Anti-apoptotic protein BCL-2 inhibitor, pharmaceutical composition and application thereof

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 a drug for treating diseases related to the 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 a potent BCL2 / BAK blocking activity and can be used to treat infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation diseases that benefit from the inhibition of the anti-apoptotic protein BCL-2.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and specifically relates to a class of BCL-2 inhibitors capable of inhibiting anti-apoptotic B cell lymphoma-2 (Bcl-2) anti-apoptotic protein, a pharmaceutical composition and application thereof. Background Art

[0002] Apoptosis, also known as programmed cell death, is regulated by both external and internal pathways. Apoptosis is closely related to the occurrence and development of many human diseases, and inhibition of apoptosis is related to the occurrence of diseases such as tumors.

[0003] 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. In some malignant tumors, anti-apoptotic Bcl-2 family members were found to be upregulated and correlated with disease stage and prognosis. Therefore, Bcl-2 protein has been studied as a potential drug treatment target and has become a hot topic in anti-tumor drug research in recent years.

[0004] It is known that 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, the Bcl-2 inhibitor Venetoclax (ABT-199) has been approved by the FDA for marketing, and there are also many literatures or patents reporting Bcl-2 inhibitors such as Nature Medicine (2013), 19 (2), 202-210; WO2021208963A / WO2021173523A / WO2020140005A2 / WO2019210828A1, etc. However, with the use of BCL-2 inhibitors, some patients develop drug 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 more suitable treatments for patients who are resistant to BCL-2 inhibitors.

[0005] 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

[0006] The purpose of the present invention is to provide a novel, unreported compound having the ability to inhibit anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins or a pharmaceutical composition of its optical isomers, stereoisomers or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, and its use in the preparation of drugs for treating diseases (such as hyperproliferative diseases, such as cancer and inflammation, as well as immune and autoimmune diseases), disorders or conditions that benefit from inhibiting anti-apoptotic B-cell lymphoma-2 (Bcl-2).

[0007] In a first aspect of the present invention, there is provided a compound as shown in Formula I, or a stereoisomer thereof or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof,

[0008]

[0009] *The marked C is R configuration or S configuration;

[0010] Ring A is selected from: absent, 3-10 membered cycloalkyl, 4-10 membered cycloalkenyl, 5-10 membered cycloalkynyl, 4-10 membered heterocyclyl, 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring; the heterocyclyl and heteroaromatic ring contain 1 to 4 heteroatoms selected from N, O, and S;

[0011] R 2 Selected from: hydrogen, deuterium, -C 1 -C 8 Alkyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, -C 1 -C 8 Alkoxy, cycloalkyl, 4-10 membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, amino, oxo, cyano, nitro, -OR g 、-SR g 、-S(O)R g 、-SO 2 R g 、-C(O)R g 、-C(O)OR g 、-C(O)NR h R i 、-OC(O)R g 、-NR h R i 、-NR h C(O)R i 、-NR h C(O)NR i R h 、-NR h C(O)OR g 、-NRh S(O)NR i R h 、-NR h SO 2 NR i R h 、-P(O)R h R i , halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Cycloalkyl, hydroxy substituted C 1 -C 8 Alkyl, hydroxy substituted C 1 -C 8 Alkoxy; when 2 R 2 When on the same atom, it can form a 3-6-membered spiro ring, and on adjacent atoms, it can form a 3-8-membered cyclic ring;

[0012] Y 1 , Y 2 , Y 3 Each independently selected from CR 7 , N;

[0013] R 7 Selected from: H, halogen (preferably F), C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkyl, cycloalkyl, alkoxy;

[0014] L 2 Selected from: chemical bond, -NR a -, -O-, -S-, -C(O)-, -C(O)NR a -、-NR a C(O)-;

[0015] L 3 Selected from: -C(O)NR 8 SO 2 -;

[0016] R 8 Selected from: H, C 1 -C 8 Alkyl, -R P OC(O)R q , -R p OC(O)OR q , -R p OC(O)NR q R s , -Rp COOR q ;

[0017] R p , R q , R s Each independently selected from: H, C 1 -C 8 Alkyl, 3-10 membered cycloalkyl, 4-10 membered heterocyclic group, aryl, 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl may be further C 1 -C 8 Alkyl, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl substitution;

[0018] R 3 Selected from:

[0019] R 10 is selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, and halogenated alkyl; wherein R 10 Can be substituted on carbon or nitrogen atoms;

[0020] Ring B is selected from: 5-12 membered spiro heterocyclic group;

[0021] Ring C is selected from: cycloalkyl, cycloalkenyl, bridged ring group, heterocyclic group, aryl or heteroaryl;

[0022] X is selected from: CR b R c NR b ;

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

[0024] p is selected from 0, 1, 2, 3;

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

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

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

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

[0029] R a , R b , R c Each independently selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, alkoxy, cycloalkyl, heterocyclic, heteroaryl, aryl; the alkyl, cycloalkyl, heteroaryl, aryl may be further replaced by one or more Rd Substituent substitution;

[0030] R d Selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, alkoxy, oxo, amino, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, fused bicyclic; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, heteroaryl, aryl, fused bicyclic may be further substituted by one or more Re substituents. When two R e It can form a 3-6-membered spiro ring on the same atom, and a 3-8-membered cyclic ring on adjacent atoms;

[0031] Re is selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, oxo, amino, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, haloalkyl, haloalkoxy, methylsulfonyl, aryl, heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, heteroaryl, aryl may be further replaced by one or more R m Replace; when 2 R m It can form a 3-6-membered spiro ring on the same atom, and a 3-8-membered cyclic ring on adjacent atoms;

[0032] R 4 Selected from: H, halogen, C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkyl, cycloalkyl, alkoxy;

[0033] R 5 Selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, aryl;

[0034] R 6 Selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, aryl;

[0035] L 1 Selected from: Chemical Bond, NR f , O;

[0036] R f Selected from: H, C 1 -C 8 Alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl;

[0037] R 1 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 、-SO 2 R g 、-C(O)OR g 、-OC(O)R g 、-NR h R i 、C(O)N(R h )R i 、-N(R h )C(O)R i 、-NR h C(O)NR i R h 、-NR h C(O)OR g 、-NR h S(O)NR i R h 、-NR h SO 2 NR i R h 、-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 replace;

[0038] R g , R h , R i , R j Selected from: hydrogen, deuterium, C 1 -C 8 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;

[0039] R m Selected from: hydrogen, deuterium, C 1 -C 8 Alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, heterocyclic group, the alkyl, cycloalkyl, heterocyclic group may be further replaced by one or more R r replace;

[0040] R r Selected from: hydrogen, deuterium, C 1 -C 8 Alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclic, alkylamino, alkylcarbonyl, alkoxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spirocyclyl, alkenyl, alkynyl, nitro, carboxyl, amide, cycloalkenyl, bridged ring, aryl or heteroaryl;

[0041] When ring A is selected from the group consisting of

[0042] X is selected from NR b , and Y 1 / Y 2 / Y 3 At least one selected from N or CR 7 , and R 7 is not H. In some embodiments, the ring A is preferably:

[0043]

[0044] Further, in some embodiments, the Selected from:

[0045]

[0046] In some embodiments, the ring B is preferably:

[0047] In some embodiments, the ring C is preferably: an aromatic ring or a heteroaromatic ring.

[0048] In some embodiments, when Ring A is selected from a 4-10 membered heterocyclyl, a 5-10 membered heteroaryl ring, Y 2 N or CH, CF; when ring A is selected from when it does not exist, Y 2 N or CF;

[0049] X is selected from NR b , and Y 1 / Y 2 / Y 3At least one selected from N or CR 7 , and R 7 Not for H.

[0050] Furthermore, the preferred compounds of the present invention have the structure of general formula I':

[0051]

[0052] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0053] *The marked C is R configuration or S configuration;

[0054] Ring A is selected from: absent, 6-10 membered heterocyclic ring, 6-10 membered aromatic ring, 6-10 membered heteroaromatic ring;

[0055] Z is selected from: N, CH;

[0056] R 2 Selected from: hydrogen, deuterium, C 1 -C 8 Alkyl, halogen, halogenated C 1 -C 8 alkyl;

[0057] Y 1 , Y 2 , Y 3 Each independently selected from CR 7 , N;

[0058] R 7 Selected from: H, halogen, C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkyl, cycloalkyl, alkoxy;

[0059] When ring A is selected from when it is absent, and when Y 1 , Y 2 , Y 3 When two of them are CH,

[0060] Another Y 1 / Y 2 / Y 3 N or CR 7 , and R 7 Not for H;

[0061] R 3 Selected from:

[0062] R 10is selected from the group consisting of: hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, halogenated alkyl; R 10 Can be substituted on carbon or nitrogen atoms;

[0063] Ring B is selected from:

[0064] o is selected from 0, 1, 2, 3, 4;

[0065] p is selected from 0, 1, 2, 3;

[0066] q is selected from 0, 1, 2, 3;

[0067] r is selected from 0, 1, 2, 3;

[0068] s is selected from 0, 1, 2, 3;

[0069] L 2 Selected from: Chemical Bond, NR a , O;

[0070] X is selected from: CR b R c NR b ;

[0071] R a , R b , R c Each independently selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, alkoxy, cycloalkyl, heterocyclic, heteroaryl, aryl; the alkyl, cycloalkyl, heteroaryl, aryl may be further replaced by one or more R d Substituent substitution;

[0072] R d Selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, alkoxy, oxo, amino, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, fused bicyclic; the alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heteroaryl, aryl, fused bicyclic may be further substituted by one or more Re substituents, when two Re on the same carbon can form a 3-6 membered spiro ring, on adjacent carbon can form a 3-8 membered cyclic ring;

[0073] Re is selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, oxo, amino, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl, haloalkoxy, methylsulfone;

[0074] R 4 Selected from: H, halogen, C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkyl, cycloalkyl, alkoxy;

[0075] R 5 Selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, aryl;

[0076] R 6 Selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, aryl;

[0077] Ring C is selected from: cycloalkyl, cycloalkenyl, bridged ring group, heterocyclic group, aryl or heteroaryl;

[0078] L 1 Selected from: NR f , O;

[0079] R f Selected from: H, C 1 -C 8 Alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl;

[0080] R 1 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 、SO 2 R g 、C(O)OR g 、OC(O)R g NR h R i 、C(O)N(R h )R i 、N(R h )C(O)R i 、-P(O)R h R i The alkyl, bridged ring, spirocyclic, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl group may be further substituted by one or more Rj replace;

[0081] R g , R h , R i , R j Selected from: hydrogen, deuterium, C 1 -C 8 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;

[0082] R m Selected from: hydrogen, deuterium, C 1 -C 8 Alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, heterocyclic group, the alkyl, cycloalkyl, heterocyclic group may be further replaced by one or more R r replace;

[0083] R r Selected from: hydrogen, deuterium, C 1 -C 8 Alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclic, alkylamino, alkylcarbonyl, alkoxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spirocyclyl, alkenyl, alkynyl, nitro, carboxyl, amide, cycloalkenyl, bridged ring, aryl or heteroaryl;

[0084] Furthermore, the preferred compounds of the present invention have the structures shown in the general formula IIa and IIb:

[0085]

[0086] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0087] Furthermore, the preferred compounds of the present invention have the structures shown in the general formula IIIa and IIIb:

[0088]

[0089] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0090] Furthermore, the preferred compounds of the present invention have the structures shown in the general formula IVa, IVb, and IVc:

[0091]

[0092] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0093] R 2 Selected from: hydrogen, deuterium, C 1 -C 8 Alkyl, halogen, halogenated C 1 -C 8 Alkyl; R 2 The substitution may be on carbon or nitrogen. Further, the preferred compounds of the present invention have the structures shown in the general formulas Va to Vf:

[0094]

[0095] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0096] R 10 Selected from: hydrogen, deuterium, alkyl, cycloalkyl, halogen, nitro, cyano, halogenated alkyl;

[0097] R 2 Selected from: hydrogen, deuterium, C 1 -C 8 Alkyl, halogen, halogenated C 1 -C 8 Alkyl; R 2 The substitution may be on carbon or nitrogen. Further, the preferred compounds of the present invention have the structure shown in the general formula VIa or VIb:

[0098]

[0099] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0100] When Y 1 , Y 2 , Y 3 When two of them are CH, the other one is Y 1 / Y 2 / Y 3 N or CR 7 ;

[0101] R 7 Selected from: halogen, C 1 -C 8Alkyl, halogenated C 1 -C 8 Alkyl, cycloalkyl, alkoxy.

[0102] Further, preferred compounds of the present invention are:

[0103] Ring A is selected from: 4-membered heterocyclic ring, 5-membered heterocyclic ring, 5-membered heteroaryl;

[0104] L 3 Selected from: -C(O)NHSO 2 -;

[0105] Ring C is selected from: aryl or heteroaryl; further preferably, ring C is preferably selected from benzene ring;

[0106] Ring B is selected from: Where nitrogen is attached to a Y-containing 1 / Y 2 / Y 3 On the ring;

[0107] Further, the preferred compounds of the present invention and their stereoisomers or their stereoisomer mixtures or their pharmaceutically acceptable salts are:

[0108] X is selected from: CR b R c ;

[0109] R b , R c Each independently selected from: H, deuterium, halogen, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, cycloalkyl, heterocyclyl, heteroaryl, aryl;

[0110] O Selected from: 0, 1, 2;

[0111] L 2 Selected from: chemical bond, -NH-, -O-;

[0112] Furthermore, the preferred compounds of the present invention have the following general formula (VII):

[0113]

[0114] or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

[0115] in:

[0116] Y 1 , Y 2 , Y 3 Each independently selected from CR 7, N;

[0117] R 7 Selected from: H, halogen, C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkyl, cycloalkyl, alkoxy.

