroxy-4-methylcyclohexyl)methyl, (1,4-dioxane-2-yl)methyl; the spirocyclic structure formed by sharing a C atom with the B ring is a cyclopropane, cyclobutane, cyclopentane, N-methyl substituted azacyclopentane, N-methyl substituted azacyclohexane and the spirocyclic structure formed by sharing a C atom with the B ring; When there is no ring B, R2 is selected from deuterium, methyl, ethyl, propyl, ethyl-Rg, NH(CH)R g 、C(O)R g 、S(O)R g 、SO2R g 、C(O)OR g 、OC(O)R g The methyl, ethyl and propyl groups may be further replaced by one or more R j Substitution; R7 can be substituted on the carbon or nitrogen atom of the azaindole fragment; When there is no ring B, two R2 and X can form 6-(oxetane-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl, 6-(oxetane-3-yl)-2,6-diazaspiro[3.4]octan-2-yl, 7-(oxetane-3-yl)-2,7-diazaspiro[3.5]nonane-2-yl); R1 is selected from nitro; R3 is selected from hydrogen; R4 is selected from hydrogen; R5 is selected from hydrogen; R6 is selected from hydrogen, methyl, ethyl, isopropyl, halogen, cyclopropyl, NR h R i , cyano, methoxy, trifluoromethyl; R h , R i Each independently selected from methyl; R7 is selected from hydrogen; R8, R8' are each independently selected from hydrogen; R9 is selected from halogen, methyl; R g , R j Each independently selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, isopropoxy, aminomethyl, cyclobutyl, cyclohexyl, 4-6 membered heterocyclic group, wherein the isopropoxy, aminomethyl, cyclobutyl, cyclohexyl, heterocyclic group may be further replaced by one or more R m replace; R m Selected from deuterium, methyl, isopropyl, isobutyl, isopentyl, halogen, cyano, amino, nitro, hydroxy, oxo, halomethyl, haloethyl, haloisopropyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, methylcarbonyl, methyloxycarbonyl, ethyloxycarbonyl, isopropyloxycarbonyl, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, 4-membered heterocycloalkyl; * The marked C is R configuration or S configuration.

3. The compound according to claim 2, characterized in that Having the structure shown in general formula (III-A) or (III-B): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, characterized in that Having the structure shown in general formula (IV-A) or (IV-B): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, characterized in that It has the structure shown in the general formula (VA): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 4, characterized in that Having the structure of general formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 5, characterized in that Having the structure of general formula (VI-A1), (VI-A2): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; Wherein, T is selected from non-existent, NR n , O, S; R n is selected from hydrogen, methyl; R k is selected from hydrogen, deuterium, methyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, and amide; n1 is selected from 0, 1, 2, 3.

8. The compound according to any one of claim 2, characterized in that: When forming a B ring, Z is selected from O, NH, CH2, CO; when not forming a ring, Z is selected from H; Two of Y1, Y2, and Y3 are CH, and the other Y1 / Y2 / Y3 is N or CR9, and R9 is not H; R1 is H or nitro; R3 is H; R4 is H; R5 is H; R7 is H.

9. The compound according to claim 1, characterized in that It has the structure of general formula (VII): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, characterized in that Having the structure of general formula (VIII-A1), (VIII-A2), (VIII-A3), (VIII-A4), (VIII-A5): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, characterized in that It has the structure shown in the general formula (IX): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; X is selected from NR 11 , O; L1 is selected from a chemical bond, a methyl group, an ethyl group, and a propyl group; Ring C is selected from cyclobutyl, cyclohexyl, and 4-6 membered heterocyclic group; R 10 is selected from hydrogen, methyl, isopropyl, isobutyl, isopentyl, halogen, halomethyl, haloethyl, haloisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, a 4-membered heterocyclic group, hydroxy, methylcarbonyl, methyloxycarbonyl, ethyloxycarbonyl, isopropyloxycarbonyl; R 11 Selected from H; f is selected from 0, 1, 2, 3, 4.

12. The compound according to claim 1, characterized in that * The marked C is selected from the S configuration.

13. The compound according to claim 1, characterized in that Has one of the following structures: or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition, characterized in that The invention comprises one or more compounds described in any one of claims 1 to 13.

15. Use of a compound according to any one of claims 1 to 13 in the preparation of a medicament for the sole treatment of a disease, disorder or condition which benefits from inhibition of BCL-2 activity.

16. A use according to claim 15, characterized in that The disease, disorder or lesion is selected from infectious diseases, immune diseases, inflammatory diseases and abnormal cell proliferation diseases.

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