[0118] Ring B is selected from:

[0119] In some embodiments, the fragments of formula (I), (I'), II (b), III (b), IV (c), Ve to Vf, VIa to VIb, VII The Rb is preferably selected from:

[0120]

[0121] In some embodiments, R 1 Selected from: Any carbon atom in the ring may be substituted by one or more N or O;

[0122] y is selected from 0, 1, 2, 3, 4;

[0123] v is selected from 0, 1, 2, 3.

[0124] In some embodiments, in Formula I, I', IIa-IIb, IIIa-IIIb, IVa-IVc, Va-Vf, VIa, VIb, VII, -L 1 -R 1 The excerpt is selected from:

[0125]

[0126] Preferably, the compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt is selected from the following compounds:

[0127] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 001

[0128] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 002

[0129] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 003

[0130] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 004

[0131] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 005

[0132] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 006

[0133] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-1-methyl-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 007

[0134] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-1-methyl-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 008

[0135] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-indol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 009

[0136] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-indol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 010

[0137] 2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 011

[0138] (S)-N-((7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 012

[0139] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 013

[0140] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 014

[0141] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-hydroxycyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 015

[0142] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-hydroxycyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 016

[0143] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1S,3S)-3-hydroxy-3-methylcyclobutyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 017

[0144] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1S,3S)-3-hydroxy-3-methylcyclobutyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 018

[0145] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 019

[0146] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 020

[0147] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 021

[0148] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 022

[0149] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-(tetrahydro-2H-pyran-4-yl))piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 023

[0150] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 024

[0151] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-neopentylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 025

[0152] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluoro-1-neopentylpiperidin-4-yl)methyl))amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 026

[0153] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((1-acetyl-4-fluoropiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 027

[0154] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((1-acetyl-4-fluoropiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 028

[0155] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((1-(dimethylglycyl)-4-fluoropiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 029

[0156] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((1-(dimethylglycyl)-4-fluoropiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 030

[0157] (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 031

[0158] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluoro-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 032

[0159] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1S,4S)-4-(dimethylamino)cyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 033

[0160] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1S,4S)-4-(dimethylamino)cyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-5-fluoro-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 034

[0161] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-1-methyl-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 035

[0162] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-1-methyl-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 036

[0163] 4-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 037

[0164] (S)-5-Fluoro-N-((7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 038

[0165] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 039

[0166] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(6-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide 040

[0167] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(4-isopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 041

[0168] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(6-(4-isopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide 042

[0169] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 043

[0170] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(6-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide 044

[0171] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 045

[0172] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(6-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide 046

[0173] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 047

[0174] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 048

[0175] 2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 049

[0176] N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 050

[0177] 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-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 051

[0178] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(6-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)nicotinamide 052

[0179] 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)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 053

[0180] 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-(6-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)nicotinamide 054

[0181] 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-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 055

[0182] 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-(6-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide 056

[0183] 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)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 057

[0184] 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-(6-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide 058

[0185] 4-((3-fluoro-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-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 059

[0186] 5-Fluoro-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 060

[0187] N-((4-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 061

[0188] 5-Fluoro-N-((4-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 062

[0189] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)nicotinamide 063

[0190] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 064

[0191] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 065

[0192] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 066

[0193] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 067

[0194] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(6-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)nicotinamide 068

[0195] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 069

[0196] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(6-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)nicotinamide 070

[0197] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 071

[0198] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(6-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide 072

[0199] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 073

[0200] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(6-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide 074

[0201] 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazol-4-yl)sulfonyl)nicotinamide 075

[0202] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazol-4-yl)sulfonyl)benzamide 076

[0203] 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 077

[0204] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 078

[0205] 2-(2,3-Dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 079

[0206] (S)-2-(2,3-Dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 080

[0207] 4-(2,3-Dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 081

[0208] 2-(2,3-Dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 082

[0209] (S)-4-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 083

[0210] (S)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-5-fluoro-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 084

[0211] 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 085

[0212] (S)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)-N-((7-(((4-fluoro-1-isopropylpiperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 086

[0213] (S)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 087

[0214] (S)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 088

[0215] 2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 089

[0216] 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 090

[0217] 2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazol-4-yl)sulfonyl)benzamide 091

[0218] 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazol-4-yl)sulfonyl)benzamide 092

[0219] 2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 093

[0220] 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 094

[0221] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzofuran-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 095

[0222] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 096

[0223] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d]oxazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 097

[0224] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d]thiazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 098

[0225] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((8-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 099

[0226] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-2,3-dihydrobenzofuran-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 100

[0227] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 101

[0228] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzofuran-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 102

[0229] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]oxazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 103

[0230] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]thiazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 104

[0231] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-2,3-dihydrobenzofuran-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 105

[0232] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 106

[0233] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]oxazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 107

[0234] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl))amino)-6-nitrobenzo[d]thiazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 108

[0235] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzofuran-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 109

[0236] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((8-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 110

[0237] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-2-methyl-6-nitrobenzofuran-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 111

[0238] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-2,3-dihydrobenzofuran-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 112

[0239] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenz[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 113

[0240] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d]oxazol-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 114

[0241] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzofuran-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 115

[0242] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d]thiazol-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 116

[0243] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-2-methyl-6-nitrobenzofuran-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 117

[0244] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((8-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 118

[0245] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-2,3-dihydrobenzofuran-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 119

[0246] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 120

[0247] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d]oxazol-4-yl)sulfonyl)benzamide 121

[0248] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d]thiazol-4-yl)sulfonyl)benzamide 122

[0249] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 123

[0250] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d]oxazol-4-yl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 124

[0251] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d]thiazol-4-yl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 125

[0252] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 126

[0253] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]oxazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 127

[0254] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]thiazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 128

[0255] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzofuran-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 129

[0256] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(4-((2-fluoro-6-methoxypyridin-3-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 130

[0257] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(4-((2-fluoro-6-methoxypyridin-3-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]oxazol-4-yl)sulfonyl)benzamide 131

[0258] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 132

[0259] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]oxazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 133

[0260] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]thiazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 134

[0261] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzofuran-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 135

[0262] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((8-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 136

[0263] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 137

[0264] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d]oxazol-4-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 138

[0265] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzofuran-4-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 139

[0266] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d]thiazol-4-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 140

[0267] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((8-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-7-nitro-3-oxy-2,3-cinnolin-5-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 141

[0268] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-5-nitro-2,3-dihydrobenzofuran-7-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 142

[0269] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-5-nitrobenzofuran-7-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 143

[0270] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((8-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-1-methyl-7-nitro-2-oxy-1,2-dihydroquinolin-5-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 144

[0271] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 145

[0272] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-nitro-8-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)sulfonyl)benzamide 146

[0273] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 147

[0274] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 148

[0275] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 149

[0276] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolan-4-yl)sulfonyl)nicotinamide 150

[0277] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 151

[0278] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 152

[0279] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 153

[0280] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((2R,5S)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)-5-methylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 154

[0281] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((2R,5R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)-5-methylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 155

[0282] (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-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 156

[0283] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-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)benzamide 157

[0284] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 158

[0285] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 159

[0286] (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-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 160

[0287] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-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 161

[0288] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-2,2-dimethyl-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 162

[0289] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-2,2-dimethyl-6-nitrobenz[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 163

[0290] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((2,2-difluoro-7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 164

[0291] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((2,2-difluoro-7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 165

[0292] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 166

[0293] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 167

[0294] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 168

[0295] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 169

[0296] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(2,6-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 170

[0297] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((7-methoxy-2-methylbenzofuran-5-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 171

[0298] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-cyclopropylbenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 172

[0299] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-cyclopropyl-3-methoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 173

[0300] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl))amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 174

[0301] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenz[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 175

[0302] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenz[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 176

[0303] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(2,6-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenz[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 177

[0304] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(4-cyclopropylbenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenz[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 178

[0305] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(4-cyclopropyl-3-methoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenz[d][1,3]dioxolan-4-yl)sulfonyl)benzamide 179

[0306] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolan-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-((7-methoxy-2-methylbenzofuran-5-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 180

[0307] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((8-((((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 181

[0308] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((8-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 182

[0309] N-((8-((((S)-1,4-dioxan-2-yl)methyl)amino)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 183

[0310] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 184

[0311] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 185

[0312] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 186

[0313] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 187

[0314] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 188

[0315] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(2,3-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 189

[0316] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 190

[0317] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 191

[0318] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(2,6-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 192

[0319] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(4-(4-isopropylbenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 193

[0320] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(4-(4-isopropyl-3-methoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 194

[0321] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-cyclopropylbenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 195

[0322] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-cyclopropyl-3-methoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 196

[0323] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(3,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 197

[0324] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-(dimethylamino)benzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 198

[0325] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-cyanobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 199

[0326] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-acetylaminobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 200

[0327] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-(methylsulfonylamino)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 201

[0328] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((7-methoxy-2-methylbenzofuran-5-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 202

[0329] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(benzo[d][1,3]dioxolan-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 203

[0330] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(benzo[d][1,3]dioxolan-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 204

[0331] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((7-methoxybenzo[d][1,3]dioxolan-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 205

[0332] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 206

[0333] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 207

[0334] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 208

[0335] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 209

[0336] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(4-((1-isopropyl-1H-pyrazol-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 210

[0337] (R)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(pyridin-4-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 211

[0338] (R)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(pyridin-2-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 212

[0339] (R)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(pyridin-3-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 213

[0340] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(4-cyanobenzyl)-2-(2-isopropylphenyl)piperazin-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 214

[0341] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-((R)-4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 215

[0342] 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-((R)-2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 216

[0343] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(2,6-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-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 217

[0344] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(2,3-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-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 218

[0345] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(4-cyclopropylbenzyl)-2-(2-isopropylphenyl)piperazin-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 219

[0346] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(4-cyclopropyl-3-methoxybenzyl)-2-(2-isopropylphenyl)piperazin-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 220

[0347] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(3,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-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 221

[0348] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(benzo[d][1,3]dioxolan-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-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 222

[0349] 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-((R)-2-(2-isopropylphenyl)-4-((7-methoxybenzo[d][1,3]dioxolan-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 223

[0350] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(benzo[d][1,3]dioxolan-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-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 224

[0351] 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-((R)-2-(2-isopropylphenyl)-4-((7-methoxy-2-methylbenzofuran-5-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 225

[0352] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-(2-isopropylphenyl)piperazin-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 226

[0353] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-2-(2-isopropylphenyl)piperazin-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 227

[0354] 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-((R)-2-(2-isopropylphenyl)-4-((8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 228

[0355] 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-((R)-2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 229

[0356] 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-((R)-4-((1-isopropyl-1H-pyrazol-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 230

[0357] 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-((R)-2-(2-isopropylphenyl)-4-(pyridin-4-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 231

[0358] 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-((R)-2-(2-isopropylphenyl)-4-(pyridin-3-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 232

[0359] 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-((R)-2-(2-isopropylphenyl)-4-(pyridin-2-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 233

[0360] 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-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 234

[0361] 5-Fluoro-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 235

[0362] 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-((R)-2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 236

[0363] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(3,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-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 237

[0364] 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-((R)-2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 238

[0365] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 239

[0366] (R)-5-Fluoro-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 240

[0367] N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 241

[0368] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 242

[0369] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-((methylamino)methyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 243

[0370] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-((dimethylamino)methyl)benzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 244

[0371] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-(pyrrolidin-1-ylmethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 245

[0372] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(3-methoxy-4-((methylamino)methyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 246

[0373] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-((dimethylamino)methyl)-3-methoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 247

[0374] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(3-methoxy-4-(pyrrolidin-1-ylmethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 248

[0375] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxy-3-((methylamino)methyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 249

[0376] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(3-((dimethylamino)methyl)-4-methoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 250

[0377] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxy-3-(pyrrolidin-1-ylmethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 251

[0378] (R)-5-Fluoro-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 252

[0379] (R)-4-(2-(4-(3,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 253

[0380] (R)-5-Fluoro-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 254

[0381] (R)-5-Fluoro-2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 255

[0382] 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)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 256

[0383] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)nicotinamide 257

[0384] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 258

[0385] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 259

[0386] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazol-4-yl)sulfonyl)benzamide 260

[0387] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 261

[0388] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 262

[0389] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazol-4-yl)sulfonyl)benzamide 263

[0390] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 264

[0391] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((7-nitro-8-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)sulfonyl)benzamide 265

[0392] 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 266

[0393] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazol-4-yl)sulfonyl)nicotinamide 267

[0394] (R)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 268

[0395] Terminology

[0396] 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.

[0397] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and are not limiting of any claims. It should be noted that in the specification and the appended claims, unless otherwise specified herein, singular references such as "a", "an", "the" include plural references. It should also be noted that, unless otherwise specified, "or" means "and / or". In addition, "include", "comprises", and similar terms are not limiting.

[0398] "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 -C 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- C 4 , C 1- C 8 , C 3- C 8 wait.

[0399] The C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopes. At the same time, the C, H, O, S, N, F, Cl, Br, I involved in the groups and compounds of the present invention may be optionally replaced by one or more of their corresponding isotopes, including but not limited to carbon isotopes. 12 C. 13 C. 14 C, isotopes of hydrogen: protium (H), deuterium (D), tritium (T), isotopes of oxygen 16 O. 17 O. 18 O, isotope of sulfur 32 S. 33 S. 34 S. 36 S, isotope of nitrogen 14 N. 15 N, isotope of fluorine 17 F. 19 F, isotope of chlorine 35 Cl, 37 Cl, isotope of bromine 79 Br, 81 Br et al.

[0400] The term "alkyl" used in the present invention refers to a straight or branched saturated hydrocarbon group containing 1 to 8 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, isooctyl, etc. The alkyl group may be substituted by one or more substituents, and the substituents may be the same or different when multiple substitutions are made; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, halogenated C3 -C 12 Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl, C 3 -C 12 Heterocyclic group.

[0401] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain group containing 1 to 8 carbon atoms and at least one C=C double bond, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3- Hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-methyl-2-hexenyl, 2-methyl-2-hexenyl, 2-methyl-3-hexenyl, 3,5-dimethyl-2-hexenyl, 3,3-dimethyl-1-pentenyl, 3-methyl-2-ethyl-1-butenyl, 1-octenyl, 2-octenyl, etc. Alkenyl may be substituted with one or more substituents, and the substituents may be the same or different when multiple substitutions are made; the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclic group, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, amide, sulfonamide, spiroalkyl.

[0402] As used in the present invention, the term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon chain group containing 1 to 8 carbon atoms and having at least one C≡C triple bond, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 4-methyl-1-butynyl, 2-methyl-3-butynyl, 1-methyl-4-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2,2-dimethyl-4-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-methyl-3-hexynyl, 3-methyl-1-hexynyl, 3,3-dimethyl-1-hexynyl, 4-methyl-1-hexynyl, etc. The alkynyl group can be substituted by one or more substituents, and when there are multiple substituents, they can be the same or different; the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halo-hydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclic group, aryl, heteroaryl, hydroxy, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, amido, sulfonamido, spiroalkyl.

[0403] As used in the present invention, the terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

[0404] As used in the present invention, the term "alkoxy" refers to alkyl-O-, where the alkyl is as defined above. Examples of the "alkoxy" used in the present invention include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc. "Alkoxy" also includes substituted alkoxy, and the substituents can be D, halogen, oxo, amino, hydroxy, cyano, nitro, carboxyl, amido, sulfonamido, spiroalkyl, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, haloC 1 -C 8 alkyl, haloC 1 -C 8 hydroxyalkyl, haloC 1 -C 8 alkoxy, haloC 1 -C 8 alkylamino, C3 -C 12 Cycloalkyl, C 3 -C 12 Heterocyclic group, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl.

[0405] 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, hydroxybutyl, hydroxypentyl, and the like. "Hydroxyalkyl" also includes substituted hydroxyalkyl, whose substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, spiroalkyl, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, C 3 -C 12 Heterocyclic group, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl.

[0406] The term "aminoalkyl" as used herein refers to NH 2 -alkyl-, wherein alkyl is as defined above. Examples of "aminoalkyl" used in the present invention include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminopentyl, etc. "Aminoalkyl" also includes substituted aminoalkyl, whose substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, spiroalkyl, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkoxy, C 1 -C 8Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, C 3 -C 12 Heterocyclic group, C 6 -C 12 Aryl, C 5 -C 14 The substituent of the heteroaryl group may be substituted on the alkyl group or on the nitrogen group.

[0407] The term "alkylamino" as used in the present invention refers to alkyl-NH-, wherein alkyl is as defined above. Examples of "alkylamino" as used in the present invention include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, pentylamino, etc. "Alkylamino" also includes substituted alkylamino, whose substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, spiroalkyl, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, C 3 -C 12 Heterocyclic group, C 6 -C 12 Aryl, C 5 -C 14 The substituent of the heteroaryl group may be substituted on the alkyl group or on the nitrogen group.

[0408] The term "cycloalkyl" as 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 3 to 12 carbon atoms, and one or more chemical bonds may be double bonds or triple bonds. “Cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydroindenyl, decahydronaphthalenyl, bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[4.1.1]octanyl, bicyclo[3.2.1]octan ... [3.2.1]octyl, bicyclo[5.1.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]nonyl, bicyclo[3.2.2]nonyl, bicyclo[5.2.1]decyl, bicyclo[4.2.2]decyl, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.5]nonyl, spiro[3.4]octyl, spiro[3.3]heptyl, spiro[4.5]decyl, spiro[4.4]nonyl, and the like. The cycloalkyl group may be substituted with one or more substituents, and the substituents may be the same or different when multiple substitutions are performed; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, halogenated C 3 -C 12 Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 6 -C 12 Aryl, C5 -C 14 Heteroaryl, C 3 -C 12 Heterocyclic group.

[0409] The term "cycloalkenyl" as used in the present invention refers to a non-aromatic monovalent hydrocarbon group having 3 to 12 carbon atoms and containing at least one C=C double bond, which is a monocyclic or polycyclic (two monocyclic rings are connected by a chemical bond or are bridged or spirocyclic or fused) ring, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloalkenyl, spiro[2.2]pent-1-enyl, spiro[2.2]penta-1,4-dienyl, spiro[2.3]hex-1-enyl, spiro[2.3]hex-1,4-dienyl, spiro[3.3]hept-1-enyl, Spiro[3.3]hept-1,5-dienyl, spiro[3.4]oct-1-enyl, spiro[3.4]oct-1,6-dienyl, spiro[3.4]oct-5-enyl, spiro[3.4]oct-6-enyl, spiro[3.4]oct-1-enyl, bicyclo[2.1.1]hex-1-enyl, bicyclo[2.1.1]hex-2-enyl, bicyclo[3.1.1]hept-1-enyl, bicyclo[3.1.1]hept-2-enyl, bicyclo[2.2.1]hept-1-enyl, bicyclo[2.2.1]hept-2-enyl, and the like. The cycloalkenyl and cycloalkenyl groups may be substituted with one or more substituents. When multiple substituents are present, the substituents may be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, halogenated C 3 -C 12 Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 6 -C 12 Aryl, C 5 -C 12 Heteroaryl, C3 -C 12 Heterocyclic group.

[0410] The term "heterocyclic group" as used in the present invention refers to a non-aromatic cyclic group having 3 to 12 ring atoms, which is monocyclic or polycyclic (two monocyclic rings are connected by chemical bonds or bridged or spirocyclic or fused), has one or more heteroatoms selected from N, O, and S, and may have one or more chemical bonds that are double bonds or triple bonds. Heterocyclic groups include, but are not limited to, pyranyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, oxirane, oxetanyl, oxhexyl, oxepinyl, oxocinyl, aziridine, azetidinyl, aziridine, azetyl, azepanyl, thietanyl, thiirane, azoctanyl, oxazepine Base, diazepine Thiazepine 1-azaspiro[2.2]pentanyl, 1-azaspiro[2.3]hexanyl, 4-azaspiro[2.3]hexanyl, 5-azaspiro[2.3]hexanyl, 2-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-azaspiro[2.5] octanyl, 2-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2-azaspiro[3.5]nonanyl, 6-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 1-azaspiro[4.4]nonanyl, 2-azaspiro[4.4]nonanyl, 8-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl alkyl, 1-oxaspiro[2.2]pentanyl, 1-oxaspiro[2.3]hexanyl, 4-oxaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 2-oxaspiro[3.3]heptanyl, 1-oxaspiro[2.5]octanyl, 2-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 2-oxaspiro[3.5]nonanyl, 6-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 1-oxaspiro[4.4]nonanyl, 2-oxaspiro[4.4]nonanyl 1.1]decyl, 8-oxaspiro[4.5]decyl, decahydroquinolyl, decahydroisoquinolyl, 2-azabicyclo[1.1.1]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, azabicyclo[2.1.1]hexanyl, oxabicyclo[2.1.1]hexanyl, azabicyclo[3.1.1]heptanyl, oxabicyclo[3.1.1]heptanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[4.1.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl and the like. The heterocyclic group may be substituted by one or more substituents. When multiple substitutions occur, the substituents may be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C1 -C 8 Alkoxy, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, halogenated C 3 -C 12 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl, C 3 -C 12 Heterocyclic group.

[0411] The term "aryl" used in the present invention refers to an aromatic ring group of an all-carbon monocyclic ring or fused polycyclic ring with 6 to 12 carbon atoms (one of the fused rings may be partially saturated when fused or polycyclic), including but not limited to benzene ring, naphthalene ring, anthracene ring, indene ring, dihydroindenyl (indanyl), dihydronaphthalene ring, tetrahydronaphthalene ring, etc. The aryl group may be unsubstituted or substituted, and may be monosubstituted (such as ortho-, meta-, para-substituted), disubstituted or trisubstituted, etc., and the substituents may be the same or different when multiple substitutions are made; the substituents are independently D (deuterium), halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, acyl, amide, alkylamide, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, halogenated C 3 -C 12 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl, C 3 -C12 Heterocyclic group.

[0412] The term "heteroaryl" used in the present invention refers to a monocyclic or fused polycyclic aromatic ring group having 5 to 14 ring atoms (one of the fused rings may be partially saturated in the case of fused polycyclic rings), which is equivalent to one or more carbon atoms in the above-mentioned "aryl" being replaced by heteroatoms such as N, O, S, etc. The heteroaromatic ring may be a monocyclic ring or a bicyclic ring, i.e., formed by the fusion of two rings. Heteroaryl includes, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, thienyl, furanyl, triazolyl, oxazolyl, imidazolyl, indazolyl, indolizinyl, indolyl, dihydroindolinyl, isoindolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, cinnolinyl, pteridinyl, purinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzotriazolyl, benzotriazinyl, benzoxadiazolyl, benzoxazolyl, benzisoxazolyl, imidazopyridinyl, imidazothiazolyl, pyrrolopyridinyl, thienopyrrolyl, thienothienyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrrolyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl and the like. The heteroaryl group may be unsubstituted, monosubstituted or polysubstituted. When polysubstituted, the substituents may be the same or different; the substituents are independently D (deuterium), halogen, cyano, nitro, amino, aminoalkyl, hydroxyl, carboxyl, carboxylate, acyl, amide, alkylamide, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, halogenated C3 -C 12 Cycloalkyl, C 3 -C 12 Heterocyclic group, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl.

[0413] The terms "spiro ring" and "spirocyclyl" used in the present invention refer to a polycyclic structure in which at least two rings share an atom (generally a C atom), and in which one or more chemical bonds may be double bonds or triple bonds, and one or more heteroatoms may be present. Spirocyclyl includes but is not limited to cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiroazetidinyl, azetidin ... The spirocyclic group may be unsubstituted, monosubstituted or polysubstituted, and the substituents may be the same or different when polysubstituted; the substituents may be independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, halogenated C 3 -C 12 Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C6 -C 12 Aryl, C 5 -C 14 Heteroaryl, C 3 -C 12 Heterocyclic group.

[0414] 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 exist. The bridged ring group may be unsubstituted or monosubstituted or polysubstituted, and the substituents may be the same or different when polysubstituted; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkylamino, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, halogenated C 3 -C 12 Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl, C 3 -C 12 Heterocyclic group.

[0415] The term "fused bicyclic group" used in the present invention refers to a bicyclic group composed of 5 to 14 carbon atoms, in which the two rings are connected by a chemical bond. In such a bicyclic structure, one or more chemical bonds can be double bonds or triple bonds, and one or more heteroatoms can be present. The heteroatoms include, but are not limited to, N, O, S, etc. The "fused bicyclic group" can be unsubstituted, monosubstituted or polysubstituted. When polysubstituted, the substituents can be the same or different; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxy, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylic ester group, acyl, amide group, methylsulfonyl, alkylamide group, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halo C 1 -C 8 alkyl, halo C 1 -C 8 alkoxy, halo C 1 -C 8 hydroxyalkyl, halo C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halo C 3 -C 12 cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide group, sulfonamide group, C 6 -C 12 aryl, C 5 -C 14 heteroaryl, C 3 -C 12 heterocyclic group.

[0416] The terms "alkylcarbonyl" and "alkanoyl" used in the present invention refer to alkyl-C(O)-, where the alkyl is as defined above. "Alkylcarbonyl" also includes substituted alkylcarbonyl, and the substituents can be D, halogen, oxo, amino, hydroxy, cyano, nitro, carboxyl, amide group, sulfonamide group, spiroalkyl, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halo C 1 -C 8 alkyl, halo C 1 -C 8Hydroxyalkyl, halo C 1 -C 8 Alkoxy, halo C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, C 3 -C 12 Heterocyclic group, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl. Wherein "C(O)" represents C=O.

[0417] The term "alkoxycarbonyl" as used in the present invention means alkyl-O-C(O)-, wherein alkyl is defined as above. "Alkoxycarbonyl" also includes substituted alkoxycarbonyl, and the substituents can be D, halogen, oxo, amino, hydroxy, cyano, nitro, carboxyl, amido, sulfonamido, spiroalkyl, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Alkylamino, halo C 1 -C 8 Alkyl, halo C 1 -C 8 Hydroxyalkyl, halo C 1 -C 8 Alkoxy, halo C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl, C 3 -C 12 Heterocyclic group, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl. Wherein "C(O)" represents C=O.

[0418] The term "alkylthio" as used in the present invention means alkyl-S-, wherein alkyl is defined as above. Alkylthio includes but is not limited to methylthio, ethylthio, propylthio, butylthio, etc.

[0419] The term "alkanoyl" as used in the present invention means alkyl-C(O)-, wherein alkyl is defined as above.

[0420] The term "alkylsulfonyl" as used in the present invention means alkyl-S(O) 2 -, wherein alkyl is defined as above.

[0421] The term "haloalkyl" as used in the present invention refers to a straight or branched alkyl group substituted by a halogen (preferably fluorine, chlorine, bromine, iodine), wherein "alkyl" is as defined above. Examples of "haloalkyl" as used in the present invention include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, tetrafluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, fluorobutyl, etc. "Haloalkyl" may be substituted one or more times by a halogen.

[0422] 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.

[0423] The term "haloalkoxy" as used herein refers to a hydroxyalkyl group substituted by halogen (preferably fluorine, chlorine, bromine, iodine), wherein alkoxy is as defined above. "Haloalkoxy" may be substituted by halogen one or more times.

[0424] 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.

[0425] The term "pharmaceutically acceptable salt" used in the present invention refers to a salt suitable for use as a drug formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred salt is a salt formed by the compound of the present invention and an acid. Acids suitable for forming salts include but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzenesulfonic acid, isethionic acid, pamoic acid, and tannic acid; and acidic amino acids such as aspartic acid and glutamic acid. A preferred salt is a salt formed by the compound of the present invention and a base. Suitable bases for forming salts include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, and organic bases such as ammonia, triethylamine, diethylamine, piperazine, guanidine, and diethanolamine.

[0426] 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.

[0427] In another aspect, the present invention provides the use of compounds of Formula I to Formula VII disclosed herein in the preparation of drugs for treating diseases, disorders or conditions that benefit from the inhibition of BCL-2 activity, either alone or in combination with other drugs.

[0428] On the other hand, the compounds or pharmaceutically acceptable salts of the present invention can be used alone or in combination with other therapeutic agents.

[0429] On the other hand, the compounds described herein are used in combination with other therapeutic agents, and the administration route can be the same as that of other drugs, or due to different physical and chemical properties, the administration route can be different. Therefore, the compounds described herein and another therapeutic agent can be administered simultaneously, sequentially or separately.

[0430] On the other hand, the present invention provides a method of using the compounds or pharmaceutically acceptable salts of Formula I to Formula VII disclosed herein in combination with one or more of the following drugs, which is expected to be effective: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, 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 homologous gene (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone acetylcholinesterase inhibitors, cytotoxic T cell ... 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.

[0431] Specifically, the conditions, disorders or lesions include but are not limited to infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation diseases.

[0432] 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.

[0433] Specifically, the abnormal cell proliferation disease includes cancerous proliferative diseases, non-cancerous proliferative diseases, including but not limited to blood diseases and / or solid tumors; wherein the blood tumor is preferably acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, myelofibrosis, myelodysplastic syndrome, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, T-cell lymphoma, or one or more; the solid tumor is preferably osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, glioma, neuroblastoma, epidermoid carcinoma, hemangioma, lung cancer or gastric cancer, restenosis and benign prostatic hypertrophy (BPH), melanoma, or one or more.

[0434] 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.

[0435] The compounds of the present invention can be prepared as pharmaceutical compositions of the compounds in the form of free bases or pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier or diluent, which can be prepared in conventional manner by mixing, granulating, coating, dissolving or freeze-drying processes.

[0436] Experiments have confirmed that the compounds of the present invention have potent BCL-2 / 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.

[0437] The experiments confirmed that the compound of the present invention has a potent BCL2 (G101V) inhibitory activity.

[0438] The experiments confirmed that the compound of the present invention has potent BCL2 (D103Y) inhibitory activity.

[0439] The experiment confirmed that the compound of the present invention has obvious proliferation inhibition activity on RS4;11 cells.

[0440] Experiments have confirmed that the compounds of the present invention have no obvious toxicity to platelets.

[0441] Experiments have confirmed that the compounds of the present invention have no inhibitory effect on CYP3A4.

[0442] Experiments have shown that the compounds of the present invention have good pharmacokinetic properties.

[0443] Experiments have confirmed that the compound of the present invention has a highly effective anti-tumor effect in vivo. DETAILED DESCRIPTION

[0444] Intermediate 1: (S)-2-(2-isopropylphenyl)pyrrolidine

[0445]

[0446] Synthesis step 1: (S)-2-(2-isopropylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 1-1)

[0447] (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.5 g, 13.85 mmol) and isopropylboric acid (3.1 g, 35.22 mmol) were dissolved in a mixed solvent of 15 mL 1,4-epoxyhexacyclopentane and 3 mL water. Potassium carbonate (6 g, 43.40 mmol), Pd(dppf) and 1,4-dihydropyrrolidine were added under nitrogen protection. 2 Cl 2 (0.9 g), heated to reflux and reacted overnight. After the reaction was completed, the mixture was cooled to room temperature, EA was added, washed with water / saturated brine respectively, the organic phase was separated, dried and filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the product (S)-2-(2-isopropylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester 3.4 g, with a yield of 85%, ESI-MS (M+H) + =290.2.

[0448] Synthesis Step 2: (S)-2-(2-isopropylphenyl)pyrrolidine (Intermediate 1)

[0449] Intermediate 1-1 (3 g, 10.40 mmol) was dissolved in 18 mL of dichloromethane, 9 mL of TFA was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 1.92 g of colorless oily product of Intermediate 1, with a yield of 97%. ESI-MS (M+H) + =190.2.

[0450] Intermediate 2: 4-((dimethylamino)methyl)-3-methoxybenzaldehyde

[0451]

[0452] Synthesis step 1: 1-(4-bromo-2-methoxyphenyl)-N,N-dimethylmethanamine (Intermediate 2-1)

[0453] Dissolve 4-bromo-2-methoxybenzaldehyde (3 g, 13.95 mmol) in 50 mL DCM, add 2 mol / L tetrahydrofuran solution of dimethylamine (8.4 mL, 16.74 mmol), stir at room temperature for 30 min, then add STAB (3.85 g, 18.14 mmol), and react at room temperature for 4 h. After the reaction is completed, add saturated sodium bicarbonate aqueous solution for extraction, separate the DCM phase, and concentrate under reduced pressure. The crude product is purified by column chromatography to obtain 1.8 g of the product 1-(4-bromo-2-methoxyphenyl)-N,N-dimethylmethylamine, with a yield of 53%. ESI-MS (M+H) + =244.0.

[0454] Synthesis Step 2: 4-((Dimethylamino)methyl)-3-methoxybenzaldehyde (Intermediate 2)

[0455] The intermediate 2-1 (1.8 g, 7.39 mmol) was dissolved in 30 mL of anhydrous THF. After the system was cooled to -70°C, a 2.5 mol / L hexane solution of n-butyl lithium (3.6 mL, 8.87 mmol) was slowly added dropwise. The mixture was kept at -70°C for 1 h. Anhydrous DMF (1 mL, 14.78 mmol) was then added. The mixture was kept at room temperature for 1 h. Water was added to quench the reaction. EA was added for extraction (100 ml*2). The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to obtain 871 mg of the intermediate 2 product. The yield was 61%. ESI-MS (M+H) + =194.1.

[0456] Intermediate 3: 3-methoxy-4-(pyrrolidin-1-ylmethyl)benzaldehyde

[0457]

[0458] Referring to the synthetic route and method of intermediate 2, 4-bromo-2-methoxybenzaldehyde in synthetic step 1 was replaced with 5-bromo-2-methoxybenzaldehyde to synthesize intermediate 3. ESI-MS (M+H) + =194.1.

[0459] Referring to the synthetic route and method of intermediates 2 to 3, the following intermediate structure was synthesized:

[0460]

[0461]

[0462] Intermediate 8: 4-(((2,4-dimethoxybenzyl)(methyl)amino)methyl)benzaldehyde

[0463]

[0464] Synthesis step 1: N-(4-(diethoxymethyl)benzyl)-1-(2,4-dimethoxyphenyl)-N-methylmethanamine (Intermediate 8-1)

[0465] 4-(diethoxymethyl)benzaldehyde (500 mg, 2.4 mmol) was dissolved in 20 mL DCM, and 1-(2,4-dimethoxyphenyl)-N-methylmethylamine (522 mg, 2.88 mmol) and STAB (1.5 g, 7.2 mmol) were added in sequence, and the mixture was reacted at room temperature for 10 h. After the reaction was completed by TLC monitoring, water was added to extract the liquid, the DCM phase was separated, and the phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain 600 mg of the product N-(4-(diethoxymethyl)benzyl)-1-(2,4-dimethoxyphenyl)-N-methylmethylamine, with a yield of 67%. ESI-MS (M+H) + =374.2.

[0466] Synthesis step 2: 4-(((2,4-dimethoxybenzyl)(methyl)amino)methyl)benzaldehyde (Intermediate 8)

[0467] Intermediate 8-1 (600 mg, 1.6 mmol) was dissolved in 10 mL THF, 10 mL of 2N HCl aqueous solution was added, and the mixture was stirred at room temperature for 1 h. THF was concentrated, and EA and water were added for extraction. The organic phase was separated and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain 426.3 mg of intermediate 8 with a yield of 89%. ESI-MS (M+H) + =300.2.

[0468] Intermediate 9: 3-(2-isopropylphenyl)-1-(4-methoxybenzyl)piperazine

[0469]

[0470] Synthesis step 1: (2-isopropylphenyl)boronic acid (Intermediate 9-1)

[0471] Dissolve 1-bromo-2-isopropylbenzene (20g, 0.10mol) in 200mL THF, stir at -80℃ for 10min, then add n-BuLi (44mL, 0.11mol) dropwise, and keep at -80℃ for 1h after the addition is complete. Add 50mL of THF containing triisopropyl borate to the system, continue to keep at -80℃ for 1h, then transfer to 20℃ and stir for 1h, while adding HCl aqueous solution (150mL, 0.15mol, 1N) dropwise and continue stirring for 1h. After the reaction is completed, add EA for extraction, separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude (2-isopropylphenyl) boronic acid, which is directly used in the next reaction. ESI-MS (M+H) + =165.1.

[0472] Synthesis Step 2: 2-(2-isopropylphenyl)pyrazine (Intermediate 9-2)

[0473] 150 mL of dioxane and 150 mL of water were added to the intermediate 9-1 (16.5 g, 0.10 mol). After stirring to dissolve, 2-chloropyrazine (13.80 g, 0.12 mol), Pd(PPh 3 ) 4 (1.74 g, 1.50 mmol), Na 2 CO 3 (21.20 g, 0.20 mol), reacted at 90 ° C for 12 h. After the reaction was completed, cooled to room temperature, filtered through diatomaceous earth, extracted with EA, separated the organic phase, dried and filtered, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain 13 g of colorless oily product 2-(2-isopropylphenyl)pyrazine, with a yield of 65%, ESI-MS (M+H) + =199.1.

[0474] Synthesis Step 3: 2-(2-isopropylphenyl)piperazine (Intermediate 9-3)

[0475] Add 150mL of anhydrous ethanol and 10mL of glacial acetic acid to the intermediate 9-2 (10.2g, 51.55mmol), stir until dissolved, add Pd / C (5g) to the reaction solution, and then place the system in a hydrogen (4atm) environment at 60°C for 10h. After the reaction is completed, filter to remove diatomaceous earth, wash with methanol (300mL) and water (100mL), respectively. Concentrate under reduced pressure to remove most of the methanol, extract with EA, separate the aqueous phase, adjust the pH to 13-14 with 10% NaOH aqueous solution, then extract with DCM, separate the organic phase, dry and filter, and concentrate under reduced pressure. The crude product is purified by column chromatography to obtain the product 2-(2-isopropylphenyl)piperazine 9.66g, with a yield of 91%, ESI-MS (M+H) + ==205.2.

[0476] Synthesis Step 4: 3-(2-isopropylphenyl)-1-(4-methoxybenzyl)piperazine (Intermediate 9)

[0477] Intermediate 9-3 (2.00 g, 9.80 mmol) and 4-methoxybenzaldehyde (1.20 mL, 9.80 mmol) were dissolved in 40 mL DCM, and STAB (6.20 g, 29.40 mmol) was added to react at room temperature for 3 h. After the reaction was completed, DCM was added for extraction, the organic phase was separated, dried and filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography to obtain 1.7 g of solid product of intermediate 9, with a yield of 53%. ESI-MS (M+H) + =325.2.

[0478] Intermediate 10: (R)-3-(2-isopropylphenyl)-1-(4-methoxybenzyl)piperazine

[0479]

[0480] Synthesis step 1: (R)-2-(2-isopropylphenyl)piperazine (Intermediate 10-1)

[0481] The intermediate 9-3 (2g, 9.8mmol) was dissolved in a mixed solvent of 650mL MeOH / EA (V / V=1:10), and N-acetyl-D-leucine (17g, 98mmol) was added to reflux for 1h until the solution was clear, and then the system was naturally cooled to room temperature and stirred for 16h. After the reaction was completed, the filter cake was rinsed with ethyl acetate and concentrated at 45°C under reduced pressure for 1h to obtain about 15g of crude product. The crude product was extracted and separated three times (100mL*3) with DCM / 1N NaOH aqueous solution (V / V=3:2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 5.3g of (R)-2-(2-isopropylphenyl)piperazine, with a yield of 26.5%, ESI-MS (M+H) + =205.2. 1 H NMR(400MHz,Chloroform-d)δ7.55(dd,J=7.6,1.6Hz,1H),7.30–7.10(m,3H),4.06(dd,J=10.1,2.7Hz,1H),3.31(he pt,J=6.9Hz,1H),3.16–3.07(m,1H),3.04–2.83(m,4H),2.69(dd,J=12.1,10.0Hz,1H),1.23(dd,J=6.9,1.9Hz,6H).

[0482] Synthesis Step 2: (R)-3-(2-isopropylphenyl)-1-(4-methoxybenzyl)piperazine (Intermediate 10)

[0483] The intermediate 10-1 (5 g, 24.5 mmol) was dissolved in 50 mL of DCM, 4-methoxybenzaldehyde (3.33 g, 24.5 mmol) was added, and the mixture was stirred at 0°C for 30 min, and then STAB (7.8 g, 36.7 mmol) was added and stirred evenly for reaction, and the reaction was continued at 0°C for 16 h. After the reaction was completed, DCM and water were added to extract and separate the liquids, and the organic phase was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 6.9 g of the solid product of the intermediate 10, with a yield of 87%. ESI-MS (M+H) + =325.2. 1 H NMR(400MHz,Chloroform-d)δ7.53(dd,J=7.5,1.3Hz,1H),7.28–7.19(m,4H),7.15(ddd,J=7.7,6.5,2.2Hz,1H),6.87–6.80(m,2H ),4.33(dd,J=10.5,2.7Hz,1H),3.77(s,3H),3.57(d,J=1.8Hz,2H),3.24–3.06(m,3H),2.91(td,J=12.2,11.2,2.3Hz,2H),2.44–

[0484] 2.33(m,1H),2.23(dd,J=11.8,10.5Hz,1H),1.22(d,J=6.7Hz,3H),1.12(d,J=6.8Hz,3H).

[0485] Intermediate 11: 3-(2-isopropylphenyl)-1-(tetrahydro-2H-pyran-4-yl)piperazine

[0486]

[0487] Referring to the synthetic route and method of intermediate 9, 4-methoxybenzaldehyde in synthetic step 4 was replaced with tetrahydro-4H-pyran-4-one to synthesize intermediate 11. ESI-MS (M+H) + =289.2.

[0488] Intermediate 12: (R)-3-(2-isopropylphenyl)-1-((6-methoxypyridin-3-yl)methyl)piperazine

[0489]

[0490] Referring to the synthetic route and method of intermediate 10, 4-methoxybenzaldehyde in synthetic step 2 was replaced with 6-methoxynicotinaldehyde to synthesize intermediate 12. ESI-MS (M+H) + =326.2.

[0491] Referring to the synthetic routes and methods of intermediates 9 to 12, the following intermediate structures were synthesized:

[0492]

[0493]

[0494]

[0495]

[0496] Intermediate 55: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0497]

[0498] Synthesis Step 1: 7-Azaspiro[3.5]nonan-2-one trifluoroacetate (Intermediate 55-1)

[0499] 2-Oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (5 g, 20.6 mmol) was dissolved in 40 mL of DCM, TFA (14 mL, 206 mmol) was added, and the mixture was stirred at 25° C. for 2 h. After the reaction was complete, the solvent and TFA were removed by concentration, and the mixture was used directly in the next step without further purification.

[0500] Synthesis Step 2: Methyl 2-fluoro-4-(2-oxo-7-azaspiro[3.5]nonane-7-yl)benzoate (Intermediate 55-2)

[0501] Methyl 2,4-difluorobenzoate (3.5 g, 20.6 mmol) was dissolved in 100 mL DMF, and intermediate 55-1 (5.2 g, 20.6 mmol) and sodium carbonate (6.5 g, 61.8 mmol) were added in sequence, and the mixture was reacted at 80° C. for 10 h. TLC showed that the reaction was complete, and the DMF was removed by concentration, and EA and water were added for extraction. The organic phases were separated and combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 4.7 g of methyl 2-fluoro-4-(2-oxo-7-azaspiro[3.5]nonane-7-yl)benzoate, with a yield of 78%, and ESI-MS (M+H)+=292.1.

[0502] Synthesis Step 3: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (Intermediate 55)

[0503] Intermediate 55-2 (4.7 g, 16.17 mmol) and 1H-pyrrolo[2,3-b]pyridin-5-ol (2.17 g, 16.17 mmol) were dissolved in 100 mL of diethylene glycol diethyl ether, potassium phosphate (6.9 g, 32.34 mmol) was added, and the mixture was sealed and reacted at 130° C. for 8 h. TLC showed that the reaction was complete, and the oil pump was pulled dry. The crude product was purified by column chromatography and PE slurry to obtain 1.3 g of solid product of intermediate 55, with a yield of 20%, and ESI-MS (M+H)+=406.2.

[0504] Intermediate 56: methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0505]

[0506] Referring to the synthetic route and method of intermediate 55, methyl 2,4-difluorobenzoate in synthetic step 2 was replaced with methyl 2,4,5-trifluorobenzoate to synthesize intermediate 56. ESI-MS (M+H) + =424.2. 1 H NMR(400MHz,Chloroform-d)δ10.09(s,1H),8.12(dd,J=2.6,0.4Hz,1H),7.65(d,J=13.5Hz,1H),7.49(dd,J=2.5,0.6H z,1H),7.36(dd,J=3.5,2.4Hz,1H),6.45–6.38(m,2H),3.79(s,3H),3.09–3.00(m,4H),2.79(s,4H),1.87–1.78(m,4H).

[0507] Intermediate 57: Methyl 2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0508]

[0509] Synthesis Step 1: 5-Bromo-3-fluoro-1H-pyrrolo[2,3-b]pyridine (Intermediate 57-1)

[0510] 5-Bromo-1H-pyrrolo[2,3-b]pyridine (20 g, 101.50 mmol) was dissolved in a solution of 400 mL acetonitrile and 100 mL acetic acid, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (54 g, 152.25 mmol) was added, and the mixture was reacted at 90°C for 16 h. TLC showed that the reaction was complete, acetonitrile and acetic acid were removed by concentration, EA was added to the residue to dissolve, and then saturated sodium bicarbonate aqueous solution was slowly added to neutralize, the pH of the aqueous phase was adjusted to 8-9, the EA phase was separated and combined, dried and concentrated, and the crude product was subjected to column chromatography to obtain 5.2 g of the product 5-bromo-3-fluoro-1H-pyrrolo[2,3-b]pyridine, with a yield of 24%, ESI-MS (M+H) + =215.0.

[0511] Synthesis Step 2: 3-Fluoro-5-methoxy-1H-pyrrolo[2,3-b]pyridine (Intermediate 57-2)

[0512] The intermediate 57-1 (5.2 g, 24.18 mmol) was dissolved in 100 mL of anhydrous DMF, and cuprous bromide (6.9 g, 48.36 mmol) and sodium methoxide (3.9 g, 72.54 mmol) were added at room temperature, and then the temperature was raised to 130°C for reaction for 3 h. TLC showed that the reaction was complete, and the mixture was cooled to room temperature, and ice water was slowly added to quench the reaction. EA (60 mL*3) was added for extraction, and the organic phases were separated and combined, dried over anhydrous sodium sulfate, and filtered. The crude product was purified by column chromatography to obtain 1.4 g of the product 3-fluoro-5-methoxy-1H-pyrrolo[2,3-b]pyridine, with a yield of 36%, and ESI-MS (M+H) + =167.1.

[0513] Synthesis Step 3: 3-Fluoro-1H-pyrrolo[2,3-b]pyridine-5-ol (Intermediate 57-3)

[0514] The intermediate 57-2 (1.4 g, 8.43 mmol) was dissolved in 30 mL DCM, the system was cooled to -20 ° C, and a DCM solution of boron tribromide (6.4 g, 25.29 mmol) was slowly added dropwise, the internal temperature was maintained between -20 ° C and -10 ° C, and the temperature was kept at -20 ° C for 1 hour after the addition was completed. After the reaction was completed, the reaction solution was slowly poured into ice water, saturated sodium bicarbonate aqueous solution was added to neutralize the pH to between 7 and 9, EA was added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography to obtain 743 mg of the product 3-fluoro-1H-pyrrolo[2,3-b]pyridine-5-ol, with a yield of 58%, ESI-MS (M+H) + =153.0.

[0515] Synthetic Step 4: Methyl 2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (Intermediate 57)

[0516] Referring to the synthetic route and method of intermediate 55, 1H-pyrrolo[2,3-b]pyridine-5-ol in synthetic step 3 was replaced with intermediate 57-3 to synthesize the target intermediate 57. ESI-MS (M+H) + =424.2.

[0517] Referring to the synthetic routes and methods of intermediates 55 to 57, the following intermediate structures were synthesized:

[0518]

[0519] Intermediate 61: methyl 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0520]

[0521] Synthesis step 1: 5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate 61-1)

[0522] 5-Bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine (10 g, 46.50 mmol) was dissolved in 200 mL DMF, and 60% NaH (846.4 mg, 51.16 mmol) was added, and the mixture was stirred at room temperature for 30 min, and then SEMCl (10.08 g, 60.45 mmol) was added, and the reaction was continued at room temperature for 3 h. After the reaction was completed, water and EA were added for extraction, the EA phase was separated, dried and filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography to obtain 13 g of the product 5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine, with a yield of 80%, ESI-MS (M+H) + =345.0.

[0523] Synthesis step 2: N-(3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide (Intermediate 61-2)

[0524] N-(3-Hydroxypropyl)-4-methylbenzenesulfonamide (10.62 g, 46.32 mmol) was dissolved in 400 mL THF, cooled to 0 degrees Celsius, and 60% NaH (2.3 g, 57.90 mmol) was added in batches and reacted for 1 hour, and then intermediate 61-1 (8 g, 23.16 mmol) was added and reacted at room temperature overnight. After the reaction was completed, a saturated ammonium chloride solution was added to quench the reaction, EA and water were added for extraction, the EA phase was separated, dried and filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography to obtain 5.8 g of the product N-(3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide, yield: 45%, ESI-MS (M+H) + =554.1.

[0525] Synthesis Step 3: 1-Tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane (Intermediate 61-3)

[0526] The intermediate 61-2 (5.04 g, 9.1 mmol) was dissolved in 100 mL DMSO, and 2-picolinic acid (900 mg, 7.3 mmol), cuprous iodide (2.1 g, 10.92 mmol), and potassium carbonate (3.8 g, 27.3 mmol) were added in sequence, and the mixture was reacted at 140° C. overnight. After the reaction was completed, EA and water were added for extraction, the EA phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 2.1 g of the product 1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazacycloheptane, with a yield of 48.6%, ESI-MS (M+H) + =474.2.

[0527] Synthesis Step 4: 7-((2-(Trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane (Intermediate 61-4)

[0528] The intermediate 61-3 (1.9 g, 4 mmol) was dissolved in 100 mL of anhydrous methanol, magnesium powder (2.9 g, 120 mmol) was added, and saturated aqueous ammonium chloride solution was added to reflux for 1 h to quench the reaction. EA and water were added for extraction, the EA phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography to obtain the product 7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazazepane 1.1 g, yield 86%, ESI-MS (M+H) + =320.2.

[0529] Synthesis step 5: 4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-2-(7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)benzoic acid methyl ester (Intermediate 61-5)

[0530] Intermediate 55-2 (669 mg, 2.3 mmol) was dissolved in 70 mL of toluene, and intermediate 61-4 (500 mg, 1.57 mmol), cesium carbonate (1.53 g, 4.7 mmol), XantPhos (700 mg, 0.80 mmol), Pd(dba) were added in sequence. 2 (144 mg, 0.16 mmol), nitrogen protection, reacted at 110 ° C overnight. After the reaction was completed, cooled to room temperature, EA and water were added for extraction, the EA phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was separated and purified by column chromatography to obtain the product 4-(2-oxo-7-azaspiro[3.5]nonane-7-yl)-2-(7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazazepan-1(7H)-yl)benzoic acid methyl ester 471 mg, yield 51%, ESI-MS (M+H) + =591.3.

[0531] Synthesis step 6: 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoic acid methyl ester (Intermediate 61)

[0532] The intermediate 61-5 (471 mg, 0.80 mmol) was dissolved in 20 mL THF, and 30 mL TBAF solution (1 mol / L THF solution) was added. After heating under reflux overnight, the mixture was cooled to room temperature, and EA and water were added for extraction. The EA phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to obtain 326 mg of the solid product of the intermediate 61. The yield was 89%. ESI-MS (M+H) + =461.2.

[0533] Referring to the synthetic route and method of intermediate 61, the following intermediate structure was synthesized:

[0534]

[0535] Intermediate 64: 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0536]

[0537] Dissolve (4-fluorotetrahydro-2H-pyran-4-yl)methylamine (0.5 g, 5 mmol) in 15 mL THF, add 4-fluoro-3-nitrobenzenesulfonamide (1.1 g, 5 mmol) and triethylamine (4 g, 40 mmol), and react at room temperature for 8 h. TLC shows that the reaction is complete, concentrate the reaction solution, add DCM / H 2 O extraction, separation of the organic phase, drying over anhydrous sodium sulfate, filtration and concentration, the resulting crude product was separated and purified by column chromatography to obtain 1.23 g of solid intermediate 64, with a yield of 74%. ESI-MS (M+H) + =334.1.

[0538] Intermediate 65: 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

[0539]

[0540] Referring to the synthetic route and method of intermediate 64, (4-fluorotetrahydro-2H-pyran-4-yl)methylamine was replaced with (1r, 4r)-4-(aminomethyl)-1-methylcyclohexan-1-ol to synthesize intermediate 65. ESI-MS (M+H) + =344.1.

[0541] Intermediate 66: 4-((4-fluoro-1-(oxacyclo-3-yl)piperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0542]

[0543] Synthesis Step 1: tert-Butyl 4-fluoro-4-(((2-nitro-4-sulfamoylphenyl)amino)methyl)piperidine-1-carboxylate (Intermediate 66-1)

[0544] Referring to the synthetic route and method of intermediate 64, (4-fluorotetrahydro-2H-pyran-4-yl)methylamine was replaced with 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester to synthesize 4-fluoro-4-(((2-nitro-4-sulfamoylphenyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester. ESI-MS (M+H) + =433.1.

[0545] Synthesis Step 2: 4-((4-Fluoro-1-(oxacyclo-3-yl)piperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide (Intermediate 66)

[0546] The intermediate 66-1 (2g, 4.62mmol) was dissolved in 30mL DCM, 15mL TFA was added, and the mixture was reacted at room temperature for 4h. TLC showed that the reaction was complete, and the reaction solution was directly spin-dried to obtain 1.96g of a yellow viscous liquid. The obtained yellow liquid product was dissolved in 20mL DCM, 3-oxetanone (475mg, 6.58mmol) was added, and after stirring at room temperature for 30min, STAB (1.39g, 6.58mmol) was added, and the reaction was continued at room temperature for 2h. TLC showed that the reaction was complete, DCM and water were added for extraction, the organic phase was separated, dried and filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.61g of a yellow solid product of the intermediate 66, with a yield of 63%. ESI-MS (M+H) + =389.1.

[0547] Referring to the synthetic routes and methods of intermediates 64 to 66, the following intermediate structures were synthesized:

[0548]

[0549] Intermediate 70: 6-Nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazole-4-sulfonamide

[0550]

[0551] Synthetic Step 1: 4,7-Dibromo-1H-benzo[d]imidazole (Intermediate 70-1)

[0552] 3,6-dibromobenzene-1,2-diamine (4.5 g, 16.92 mmol) was dissolved in 100 mL THF, trimethyl orthoformate (2.70 g, 25.38 mmol) was added, and p-toluenesulfonic acid (291 mg, 1.69 mmol) was added after stirring for 5 min. The system was left to react at room temperature for 1 h. TLC showed that the reaction was complete, and the solid was filtered, washed with mother liquor, and then dried in a 60°C oven to obtain 4.3 g of a yellow solid product, 4,7-dibromo-1H-benzo[d]imidazole, with a yield of 93%. ESI-MS (M+H) + =274.9.

[0553] Synthetic Step 2: 4,7-Dibromo-6-nitro-1H-benzo[d]imidazole (Intermediate 70-2)

[0554] At 0°C, intermediate 70-1 (4.30 g, 15.58 mmol) was dissolved in 45 mL of concentrated sulfuric acid, stirred for 5 min, and then HNO was slowly added dropwise. 3 (830mL, 18.70mmol), control the system temperature between 0-10℃, and continue to stir at 0℃ for 1h after the addition is complete. After the reaction is complete, slowly pour the reaction solution into iced ammonia water to quench. After quenching, the pH is about 8. Filter, wash the solid with water, and then send it to a 60℃ oven for drying to obtain a yellow solid product 4,7-dibromo-6-nitro-1H-benzo[d]imidazole 4g, with a yield of 80%, ESI-MS (M+H) + =319.9.

[0555] Synthetic Step 3: 4-Bromo-6-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-7-amine (Intermediate 70-3)

[0556] The intermediate 70-2 (3 g, 9.35 mmol) was dissolved in 20 mL of dioxane, and (tetrahydro-2H-pyran-4-yl)methylamine (1.62 g, 14.03 mmol), K 2 CO 3 (3.9 g, 28.05 mmol), sealed at 120 ° C for 48 hours. TLC showed that the reaction was complete, concentrated to remove dioxane, added water and EA for extraction, separated the organic phase, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain a yellow solid product 4-bromo-6-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazole-7-amine 2.9 g, yield 88%. ESI-MS (M+H) + =355.0.

[0557] Synthetic Step 4: 4-(Benzylthio)-6-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-7-amine (Intermediate 70-4)

[0558] The intermediate 70-3 (2.9 g, 8.23 ​​mmol) was dissolved in 30 mL of toluene, and benzyl mercaptan (2.04 g, 16.46 mmol), Xantphos (952 mg, 1.65 mmol), Pd 2 (dba) 3 (754 mg, 0.823 mmol), DIPEA (3.2 g, 24.69 mmol), sealed at 110 ° C for 16 h. LCMS showed that the reaction was complete, water and EA were added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain a yellow solid product 4-(benzylthio)-6-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazole-7-amine 1.26 g, yield 38.5%. ESI-MS (M+H) + =399.1.

[0559] Synthetic Step 5: 6-Nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazole-4-sulfonamide (Intermediate 70)

[0560] To a single-necked bottle were added intermediate 70-4 (1.26 g, 3.17 mmol), MeCN (14 mL), H 2 O (1.4mL), AcOH (0.7mL), the reaction system was cooled to 0℃, NCS (1.27g, 9.51mmol) was added in batches, stirred at 0℃ for 1h, then transferred to room temperature and continued to react for 1h, then the reaction solution was added dropwise to an iced 25% ammonia solution (22.5ml, 158.45mmol), and the reaction was continued to stir at room temperature for 1h. After the reaction was completed, water was added to dilute, the aqueous phase was extracted with 10% ethanol in ethyl acetate solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain 338mg of intermediate 70 as a yellow solid product with a yield of 30%. ESI-MS (M+H) + =356.1.

[0561] Intermediate 71: 7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazole-4-sulfonamide

[0562]

[0563] Synthesis Step 1: tert-Butyl 4-fluoro-4-(((6-nitro-4-sulfamoyl-1H-benzo[d]imidazol-7-yl)amino)methyl)piperidine-1-carboxylate (Intermediate 71-1)

[0564] Referring to the synthetic route and method of intermediate 70, the (tetrahydro-2H-pyran-4-yl)methylamine in the synthetic step 3 was replaced with 4-(aminomethyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester to obtain 4-fluoro-4-(((6-nitro-4-sulfamoyl-1H-benzo[d]imidazol-7-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester. ESI-MS (M+H) + =473.2.

[0565] Synthetic Step 2: 7-(((4-Fluoro-1-(oxetane-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazole-4-sulfonamide (Intermediate 71)

[0566] The intermediate 71-1 (190 mg, 0.40 mmol) was dissolved in 10 mL DCM, 2 mL trifluoroacetic acid was added, and the reaction was carried out at room temperature for 6 h. TLC showed that the reaction was complete, and the reaction solution was concentrated to obtain a yellow oil. The above product was dissolved in 10 mL DCM, 3-oxetanone (44 mg, 0.60 mmol) was added, and after stirring at room temperature for 30 min, STAB (128 mg, 0.60 mmol) was added, and the reaction was continued at room temperature for 2 h. TLC showed that the reaction was complete, DCM and water were added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain 145 mg of the intermediate 71 yellow solid product, yield: 85%. ESI-MS (M+H) + =429.1.

[0567] Referring to the synthetic route and method of intermediates 70 to 71, the following intermediate structure was synthesized:

[0568]

[0569]

[0570] Intermediate 86: 6-Nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolane-4-sulfonamide

[0571]

[0572] Synthesis Step 1: 2-Bromo-6-methoxy-3-nitrophenol (Intermediate 86-1)

[0573] 2-Methoxy-5-nitrophenol (100 g, 591.2 mmol) was dissolved in 500 mL of glacial acetic acid, and 30 mL of Br was added dropwise at room temperature. 2 , react at room temperature for 14 hours. After the reaction is completed, saturated sodium sulfite is added to quench the reaction, water is added to precipitate the solid, filter, rinse the filter cake with water, and dry under reduced pressure at 50°C to obtain 99g of brown solid crude 2-bromo-6-methoxy-3-nitrophenol, yield: 67.51%. ESI-MS (M+H) + =247.9.

[0574] Synthesis Step 2: 3-Bromo-4-nitrobenzene-1,2-diol (Intermediate 86-2)

[0575] Intermediate 86-1 (99 g, 399.15 mmol) was dissolved in 1000 mL of dichloromethane and anhydrous AlCl 3 Solid (243g, 1.82mol), heated to 40℃ and refluxed for 13h. After the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was separated and concentrated. The crude product was separated by column chromatography to obtain 82g of the product 3-bromo-4-nitrobenzene-1,2-diol, with a yield of 87.8%. ESI-MS (M+H) + =233.9.

[0576] Synthetic Step 3: 4-Bromo-5-nitrobenzo[d][1,3]dioxolane (Intermediate 86-3)

[0577] The intermediate 86-2 (10 g, 42.74 mmol) was dissolved in 100 mL DMAC, and bromochloromethane (3.32 mL, 51.20 mmol) and cesium carbonate (27.86 g, 85.48 mmol) were added, and the mixture was reacted at 110°C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and ethyl acetate (500 ml*3) and water were added for extraction. The organic phases were separated and combined, dried and concentrated, and the crude product was purified by column chromatography to obtain 7.3 g of the product 4-bromo-5-nitrobenzo[d][1,3]dioxolane, with a yield of 69.4%. ESI-MS (M+H) + =245.9.

[0578] Synthetic Step 4: 5-Nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzo[d][1,3]dioxolane-4-amine (Intermediate 86-4)

[0579] Intermediate 86-3 (2.5 g, 10.2 mmol) was dissolved in 35 mL of tetrahydrofuran, and (tetrahydro-2H-pyran-4-yl)methylamine (3.5 g, 30.6 mmol), BINAP (635 mg, 1.02 mmol), Pd 2(dba) 3 (934 mg, 1.02 mmol), cesium carbonate (6.6 g, 20.4 mmol), reflux reaction at room temperature for 16 h. After the reaction, the reaction solution was passed through diatomaceous earth, tetrahydrofuran was concentrated, ethyl acetate and water were added for extraction, the organic phase was separated, dried and concentrated, and the obtained crude product was purified by column chromatography to obtain 650 mg of the product 5-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzo[d][1,3]dioxolane-4-amine, with a yield of 22.7%. ESI-MS (M+H) + =281.1.

[0580] Synthetic Step 5: 7-Bromo-5-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzo[d][1,3]dioxolane-4-amine (Intermediate 86-5)

[0581] The intermediate 86-4 (650 mg, 2.32 mmol) was dissolved in 7 mL of anhydrous DMF, and NBS (413 mg, 2.32 mmol) was slowly added and reacted at room temperature for 4 h. After the reaction was completed, ethyl acetate (20 mL*3) and water were added for extraction, and the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain 300 mg of the product 7-bromo-5-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzo[d][1,3]dioxolane-4-amine, with a yield of 36%. ESI-MS (M+H) + =359.0.

[0582] Synthetic Step 6: 6-Nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolane-4-sulfonamide (Intermediate 86)

[0583] Referring to the synthetic route and method of steps 4 and 5 of the synthesis of intermediate 70, intermediate 70-3 in the synthesis step 4 was replaced with intermediate 86-5 to obtain 80 mg of yellow solid intermediate 86. ESI-MS (M+H) + =360.1.

[0584] Intermediate 87: 7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenz[d][1,3]dioxolane-4-sulfonamide

[0585]

[0586] Referring to the synthetic route and method of intermediate 86, (tetrahydro-2H-pyran-4-yl)methylamine in synthetic step 4 was replaced with (1r, 4r)-4-(aminomethyl)-1-methylcyclohexan-1-ol to synthesize intermediate 87. ESI-MS (M+H) + =388.1.

[0587] Intermediate 88: 5,8-Dibromo-6-nitro-2,3-dihydrobenzo[b][1,4]dioxin

[0588]

[0589] Referring to the synthetic route and method of intermediate 86, the bromochloromethane in the synthetic step 3 was replaced with 1-bromo-2-chloroethane to synthesize intermediate 88. ESI-MS (M+H) + =374.1.

[0590] Referring to the synthetic routes and methods of intermediates 86 to 88, the following intermediate structures were synthesized:

[0591]

[0592]

[0593] Intermediate 98: 7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]oxazole-4-sulfonamide

[0594]

[0595] Synthetic Step 1: 7-Bromobenzo[d]oxazol-4-amine (Intermediate 98-1)

[0596] Benzo[d]oxazol-4-amine (2 g, 14.92 mmol) was dissolved in 20 mL DMF, cooled to 0°C, and NBS (2.65 g, 14.92 mmol) was added for selective bromination. The reaction was terminated after 1 h, and water and ethyl acetate were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to obtain 2.2 g of the product 7-bromobenzo[d]oxazol-4-amine, with a yield of 71%. ESI-MS (M+H) + =213.0.

[0597] Synthetic Step 2: 7-Bromobenzo[d]oxazole-4-sulfonyl chloride (Intermediate 98-2)

[0598] Intermediate 98-1 (1.1 g, 5.29 mmol) was suspended in 11 mL of 6N sulfuric acid solution, the system was cooled to 0°C, sodium nitrite (474 ​​mg, 6.88 mmol) was added, the suspension gradually dissolved, reacted at 0°C for 1 hour, 20 mL of saturated sulfur dioxide acetic acid solution was added, and then the reaction was transferred to room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into ice water, and ethyl acetate was added and stirred for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain 639 mg of the product 7-bromobenzo[d]oxazole-4-sulfonyl chloride, with a yield of 41%. ESI-MS (M+H) + =295.9.

[0599] Synthetic Step 3: 7-Bromo-6-nitrobenzo[d]oxazole-4-sulfonamide (Intermediate 98-3)

[0600] The intermediate 98-2 (639 mg, 2.16 mmol) was added to 10 mL of concentrated sulfuric acid at 0°C and stirred, followed by the addition of 0.2 mL of 68% concentrated nitric acid, and the temperature was raised to 80°C for reaction for 1 hour, and then the reaction solution was poured into 50 mL of iced ammonia solution and continued to stir for 1 hour. After the reaction was completed, water was added for dilution, and ethyl acetate (100 mL*2) was added for extraction, and the organic phases were separated and combined, dried and concentrated. The crude product was separated and purified by column chromatography to obtain 332 mg of the product 7-bromo-6-nitrobenzo[d]oxazole-4-sulfonamide, with a yield of 48%. ESI-MS (M+H) + =321.9.

[0601] Synthetic Step 4: 7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]oxazole-4-sulfonamide (Intermediate 98)

[0602] Dissolve the intermediate 98-3 (332 mg, 1.03 mmol) in 10 mL 1,4-dioxane solution, add potassium carbonate (285 mg, 2.06 mmol) and (4-fluorotetrahydro-2H-pyran-4-yl)methylamine (179 mg, 1.34 mmol) in sequence, seal the tube and react at 120°C for 9 h. After the reaction is completed, cool the system to room temperature, add ethyl acetate (30 mL*2) and water for extraction, separate and combine the organic phases, dry and concentrate, and the obtained crude product is separated and purified by column chromatography to obtain 300 mg of the solid product of intermediate 98 with a yield of 78%. ESI-MS (M+H) + =375.1.

[0603] Intermediate 99: 7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]thiazole-4-sulfonamide

[0604]

[0605] Referring to the synthetic route and method of intermediate 98, the benzo[d]oxazol-4-amine in the synthetic step 1 was replaced with benzo[d]thiazole-4-amine to synthesize intermediate 99. ESI-MS (M+H) + =391.0.

[0606] Intermediate 100: 7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzofuran-4-sulfonamide

[0607]

[0608] Referring to the synthetic route and method of intermediate 98, the benzo[d]oxazol-4-amine in the synthetic step 1 was replaced with benzofuran-4-amine to synthesize intermediate 100. ESI-MS (M+H) + =374.1.

[0609] Intermediate 101: (S)-7-(((1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d]oxazole-4-sulfonamide

[0610]

[0611] Referring to the synthetic route and method of intermediate 98, (4-fluorotetrahydro-2H-pyran-4-yl)methylamine in synthetic step 4 was replaced with (S)-(1,4-dioxane-2-yl)methylamine to synthesize intermediate 101. ESI-MS (M+H) + =359.1.

[0612] Referring to the synthetic routes and methods of intermediates 98 to 101, the following intermediate structures were synthesized:

[0613]

[0614]

[0615]

[0616] Example 1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (001)

[0617]

[0618] Synthesis step 1: (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)benzoic acid methyl ester (001-1)

[0619] Intermediate 55 (772 mg, 1.902 mmol) and intermediate 1 (300 mg, 1.585 mmol) were dissolved in 30 mL DCM, stirred and slowly added with STAB (1007 mg, 4.755 mmol), and reacted at room temperature for 3 h. LCMS showed that the reaction was complete, and water was added to quench, and DCM and water were added for extraction. The organic phases were separated and combined, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the 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)benzoic acid methyl ester 587 mg, yield 64%, ESI-MS (M+H) + =579.3.

[0620] Synthesis step 2: (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 (001-2)

[0621] Compound 001-1 (587 mg, 1.014 mmol) was dissolved in 6 mL THF, and 6 mL 3N NaOH and 6 mL MeOH were added in sequence, and the mixture was reacted at room temperature for 2 h. LCMS showed that the reaction was complete, 2N HCl was added to adjust the pH to 6-7, and the mixture was concentrated to remove methanol and tetrahydrofuran. 2-methyltetrahydrofuran and water were added for extraction, and the organic phases were separated and combined, dried and concentrated. The crude product was slurried with MTBE, filtered, and the solid was dried at 60 ° C for 3 h to obtain the 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 418 mg, with a yield of 73%, ESI-MS (M+H) + =565.3.

[0622] Synthetic step 3: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (001)

[0623] Add intermediate 72 (228 mg, 0.595 mmol) to reaction flask 1, add 15 mL DCM to form a suspension, then add DMAP (145 mg, 1.19 mmol) and EDCI (171 mg, 0.893 mmol), and stir at room temperature for 5 min. Add compound 001-2 (336 mg, 0.595 mmol) to reaction flask 2, add 15 mL DCM, and then add triethylamine (151 mg, 1.49 mmol), and stir at room temperature for 5 min. Slowly add the reaction solution in reaction flask 2 to reaction flask 1 for 1 h. After the addition is complete, continue to react at room temperature for 14 h. After the reaction is completed, add water and DCM to extract, separate and concentrate the DCM phase, and the crude product is purified by column chromatography to obtain 385 mg of yellow solid product of compound 001 with a yield of 56%. ESI-MS (M+H) + =930.4.

[0624] Example 2: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((4-fluoro-1-(oxetane-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (002)

[0625]

[0626] Referring to the synthetic route and method of Example 1, intermediate 72 in synthetic step 3 was replaced by intermediate 71 to synthesize the target compound 002. ESI-MS (M+H) + =975.4. 1H NMR(400MHz,Chloroform-d)δ11.26(s,1H),9.53(t,J=6.2Hz,1H),9.26(s,1H),8.75(s,1H),8.13(d,J=2.6Hz,1H),7.97(s,1 H),7.84(d,J=9.2Hz,1H),7.66(d,J=2.5Hz,1H),7.47–7.41(m,1H),7.20(s,3H),6.54–6.46(m,2H),5.92(d,J=2.2Hz,1H),4.8 0(d,J=6.3Hz,1H),4.75(d,J=6.3Hz,1H),4.66(t,J=6.5Hz,2H),4.58(t,J=6.2Hz,2H),3.50–3.48(m,1H),3.21(s,2H),2.95–2 .82(m,5H),2.58–2.47(m,3H),2.19–2.10(m,4H),2.04–1.89(m,4H),1.52–1.36(m,6H),1.24–1.21(m,5H),1.19–1.08(m,6H).

[0627] Example 3: 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepan-1(7H)-yl)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitro-1H-benzo[d]imidazol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (085)

[0628]

[0629] Referring to the synthetic route and method of Example 1, the intermediate 55 in the synthetic step 1 was replaced by the intermediate 61 to synthesize the target compound 085. ESI-MS (M+H) + =985.5.

[0630] Example 4: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolan-4-yl)sulfonyl)benzamide (145)

[0631]

[0632] Referring to the synthetic route and method of Example 1, the intermediate 1 in the synthetic step 1 was replaced by the intermediate 10, and the intermediate 72 in the synthetic step 3 was replaced by the intermediate 86 to synthesize the target compound 145. ESI-MS (M+H) + =1041.4. 1 H NMR(400MHz,Chloroform-d)δ9.22(s,1H),8.63(s,1H),8.14(t,J=6.4Hz,2H),7.90(d,J=9.1Hz,1H),7.66 (d,J=2.3Hz,1H),7.43(t,J=2.9Hz,2H),7.18(d,J=6.1Hz,2H),7.08(d,J=7.4Hz,1H),6.80(d,J=8.1Hz,2H) ,6.52(q,J=3.4Hz,2H),5.96(s,2H),3.98(dd,J=11.6,4.4Hz,2H),3.76–2.62(m,4H),3.54–3.27(m,9H),3. 01–2.82(m,9H),2.64(s,1H),2.22–2.09(m,3H),2.03–1.96(m,1H),1.18–1.13(m,5H),1.10–0.85(m,12H).

[0633] Example 5: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (152)

[0634]

[0635] Referring to the synthetic route and method of Example 1, the intermediate 1 in the synthetic step 1 was replaced by the intermediate 10, the intermediate 55 was replaced by the intermediate 56, and the intermediate 72 in the synthetic step 3 was replaced by the intermediate 64 to synthesize the target compound 152. ESI-MS (M+H) + =1033.4. 1H NMR(400MHz,Chloroform-d)δ9.45(s,1H),8.87(d,J=2.3Hz,1H),8.66(t,J=5.8Hz,1H),8.14(dd,J=8.8,2.4Hz,2H),7.68–7.58(m,2H),7.5 2–7.37(m,2H),7.23–7.14(m,4H),7.10(d,J=7.2Hz,1H),6.97(d,J=9.3Hz,1H),6.84–6.78(m,2H),6.52(dd,J=3.5,1.9Hz,1H),6.03(d,J=7 .0Hz,1H),3.93–3.83(m,2H),3.77(s,4H),3.74(d,J=2.4Hz,1H),3.71(d,J=2.4Hz,1H),3.56–3.53(m,1H),3.42–3.38(m,3H),3.30–3.28(m ,1H),3.02–2.62(m,6H),2.25–2.18(m,4H),1.98–1.57(m,4H),1.39– 1.31(m,4H),1.28–1.23(m,2H),1.18–1.13(m,3H),1.10–1.01(m,6H).

[0636] Example 6: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-((methylamino)methyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (243)

[0637]

[0638] Synthesis step 1: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-(((2,4-dimethoxybenzyl)(methyl)amino)methyl)benzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (243-1)

[0639] Referring to the synthetic route and method of Example 1, the intermediate 55 in the synthetic step 1 was replaced by the intermediate 56, the intermediate 1 was replaced by the intermediate 52, and the intermediate 72 in the synthetic step 3 was replaced by the intermediate 64 to obtain the product (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-(((2,4-dimethoxybenzyl)(methyl)amino)methyl)benzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide. ESI-MS (M+H) + =1196.5.

[0640] Synthetic step 2: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-((methylamino)methyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (243)

[0641] Compound 243-1 (408 mg, 0.35 mmol) was dissolved in 20 mL DCM, and 10 mL TFA was added to reflux for 18 h. After the reaction was completed, the reaction solution was concentrated and removed, and a saturated sodium bicarbonate aqueous solution was added to neutralize the pH to between 8 and 9, and dichloromethane was added for extraction, the organic phase was separated and concentrated, and the obtained crude product was purified by column chromatography to obtain 125 mg of a solid product of compound 243 with a yield of 34%, ESI-MS (M+H) + =1046.5.

[0642] Referring to the synthetic routes and methods of Examples 1 to 6, the following target compounds were synthesized:

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

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[0688] Example 269 Molecular-Level Activity Test of Anti-Apoptotic Protein BCL2

[0689] The detection of the binding ability between anti-apoptotic protein BCL2 and pro-apoptotic protein Bim was carried out by time-resolved fluorescence resonance energy transfer (TR-FRET) technology. The reaction was carried out in a 384-well white microplate with a total reaction volume of 10 μL. Specifically, it included 2 μL of the test compound (2% DMSO), 4 μL of His-tagged recombinant protein, and 4 μL of Biotin-tagged BIM protein polypeptide. After reacting for 1 hour, 5 μL each of Anti-His and streptavidin-tagged XL665 antibody dilutions diluted with the detection buffer were added respectively. After incubating at room temperature for 4 hours, readings were taken using an Envision multi-functional microplate reader to detect the effect of the test compound on the binding ability of BCL2 to the Bim protein polypeptide. The Envision parameter settings were excitation wavelength 320 nm, emission wavelengths 615 nm and 665 nm. The binding ability of the anti-apoptotic protein to the Bim protein polypeptide was indirectly reflected by the signal ratio of 665 nm to 615 nm. Background wells without BCL2 and full-binding activity wells of recombinant protein and Bim protein polypeptide without the compound were set up in the reaction.

[0690] IC of the compound inhibiting the binding ability of the anti-apoptotic protein to the Bim protein polypeptide 50The values ​​were calculated using Graphpad Prism 7.00 software using the formula: Y = 100 / (1 + 10^((LogIC50-X)*HillSlope)).

[0691] Table 1 Inhibitory activity of the compounds of the present invention on BCL2

[0692]

[0693]

[0694]

[0695] +:IC 50 <10nM;++:10nM <IC 50 <100nM;+++:100nM <IC 50 <1000nM;++++:1000nM <IC 50

[0696] The results in Table 1 show that the compounds of the present invention have potent BCL2 inhibitory activity.

[0697] Example 270 Molecular Activity Test of Anti-apoptotic Protein BCL2 (G101V)

[0698] 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 320nm for excitation light, 615nm and 665nm for emission light. The signal ratio of 665nm and 615nm indirectly reflects the binding ability of the anti-apoptotic protein and the 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.

[0699] IC of the compound's ability to inhibit the binding of anti-apoptotic proteins to Bim protein peptides 50The values ​​were calculated using Graphpad Prism 7.00 software using the formula: Y = 100 / (1 + 10^((LogIC 50 -X)*HillSlope)) is calculated.

[0700] Table 2 Inhibitory activity of the compounds of the present invention on BCL2 (G101V)

[0701]

[0702]

[0703] +:IC 50 <10nM;++:10nM <IC 50 <100nM;+++:100nM <IC 50 <1000nM;++++:1000nM <IC 50

[0704] The results in Table 2 show that the compounds of the present invention have potent BCL2(G101V) inhibitory activity.

[0705] Example 271 BCL2 (D103Y) molecular activity test

[0706] 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.

[0707] IC of the compound's ability to inhibit the binding of anti-apoptotic proteins to Bim protein peptides 50The values ​​were calculated using Graphpad Prism 7.00 software using the formula: Y = 100 / (1 + 10^((LogIC50-X)*HillSlope)).

[0708] Table 3 Inhibitory activity of the compounds of the present invention on BCL2 (D103Y)

[0709]

[0710]

[0711] +:IC 50 <10nM;++:10nM <IC 50 <100nM;+++:100nM <IC 50 <1000nM;++++:1000nM <IC 50

[0712] The results in Table 3 show that the compounds of the present invention have potent BCL2(D103Y) inhibitory activity.

[0713] Example 272 Tumor Proliferation Inhibition Activity Test

[0714] The ability of the compound to inhibit cell proliferation of RS4;11 was tested using the MTS method. MTS is a tetrazolium blue salt compound that can be reduced by various dehydrogenases in the mitochondria of living cells into respective colored formazan products, and the depth of its color is highly correlated with the number of live cells of certain sensitive cell lines within a certain range. RS4;11, RS4;11 (BCL-2-G101V) and MOLT-4 tumor cells were cultured and collected, and 180 μL of cell suspension was added to each well of a 96-well cell plate, 20 μL of DMSO with a final concentration of 0.2% was added to the control cell wells, and 20 μL of gradient diluted compounds were added to the cell wells. The treated cells were placed at 37°C and 5% CO 2 Incubate in the incubator for 3 days. After the incubation is complete, prepare the reaction solution according to the MTS kit and add 20 μL to each well and incubate at 37°C with 5% CO 2 Incubate in the incubator for 3-4 hours. Read the absorbance at 490nm using an ELISA plate, and use the absorbance at 690nm as the background value. 490 nm-OD 690 nm is the final raw data. The calculation formula of the inhibition rate of the compound is: Inhibition rate = (OD DMSO -OD Compound ) / (OD DMSO -OD blank )×100%.

[0715] Proliferation inhibition IC of compounds 50The data were fitted by GraphPad Prism software and calculated using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0716] Table 4 Proliferation inhibition activity of the compounds of the present invention on RS4;11

[0717]

[0718]

[0719] +:IC 50 <0.5nM;++:0.5nM <IC 50 <1nM;+++:1nM <IC 50 <100nM;++++:100nM <IC 50 The results in Table 4 show that the compounds of the present invention have significant proliferation inhibition activity on RS4;11 cells.

[0720] Example 273 Experimental Protocol for BCL-XL Enzyme Molecular Level Activity Test and Platelet Viability Detection

[0721] (1) BCL-XL enzyme molecular level activity test

[0722] 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.

[0723] 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^((LogIC 50 -X)*HillSlope)) is calculated.

[0724] (2) Platelet activity test

[0725] Add 10mL of platelet-rich plasma to 30mL of ACD-A solution, mix well, centrifuge at 1200g, and discard the supernatant; add 10mL of ACD-A solution to resuspend, mix well, centrifuge at 1200g for 10min, and discard the supernatant. Add 5mL of HEPES-Tyrode's buffer containing 1μM PGE1 and 0.2U / mL Apyrase, invert slightly, centrifuge at 800g for 5min, and discard the supernatant. Add 10mL of HEPES-Tyrode's buffer containing 1μM PGE1 and 0.2U / mL apyrase to resuspend, centrifuge at 1000g for 5min, and discard the supernatant. Add 2mL of HEPES-Tyrode's buffer + 10% FBS containing 1μM PGE1 to resuspend the platelets, take 200μL to a centrifuge tube, and dilute to 2mL. Then dilute to 1, 0.8, 0.6, 0.4, 0.2, 0.1, 0.08, 0.06, 0.04, 0.02, 0.01 times, fill the volume to 100μL, add 50μL CTG reagent to detect cell viability. Select the maximum release multiple with a fluorescence value not exceeding 108 for dilution, and connect 96-well cell plates for chemiluminescence detection at 90μL / well. Prepare the compound with HEPES-Tyrode's buffer + 10% FBS containing 1μM PGE1 and add it to the cells, gently beat it, and add 50μL CTG after 24h for cell viability detection.

[0726] IC of compounds inhibiting platelet activity 50 The values ​​were calculated using Graphpad Prism 7.00 software using the formula: Y = 100 / (1 + 10^((LogIC 50 -X)*HillSlope)) is calculated.

[0727] Table 5 Inhibitory activity of the compounds of the present invention on BCL-XL

[0728] serial number BCL-XL serial number BCL-XL serial number BCL-XL 002 >500nM 197 >1μM 243 >500nM 019 >1μM 203 >500nM 244 >500nM 058 >1μM 204 >500nM 245 >500nM 062 >1μM 205 >500nM 246 >500nM 063 >1μM 207 >500nM 247 >500nM 066 >500nM 209 1.9μM 248 >500nM 120 1.6μM 213 >500nM 249 >500nM 145 >1μM 216 >500nM 250 >500nM 146 2.7μM 217 >500nM 251 >500nM 152 >1μM 224 >500nM 252 >500nM 184 >500nM 226 >500nM 253 >500nM 185 >500nM 227 >500nM 254 >500nM 186 >500nM 234 >500nM 255 >500nM 187 >500nM 236 >500nM 260 >500nM 188 >500nM 237 >500nM 262 >1μM 189 1.9μM 238 >500nM 263 1.3μM 190 >500nM 239 >500nM 265 >20μM 193 >500nM 240 >500nM 267 >500nM 195 >500nM 241 >500nM 268 >500nM 196 >500nM 242 >500nM Compound a 233nM

[0729] Table 6 Results of the effects of the compounds of the present invention on the activity of human platelets

[0730]

[0731]

[0732] Note: Compound a is selected from WO2021208963

[0733] The results in Table 5 and Table 6 show that the compounds of the present invention have no inhibitory activity on BCL-XL and no toxic effect on human platelets.

[0734] Example 274 CYP3A4 Enzyme Inhibitory Activity

[0735] The inhibitory activity of the compounds on human CYP3A4 enzyme was determined using VIVID TM CYP3A4GREEN SCRNING KIT kit for detection. Vivid TM CYP450 screening kits include Vivid TM Substrate, Vivid TM Fluorescence standards, reaction buffer, Vivid TM Regeneration System, NADP+ and CYP450 BACULOSOMES TM Plus reagent. Follow the instructions and set up a blank control group without adding the compound.

[0736] IC of compounds inhibiting human CYP3A4 enzyme 50 The values ​​were calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0737] Table 7 Results of the inhibitory effect of the compounds of the present invention on CYP3A4 enzyme

[0738]

[0739] The results in Table 7 show that the compounds of the present invention have no inhibitory effect on CYP3A4 enzyme.

[0740] Example 275 Rat Absorption Test

[0741] Experimental method: SD rats were used as experimental animals and 10 mg / kg was administered by gavage. The blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after gavage. 3 mL of whole blood was collected, and 1 mL of plasma was collected after centrifugation for analysis using LC-MS.

[0742] Table 8 Results of rat absorption test of the compounds of the present invention

[0743]

[0744]

[0745] Note: Compound b is selected from CN114478520A compound number 142.

[0746] The results in Table 8 show that the compounds of the present invention have good pharmacokinetic properties in SD rats, supporting oral administration.

[0747] Example 276 Dog Absorption Test

[0748] Experimental method: Beagles were used as experimental animals and 5 mg / kg was administered by gavage. The blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours. 3 mL of whole blood was collected, and after centrifugation, mL of plasma was collected for analysis using LC-MS.

[0749] Table 9 Results of dog absorption test of the compounds of the present invention

[0750] Compound No. DNAUC 152 13685 234 9103 Compound a 3790

[0751] Note: DNAUC means AUC (h*ng / mL) / dose (mg / kg).

[0752] The results in Table 9 show that the compounds of the present invention have good pharmacokinetic properties in beagle dogs, supporting the oral administration route.

[0753] Example 277 In vivo antitumor efficacy

[0754] A tumor model was established by subcutaneously inoculating RS4;11 cells in NOD / SCID mice. When the tumor grew to about 100 mm3, the mice were divided into groups and given medication as follows: the control group was gavaged with a corresponding volume of CMC-Na solution; the experimental group was gavaged with 5 mg / kg of the test compound; the body weight of the mice and the changes in tumor size were measured twice a week, and the efficacy of the compound on RS4;11 mouse transplanted tumors was examined after 8 days.

[0755] Relative tumor proliferation rate T / C% = T RTV / C RTV ×100%(T RTV : Average RTV of the treatment group; C RTV : Average RTV of negative control group) The relative tumor volume (RTV) was calculated based on the results of tumor measurement. The calculation formula is RTV = V t / V 0 , where V 0 When the drug is administered in groups (i.e. D 0 ) is the tumor volume measured, Vt is the tumor volume at a certain measurement, T RTV With C RTV Get data from the same day.

[0756] Table 10 In vivo antitumor activity of the compounds of the present invention

[0757] Compound No. T / C% 152(5mg / kg) 0.35 234(5mg / kg) 1.26 261(15mg / kg) 5.35 266(5mg / kg) 15.38 Compound b (15 mg / kg) 14.87

[0758] Note: Compound b is selected from CN114478520A compound number 142.

[0759] The results in Table 10 show that the compounds of the present invention have significant tumor inhibition effects, and the animals had no abnormalities during the test.

Claims

1. A compound, It is characterized in that It has the structure shown in the general formula VIa or VIb: or a pharmaceutically acceptable salt thereof; Y 1 , Y 3 Selected from CH; Y 2 selected from CR 7 ; R 7 Selected from: fluorine; R 10 Selected from: hydrogen, halogen; R 10 Can be substituted on carbon or nitrogen atoms; R 5 Selected from: H, methyl; R 6 Selected from: H, deuterium, halogen, C 1 -C 8 alkyl; p is selected from 0 and 1; q is selected from 0 and 1; -L 1 -R 1 The fragment is selected from R b Selected from:

2. A compound, It is characterized in that Selected from the following compounds: or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition, It is characterized in that The invention comprises one or more compounds described in any one of claims 1 to 2.

4. Use of a compound as claimed in any one of claims 1 to 2 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.

5. A use as claimed in claim 4, It is characterized in that The other drugs are selected from alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, Aurora kinase inhibitors, other apoptosis promoter inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, antibodies of bispecific T cell engagers, antibody-drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogene homolog 2 receptor inhibitors, growth factor inhibitors, heat shock protein inhibitors, histone acetylase inhibitors, hormone therapy, immune preparations, apoptosis protein inhibitors. inhibitors, 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, poly ADP (adenosine diphosphate)-ribose polymerase inhibitors, platinum-based chemotherapy agents, polo-like kinase inhibitors, phosphoinositide 3-kinase inhibitors, BTK inhibitors, immune checkpoint inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoid / deltoid plant alkaloids, small interfering RNAs, topoisomerase inhibitors, ubiquitin ligase inhibitors and analogs.

6. A use as claimed in claim 4, It is characterized in that The disease, disorder or lesion is selected from infectious diseases, immune diseases, inflammatory diseases and abnormal cell proliferation diseases.

7. The use according to claim 6, It is characterized in that The disease is a blood disease and / or a solid tumor; wherein the blood disease is one or more of acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, myelofibrosis, myelodysplastic syndrome, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, and T-cell lymphoma; the solid tumor is one or more of osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, glioma, neuroblastoma, epidermoid carcinoma, hemangioma, lung cancer or gastric cancer, restenosis and benign prostatic hypertrophy, and melanoma.

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